Note: Descriptions are shown in the official language in which they were submitted.
219~107
COMPOSITIONS FOR TREATMENT OF CHRONIC INFL~MMATORY DISEASES
BAC}CGROUND OF TXE I~VENTION
l Field of the Invention
This i.nvention relates to the clinical treatment of
chronic ;nfl, ~ r~ry aiseases inrl-l~;n~ chronic gingivitis;
chronic periodontitis; chronic ~ tA~ - ~astritis; ileitis;
;nfl~ -r,ry bowel disea8e, Int~ ;n~l colitis; interstitial
cystitis; psoriasis; arthritis; tendinitisi carpel tunnel
syndrome and other cumulative trauma disorders; lupus
erythemato8us; 1 ~ iOsis; chronic ob5tructive F1l1 y
disease; ;nfll '-~ry myopathies; ;nfl: nry neuropathieu,
;nr111~l;n~ ~17h~i 's disease, myasthenia gravis and multiple
sclerosis; epilepsy; as well as lessening of ;nfl. trlry site
edema, and treatment of post-event ischemia and reperiusion
y regulting from acute central nervous system
trauma, stroke, kidney ischemia or myocardial infarction.
2. Description of Prior Art
The logic and potential value, even synergis~ic value, of
using two or more th~r~n~lt;c agents in . ' nAti~m for
~ ~ ~ of chronic; nfl nry diseases has been r-~cn~n; 7~.1
previously (Calhoun and ~ L}.e~, 1992; Hirs--h~ nn and
coworkers, l99l; Brooks and Schwarzer (l99l); Nright and
coworkers, l 9 77 ) .
The present disclosure describes the inventive concept of
using the therapeutic technology of US Patent Application
0~/906,909 in, ' nAt~n with ~hArr-~~ t;~-A1 agents having
some ~r~n~l value for treatment of the disease entities
noted above. The inventive concept cm'Jodied in my earlier tJS
Patent Application 07/906,909 filed 30 ;rune 1992 is the use of
compositions ~-nnA;~t;n~ of a primary agent which se~uesters
carbonyl products in ~ ' :n~t;~ln with co-agents that have
known anti-oxidant properties. The primary agents of the
present invention, such as p- 'n~h~n7O;I- acid (PABA), contain
2190107
a primary amine group, so as to enahle reaction with carbonyl
groups of disease-related C~lhst~nroc~ No rh~rr--nlnr;;rc1
treatment of comprehensive effectiveness is currently avail-
able for any of the chronic inflammatory disorders Ai ccl-cco~l
herein. Elowever, a variety of rhArr--oll~ir~l agents have been
AocrT~heA which may offer at least some degree of ~ ir
relief from the clinical effects of these diseases.
Clinical use of the drug 5111fAq~l~7;nO (SA~I eyL~souts
a well .: oA example of the use of a henzoic acid deriva-
tive as a trapping agent for the hydroxyl radical and other
free radicals in the L~ of a chronic ;nfl: tn~y dis-
ease. In the colon SA~7 uudely~ reductive cleavage to liber-
ate 5-~; nnc:-~ i rylic acid ~5-amino-2-l.ydLu,.y~ ic acid, or
5-ASA), which is the thor~rellttr~lly active agent. Ahnfelt-
~onne and - - ' (1990~ presented research findings which
docoment the use of SA., for ~,u~ rul t ~ of chronic
inflamatory bowel disease (CIBD~, also ~cnown as ulcerative
colitis. SAZ is also r~rnr,ni70A for use in treatment of
ileitis (Budavari and ' , 1989, pg. 14~2). Ahnfel~-
Ronne (1990~ compared their in vivo 5-ASA ~:lhr~l i r products
to products observed after ;~ y~ hydroxylation of 5-ASA }~y
the Fenton reaction and tentatively iAontifioA 5-ASA metab-
olites as heing hydroxylated deriYatives. They never at-
tempted to look for evidence of ' y~yQ trapping of carhonyl
products. Under the brand name A3acol and the generic name
lAm;no, 5-amino-2-hy~ yl,eu-oic acid in delayed-release
tablets has also been mar~ceted in the l~nited States for use in
~L~ ' ' of CIBD (Dowd and coworkers, 1993, pgs. 1868-1869~.
Dull and ~ Jl~e~ (1987, pg. 2469~ used mass spectrometry to
definitively identify two of the several hydroxylation/oxida-
tive deamination products which result from n ~ incuba-
tion of 5-ASA with activated human mnnnn~ rl~ r cells. They
1~ontif;~A thege products as gentigic acid (2,5-dihydroxy-
benzoic acid) and salicylic acid (2-hy~h~yb~ Jic acid),
while five other 5-ASA ':~hol;r products remained uniden-
tified (pg. 2470~.
Ahnfelt-Ronne and colleagues, Dull and ~ ' , and
earlier investigators never rorosn;70A the rns~;h;l;ty of
using a therapeutic ayent to scavenge carhonyl pro~ cts of
2 ~ 7
inflammation. ~Ience they never recognized the pnq~3ihil;ty of
int~ntinn:~ly using a composition consisting of a primary
agent which seguesters carbonyl products in ;nAt;rn with
co-agents that have known anti-oxidant propertie3.
Further fliqt;nrt;nnq should be not~d between the inven-
tion fl;qrlrc~fl in US Patent Application 07/906,909 and previ-
ously rernsn;7efl clinical use of S~Z. SAZ releases sulfapyri-
dine, a somewhat toxic aubstance, into the body ~ L-U,L ',
1984, pgs. 377-379 and 3833, while the invention of US Patent
~rp1;rilt;nn 07/906,909 does not. In addition, use of sulfa-
salazine depends on intestinal bacteria for activation of the
drug, while the primary agents of the present invention do
not. Besides use in ~L~ ' ' of CIBD, SA.7. has been recog-
nized, at least at the ~ r; -Rl level, for L~. of
ileitis, radiation bowel diseage, gcleroderma, APrr-t;t;s
herpetiformis and rh/ n1fl arthritis (P~ L~UL", 1984, pgs.
380-381) .
other example3 of amine drugs recogni2ed aG having anti-
1nfl nry propertieg include para-substituted N-benzene-
sulfonyl derivatives of ~nthr; l; ~ acid (Borne and ~ ,
1974~, 4-~mino benzoic acid anilides (Thiele, 1971; Deutsche
Gold- undSilber-srh~;fl~nqtilt vorm. Roessler, 1972), tinori-
dine (Shimada and Yasuda, 1979) and benzoth;:~7n7;nnnP deriva-
tives (T~k~ch;r-- and U..JLr~L~i, 1972) . The chemical struc-
tures of these agents lie beyond those of the primary agents
of the present invention. They are not presently r~ o~n; 7~
as car}~onyl q~ 4t~ring th,-r~n~l1t;c agents. They have not
been used in multiple ingredient compositions ;lnA1o~o-1q to
those of the precent invention.
Several drug products rnnt~tn;nr PABA have been marketed
for human use in the United States. Powever, it is believed
that none have been propoged ag ef ~ective for the treatments
claimed herein. Potassium p-~m;nrh~n~nate has been marketed
as Potaoa (R) in the pure form as an antifibrotic, that is,
skin softening, agent (Druq Tnform~t;nn fnr thr ~lo~lth f'~re
Prof,-qq;nn~l. 8th ed., 1988, pgs. 111-113). Ag such it has
been r~rn~n;7.~d for treatment of Peyronie~s digeasei diffuse
_ystemic ~rl~rnq;c; morphea and linear scleroderma; and
dermatomyositis. For guch purpo5es, Potai~a is taken orally in
2190107
average doYes of 12 gm/day for up to two years, although human
use of 15 - 20 gm/day is rProrJn;7e~1. As an ingredient in
analgesic tablets, PABA ha6 bee~ marketed for domestic human
use (300 mg/tablet) in Pabirin (R) buffered tablets (with
aspirin), in Paoa7ate (R) tablets (with sodium salicylate) and
in Paoalate-SF (R) tablets (with potassium salicylate), a3
~,pclrr;h~ in PhVF:;r;nn~ Desk p~f~r~r~ uff and
1980, pgs. 849, with aspirin and 1430, with salicylates).
Five percent PASA in a cream base has also been marketed as a
~ulls~leell product (phvcir;Anc~ Desk ~f~f~.r~.nr~ uff and
coworkers, 198 0, pg . 849 ) .
In its summary on systemic uge of rntA~c; p_ nnhf~n7O-
ate the Drua Infrrr-t;nn for th~ UAAlth C~re Profe~:irnAl text
(8th ed., 1988, pg. 111) presented the following statement
regarding r~rrrJn;7~9 rhArr-^r,lr~y (le~L~Iue.~ herein its
entirety):
Mechanism of action: The ~ i-~ by which :lminrhl~n70:1t~
potassium exerts its antifibrotic effect is not known.
It has been postulated that fibrosis results from an im-
balance of serotonin and, n~ oxidase (MAO) mechan-
isms at the tissue level. Fibrosis is believed to occur
when an excessive 6erotonin e_fect is sustained over a
period of time. This could }~e the result of too much
serotonin or too little MAO activity. ~`-innh~n7n:lt~.
potassium increases oxygen ~lt i 1 i 7~t i nn at the tissue
level. It has been R~rJ~ct~ that this increased oxygen
~tili~s~tirn could enhance the ~ArJrAr~Atirn of serotonin by
~nhAnring MAO activity or other activitie5 that decrease
the tissue ~U~l~,el~L . ~ion of serotonin .
In its summary on systemlc use of potAacj p---inrh-~n7r,_
ate the E~hvciri~n~s Desk 'Rf.f~renr~ (Dowd and . - ' :~, 1993,
pg. 1103) presented the following StAt~ (~e~/du~ed herein
its entirety):
I~DICA~IONS
Based on a review of this drug by the National Acad-
emy of Sciences-National Research Council and/or other
information, FDA has r~ sif;~A the ;na;rAt;rnc aG
follows:
~Possibly~ effective: Potassium :m;nnh~n7rAt~ is possi-
, ~ 2~90107
bly effective in the treatment of ~rll~ro~ rr-, dermato-
myositis, morphea, linear scleroderma, ~ _ ~;rJllc, and
Peyronie ' 8 disease .
Final rlRRc;firRt;rn of the less-than-effective indi-
cations requires further investigation.
ADVANTAk:ES
POTADA offers a means of L~ . ' ' of serious and often
chronic entities involving fibrosis and n~ U~U~.ltiVe
;nfl ;rn,
pp7~D~-~ ~r~GY
p_r-~;nnh~n7rRt~ ig congidered a member of the vitamin
B complex. S~mall amounts are found in cereal, eggs,
milk _nd meats. r~t~r~Rhl~ amounts are normally pre-
sent in human blood, spinal fluid, urine, and sweat.
PAD~A is a ~ _ of several h;~lrrJ;rRlly important
systems, and it part;r;r~t-~R in a number of funda-
mental h; rl ~s; rR l ~ .5~_8 . It has been suggested
that the antifibro3is action of POTADA is due to its
- Rt; nn of increaged oxygen uptake at the tissue
level. Fibrosi3 is believed to occur from either too
much serotonin or too little m~nr^--; n~ oxidase activity
oYer a period of time. Monoamine oxidase reouires an
adequate supply of oxygen to function properly. By
increasing oxygen supply at the tissue level PO'rABA may
eDhance MA0 activity and prevent or bring about re-
gression of fibrosis.
This inventor sees no rol Rt;r~nch;r of such comments tothe present invention. In particular, the comments noted
above clearly do not recognize the ~ot-~n~-~ R~ use of PABA and
derivatives thereof as carbonyl trapping agents, that is, as
agents which may generally inhibit chronic inflammatory
disorders by virtue of their ability to rh~.m;rRl ly bind to and
5~rl- Rt~r aldehyde and ketone productg of lipid perrY;~Rt;nn
which result from and rnntr; h~te to the continuation of
chronic ~nfl: -rry disorders. In addition, prior art
in~rr~~;rn ha8 not Rnt;r;rRt~1 or ~i;qrlr~c~ the particular
co_positions set forth in the pregent digclogure. Hence the
clinical Rrrl;r:~t;r~n~ of PABA and derivativeg thereof claimed
in the present invention are regarded by the inventor as new
~ 2 1 9~ 7
and novel.
Certain amine agents have rf~n~in; 7Pd anti-oxidant proper-
ties. These include N,N' -di- (sec-butyl) -p-phenyl~n~ri;~m;nP
(Scott, 1965, pg. 120), aniline (Scott, 1965, pg. 125),
nniline N-~--hqti~l-t~-l agents (Scott, 1965, pg. 125), N,N'-
diphenyl-p-phenyl-~n~ri; n~ (Swingle and ~ , 1985, pg.
112) and ethoxyguin (Swingle and ~ , 1985, pg. 112).
In the present invention focus is placed on primary amine
agents, as such agents are known to covalently react with
carbonyl agents to yield Schiff base-type products (Feeney and
, 1975, pg. 141). By contrast, N-substitution with
1, f~ln~-t;nn~l groups tends to increase amine anti-
oxidant activity (Scott, 1965, pgs. 125 and 148). These are
two distinct chemical L~ . The anti-oxidant property of
amines depends on their ability to act as electron donors to
alkoxy or alkylperoxy radicals (Scott, 1965; pgs. 127, 145 and
158). The carbonyl trapping property of amines depends on
their ability to form Schiff base-type addition products.
Zarafonetis (1953) has reported some success in L~ '
Of ~ n;fi arthritis by use of rnt7~c~; p-:~m;n, .l ,, ~ in
n~t jnn with acetyl8alicylic acid and cortisone. In this
report ~rrafnn~.t;~ also ~ rihr~i some success in clinical
Ll- - of ri~rr-t ~.,sitis and scleroderma by use of potas-
sium p-r-;nnhf~n7nslt~ alone, and referred to earlier work on
these ~ rri~r~ and other r~l;n;c~lly related ~ylld~. , in-
cluding forms of lupus eryti Oc~
Yet 7~r:1fnnot;q hased his logic for diversifying clinical
studie~ on PABA or its potassium salt solely on similarities
of clinical symptoms, comparisons among clinical ~ylldLI
which feature some common symptomology (Zarafonetis, 1953,
pgs. 667-668; Zarafonetis, 1964, pgs. 550 and 560; Priestley
and Brown, 1979, pg. 161; 7rrilfnn~t;~ and ~: ' , 1988, pg.
194) . 7:~r~fnn~t;~ never stated an under8tanding or rl~nnrin;7~.ri
that PABA has the physiological rnt~nt;:~l of serving as an
aldehyde chemical trapping agent (,7~r~fnn~.tic:, 1953, pg. 671) .
Hence, he never rr~nrJn;7rri its rnt~nt;rl to seguester aldehyde
products resulting from increased lipid peroxidation secondary
to site-specific ;nfl: ;r~n, In failing to recognize this
principle, 7Ar:lfnn~t; s, failed to recognize the potential full
~ 2~01~7
scope o~ clinical 7rrl;nAtinnq of PA3A.
Failing to recognize the pot~ntiAl of synergistic anti-
oxidant co-~gents, the ~Jeedu~:S of 7~rAf~n,otic for L-.
of scleroderma, ' i~l arthritis and dermatomyositis re-
lied on use of high PABA dosages (12-18 gm/day; see Zarafone-
tis, 1953, pg. 666) . In rr;nrirl~, it is the understanding of
the present inventor that the clinical progno8is of any
disease which features increased lipid pern~;~9At;nn as part of
its etiology may be improved by clinical Arrl; ~ at; nrl of the
inventive concept embodied herein.
7:~r~fnn~t;q (1953) also referred to an earlier study
which used a combination of p-, 'nnh~n7n~c acid and a-toco-
pherol to treat scleroderma. Gougerot and Hewitt (1951)
described the logic of their scleroderma ~, ~ protocol as
follows:
This observation is to be added to the file of the
treatment of sclerodermas. 7ArAfnn.~t;q and his collab-
orators have already r--hliqh~ 5 cases of sclerodermas
improved by para-~m;nnh~n7n;c acid, and in the same
th~rAr~l-t;n series Shaffer and hi3 nnllAhn~At~rq treated
a generalized scleroderma with para . 'nnh~.n7ni~- acid
with; , ~,. . In a study of a . _ 1 ~t.~l y different
nature, vitamin E (a-tocopherol) was used by Rl ~ , el,
etc. and in France by 3azex (Lyon, July 1949). This
is why we have Aqcnn;~tl.l9 the two therapies because of
their effect on dlseases of collagen.
As such, they perceived their clinical t~A strategy
to address the status of collagen, with no discussion of pO8-
sible phyq;n1ngir:ll ^hAn; . Compared to the invention
embodied herein, Gougerot and Hewitt: (1) failed to recognize
that either of their therapeutic agents may interfere with the
~nfl: nry cascade, (2) failed to recognize that primary
amine and amine-related derivatives of benzoic acid, as a
class, may bind to and sequester aldehydes which result from
the infl ' nry prOcegs, (3) failed to understand that the
~ ;nAt;nn of a water soluble aldehyde-trapping primary amine
agent and a l;rorh;1ic anti-oxidant agent may have clinical
application to the treatment of a broad spectrum of chronic
;nfl: nry digeages, and (4~ failed to disclose the unique
2190~07
.
positions of the present invention.
In 1967 Mel'nikova and Ryzhova pre6ented the results of
a clinical trial wherein PA3A was used to treat post-event
trauma in PYrl~r; ~1 myocardial infarction, a6 studied in
rabbits and dogs . They reported a coronary v~cn~; 1 Atnr effect
of PAP,A based on their lln~-rqt~n~in~ of the drug's antihist-
amine property. They r~rqrJn; 7~ no anti-infl tnry proper-
ty of PABA and did not l~nfl~rqt~n~ their findings within such
a context.
S~h~P~rlupnt work by Kurdin (1978) has presented evidence
of increased lipid pernYi ~ -t; nn in the process of myocardial
infarction. Actually, the :lccori~t;rn of increased levels of
reactive o_ygen species with ischemic myocardial dysfunction,
with resulting lipid perrYi~t;nn is now well r~rnrJni7 ~
(Dowling and, ' , 1990, pg. 465~. Viewing the reports
of Mel'nikova and Ryzhova, Rurdin, and Dowling and ~ '
within the context of the present invention, the inventor
proposes that, to some degree, the bpnpfir;~l effects of PAE~A
in the Mel'nikova and Ryzhova study reflected an anti-inflam-
matory property of PA~3A unrer-nJn;7p~l by the investigators, and
that such a hPn-~f;r;~l effect may be nr~;mi7~rl by use of the
multi~ t;nnc ac defined in the present inven-
tion. Seekamp and Ward 11993), using a rodent hind limb
ligature model of ischemia/reperfusion, have presented some
data which demonstrated the value of anti-oxidant pre-treat-
ment of animals with catalase, superoxide 1;l ~ce, dimethyl-
sulfoxide, dimethylthiourea or def~L~ nP, As itemized by
Entman and ' (1991), a variety of therapeutic strat-
egies has been proposed for treatment of ischemia/reperfusion
trauma, yet none of these proposed strategies include the
present invention.
The rhPnl of hypoxia/reperfusion in~ury is now un-
derstood to be an important aspect of several ~ t; r dis-
ease states, including coronary infarction, ischemic acute
renal failure and cerebral ischemia (Dowling and - LeL~,
l990, pg. 466). Hence, the present invention has significant
clinical value in the post-event treatment of ischemia and
rPrl~rfllc; nn injury l~ul~ uell~, to myocardial infarction, acute
kidney failure, and acute central nervous sygtem trauma and
~1qO Ic~ `
stroke. ~n light of the coomon phyGiological rPl~ti^nPhir of
hypoxia/rPrprfllqi~n rnnflitinnq and chronic infl: ~ry
diseases, both of which include tissue damage caused by lipid
pernYi~Ati~n and s~lhqpr~ nt lihPrAt;nn of carbonyl 5~lhQtAn~-~c,
hypoxia/reperfusion cpnditions are considered to be varieties
of chronic ~nfl: t~lry digeages within the context of this
invention. Likewise, as the etiology of Al 7hPi ' S disease
is believed to have an A~tni -, ~ , and use of drugs
such as deferoxamine (McGeer and Rogers, lg92, pg. 448;
TTAll;---ll, 1991, pg. 593) and 1 ~hArin (Schnabel, 1993~
has been previously noted in this regard, this disease also
will be considered to be a variety of chronic infl. nry
diGease within the context of this invention.
Broad spectrum clinical use of anti-1nfl: ~nl-y vitamin
compositions which feature PABA aq a primary agent, and the
hrfl~logical rea60ning for doing 80, has not been previously
rero~ni7Pfl or floQrrihf-fl prior to s~lhmicqinn of US Patent
Application 01/9D6,909. p-r-in~hpn7oir acid is not presently
rer~Jrn;7Pfl as a nonsteroidal anti-;nfl ~~ry drug (NSAID).
Hence, for example, it is not included in the lists of such
drugs F.-hl;~h~d in (a) the hlProk Tnfl~Y (Budavari and cowork-
ers, lgag, pgs. TH13R-lS to TP,ER-16), (b) ,cr;~ntific 1 rRn
;~ nn, 1991, pg. 86), (c) TTn-~Prcr=n~;nn Arthritiq
~Kushner, l9B4, pgs. 52-s3) and (d) the ~ irAn ~o-lrnAl of
~is~i~ rE~oUston, 1991) . Likewise, PABA is not recognized as
being a "slow acting~ anti-inflammatory agent ~ITn~Prqt:lnfl;
Arthrit;q, Xushner, 1984, pgs. rjS-57).
Both PABA and D-F~n;n;ll: 'nP are primary amine agents
which also function as anti-oxidant free radical trapping
agents. Yet as anti-oxidant agent8 PABA and D-penir; 1 1: nP
are presently regarded as bei~g of gecondary, nominal value,
due either to weak anti-oxidant properties or toxic side
effects, respectively. Thu8 their u8e as anti-;nfl ~ry
agents has been ~uite limited. Their potential value for
trapping the aldehyde products of ;nfl inn-related lipid
peroxidation has never been rP~n~n~7Pfl ~lence the f~ lAti~n
of a new, t;~n, guch ag one having PABA as its primary
agent, optionally having known anti-oxidant free radical
scavenging chemicals as co-agents, lacking vitamin C in excess
219~07
of its RDA and i~ ;tinn~1ly including a recognized ';~
as defined herein, has never been previously described, and
the rnt~ntiAl for clinical use of such a novel . ~tion in
treatment of chronic infl: tnry diseages has never heen
rern~n i 7~rl
Further ~;Ctinrt;nnA should be made between the preseAt
invention and previously r~rr,~n;7~ use of penir;llAm;n~, one
of the ~slow-~cting" anti-tnfl nry drugg 1 ~;nn~l in
T~n~rAt~n~;nr A~thrit;~ (Rushner, 1984~, a r-lh1;rAt;nn of the
Arthritis Fn ~nrl~t;nn. ~he primary amine agents r~qrrih~A in
the present invention are all derivatives of _m;nnh~n7nic acid
or: nnphrnylacetic acid, which should facilitate their safe
;m;nAt;nn from the body by normal kidney filtration. D-
p~n;r;1l~m;nn is not a derivative of nnh~.n7n;r acid or
nnrhl~nylacetic acid. In addition, D-penir; l 1 ~m; n~ has a
reduced sulfhydryl group, unlike any of the primary agents
claimed herein.
~ he invention embodied herein rnnct;tl~t~ an alternative
slow-acting anti-;nfl, -nryprotocol which is believed to be
inherently safer for the patient and to act via a ~ ; r-
not previously reco~n;~l or ~ crr;h~l pAsA is not among the
Ant;rA-l~rial drugs ~;crllcso~l ~y Rushner (1984, pg. s7), nor is
it among the Ant;r-lArial drugg ligted in the Merrk rn~ y
(Budavari and r,~t ' , 1989, pg. TE~-16).
Many NSAID' 8 are known to commonly induce side effects
which include gastrn;ntrst;nAl damage, liver toxicity and
kidney toxicity (Brune and Beck, 1991; Rraag, 1985). Most of
theee drugs ~ntArJnn;7~ the actions of many antihypertensive
drugs (Houston, 1991) . A variety of less common side effects
of these drugs have also been reported (o' srien and Bagby,
198~). Use of the present invention in ;nAt;nn with such
previously r~rn_n;7e~ c perntits the effective use of
such drugs at lower dosage levels, serves to permit use, in at
least some cases, of previously known medicaments for more
extended periods of time and serve8 to cl~rF1 - the overall
clinical benefit to patients. R~ nr~r;7r-1 nongteroidal anti-
inflammatory drug3 include aminoarylcarboxylic acid deriva-
tives, arylacetic acid derivativeg, arylbutyric acid deriva-
tives, arylcarboxylic acids, arylpropionic acid derivatives,
~ 2~90~07
11
pyrazoles, pyr77n~nnf~q, salicylic acid derivatives, thiazine-
r:lrhnY:~m;~1~c, ~_~n/~t~mi~nn~rroie acld, S-~deno9yl hinn;n~,
amixetrine, bendazac, J~:~y~' n~, bueoloDe, difenpiramide,
ditazol, I ...~L~c~lJlle, ~-~;~7l~1.on.., r~ '~ nn~, n; 1 ;~..,
orgotein, oxaeeprol, perisoxal, pifoxime and l,L~ z~ e.
Within the eontext of the pregent invention, the fnllnwi
additional drugs should also be regarded ~8 nonsteroidal anti-
;nfl: tnry drugs: rh~n;~nn~; k~tn~-nn:-7n1~; disodium
~7n~1;c~1;nylate (a dimer of 1, n~.~; diazo 5~1fAn;1
ethylene polymer of s- 'nnq~ ylate; cyrl~.l,71n~ ; 6-
~2,4-difluorophenoxy) -S-methylsulfonylamino-1-indanone;
ditazol; droxieam; azel~L~ z~ ; etoclofene; ~L~ ul~e; 7- [3-
(4-acetyl-3 -methoxy-2-propylphenoxy) propoxy] -3, 4-dihydro-8 -
propyl-2N-l-ho~..z~,~yL~ -2-carboxylicacid; IV-acetylcysteine; S-
thylcysteine: naphthypramide; flavonoids 3uch asci~r;tnf1i~vone, n;rq;1;o1, hypolaetin-8-glucoside, hypo-
laetin, oroxindin, quercetagetin-7-s~ -nc~ gossypin, hibi-
folin, gossypetin and leucocyanidol; tepoxalin, sodium 2- [4-
(2-oxocyclopentylmethyl)phenyl]propionate dihydrate, l- [ (4-
chlorophenyl) methyl3 -2-methyl-5- l~uinolinylmethoxy) -lH-indole-
3-acetie aeid, DL-2- (4-hexyloxyphenyl)glyeine oetyl ester, DL-
2 - [4 - ( 5 . ~ - dimethylhexyloxy) phenyl ] glyeine oe tyl es ter and 6 -
methoxy-2-naphthylacetic acid. Likewise, within the context
of the present invention variou~ gastrn;nti~ct;n~l anti-inflam-
matorydrugs, :3nr;r-l~rialdruggandantiarthritic/~nt;rh~ _
tic drugs as ~llc~-1ncq,l In the M~rck Tn~Pr, 11th edition (suda-
vari and ~ ' , l989~ are regarded as nonsteroidal anti-
;nfl tnry drugs.
Glucocorticoid drugs are well known. A more complete
listing of 6pecifie examples of such drugg, and of the various
forms in which these th.or~r~ ;c agents may be ` n;qt.~red,
can be found in various well known reference works such as,
for exan~ple, the Merck rn~ ~r, 11th edition (sudavari and
coworkers, l 9 8 9 ~ .
~ enceforth reference to ganguinarine will include refer-
ence to hydrated and salt derivatives thereof, such as for
example sanguinarine I ' y-lL,ILe, sanguinarine chloride and
q~n~l;n:lr;nP chloride dihydrate. Co-agent uge of all forms of
amino-glycogide, -~~rhf~n;~-nl, ansamycin, ~-lactam, l;nnnc '~
. ~ 2t90~07
12
macrolide, polypeptide and tetracycline anitbiotics are
claimed within the scope of the present invention, as well as
use of cyr~rq~ n~, mupirocin and tuberin. l'he various forms
of these Ant~h;ntir~ are known to those skilled in the art and
infr~ tion regarding them can be found in various Leré~e~ce
works, for example, the Merrk In~lpy 11th edition (Budavari
and .,~. ~ ' s, 1989) . Tnfrrr-tirn regarding nonsteroidal
anti-inflammatory drugs rl~rrJni7e~ for use Lhy local adminis-
tration or oral administration is known to those skilled in
the art and may be found in reference works such as the ~-
c;:~nA~ n.,-k '7-~fer nr~, 47'~' edition (Dowd and ~ - ' , 1993) .
Henceforth reference to prednisone will include reference
to its rh~ t~r-lly acceptable ester derivatives thereof,
such as for eample prednisone 21-acetato. Henceforth refer-
ence to prednisolone will include reference to its rh~
tically ?cr~rtAhle ester and salt derivatives thereof, such as
for eYample prf~qni~olrn~ 21-diethyl 'nr:~r~t~te, pr~.~3n;~rlrn~
21-stearoylglycolate, pr~ n1crlrn 21-tert-butylacetate,
pr.--in;aolnn~ 21-trimethylacetate, pr~n~rlrn~ 21-acetate,
prP~ni~rlrn sodiumsuccinate, pr~in~olrnPsodium21-m-sulfo-
benzoate, and pr-.rlni~rlrn~ sodium rhrsrh:~te. II~ ,fu,Lh
reference to cortisone will include L~èL~.c to its pharma-
r~ tirA7ly acceptable egter and salt derivatives thereol~, such
~8 for example cortisone 21-acetate, 21-,~7-cyrl ~r n2 An~orropion-
ate cortisone, cortisone rhrArhAt, cortisone ~ nr~rrl1 phos-
phate, cortisone disodium phre~rh~rF. and cortigone rhr~:rhAt~
dimethyl ester. Henceforth reference to hydrocortisone will
include reference to its rhAr~ tirAlly acceptaole ester and
salt derivatives thereo~, such as for example hydrocortisone
21-acetate, llydLu-u,Lisone 21-benda2ac, hydrocortisone 17-
butyrate, I,ydL~uLLisone 17-valerate, hydrocortisone tebutate,
hydrocortisone 21-sodium succinate, hydrocortisone di30dium
phosphate and its progenitor, hydrocorti90ne rhr~rh~t~.
Xenceforth re~erence to methylprednisolone will include refer-
ence to its phA~-~~oltirAlly Arc rtAhl~ egter and salt deriva-
tives thereof, such as for example methylprednisolone 21-acet-
ate, methylprednisolone sodium 21-guccinate and methylpredni-
solone disodium 21-rhrrrhAte. T7r.nrl~frrth reference to triam-
cinolone will include reference to itg rhArr~~ l1tirAlly ac-
` 2190107
13
ceptable ester and ether derivatives thereof, such as for
example tri: 'n~ n.- 16~,21~ r~t3t~, ~ri ~nnl~n~ aceton-
ide, tr;A~--in~l~nP ~r~trn;rl~ 21-acetate, ~ri: 'nnlnn-~ aceton-
ide di-sodium 21-rh^arhAt", tr; 'n~l~n~ ~r~tr~nif~ 21-hemi-
8~rr;nAt~., tr; 'n~l~nr h~nf~t~n;~ and tr~; 'n-~l~n~ hexace-
tonide. Yenceforth reference to h, h~crn-~ will include
reference to its rhArr~ t;rAlly Arr~.rtAhl~ ester and salt
derivatives thereof, such as for example het hAc~m~ 21-
acetate, het -hAg~n~ 21-A-' ~.t~., h~tAm~th~c~n~ 17-
benzoate, het ~hAcf~nf~ 17,21-dipropionate, hetAm~'thARrn~ 17-
valerate, '~--t: hAn~nF. 17,21-divalerate, h~t hAa~n~ di-
sodium rhrarhAte and 1 ~ hAa~n~ m~n~g~rii rh~arhAt~
II~efuLI h reference to ;` hAqrnD will include 1~ reL~ e
to its phar~ t;rAlly ;7rrPrtAhl~ ester and salt derivatives
thereof, such as for example ~' ~hAc~rn~ 21-a.cetate, dexa-
- h~c~ 21- (3,3-dimethylbutyrate~, ~' hAc~notetrahydrO-
rhthAlAtF~ ~' ' hAc~nf.21-d~,ethylAminr-^Pt:~t~, i 'hAarne~
21-isonicotinate, ' -hAcrnf.17,21-dipropionate, ~' hA-
sone 21-palmitate, dexamethasone 2l-rh^arhAt~ and ' h~-
sone disodium 21-phosphate. Additional forms of glucocorti-
coids are known to those skilled in the art and information
rer~ardinr~ them can be found in various reference works, for
example, the Merck Tn~.-Y, 11th edition (Budavari and cowork-
ers, 1989).
l'he various forms of ~nt;rh~lin~rgic drugs such as sco-
polamine, trihexyphenidyl, benztropine mesylate, procyclidine,
biperiden, ethopropazine, pr^rAnth~-l; n~. and oxybutynin are
known to those skilled in the art and inforr-ti~n regarding
them can be found in various reference works, for example, the
Merrk rn~ , 11th edition (Budavari and . ~ ' , 1989~.
S~licylic acid is r~r~r~ni7~ as being both an Anticl~ptic
and a keratolytic agent (sudavari and coworkers, 1989~.
sased on its clinical and structural similarities to D-
F~nir;ll n~, 5-thiopyridoxine may be rer,arded within the
context of the present inventiOn as an example of a non-
steroidal anti-inflammatory drug which may be useful in the
~L~ ' ' of ' ~ arthritis.
T ~ lAt~r substances as defined within the context
of the present invention include, for example, those noted in
-
<
~lqolo~
1~
Budavari and L~:, (1989, pg. T~-25), as well as leilu-
nomide, diaveridlne, apocynin, 1-p-chlorobenzyl-2-dimethyl-
Rmi~ -hylcyclohexen-1,2, (z) -3- [4- (acetyloxy~ -5-ethyl-3-
methoxy-l-nArhrh~-lGnyl]-2-methyl-2-propenoic acid, diacetyl-
srl~nnr~nr;n, q,~ h;l ;7~rl chicken type II collagen, dapsone,
rRrqR;~-;n, (lO-methoxy-4~i-benzo[4,5~-CYClohepta-[1,2-b]-thiO-
phene-4-yliden)aceticacid, G;~ onr~ acid, lobenzarit,
tiopronin (also known as N-2-mercaptopropionylglycine), teni-
dap, diacetylrhein, interferon~, copolymer-1 and 2,6-Diamino-
N-~ [1- (1-oxotridecyl) -2-piperidinyl]methyl} '~G, tilomi-
qole, indoxole, bimetopyrol, rl 7~1e, qrAlArRrl;Rl, kojic
acid, misoprostol, 1- [3- (naphth-2-ylmethoxy~phenyl] -1-
(thiazol-2-yl)propyl methyl ether, and 4- (2-~ hl Tnrh.~nyl) -2-
~2 - (4-isobutylphenyl~ -ethyl] -6, 9-dimethyl-6H-thieno [3, 2-
fl [l,2,4]triazolo-~4,3a] [1,4]-~iR7F.r;n~
~ ydroxychloroquine, q~l;nRrr;no, chlororiuine and amodia-
r{uine are exampleg of Ant;r~lRrial drugs in the present in-
vention. A more complete listing of specific examples of this
group, and of the various forms in which the respective thera-
peutic agents may be ~, n; qtGred, can be found in various
well known ~ efe~ e works such as, for example, the ~9~k
1~, 11th edition (Budavari and ~, 1989).
Within the context of the present invention, diazepam and
lorazepam are regarded ag anxiolytic drug8 of the h~n7mrl; 77G-
pine variety. A more complete listing of specific examples of
h~n7r~1iA7~r;n~ anxiolytic drug8, and of the various forms in
which the respective rhGrAr~l~t; agents may be administered,
can be found in various well known reference works such as,
for example, the ~Grck rn~ , 11th edition (Budavari and
, 1989~ . r- ~ nG, -l~ nA7~rRm, e h~q~Y;mi lG,
lamotrigine, 1~ A~ phenytoin, primidone, valproic
acid, vigabatrin and 7~ n; r~ G are anticonvulsant drugs .
Likewise, ag phenytoin-polyvinylpyrrolidone coprecipitate
releases phenytoin ~ Yi~ o, thig drug may also be regarded
within the cortext of thig invention ag an example of an
anticonwlsant drug. Ag A GrA7 1Am;~G is regarded as an al-
ternative to .~rh~q~ mirl~"~lrmr r or valproate for treat-
ment of petit mal gei2ures, this drug and its sodium salt
derivative may algo be regarded ag exampleg of anticonvulsarlt
. ~ 21~0107
drugs within the context of the present i vention. A more
complete listing of specific examples of anti-convulsant
drugs, and of the various forms in which the respective
thc~r:lr~ t;e~ agents may be Al' 'n~:tf~red, can be found in
various well known reference works such as, for example, the
Nerck rn~OY 11th edition (Budavari and ~ '~ , 1989).
Captopril and k~.t~n~rin are examples of antihypertensive
drugs. A more complete listing of specific examples of anti-
hypertensive drugs which may be useful in the L-. of
~1 7h,.i s disease as defined herein, and of the various
forms in which the respective th~r~r~t~C agent5 may be admin-
istered, can be found in various well known reference works
such as, for example, the Mernk In~r, 11th edition (Budavari
and ' a, 1989).
Benceforth reference to ephedrine will include reference
to derivatives thereof, such as, for example, ephedrine hydro-
chloride, ephedrine sulfate and ephedrine tannate. Pyrido-
stigmine and r~n~ti~;n~ are cholinergic drugs. A more com-
plete listing of specific examples of cholinergic drugs, and
of the various forms in which the respective therapeutic
agents may be -,' ni ~t~red~ can be found in various well known
~GfGLGll~G work3 such as, for G^xample, the M~r~--k rn~Y, 11th
edition (3udavari and a, 1989) . Atropine and proPan-
theline are anticholinergic drugs. A more complete listing of
specific examples of Anti~-hnl in~rgic drugs, and of the various
forms in which the respective th~.ri~r~--t;c agents may be admin-
istered, can be found in various well known reference works
such as, for example, the Mer--k Tn~r~Y, 11th edition ~Budavari
and, ` a, lg89).
Baclofen and ~ n;~1;n~ are skeletal muscle relaxant
drugs~ A more complete listing of specific examples of
skeletal muscle relaxant drugs, and of the various forms in
which the reâpective therapeutic agents may be administered,
can be found in various well known reference works such ae,
for example, the Merck rnfl~, 11th edition (Budavari and
coworkers, 1989). Amitriptyline and imipramine are tricyclic
anti-d~yL~a~ L drugs. A more complete listing of specific
examples of tricyclic antid~Lc,,~.~.L drugg, and of the vari-
ous forms in which the respective therapeutic agents may be
`7
16
admini6tered, can be found in various well known reference
works such as, for example, the Merrl~ Tnfl~Y, 11th edition
(Budavari and, . ' -, 198 9 ~ .
Cyproheptadine iq an example of an ~ntihiatr-;nir drug of
the tricyclic variety, and clemastine and setastine are exam-
ples of anti-h; ct~min; r drugs of the aminoalkyl ether variety.
A more complete li8ting of specific examples of ~nt;hiatr-in;r
drugs, and of the various forms in which the respective thera-
peutic agents may be administered, can be found in various
well known reference works such as, for example, the
~, 11th edition (Budavari and ~ ' D, 1989~.
A more complete listing of specific examples of antico-
agulant drugs beyond those fl1arlncefl below, and of the various
forms in which the respective thar~r~ t;r agents may be admin-
istered, can be found in various well known reference works
such as, for example, the Merrl~ Tnflf~Y. 11th edition (Budavari
And ~ .~ ' rC~ 1989~ . Tissue rlr nrJ~n activator and strep-
tokinase are thrombolytic drugs. Likewise, a more complete
listing of specific examples of thrombolytic drugs than those
~1; ar~nq~9 below, and of the varioug forms in which the re-
_pective therapeutic agents may be administered, can be found
in various well known reference works such as, for example,
the Merck Infl~T 11th edition (Budavari and coworkers, 1989~.
Aminophylline i3 a mem}~er of the xanthine derivative
class of brnnrhrfl;l:3tnrs Isoproterenol is a member of the
h~flr;nr class of brnnrhnfl;l:-trrq. A more complete listing
of specific examples of brrnrhn~ tnr drugs, and of the
various formg in which the respective th-~r~re--t;r agents may
be ~' n;qt.-red, can be found in various well known reference
works such as, for example, the r~erck TnflloY, 11th edition (Bu-
davari and ' , 1989). Within the context of the pres-
ent invention, aminophylline, igoproterenol and m~.thnh~Y; tal
sodium may be regarded as exampleg of antithrombotic drugs.
The various forms of ~-adrenergic blockers are known to
those skilled in the art and ;nfrrr~t;nn regarding them can be
found in various reference works, for example, the ~k
~, 11th edition (Budavari and ~ ./ ' ,, 1989). The
various forms of calcium channel blockers are known to those
skilled in the art and ;nfrrm~t;nn regarding them can be found
17 :-~l q~ 1~7
in various reference works, for example, the t~(~rrk I~ Y 11th
edition (Budavari and ' , l9B9). Glyceryl tr;nitr;~t~.,
isosorbide dinitrate and; qncnrh; 9~ 5-mononitrate are eYamples
Of ,:3nt;an~;na1 drugs. A more complete listing of specific
examples of ~nt;an~;n~l drugs, and of the various forms in
which the respective therapeutic agents may be administered,
can be found in various well known reference works such as,
for e_ample, the Merrk ~nrl~Y, 11th edition (Budavari and
~ - ' , 1989).
SllMMARY 01~ T~ V~
These and other objects of this invention are achieYed by pro-
viding a novel method and I ~ 'tinnq for clinical t ~ '
of chronic inf7 tLlly diseases. This invention involves use
of orally ~' niqtrred amine derivatives of benzoic acid and
partially or fully saturated analogs as carbonyl trapping
agents. ~hese primary thr.rnr.o1~t;c agentg act by rh-~mirally
binding to and serluestering the aldehyde and/or ketone prod-
ucts of lipid pernY;rlat;nn, Increased levels of lipid perox-
idation have been repeatedly ~m~mqtr~r.o~1 as a part of the
~infll nry cascaden procesg which ~ln~ rli~a the ~e.~ y
etiology of chronic ;nfl tnry diseases. p-~ 'nnh..n7n;r
acid (or PABA) ifi an example of the primary ~hqrrh~hl~. pharma-
cn~nr;rAl agent of the pregent invention. PABA has a small
mnl~rl11ar weight, ig water soluble, has a primary amine group
which should react with carbonyl-rrnt=;n;nr metabolites under
physiological rnn~l;t;nnq and is tn1~r:lt~ by the body in
relatively high dosages and for extended periods. The present
invention is directed to the use o~ carbonyl ser~uestering
agents ' n; qt-~red in oral dosages, nrt; nn~l 1 y in, ; nat; nn
with co-agents rnnq;qt;n~ of rl;n;rs~11y effective anti-oxidant
free radical trapping agents and agents related thereto, and
in, ' ;nat;rn with m ~;. ' q 80 as to produce a physiologi-
cal effect o an anti-inf1 -n~y nature. Optional co-agents
of the present invention include anti-oxidants (e.g., alpha-
tocopherol), q11qr~ntl;n~ reagentg (e.g., ..~ -hyl cellu-
lose), other vitaming, vitamin-related agents, chemical con-
jugating agentg which may far;l;tRt~ kidney drug ~1;m;n:~t;nn
(e.g., glycine), and orally :,. n;ct~re~ non-ahcnrh~hl~
21901~7
1~3
polyamine or polyamine-related agents ~e.g., chitosan or
cholestyramine). Particular additional ' ~ ~ useful in
the present invention are r~ crl nce~1 herein.
OBJ13CTS OF TEE INVENTION
Accordingly, it i8 a general object of this invention to
treat chronic infl: tnry digeages by use of compositions
comprising carbonyl trapping agents nrt;nn~11y but preferably
in, in:~t;nn with known anti-oxidant free radical trapping
co-agents, factors related to anti-oxidant free radical trap-
ping co-agents, and ~ t~1n~1~y with known, ';. c, 80 as
to create _ t;nnc with additiYe or synergistic physiolog-
ical therapeutic char~-t~Tictinc and 80 as to overcome the
disadvantages of the prior art.
It i3 a further object of this invention to f~-i 1; t~t~
the effectiveness of this anti-infl tnry ,~LU~d~ by use
of orally con3umed carbonyl trapping polymeric co-agents which
are of a nnn~h~3nrh~h1~- nature, 80 as to bind and sequester
carbonyl chemical agents which are present in food, thus pre-
venting such toxic agents from being absorbed into the body.
In particular, it is an object of the present invention
to use ~hcnrh~hl~ amine primary agentg; optional nnn~hq<~rh-
able amine polymeric co-agents, co-agents which inhibit lipid
pern~1~t;nn, vitamin co-agents which may be inadvertently
depleted, co-agent, ~hnl ;t.oq such as glycine which may be
depleted within the body, sulfhydryl co-agents as defined
herein, co-agents which may f~.-;1;t:-t.~ g111t~th;nn~ activity;
and various additional known ~' co-agents which have
been shown to or may contribute to the alleviation of symptom-
ology of the diseases addresged herein, thus improving upon
the prior art.
It is an object of the present invention to provide
compositions that may be used to provide increaged clinical
value in the treatment of diseage symptomology for disorders
featuring lipid pern~;~ ~t;nn and resultant formation of toxic
carbonyl . , ~, ;n~ ;n~7: chronic gingivitis; chronic
F~1n'lnnt;tisi chronic ~lltn; ~ gastritis; ileitis; inflam-
matory bowel disease, ;nr111ri;ng colitig; interstitial cysti-
tis; psoriasis; arthritig; t~n~l; n; t; c; carpel tunnel syndrome
~ 2190107
19
and other cumulative trauma disorders; lupus erytl rc~lc;
ir~ic; chronicnhetrl-rt;vepulmonarydi5ease; inflam-
matory myopathies; inflammatory neuropathies, ;nrl~l~1ng Alz-
heimer's disease, myasthenia gravis and multiple sclerosis;
epilepsy; as well ag legsening of ;nfl. ' y æite edema, and
L of post-event ischemia and reperfusion ,~ rJy
resulting from acute central nervous system trauma, stroke,
kidney ischemia or myocardial infarction.
It is another object of the present invention that in so
far as the therapeutic ~ c.u~ rr;h~1 herein may serve
to delay the necessity of ;n;ti~tinrJ the use of known medica-
ments or to decreage the dosage5 of known r ~i~ c required
to achieve bon~fir;Al effects, the period of prior art drug
th~.r~r~ t;r value may be eYtended and riPtr~ ~1 clinical
Qide effects resulting from use of known ~i. c may be
decreased, 80 that overall patient ~1. may be improved.
It is a further object of this invention that the absorb-
able amine and amine-related ~l~hct~nr~ and derivatives there-
of described herein when used in ~ ' ~n~-tirn with ~rer;f;~d
co-~gents may be rl;n;r:llly applied to treat veterinary dis-
orders , , h~ ~ to at least some of those human disorders
crr~ h~l above .
These and other ob~ects of the present invention will be
apparent from the following detailed description.
DETAILED STATEMENT OF THE INVENTION
It is known that aldehyde chemical ~h~l itrc, which
contain carbonyl functional groups, are generated during the
process of chronic infl~ n These aldehyde products
result from rz~thrlo~ir~l ly increased lipid peroxidation, which
may be ln;t;At~fl by a variety of activated oYygen chemical
species such as the hydroxyl radical, HO (Halliwell and Gut-
teridge, 1985, pp. 119-1201. The reactive cascade of free
radical pr~r~t;rn -, lipid perrY;rlRt;rn -, aldehyde forma-
tion and other sllh~ nt effect8 of ;nl'l~ 7n is well
in the prior art (Halliwell and Gutteridge, 1985,
pp. 102-103). The se...,..dc.~y carbonyl products of lipid
F~r^Y~ t;rn include saturated and ~ lratG~1 aldehydes,
dialdehydeg, epoxyaldehydeg, lactoneg, furang, ketones and oxo
acids (~erry and ~ ` , 1991, pg. 362S). A8 reactive
oYygen species are generated ~yQ during states of limited
oxygen availability, folIowed by reperfusion, a similar series
of reactions takes place at sites of hypOXia/Lel!~LLl~iOn
injury (Demopoulos and ' ,, 1980: Dowling and ~
1990, pg. 465). Aldehyde product3 of this reactivo cascade
are known to react with amino acid3 to form Schiff bases, and
to react with free amino groups of proteins, nucleic acids and
rhncrhrl;ri~;c (RAth~rill and coworker~, l9S1, pg. 352).
Prior to s1~hmics~rn of my ahove-cited US patent applica-
tion, the method concept of u3ing carbonyl-trapping agents
such as primary amine or amine-related derivatives of benzoic
acid to treat chronic infl nry digeageg wag not r~rnrJn;7~1
or disclosed. Thus, the Arrl;r~t;nn of this principle in con-
junction with use of known anti-oxidant free radical trapping
agents to produce new and novel , ' t i ons which have
improved, synergistic th~r~r~ t;r properties also was not
r ~,-n,rn; ,,.,~
The invention embodied herein is based on use of a com-
position of a primary amine derivative as defined herein as a
primary agent for rh~;r~lly binding to and seguestering alde-
hyde products of ;nfl ~;nn site lipid pernY;r~t;nn together
with a 'il , and r,pt;nnAlly their uge in ~ ~ ~nAt;nn
with anti-oxidant free radical trapping co-agents. This
unique, multiple-level approach to int-:~ Lc~ with certain
steps in the ;nfl tnry cagcade has not been previously
recognized by other research investigators. This is, in fact,
the first anti-~fl: y agent invention which A~l~lr~ R~c
the issue of aldehyde formation at i~fl: inn sites. A8
aldehydes are highly reactive mnl~rlll~q capable of reacting
with proteins, lipids and nucleic acids (Jellum and coworkers,
1973, pg. 200; Carden and ~ Lk~L~, 1986; Ralliwell and Gut-
teridge, 1985, pg. 123), their increased formation at inflam-
mation sites can be a siJrnifirAnt rnntrihl1ting factor in the
evolution of the clinical pathology of ;nfl tnry disorders.
The results of several p--hl ;chr.~l regearch studies suggest
that dysfl-nrtirnAl lipid pernYi~Atinn may be a contributing
factor in the etiology of a variety of chronic i"fl: nry
diseases, such ag -h~ tnirl arthriti8 (Ja8in, 1993; Merry and
~21`7~tl ~1
21
, 1991; Panetta and ~ , ~991; Rowley and
, 1984), multiple 8clerosis (Hunter and,
1985~, Fi~;fny;q (l-~tcn~.lcnn and 7 , 1989, pg. 318),
Duchenne muscular ly .~ y (Kar and Pearson, 1979; Jackqon
and ~ ~, 1984), colitis (Tamai and - , 1992) and
c_ronic ;nfl nry bowel digeage (Ahnfelt-Ronne and cowork-
ers, 1990~. As exposure to asbestos fibers can stimulate
lipid per~;8:-t;nn (TTi-ll;woll and Gutteridge, 1985, pg. 152)
and a c_ronic infl ory response (~om and ~ eL:j, 1991,
pg. 415~, ~chf At~C; q should also be included in this category.
Published evidence has also ~ f.~l the ~fn~rAt;nn of high
free radical ~u~,e~ ions at the inflamed site of experi-
mental foot pad edema (Dowling and - , 1990, pg. 464~,
the ability of carbonyl, resulting from lipid peroxi-
dation to induce foot edema in the rat (i3~.n~.~Ftti and cowork-
ers, 1980), and that formaldehyde is known to be an inflamma-
tory and f ` o~n;L- agent (Wheeler-Aceto and Cowan, 1991~.
In addition, a role for reactive oxygen radicala has been
proposed for numerous other dlsorderg, in~ ;nr7 infl: nry
vasculitis, : , ` y , mineral dust ~ - Ai q and auto-
immunenephrotic ylld~ Jll;~ll and~3rootveld, 1987, py.
10~ .
Ischemia/reperfusion damage to various tissues appears to
occur by a common ;F-, involving r7~n~rAtinn o~ free
radicals and lipid pern~;~t;nn (Fl~rk~nct~n and coworkers,
1991~ . Increased lipid pern~; lf~t;nn has also been demon-
strated in acute central nervous system trauma (~7all, 1987,
pgs. 421 and 424, D, lnq and - :., 1980, pgs. 97 and
112; Kontos and -, 1981, pg. 2329~, as a result of
stroke (Zivin and Choi, 1991, pg. 61~ ,,f l"~ l to myocardi-
al infarction (Kurdin, 1978~ and in an experimental model of
myocardial ischemia (Siminiak and Wysocki, 1992~. Increased
lipid peroxidation under such CiL~ ' - appear3 to be
initiated by extravagation of blood, a8 iron_~nntA;n;ng
8 hqtAnnFc such as hematin catalytically A r~l FrAt~ lipid
autoxidation (D~ ~ lns and ~ ~ne~ 1980, pgs. 97 and
115~ . Status ~r; 1 f rt i r~F has also been linked to increased
intr~ ll -lAr ~ull~e~Ll ~ions of free radicals, with 5- hA~qn~nt
li id pe_ lAt; ~n (Del Maestro, 1980, pg. 163~ .
2`1 ~ 7
Recent studies have also ~l;qrlns~d the rrcc;h;l;ty that
the etiology of ~l7hf~; '8 disease may include an Alltr;
, thus rctAhl ;qh;n~ a . ~ l link to disorders
such as ' tr;rl arthritig and systemic lupus erytL ~C~Iq
~Saso and .: ' , 1993). Evidence of an et;nlrr~;rAl role
for lipid perrY;~lAt1rn in ~l7h~.1 s disease has been dis-
closed ~Ceballos and . ~ , l990).
It is further understood that oral use of nrnAhsrrh:ihl ,~
carbonyl trapping agents may serve tQ prevent absorption of
dietary aldehydes and ketones from the :ll; y tract into
the body, thus , ~ ;n~ the intended th~rAr~ t;r results.
(i) Mechanism of Action of Primary Agents
For the most part, these rhArr~-rlrr~;rAl reactions are
based on the ability of the primary amine . ' of the
present invention to react with aldehyde fllnrt;rnAl groups of
rrt.ont;Ally toxic agents, yielding covalently bound Schiff
base products. Several examples of rh~m;rAlly AnAlrrJ~lllc
reactions, presented within other contexts, have been publicly
presented (~oldren and Hixon, 1946; Sawicki and
1963; Chio and Tappel, 1969; Dunlop and Peters, 1953, pgs.
353, 371 and 373 ) . These mQdel chemical systems are directly
ilnAlrgQ~c to the I ^hAn;-~ of drug action which is the basis
of the present invention.
Additionally, self-pol~, 7:1t;rn of o-Am;nnh~n7Al~hyde
has been ~oqrr;h~l In the 1994 edition of the Sigma Chemical
Company catalog of biochemical reagents the following state-
ment appears on page 90 of it8 listing ~o~ Ar~n~rnr~
l~n~t~7lel ~store at3 -20C Polymerizes rapidly when eY~posed to
room t., ~LULC. May yield slightly hazy solution in ethanol
due to presence of a small amount of polymer. Shipped in dry
ice." This ;nfrrr-t;rn directly ;nrl;r~t~q that a primary
aminQ grQup covalently linked to a benzene ring possesses
sl~ff;r;~nt reactivity for sirJn;f;r:~nt reaction with aldehyde
f~nrt;rnA~ groups at room t~ e. It is apparent that no
form of activation of the amino group is reo,uired and that a
Schiff base product forms readily.
CQmments by Feeney and ~ /LkeLa (1975, pg. 141) prQvide
an appropriate summary of this prior art:
A wide variety of sllhqtAnr~c with -NH~ groups con-
1 9~ 1 07
23
den_e with carbonyl compounds...This ~-nn~ nq~t;nn of
prim~ry amineq with aldehydes and ketones to give
- imines was first discovered by Schiff (1900). The
overall equilibrium greatly favors hydrolyGis in
aqueous solution for aliphatic aldehydes. With
aromatic aldehydes, the equilibrium is shifted in
favor of Schiff base form~tion. It is important to
note that in~r~ ing the n~ nrhili~ strength of
the amine will increase the rate of the carbonyl-
amine reactio~ but will have almost no effect on
the position of the equilibrium.
These comments suggest that the amine-mnntA;n;n~ carbon-
yl-trapping drugs described herein should have particular
promise for binding furanaldehydes, which are aromatic. These
comments also suggest that doses of 7hqnrhAhl~ amine drugs may
require ~n vivo ~..,..~.c..L-~-Lions in the range of 1:100 to
1.1,000 ~carbonyl:amine) in order to achieve clinical effec-
tiveness. This, in turn, suggests that ~hl.rAr~t;m dosages
may lie in the range of gram3 per day and that only drugs of
particularly low toxicity will have human ~rrl;cAt;nnq.
Feeney and coworkers ~1975, pg. 144) also noted the
1' of Schiff base trAn~iminA~inn, which occurs to a
significant extent at neutral pH:
2 , ~ R--I~C--N ~ H I H
H
The existence of such non ~ reYersible trans-
imination reactions is important within the context of this
invention, as it suggests that .L~ vivo both bound carbonyl
agents, in addition to free carhonyl agents, may be se-
o,uestered by amine-~nntAining drugs.
The small molecular weight, :~h~nrhAhl.~, primary amine
compounds described herein have analogous behavior r ~, as
well as an additional characteristic which fp~il;t~t~q diqpos-
al as urine metabolites. All of these compounds contain a
c~rboxylic acid group to f~-; 1 i t~te uptake and processing by
the kidneys.
2~90107
The AhOl; r fate o~ PABA in humans has been actively
inveAtirAtr~l and well reported in the h;- ';rAl literature
(Young and ~ L~, 1971; Howie and Bourke, 1979~ . It is 80
actively hnl ;7~q via several ~ and r~ Ant;tAtively
removed in urine (Bingham and Cummings, 1983; Wei2man and
, 19853 that PABA excretion has become a widely
rerr~i7~ standard ~or, ng urinary clearance. Small
amounts of PABA are normally present in the human diet. It i8
r.~rn~ni7~1 as being a vitamin for many organisms and is clas-
sified as a member o the vitamin B complex (Scott and Rob-
bins, 1942; Winitz and ' , 1970, pgs. 527-528; Smith,
1976, pg. 194). As a vitamin for human use PABA is commer-
cially marketed in the dosage range of 5 to 550 mg/day.
(ii) Examples of ~hrnrhAhlf- Drug Primary Agents
Primary agents of this invention are selected from the
group rnrc~ctin~ of six-carbon cyclic, , ~- rnntA;ninr a
primary amino s~hrtit~ont group and a carboxylic substituent
group wherein the cArbon ring can be phenyl, cyrlnh~YAn~,
cyrlnhrY~on~ or cyrlnh~YAA;,~n~. The carboxyl group can be
attached directly to the carbon ring, or can be separated from
the ring by one carbon atom. The primary amino group can be
attached directly to the carbon ring, or it can be part o a
larger functional group that Ls a substituent of the ring,
either in the omega position or at some ;nt~ Atr point in
the larger f~nrt;rnA1 group. The primary amino group may be
attached to the six-member carbon ring at the p-, o- or m-
position relative to the carboxyl cllhrtitl-,~nt group. p-Amino-
benzoic acid (PABA) is an example of this group. p-Amino-
ben20ic acid is known as a water-soluble B vitamin, and sever-
al pllhl i ch,--l studies have presented evidence to the effect
that PAaA functions, in part, as a weak anti-oxidant and a
weak ree radical trapping agent (Makgimov and Rebachuk, 1985,
~able ~; Pryor and ~ , 1976, pg. 201). In 80 far as
benzoic acid or derivatives thereof have been rl~r~n;7~A as
anti-oxidants or free radical trapping agents, their ~ ; rm
of action is understood to congi6t of hydroxyl radical trap-
ping by the ben2ene ring (Grootveld and T~A11;W~11, 1988; Hal-
liwell and Gutteridge, 1985, pgg. ~105 and 130; Richmond and
coworkers, 1981; Repine and, ' , 1979, pg. 1642). This
~1 701 07
has been explicitly ~ . ted for PA3A (Nakken, 1964, pgs.
446, 448, 454-457; Nakken and Pihl, 1966, pgs. 21, 22, 24, 25
and 28).
In addition to ~ny carboxylic acid primary agent listed
herein as useful in the present invention, the ~
cally ~ rr:lhlf. salt forms, rh~ ric~lly ~-c~r~r~hl~ ester
and amide derivatiYes thereof are useful. The class of pri-
mary agents of the preYent invention are water soluble com-
pounds ~molecular weight range 100 to 1,400) of the formula:
R13~-(C)n--COOH
R R
wherein R, is -NH,; -aminoalkyl having 1-10 carbons;
-N8C(=NH)NH2; -(CH2)DNHC(=NH)NH, wherein n is 1-10; C( NH)NH,;
-(CH,)n-CP;.NCl=NH)NH, wherein n is 1-10; -NHC~=NH~NHNH,;
- (CH7~NHC(=NH~NHNH, wherein n is 1-10; - (CH,~,-CH.NC(.NH~NHNH,
wherein n is 1-10; -NHNHC( NH)NH,; - (CH,)~-NHNHC(-NH)NH,
wherein n is 1-10; and - (CH,)~-CH-N-NHC(=NH)NH, wherein n is
1 -lOL
R, is E~; -OH; -0-CH,; -0-R wherein R i8 alkyl of
2-10 carbons; aminoalkyl wherein the alkyl group i5 1-10
carbons; -SO~E}; -CH3i and -(CH~)~CH~ wherein n is 1-10;
R and Ra are -H, 0~ or CH,; and n is 0 or 1.
These compounds are used in the ;~;nn~ of the
present invention in dosage levels of from 600 mg to about 20
gm per day in one or more divided doseg, preferably from about
1 gm to about 20 gm per day, more preferably from about 3 gm
to about 20 gm per day, and most pre~erably from about 6 gm to
about 20 gm per day. Altern~tively expressed, the dosage o~
these compounds is in the range of 15 mg/kg daily to about 800
mg/kg daily, preferably 30 mg/kg daily to about 80~ mg/k~,
more preferably 60 mg/kg daily to about 800mg/kg, and moqt
pre~erably 120 mg/kg daily to about 800 mg/kg.
(iii) Mechanism of Action of Nnn:-h~nl-h~h~ Primary Amine and
Amine-Related Polymeric Co-Agents
.
2 1 9~ 1 D7
26
The pre~ence of aldehydes and ketones in the human diet
(Dunlop and Peters, 1953, pgs. 280, 308 and 403; Rice, ls72;
8chauenstein and 1;~ G~ r, 1977, pgs. 181-194; Shimizu and
Watanabe, 1979; Baltes, 1985; Lever and ' , 1985) may
be a _actor which may put a patient yl-ffPr;n~ from a chronic
;nfl, nry disease further at risk. This might be especial-
ly important for victims of chronic Alltni ~ ~-~trit;~,
ileitis and colitis, as the damaging effectg of ;nfl ;nn
site carbonyl , ' may be A~-rPnt~-Ated by direct exposure
to dietary carbonyl agents.
As such, it is apparent that the diet is a 8i~n;finAnt
source of carbonyl agents, and their presence may be a con-
trih~ltin~ factor in the etiology of çhrQnic ;nfl: -nry dis-
eases. Toxic prQperties of furAnA~ hyde derivatives have
been demonstrated in both n ViVQ and in vitro studies
~}tonecki and rc, 1974; UlbriCht and . ' ,, 1984~.
The nnnAhcnrhAhle dietary Yllrr1 ~ such as those defined
below can be of health benefit by virtue of their ability to
cQvalently trap dietary aldehydes and ketones. The agents
~Q~-r~h~c~ in this section can A. ,l;~h this function because
they bear primary amine groups or derivatives thereof. As
large m~lPI-l7lAr weight mnl~ llPel which are nQn-digestible they
have the capacity to pass through the digestive tract, acting
in effect as another form of dietary fiber. These nnnAhqnrh-
able polyamine trapping sl~hstAnnl~ may be divided into three
classes; naturally occurring polyamine polysaccharides, chemi-
cal derivatives of naturally occurring polysaccharides, and
synthetic polyamine polymers.
The fate of --lnn~;Al~phyde given orally to rats may
serve a6 an example of the, -Ahnl ;r- of dietary aldehydes,
and how an l~n~lc~rFtAnrl;n~ of this prQcess can be used to define
nnnAhcnrhAhl P carbonyl-trapping drug8 . Studies by Draper and
(1986) d_...~,..~ Ll~ted that the primary form of "bound"
MDA in rat or human urine is N-~-acetyl-~- (2-propenal) lysine.
This is the h;nln~icAlly acetylated derivative of the MDA-
lysine adduct N-e- (2-propenal) lysine. Draper and ri
(1986) were able to generate N-~- (2-propenal) lygine ~ vitro
by exposing beef muscle prQtein to MDA, followed by treatment
with pepsin and hog ;nt~t~n~l juice. This ;n~l;cAt~l that the
~ 27 90;~ Q7
~-amino groups of dietary protein lysine residues can coval-
ently bind dietary aldehyde under rnnrlitinnq found in the
intestinal tract. As such, chemically Anl1rrjrl1q primary amine
droups on nnn:~hcnrh:~hl ~ drugs should alGo be capable of coval-
ently binding dietary aldehydes under rnn~lit1nnQ to be found
in the ;nt~ct; n ~1 tract. In this case, however, the bound
carbonyl species would be excreted in the feces, thus prevent-
ing ~ubse~u~llL ~ Y Yo exposure to dietary carbonyl agents.
In their study Draper and ~ ' noted that N-a!-
acetyl-~-(2-propenal)lysine was found in urine of fasted rats
or animal6 fed on MDA-free diets, ;n~rAt;nr, that the MDA-
ly3ine adduct also forms ~,~ vivo. These investigators re-
ferred to earlier work which ~ ed that the MDA con-
centration normally found in food is in the range of ~0.1 to
10 ppm (0.1 to 10 ~LM), which gives some idea of dietary
a ldehyde rnn rrn t r:~ t ~ nn q,
(iv~ Examples of 2~nn~hsnrh~hle Drug Products Useful in the
Method of the Present Invention
(a) Naturally Occurring Amine-rnnt:~in;nrJ Polysaccharides
Any naturally occurring polysaccharide featuring ~-1,2,
~-1,3, ,~1-1,4 and/or ,~-1,6 linkageg which containg ~m;nnq-lg~rg
may be regarded as a non-digestible, rnt~.nti:~1ly active car-
bonyl trapping agent. The chitin class of biopolymers may be
cited as an example of such an agent, having the general
structure of
poly-,~- (1- ~4 ) -N-~ c~tyl-D-gl ~ ~ ' nr
A form of microcrystalline chitin has been described in which
some of the acetyl groups have been removed, revealing free
amine groups ~Austin and coworkers, 1981, pg. 7sO). Chitins
obtained from different sources feature difierent degrees of
amine deacetylation (Austin and ~ ' , 1981, pg. 752~.
(b) Chemical Derivatives of Naturally Occurring
Poly~æ~r7~:-ri ~:I~Q
Various pretreatment l~u~edu~ may be applied to natur-
ally nrr-lrr;nrJ polysaccharides prior to generation of chemical
derivatives. G~-nPr:lt;nn of microcrystalline polysaccharides
is one example of such a yL-L~.eo~ .lL yL~J~edu~. As applied
to r~ lns~ or chitin (Yalpani, 1988, pg. 389), this yields
a rnlln;~ l y~ e~6d form of polygaccharide featuring high
Q7
2a
porosity and enhanced ~l-q~Prf1h;1;ty to chemical reactions.
nPr:~t;nn of nmicrofibrillated" rpll~llnqe or chitin i~3
another example of a ~Ll. ~Lu~,.du~t which produces
enhanced surface area, increased water retention capacity and
enhanced chemical :~rrPq~;h;l;ty (Yalpani, 1988, pg. 390) . Use
of strong (~ 18~) sodium hydroxide is still another rPrrJrn;7~
Lr~ ~ or activation, ~L~ d~ found to be helpiul as
a starting point for preparing chemical derivatives of poly-
saccharides (Yalpani, 1988, pg. 214).
(b) (1) Deacetylation of Naturally Occurring Poly~Arrh~ri~q.
A variety of polysaccharides have been irlPnt;~;P~l which
are rich in N-acetylated residues. Upon chemical deacetyla-
tion these ~ LLcl.yd,,~es yield high mnlPrlll~r weight deriva-
tives bearing primary amine groups directly linked to sugar
carbons, that is, no sidearm spacer units present.
i. Chitosan. This is the deacylated form of chitin. As des-
cribed in the ~IP~rk Tn~PY (Budavari and ~, 1989, pg.
316) chitin is a cellulose-like biopolymer the composition of
which consists mostly of N-acetyl-D-gl nP residues
covalvently linked by Ig-1,4 bonds. Chemical deacylation re-
moves acetate, s7PnPr~t;nrJ primary amine groups still covalent-
ly bound to the polysaccharide. Chitosan has rPrn,rn;7ecl uses
in water ~ , in rhntnJrr~rh;r lq;nnq, and in improv-
ing the dyability of synthetic fabrics and fibers. The free
amine groups in this substance also give it rhPl~tinJr proper-
ties (Austin and ~ : ` , 1981).
ii. Chondroitin sulfate. This is a mucopolysaccharide found
commonly in, 1~ ~In tissue. It consists of repeating disac-
charide units, each of which has a D-glucuronic acid residue
~-1,4 linked to an N-acetylchondrosine residue (Budavari and
rs, 1989, pg. 344) -
iii . Hyaluronic acid . This mucopolysaccharide is also f oundcommonly in l; ~n tiggues . It consistg of glucuronic acid
and glllrn-----inP residues bound by ~-1,3 and ~1-1,4 linkaqes
(~3udavari and, ` ~., 1989, pp. 751-752) .
iv. Keratan sulfate. This I l j:ln glyl ~nnrJlycan con-
sists of a repeating disaccharide unit of a C-6 sulfated C-2
N-acetylated sugar regidue and a g~l~rtn~e regidue linked by
,~-1,4 bonds (Yalpani, 1988, pp. Z7-28).
~90~7
29
(b) (2) Chemical ~--;n:lt;c~n of Polys~rrh~r;~Pc
i. 2-Amino-2-deoxyrP~ ln~p~ Cellulose can he aminat~d by a
process of selective rY;~l~t;cn, nY;--t;nn and sllh~PrlllPnt
reduction with lithium aluminum hydride (Yalpani, 1988, pp.
281-282) .
ii. AltPrn:-t;ve ilm;nAt;rn ~lu~e~lu~s. :~--;nn~PrYy polysac-
charides can also be prepared via azide or hydrazide inter-
mediates or by reductive: n~t;nn using sodium Uy.lllCJI)ULo-
hydride (Yalpani, 1988, pg. 281). ~3esides being applied to
rPlllllnge, other non-~l;r~Qt;hlP polysaccharides such as
curdlan (Yalpani, 1988, pg. 22) may be aminated hy such
chemical ~U-~lllL-o.
iii . 3 -Aminopropy3 rPl 1 ~1l nqe . Reaction of cyanoethyl rPl 1 1ll nQP
with borane-tetral.ylLuCu~ . or borane-dimethyl sulfide com-
plexes in tetrallyl~ucu~ generates 3-aminopropylrPlllllnQe
(Yalpani, 1988, pgs. 250 and 255~. In this derivative each
primary amine group is at the end of a three carbon sidearm.
iv. AminoethylrPll--ln~P. This chemical has been previously
marketed as an anion exchange column .l, . tn~raphy resin
(Sigma Chemical Co. catalog, Feb. 1981) and used as such in
protein pur;fic~t;rn studies (Fasold, 197S, pp 481-482).
v. ûther aminoalkyl-, amino(hydroxyalkyl) -, aminoalkyl-ether-
and amino(hydroxyalkyl)-ether- derivatives of rPlll~lcaP, chi-
tin and other naturally occurring non-digestible carbohy-
drates . Noting that the chemical hn~lnl nsy for producing
such derivatives is c' P~ in public domain literature,
the biomedical ~rrl ;c;~t;n" of such derivatives for thPr:~rP~lt; r
purposes Apelrr;hp~l herein i5 also claimed. This would
include:
aminoalkyl derivatives of the formula
L2N- (C}II~z- [carbohydrate3 where n = 1 - 30, ;nrl..~;nrJ
alkyl i60mers;
amino(hydroxyalkyl)- derivatives of the formula
h2N- (CL2),-CLûL- (CL2),~ L~,Ly.l~..te], where m = o - lS
n = o - 15;
aminoalkyl-ether- derivatives of the formula
}I2N-(ClI2)~-û-t~ L~L~ te]~ where n = 1 - 30; and
amino (hydroxyaklyl) -ether- derivatives of the formula
~ 2N- (C~2),,_CLOL- (CL2)~-û- [.~ L.,L~lL..t~], where m = o - 15
. ~ ~19~D7
n o - 15
Vi. 7`-innhPn7yl- derivatives of rP11~11n~P, chitin or other
naturally occurring non-~i;rp~tihlp carbohydrates. As the aro-
matic amine group i8 a weaker base than its aliphatic counter-
part, this class of nr,n~hsnrhAhlP amines should be less chemi-
cally active than amino- and aminoalkyl- derivatives described
above . These derivatives are of the fnl 1 m./i nr general
D~LU~LUL~S3:
}I2N-C~E,- (C~2)"- ~.~LL~y~te],
}12N-C~2-C~ -(C~2)~,-t~ L~L~1- ..te3,
!I2N-C~-(C~2)"-O-t~ L~L~ tol where n = O - 30, and
~2N-C~ - (C 2)~-C~O~- (clI2)~-o- l~L~L~ lL~te~where m - 0-15
n . 0-15
This includes p-, o- and m ~ ring amino- and
hyl- isomers, and alkyl group isomers.
Vii. J~ niri;nP and: nnrl~ni~linP derivativeg of rf~ ~s~
chitin or other naturally occurring nnnRhcnrh~hl ~ carho-
hydrates selected from the group rnnFI; cr i nr Of
II2N-C(~N~ ,o. L~ te3;
~ 2N-C(~NEl)-(CII2)~ -~ L~L2~ Lo~ where n ~ 1-10, in-
cluding lly~ . isomers and hydroxylated derivatives
thereof;
~ 2N-c(~Nll)-o-(cll~)"-t~L~LJ~t~]~ where n = 1-10, in-
cluding IIYdL~ LiJ~ isomers, ether linkage isomers and hydrox-
ylated derivatives thereof;
~ 2N-C(-NEI)-NL- [o~L~L~d~Lo3
1~2N-C(~N )-Nfl-(c~2)~-t~o~L~L~ to]~ where n = 1-10, in-
cluding l1YdL~ L~11 isomers and hydroxylated derivatives
thereof;
L2N-C(~)-NL-(C~2)~-O-t~ L~L2.1~to3~ where n = 1-10,
including llylL~ Lil~/ll isomers, ether linkage isomers and
hydroxylated derivatives thereof;
~ 2N-C(=NH)-N~C}I-(C~2)"-t~L.~L~ to3, where n = 1-10,
including llydL~LI/~JIl isomers and hydroxylated derivatives
thereof;
Il2N-C(=NEI) -N~CII- (C1~2)"-O- t-~L~,L~l.,,te~, where n = 1-lo,
including lly~iLU~ LL~ll isomers and hydroxylated derivatives
thereof;
El2N-N~C ( ~N~) -Nfl- ~ L~L~ te3;
` 2l93107
31
ll~N-Nl}c(=Nl}) -Nfl- (OE~ LvL~lL~t~] ~ where n = l-lO,
inrll ~9;n~ 1~YVL~ Lb~II1 isomers and hydroxylated derivatives
thereof;
l{,N-NhC(=Nli)-Nli-(CI},),-0-~1 .LvLy~.te3, where n = l-lO,
;n~ 3 I~y~lLv-cLL-JIl isomers, ether linkage isomers and
hydroxylated derivatives thereof;
H,N-N}IC(.NL~-N.OE-(CS,),,-~...LvL~ .t~3, where n = l-lO,
;n~ Ain~ IIY~1LU~ lLLvll isomer3 and hydroxylated derivatives
thereof;
}I,N-NEIC (.NEI) -N.OE- ~OE,) ~-0- ~ LvLy ~ 3, where n ~ l - lO,
includins lly lL~ Lbull isomers, ether linkage i30mers and hy-
droxylated derivatives thereof;
L,N-C (.NEI) -NII-NEI- [~ ~LvLy~ ~te3,;
X,N-C(.NEI~-Nh-NH-(OE,),-[- rLvv~lL~Le~, where n l-lO,
~nrl~ ins llylL~J-aLL~JI.L isomers and hydroxylated derivatives
thereof;
X,N-C(.NEE)-Nfl-NEI-(OE,~,-0-~._.L/vLy~L.tO3, where n = l-lO,
including l1Y~1LV~LL~ isomers, ether linkage isomers and
hydroxylated derivatives thereof;
H,N-C (~N~1 -N!I-N=OE- (CEI,),- ~. ~.LvL~ l. .Le3, where n = l-lO,
in-ll tq;ng IIYdL~ LL~Il isomers and hydroxylated deriva-
tives thereof;
~ N-C (~NL) -NEI-N~OE- (CEi~ 0- ~ LvLylL~ ~e3 ~ where n = l-
10, in<~ l;n~ llydLu_~tLL~/Il isomers, ether linkage isomers and
hydroxylated derivatives thereof;
(h) (3) Aminated Sucrose Polyesters
Mixtures of fatty acid hexa-, hepta- and or tAoAt~rq of
sucrose, known as sucrose polyester, are not hydrolyzed by
pancreatic lipase en2ymes and are not absorbed in the intes-
tine (~andacek, 1984) It is tl;qn10s~rl and claimed herein
that primary amine, Am;nn~1Ani~l;n~. and guanidine derivatives
of sucrose polyesters are of benefit in reduction of dietary
carbonyl substances, ~nA1n~o~ to the proposed action of other
nnnYh~n~h~hl e agents described herein Such derivatives of
sucrose polyesters would include gtructures in which the
carbonyl trapping fl nrt;nnA1 group ig in the ~ or other
isomeric position(s) within the fatty acyl chaing, fatty acyl
chains having more than one nitrogen f~n-t;nnA1 group and
fatty acyl chains having hydroxyl groups Such aminated
-
~19~07
32
sucro3e polyesters may be used in pure form a5 a dietary
5l-rrl . , or may be prepared as a coating on a particulate
carrier such as, for example, cellulose or styrene divinyl-
benzene copolymer resin.
(c~ Synthetic Polyamine Polymers
(c) ~1) Synthetic poly~ArrhAr;rlr-~ consisting partly or entire-
ly of ~ nr~s~ rr~ bound by ,~-1, 2, ,~-1, 3, ,~-1, 4 and/or ,~-1, 6
linkages may be regarded as nrnAh~rrhAhl r~ carbonyl trapping
agents .
(c) (2~ Mixed polysaccharide polymeric derivatives. Primary
amine, aminoalkyl (one to ten carbons per alkyl group), amino-
hydror~yalkyl (one to ten carbons per alkyl group and one to
ten hydroxyl groups per alkyl group), Am;nrrJllAn;rlinr., amino-
guanidinyl-alkyl (one to ten carbons per alkyl group), amino-
~lkylJrl-An;rlinyl (one to ten carbons per alkyl group), guani-
, dine, nrhPn7rn~ and aminoalkylben2ene (one to ten carbons
per alkyl group) f--nrt;rmAl groups may be covalently attached
to matrices such as, for example, epi-chlorohydrin copolymers
Of r~ r~ce or chitin. F~lnrt;nnAl group spacer groups may
include alkene as well as a1kyl groups.
(c) (3) Non-polysaccharide polymeric derivatives. Primary
~mine, aminoalkyl (one to ten carbons per alkyl group),
amillGlly.lL~.y~lkyl (one to ten carbons per alkyl group and one
to ten hydroxyl groups per alkyl group), ~inrg-~nirl;nr~,
5Im~n~rJ-~An;rl;nylalkyl (one to ten carbons per alkyl group),
aminoalkyl~An;r~;nyl (one to ten carbons per alkyl group),
~Ani ~; n~ . ,r and aminoalkylbenzene (one to ten
carbons per alkyl group) f~nrtirnAl groups may be covalently
attached to a wide variety of synthetic non-digestible poly-
mers. F~lnrt;rnAl group spacer groups may include alkene as
well as alkyl groups. Like their sugar-based counterparts,
these agents should be capable of reacting with dietary
carbonyl compounds. Nitrogen-rr,ntA;ninr~ f~nrt;rnAl groups may
be covalently attached to synthetic supports such as, for
example, polystyrene, styrene-divinylbenzene copolymer, poly-
r vinyl alcohol and crr~l; nkr,rl derivatives thereof .
These n. .. ,~~ hl r polyamine /~ ds that se~uester
carbonyl R~h~tAnrr~5 present in the diet are used in the compo-
sitions of the present invention in dosage levels of irom 600
-
2 ~ 90 1 ~
mg to about 20 gm per day in one or more divided doses, pre-
ferably from about l gm to about 20 gm per day, more prefer-
ably from about 3 gm to about 20 gm per day, and most prefer-
ably from about 6 gm to about 20 gm per day. Alt~rnAtively
~ ed, the dosage of these ~ , ' is in the range of 15
mg/kg daily to about 800 mg/kg daily, preferably 30 mg/kg
daily to about 800 mg/kg, more preferably 60 mg/kg daily to
about a00mg/kg, and most preferably 120 mg/kg daily to about
800 mg/kg.
(V) Co-A~' nictration of Anti-oxidants and Lipid Pern~ At;nn
rnh; hi tnrc
A8 regards the use of anti-oxidant and lipid FPrnri~At;nn
inhibitor co-agents, vitamin co-Agents, co-agents which are
metabolites at risk of ~rl ~t;I n, sulfhydryl co-agents, and
co-agents which may facilitate r~ tAth;nnP activity, it is
assumed herein that these s~~hctAnr~ are r n; ctPred orally
unless stated otherwise. Dosage ranges for these co-~gents
refer to human use and may be ad~usted accordingly for use by
other mammals on a per kilogram basis. It is claimed herein
that the therapeutic value of the primary amine agents of the
present invention can be ~ ; m; 7-'~ by administration in
conjunction with r~ n~n; ~ ~ anti-oxidant free radical trapping
' such as ~-tocopherol (Ferrari and ~ . , l991,
pg. 97S; Stuckey, 1968, pp. 214-215~, dosage range from 100 I.
U. daily to 3,500 I. U. daily, or other agents previously
rf~rorn;7P~I as adjunts which facilitate ~ v vo rArAh;l;ty to
inhibit lipid pern~;llAt;nn 7he dosage range noted above for
~-tocopherol is also claimed for other vitamin E derivatives
such as ~I-tocopherol, y-tocopher-ol, ~-tocopherol, ~-toco-
pherol, ~l-tocopherol, ~l-tocopherol and ~1-tocopherol, as well
as ester derivatives thereof such as the corrpcrnn8;nr acet-
ate, succinate and n;rnt;nrt~ forms.
Citric acid, dosage range from 200 mg daily to 20 gm
daily, may be included in this catagory of co- ' n; ~tPred
agents, as it i8 rPrngn;7P~l as having anti-oxidant propertie~
(MPrrk Tn~lPl~ 3udavari, lgag, pg. 363) . A1t~rnr~t;Tely, this
co-~gent may be consumed as a, ' inr~t;nn of rntr~cc; citrate
yJ~ e and citric acid monohydrate in a weight ratio of
3.3 to 1, or other weight ratio selected 80 as to All~A1;n;7P
~19û1~7
a composition. Citric acid is also r~cn~ni7~ as an ;nh;hit~lr
of Maillard reactions ~Stuckey, 1968, pg. 210).
In a F~lhl i ~h~ list of agents which function to supple-
ment the chain-breaking anti-oxidant property of vitamin E3,
Tappel (1970, pg. 1138~ ~ ;nn.o~ h;~l1nnl, seleno-amino
acids and sulfhydryl ~ (e.g., ~ tAth;nn~, sulfhydryl
proteins, cysteine and I h;nninP). An illLLL~ us, intra-
muscular, sl~hr~t~n~n~l~ or oral do3age range ~rom 10 mg daily
to 500 mg daily for the class of l~h;~l;n~l~, coen2yme Q= where
n = 1 - 12, i9 proposed herein. An ill~ ...,u." i
lar, sllhmltAn~m~ or oral dosage range from 10 mg daily to 500
mg daily for g~tAth;nn~ is proposed herein. Other substances
in this general group include butylated-hydroxytoluene (Frank-
el, 1987, pg. 81), dosage range from 10 mg daily to 1 gm
daily; butylated hydroxyanisole (Sies, 1991, pg, 325), dosage
range from 5 mg daily to 40 mg daily; propyl gallate (Verhagen
~nd ~_ ' , 1991, pg. 113), dosage range from 10 mg daily
to l gm daily; dodecylgallate (Verhagen and coworkers, 1991,
pg. 113), dosage range from 10 mg daily to 1 gm daily; tert-
butylhydroquinone (Verhagen and ~ ~ ' , 1991, pg. 113),
dosage range from 10 mg daily to 1 gm daily; ,B-carotene,
dosage range from 20 mg daily to 300 mg daily (Frankel, 1987,
pg. 82); dihydrolipoic acid (Sies, l991, pgs. 33S and 36S),
illL~ve:~)us~ i--L. lAr, G--h~---t~n.om-. or oral dosage range
from 10 mg daily to 500 mg daily; N-acetyl-cysteine (Le Guen
and, rFI, 1992), dogage range from 10 mg/kg daily to 150
mg/kg daily; prn~t~lAnflin B1 oligomers (also known as poly-
meric 15-keto pro~t~lAnflin ;3 or PG~), il~L~ u~, intramus-
cular, ~- hr~lt:.n~.n--~ or oral dosage range from 5 mg/kg daily to
400 mg/kg daily; 2- - ~hyl-4-tert-butyl-6-;nflnrh~nnl,
dosage range from 0.5 mg/kg daily to 600 mg/kg daily (Swingle
and, r~, 1985, pg. 120); 2- -hyl-4-tert-butyl-6-
propionylphenol, dosage range from 20 mg~kg daily to so0 mg/kg
daily (Swingle and ... ' .., 1985, pgs. 120-121); 2, 6-di-
tert-butyl-4- [2~ -thenoyl]phenol, dogage range from 3 mg/kg
daily to 300 mg/kg daily (Swingle and .. - ' ~, 1985, pg.
121); N,N'-diphenyl-p-phenyl~n~ ;n~, dosage range from 5
mg/kg daily to 500 mg/kg daily (swins~le and ' ~, 1985,
pg. 118); ethoxy~uin, dogage range from 5 mg/kg daily to 500
2~9QfO7
.
mg/kg daily (Swingle and - ' ~, 1985, pg 118); probucol,
a synthetic anti-oxidant tllAl7i~ 1991, pg 586), dosage
range from 25 mg daily to 1 gm daily; ebselen, iLlLL~ IU~ ~,
illLL_ lAT, g~lhr1t~n~nl1~ or oral dosage range from 5 mg/kg
daily to 500 mg/kg daily; 5-L[3,s-bis(1,1-dimethylethyl)-4-
hydLu~y~hellyl] methylene] - 3 - (d$methylamino) -4 - thiazolidinone
(LY221068 ; Panetta and ~ ' , 1991), dosage range from 1
mg/kg daily to 100 mg/kg daily; s-[~3,5-bi3(1,1-dimethyl-
ethyl ) -4 -hydLu~yL he, yl] methylenel -3 - (methylamino ) -4 -thia20-
lidinone (LY269415, Panetta and coworkers, 1991), dosage range
from 1 mg/kg daily to 100 mg/kg daily; D-myoinositol-l 2 6-
tr;~.L,~ L,l,,.te (Claxson and ' , 1990), ill~L~ VelluUF ~
ill~L - lAr"311hr 1tAnOr~l~ or oral dosage range from 10 mg/kg
daily to 1 5 gm/kg daily; nordihydroguaiaretic acid, intra-
venous, iI~L ls~r~ s~hrllt:ln~nll~ or oral dosage range from
100 mg/kg daily to 2 ~r~mfkg daily; defeL~ Tr megylate~
ill~L~Vell~ls, ill~L lAr or 8lhrlltAn~ol~c dogage range from
100 mg daily to 2 gm daily; tirilazad mesylate (U-74006F),
intravenous, ill~L ~rlll ~r or " ~ dosage range from
150 /Ig/kg/hr to 15 mg/kg/hr; derivative of t;r;lA7A~ in which
the steroid portion of the chemical ~.-L~ uLe has been re-
placed with the tetramethyl chroman portion of d-m tocopherol
(U78517F, Up~ohn), ill~L --. ~ luu~, illLL~ IUl18 or g~ hrlltAnl.m
dosage range from 150 llg/kg/hr to 15 mg/kg/hr; tr; ~A7;~inl.,
dosage range from 100 flg/kg daily to 3 0 mg/kg daily; N~N'-
dimethylthiourea (Repine, 1991), ill~L ~ uus, ill~L lAr,
8 hrlltAn~nl ~ or oral do8age range from 5 mg/kg daily to 100
mg/kg daily; and 2- (2-hydroxy-4-methylphenyl) aminothia201e
hydrochloride (Bonne and ' , 1990), dosage r~nge from
0 1 mg/kg daily to 50 mg/kg daily Selenium may also be in-
cluded in this group, dosage range from 25 ~g daily to 0 5 mg
daily, as it has rl-rnrJn; 7 1 indirec~ anti-oxidant properties
(Stuckey, 1968, pg 236) Some n vivo experimental data has
been presented which indicates that ~-tocopherol; butylated-
hydroxytoluene; propyl gallate; 2-aminomethyl-4-tert-butyl-6-
;n~nrh~nnl; 2-l hyl-4-tert-butyl-6-propionylphenol; 2,6-
di - tert-butyl -4 - r2 ' - thenoyl] -phenol; N, N' -diphenyl -p -phenyl -
-n~ ' nr; ethoxyquin; ebselen; 5 - L [3, s -bis (1, 1-dimethyl -
ethyl) -4-hydroxyphenyl]methylene] -3- (dimethylamino) -4-thiazo-
~1 901 07
36
lidinone; 5-[[3,5-bis(1,1-dimethylethyl~-4-llydL~ y~llellyl]-
methylene~-3-(methylamino)-4_th;A7nl;~;nnnO; nordihydro-
; Arot i r acid; 2- (2 -hydroxy-4 -methylphênyl) aminothiazole
hydrochloride; and D-myninncitnl-1~2~6-~r;crhnsrhAto possess
both anti-;nfli nry and anti-oxidant properties (Swingle
and ~ .- ' , 1985, pgs. 114, and 118-121; Claxson and
, 1990; Schmidt and Bayer, 1990, pg. 149; ~onkanen
and U~ LkeLa, 1990, pg. 190; Gado and Gigler, 1991; Panetta
and . ' ,, 1991; Parnham and, ' , l991).
(vi) Prophylactic Vitamin Co-A.~ nictrltinn
It is yet still another obiect of this invention that the
safety and effectiveness of the products ~locrriho~l herein may
be nrt;m;7---1 by co-~' 'n;RtrAt;nn of vitamins which may be
inadvertently depleted by the treatment or which may otherwise
contribute to the clinical effectiveness of the compositions.
This group includes:
-retinol, dermal, cllhol~ti~nonllc, illLLo.~ 8, ;n
lar or oral dosage range from lO ~ug/kg daily to 1 mg/kg daily;
-vitamin A aldehyde (retinal), dermal, sl-hr-lti~non~l~, in-
LLO~ ufi~ L lAr or oral doagage range from 10 ~g/kg
daily to 1 mg/kg daily;
-vitamin A acid (retinoic acid), dermal, s~lho~ti~non~
~ L~ ua, i ' li~r or oral dosage range from 10 llg/kg
daily to 1 mg/kg daily;
-retinyl acetate, dermal, g~h~ tAn n~q~ L~vell~u8, in-
tL 1 Ar or oral dosage range from lC llg/kg daily tO
mg/kg daily;
-vitamin B (thiamine i~Cl~, do3age range from l mg daily
to 1.5 gm daily;
-thiamine propyl ~l;c~llf;flo, dosage range from 1 mg daily
to 1. 5 gm daily;
-thiamine disulfide, dosage range from l mg daily to 1.5
gm daily;
-thiamine ~lic~lfi~o 0,0-diisobutyrate, dosage range from
1 mg daily to 1.5 gm daily;
-thiamine ~lic~lfi~qo hydrochloride, dosage range from 1 mg
daily to 1.5 gm daily;
-thiamine ~ --l fi~o phosphate, dogage range from 1 mg
daily to l . 5 gm daily;
~90107
-thiamine mononitrate, dosage range from l mg daily to
1.5 gm daily;
-thiamine 1,5-salt, dosage range from 1 mg daily to l.S
gm daily;
-thiamine ~ ,l . ;c acid ester chloride, dosage range
from l mg daily to l . 5 gm dailyi
-thiamine phosphoric acid ester rhnsrh~r~ salt, dosage
ra~ge from 1 mg daily to 1. S gm daily;
-thiamine trirl~ L~ iC acid ester, dosage range from l
mg daily to l . 5 gm daily;
-vitamin B, (riboflavin~, dosage range from 1 mg daily to
1 gm daily;
-riboflavin tetrabutyrate, dosage r~nge from 1 mg daily
to 1 gm daily;
-riboflavine s'_rhn~rhAt~ ester mnnnsnAi salt, dosage
range from 1 mg daily to 1 gm daily;
-vitamin B, (pyridoxine BCl~, dosage range from lO mg
daily to 1. 75 gm daily;
-pyridoxal, dosage range from 10 mg daily to 1. 75 gm
daily;
-pyridoxal ~Cl, dosage range from 10 mg daily to 1.75 gm
daily;
-pyridoxal s-rhnRrh~e, dosage range from 10 mg daily to
1.75 gm daily;
-pyridoxal S-rhn~rh~t ~ calcium salt, dosage range from 10
mg daily to 1. 75 gm daily;
-pyri~nY~min~, dosage range from 10 mg daily to 1.7S gm
daily;
-pyri ~' n~. dihydro~hl nr~ dosage range from 10 mg
daily to 1. 7S gm daily;
-pyri a -n~ rhn~rh~, dogage range from 10 mg daily to
1. 75 gm dally;
-vitamin B~l (cy5~nn~nh~l n), i~lLL~velluus or oral dosage
range from 1 ILg daily to l mg daily;
-methyl vitamin B,, (co-methylcnh~ ;n~ L~velluu8 or
oral dosage range from 1 ~g daily to 1 mg dailyi
-vitamin D~, dosage range from 400 units daily to 40, ooO
units daily;
-vitamin D" do8age range from 400 unitg daily to 4~,000
~ 2t90~07
38
units daily;
-vitamin D~, dosage range from 400 units daily to 40, ooo
units daily;
-vltamin H (biotin), intravenous, ~llhrlltAn~nus or oral
dosage range from 150 llg daily to 200 mg daily;
-vitamin Kl (phyt^nA~3~nnP), illL~r~ uu:~, sllhr-~ltAn~r~u~ or
oral dosage range from 100 ~g daily to 100 mg daily;
-diacetyl dihydro vitamin Xl, i~lLL~v~uuu~, cllhrlltAn~mlc
or oral doaage range from 100 llg daily to 100 mg daily;
-vitamin Rl oxide, illLl~v~.luus, ~llhrlltAnPmlA or oral -
dosage range from 100 llg daily to 100 mg daily;
-vitamin(s) K2 ( _ nnn~.~, illL .L~_.,vug, gllhr~lt:~n~nl~q
or oral dosage range from lP0 ~g daily to 100 mg;
-vitamin K2"s" ill~ ..lUUI:., al~hrllfAnf~nl~c or oral dosage
range from 100 llg daily 100 mg daily;
-vitaminX~(~s) dihydr^r~ tAt~ illL.~velluu~i, r-lhr-ltAn~.~-lc
or oral dosage range from 100 ~g daily to 100 mg daily;
-vitamin X2(3~" illLl.~v~.luus, 5llhrlltAn~.~llc or oral dosage
range from 100 ,ag daily to 100 mg daily;
-vitamin X2~30 dihy~lror~ tAte~ illL~ _.luu~
or oral dosage range from 100 ~g daily to 100 mg daily;
-vitamin Ks~ LL~ uus, cllhrlltAn~mlc or oral dosage
range from 100 llg daily to 100 mg daily;
-vitamin Ks hydrochloride, intravenous, 911hrlltAn~ml~ or
oral dosage range from 100 llg daily to lOo mg daily;
-U-acetyl vitamin Xs~ illL~ llvus, 5~hr~1t~nPn~ or oral
dosage range from 100 fLg daily to 100 mg daily;
-vitamin Ks~ illL~ uu~, 511hrlltAnP~llA or oral dosage
range from 100 ,ug dally to 100 mg daily;
-vitamin X3 dihydrochloride, illL~ .luu~, sllhrlltAn~ml~ or
oral dosage range from 100 ~Lg daily to 100 mg daily;
-vitamin K7, il~L~ uu~, cl~hr~ltAn~ c or oral dosage
range from loO ~g daily to 100 mg daily;
-vitamin K7 hydrochloride, il~L~Iv.:.luu~, 51 hrlltAnP~--_ or
oral dosage range from 100 ~Lg daily to lD0 mg daily;
-vitamin X-S(II), illL~<IV~.luu~i~ guhcutaneous or or21
dosage range from 100 l~g daily to 1oo mg daily;
-vitamin L~, dogage range from lo mg daily to 500 mg
daily;
~ 219~
39
-vitamin L" dosage range from lo mg daily to Soo mg
daily;
-vitamin IJ, dosage range from 25 mg daily to 1 gm daily;
-methylmeth;nn;n,..-lllfnn; 3:romide (}~romide analog of
vitamin IJ), dosage range from 25 mg daily to 1 gm daily;
-~-carotene, dosage range from 20 mg daily to 300 mg
daily;
-,B-carotene, dosage range from 20 mg daily to 300 mg
daily;
-y-carotene, dosage range from 20 mg daily to 300 mg
daily;
-m-carotene, dosage range from 20 mg daily to 300 mg
daily;
-carotene (also known as lycopene; Sies, 1991, pg.
335~, dosage range from 5 mg daily to 300 mg daily;
-7,7',8,8',11,12-hexahydro-~ -carotene (also known as
phytofluene; Halliwell, 1991, pg. 576), dosage range from 5
mg daily to 300 mg daily;
-L-carnitine (vitamin B~; Carnitor, Sigma-~au Pharma-
ceuticals~, dosage range from 100 mg daily to 3 gm daily;
-acetyl-L-r~rn;t;n~, dosage range from 100 mg daily to 3
gm daily;
-folic acid (vitamin Bc), dosage range from o.s mg daily
to so mg daily;
-folinic acid, dosage range from 0.5 mg daily to so mg
daily;
-folinic acid calcium salt pentahydrate, dosage range
from 0.5 mg daily to 50 mg daily;
-n;~r;n:~m;r~f., dosage range from loo mg daily to lo gm
daily;
-nicotinic acid (vitamin 3,; Nicolar, Rhone-Poulenc
Rorer~, dosage range from lOo mg daily to 10 gm daily;
-nicotinic acid sodium salt sesquihydrate, dosage range
from 100 mg daily to lO gm daily;
-nicotinic acid monoeth~nnl---;nl- salt, dosage range from
lO0 mg daily to 10 gm dailyi
-r~ntnth~n;r acid, dosage range from 5 mg daily to 2 gm
daily;
-pantothenic acid sodium salt, dosage range from 5 mg
21 ~1 a1
daily to 2 gm daily; and
_rj~nt~nthonir acid ~ alcium salt, dosage range from 5 mg
daily to 2 gm daily.
8everal of these vitamins possess carbonyl ~llnrti~
groups and thus may be depleted by clinical use of the present
invention. Others have a reported anti-oxidant effect, such
as the r~rotono~ or may poggegg an anti-~nfl: -nry effect,
such as r:~rn;tino ~Elliott and ' , 1991), retinoic acid
(Fumarulo and ~ ~ ' , 1991) and retinyl acetate lFumarulo
~md ~ ' , l991).
(vii3 Co-A,` nintrAtinn of Mot~hnl ;toc at ~igk of ~orlot;rn
It is another object of this invention that the safety
and ~ffectiveness of the products rl~Rrrihorl herein may be
n!~t;m;7O~7 by co-r' n;ntration of other rh~l;t~n, auch as
glycine, which may be depleted within the body during long
term drug use. ~se of glycine within the dosage range of from
1 gm daily to 20 gm daily is claimed herein. As many of the
ilhnnrh~lhlo amine drugg ~onrr;ho<i herein are excreted from the
body as glycine con~ugates, co-o' n;.ltr?~t;nn-of glycine may
be advisable. Coenzyme A is a required cofactor for hippuric-
~se, the liver enzyme which adds glycine to benzoic acid
derivatives. Activity of hippuricage in glycinating some of
the ~hnnrh~hlo carbonyl-trapping drugs described herein may
sequester a di8proportionate fraction of the ~ n
coenzyme A pool. Ilence co-i~dminigtration of p~ntnthonir acid,
a r Rh~1; r ~JL~_U~J' of coenzyme A, may algo serve to
optimize the thorrro~lt;c ~ du~-3 described herein. A
dosage range of _rom 5 mg daily to, gm daily for r:~ntnth~n;r
acid is claimed herein.
~viii) Co-Administration of Sulfhydryl Agents
Noting the well ~1n~ o~ ability of carbonyl agents to
react with sulfhydryl groups (Jellum and ~ ' ., 1973), it
is a further object of thig invention that L i h;nn;no,
dosage range from 200 mg daily to 4 gm daily and homocysteine,
dosage range from 200 mg daily to 2 gm daily may also be of
clinical benefit as ~hn~rhrhl e drugg capable of covalently
binding aldehyde or ketone agentg. ~omOcygteine contains a
free sulfhyd yl group. Likewi8e, acetyl-homocygteine thio-
lactone, ill~aV~:lWU~ Ll l~r, ~lhrl-t~nom~c or oral
, ~ ~Iq~lQ7
dosage range from o . 5 mg/kg daily to 25 m~/kg daily may also
be included in this group. Il~thinnin~ is converted ~,~ vivo to
homocysteine by several euZ~ ' ;c reactions which remoYe a
methyl group. L-~pthirn;nr- alao has a demonstrated ability to
scavenge hypochlorous acid, a reactive oYygen specie which may
~-r,ntr;hlltP to the r~rJ~ t;nn of hyaluronic acid seen in
r;~l arthritig (Saari and ' , 1993, pgs. 404 and
408). Thioctic acid, also known as ~-lipoic acid, is also
included in this category in a dosage range from 10 mg daily
to 500 mg daily, ;nr~ ;nJ its sodium salt and ethyl-~n~ nr
derivatives, as its ~.Lu~,Lu~e includes a ~;;c--lF;~ group.
This agent, a r~rnr;n;7Pd growth factor (Budavari and cowork-
ers, 1989, pg. 1469), may tend to be depleted in the tissues
of patients having chronic infl; y diseases involving
~t;~l~7;ra which include dysfunction of aldehyde and/or ketone
h~l; r- The ability of ~r~t~ Phyde to combine with
thioctic acid, thus deactivating it, has been reported (Smith,
1976, pg. 195).
(ix) Co-Administration of ~gents Which May Facilitate Gluta-
thione Activity
~ n addition, the present invention includes u6e of vari-
OU8 co-agents which may f~-;l;t:lte glllt~th;nnP activity. Use
of N-acetylcysteine (Dansette and, ' , 1990 ), dosage
range ~rom lo mg/kg daily to 150 mg/kg daily, has been report-
ed to increase thc levels of plasma cysteine, plasma glutathi-
onê and red blood cell ~ t=th;nnP (Bernard, 1991), and to
induce a 100-fold increase in myocardial glllt~th;nnP subse-
~auent to experimental ischemia and reperfusion (Ferrari and
, 1991). N-Acetylcysteine reacts with hypochlorous
acid, HO and H,O, (Bernard, 1991), ag well as with reactive
aldehydes found in tobacco smoke (Ohman and, ' , 1992).
Other Cllhct~nrpc in this clagg include L-2-nYnth;~7n1;rl;nP-4-
carboxylic acid, reported to hydrolyse ~ v vo to cysteine
(Halliwell, 1991, pg. 590), dogaGe range from 0.3 mmol/kg
daily to 3 mmol/kg daily; ti~rn ~; r, also known as 4-thi-
5~7nl ;~9;nPr ~hnTyliC acid (Dansette and ~ - ' ~, 1990),
dosage range from 10 mg daily to 500 mg daily; cysteamine
(Dansette and, ~ke~a, 1990), dogage range from 200 mg daily
to 4 gm daily; 1 ;r .1~, derivatives (Dansette and
~ 219Q107
1990) such as malotilate ~antec), dosage range from 100 mg
daily to 2 gm daily; 5--1 fArl ~m (ADT; Dansette and . - rq,
1990), i~ JUD~; ' lAr, s~hr~ltAn~nl~q or oral dosage
range from 100 mg/kg daily to 1 gm/kg daily; and oltipraz
(Dansette and ~ ' , 1990), il~Lr~ us, i~lLL - lAr,
511hrl7tAnPnll~ or oral dosage range from 100 mg/kg daily to 1
gm/kg daily, as these co-~gents may further serve to improve
the invention described herein.
~x) Factors Aff~-t;ns Daily Dosage Schedule
A daily protocol of amine and amine-related drug consump-
tion, in . ' n~tinn with co-agents defined herein, may be
defined such that drug products are administered in timed-
release and/or color coded tablets or capsules, 50 as to
fA~ itAte patient li:~n~e and maximize therapeutic value.
Altf-rnAt~vely, a therapeutic . , ;~;nn may be ;-,~ .,.t~-i
into a fne~lqtl ff product, 80 as to ~ JULj~YC regular, long
term patient l;An~
(xi) ll.eL~I~uLic ut;l ;~At;nn
As ;nrl;n~t~.rl above the present invention is intended for
the ~ of chronic ;nfl: -nry diseases and is useful
for this purpose in various animal species, e. g., rodents,
cats, dogs, cattle, sheep, horses, pigs, monkeys and other
primates .
Two case histories regarding human subjects may serve to
;ll--~tr~t~. the rr~ t;n~31 Arrl;rAt;nn of the invention origin-
ally fi;q~lnA~o~ in US Patent Application 07/906,909
Case History One: Pearson and Shaw (lga2, pg. 299) ~A~ r;h~.~
the fnllo~;n~ summary of an arthritis patient taking vitamin
E and vitamin A:
The correct dose of :Int; n~ nt~ for effective
arthritis therapy must be ~ t~rm;n~ by experi-
At;nn The effective dose may be quite high.For example, a friend of ours who is a well-known
artist in his fifties developed arthritis in his
hands . This man~ 8 handq became 80 painful and
stiff he could no longer use hig fingers to remove
the caps from his tubes of paint. ~e tried vitamin
E at increasing dose levels. It was not until he
got up to 10,000 I.U. of E and 20,000 I.U. of A per
` 2190107
43
day that he obtained relief from the pain and erip-
pling stiffness. His hands are now flexible and ean
be used to draw without difficulty. But they remain
80 only as long as our friend takes 10, 000 I .U. of E
and 20,000 I.U. of A a day, not less (he's tried).
Ihis dosage of vitamin E far exeeeds presently aceepted
levels of daily usage, whieh are generally regarded as being
in the range of 400 I.U. per day. This particular ' n:lti~n
of vitamins E andA, both l;rrrhil;c, would not be expected to
inhibit any of the free radieal reaetions taking plaee in
aqueous microenvi e Nor would it chemically bind and
thus deactivate any reaetive aldehydes generated by the in-
fl: trry procegg, ag guch aldehydes are water soluble.
Case History Two: Patient L S. has a history of arthritis
dating back to a serious All' ' ;1~ accident in 1980. By
January of lgsl she had serious arthritic involvement of the
lumbar spine and chronic hip and knee joint pain on a eontin-
uous basis. She had rl;ff;rlllty raising herself from a ehair,
resuired the ~cn;ct~nre of a eane for activities as simple as
walking from her front door to her car, was no longer able to
go up or down a flight of stairs, and required use of a pre-
grr;rt;nn analgegic drug every two hours during the night to
sleep. She had part;r;r~tl~3 in a program at the Pain Clinic
of the University of Miami Medical School and at doctor' 8
advice had used preseription drugs which included Clinoril (R)
and Anaprox (R~, both nonGteroidal anti-;nfl Lory agents.
At the . ~ -; rn of this inventor, patient L . S . began
taking 800 I.U. vitamin E, 1. gm of i h;rn;n~ and 1.1 gm PABA
per day for two months. c~,~,c~ ly, vitamin E and methion-
ine usage remained the same and PA~ ugage was increased to
2.2 gm per day, with the protocol rrnt;n~ on an ;n~f;n;
basis .
When previously examined by an orthopedics physician a
r~nrc;q wag e8t~hl;flh~l which included:
...Lumbar spine X-Rays in AP and lateral views show
extensive -lG~J~ ;ve arthritic changes at multiple
levels of the lumbar spine . . . severe arthritic changes
lumbar spine. Bursitis left greater trorh~nt~r clin-
ically...She will always have a problem rel~ted to her
21qO197
4~
underlying ~ ellè~ ive disease involving her lower
back...She is favoring her left leg...Her straight leg
: raising ls limited on the left side
Ten weeks after after initiating this inventor~ 8 PABA/hinn;nF./vitamin E: protocol, patient L.S. reported that her
arthitis-related pain was much ~ ea~ and her fl~nrt;rn:~l
status much improved. By four months into use of this thera-
peutic protocol patient L.S. had stopped using her cane, had
a walking gait which was much improved, had taken to raking
leaves in the yard as a form of exercise, and no longer
re~uired nighttime sln~lrJo~ to sleep. At twelve months on
this protocol, patient L. S. reported climbing and ~nrDn~tn~
a flight of stairs without difficulty, and her ability to
climb stairs has rnnt;m-~ to improve. When re-examined by
her orthopedic physician, who was not informed of her use of
the PABA/ I -h;nn;n~/vitamin ~ protocol, seven months after
h~;nn;n5 therapy the doctor noted, in part:
This patient is markedly better. She has normal
straight leg raising. She has no s~n;f;rRnt leg
pain. She walks well on her toes and walks well
on her heels now without any evidence of motor
weakness. There is no limp present.
IJnaware of the patient's collaborative effort with this
inventor, the orthopedic physician was unable to provide an
~.Ynl~nnt;rn of the marked i ~ in the clinical status
of patient L.S. At her office visit patient L. S. noted that
she had stopped taking An~prox, which her orthnr.
physician had prescribed seven months earlier.
This inventor r~rn~n;7.~ the novel and original combina-
tion of primary amine benzoic acid derivatives as a primary
agent to be used with anti-oxidant free radical trapping co-
agents as a type of composition likely to have increased, or
possibly even synergistic properties for the treatment of
chronic ;nfl n~-y digeageg. Thi8 inventive 6trategy for
the clinical L~, of these diseases has not been
previously r~rn ~n; 7P~
PAEIA, many of the other amine primary agents, the anti-
oxidant free ra~ical trapping co-agents, ~ h~t~nr~ related
~ 2190~07
thereto and previously Icnown, ';r~rn ntc described herein are
rhPm;~rAln which have been previously 5ynthPqi7~1 and des-
cribed. Yet the present invention recognizes a new and novel
' nslt;nn of thPr51rPl-t;r propertieE, never rPrnrni7~ previ-
ously, and the clinical applications thereof. My original
invention, as defined in US patent ~rrlirAf;nn 07/906,909,
rnnqt;t~tPc a cirn;fir:lnt and rrlrt;rAl a~ Of clini-
cal therapeutic technology available for treating chronic
infl. tnry diseageg, and the pregent invention rnnctit11t~.c
a further practical Pyt~rcinn of the original inventive
concept .
(xii) Use of the Invention of IJS Patent Application 07/906,909
in Cc ' ;nAt;nn with Previougly l7~nown ~ P~ c
As summarized above, it is evident that presently avail-
able r~ i cal technology for 1.~ of the diseases
addressed herein is almost entirely ~ t;c, as well as
t y and of partial clinical benefit, at best. The
dosages of any of the l~nown ' ' I c ~i qr11cqe~i herein,
fxcept those which are still the subiects of preliminary
laboratory studies, are well k~nown to those skcilled in the
art. Sisnifirs~nt adverse side effects 5~ , y many of these
treatments, which limit their use. The present invention de-
fines the use of previously rprnsn;7~ technology in combina-
tion with the invention originally ~iPqrr; hP-l in US patent
Arrl;rAt;nn 07/906,909, GO a8 to achieve greater clinical
effectiveness in treatment of these diseases. In using the
thPrArP,1t;c terhnnl~y defined herein, physicians may achieve
in some cases the clinical benefit8 of previougly rPrnrJn; 7~.~
drugs while using lower dosage levelg, thuq m;n;m;7;nr adverse
side ef_ects. Within the contect of the present invention, it
is important to note the ,' At;nn provided by Flood and
coworkers (198~ heir findings indicate that when drugs are
used in, 'nAt;nn they may provide b~nPf;r;Al effect at re-
duced dosages which are ineffective when drugs are adminis-
tered alone. This approach may permit wider and more effec-
tive use of previously recognized drug technolory~ It is
Arknno~l P~lr~; herein that for many of the previously Icnown
' ' ~ q the optimum dosage must be ~;Pt~.rm;nPil on an in-
div;ri ~,1 i7P~ basig, and may be below or above the dosage range
~ . 2tqol~7
46
generally recognized for public use. ~t i9 to be understood
that dosage ranges listed below refer to adult usage and that
in particular cases it may be desirable to go beyond the dos-
age ranges noted below. Various oral compositions as noted
below which exemplify the present invention may be f, lr~ted
with r~i~itinnAl, c or coatings 80 as to function in a
810w acting, delayed release manner. Except where stated
otherwise, the drugs listed in the f~ in~ examples are to
be A~' 'n;ct,ored orally. It is l-n~l~rctnn-l, however, that var-
ious, ' nAt;rmc of r' 'n;ctration via oral route and admin-
i~t~At;~n via injected route or topical route may be en-
visioned for the compositions listed below.
Example 1
Clinical L~. of chronic gingivitis and/or chronic
r~.r;~ntitig can be improved by use of a ~ , ti~n, admin-
istered in various oral, topical, i~ us,; lAr,
8~hr- tAn o~ and intrAl~c;^nAl ~ n:~ti~nc, comprising from
about 1 gm to about 20 gm of at least one primary thPrAre~tic
agent comprising a primary amine benzoic acid derivative
having a; l~ lAr weight of from about 100 to about 1,400
Daltons, and optionally at least one substance selectea from
those noted above in section (v) through section ( ix), and a
, '-1 r~ n;7~-~ as effectiYe to treat chronic gingivitis
and/or chronic p~.ri~ nt~tic, such as, for example,
(a) antibioticæ such as
r n;~-;ll;n G potassium ~Pl'ize~pen, Roerig), illL~ - lAr,
iU~ lV~ JU_, local infusion or intrathecal dosage range from
one million units daily to twenty million units daily;
pPni~ n G b n7Athin and F n;r;ll;n G procaine combination
(B~cillin C-R, Wyeth-Ayerst Laboratories),; ' 1Ar dos-
age range from 300,000 units to 2,400,000 units .,' nict ~ed
for one day or daily until s1lhc;~n~ of Ahn~rmAlly high body
L u ~
p n;t-i 11 ;n V p~ q~illm (Veetid8, Apothecon~, dogage range from
soo mg daily to 2 gm daily;
erythromycin (E~-Mycin, soots Laboratories), dosage range from
250 mg daily to 5 gm daily;
Am~Y;~-;llin (Amoxil, ~-;th~l;n~. seecham), dosage range from
7so mg daily to l.S grams daily;
.
~ 21 9~1 07
47
amoxicillin in , ;n~t;~nn with clavulanate rot~qqi
'n, SmithKline Beecham), dosage range from 750 mg
'r;llin and 187.5 mg clavulanate rntAr~qi~m daily to 1.5
grams ~ ; rl 11; n and 375 mg clavulanate rnt~Rq; daily;
tetracycline {Achromycin V, Lederle~, dosage range from 500 mg
daily to 2 gm daily;
doxycycline lVibramycin, P~izer), dosage range from 50 mg
daily to 300 mg daily; and
minocycline (Minoci~l, Lederle), dosage range from 50 mg daily
to 300 mg daily;
(bl nitrnim;~7nl~q such as
metrnn;~7n1~ ~Flagyl, Searle), dosage range from 250 mg daily
to 2 5 gm daily;
(c) antiseptics such as
rhlnrhl~Y;tlin~ gluconate (Per~deY oral rinse, Proctor &
Gamble), one to three oral rinses per day;
(d) surfactants such as
tr;rlnqAn, ag ingredient in mrllthw:~qh or toothpaste, dosage
range of one to three Arrl;r~t;nnc of o.Ol~ to 5~ solution or
51~CrF.nC; nn daily; and
sanguinarine, as ingredient in--~ -th~-ch or toothpaste, dosage
range of one to three 5~rr'; r~t; nnq of o . ol~ to 5~ solution or
ql'qr""q; nn daily;
(e) ebselen, i~lLL~v~ u~ls,; rlll~r, sl~hrllt~nPmlq or oral
dosage range from 5 mg/kg daily to 500 mg/kg daily, or
l;r~t;rn of 1'~ to 25~ topical compositions;
(f) nonsteroidal anti-;n~l nry drugg administered orally
including
suprofen; dosage range from 5 mg/kg daily to loo mg~kg daily;
and
(g~ locally ~I' n; qt~red corticosteroid preparations such as
hydrocortisone acetate, 0.5~ (orabase ~CA, Colgate-Hoyt/Gel-
Kam), topical application one to four times daily.The following illustrate specific f~ l~t;nnq according to
the present invention.
p_~m;nrhr~n7n;r acid 1 gm
2~ ~1 07
~8
d-cr-tocopheryl 8~rrin:~t~ ~ SOC I.U.
r~n; r; 11; n G pnt:~ ; one million units
p_~m;nnh~n7nir acid, potassium salt 20 gm
N-acetylcysteine 10 gm
suprof en 5 gm
p-i~l--; ' hylbenzoic acid S gm
acety-'' y~Leine th;nlilrl~nn~ 1 gm
metronida7ole 2 gm
Example 2
Clinical L, . of chronic ~ tn; gastritis can be
improved hy use of a composition comprising from about 1 gm to
about 20 gm of at least one primary th~r~r.ollt;r agent compris-
ing a primary amine benzoic acid derivative having a, lrr~ r
weight of ~rom about 100 to about 1,400 Daltons, and option-
ally at least one substance selected from those noted above in
section (v~ through section ~ix), and a, ' r~rnrJn;7,..l
as effective to treat :~ tn; rJ~atr;t;c~ guch a8, for
example,
(a~ sodium r~ 7--l~n~_3-s--l~nn~tr, dosage range from 1 mg/~cg
daily to 20 mg/lcg daily; and
(b~ ebselen, i~ veuuus~ lAr, ~,. ,I, "l ,..~r ..~fl or oral
dosage range from S mg/kg daily to sO0 mg/kg daily.
The following illustrate specific c~ t;nn~ according to
the present invention.
~-amino-3-hydLu~yLe~z~Jic acid 1 gm
mixed tocopherols 1, 000 I.U.
sodium ~ 7~1~n~-3~ l fnn:lte 75 mg
p- nnh~.n7n; r acid, rnt:~ _; salt lS gm
L-Mrth;nn;nf. 1 gm
sodium g~ lr~n~-3-sulfonate 1.5 gm
5-amino-2-~ly~hu~yLeLl~uic acid 5 gm
N, N' - diphenyl -p - phenyl ~n ~.A ;: ' n ~ 5 gm
ebselen 5 gm
~ 2~901~7
Example 3
Clinical treatment of ileitis, inrl~l~9;n3 Crohn s disease
can be improved by use of a composition compri3ing from about
1 gm to about 20 gm of at least one primary therapeutic agent
comprising a primary amine benzoic acid derivative having a
molecular weight of from about 100 to about 1,400 Daltons, and
pt;mn:~lly at leagt one D"~ selected from those noted
above in section (v) through section ( ix), and a
r~ nt7n;7~d as effective to treat ileitis, ;n--lllA;n~ Crohn 8
disease, such as, for example,
(a) clllf~c~l~7;nP (D7117fi~in E~-taosdelayedreleasetablets
and D7ll7fir~i~.o tablets, ~7abi Pharmacia), dosage range from 1
gram daily to 5 grams daily;
~b) -hJ-n~n~. (Decadron, Merck & Co. ), dosage range from
0.25 mg daily to 18 mg daily;
(c) methylpr~n;c-~lrn~ acetate (Depo-~edrol, Up~ohn), intra-
synovial, ;nrr~l~.cir,nAl or; lAr dosage range from 0.5
mg daily to 50 mg daily, or weekly dosage of from 20 mg to 120
mg;
(d) hydrocortisone (~l~u~u~vlle, Merck & Co.~, dosage range
from 1 mg daily to 400 mg daily;
(e~ metr~ n;.l~ . IFlagyl, Searle~, dosage range from 250 mg
daily to 2 . 5 gm daily;
(f~ ebselen, i:lL ~..uu~ lcr, sllhcllt~nl~^llc or ora
dosage range from 5 mg/kg daily to 500 mg/kg daily;
~g~ cllq~in~-i-releage tabletg of s- nr Al ;rylic acid
(j 1iim;n~; (Agacol delayed-release tablets, a -itirn
t~)nc;c~;n~ of s--~-;nmc~l;rylic acid coated with Eudragit-S, an
~crylic-based resin pE~ r~-n~ nt delayed relea8e cllh t:~nr~.;
Procter & Gamble Pl,..,. ~ I;c:~ln~, dosage range from 500 mg
daily to s grams daily;
(h~ sustained-release tablets of s---;n~c~l;rylic acid
(Pentasa, a, , ~;r,n congigting of 5-; nr~c~l;mylic acid
coated with a ~Pm;7- hl~ membrane of ethyl r~lllllr~c~;
Ferring A/S Vanlose~, dosage range from 500 mg daily to 5 gm
daily;
(i~ pr~-ln; -G-n~ (Pedi~pred, Figong), dosage range from 1 mg
daily to 250 mg daily, or alternate day dosing;
(j~ cortisone (Cortone, Merck & Co.~, dogage range from 5 mg
2~ 901 ~7
so
daily to 400 mg daily;
(k) prednisone (Delta60ne, Upjohn), dosage range from 1 mg
daily to 250 mg daily, or A1 t~.rnAte day dosing;
(l~ methylpr~lniq~lnnF~ (Medrol, l~pjohn), dosage range from 1
mg daily to 250 mg daily, or A't~rnAte day dosing;
(m~ rr;, n~ l~>nf~ (~rlstocort, Fujisawa~, dosage range from
1 mg daily to 200 mg daily, or ~1t ~rn~te day dosing;
(n~ tri nn~ n~ otAte (Aristocort s~qr~nc;~ nc~
Pujisawa~, ; lAr, intrasynovial or intr~l~c;r,n~l
dosage range from 1 mg daily to 200 mg daily, or alternate day
dosing;
(o~ h~t hAqr~n~ (Celestone, Schering), dosage range from
0 . 2 mg daily to 12 mg daily, or alternate day dosing;
(p) h h~qnnP (Celestone soluspan sllcr~n~ n~ schering~,
iuL~ lAr or intrAlec;^n~ dosage range from 0 1 mg daily
to 10 mg daily, or alternate day dosing;
(q) ~7 ' hAc~)n~ (Decadron ~hGqrh~te in~ection, Merck &
Co.), i lAr, ill~L~ U~or;ntr~ nA1 dosagerange
from 0.1 mg daily to 10 mg daily;
Ir~ cortisone (Cortone 5~cr~nci~n, Merck & Co. ),
iULL lAr dosage range from 5 mg daily to 400 mg daily;
(8) llydL.,~ ~L~isone (NY~ rhrgrh tf injection, ~erck
& Co.~, ; lAr, il.LL..~ or 8 h~ tAnPouq dosage
range from 1 mg daily to 400 mg daily;
(t~ rr~qn; q~ n~ (Nydeltrasol injection, Merck & Co ~,
il~LLc~ve~ u~,; lAr, intra-articular, intrAl~ nAl and
soft tissue dosage range from 1 mg daily to 100 mg daily;_
(u~ diphenoxylate, dosage range from 2.5 mg daily to 20 mg
daily;
(v) diphenoxylate in nAt;r-n with atropine sulfate
~Lomotil, Searle), dosage range from 2.5 mg diphenoxylate and
25 ~Lg atropine sulfate daily to 20 mg dichenoxylate and 200 ~g
atropine sulfate daily;
(W) ~ :r;7~d opium tincture, dosage range from o s ml daily
to 3 ml daily;
(x) codeine, dosage range from 1 mg daily to 150 mg daily;
(y) A7Ath; ~rrine (Imuran, Burroughs Wellcome), dosage range
~ 21 901 ~7
~1 .
from 0.1 mg/kg daily to 2 5 mg~kg daily;
(z~ 6-merrArtnrl~r;n~ (pl~rin~hn7, 3urroughs Wellcome), dosage
range from 0.1 mg/kg daily to 2.5 mg~kg daily;
(a' ) cyclosporin A (SAn~7; -, Sandoz Pharmaceutical), dosage
range from 1 mg/kg daily to 15 mg/kg daily;
(b' ) methotrexate ~Lederle), dosage range from 2 5 mg daily to
30 mg daily, or doses from 5 mg to 50 mg once or twice weekly;
and
(c' ) methotrexate sodium (X. ,lloLL~te LPF, Lederle), intra-
muscular, illLL ~ U~lS, intra-~rterial or intrathecal dosage
range from 2 5 mg daily to 30 mg daily, or dose3 from 5 mg to
so mg once or twice weekly.
The fnll~inr~ trAte specific r l:~tinnq according to
the pre3ent invention.
trans-4 -aminocyrl nho~ :~n~.-
carboxylic acid 1 gm
a-tocopherol 500 I IJ
pr~rlnicmlnn~ S mg
p nnh~nsrni r acid 15 gm
rr,tAc~; citrate ~ vllvllydL~ste 15 gm
diphenoxylate 20 mg
5-amino-2-methu,~yi,~.. l,soic acid 5 gm
butylated-hydroxytoluene 500 mg
dihydrolipoic acid 250 mg
ebselen 5 gm
E~xample 4
Clinical LL~ of ulcerative colitis, a form of
in~l tnry bowel disease can be improved by use of a
composition , ~i n~ from about 1 gm to about 20 gm of at
least one primary therapeutic agent comprising a primary amine
benzoic acid derivative having a mnl orl~ r weight of from
about 100 to about 1,400 Daltons, and npt;nnAlly at least one
~7 ~hc~t~nro gelected from tho3e noted above in section (v~
through section (ix), and a I '' recogni2ed a3 effective
to treat ulcerative colitis, a form of ;nfl: nry bowel
~ 2~9û107
disease, such as, for example,
(a) ~lllfA~ 7;n~. (A7~fir7in~ tab8 delayed release tablets
and Azul~idin tahlets, Eaoi Pharmacia~, dosage range from 1
gm daily to 5 gm daily;
5-~minn~l; ylic acid, oral or intrarectal dosage range
from 10 mg/kg to 500 mg/kg;
(c~ 7- ~3 - (4-acetyl-3-methoxy- 2 -propylphenoxy~ propoxy] -3, 4 -
dihydro-8-propyl-2~-l-~ yL~ll-2-car}~oxylic acid, oral or
intra-rectal dosage range from 0.1 mg/kg to 80 mg/kg;
(d) glllt~hinn~, intrarectal dosage range from 1 mg/kg to 20
mg/kg;
(e~ zileuton, dosage range from 100 mg daily to 1 gram daily;
(f) nlr-1~7in~ (n~r~ Pharmacia Ltd.~, dosage range from
200 mg daily to 2 gm daily;
(g~ disodium ~7n~ ylate~ dosage range from 200 mg daily
to 4 gm daily;
(h~ ,~ h, :nn~ (Decadron, ~erck & Co.~, dosage range from
o . 25 mg daily to 18 mg daily;
imo~ r~nt~ ~nn;c acid (or commercial productg .nntilinin~
this sllh~t~nne as the active ingredient, including ~axEPA
capsules, 18 gm of which contains 3.2 gm ~ n~2r~nt71~nni-~
acid~, dosage r~nge from soo mg daily to 10 gm daily;
( j~ salicylsulfapyridine (Salazopyrin, Pharmacia Ai3~, dosage
range from 1 gm daily to 5 gm daily;
(k~ t ~;n~d-release tablets of 5-~m;nnssll;rylic acid
~Pentasa, a composition nnn~;Rt;n~ of 5_.--;nnq~l;rylic acid
coated with a q~m;~ hl~ memorane of ethyl m.ll~ e;
Ferring A/S Vanlose~, dosage range from 500 mg daily to 5 gm
daily;
(1~ s~t~;n~i-release tahlets of S_~m;nnq~ ylic acid
. nr; Agacol delayed-releage tablets, a ~ t;nn
l nn~;~t;n~ of s-~m;nng~ ylic acid coated with Eudragit-S~ an
acrylic-hased resin pH-~l ~r~nrll~nt delayed release su}~stance;
Procter & ~amole ph~ t;r~ , dosage range from soo mg
daily to 5 gm daily; ~ :
(m~ diazo slll L:In; l ~m; rl.o ethylene polymer of 5-. nnq~1; -ylic
acid, dosage range from 500 mg daily to 5 gm daily;
(n~ llylL~_vLLisone (~y<lLvl, L~v~ erck & Co.~, dosage range
from 1 mg daily to 400 mg daily;
-
~ ~90~97
53
(o) prednisolone (Pediapred, Fisons~, dosage range from 1 mgdaily or every other day to 250 mg daily;
(p) cortisone (Cortone, Merck & Co.), dosage range from 5 mg
daily to 400 mg daily;
(q) prednisone (Deltasone, Upjohn), dosage range from l mg
daily to 250 mg daily, or al t.~rnAt~ day dosing;
~r) methylprP~ni~nl~n~ (Wedrol, Up~ohn~, dosage range from 1
mg daily to 250 mg daily, or Alt~rnAt~ day dosing;
(8) methylprP~n;anlnn~o acetate (Depo-lJedrol, Upjohn), intra-
synovial, intrAl~inn~l or i lAr dosage range from 0.5
mg daily to 50 mg daily, or weekly dosage of from 20 mg to 120
mg;
(t) tri: 'nnlnn~ (Aristocort, Eiu~isawa), dosage range from
1 mg daily to 200 mg daily, or Al t~rn~te day dosingi
(u) tri: 'nnlnn~. diacetate (Ari~tocort ~ r~n_;nnc, Fujisa-
wa), il~ ular, intrasynovial or intrAl-~;nnAl dosage
range from 1 mg daily to 200 mg daily, or alternate day
dos ing i
(v) h~t: h~cnnf. (celestone, Schering), dosage range from
0.2 mg daily to 12 mg daily, or alt.ornAte day dosing;
(w) h~t: hA~nn~ (celestone Soluspan suspension, Schering),
lAr or ;ntrAlf~4;nnAl dosage range from 0.1 mg daily
to 10 mg daily, or Al t~rnAtr- day dosing;
(X) ~ hA4nn~ (Decadron rhn/~rhAtr. injection, Merck &
Co.), i~ lAr~ ~u~ or intrA1~4inn~1 dosage range
from 0.1 mg daily to 10 mg daily;
(y) cortisone (Cortone ~ n4inn~ Merck & Co.), intramus-
cular dosage range from 5 mg daily to 400 mg daily;
(z) llyd~u~ulLisone (~ v~ul l.ul~a phosphate injection, Merck
& Co. ), ; nt l Ar, i~ v~:llu~l~ or s~hPl~tAnP~l~ dosage
r~nge from 1 mg daily to ~00 mg daily;
(a') prl~-lni~nlnn.- (~ydeltrasol iniection, Merck & Co.), in-
travenous, i~ lAr, intra-articular, intralesional and
soft tissue dosage range from l mg daily to lO0 mg daily;
(h~) A7Ath;nrrino (Imuran, Burroug_s Wellcome), dosage ra.nge
from 0 . l mg/kg daily to 2 . 5 mg/kg dailyi
(c' ) 6-mercaptopurine (Purinetnol, Burroughs Wellcome), dosage
range from 0.1 mg/kg daily to 2.5 mg/kg daily;
(d') diphenoxylate, dogage range from 2.5 mg daily to 20 mg
~ 2~ 7
daily;
(e~) diphenoxylate in, ` nAt;nn with atropine sulfate
(LQmoti7, Searle), dosage range from 2.5 mg diphenoxylate and
25 llg atropine sulfate daily to 20 mg diphenoxylate and 200 llg
atropine sulfate daily;
(f'~ deodorized opium tincture, dosage range from O.S ml daily
to 3 ml daily;
(g' ) codeine, dosage range from l mg daily to 150 mg daily;
(h' ) l ~ r ~ (Imodium, Janssen ph~ i ca), doGage range
from 2 mg daily to 16 mg daily;
(i' ) corticotropin (ACTE~), il~ClV~.lC~U~ dosage range from 25
units daily to lS0 units daily;
(j') cyrlrqrrr~n A (S:-n,'' , Sandoz pl~A~ .I irAl), dosage
range from l mg/kg daily to lS mg/kg daily;
(k' ) benztropine mesylate (Cogent~n, Merck & Co.), do3age
range from o.S mg daily to 10 mg daily;
(1' ) trihexyphenidyl (Artane, Lederle), dosage range from 2 mg
daily to 20 mg daily;
(m~ ) procyclidine ~Kemadrin, Burrough~ Wellcome), dosage range
from 2 mg daily to 50 mg daily;
(n') hi~ r;flen (Akineton, KnollPhar~ t~rAlq), dosagerange
from o . s mg daily to 10 mg daily;
(o' ) ethopropazine, dosage range from 10 mg daily to S00 mg
daily;
(p') Ycrr~ in, dosage range from 0.1 mg daily to l mg
daily;
(rl~ ) benztropine mesylate (Cogent~n in~ection, Merck & Co.l,
iuL~Iv~ u~ r or s~1hr~t~n rllq dosage range from
O.S mg daily to 10 mg daily;
(r' ) biperiden lactate (parenteral Akineton, Knoll Pharmaceu-
ticals), intravenoug, i lAr or sllhrllt~n~rus dosage
range from O.S mg daily to 10 mg daily;
~5~) prnrAnth lin-~ bromide (Pro-santhine, Schiapparelli
Searle), dosage range from 7 . S mg daily to 120 mg dailv; and
(t' ) oxybutynin chloride (D~tropan, Marion Merrell Dow),
dosage range from S mg daily to 20 mg daily.
The f~rllrwin~ illustrate specific f~ tirnq according to
the present invention.
~ 2~90~07
p_,~m;nnh~n7n;C acid 1 gm
N-acetylcysteine 1 gm
zileuton 100 mg
p_~m;nnhf~n7n;~ acid, rrt~qC; salt 20 gm
d-~-tocopheryl s~ n~tf~ 2,000 I.U.
,~ h:-enn~ 10 mg
4-~l~ni~;n~lh~n7nil- acid EICl 5 gm
prnct~ n~l;n Bl ~l i5 5 gm
acetyll _y2~eine thio~ tnn~ 1 gm
trihexyphenidyl 10 mg
Example 5
Cllnical treatment of ~nt~.rct~t;~l cystitis can be im-
proved by use of a composition . _ c;n~ from about 1 gm to
about 20 gm of at least one primary ~h~rnre~tir agent
comprising a primary amine benzoic acid derivative having a
mAl~ lRr weight of from about 100 to about 1,400 Daltons, and
nrti~n:~lly at lea8t one g-.her~n,-~ selected from those noted
above in gection (v~ through section (ix), and a medicament
r-~-oJn;7ed as effective to treat interstitial cystitis, such
, for example,
(a) prnrAnth~l ;nF. bromide (Pro-Banthine, Schiapparelli
Searle~, dosage range from 7 . S mg daily to 120 mg dailyi
(b) oxybutynin chloride (Ditropan, Marion Merrell Dow),
dosage range from 5 mg daily to 20 mg daily;
~cl benztropine mesylate (Cogen~in, Merck & Co. ), dosage
range from 0.5 mg daily to 10 mg daily;
(d) trihexyphenidyl (Ar~ane, Lederle), dosage range from 2 mg
daily to 20 mg daily;
~e) procyclidine (.7emadrin, Burroughs Wellcome), dosage range
from 2 mg daily to 50 mg daily;
(f) biperiden (~in~.~nn, ~noll Fl-~.~ c), dosage range
from 0.5 mg daily to 10 mg daily;
(g) ethopropazine, dogage range from 10 mg daily to 500 mg
daily;
56
(h) s~ r~lr-in~, dosage range from 0.1 mg daily to l mg
daily;
~i) benztropine mesylate (Cogentin injection, Merck & Co. ),
iu~ uug, i lAr or ~ dosage range from
o . 5 mg daily to 10 mg daily; and
~j~ biperiden lactate (parenteral Alrin~t- n, Knoll Pharmaceu-
ticals), ill~L~ /UI~, ~ ' lAr or ~ dosage
range from 0 . 5 mg daily to 10 mg daily.
The following ;ll~lctrAt~ specific f~ lAtir~na according to
the present invention.
p_~mint~hrn7~Aic acid 1 gm
d-a-tocopheryl cl~rrin~te 503 I.U.
benztropine mesylate 1 mg
p_~m;n~hon7nic acid, potassium salt 20 gm
mixed tr~ Fh~rrlla 3,500 I.IJ.
N-acetylcysteine lO gm
oxybutynin chloride 20 mg
o-Aml hylbenzoic acid 5 gm
~-tocopherol n;~rt;n~te 1,500 I.U.
dihydrolipoic acid 250 mg
ethopropazine 200 mg
13xample 6
Cllnical ~ of psoriasis can be improved by use of
a com-position, ' 'n;~t~red in various oral, topical, intra-
venous, i~ .ular, R- hc~t~n~ R and intrAl ~ nAl combina-
tions, comprising from about 1 gm to about 20 gm of at least
one primary t h~r:lr~ t i r agent comprising a primary amine
benzoic acid derivative having a m~ r weight of from
about 100 to about 1,400 Daltons, and optionally at least one
subEitance selected ~rom those noted above in section (v)
through section (ix~, and a ', r~-o~ni7erl as effective
to treat psoriasis, such as, for example,
(a ) 7- ~3 - (4 -acetyl -3 -methoxy- 2 -propylphenoxy) propoxy] - 3, 4 -di-
hydro-8-propyl-2N-l-L._.",u~y~,",-2-carboxylicacid, dosagerange
from 0.1 mg/kg daily to 80 mg~kg daily;
~ 2~90~07
5'7
(b) ~;rnqAr~ntRPnnir acid, dosage range from 1 gm daily to 5
gm daily;
(c~ I hAann~ (Decadron, Merck & Co. ~, dosage rAnge from
0.25 mg daily to 1~ mg daily;
(d) methotrexate (.:2heumatrex, I,ederle T.=hnrAtnries), dosage
range ~rom i mg weekly to 20 mg weekly;
(e) llylL~ LLisone (NY~1~O~UL~ULI-~ Merck & Co.~, dosage range
from 1 mg daily to 400 mg daily;
(f) prednisolone (Pediapred, Fisons~, dosage range from 1 mg
daily or every other day to 250 mg daily;
(g) cortisone (Cortone, Merck & Co. ), dosage range from s mg
daily to 400 mg daily;
(h) rr-.rln~ nnn-o ~Delt sone, Upjohn), dosage range from 1 mg
daily to 250 mg daily, or alternate day dosing;
(i) methylprt~ln;cnl^n~ (~edrol, Upjohn), dosage range from 1
mg daily to 250 mg daily, or alternate day dosing;
(j) methylpre~ln;~nlnn-~ acetate (Depo-Nedrol, upjohn), intra-
synovial, intralesional or; lAr dogage range from 0.5
mg daily to 50 mg daily, or weekly dosage of from 20 mg to 120
mg;
(k) tri 'nnlnn~ (Arigtocort, Pu~igawa), dosage range ~rom
1 mg daily to 200 mg daily, or Al t-~rn~te day dosing;
(1) tri, 'nnlnn~ r~tAt~ (Aristocort S-lar~-nqinnq, Fuji3a-
~a~ LL - lAr, il~L~-iy~ vial or intrAl~q;nnAl dosage
range from 1 mg daily to 200 mg daily, or Alt~rnAt~ day
do:;ing;
(m) betamethasone (celestone, Schering), dosage range from
0.2 mg daily to 12 mg daily, or A1t~-rnAte day dosing;
(n) bet -hAqnn~ (Celegtone 501uspan 6uspension, Schering~,
lAr or intr~l~.qinnAl doaage range from o.l mg daily
to 10 mg daily, or ~1 t.~rn~t~ day dosing;
(o~ h~qnn/. (Decadron rhnqrhAt~ injection, Merck &
Co ~ r, iLlLLo.~ u8 or intrAl~q;nnA- dosage range
from 0.1 mg daily to 10 mg daily;
(p~ cortisone (Cortone s~qr~n~inn, Merck & Co.~, intramus-
cular dosage range rom 5 mg daily to 400 mg daily;
(q~ hydrocortisone (NY.1LU. "L~UUC rhnqrhAt~. injection, MerCk
& CO ~ lAr, illLLqve,~uug or qllhr1~tAnl~ol1q dosage
rang~ ~rom 1 mg daily to ~00 mg daily;
2~90i~
.
58
(r) l~yJ~u~u~Lisone (}~y.l~u~ Lu~: acetate q-lcr~nq~rn, Merck &
Co.), intra-articular, intr~lPqinn~l or 30ft tissue injection
dosage range from 1 mg daily to 400 mg daily;
(5~ rre~n;qnlnnf~ (Nydeltra801 in~ection, Merck & Co.), intra-
venous,; ' l~r, intra-articular, lntrl-l.oqinn~l and soft
tissue dosage range from 1 mg daily to 100 mg daily;
(t) tri: 'n~lnn~ r~tnn;rl-~ (Ari8tocort A topical cream,
Fujisawa), dosage range of from one to four ~rrl;r~t~nc per
day to af ected skin areas;
~U) i:llrl~ :~qnn~ 17, 21-dipropionate (Aclovate, Glaxo Derma-
tology), dosage range of from one ~o three ~rrl;r~t;nnc per
day;
(v) l~y~hu~u~Lisone (Anusol-HC, Parke-Davis), dosage range of
from one to four ~rrl;r~tinna per day;
(w) fluticasone propionate (Cutivate cream, Glaxo Derma-
tology), dosage range of from one to three applications per
day;
(X) h~ h~lcnn~. 17,21-dipropionate (Diprolene, Schering),
dosage range of from one to three :~rrlir:?ti~nq per day;
(y) :~crnr 17- (2-furoate) (Elocon, Schering), dosage
range of from once weekly to once daily;
(z) rlrh~t~nn~ propionate (Temovate, Glaxo n~rr-tnlogy),
dosage range o from one to three ~rrlir~tinnq per day;
(a') o.os~ coal tar topical . , 'tirn (DNS ~rar ~el Shampo o,
Person & Covey), dosage range of from one use per day to one
use per week;
(b' ) 12.5% coal tar topical composition (Denorex Extra
Stre"gth &oo, Whitehall T.:-hnr~tnries), dosage range of
from one use per day to one use per week;
(C' ) hn~q~ n (O~ oralen lotion, 1~, ICN), dosage range
from a topical :lrrl;r:3tinn plus ultraviolet light exposure
once per month to applications plus ultraviolet light exposure
three times per week;
(d~ ) -hnYq~ n (07cgoralell-Ultra capsules, ICN), doqage range
from one 10 mg capsule plus ultrav;iolet light exposure once
per mon~ch to two lo mg capsules plus ultraviolet light
~ - ~19DJû1
exposure three times per week;
~e') etretinate (~egisor/ Roche DPrr-tn~ ;cc)~ dosage range
from 0.125 mg/kg daily to 1.5 mg/kg daily;
(f') isotretinoin (Accutane, Roche DPr~tnlo~ics), dosage
range from 0.1 mg/kg daily to 2 ms/kg daily;
(g~ ) AnthrAl in (Drithocreme topical creams, American Dermal),
dosage range of from one Arrl;~~A~;nn per week to one
Arrl;nAt;nn per day for each .:..,.._,.l ..,ti~n of drug, ranging
from 0.1% to 1%;
(h~ ) cy~ l nqrnr; n A ( .qAn~i -~ Sandoz ph~r~ t'; r:~l ), dosage
range from 1 mg/kg daily to 15 mg~kg daily;
(i~) vitamin D3, 0.001% to 0.5 % in cream, lotion or gel base,
topical Arrl;~ ;nn from once weekly to four times daily; and
(j' ) salicylic acid, 0.001% to 0.5 '~ in cream, lotion or gel
base, topical Arrl;rAt;on from once weekly to four times
daily .
: The following ;lll-ctrAtP specific '' lAr;nnc according to
the present invention.
_( nn~lAn;~l;nn)benzoic acid 1 gm
nordihydroguaiaretic acid 7 5 gm
methylpr~lln;cnlnnP 2.5 mg
p_5~n.;nnrhPnylacetiC acid 20 gm
probucol 1 gm
etretinate 100 mg
p_~--;nnhPn7n;r ~cid 5 gm
t;~nnnAn;~ 250 mg
cyrl ncrnri n A 500 mg
~xample 7
Clinical treatment of ' tn; ~l arthritis can be im-
proved by use of a composition compriging from about 1 gm to
r about 20 gm of at least one primary therapeutic agent compris-
ing a primary amine benzoic acid derivative having a rnnlpcl`lAr
weight of from about 100 to ahout 1,400 Daltong, and optional-
ly at least one q~lhAtAn~_P gelected ~rom thoge noted above in
~1 9Ql 0~
section (v) through section (ix), and a ;. re.-~nt7,.,~
as effective to treat ~~ ---;-1 arthritis, such as, for
example,
~a) -lnf te (M,or~7l ), dosage range from 100 mg dally
to 800 mg daily;
(b) f~n~rl;n acid (P2nstel), dosage range from 200 mg daily
to 1. 5 gm da$1y;
(c) flllf~n c acid, dosage range ~rom 100 mg daily to 1 gm
daily;
(d) amfenac, dosage range from 1 llg/kg daily to 1 mg/kg
daily;
(e) ethyl 2-amino-3-benzoylphenylacetate, dosage range from
10 ~Lg~kg daily to 10 mg/kg daily;
(f) diclofenac (VoltareQ), dosage range from 10 mg daily to
200 mg daily;
(g) etodolac (Lodine, Wyeth-Ayerst T.~hnrltnries), dosage
range from 200 mg daily to 2 gm daily;
(h) i:i7;ni~ acid, dosage range ~rom 1 mg/kg daily to 100
mg~kg daily;
(i) i ~ ' h:lrin (Irdocin), dogage range from 25 mg daily to
250 mg daily;
(j) fenclo2ic acid, dosage range from 25 mg daily to 500 mg
daily;
(k) isofezolac, dosage range from 0.1 mg/kg daily to 25 mg/kg
daily;
(1) sulindac (Cl-noril, Merck & Co.), dosage range from 50 mg
daily to 500 mg daily;
(m) tolmetin (Tolecti~), dosage range from 100 mg daily to 2
gm daily;
(n) g ~ I-i n ~ do8age range from 50 mg daily to 600 mg
daily;
(o) ni ~;n, dogage range from 2 mg~kg daily to 400 mg/kg
daily;
(p) fenclofenac, dosage range from 200 mg daily to 2 gm
daily;
(q) fenbufen, dosage range from 250 mg daily to 1.25 gm
daily;
(r) hlltihllf~n, dosage range from 40 mg/kg daily to 400 mg/kg
daily;
2190107
61
(5) k~nrnlAe L,, ~1 'n~ ~Toradol, synte~), do3age range
from 5 mg daily to 150 mg daily;
~t) ~;nnri~;n~, dosage range from 2.5 mg/kg daily to 250
mg/kg daily;
(u) fenoprofen (Nalfon), dosage range from 250 mg daily to
3.2 gm daily;
(v) flurbiprofen (Ansaid), dosage raLtge from 50 mg daily to
S00 mg daily;
(w) ibuprofen (Motrin), dosage range from 200 mg daily to 3.2
gm daily;
(x) ketoprofen (OrudiG), dosage range from 25 mg daily to 500
mg daily;
(y) naproxen (~laprosyr~), do3age raLtge from 125 mg daily to
1.25 gm daily;
(z~ bucloxic acid, dosage raLtge from 200 mg daily to 2 gm
daily;
(a~ ) the (S) (~) ~n:~nt;~ of carprofen, dosage range from 10
mg daily to 750 mg daily;
(b~) phenylht~t~7nn~ (Azolid), dosage range from 2 mg/kg daily
to 100 mg~kg daily;
(C' ) J~LyS~ R7. ~IIG (~raner~1), dosage range from 100 mg daily
to 1 gm daily;
(d~ ) f~rr~7nn~, dosage range from lOo mg daily to 1.5 gm
daily;
(e~) imiriR7nle salicylate, dosage range from S0 llmol/kg daily
to o . 5 mmol/kg daily;
(f~) fi;fll~n;c:~, dosage range from 250 mg daily to 1.5 gm
daily;
(g~) g~llf~c~lA7ini., dogage range from 200 mg daily to 3 gm
daily;
(h~ ) benorylate, dosage range from 1 gm daily to 7 gm daily;
(i~ ) piroxicam (Felden~), dosage range from 5 mg daily to 25
mg daily;
(j') isoxicam, dosage range from S0 mg daily to sO0 mg daily;
(k~) auranofin (Rldaura, ''~;th,7~1 ;n~. ~eecham), dosage range
from 1 mg daily to 9 mg daily;
(1') auroth;n~ n~e (Solgalal, ScheriLtg), i ' ~ r
dosage range from 1 mg weekly to 40 mg weekly;
(m~) gold sodium ~h;~ s~ (Myoch~yisine, Merck ~ Co.),
2 1 9~ T 0 7
62
int l:~r dosage range from 1 mg weekly to 50 mg weekly;
~n~ y~u,~y~ rr~pl;n~ (Pla~uenil, SanofiWinthropPh~LIl~Cc~
ticals~, dosage range from 50 mg (equivalent to 39 mg base)
daily to 600 mg (equivalent to 465 mg base) daily;
(o ) chloroS~uine, dosage range from 50 mg daily to 500 mg
daily;
(p ) methotrexate (Rh, ~r~r, Lederle T,:~h< r~tnr;f-q), dosage
range from l mg weekly to 20 mg weekly;
(~') D-pon;~ 'n~. (Cuprim~ne, Merck & Co.), dosage range
from 25 mg daily to 1. 5 grams daily;
(r~ ) cyrl~y~ (Cytoxan, Bristol-Myers Oncology), dos-
age range from 0.1 mg/kg daily to 5 mg~kg daily;
(8~ ) prednisone ~Delta~one, Up~ohn), dosage range from 1 mg
daily to 250 mg daily, or ~lt~rn~t~ day do8ing;
(t ) , h:~c~n~. (Decadron, Merck h Co. ), dosage range from
0.25 mg daily to 18 mg daily;
(u~) methylpr-~l";qol~n~ (~edrol, ~Jp~ohn), dosage range from 1
mg daily to 250 mg daily, or ~3l t~r~ It~ day dosing;
(v ~ ) ( 10 -methoxy- 4 H- benzo t4, 5 ] cyclohepta - L 1, 2 -b] - thiophene - 4 -
yliden)acetic acid, dosage range from 0.5 mg/kg daily to 100
mg/kg daily;
(w~ ) cyclogporin A (.S-~i , Sandoz p~ l ), dosage
range from 1 mg/kg daily to 250 mg/kg daily or three times
weekly;
(x~ ) neutral macrolide of ~ e~_1ll ~r formula C~ H6~ NOI,- H20
derived from Stre~tomvces t....~..1. ..q;q No. 9993 (FK506),
dosage raLge from 0.5 mg/kg daily to 50 mg/kg daily;
(y ) rapamycin, dosage range from 1 mg/kg daily to 250 mg/kg
daily or three times weekly;
(z ) ~7:-thinrrine (Imuran, Burroughs Wellcome), oral or intra-
venous dosage range from 75 ,~ g/kg daily to 2.5 mg/kg daily;
(a~) n51l ~ln~ (Relafen, r-;thRl;n-- Beecham~, dosage range
~rom 200 mg daily to 2 gm daily;
(b~ q~r~nt~ n~;c acid, dogage range from 500 mg daily to
10 gm daily;
(c~ ~ ) aloxiprin, dosage range from l gm daily to 7 gm daily;
(d~ yLUl a .U116, dogage range from 500 mg daily to 5 gm
daily;
(e~ ~ ) a--iprilose, dosage range from 1 gm daiIy to 8 gm daily
o l
63
(f' ' ~ chl./~ ' r; 1 (Leukeran, Burroughs Wellcome), dosage
range from 0 . S mg daily to 10 mg daiiy;
(g~ ~ ~ Arer1nfl~nA~-~ dogage range from 0.2 mg/kg daily to 10
mg/kg daily;
(h' ' ~ apocynin, dosage ranse from l mg/kg daily to 100 mg/kg
daily;
(i' ~ ) r~ra~;r;n, i~ ."; lAr, c-lhrl~tAn~-n7-~ or
oral dosage range from 5 mg/kg daily to 200 mg/kg daily;
6- (2,ç-~; f1 ~ y) -5-methylsulfonylamino-1-indanone
(Ciba-Geigy AG), dosage range from 0.2 mg/kg daily to 20 mg/kg
daily;
(k' ' ) dapsone, dosage range from 20 mg daily to 200 mg daily;
(1'') $nl--h;1;7~1 chicken type II collagen, dosage range from
So llg daily to 20 mg daily;
(m~) 15-de~y~cl!~ualin, inL~ ,; 1Ar, subcuta-
neous or oral dosage range from 0.5 mg/kg daily to 10 mg/kg
daily;
(n''~ diacetyl-~r1-~n^r~nt;n, illL~a..,.l/L15~ rl~ r or
3llhr1lt:ln~0ll~ do8age range from 100 ,I g/kg daily to 3 mg/kg
daily;
(o' ' ~ diaveridine, dosage range from 25 mg/kg daily to 500
mg/kg daily;
(p' ' ~ ditazol, dosage range _rom 25 mg/kg daily to 750 mg
daily;
(q''~ droxicam, dosage range from 0.1 mg/kg daily to S0 mg/kg
daily;
(r~ ' ~ (Z~ -3- [4- (acetyloxy~ -S-ethyl-3-methoxy-1-nArhthA1 ~nyl] -
2-methyl-2-propenoic acid, dogage range from 10 mg/kg daily to
S00 mg/kg daily;
(S''~ eb8elen, illL~ u8, illL~ lAr, sllhrlltAn~nll~ or
oral dosage range from S mg/kg daily to 500 mg/kg daily;
(t' '~1-p-chlorobenzyl-2-dimethyl-amino-methylcyclohexen-1,2,
dosage range from 2.5 mg/kg daily to 250 mg/kg daily;
(u''~ etoclofene, illLL~ s, i~ lAr, g11h~1tAn~-n11~ or
oral dosage range from 1 mg/kg daily to 400 mg/kg daily;
(v~ ' ~ felbinac, dogage range from 100 mg daily to 1.25 gm
daily;
(w~ ~ ~ fenclorac, dosage range from 0.5 mg/kg daily to S0 mg/kg
daily;
2~90~7
64
(x' ' ) fenclozic acid, dosage range from 2 .5 mg/kg daily to 250
mg/kg daily;
(y~ ~ ) fendosal, dosage range from S mg/kg daily to 200 mg/kg
daily;
(2'') isoxepac, dosage range from 200 mg daily to 2 gm daily;
(a''~) l~fl ~, dosage range from 50 llg daily to 50 mg
daily;
(h' ~ ~ ~ lohenzarit, dosage range from S0 mg daily to 750 mg
daily;
(C' ' ' ) 1 nnA7nla~--Ca, dosage range from 100 mg daily to 1 gm
daily;
(d''') S-t~3~s-~ois(l~l-dimethylethyl~-4-lly~hv~y~ -.lyl]methyl-
ene3 -3- (dimethylamino~ -4-th;A7nl ;rlinnnl~, dosage range from 1
mg/kg daily to 100 mg/kg daily;
(e'''~ 5-[[3,5-'ois(1,1-dimethylethyl~-4-lly~ yyh~ yl]methyl-
ene3-3-~methylamino~-4-th;A7ol;~l;nnn~ dosage range from 1
mg/kg daily to lO0 mg/kg daily;
(f' ' ' ~ L -;7nn-calcium (Eumotol~, dosage range from 100 mg
daily to 1 gm daily;
(g~ azapropazone, dosage range from lO0 mg daily to 1 gm
daily;
(h'''~ D-my^;nn~;tnl-1.2.6-tri~ t~ L~ s, intra-
muscular, ~llhcl~tAn~o~ or oral dosage range from 10 mg/kg
daily to 1. S gm daily;
n~; c acid (as commercial products contain-
ing this suhstance as the active ingredient, ;nr~ ;n3 l~axEE~A
capsules, 18 gm of which contains 3.2 gm eicosap-~ntA-~n^;c
Acid~, dosage range of ei~-n~3Ar~nt~nn;-- acid from sO0 mg daily
to 10 gm dailyi
(j'''~ i_ufenac, dosage range from 1 mg/kg daily to 100 mg/kg
daily;
(k~ n; 1;~, dosage range from 100 mg daily to 2 gm
daily;
A~;np~ dogage range from so mg daily to S00 mg
daily;
(m' ~ ~ ~ oxaprozin, dosage range from lS0 mg daily to l.S gm
daily;
(n~ --Y;hl-7nn~, dogage range from 2 mg/kg daily to 150
mg/kg daily;
, ~ ~lq~D~
(o~ ~ ~ ) pirprofen, dosage range from 100 mg daily to 1 5 gm
daily;
(p~ U~U~Z~ dosage range from 150 mg daily to 1.5 gm
daily;
(q ~ tri nnl~ n~. A.~-~t^n;rlo~ La~ 6~; ' ~ 1 Ar,
Sv~ l or oral dosage range from 5 ~g/kg daily to 0 1
mg/kg daily;
(r ? suprofen; dosage range from 5 mg~kg daily to 100 mg/kg
daily;
(8 ) t~n~ ~icAm, dosage range from 5 mg daily to 40 mg daily;
(t ) tiaprofenic acid, dosage range from 100 mg daily to 1
gm daily;
(u~ ~ ~ ) t l f, c acid, dosage range from 100 mg daily to 600
mg dailyi
(v~ ~ ~ ) difenpiramide, dosage range from 250 mg daily to 1.5 gm
daily;
(W ) ;~ f.~7~.1A~, dosage range from 0.5 mg/kg daily to 50
mg/kg dai ly i
(x~) tiopronin, il~L~ ,;wls~ illLL l:lr, s~lhclltAn lla or
oral dosage range from 5 mg/kg daily to 100 mg/kg daily;
(y ) 5-thiopyridoxine, dosage range from 50 mg daily to 2 gm
daily;
(Z ~ llydl ~u~Lisone (firyl~u.,u~ Lu~.e, Merck & Co ), do3age
range from 1 mg daily to 400 mg dailyi
(a ~ pr~ n; crl~ (Pediapred, Fisons~, dosage range from 1
mg daily or every other day to 250 mg dailyi
(b~ cortisone (Cortone, Merck h Co.~, dosage range from 5
mg daily to 400 mg daily;
(c ~ metkylprl~n;~l lnn~ acetate (Depo-Medrol, ~p~ohn),
illL~ rlluvial~ ;ntr~lP~;~mAl or il~L~ _ lAr dosage range
from 0 5 mg daily to 50 mg daily, or weekly dosage of from 20
mg to 120 mg;
(d~ ) trl n lone (Ari8tocort, Fu~igawa), dosage range
from 1 mg daily to 200 mg daily, or alternate day dosingi
(e~ ) tr; nnl~ n~ etAte (Aristocort 5-l~r~n~ n~ Fuji-
sawa), illL~ lAr, intra8ynovial or ;nt A1~A;rnAl dwsage
range from 1 mg daily to 200 mg daily, or alternate day
dosing;
(f ) betamethasone (celegtone, Schering), dosage range from
~ 21 9~ 0~
o . 2 mg daily to 12 mg daily, or alternate day dosing;
~g' ' ' ' ) he- hAcf~nr. (Celegtone Soluspa~ qpt~nci~n, Scher-
ing), illL~ 1Ar or intrAl~qir~nal dosage range from O.l mg
daily to lo mg daily, or Al t~rnAt~ day dosing;
(h' ' ' ' ) ~' hac~ Decadrcn phosphate injection, Merck &
Co.1, i lAr, i~lLL"~ u8 or ;ntr~ c~nA1 dosage range
from O.1 mg daily to 10 mg daily;
(i' ' ' ~ ) cortisone (Cortane s~lcr~nci~n~ Merck & Co. ), intramus-
cular dosage range from 5 mg daily to 400 mg dailyi
(~ ' ' ' ' ) hydrocortisone (Hyd~v,v~ Lv~i_ pho~7phate in~ection,
Merck & Co. ), ; l i~r, illLl~-veuuu9 or s~lh~ t8n~0us dos-
age range from l mg daily to 400 mg daily;
(k''''~ l~yJ~u~ sone (~yllLv~vlLv~eacetatec~lcr~ncir~n~ Merck
& Co.), intra-articular, intrAl~ci~ln~l or soft tissue injec-
tion dosage range from 1 mg daiLy to 400 mg daily;
(l'~'~) pr~ niq~ n~ (~ydeltrasol in~ection, Merck & Co.),
ug~ i lar, intra-articular, ~ntrAl~ci~n:~l and
soft tissue dosage range from 1 mg daily to 100 mg daily;
(m~ ) aspirin, dosage range from 300 mg daily to 6 . 5 gm
daily;
(n' ~ ' ~ ) calcium acetylsalicylate, dosage range from 300 mg
daily to 6 . 5 gm daily;
~o~ ) choline salicylate, dosage range from 500 mg daily to
4 gm daily;
~p~ ) choline r-~n~ci triaalicylate ~rilis~te, Purdue
Frederick), dosage range from 500 mg daily to 4 gm daily;_
(q~ nf-ct salicylate, dosage range from 500 mg daily
to ~ gm daily;
(r'''') C.~lC::lliltP (Salflex, Carnrick Laboratories), dosage
range from 500 mg daily to 4 gm daily;
(8~ clllf~cAlA7in~ (p7~.7fi,11~ N-taoa delayed release
tablets and A7-17fi~1n~ tablets, Kabi Pharmacia), dosage range
from l gm daily to 5 gm daily;
(t' ~ ~ ~ ) cyclorh~crl ~ (Cytoxan for injection, Bristol-Myers
Oncology), dosage range from 0.1 mg/kg daily to s mg/kg daily,
2 mg~kg to 5 mg/kg twice weekly or 10 mg/kg to 15 mg/kg every
seven to ten days;
(u' ' ~ ' ) ~, lV~ -diphenyl -p-phenyl ~.nt~ ' n~., dosage range from lo
~ ~1 SOl 07
67
mg/kg daily to ~50 mg/kg daily;
~v~ ) tenidap (Pfizer), dosage range from 25 mg daily to 2
gm daily;
(w' ' ~ ~ ) ketorolac t._ I n~ (Toradol ~, Syntex), intramus-
cular dosage range from 5 mg daily to lS0 mg daily; and
(x' ' ' ' ~ carprofen, dosage range from 0 .2 mg/kg daily to 50
mg/kg daily;
The following illustrate specific f, l~tinn~: according to
the present invention.
4-~lAn;~innh~n7n;r acid E~Cl 1 gm
mixed tocopherols 500 I.U.
prednisone 5 mg
p nnh~n7nin acid 20 gm
d-tY-tocopheryl S~ inAt~ 3,500 I.U.
L: 'h;nntn~ 2 gm
sulindac S00 mg
4_~ nn~ ni~nn)benzoic acid 5 gm
acety~ eine thinl:~ tnn~ l gm
A7.thi nrrine 75 mg
Example 8
Clinical ~- of ankylosing spondylitis can be im-
proved by u3e of a, ~t;nn comprising from about l gm to
about 20 gm of at least one primary th~rAr~llt;- agent
comprising a primary amine benzoic acid derivative having a
.~n1~ 1Ar weight of from about 100 to about 1,400 raltons, and
npt;nnA11y at leagt one c~h.ltAn~-e 8elected from those noted
above in section ~v) through section (ix), and a, a; ~
r^rn~n; 7^~ as effective to treat ankyloging gpondylitis, such
as, f or example,
(a) isoxicam, dosage range from 25 mg daily to 400 mg daily;
(b) ketoprofen, dosage range from ~o mg daily to 500 mg
daily;
(c) ~l;r-lnf~n~, dogage range from 25 mg daily to 500 mg
daily;
` 2~9~107
68
(d) fenclofenac, dosage range from lS0 mg daily to l.S gm
daily;
(e) phenylhl~t~7^"~-, dosage range from 50 mg daily to 400 mg
daily;
(f~ ~L.~.aL.v.le, dosage range from 1 mg/kg daily to lC0 mg/kg
daily;
(g) n~r -rn~, dogage range ~rom 200 mg daily to 2 gm daily;
(h) indomethacin, dosage range from S0 mg daily to S00 mg
daily;
(i? sulindac (Clinoril, Merck & Co.), do~age range irom S0 mg
daily to S00 mg daily;
(j ) carprofen, dosage range from 25 mg daily to 300 mg daily;
(k) d h~ n~. (Decadron, Merck & Co ), dosage range from
0.25 mg daily to 18 mg daily;
(1) ~L~ ~Z~ dosage range from lSo mg daily to 1.5 gm
daily;
(m) irouprofen, dosage range from 200 mg daily to 2 gm daily;
(n) t~n~i r--, dosage range from S mg daily to 50 mg daily;
(o) piroxicam, dosage range from 5 mg daily to sO mg daily;
(p) tiaprofenic acid, dosage range from loO mg daily to 1 gm
daily;
(q) tolfenamic acid, dosage range from 100 mg daily to 1 gm
daily;
(r) pirprofen, dosage range from lS0 mg daily to l.S gm
daily;
(8) hydrocortisone (~iy~rLV~VL~Jlle, Merck & Co.), dosage range
from 1 mg daily to 400 mg da$1y;
(t) pr~ q^~ (Pediapred, Fisons), dosage range from 1 mg
daily or every other day to 250 mg daily;
(u) cortisone (Cortone, Merck & Co. ), dosage range from S mg
daily to 400 mg daily;
(v) prednigone (Deltagone, Jpjohn), dogage range from 1 mg
daily to 250 mg daily, or ~1 tPr":~t~ day dosing;
(w) methylpr-~-iniq^l~nf~ (~edrol, Upiohn), dogage range from 1
mg daily to 250 mg daily, or alternate day dosing;
~x) methylprf~n;q^lmn~ acetate (Depo-~edrol, Upjohn), intra-
synovial, intr~ qi^n:-l or; li~r dogage range from O.S
mg daily to S0 mg daily, or weekly do8age of from 20 mg to 120
mg;
2~ ~D~ ~7
(y) tr~ nnl nn~ (Aristocort, Fu~ lsawa), dosage range from
1 mg daily to 200 mg daily, or i31tF~rni3t~- day dosing;
(z) tria nn~nno ~ ~eti~t-~ (Aristocort sllqp.~nqinnq, Fujisa-
wa), ; li~r, intragynovial or ;ntri31~.q;nn:l1 dosage
range from 1 mg daily to 200 mg daily, or ~l t~rni3t~ day
dosing;
(a' ) betamethasone (Celestone, Schering), dosage range from
0.2 mg daily to 12 mg daily, or i~ltFlrnslt~ day dosing;
(b') heti h~Rnn~ ~celestonesoluspanct~qr~nc;nn~ Schering),
1A1- or intr~ q;nni3l dogage range from 0.1 mg daily
to 10 mg daily, or alternate day dosing;
(c' ) dexamethasone (Decadron rhnsrhi~t~ injection, Merck &
Co.), i~lL~ li3r, i~L~ ...luul~ or intrAl~q;nn~l dosage range
from 0.1 mg daily to 10 mg daily;
(d') cortisone (Cortone gllcr~nq;nn, Merck & Co.), intramus-
cular dosage range from 5 mg daily to 400 mg daily;
(e') l~ydiLu~urLisone (8y~1-u~u~,u~le rhncrh~t~ in~ection, Merck
& CO.), i c~-lll;~r, illL~.~vellu~ or sl-hruti~n~ollq dosage
range from 1 mg daily to 400 mg daily;
(f') pr~ln;cnl~n~ ydeltrasol injection, Merck & Co.), intra-
VellOUg~ r~ intra-~rticular, intri3loqinni3l and soft
tissue dosage range from 1 mg daily to 100 mg daily;
(g') aspirin, dosage range from 300 mg daily to 6.5 gm daily;
(h' ) calcium acetylsalicylate, dosage range from 300 mg daily
to 6 . 5 gm daily;
(i' ) choline salicylate, dosage range from soo mg daily to 4
gm daily;
(j') choline magnesium trisalicylate (I'rllisate, Purdue Fred-
erick), dosage range from 500 mg daily to 4 gm daily;
(k' ) mi~n~c; salicylate, dosage range from 5~0 mg daily to
4 gm daily;
i31~i~li3te (Salflex, Carnrick r.~hn~i~tnr;f~-l), dosage range
from 500 mg daily to 4 gm daily;
(m' ~ im;~ 7nl~. 2-hyd~u~yb~l.Lv~Le, dosage range from so ~mol/kg
daily to 0 . 5 mmol/kg daily;
(n' ) diflunisal, dosage range from 2s0 mg daily to 1.5 gm
daily;
(o' ) slll f~ 7;n/~, dosage range from 200 mg daily to 3 gm
daily;
2~ 9~t ~7
(p~ ) benorylate, dosage range from 1 gm daily to 7 gm daily;
(5[~ ) naproxen (Naprosyn), dosage range from 125 mg daily to
1.25 gm daily; and
(r' ) ~yllh~ 7~n~ (I'aneril), dosage range from 100 mg daily
to 1 gm daily.
The following ;~ ctr~te specific f l~r~mn according to
the present invention.
4_~m; nrlrh~nylacetic acid 1 gm
propyl gallate 100 mg
;- ~ h:-cin 50 mg
4- (guanidino~ -2-methu~y~ L2uic acid 15 gm
tert-butylhydroquinone 1 gm
glycine 10 gm
cortisone 400 mg
~- (aminoguanidino) benzoic acid 5 gm
homocysteine - 1 gm
naproxen ~00 mg
Example 9
Clinical L~ ~ of osteoarthritis can be improved by
use of a . , 't;-~n . , cin~ from about 1 gm to about 20 gm
of at least one primary therapeutic agent, ' cln~ a primary
amine benzoic acid derivative having a ~ r weight of
from about 100 to about 1,iOO Daltons, and ~.rrir~n~lly at least
one substance selected from thoge noted above in section (v)
through section (ix), and a ';, r~ 3n~7~1 as effective
to treat osteoarthritis, such as, for example,
(a) prednisone (~eltasone, IJpjohn), dosage range from 1 mg
daily to 250 mg daily, or i-l t~rn~ day dosing;
(b) n~ nF. (l~elafen, SmithKline Beecham), dosage range
from 200 mg daily to 2 grams daily;
(c) ketoprofen (orudig), dosage range from 25 mg daily to 500
mg daily;
(d) phenylh~r~7~n-~, dosage range from 100 mg daily to 500 mg
daily;
(e) the (s~ (+) ~.n:~n~;~ of carprofen, dosage range from 50
. ~ 21~0~
71
mg daily to 750 mg daily;
(f) ,~ h:lnone (Decadron, Merck & Co.), dosage range from
0.25 mg daily to 18 mg daily;
(g) ~; rlrf~n:lr (Voltaren1, dosage range from 10 mg daily to
200 mg daily;
(h~ ~lifl~-ni~Al, doaage range from 250 mg daily to 1.5 gm
daily;
(i~ di~ y~ , dosage range from 250 mg daily to 1.5 gm
daily;
(j~ fenhufen, dosage range from 250 mg daily to 1.25 gm
daily;
(k~ oxyrh ~nhl~t~7rn~ (~aneril), dosage range from 100 mg daily
to 1 gm daily;
h:lrin (Indocin~, dogage range from 25 mg daily to
250 mg daily;
(m~ rJ~ rin, dosage range from 50 mg daily to 600 mg
daily;
~n) isoxicam, dosage range from 50 mg daily to 500 mg daily;
(o) l.rnA7rl~r-Ca, dosage range from 100 mg daily to 1 gm
daily;
~p) S-adenogyl hirn1nf~, dogage range from 500 mg daily to
10 g,m daily;
(q) ~ ~; 7rn-calcium (Eumotol), dogage range from 100 mg
daily to 1 gm daily;
(r~ diacetylrhein, dosage range from lQ mg daily to 500 mg
daily;
(8~ 4~,11.t:, dosage range from 150 mg daily to 1.5 r~m
daily;
~t~ naproxen ~Naprosyn~, dosage range from 0.5 mg/kg daily to
25 mg/kg daily;
(u~ nimesulide, dogage range from loo mg daily to 2 gm daily;
(v) ~:~r;n~ do8age range from 50 mg daily to 500 mg
daily;
~w) pirprofen, dosage range from 100 mg daily to 1.5 gm
daily;
~x) prenazone, dosage range from 150 mg daily to 1.5 gm
daily;
~y) sulindac ~Cl~noril, Merck ~ Co.), dogage range from 50 mg
daily to 500 mg daily;
~ 2i~0~07
72
~z) suprofen, dosage range from 5 mg/kg daily to 100 mg/kg
daily;
(a' ~ tPnrY; I , dosage range from 5 mg daily to 40 mg daily;
(b' ~ tiaprofenic acid, dosage range from 100 mg daily to 1 gm
daily;
(c') hyd~ uLLisone (HY~ L~ Merck & Co.~, dosage range
from 1 mg daily to 400 mg daily;
td'~ prP~n;~^lrnp (Pediapred, Fisons), dosage range from 1 mg
daily or every other day to 250 mg daily;
(e') cortisone (Cortone, Merck ~ Co.), dosage range from 5 mg
daily to 400 mg daily;
(f') methylprP~lni~nl^nP (Medrol, Upjohn), dosage range from 1
mg daily to 250 mg daily, or altprnAte day dosing;
(g~) methylprPfln;qnl-~nG~ acetate (Depo-~edrol, lJp~ohn),
iU~L. I~yllvvi-al~ int~:~l P.l;rnAl or i lA~ dosage range
from 0.5 mg daily to 50 mg daily, or weekly dosage of from 20
mg to 120 mg;
(h'~ tr;: 'n~lnnP (Ari8tocort, Fujisawa), dosage range from
1 mg daily to 200 mg daily, or Al tPrnAtP day dosing;
tr; 'nnlrn~ diacetate (Aristocort $--~r~ncirn_~ Fuji-
sawa), ; lAr, il.LL,~ I.v~ial or ;nt~RlPc;nn~l dosage
range from 1 mg daily to 200 mg daily, or AltPrnAte day
dosing;
(; ~ ) hPt: hAI~nnP ~Celestone, Schering), dosage range ~rom
o .2 mg daily to 12 mg daily, or Al tPrn:~te day dosing;
(k' ) bet hA~nnP (Celestone soluspan yll~rPny;nn, Scheri~g),
~.ular or ;nt~AlPA;rnill dosage range from 0.1 mg daily
to 10 mg daily, or alternate day dosing;
h ~crnP (Decadron rhr~rhAtP injection, Merck
Co.) ~; ' lAr~ L~._.wus or ;nt-~Al~Cl;rnAl dosage range
from o.1 mg daily to 10 mg daily;
(m'~ cortisone (Cortone s-~rPn~;r,n, Merck & Co.~, intramus-
cular dosage range from 5 mg daily to 400 mg daily;
(n' ) 1~ydL~ LLisone (Hydrocortone phrsrhAtP injection, Merck
& CO. ), illLL 1 A~-, illLL.-~._.WU~ or yl~hr~lt~n~n~q dosage
range from 1 mg daily to 400 mg daily;
(o' ~ hydrocortisone (HY.1LU.~,L L~,lle acetate S~rPnY;nn, Merck &
Co.~, intraarticular, intrAlP~;r,nAl or so~t tissue injection
dosage range from 1 mg daily to 400 mg daily;
0107
73
(p' ~ pr-~7n; ~ n~. (Nydeltrasol injeetion, Merck & Co.), intra-
venous,; l:lr~ intra-articular, intri3l~c;-~n~1 and Goft
tissue dosage range from l mg daily to lO0 mg daily;
(q') aspirin, dosage range from 300 mg daily to 6.5 om daily;
(r' ) caleium aeetylsalieylate, dosage range from 300 mg daily
to 6 . 5 gm daily;
(8' ) choline salicylate, dosage range from 500 mg daily to 4
gm daily;
(t') choline ~-3n~i trisalicylate (Trilisate, Purdue Pred-
eriek), dosage range from 500 mg daily to 4 gm daily;
(u' ) -~3nF n; salicylate, dosage range from 500 mg daily to
4 gm dailyi
(v~) ~c~lnA1Atf~ (Salflex, Carnriek LahoratorieG), dosage range
from 500 mg daily to 4 gm daily; and
(w~ ) etodolae (Lodine, Wyeth-Ayerst Lahoratories), dosage
range from 200 mg daily to 2 gm daily.
The following ;l11~ctr~t~. specific f, 1At;~nq aecording to
the present invention.
4-amino-2-methylhoen20ie aeid 1 gm
N,N'-dimethylthiourea 300 mg
etodolac 200 mg
p ~--in,~h-~n7~1;r acid lS gm
~-carotene 300 mg
dexamethasone lO mg
(4-aminocyrl-h~ An-~)acetic acid 5 gm
D-myo-inositol-1.2.6-t~;~rhncrh:,t., 20 gm
suprofen 3 gm
Example lO
Clinical L............. of t~n~l;n;t;n or tenosynovitis can he
improved hy use of a, _ ~;t;rn compriging from about 1 gm to
ahout 20 gm of at least one primary therapeutic agent
comprising a primary amine hoenzoic acid derivative having a
rll1A~ weight of from ahoout 1oo to a_out 1,400 Daltons, and
''rt;'`n~Y at lea8t one substanee selected from those noted
ahove in 6ection (v) through Gection (ix~, and a ~
~ 107
74
r~ nJn;7~-1 as effective to treat t~nt1;nit;c or tenosynovitis,
such as, for example,
(a~ the (S) (+) ~nAnti of carprofen, dosage range from S0
mg daily to 750 mg dailyi
(O) -hARnn~ (Decadron, Merck & Co.), dosage range from
0.25 mg daily to 18 mg daily;
(c) ~ ln~n~- (Voltaren), doGage range from 10 mg daily to
200 mg daily;
(d~ fenoufen, dosage range from 2~0 mg daily to 1.25 gm
daily;
(e~ n; 1;~, do3age range from 100 mg daily to 2 gm daily;
(f~ oYamethacin, dosage range irom 50 mg daily to 500 mg
daily;
(g~ pirprofen, dosage range from 100 mg daily to 1.5 gm
daily;
(h~ d4u~e~ dosage range from lS0 mg daily to l.S gm
daily;
~i1 sulindac (Clinoril, Merck & Co.~, dosage range from so mg
daily to sO0 mg daily;
(j) tPnnY;~ , dosage range from S mg daily to 40 mg daily;
(k) tiaprofenic acid, dosage range from 100 mg daily to 1 gm
daily .
(1) I~ L.,..L~isone (~;y~i~u.~,L~,..e, Merck & Co.), dosage range
from 1 mg daily to 400 mg daily;
(m) prF~rln;cnlnn~ (Pediapred, Fisons), dosage range from 1 mg
daily or every other day to 250 mg daily;
(n) cortisone (Cortone, Merck & Co.), dosage range from s mg
daily to 400 mg daily;
(o) prednisone (Deltaso~e, Upjohn), dosage range from 1 mg
daily to 250 mg daily, or ~1 t~rnAtl~ ddy dosing;
(p) methylprl~-ln; cnl n~ (~edrol, Upjohn), dosage range from 1
mg daily to 250 mg daily, or :1l t~rn~te day dosing;
methylprf~-ln;cnlnnF acetate (Depo-~edrol, l~pjohn), intra-
synovial, intralesional or; ~ c~ r dosage range from 0.5
mg daily to so mg daily, or weekly dosage of from 20 mg to 120
mg;
(r) tr;. nnlnn (Aristocort, Fujisawa), dosage range from
1 mg daily to 200 mg daily, or alternate day do3ing;
(9) tr; nnlnn~. 9;A. ~tAtf. (Ari.Rtocort 5 1crl~nc; -nC, Puji-
~ 2~qO107
sawa), i~.L-. l Ar, intrasynovial or intralesior,al dosage
range from 1 mg daily to 200 mg daily, or alternate day
dosing;
(t) het hAa~ln~ (celestone, Schering), dosage range from
0.2 mg daily to 12 mg daily, or Al t~rnAte day dosing;
(u~ hAannD (Cele3tone Solu~pan qllar~onqinn, Schering),
lAr or ;ntrAl~RirnAl dosage range from 0.1 mg daily
to 10 mg daily, or ~l t~rnAt~ day dosing;
(v) dexamethasone ~Decadron rht~arhAte injection, Merck &
Co.), i lAr, illL-"~ uus or intrAl~a;nnAl dosage range
from 0 1 mg daily to 10 mg daily;
(w) cortisone (Cortone sllqr~na;nn~ Merck h Co.), intramus-
cular dosage range from 5 mg daily to 400 mg daily;
~x) hydrocortisone (~y<~ Ull,U~.~ rhnqrhAt~ in~ection, Merck
& Co.),; ' lAr~ illL~ uu~ or qllh~ltAnpnllq dosage
range from 1 mg daily to 400 mg daily;
(y) llyd~u~u-Lisone (~yllLu~u~ acetate ~qllar~nal nn, Merck h
Co.), intra-articular, ;ntrAl~q;nnAl or soft tissue injection
dosage range from 1 mg daily to 40Q mg daily;
(z) pr~ofln;qolnn~ (~ydeltrasol injection, Merck & Co.), intra-
venous,; lAr~ intra-articular, ;ntrAlf~a;nnAl and soft
tiqsue dosage range from 1 mg daily to 100 mg daily;
(a~) ' hAannl~ acetate (Decadron-l,A, Merck & Co.), intra-
muscular and local soft tissue injected dosage range from 0.1
mg daily to 10 mg daily;
~b~ hA~-;n (Indocin), dosage range from 25 mg daily to
250 mg daily;
(c' ) aspirin, dosage range from 300 mg daily to 6.5 gm daily.
(d' ) vitamin B, (pyridoxine HCl), dosage range from lO mg
daily to 1. 75 gm daily;
(e') pyridoxal, dosage range from 10 mg daily to 1.75 gm
daily;
(f~ ) pyridoxal HCl, dosage range rom lo mg daily to 1.75 gm
daily;
(g') pyridoxal S-rh~qrhAt.., dosage range from 10 mg daily to
1.75 gm daily;
(h' ) pyridoxal S-rhnqrh~lt~ calcium salt, dogage range from 10
mg daily to 1. 75 gm daily;
(i~) pyr;fl~ 'n~-, ,sage range from lO mg daily to 1.75 gm
07
daily;
(j~) pyri~l~Y~m;n~ dihydrn-hlnr;~, dosage range from lO mg
daily to 1.75 gm daily; and
(k~ ) pyri-ln~m;n~ rhnqrh:~t~, dosage range from lO mg daily to
1.75 gm daily.
~he fnllno~ing illustrate qpecific f~ lAt;nnq according to
the present invention.
4-amino-2-llyd~Ay~yl 1nh ~ ylic acid l gm
2-~ - hyl-4-tert-butyl-6-propionylphenol 1.5 gm
pyridoxine ~ICl 200 mg
p-,-;nnh~n7nic acid, potassium salt 20 gm
ebselen 20 gm
~ carprofen l gm
i`,
3, 5-~: nnh~n7n; ~ acid 5 gm
butylated llyd~Ayallisole 20 mg
~ h:lqnne~ acetate - 5 mg
13xample 11
Clinical treatment of carpel tunnel syndrome and other
cumulative trauma digorders can be improved by use of a com-
po3ition comprising from about 1 gm to aoout 20 gm of at least
one primary therapeutic agent compri3ing a primary amine
benzoic acid derivative having a -~ n~ r weight of from
about 100 to ahout 1,400 Daltong, and nrt-;nn~lly at least one
substance selected from those noted above in section (v)
through section (ix~, and a medicament recognized aG effective
to treat carpel tunnel syndrome and other cumulative trauma
disorders, such as, for example,
(a) diclofenac (Voltare~), dogage range from lO mg daily to
200 mg daily;
(b) ~`~ h:-qone acetate (Decadron~ , Merck ~ Co.), intra-
muscular and local soft tisgue injected dogage ranc-e from 0.1
mg daily to lO mg daily;
(c) hydrocortisone acetate (~y~ ,.le qllqrPnq; nn, Merck ~
Co. ), ; l ~r or local soft tigsue injection dosage
range from l mg daily to 400 mg daily;
~ ~1 qO ~ 07
77
(d) methylpr~qn;qQlnn~ acetate (Depo-~edrol, Up~ohn), intra-
muscular or local soft tissue do9age range from 0.5 mg daily
to SC mg daily, or weekLy dosage of from 20 mg to 120 mg;
(e) vitamin B~ (pyridoxine HCl), dosage range irom 10 mg
daily to l . 75 gm daily;
(f~ pyridoxal, dosage range from 10 mg daily to 1.75 gm
daily;
(g) pyridoxal HCl, dosage range from lO mg daily to 1.75 gm
daily;
lh) pyridoxal 5-phnqrhAte, dosage range from 10 mg daily to
1.75 gm daily;
(i) pyridoxal 5-rhncrhAte calcium salt, dosage range from 10
mg daily to 1.75 gm daily;
(~) pyr;~ in~, dosage range from 10 mg daily to 1.75 gm
daily;
(k) pyr;5 'n~ dihydrorhlnn;~ dosage range from 10 mg
daily to 1.75 gm daily; and
(1) pyril' 'n~ rhn~qrhAt~, dogage range from 10 mg daily to
l . 75 gm daily.
The fnlln~.~in~ qt~Ate specific r lAt;nnq according to
the present invention.
4-~mino-2- (methoxy) cy~ h~ ylic acid I gm
2- (2-hydroxy-4-methylphenyl) aminothiazole ~}Cl loO mg
pyridoxal s-rh~ hAt~ calcium salt 50 mg
p-A~nnrh~nylacetic acid, rntA~q; salt 20 gm
d-~-tocopheryl succinate 3,000 I.IJ.
diclofenac 200 mg
4-amino-2-methylbenzoic acid, pot ~eq; salt 5 gm
N,N'-diphenyl-p-phenyl-~n~ n" lO gm
hydrocortisone acetate lOo mg
Example 12
Clinical treatment of chronic discoid or systemic lupus
erythematosus can be improved by use of a composition compri3-
ing from about 1 gm to about 20 gm of at leagt one primary
th"~:3re~t;c agent comprising a primary amine benzoic acid
~f9ai~7
78
derivative having a ~nnl~-r~ r weight of from about 100 to
about 1,400 Daltons, and npt~nn~lly at least one substance
selected from those noted above in section (v) through section
~ix~, and a a~l recog-nized as effective to treat
chronic discoid or systemic lUpug erytl '~ q~ such as, for
example,
(a) l~ydL ~Ay~llloroquine ( Plaslucnil, Sanof i Winthrop Pharmaceu-
ticals), dosage range from 50 mg (er~uivalent to 39 mg base)
daily to 400 mg (eriuivalent to 310 mg base) daily;
(b) rl.-;n~rrin,~, dosage range rom 10 mg daily to 200 mg
daily;
(c) chlororiuine~ dosage range from 50 mg daily to ~50 mg
daily;
(d) ~ inf., dogage range from 10 mg daily to 50D mg
daily;
(e) triquine composition tablets (each tahlet r~n~;Qt;n~ of
25 mg rlll;nslrr~n~, 65 mg chloroquine and 50 mg
l1Yd~lAY~I~10rOriUine), dosage range from one rluarter tablet
daily to two tablets daily;
(f ) lS--d~vAy~c~yu~lin~ iu~Lc~ s ~; 1 Qr, subcuta--
neous or oral dosage range from 0 . 5 mg/kg daily to 10 mglkg
daily;
(g) ,~ h~ ~n~ (Decadron, Merck & Co. ), dosage range from
o . 25 mg daily to 18 mg daily;
(h) lPfl ~, dosage range from 50 ~g daily to 50 mg
daily;
(i) cyrlrQpnr;n A, dosage range _rom 0.1 mg daily to 100 mg
daily;
(j~ methylprP~lni ~ n.o (~edrol, ~p~ohn~, dosage range from 1
mg daily to 250 mg daily, or alternate day dosingi
(k~ n~;r acid (or commercial products rnnt: ;n;n~
this Q-lhqt:lnr~ as the active inr,redient, ;nrll1~9inrJ ~aAl~P~
capsules, 18 gm of which contain3 3.2 gm ~;r~ rf~nt:l~n~ir
acid~, dosage range f~rom 500 mg daily to 10 gm daily.
(1) Ilyl~ Lisone (~u V~Lu~i~, Merck & Co.), dosage range
from 1 mg daily to 400 mg daily;
(m) pr.o~n;Q~lnn~ (Pediapred, Figons), dosage range from 1 mg
daily or every other day to 250 mg daily;
(n) cortisone (Cortone, Merck & Co. ), dosage range from s mg
-
2190107
79
d~ily to 400 mg daily;
(o) prednisone (Delta80ne, Upiohn), dosage range from 1 mg
daily to 250 mg daily, or Altr~rnAte day dosing;
(p~ methylpr~ln; n1^n~ acetate (Depo-Medrol, Upjohn), intra-
synovial, intrAlrqir~n=l or; 1Ar dogage range from 0.5
mg daily to 50 mg daily, or weekly dosage of from 20 mg to 120
mg;
(q) tri nnlnnr~ (Arigtocort, Fu~isawa~, doGage range from
l mg daily to 200 mg daily, or AltrrnAtr~ day do8ing;
(r~ tri, nnlnn" ~A ~-t=tr. (Arigtocort sllcrrn~;nn~, Fuji-
sawa~ L lAr, intragynovial or lntr~lra;nn~l dosage
range from l mg daily to 200 mg daily, or alternate day
dosing;
(8~ -hA~nnr~ (Decadron rhrlcrhAte injection, Merck &
Co.~ Ll 1=r, i~L~ 9 or intrAl~;^n~l dosage range
from 0.1 mg daily to 10 mg daily;
(t~ cortisone (Cortone s ~rr~n;nn, Merck & Co.), intramus-
cular dosage range from 5 mg daily to 400 mg daily;
(u) I-y l,, vL~isone (~y lLv~v~ rhnqrh~tr inj~ction, Merck
& Co. ~ l =r, i~L~ vu8 or ~ ,r, ,~ dosage
range from 1 mg daily to 400 mg daily;
(v) I.ylLv.vL~isone (HYVLV.VLLVLI~ acetate ~-Rprnc;~n~ Merck &
~o.), intra-articular, ;ntrAlrq;nnAl or soft tissue in~ection
dosage range from 1 mg daily to 400 mg daily;
~w) pr~n;<nl^nr~ (Hydeltrasol injection, Merck & Co.), intra-
venous, il~l lAr, intra-articular, intrAlrc;nn=l and soft
tissue dosage range from 1 mg daily to 100 mg daily;
(x) trl nnlnnr~ tnn; 1~. (Arigtocort A topical cream, Fu-
~isawa), dosage range of from one to four applications per day
to affected skin areas;
(y) fl~nr1nnl~nr. Rf-~tnn1-lr~ (Synalar-HPcream, Syntex), dosage
rzmge of from one to four Arrl;r=tinnr per day to affected
skin areas;
(z) ~ nr-irnnirlr. (L.~dex gel, Syntex), dogage range of from
one to four rrl;r=t;nn~ per day to affected skin areas;
(a~ ) fluLG~ L~.~olide 0 05% cream, lotion or ointment, dosage
range of from one to four =rrl;.~t;ons per day to affected
skin areas;
(b ) bet h=c~nr. valerate (Betatrex ointment, Savage ~abor-
21qOlQ7
ao
atories), dosage range of from one to four applications per
day to affected skin areas;
(c' ) h~.t~ h~nn~ 17, al-dipropionate (L7iprolene, Schering),
dosage range o~ from one to three applications per day;
(d') aspirin, dosage range from 300 mg daily to 6.5 gm daily;
(e') ~th;nrl-ine (lmuran, Burroughs Wellcome), dosage range
from 0 .1 mg/kg daily to 2 . 5 mg/kg daily; and
(f') cyt~ L~h~ , dosage range from 0.1 mg/kg daily to 5
mg/kg daily .
'rhe following illustrate specific f. l~t;nnq according to
the present invention.
3, 5~ nnh~n~nir acid 1 gm
(~) -c~-l ouu~.h~ul acetate 500 I.U.
I~l~u~y~:l.loroquine 50 mg
p_~ n~rl~nylacetic acid ao gm
mixed tocopherols 3, 500 I .U.
15-Gc~,~y~e~u~lin 500 mg
4_g~-~n;-l;nnh~n7n;-~ acid, rnt~; salt 5 gm
coenzyme Q 200 mg
Cy'`l '7~ 150 mg
Example 13
Clinical treatment of ~ nn;nqic due to ;nh~ t;nn of
asbestos particles (asbestosis), inh~ t;nn of stone dust or
o,uartz (silic-osis) or ;nh~ t~m of other causitiYe agents
such as graphite, coal dust, particles produced by metal
grinding, talc or corn dust can he improved hy use of a
composition comprising from about 1 gm to about 20 gm of at
least one primary therapeutic agent compriging a primary amine
benzoic acid derivative having a molecular weight of from
about 1oo to about 1,400 Daltong, and optionally at 3east one
substance selected from thoge noted above in section (v)
through section (ix), and a medicament re~n3n;~fl as effective
to treat 1 ; ns; ~ due to; nhJ~ t; nn of asbestos parti-
cles (asbestosis), ;nh~ t;nrl of stone dust or quartz (silico-
sis) or ;nh~l~t;nn of other causitive agentg guch as graphite,
2~90107
81
coal dust, particles produced by metal grinding, talc or corn
dust, such as, for example,
(a) D-r~n;~ill n,. (~-rlrrim;n~ Merck & Co.), dosage range
from 2S mg daily to 1. 5 om daily;
(b) 4H-4-phenylthieno- [3,2-c] - [1~ -L~ ~yLo~l-2-carboxylic
acid, dosage range from O.S mg/kg daily to 50 mg/kg daily;
(c) 48-2 -~_O.L~ '~n_4-phenylthieno- [3,2-c~ - [13 -L~IZ~YL~
dosage range from 0 . 5 mg/kg daily to 50 mg/kg daily;
(d) N-acetylcysteine, dosage range from 10 mg/kg daily to 150
mg/kg daily;
le) ~' hA~nn~ (Decadron, Merck & Co. ), dosage range from
0.2S mg d~ily to 18 mg daily;
(f) i hArin (~ndocin~, dogage range from 2S mg daily to
2S0 mg daily;
(g) pr~n;~nlnn~. (Ped~apred, Figons), dosage range from 1 mg
daily or every other day to 2S0 mg daily;
(h) lly.lL~_vLLisone (8ydL~u~ e, Merck & Co.), dosage range
from 1 mg daily to 400 mg daily;
ydLI~uLLisone (8yd~ J~v LVL~C phosphate injection, Merck
& Co . ), i l Ar, illLL.~ ,... or s~lh~lltAn~oll~ dosage
range from 1 mg daily to 400 mg daily;
(j) flurbiprofen (~nsaid), dosage range from sO mg daily to
S00 mg daily;
(k) S-._.,LL.,~, hylcysteine~ dosage range from 1 mg/kg daily
to loO mg/kg daily; and
(1) ' h~ nn~ (Decadron ph~.~rhAte injection, Merck &
Co.),; lAr, illLL'.~ or ;ntrAlf-~innA1 dosage range
from 0.1 mg daily to 10 mg daily.
rhe following illustrate specific f~ tinn~ according to
the present invention.
3,S-~iAminnrh~nylacetic acld 1 gm
butylated l~ydLv~y~llisole 10 mg
N-acetylcysteine Soo mg
p_~innh~.n7ni c aoid 20 gm
2-ominomethyl-4- tert-butyl-6-propionylphenol 20 gm
pr~ n;~nl~n~ 100 mg
21901~7
82
4-amino-2-methoxycyrl nhoyAnoo=rhnyylic acid 5 gm
tert-butylhydroquinone 500 mg
D-ponsr~ls 'nf. 100 mg
Example 14
`; Clinical LLI of chronic obstructive pulmonary
disease can be improved by use of a composition comprising
from about 1 gm to about 20 gm of at least one primary
therapeutic agent compri3ing a primary amine benzoic acid
derivative having a ~ l Ar weight of from about 100 to
slbout 1,400 Daltons, and nrt;nnA-ly at leagt one ~;llhqtRnr~
selected from those noted above in section (v) through section
~ix1, and a I '5~ rocn~s~ as effective to treat
chronic obstructive r--l y diseaser such as, for example,
(a) D-roni~ 'n~ (C~primine, Merck & Co.), do3age range
from 25 mg daily to 1. 5 gm daily;
(b) 4H-4-phenylthieno- [3,2-c] - [1] -~ u5~JyLeul-2-carboxylic
acid, dosage rAnge from 0.5 mg/kg daily to 50 mg/kg daily;
(c) 4N-2-~ ' ~Sn_4-phenylthieno- [3,2-c] - [1] -b .L UI!y~
dosage ra~ge from o.5 mg/kg daily to 50 mg/kg daily;
(d) ~T-acetylcysteine, dosage range from 10 mg/kg daily to 150
mg/kg daily;
(e) .' hAann~ ~Decadron, Merck & Co. ~, dosage range from
0.25 mg daily to 18 mg daily;
(f~ indomethacin (Tndoci~), dosage range from 25 mg daily to
250 mg daily;
(g) pr~niqnlnn~. (Pediapred, Figons), dosage range from l_mg
daily or every other day to 2S0 mg daily;
(h) hydrocortisone ~HYdL~ one, Merck & Co.~, dosage range
from 1 mg daily to 400 mg daily;
(i~ hydrocortisone ~Hyd~ v~_ rhncrhAto injection, Merck
& Co. ~ _ 1 Ar~ ~vGIluug or s~lhcl~tAnon~ q dosage
range from 1 mg daily to 400 mg daily;
~ j ~ flurbiprofen ~ aid~, dosage range from sO mg daily to
500 mg daily;
(k~ S-caLI,w.~., hylcysteine, dosage range from 1 mg/kg daily
to loo mg/kg daily;
hAqnn~ (Decadron rhnqrhAte injection, Merck &
Co,), S lAr, illLL~ )u8 or SntrAl~qinnAl dosage range
2~9~
83
from 0.1 mg daily to 10 mg daily;
(m~ prednisone (Delta~one, Upjohn~, dosage ra~ge from 1 mg
daily to 250 mg daily, or alternate day dosing;
(n~ methylpre~ln;cnlnn~ edrol, Up~ohn~, dosage range from 1
mg daily to 250 mg daily, or Al t~ rnAte day dosing; and
(o) methylpr~lnicnlnn~ (Solu ~edrol, Up~ohn), i~lLL~ U~ or
iLLL lAr dosage range from 0.25 mg/kg daily to 3 mg/kg
daily .
~he following illustrate specific f~ lAt;nnq according to
the present invention.
4-amino-2-methylphenylacetic acid 1 gm
N-~cetylcysteine soo m3
~-2- ~n-4-phenylthieno- [3,2-c] - [1] -L~ yLall 25 mg
p nnh .n~n;r acid, pntAnn;llm salt 20 gm
2 hyl_4- tert-butyl-6-in~qnrh~nnl 20 gm
flurbiprofen 500 mg
4-amino-2-meth~,~yL.,.lzoic acid, potassium salt 5 rJm
acetyl - L- rArn; t ~ n~ 1. 5 gm
methylpr~in;qnlnn,. 50 mg
Example 15
Clinical LLC of ;nfl nry myopathies can be
lmproved by use of a composition cjnJr from about 1 gm to
about 20 gm of at least one primary therapeutic agent
q;nJr a primary amine benzoic acid derivative having a
molecular weight of from about 100 to about 1,400 Daltons, and
nrt;nnAlly at leagt one g~hctAnre selected from those uoted
above in section (v) through section (ix~, and a ; ~
r.~n,rn;7c~-1 as effective to treat infl; tnry myopathies
disease, such as, for example,
(a) prednisone (Deltacone, Upjohn~, dogar1e r~nqe from 1 mg
daily to 250 mg daily, or Al ~ rnAtP day dosing;
(b) methotrexate (~ ~, Lederle T,AhnrAtnries), dosage
range from 1 mg weekly to 20 mg weekly;
(c) methotrexate sodium (r~ethotrexate LPF, Lederle), intra-
muscular, illLL.~ 8, intra-arterial or ;ntr~th-~nAl dosage
~ , 07
84
range from 2.5 mg daily to 30 mg daily, or doses from S mg to
50 mg once or twice weekly;
~d) cy~ 1~ r --qF ,i~ toxan~ Bristol-Myers Oncology),
dosage range from 0.1 mg/kg daily to 5 mg/kg daily;
(e) cy~ L~ k- ir;P (~ytoxan for injection, Bristol-Myers
Oncology), dosage range from 0.1 mg/kg daily to 5 mg/kg daily,
2 mg/kg to 5 mg/kg twice weekly or 10 mg/kg to 15 mg/kg every
seven to ten days;
(f) rhl~ ' ~1 (Leukeran, Burroughs Wellcome), dosage range
from 0 . 5 mg daily to 10 mg daily; and
(g) ~7.th;~rrin~ (Imuran, Burroughg Wellcome), dosage range
from 0.1 mg/kg daily to 2.5 mg/kg daily;
(h) diazepam (Valium, i~oche Products), dosage range from Z mg
daily to 40 mg daily;
(i) diazepam (Valium injectable, 3~oche ProductG), dosage
r~ge from 2 mg daily to 40 mg daily; and
(j) diazepam (Valrelease, i~oche T~hor~rripa), do3age range
from S mg daily to 30 mg daily.
The following ;1111Qtr~rP specific ~l lAtirnQ according to
the present inYention.
4- (aminoguanidino) benzoic acid 1 gm
ehselen 250 mg
rrPrqn; Q~nP 1 mg
p-gl~n;~iinnhPn7~ir acid, Fot~Q; salt 20 gm
5-[~3,5-bis(l,1-dimethylethyl)-4-1~ y~l.~ yl~- _
methylene~ -3 - (dimethylamino) _4_~h; :, 7rll; ~ii nr~nP 7.5 om
Cy~l. r'--~F'- -~1P 500 ~g
4-amino-2-meth~yL~ oic acid, ro~cQ; salt 5 gm
acetyli y-.~eine ~h;~ n~ 750 mg
chl~. ' 1 5 mg
Example 16
Clinical Lr~ of infl~ ry neuropathies can be
improved by use of a compogition compri8ing from a~out 1 gm to
about 20 gm of at leagt one primary ~h.~r:-rP~ agent compris-
ing a primary amine benzoic acid derivative having a ~lP~ r
~iqO1~7
weight of from about 100 to aoout 1,400 I)altons, and option-
ally at least one fiuhstance selected from those noted ahove in
section (v~ through section (ix), anda I re~-~n17p-l
as effective to treat ;nfl -~ ry neuropathies disease, such
as, for example,
(a) cortisone (Cortone, Merck & Co.~, dosage range from 5 mg
daily to 400 mg daily;
(h~ prednisone (Deltasone, Upjohn~, dosage range from 1 mg
daily to 250 mg daily, or AltornAt~ day dosing;
(c~ methylpre~lnicolnn~ (~edrol, IJpjohn~, dosage range from 1
mg daily to 250 mg daily, or Al ~rnAt~. day dosing;
(d) methylpr~ n;co1~n.o acetate (Depo-~edrol, IJpjohn), intra-
synovial, ;ntr~l~qi~n-1 or i lAr dosage range from 0 5
mg daily to 50 mg daily, or weekly dosage of from 20 mg to 120
mg;
(e) tri nnl~n~. (Ar~stocort, Fu~isawa), dosage range from
1 mg daily to 200 mg daily, or Alt~rnAt~. day dosing;
(f) tr; n ~ ;A tAte (Aristocort q~lqrGnc; nq, Fu~i-
sawa), ; lAr, intrasynovial or intrAl~c;~nAl dosage
range from l mg daily to 200 mg daily, or alternate day
dosing;
(g~ h~-t hAn~n~ (Celeatone, Schering~, dosage range from
0 2 mg daily to 12 mg daily, or Al t~rnAte day dosing;
(h~ h~t hAqr~n~ (CelestoDe soluspan s~lcr~nci~n~ Schering~,
iULL c~-lllar or ;ntr~ qi~nAl dosage range from 0 1 mg daily
to 10 mg daily, or ~lt~.rn:-t~. day dosing;
hAcnnP (Decadron, Merck & Co ), dosage range from
o . 25 mg daily to 18 mg dailyi
(j) , h:~R~-n~ (Decadron rhnc}~hAte injection, Merck &
Co.~ Ar, intravenoug or ;ntrAl~c;--nAl dosage range
from o.1 mg daily to 10 mg daily;
(k~ cortisone (Cortone 8 ~cr nq; n, Merck & Co ~, intramus-
cular dosage range from 5 mg daily to 400 mg dailyi
yl~ )~u~Lisone (l~yd~u~u~ c, Merck & Co.), dosage range
from 1 mg daily to 400 mg daily;
(m) llylL~u~Lisone (}~yll~ul,u~ I.u~-~ rh~.CrhAte injection, Merck
& Co ~, ; l Ar, illL~ uus or 8 h(- -t; n~ c dosage
range from 1 mg daily to 400 mg daily;
(n~ pr~ln;c~ nf (~ydeltraso~ in~ection, Merck & Co ~, intra-
. ` 2~tO7
.
86
venous,; la~, intra-articular, intr~ ni~n~l and soft
tissue dosage range from 1 mg daily to 100 mg daily;
(o) pr~ni~rlnn~ (Pediapred, Fi80ns), dosage range from 1 mg
daily or every other day to 250 mg daily; and
~p~ ebselen, illL~ .uus, ~ , gl-h~ t~no~ or oral
dosage range from 5 mg/kg daily to 500 mg/kg daily.
~he following illustrate specific f- lAti~n~ according to
the present invention.
4-aminocyrl~h-~~.,,~.. l,.,.ylic acid 1 gm
d~ tocopheryl acetate 500 I.U.
prednisone 1 mg
p_ n~rh~nylacetic acid, p~t~i salt 20 gm
2, 6 -di - tert- butyl - 4 - [2 ' - thenoyl ] phenol 2 0 gm
hf.t: h:~ n~ 12 mg
4-amino-2-~,y~hu~yb~ uic acid S gm
L ' hir~nin~ 2 gm
hydLu~_u. ~isone 50 mg
Example 17
Clinical treatment of epilepsy can be improved by use of
a com-position compriGing from about 1 gm to about 20 gm of at
least one primary therapeutic agent comprising a primary amine
benzoic acid derivative having a molecular weight of from
about 100 to about 1,400 Daltons, and ~rt;~n~lly at least one
substance selected from those noted above in section (v)
through section (ix), and a, ~1, recognized as effective
to treat epilepsy, ~uch as, for example,
(a) ~ r;lrin~ ~v~ .1, Merck Sharp & Dohme), dosage
range from 0.1 ~g/kg daily to 10 mg~kg daily;
(b) phenytoin (Dilantin-125, Parke-Davis), dosage range from
50 mg daily to 625 mg daily;
(c) phenytoin-polyvinylpyrrolidone coprecipitate, dosage
range from 50 mg daily to 1 gm daily;
(d) phenytion in ~ nslt;~n with ~ .l.;tal (Dilantin
capsules, Parke-Davig), dogage range from 100 mg phenytoin
sodium and 16 mg ~ it:~1 daily to 600 mg phenytoin
~ 219(~07
87
sodium and 192 mg r'~ itAl daily;
(e) rh~.nnh:-rhit~l ~Lilly1, dosage range from 5 mg daily to
Zoo mg daily;
(f) primidone (Mysoline, Wyeth-Ayerst T,r~hor~tnri~c~, dosage
range from 25 mg daily to 1.75 gm daily;
(g) U~-LL ~ n~. (Tegretol, Basel~, dosage range from 50 mg
daily to 1. 2 gm daily;
(h) ethosuximide (Zarontin, Parke-Davis~, dosage range from
250 mg daily to 2 gm daily;
lnnr (Rlonopin, Roche Laboratories), dosage range
from 0 . s mg daily to 20 mg daily;
(j) valproic acid (Depakene, ~hhott T,=hnr~tnries), dosage
range from 1 mg/kg daily to 60 mg/kg daily~
(k) divalproex sodium (Depakote, ~hbott T,~ho~tnries), dosage
range ~rom 1 mg/kg daily to 60 mg/kg daily;
etR7nl~ Diamox, Lederle), dosage range from 50 mg
daily to 2 gm daily;
(m) acetr~7nlr~ sodium (Diamox, Lederle), ill~La~ JU:I
dosage range from 50 mg daily to 2 gm daily;
(n) predr,isone (Delta60ne, Upjohn), dosage range from 1 mg
daily to 250 mg daily, or alternate day dosing;
~o) corticotropin, il~L l::lr dogage range from 5 units
daily to 60 units daily;
(p) diazepam (Valium, Roche Products), dosage range from 2 mg
daily to 40 mg daily;
( I) diazepam (Valium injectahle, ~oche Products), dosage
range from 2 mg daily to 40 mg daily;
(r) ' (Ativan, Wyeth-~yerst Lahoratories),
illLL~v~ uus dosage range from 50 llg/kg daily to 300 ~g/kg
daily;
(8~ felhamate (I;elbstol, Wallace .rhnrAtnries~, intravenous,
c~ l:3r, cl~hrl t ~nf.mlq or oral dosage range from loo
g/kg daily to 2 mg/kg daily;
(t~ 7nni~ xce~Tran, nRinirpnn~ LL V~ us, intramus-
cular, suo l~tr~n~n~lq or oral dosage range from 100 llg/kg daily
to 2 mg/kg daily;
(u~ g~hrr~ntin (Neurontin, Warner-Lamoert~, dosage range from
100 ,ILg/kg daily to 2 mg/kg daily;
(v~ lamotrigine (Ls~ictgl, Burroughs Wellcome~, dosage range
. ~ 219~1~7
8~3
from 100 ~g/kg daily to 2 mg/kg daily; and
~w) vigabatrin (Saoril, Marlon Merrell Dow), dosage range
from lOo ~g/kg daily to 2 mg/kg daily.
'rhe following ;llll~t~-Ate specific ~, lAtinn~ according to
the present invention.
5-amino-2-llyd~ybe~ Jic acid 1 gm
d-o!-tocopheryl S~ r~ nA te 750 I . U
phenytoin 50 mg
p_, 'nnh~n7ni(~ acid 10 gm
ebselen 10 gm
~; ~ 7nri 1 ri n~ 500 mg
4_,,~i n~-rh~nylacetic acid 5 gm
proStA~7An~7in B~ nl ;5 ~ 7,5 om
primidone 1 gm
Example 1~3
Clinical treatment of Al 7h~i ' 5 disease can be improved
by use of a, , 't;on compri3ing from about l gm to about 20
gm of at least one primary therapeutic agent comprising a
primary amine benzoic acid derivative having a . l ~ r
weight of from about 100 to about 1,400 Daltons, and option-
ally at least one 8l h~tAnr~ selected from those noted above in
section (v) through section (ix), and a ';< ~ r~-n~7ni7~
as effective to treat ~17h..i '5 disease, such as, for
example,
(a) V:~an~i 1 Atnr or other nootropic direct brain metabolic
enhancer drugs such as
h~nnn~, dogage range from s mg/kg daily to 150 mg/kg daily;
propentophylline, in-~vel ~/u~,; f~ r~ 51lhrllt~n~nllc or
oral dosage range from 50 mg daily to 3 gm daily;
pentoxifylline, dosage range irom so mg daily to 3 gm daily;
citicoline, dosage range from 50 mg daily to 5 gm daily;
ebiratide, 8l1h~ tAn~ u8 dosage range from 3 llg/kg daily to 1
mg/kg daily;
v~nrn-F~tin~ (Cavin~on, Chemical Workg of Gedeon Richter,
Ltd.), i~L,.IVel~JU8,; 1 Ar~ ~llh~ t~n~ ororal dosage
21~0~7
range from 5 mgJkg daily to 300 mg/kg daily;
bromvincamine, dosage range from 25 mg daily to 3 gm daily;
cy~l 7n~ t~, aosage range from 25 mg daily to 3 gm daily;
.uyL_.~c, dosage range from 25 mg daily to 3 7m daily;
nafronyl, dosage range from 25 mg daily to 3 gm daily;
papaverine, dosage range from 25 mg daily to 3 gm daily;
sl~7n~-ti~17, dosage range from 25 mg daily to 3 gm daily;
vinh rn;n~, dosage range from 25 mg daily to 3 gm daily;
vincamine, dosage range from 25 mg daily to 3 gm daily;
vin~ hl1rnrl ~ dosage range from 25 mg daily to 3 gm daily;
naloxone, i~ veu~u~; ' cr~ r, ~lhr1~t~norus or oral~
dosage range from 5 mg daily to 300 mg daily;
ethyl 5-isopropyloyy-4-methyl-~-cArhcl ;n~-3-carhoxylate,
i~lL~ vell~u~ r, ~ r ...~: or oral dosage range
from 2 mg/kg daily to 100 mg/kg daily;
N' -methyl-,~1-r~hrl i~-3-r~rhnY~mi ~lo~ illL~v~u~us, intramus-
cular, ,q7~hc~t~nPo~lq or oral dosage range from 2 mg/kg daily to
1~0 mg~kg daily;
methyl ~,7-dimethoxy-4-ethyl-,~-carholine-3-carl~cylate, intra-
venous, in~ lAr, 5l~h~ n~rllc or oral dosage range from
o.1 mg/kg daily to 10 mg/kg daily;
ethyl 5-methoxy-4-ethyl-,~-r~-rh-l;n~-3-c;sr})oxylate, intraven-
OU8,; ~ r, 7,.1,..,1,."r~...._ or oral dosage range from 1
mg/kg daily to 30 mg/kg dailyi
ifenprodil tartrate, dogage range from o.S mg/kg daily to 120
mg/kg daily;
ri r:l -e~=m~ dogage range from l mg daily to 100 mg daily;
aniracetam, dosage range from 50 mg/kg daily to 1 gm/kg daily;
pyroglutamic acid, illL~ Jut~, i lAr, q~hr~t~n~r-l~q or
oral dosage range from 100 mg/kg daily to 5 gm/kg daily;
t ~n~ t ~m, do8age range ~rom 10 mg daily (or ~l t~n~t~ day)
to 1 gm daily (or alternate day), or from 25 mg once a week to
1 gm once a week;
pramiracetam, dosage range from 50 mg/kg daily to 3 gm/kg
daily;
~ r~rPtr-, dosage range from 200 mg daily to 2 gm daily;
rol7;r~r~tPm, illLL. ~ ,u:" illL~ r~ sllhr~t~n~r~-q or oral
dosage range from 1 mg daily to 1 gm dailyi
L r clvelllJus ~ illL~ r, c~hr--~t:3nl~r ~q or oral
2~9~1~7
dosage range rom 0 1 mg/kg daily to 25 mg/kg daily;
exi_one, i~L~lcLVellUU8,; ' crlllAr, ~.~1,.. 1,.1._.. or oral
dosage range from 1 mg daily to 1 gm daily;
rolipram, illL~ .lluu~ r, 8llhr~tAn~n~lR or oral
dosage range from 1 mg daily to l gm daily;
."-h~ 7~l ~, dogage range from 2 mg daily to 40 mg daily;
n;m~l;rin~ (Nlmotop, Miles phlrm-~ tir~l), dosage range from
300 mg daily to 3.6 gm daily;
flunarizine, dosage range from 2 mg daily to lO0 mg daily;
nicergoline ~SenDion), illLl~v~=~luu&~ i lar, gu_cuta-
neous or oral dosage range from 6 mg daily to lO gm daily;
phn~rh:~tiAylgerine, intravenous or oral dosage range from 1
mg/kg daily to 250 mg/kg daily;
~t;raret:~m~ dosage range from 50 mg/kg daily to 8 gm/kg daily;
dupracetam, ill~ C~UU~, ; 1 Rr, R~lhr~tAn~nlla or oral
dosage range from 1 mg daily to 1 g~n daily; and
ergoloidmesylates (Hydergine, SandozPharm~-e~lt;r~la), dosage
range from 0.5 mg daily to 40 mg daily;
(mh) I~l~u~r-~l aa;nn enhancer drugs ~uch as
-~;n~ (Synunetrel, Du Pont Multi-Source Products), dosage
range from 10 mg daily to 400 mg daily;
calcium hnp:~nt nat~ dosage range from 100 mg daily to 4 gm
daily;
lisuride, dosage range from 0.1 mg daily to 2 mg daily; and
;~.lGln~ ~7;~f-, dogage range from ~0 mg daily to 1.5 gm daily;
(c~ tiapride, dosage range from 1 mg daily to 400 mg daily;
(d) psyrhnthorAreutic drugs such as
haloperidol (Haldol, McNeil phArr---~.llt;rAl~, dosage range from
0.2 mg daily to 1rj mg daily;
r;r~nl, do8age range from 20 ~.Lg/kg daily to 0.25 mg/kg
daily;
thioridazine (l~ellaril, Sandoz PhAr---.o~t;cal~, dosage range
from 10 mg daily to 800 mg daily;
th;nth;~r~n~ (Navane, Roerig~, dosage range from 2 mg daily to
60 mg daily;
flllrhPnA7in~ (Prolixin, Ancth~cnn), dosage range from 0.2 mg
daily to 40 mg daily;
perrh~"A7in-~ in amitriptyline/perrh-~nA7inf. ~ :nAtinna
(~tra~on, Schering~, dosage range from 4 mg p~rrh~nA7;nF~ and
~19û~7
91
So mg amitriptyline daily to 16 mg per?h~nA7; n~ and lO0 mg
amitriptyline daily; and
molindone (~oban, Du Pont Multi-SourCe Products), dosage range
from 3 mg daily to 225 mg daily;
(e) acety1rhr1;n~qt-~rJ~e ;nh;h;trr~ such as
physostigmine (~nti7ir~ I.~ectaole, Fore8t P~ ;rllc),
oral dosage range from O.l mg daily to 20 mg daily, or
iU~Ll~ )U~I, iLl~L 1nr or g11hr11t~nPr~1c dosage range from
S ~Lg daily to 3 mg daily, npt;rn~lly with rhrc7?h:ltidylcholine
co-agent, oral dosage range from zero to lS gm daily;
heptylphysrct;; n", dosage range from l mg daily to 1 gm
daily;
taine (Cor~nex, Warner-LamLhert), dosage range from 5 mg daily
to 200 mg daily, rrt;rn~11y with rhr-~ph:lt;rlylcholine co-age~t,
dosage range from 2ero to 15 gm daily;
9-~mino-l~2~3~4-teLLll~dL~cridin-l-ol~ dosage range from
2 mg daily to 200 mg daily;
r;frn:ltP,; ~ular, illLLa~ ua, sl~hr~t~npr~us or oral
dosage range from o . l mg/kg daily to 125 mg/kg daily;
vf~1n~rr;n~ (~entane, Hoechgt-Rouggel), dosage range from lO mg
daily to 350 mg daily;
phenylmethylsulfonyl fluoride, iuLL,~ g, 5~hr~t:-n~.r,~c,
1 :-r or oral dogage range from 5 mg/kg daily to 60
mg/kg daily;
h:lnoc1~1 f~nyl fluoride, ill~La~ Ju~ L 1 ;Ir, su---
cutaneous or oral dosage range from 5 mg/kg daily to 350 mg/kg
daily;
hupersine A, intL 1i~r, ill-La~ u~ q~1hr1~t~n~ c or oral
dosage range from lO ~Lg/kg daily to 1 mg/kg daily;
h~1~/.r7;n~ !3,; 1~r~ LL~ U--, s~hr~1t:~nPrus or oral
dosage range from lO ~Lg/kg daily to l mg/kg daily;
edrophonium chloride (Hoffman LaRoche), ill~Lavell~ul~ intramus-
cular, s~hr11t~n~r1~q or oral dogage range from 2 mg daily to
400 mg daily;
rJ~ nth n , intravenous, illLL l ar, q~1hr1~t:7nf.rus or oral
dosage range from 5 mg daily to lO0 mg daily; and
miotine, intravenous, ill~L - 1 ~r, g~1hr~t:~n~ q or oral
dosage range from 2 mg daily to 400 mg daily;
(f) calcium channel hlocker agents such as
2 1 90 ? 07
92
t; A7pm ( Cardizem or Cardizem SR3, dosage range from 10 mg
daily to 360 mg daily;
v~ , l (Calan or Calan SR), dosage range from 10 mg daily
to 480 mg daily;
n~fP~;rinP (Procard~a~, dosage range from 3 mg daily to 180 mg
daily;
n;fP~q~rinP (Procardia XI,), dogage range from 3 mg daily to 90
mg daily;
nicardipine (Cardene), dosage range from 6 mg daily to 120 mg
daily;
;cr~ rinP (DynaClrc), dosage range from 0.5 mg daily to 20 mg
daily;
7O~irin~o INorvagc, Pfizer Labs Division), dosage range from
0.5 mg daily to 10 mg daily; and
f~ 'irinP (Plendil, Merck & Co.), do9age range from O.S mg
daily to 20 mg daily;
(g~ biogenic amines and ~llhctAnrPC related thereto such as
clonidine (Catapres, l~ phrin~pr Tn~PlhPim~, dosage range from
0 . 25 mg daily to 2 . 4 mg daily;
~nfA~-;n~ (Tellex, Robing), dogage range from 0.25 mg daily to
3 mg daily;
dlaproclate, dosage range from 0.25 mg daily to 3 mg daily;
fipexide, dosage range from 0.25 mg daily to 3 mg daily;
7~m~1A;n~., dogage range from 0.25 mg daily to 3 mg daily; and
citalopram, dosage range from 0 . 25 mg daily to 3 mg daily;
(h) antirage drugs such as
prr~rrAn~ (Inderal, Wyeth-Ayergt Laboratories), dosage range
from 30 mg daily to 640 mg daily;
- nP (l~egretol, Geigy), dosage range from 40 mg daily
to 1. 6 gm daily; and
fll~ns tinP (Prozac Pulvule8, Dista), dosage range from 20 mg
daily to 80 mg daily;
(i) minor trAnq- il;7Prs ~uch as bpn7nr;iA7pr;np agents
~ n ~ ; n ~
diazepam (Valium, Roche Products), dosage range from 0.5 mg
daily to 40 mg daily;
~ r~r. - ~ (Ativan, Wyeth-Ayerst r.Ah~rAt~ri PC), dosage range
from 0.5 mg daily to 10 mg daily;
prazepam (Centrax, Parke-Davis), dosage range from 5 mg daily
2~90i~7
93
to 60 mg daily;
rhlnr~iA7e~rrY;5-~ (Libritabs, Roche Products), dosage range
from 5 mg daily to 300 mg daily;
chlor~;a7.~rnYi-l"/r~ ;n; 'natlnn (Librax, Roche
Products), dosage range from 5 mg chlor5;~7~rnY~ and 2.S mg
rl;~in; daily to 20 mg chlor~ 70rnY;~ and lO mg rl1fl1nil--
daily;
chlor~ 7^rnYi~ /amitriptyline ~ n~t;nn (Limbitrol DS,
Roche Products), dosage range from 10 mg chlor~ 7.-rnYi~ and
25 mg daily to 60 mg chlor~ 7~rnY;~f~ and 150 mg amitriptyline
daily;
rh7n~;~7~rnY;~ at~r;f;~l e8trogen ;natinn (~enrium,
Roche Products), dosage range from 5 mg chlor~ 7~-rr,Y;5e~ and
0.2 mg esterified estrogen daily to 30 mg chlor~ rnY;~ and
1.2 mg "~It.,.-;f;~"l estrogen daily;
oY~azepam (Serax, Wyeth-~yerst), dosage range from 10 mg daily
to 120 mg daily; and
rlnr~7~.rat~ dipotassium (TranYene, Abbott Laboratories),
dosage range from 3 . 75 mg daily to 60 mg daily;
nJ;nt~nR;n converting enzyme ;nh;h;tnrs such as
captopril ( Capoten, S~r,~uibb), dosage range from s mg daily to
300 mg dailyi
captopril in n~t;nn with hydrochlornthi~7i~ (Capozide,
Sr~uibb), dosage range from 5 mg captopril and 3 mg
hydrochloro-thiazide daily to 150 mg captopril and so mg
hydrochlornthi ~7; ~o daily;
enalapril maleate ( Vasotec, Merck & Co . ), dosage range from
O.S mg daily to 100 mg daily;
enalaprilat, dosage range from 0.5 mg daily to lO0 mg daily;
enalapril maleate/hydrochloroth;a7;,7~ nAt;rn (Vaseretic!
Merck ~ Co~), dosage range from 2.5 mg enalapril maleate and
6.2S mg hydrochlorothiazide daily to 20 mg enalapril maleate
and S0 mg hydrochlorQth;~7;tl~ daily;
fosinopril (~onopril, Mead ~ohnson pharr~ t;cals), dosage
range from 2 mg daily to 60 mg daily;
lisinopril (Zestril, Stuart), dosage range from l mg daily to
~0 mg daily;
ramipril (Altace, Hoechst-Roussel), dosage range from O.S mg
daily to 1o mg daily;
-
2t qO1 07
94
epi-captopril, dosage range from 1 mg daily to 300 mg daily;
alacepril, doaage range from S mg daily to 300 mg daily;
quinapril, dosage range from O.S mg daily to 40 mg daily;
p~rinrl~rril, dosage range from 0.2 mg daily to 40 mg daily;
delapril, dosage range from 4 mg daily to 1.5 gm daily;
cilazapril, dosage range from 0.2 mg daily to 40 mg daily;
pivalopril, do6age range from 2 mg daily to 250 mg daily;
r-.nt;;.rr~l ~ dogage range from 1 mg daily to lS0 mg daily;
zofenopril, dosage raLge from l mg daily to lS0 mg daily; and
zofenoprilat, dosage range from 1 mg daily to lS0 mg daily;
(k~ cllhatAnr~.C which may enhance acetylcholine synthesis,
6torage or release 3uch as
rhnYrhAti~lylcholine~ dogage range from l gm daily to 15 gm
daily;
4-aminopyridine, illLL~ lUs, intL li~r, cl~hrlltAn~nllq or
oral dosage range from 0 . 25 mg/kg daily to 10 mg/kg daily;
3,4-diaminopyridine, illLLo,~ wus~ i - l;~r~ gllhrlltAnr~r~lc
or oral dwsage range from 50 ~Lg daily to 100 mg daily;
choline chloride, dosage range from S00 mg daily to 30 gm
daily; choline hitartrate, dosage range from soo mg daily to
30 gm daily;
h1f. lAn~, do8age range from 1 mg/kg daily to 1.2 gm/kg
daily;
vesamicol, dogage range from so ~lg/kg daily to 500 mg/kg
daily;
secoverine, dosage range from S0 ,~g/kg daily to 500 mg/kg
daily;
tetraphenylurea, dosage range from So llg/kg daily to 500 mg/kg
daily; and
nirrtin:~m;~l~., do8age range from 1 mg/kg daily to 500 mg/kg
daily;
tl) postsynaptic receptor agonists such as
arecoline, i~lLLclve:llu~ LL ~ lar, Qllhrllt=n~r-1c or oral
dosage range from 2 mg daily to 25 mg daily;
LI lne, illLL.lVel~U~, illLL l ~r, c lhrllt:~n-~rllc or oral
dosage range from 1 ~g/kg daily to 0.2 mg/kg daily;
ethyl nirF-rot:-te, il~LLClV~:L~JlU), illLL l~r, 511hrlltAnPrllY or
oral dosage range from 2 mg daily to 250 mg dailyi
herh~n~rhrl (r~r~rhn7inr~ Merck & Co.), dosage range from S mg
2~qo~0~
9s
daily to 200 mg daily; and
lev~ r~n;nY (acetyl-L-carnitine or Alcar, Sigma~Tau), dosage
range ~rom 500 mg daily to 5 gm daily;
(m~ rJ-nrJl ;nq;~f~ GM~ L~.Ivell~Jus, intramuscular or
511hr~1tYnf.nllq dosage range ~rom 20 mg daily to 200 mg daily;
~n) mixed cow brain ~Yn~1~nqi~7Yr (f~rnn~qci~7, Fidia Pharma-
ceutical, marketed i~ several rOllntri~a in Wester~ Europe,
50uth America and the Far EaEit), illLL~ us, ;nt l.qr or
.lhr~t~nf.n.-q do8age range from 20 mg daily to 200 mg per day;
(o) speciic mnn~m; n~ oxidase-A inhibitors 6uch as
mnrlnh~m;~ (Aurorix, Hoffmann-La Roche), dosage range from 50
mg daily to 600 mg daily;
(p) ~-methy1-D-aspartate rJl ~t -e receptor =nt:~nn; qt~ ad-
ministered orally, i--L ~d~_ ~uuEly, intramuscularly or Eubcuta-
neously such as
m;1ArPm;A-~, dogage range from 50 mg daily to Z.S gm daily;
trihexyphenidyl (~rtane, Lederle), do8age range ~rom 0.1 mg
daily to 20 mg daily;
ethopropazine (Paridol), dosage range from 10 mg daily to 400
mg daily;
procyclidine (l~emadrin~ 3urroughE Wellcome), dosage range from
1 mg daily to 40 mg daily;
di~ y-l~ 'n~ enadryl, Parke-Davis), dosage range from 5
mg daily to Z00 mg daily;
A;7nr~ l~;n~. (Neuros~ard, Merck Sharp & Dohme), dosage range
from 0.1 I~g/kg daily to 10 mg/kg daily;
~ Ain~ (s~mmetrel, Du Pont Multi-Source Products), dosage
range from 10 mg daily to 400 mg daily; and
;n~, doqage range from 10 mg daily to 400 mg daily;
(r~) nonsteroidal anti-; n Fl . I~ory agents such as those
r~rnrJn;7~A for treatment of ' -n;~ arthritis, including
~lurbiprofen (Ansaid, Upiohn), dosage range from 20 mg daily
to 300 mg daily;
aspirin (Arthritis Pain Pormula, Whitehall Laboratories),
dosage range from 250 mg aEpirin daily to 4 gm daily;
l~m;nl. ~A8acol, Procter & Gaml~le pl.~ ir~lq), dosage
range frrm 250 mg daily to Z.4 gm daily;
phenylh~ti37nn~ t~7nl ir~in, Geigy), dosage range from 30 mg
daily to 400 mg daily;
~ qO1~7
~ .
96
sulindac (Clinoril, Merck & Co), dosage range from 40 mg daily
to 400 mg daily;
D-penirlll~m;nP (~q~rr~minF, Merck & Co.), dosage range from 25
mg daily to 2 gm daily;
oxaprozin (Daypro, Searle~, do3age range from 25 mg daily to
2 gm dailyi
R~ lAt~ (Disalcid, 3M phRr~~ellt;r:~lR), dosage range from
~oo mg daily to 3 gm daily;
i~fl~n;c:~l (Dolobid, Merck & Co.), dosage range from 100 mg
daily to 1. 5 gm daily;
piroxicam (~eldene, Pfizer Lab3 Division~, dosage range from
2 mg daily to 20 mg daily;
in' th:~r;n (Indocin, Merck & Co ), dosage range from 10 mg
daily to 200 mg daily;
etodolac (Lodine, Wyeth-Ayerst Laboratories), do3age range
from lOo mg daily to 1 2 gm daily;
-lnf~ t/~ sodium (M~ 7 , Parke-Davis), dosage range
from 20 mg daily to 400 mg daily;
ibuprofen (~otrin, i7p~ohn), dosage range from 100 mg daily to
3.2 gm daily;
feprofen calcium (Nal~on, Dista1, dosage range from 100 mg
daily to 3 2 gm;
naproxen sodium (Anaprox, Syntex), dosage range from 50 mg
. daily to 1. 65 gm daily;
naproxen (Naprosyn, Syntex), dosage range rom so mg daily to
1.5 gm daily;
3cetoprofen (Orudis, Wyeth-Ayerst), dosage range from 15 mg
daily to 300 mg daily;
mefenamic acid (Ponstel, Parke-Davig), dosage range from 150
mg daily to 1.5 gm daily;
n~ nnf. (Relafeu, "-ithYl;nl~ 3eecham), dosage range from
100 mg daily to 2 gm daily;
~1rJ~nnf;n ~R~daura, Smith~line Peecham), dosage range from 1
mg daily to 9 mg daily;
tolmetin sodium (~olectin, McNeil Pl.~iL,.,~.euLical), dosage
range from 100 mg daily to 1 8 gm daiiy;
ketorolac L h--;nl~ ~Toradol, Syntex Laboratories), dosage
range from 4 mg daily to 40 mg daily;
diclofenac sodium ~Voltaren, Geigy), dogage range from 10 mg
2~ Q~
97
daily to 200 mg daily; and
deferoxamine mesylate (Desferal, CIBA ph~ tir~l), intra-
venous, illLL qr~ r or 51lhrl~tAn~'r,l-R do3age range from 100 mg
daily to 2 gm daily;
(r) s~ rJil;n~ (Eldepryl, Somerset~, dosage range from 5 mg
daily to 10 mg daily;
(5) thiamine, dosage range from 500 mg daily to 3 gm daily;
(t) anfacine, il~ , sllhrl~t~n-~rllc or
oral dosage range from l mg/kg daily to 350 mg/kg daily;
(U) S17lhlltiAm;n~o (Arcalion, Laboratories Servier~, dosage
range from 1 mg/kg daily to 350 mg/kg daily;
(v) anti-oxidant agents which may be used in, ' n~tirn such
as
ascorbic acid, dosage range from 1 mg daily to 60 mg daily;
~Y-tocopherol, dosage range from 100 I. IJ. daily to 3,500 I. U.
daily;
~-acetylcysteine, dosage range from 100 mg daily to 1 gm
daily;
~3-carotene, dosage range from 20 mg daily to 300 mg daily;
F~n;r;ll n~., dosage range from 25 mg daily to 2 gm daily;
cysteamine, dosage range from 200 mg daily to 4 gm daily;
fll.fl 'n~. mesylate (Desferal, CIBA ph~ -el~t;r~l ~, intra-
venoug, i~ r or 5l~hrllt:~n~mlc dosage range from 100 mg
daily to 2 gm daily; and
ebselen, dosage range from 5 mg/kg daily to 1 gm/kg daily;
(w~ specific m~ m;nl~ oxidase-13 inhibitors such as
1:~7:-h~m;tl~. (Hoffmann-La Roche), dosage range rom 10 mg daily
to 200 mg daily;
(x~ linopirdine (Aviva, DuPont Merck~, dosage range from l mg
daily ~o 500 mg daily;
(y) D-cyrlrc~in-~, dosage range ~rom 0.1 mg/kg daily to 15
mg/kg daily;
(z) serotonergic receptor nnt~rJnn;ctq such as
ketanfierin (~etan, Janssen Pharm--~--t;~ , illL~ s~ intra-
muscular, L..hr--t~n~r--c or oral dosage range from o.1 mg/kg
daily to 20 mg/kg daily; and
mianserin (~ian, Organon Tnt-~rnnt;rn~ , intravenous, intra-
muscular, subr11tslnf~r-1c or oral dogage range from 0.1 mg/kg
daily to 20 mg/kg daily; and
. ~ 2~9Q107
98
(a~ ) estrogen, dosage range from 0 .2 mg daily to 1.2 mg daily.
The fnll~oinrJ illllctrAte specific fl l~tinnc according to
the present invention.
trans-4-aminocyrl nhrY:~n~_
carboxylic acid l gm
d-~Y-tocopherol 500 I.U.
N~-methyl-~B-r:~rhnlinr-3-r~rhnln~mirl~ 200 mg
p, -; nnh~.n7ni r acid, potassium salt 15 gm
2- (2-hydroxy-4-methylphenyl) -
'nnthiA7nl-~ hydrochloride 4 gm
l;l.~h~m;A~. 200 mg
4_~1l:~n;~i;nrrh~nylacetic acid 5 gm
tert-butylhydror,uinone 500 mg
dizocilpine 100 mg
Example 19
Clinical ~L~ ' ' of myasthenia gravis can be improved
by use of a composition comprising from about 1 gm to about 20
gm of at least one primary th~r~r~tlr agent comprising a
primary amine benzoic acid derivative having a ~ rl-l Ar
weight of from about lO0 to about 1,400 Daltons, and option-
ally at least one .~L~ selected from those noted above in
section (v~ through section (ix~, and a ' t recognized
as effective to treat myasthenia gravis, such as, for example,
(a~ prednisone (Deltasone, Upjohn~, dosage range from 1 mg
daily to 250 mg daily, or alternate day dosing;
(b~ th;nrrine (lmuran, ~urroughs Wellcome), dosage range
from 0.1 mg/kg daily to 2.5 mg/kg daily;
(c) pyridostigmine (l~estinon, IC~), dosage range from 100 mg
daily to 1. S gm daily;
(d) pyr;~nct;S n~ estinon injectable, ICN), illLL l~r
or slow intravenous dosage range fro,m 100 mg daily to 1. s gm
daily;
(d) neostigmine bromide (Prostig~1ir, ICN~, dosage range from
s mg daily to 375 mg daily;
(e) neostigmine methylsulfate (Progti~min injectable, ICN~,
~ 07
99
ill~L R.~ r or s~lh~llt=n~ dosage range from 0.5 mg daily
to 10 mg daily;
(f~ atropine, dosage range from 0.2 mg daily to 2 mg daily;
(g) p~r~nth~l in~ (Pro-Banthine, Schiapparelli Searle),
dosage range from 15 mg daily to 7~ mg dally; and
(h) ~rh~ ;n~-, dosage range from 10 mg daily to 100 mg daily.
The fnll~in~ ctr:~te specific ~ t;ons according to
the present invention.
4-amino-2-methylbenzoic acid 1 gm
mixed tocopherols 500 I.U.
pyrj~ ti,D n~. 100 mg
4-amino-2-methw~y~d~vic acid, potassium salt 15 gm
D-myo-inositol-1.2.6-tr;~rhn~rh~te 20 gm
~,~rh;nr~ine 150 mg
4-(:Im;nt~ n;~;nn)phenylacetic acid 5 gm
deferoxamine meaylate 200 mg
rrnr~nth~l ;n~ 25 mg
E~cample 20
Clinical L,~ of multiple sclerosis can be improved
by u5e of a composition , '~;n~ from about 1 gm to about 20
gm of at least one primary th~r~r~ t;~ agent comprising a
primary amine benzoic acid derivative having a mnl ~
weight of from about 100 to about 1,400 Daltons, and option-
ally at least one sub-stance 3elected from those noted above
in section ~v) through section (ix), and a l recog-
nized as effective to treat multiple sclerosis, such as, for
example,
(a) 15-deoxyspergualin, illL~ u~" i l Ar, subcuta-
neous or oral dosage range from 0 . 5 mg/kg daily to 10 mg/kg
daily;
(b) l f~fl de, dosage range from ~0 ~Lg daily to 50 mg
daily;
(c) methylpr~rln;~nln~ edrol, Upjohn~, dosage range from 1
mg daily to 250 mg daily, or ~1 t~rn~t~ day dosing;
(d) prednisone (Delt~sone, Upjohn), dogage rang~ from 1 mg
~ 90 1 ~
100
daily to 250 mg daily, or alternate day dosing;
te) dexamethaaone ~Decadron, Merck & Co. ), dosage range from
0.1 mg daily or every other day to 10 mg daily or every other
day;
(f) corticotropin (Depo-ACTf~, up~ohn), il-~L.~ lVU8, intramuD-
cular or E1~hrl1t~nPr~1- dosage range from from 10 unit3 daily to
150 units dailyi
(g) cyclosporin A (,r~_n~li , Sandoz Ph~rr--P~t;r ~ dosage
range from 1 mg/kg daily to 15 mg/kg daily;
(h) ~;nP (sy~ etrell Du Pont Multi-Source Products),
dosage range from 10 mg daily to ~00 mg daily;
(i) dia2epam (Valiun7, Roche Products), dosage range from 0.5
mg daily to 40 mg dailyi
(j) rlrnr-~, (Rlonopin, Roche Laboratories), dosage range
from 0 . 5 mg daily to 20 mg daily;
(k) ~ ' , nP (l~eyretol, C,eigy), dosage range from 40 mg
daily to 1. 6 gm daily;
phenytoin (Dilantin-lZ5, Parke-DaviG), dosage range from
50 mg daily to 625 mg daily;
(m) iqrn;_7;cl (I~ ~crnir7~ CI!3A), dosage range from 10 mg
daily to 300 mg daily;
(n) primidone (r~ysoline, Wyeth-Ayerst La~oratories), dosage
range from 25 mg daily to 1.75 gm daily;
(o) propranolol (Inderal, Wyeth-Ayerst Laboratories), dosage
range from 30 mg daily to 640 mg daily;
(p) amitriptyline (Elavil, Stuart), dosage range from 50 mg
daily to 300 mg daily;
(q) oxybutynin (Ditropan, Marion Merrell Dow), dosage range
from 2.5 mg daily to 20 mg daily;
(r) prrr~nthP1;nP (Pro-Eanthine, qrh;~rrArelli Searle),
dosage range from 2.5 mg daily to 7S mg dailyi
(8) imipramine, dosage range from 2 mg daily to lS0 mg daily;
(t) r_rh~rhrl, dosage range from 50 ~Lg/kg daily to S mg/kg
daily;
(u) heth~nPrhrl (Urecholine, Merck & Co.), dosage range from
5 mg daily to 200 mg daily;
(v) phen~,Ay' 'nP (Dihen2yline, SmithKline Beecham),
dosage range from 5 mg daily to 150 mg dailyi
(W) t~7~n~ nP, do8age range from S0 ~g/kg daily to S mg/kg
.
~1 9~~ 07
101
daily;
(X) Chlu-}JLI ~ n~. (rhnr~ , SmithKline Beecham), dosage
range from 10 mg daily to 200 mg daily;
(y~ baclofen (Atrofen, Athena Neuroqri ~nr~q~, dosage range
from 1 mg daily to 80 mg daily;
(z~ diacetylrhein, dosage range from 10 mg daily to 500 mg
daily;
(a ~ alfa-2a interferon (l~oferon-A, Roche Laboratories~, in-
~La~.luu ~, i lAr or c1lhrl-tAn,~nug dosage range from
300,000 IU daily to 3Ç,000,000 IU daily;
(b~ ~ alfa-2b interferon (Intron-A, Schering~ LLavell~us,
iU~L 1 ~r or q-lh ~l.tAnf.rllq dosage range from 300, 000 IU
daily to 5, 000, 000 IU daily;
(c ~ alfa-N3 interferon (Alferon N Injectfon, Purdue
Frederick~, ill-La-_.lvU~, illL. lAr or ,qllhcl tAn~n~q dosage
range from 250,000 IU daily to 2,500,000 I~J daily;
(d~ ) beta interferon (Betaseron, ~3erlex), i~lLLa~c~luus~ intra-
muscular or 8--hr--tAn~r~q dosage range from 5, 000 U/kg daily to
50, ooo U/kg daily;
(e~) galmna-lbinterferon (,~f't; -, (~.nF.nt~rh), illLLo-_.luu~,
iuLL :lr or ~ q dosage range from 5, 000 U/kg
daily to 50, o00 U/kg daily;
(f ) copolymer-l (random polymer of L-alanine, L-glutamic
~cid, L - lys ine and L - tyros ine, ratio o f 6 . o :1. 9: 4 . 7 :1. 0, o f
molecular weight between 14,000 and 23,000 Daltons), intra-
venous, q~lhr~tAn~r~q or illLL l_ular dosage range 2 mg daily
to 40 mg daily;
(g~) 4-aminopyridine, illLL .~uu~ lAr, 8..hr--tAn,.r,..q
or oral dosage range from 0.25 mg/kg daily to 10 mg/kg daily;
(h~) 3,4-diaminopyridine, dosage rar~ge from 50 I:Lg daily to 100
mg daily;
(i~) cyrlnrhrqrh~ (Cytoxan, Bristol-Myerg Oncology), dos-
age range from 0.1 mg/kg daily to 5 mg/kg daily;
(j ) cyrlrrhr~ lo (Cytoxan for injection, ;3ristol-Myers
Oncology), illLLa-_.luus, illLL ~ lAr or q~hr~tAn~r~q dosage
range from o.1 mg/kg daily to 5 mg/kg daily, 2 mg/kg to 5
mg/kg twice weekly or 10 mg/kg to 15 mg/kg every seven to ten
day3;
(k~ pr~ niqn1rn,o (Pediapred, Fisons), do8age range from 1 mg
77-~1 07
102
daily or every other day to 250 mg daily;
(l ~ methylpr-~n; e~ l -n-~ acetate (Depo-Q~edrol, Upjohn~, intra-
synovial, intrale~ional or; lAr dosage range from 0.5
mg daily to 50 mg daily, or weekly dosage of ~rom 20 mg to 120
mg;
(m ) tri: n~1~n~ (Ar{8tocort, Fu~igawa~, dosage rangc from
1 mg daily to 200 mg daily, or ~1t.~rn~t~ day dosing;
(n~ tri: nr:l~n~ A~Ar~.t~t~ (Ar~stocort ~-1ep~.ne;~nl2, Fujisa-
wa~ lLL lAr, i.,LLO.Oy,..,vial or ;ntra1~ n~l dosage
rAnge from 1 mg daily to 200 mg daily, or alternate day
dosing;
(o ~ methylpr~inia~ 1nnl~ (Solu ~edrol, ~piohn), i - 1~r
or illLL~ lo ---~nt~.n~nre dosage range from 0.25 mg/kg daily
to 3 mg/kg dailyi
(p ~ R~th~lrrine (Imura.n, R1lrro~t~h~ Wellcome~, dosage range
from 5 mg daily to 300 mg daily; and
(q ~ bovine myelin, dosage range from 2S mg daily to l gm
daily .
The _ollowing illustrate specific f~LI 1i t~one according to
the present invention.
n; l~n~_2-methylbenzoiC acid 1 gm
prost~ nrl;n Bl oligomers 300 mg
diacetylrhein lO mg
4-amino-2-l,ydLv~ybe~ uic acid 20 gm
N, N -dimethylthiourea 5 gm
baclo~en 80 mg
4-(~-;n~ ni~in~-2-met}l~y~lle.lylacetic acid S gm
N,N -diphenyl-p-phenyll~nP~ ni- 10 gm
c~ine soo mg
Example 21
Clinical treatment of ;nfl: ~ry site edema can be
improved by use o a ~~;t;~m compri8ing from about 1 gm to
about 20 gm of at leagt one primary therapeutic agent compris-
i~g a primary amine benzoic acid derivative having a molecular
weight o~ ~rom about lO0 to about 1,400 Daltong, and option-
2~ 7
103
ally at least one s ~hctAn -P selected from those noted above in
section (v) through section lix), and a ~il ~ rP~n~n;7Pfl
as effective to treat ~nf~ nry site edema, such as, for
example,
(a) cyproheptadine, illLL~ luu~ Ar~ Sllhr ~tAn~n~a
or oral dosage range from 5 mg~kg daily to 50 mg/kg daily;
lb) -1 ct i nP ~ LL ~ ~ IUU~, i l Ar, 8 hP tAnP- a or
oral dosage range from 20 mg/kg daily to 200 mg/kg daily;
(C) jPtACtinP, ill~Lc~ lU 8, ; ~ lAr or
dosage range from 20 mg/kg daily to 200 mg/kg daily;
(d) indomethacin, illLLel~luus~ i - lAr, s~hc~tRnl~n~or
oral dosage range from 1 mg/kg daily to 100 mg/kg daily;
(e) piroxicam, illLLa~uu~, i ~ l Ar, s hP ltAn ~n a or
oral dosage range from 20 mg/kg daily to 200 mg/kg daily;
(f) phenylh t 7nn~, ill~L~ W~ls, ill~L lAr, 811h,- ltAnPn c
or oral dosage range from 50 mg/kg daily to 500 mg~kg daily;
(g) ,~ ~hAcnnP (Decadron, Merck & Co ), dosage range from
0 2s mg daily to 18 mg daily;
(h) rh~niflnn., illLL l~ wu~, i lAr, sllh~- ltAnPnllq or
oral dosage range from 25 mg/kg daily to 1 gm/kg daily;
(i) nordihydroguaiaretic acid, ill~..lV~llUU~, ill~L li~r,
c hC t~nPn~a or oral dogage range from loO mg/kg daily to 2
gm/kg daily;
(j) kf~tn~-nn~7n3e, intravenous, intramuscular, s hf ltAn~n~a or
oral dosage range from 100 mg/kg daily to 2 gm/kg daily;
(k) suprofen, dosage range from s mg/kg daily to loO mg/kg
daily;
(1) ketoprofen, dosage range rom 2 mg/kg daily to so mg/kg
daily;
(m) indoprofen, dosage range from 1 mg/kg daily to 30 mg/kg
daily;
(n) sudoxicam, dosage range from 0 5 mg/kg daily to 40 mg/kg
daily;
(o~ naproxen, dosage range from 1 mg/kg daily to 100 mg/kg
daily;
(p) meclofenamic acid, dosage range from 15 mg/kg daily to
50 mg/kg daily;
(~) ibuprofen, dosage range from 15 mg/kg daily to 150 mg/kg
daily;
2~9~rJ7
104
~r) ~l;rl~fPn~-, dosage range from 1 mg/kg daily to 25 mg/kg;
(8) fenoprofen, dosage range from 5 mg/kg daily to 100 mg/kg
daily;
(t) l~ydLu~y~ 1Oroquine, dosage range from 20 mg/kg daily to
40 o mg/kg daily;
(u~ 2,6-diamino-N-{ [1- (l-oxotridecyl) -2-piperidinyll -methyl~-
h~.Y:~nAmi~l~', dosage range from 0.5 mg/kg daily to 50 mg/kg
daily;
(v) bucloxic acid, dosage range from 200 mg daily to 2 gm
daily;
~w) butibufen, dosage range from 40 mg/kg daily to 400 mg/kg
daily;
Ix) carprofen, dosage range from 0.2 mg/kg daily to 50 mg/kg
daily;
ly) the (s) (+) ~n:~ntt~ of carprofen, dosage range from So
mg daily to 750 mg daily;
(z~ 6- (2,4-diflu~Lu~ ~y) -5-methylsulfonylamino-1-indanone
(Ciba-Geigy AG), dosage range from 0.2 mg/kg daily to 20 mg/kg
daily;
(a'~ loxoprofen, dosage range from o.l mg/kg daily to 25 mg/kg
daily;
(b' ~ diaveridine, dosage range from 25 mg/kg daily to 500
mg/kg daily;
(c' ~ ditazol, dosage range from 25 mg/kg daily to 750 mg
dally;
(d' ~ droxicam, dosage range from 0.1 mg/kg daily to 50 mg/kg
daily;
(e' ~ (Z~ -3- [4- lacetylo-Yy) -5-ethyl-3-methoxy-1-n~phth~ nyl] -2-
methyl-2-propenoic acid, dosage range from 10 mg/kg daily to
5 o o mg/kg dai ly;
(f' ) ebselen, il~LLC~Vt~ u8~ T~ gubcutaneous or oral
dosage range from 5 mg/kg daily to 5Do mg/kg daily;
(g~ ) 1-p-chlorobenzyl-2-dimethyl-aminomethylcyclohexen-1,2,
dosage range from 2.5 mg/kg daily to 250 mg/kg daily;
(h' ~ etoclofene, il~LL~ Ua, ; .,l . . ,c. .,l :~r, sllhrllt:~n~oll~ or
oral dosage range from 1 mg/kg daily to 400 mg/kg dailyi
(i' ) flufenamic acid, dosage range from 1 mg/kg daily to 400
mg/kg daily;
(j~ lJtll~y~' n~, dosage range from lo mg/kg daily to 1 gm/kg
~ 90 1 û~
105
dailyi
(1' ) mefenamic acid, dosage range from 1 mg/kg daily to 400
mg/kg daily;
(m~ ) fenhufen, do3age range from 250 mg daily to 1.25 gm
daily;
(n~ ~ felbinac, do3age range from 100 mg daily to 1 25 gm
daily;
~o'~ fenclorac, do3age range from 0.5 mg/kg daily to 50 mg/kg
daily;
(p' ~ fenclo2ic acid, do3age range irom 25 mg daily to 500 mg
daily;
(q' ) fendo3al, dosage range from 5 mg/kg daily to 200 mg/kg
daily;
(r~ ) i30xepac, dosage range from 200 mg daily to 2 gm daily;
~3~) im;~ 3alicylate, do3age range from 50 Imol/kg daily
to 0 . 5 mmol/kg daily;
(t~) i30xicam, do~age range from 50 mg daily to 500 mg daily;
(u~ ) tolmetin, dosage range from 50 mg daily to 500 mg daily;
(v') l-~fl '~, dosage range from sO ~g daily to 50 mg
daily;
(w~) isofezolac, dosage range from 0.1 mg/kg daily to 25 mg/kg
daily;
(x~ i30butyl-3,4-diphenylpyrazole-S-acetic acid, do3age
range from 0 . 5 mg/kg daily to so mg/kg daily;
(y' ) S-adenOsyl hi~nin~ do3age range from 500 mg daily to
10 gm daily;
(z~) D-myo-inositol-l. 2 6-1-riqrh~ qrhAte, il~L~ S, intra-
muscular, 5'1h~ n~.~111q or oral dosage range from 10 mg/kg
daily to 1~5 gm daily;
(a~ ~ ) diacetylrhein, do3age range from 10 mg daily to 500 mg
daily;
(b~ ~ ) cinmetacin, do3age range from 2 mg/kg daily to 400 mg/kg
daily;
(c~ ~ ) tinoridine, dosage range from 2 5 mg/kg daily to 250
mg/kg daily;
(d' ~ ) n; 1;~1~, dosage range _rom 100 mg daily to 2 gm
daily;
(e~ ~ ) prenazone, dosage range from 0.5 mg/kg daily to 400
mg/kg daily;
2190107
~ .
106
(~ ~ napht~ly~L ~f, dosage range from 0.s mg/kg daily to 400
mg/kg daily;
(g ) r~ricnYRl, dogage range from 0.5 mg~kg daily to 400
mg/kg daily;
(h ) proquazone, dosage rRnge from 150 mg daily to 1.5 gm
dR ily;
(i ) ketorolac, dosage range from 20 ~ug/kg daily to 2 mg/kg
daily;
( j ) ;IydL .~ ,L ~isone (h~y 1~ JL ~ , Merck & Co . ), dosage range
from 1 mg daily to 400 mg daily;
(k ~ ) prednisolone (Pediapred, Fison3), do3age range from 1 mg
daily or every other day to 250 mg daily;
(1 ) cortisone (Cortone, Merck & Co.~, dosage rang from s mg
daily to 400 mg daily;
(m ) prednisone (Del tason~, Upjohn~, dosage range from 1 mg
daily to 250 mg daily, or alternate day dosing;
(n ) methylpr~n;cnlrn~o (Nedrol, T~p~ohn~, dosage range from
1 mg daily to 250 mg daily, or alternate day do3in$;
(o~ methylpr-~nic~ nf~acetate (Depo-~Vedrol, Up~ohn~, intra-
synovial, intrRlf~c;nn~7 or i lA~ dosage range from 0.5
mg daily to so mg daily, or weekly dosage of from 20 mg to 120
mg;
(p ~ ) tri~ nnlr.n~ (Arigtocort, Fujisawa), dosage range from
1 mg daily to 200 mg daily, or alternate day dosing;
(q ) tri nnlnn~ i~AretAte (Aristocort Sl-cr~nqinnR, Fujisa-
wa), intL lAr, illLL~ylwvial or intrAl~ nA' dosage
range from 1 mg daily to 200 mg daily, or Alt~rnatf- day
dosing;
(r~ ~ ) betamethasone (Celestone, Schering), do3age range from
.2 mg daily to 12 mg daily, or alt-.rnAt~ day do3ing;
(s~ ~ ) betametha30ne (Celestone Soluspan Ez~Ar~ncinn~ Schering~,
illLL ~ lAr or ~ntr~ cinnAl dogage range from 0.1 mg daily
to lO mg daily, or alternate day do3ing;
(t ) - h~nn~ (Decadron rhncrhAte injection, Merck &
.), illLL l il~-, illLL~:lVell~Ui1 or intrAl~;< nAl do3age range
~rom o.1 mg daily to lo mg daily;
(u ) cortisone (Cortone s-.cr~nc;nn, Merck & Co.), intramu3-
cular do3age range from 5 mg daily to 400 mg daily;
(v~ ~ ) hydrocorti30ne (~ydLL ~ e rhncrh~t~ injection, Merck
. ~ 21~0~07
107
& Co 3, i lLL c, ~ r, i~ ve~uu~ or sllhrllt~nJ nus dosage
range from l mg daily to 400 mg dailyi
~w~) pre~ln;colnn~ ydeltrasol in~ection, Merck & Co ),
~uus~ r, intra-articular, ~ntr~ n~1 and
soft tissue dosage range from 1 mg daily to 100 mg daily; and
(x~ N,N'-diphenyl-p-phenyl~n~ mino, dosage range from 10
mg/kg daily to 250 mg/kg daily
The following illustrate specific f~ l ~tinnc according to
the present invention
4_glini~innryr1nl~ ylic acid l gm
N-acetylcysteine 750 mg
'-Yl'J''I - 1~1 8rl;n/ 300 mg
p, ~nnh~ n7nic acid, potassium salt 15 gm
ebselen 20 gm
S-adenosy1 h; nn; n ~ lO gm
4_( nn~lnn;~;nn)-2-metllu~yl~e ~z~ic acid 5 gm
defel~ n~ mesylate 500 mg
meclofenamic acid 5 gm
Example 22
Clinical t~ of post-event acute central nervous
system trauma, ~n~ ;n~ stroke and spinal cord trauma can be
improved by use of a, , ~tinn comprising from about 1 gm to
about 20 gm of at least one primary thl~r~r~ t;c agent compris-
ing a primary amine benzoic acid derivative having a ~nnl~rlll r
weight of from about lO0 to about 1,400 Daltons, and option-
ally at least one substance selected from those noted above in
cection (v) through section (ix), and a ';~ r~orn~n;7e~l
as effective to treat post-event acute central nervous system
trauma, ~nf lll~iin~ stroke and spinal cord trauma, such as, for
example,
(a~ heparin calcium ( Calciparine, Du Pont Multi -SourCe),
~ L~ve uus or ~11hc~llt~n~nllq dogage range from s,oO0 units
daily to 40,000 units daily;
~b) heparin sodium (~eparln Lock Flu8h.801ution, Wyeth-Ayerst
Iaboratories), i~ ,us or gllh, l t~n~ol1c dosage range from
~1 9~1 07
108
5,000 units daily to 40,000 units daily;
(c) warfarin ~Co~madin, Du Pont~, dosage range from 1 mg
daily to 15 mg daily;
(d) ti~ lnFirl;nP (Tlcl~d, Syntex), dosage range from 50 mg
daily to 750 mg daily;
(e) aminophylline, i lar, ill~La~ uS, cllhrllt:lnP~llc
or oral dosage range from 5 mg/kg daily to 75 mg/kg daily;
(~) isoproterenol (Isuprel, Sanofi Wint_rop3, illLL~vc~ u~,
r or !~ P.~ dosage range from 10 ~Lg daily to
1 mg daily;
~g) -hnhPYit~l sodium, i..L~ wus dwsage range from 5
mg/kg/hr to 50/kg/hr post-trauma;
(h) t~ril~ 1 mesylate (tJ-74006F), ill~L~ U5 dosage range
from 150 ~g/kg/hr to 15 mg/kg/hr;
(i) derivative of t;rilA7~-1 in which the steroid portion of
the chemical ~LLu.LuLe has been replaced with the tetramethyl
chroman portion of d-~ tocopherol (U78517F, Up 30hn), intra-
venous dosage range from ~50 ~Ig/kg/hr to 15 mg/kg/hr;
(j) allopurinol (Zyloprim, 3~1LLuuyll~ Wellcome), dosage range
from 50 mg daily to 800 mg daily;
(k) ebselen, intravenous,; 1 ~r, sl~h~m~trnpn~c or oral
dosdge range from 5 mg/kg daily to 500 mg/kg daily; and
(1) methylprP~1n; qn1 nn~ ~-; ntPn~n~P iULL ZV~ 9, intramus-
cular, cllh~ tr~n~o~c or oral dosage range from 5 llg/kg daily to
0 1 mg/kg daily or immediate po3t-event treatment iUL~ c.wu="
1 Ar or s~h~- ~t:lnPnl1q dosage range from 30 mg/kg to
160 mg/kg during a 24 hour period;
(m) aspirin, dosage range from 50 mg daily to 1 3 gm daily;
(n) sulfi~l~yLeiz~ t ~Ant~-rane, CIBA), dosage range from 50 mg
daily to 800 mg daily;
(o) dipyridamole ~Persantine, Boehringer Ingelheim), dosage
range from 25 mg daily to 400 mg daily;
(p) clofibrate (Atromid-S, Wyeth-Ayerst ~aboratories), dosage
range from 100 mg daily to 2 gm daily;
(q) tissue rlr n~gPn activator ~Activase, r.Pnf,nfPnh) ~ in-
LL~IV~:U~U8 dosage range from 5 mg daily to 150 mg daily;
(r) strPr-t~k;n~ce (streptase, Agtra), intravenous dosage
range from 50,000 IU daily to 500,000 IIJ daily; and
(s) N-methyl-D-aspartate glutamate receptor :/ntr.~nn; qt~ ad-
lQ9
ministered orally, illL~ rly, ~llhrllt~nf-nll~ly or intra-
veneougly such a6
trihexyphenidyl (Artane, Lederle), dosage range from 0 . 1 mg
daily to 20 mg daily;
ethopropazine (Paridol~, dosage range from 10 mg daily to 400
mg daily;
procyclidine (~.~m~1r1n, Burroughs Wellcome~, doGage range from
l mg daily to 40 mg daily;
diphenhydramine (Benadryl, Parke-Davis~, dosage range from s
mg daily to Z00 mg daily;
m-ilrin~ Luy~d, Merck Sharp & Dohme), dosage range
from 0.1 ~g/kg daily to lO mg/kg daily;
~ in~ (Sy~etrel, Du Pont Multi-Source Products~, dosage
range from 10 mg daily to 400 mg daily;
inl~, dosage range from lO mg daily to 400 mg daily;
mil~ , dosage range from 50 mg daily to 2.5 grams daily;
and
d .bL.U~ (Roche), doiage range from lO mg daily to 400 mg
daily;
(t~ low ~ r weight sulphate/dermatan sulphate glyco-
amino-glycan heparinoid mixtures, 6,500 Dalton mean -~n7~ ~ ~llAr
weight, illL~ ~auus~ ilL~ - lnr or Rl~hrl~t:ln~n-l~ dosage
range from 250 anti-factor-~a units daily to lO, oO0 anti-
factor-Xa units daily; and
~u~ mnrlnh~m;~ (Aurorix, Eioffmann-La Roche~, dosage range
from so mg daily to 600 mg daily.
The ~nllnloin~ illustrate specific ~ lnti~nR according to
the present invention.
4-aminocyrl.,h.~ .,ylic acid l gm
deferoxamine mesylate 500 mg
heparin calcium s,ooO units
p_ nnh~n7n~ acid 15 gm
d-~-toccpheryl succinate 3,500 I.U.
ehselen 20 gm
methylpr,~-in~ Rnl nnf. 5 mg
4, nnrh~nylacetic acid 5 gm
2~9(~ 07
110
ebselen 10 gm
m~rlrh~m;~ 250 mg
Example 23
Clinical LLI of post-event ~,ulL~2~lue~ 3 of kidney
ischemia and reperfusion can be improved by use of a COmFJOsi-
tion comprising from about 1 gm to about 20 rlm of at least one
primary therapeutic agent . , cinrJ a primary amine benzoic
acid derivative having a molecular weight of from about 100 to
about 1,400 Daltons, and rrtinnAl1y at least one sl~hctAnr~-
selected from those noted above in oection (v) through section
(ix~, and a I rPr rJni7~rl ag effective to treat post-
event ~ r._~u-~ s of kidney ischemia and r~r~rfl-ci- n, such
, for example,
(a) tr; A7;rl;n~., dogage range from 100 ,ug/kg daily to 3.0
mg/kg daily;
~b~ allopurinol ~Zyloprzm, Burroughs Wellcomej, dosage range
from 50 mg daily to 800 mg daily;
~c~ bucloxic acid, dosage range from 200 mg daily to 2 gm
daily;
~d~ indometacin, dosage range from 25 mg daily to 300 mg
daily;
(e~ ebselen, dosage range from s mg/kg daily to 1 gm/kg
daily;
~f~ methylpre~n;cr~rn-~ (Nedrol, IJpjohn), dosage range from 1
mg daily to 250 mg daily, or Al t~rnAt~ day dosing;
(g) methylpr~ln;q^'rnP (solu Nedrol, Upjohn~ lAr
or inLl.lvcll,u~ dosage range from 0.25 mg/kg daily to 3 mg/kg
daily;
(h~ prednisone (DeltasQne, Up~ohn~, dosage rarlge from 1 mg
daily to 250 mg daily, or Altl~rnAte day dosing;
(i) cyrlrrh~ (CytoXar, Bristol-Myers oncology~,
dosage range from 0.1 mg/ks~ daily to 5 mg/kg daily;
(j) cyrlrrhr F r9., (Cytoxan for injection, Bristol-~yers
Oncology~ LL~ us, ill~.L lar or g~hr1ltAnGrllc dosage
range from 0.1 mg/kg daily to 5 mg/kg daily, 2 mg/kg to 5
mg/kg twice weekly or 10 mg/kg to 15 mg/kg every seven to ten
days;
(k~ rhl, ~ r.. ~ rJ~n Burrough8 ~ellcome), dosage range
901 07
111 :
from 0.5 mg daily to lO mg daily;
(1) cyclo3porinA (C~n~ , sandoz ph~rr~ lt;- 1~, dosage
r~nge from l mg/kg daily to 15 mg/kg daily;
(m~ Fl7~thir~rrine (Imuran, Burroughs Wellcome~, dosage range
from o . l mg/kg daily to 2 . 5 mg/kg daily; and
(n~ N, N - diphenyl -p-phenyl F ~ ; Fl m; n~, dosage range from l 0
mg/kg daily to 2s0 mg/kg daily.
The following i11~qtrAte specific f 1i~t; ~nq according to
the presenr invention.
4-amino-Z-ll~ lLv. y~ll~uylacetic aeid 1 gm
nordihydroguaiaretic aeid s gm
tr; -; t1n~ 7,5 mg
p, n~h~n7ni r acid lS gm
mixed toeopherols 3,500 I.U.
N,N -diphenyl-p-phenyl FTlF.~ n~ 15 gm
4_ (: n~ nirttnr-~phenylaeetic acid 5 gm
D-myo-inositol-l.2.6-tr;qrh~Rrh:-t~ 20 gm
ebselen 5 gm
cy l~.rh~qr ~1~. 200 mg
Example 24
clinicFll ~L~ ' ' of post-event ..~.~ F.l....~nPq of reper-
fusion 7 ~' s~ to myoeardial infaretion ean be improved by
use of a composition, , Rin~ from about l gm to about 20 gm
of at least one primary therapeutie agent comprising a primary
amine benzoic acid derivative having a --~1F.m11~r weight of
from about lO0 to about 1,400 Daltons, and ort;nn~11y at least
one substanee selected from tho3e noted above in 3ection (v~
through 3ection (ix~, and a I -i; r~nm~ni7e~l as effective
to treat post-event CAncF ~I-1F~nn~q of reperfusion ~ub__~luelL to
myocardial infarction, such as, for example,
(a~ trimetazidine, dosage range from lO0 ug/kg dFlily to 3.0
mg/kg dailyi
(b) allopurinol (Zyloprim, Burroughs Wellcome), dosage range
from 50 mg daily to 800 mg daily;
(c) 1 i ~t~ n ~ ( r~7n~lrF~; , Polfa), illL ~ v.~llvuS, qllh~llt::~n~ lq
~ t ~ 7
. ~
112
or int~ lAr dosage range from o.s mg/kg to 1 mgJkg until
ectopy resolves, followed by ill-LCLVel~V~8 -nntinllm1q infugion
at a rate oi from 20 ~g/kg/min to So ug/kg/min;
(d) pro~ n~ (Procan 5~ extended-relea6e tablets, Parke-
Davis), dosage range from 200 mg daily to 5 gm daily;
(e) ~-~d~ L~I nr blockerg such as
h.-tnlol (Sectral), dosage range from 20 mg daily to 1.2 gm
daily;
alprenolol, dosage range from 0.5 mg/kg daily to 5 mg/kg
daily;
atenolol (Tenormin), dosage range from 2.5 mg daily to 200 my
daily;
het~ l nl (Kerlone), dosage range from 1 mg daily to 20 mg
daily;
carteolol (Cartrol), dosage range from 0.25 mg daily to 10 mg
daily;
esmolol (Brevibloc, Du Pont p~ l q), intravenous
dosage range from 50 ~Lg/kg/min to 0.2 mg/kg/min;
l~hf.t:~lnl (Nv~ v~.ly~ dogage range from 20 mg daily to 1.8 gm
daily;
metoprolol ~liopre6sor), dosage range from 5 mg daily to 200 mg
daily;
nadolol (Cor~ard), dosage range ~rom 4 mg daily to 240 mg
daily;
oxprellolol, dosage ri~nge from O.s mg/kg daily to 5 mg/kg
daily;
p~nh~ltnl~l (l,evatol), dogage range from 2 mg daily to 80 mg
daily;
pindolol (Vislcen), dosage range from 0.5 mg daily to 60 mg
daily;
propranolol (In~leral or Inderal l,A~, dosage range from 4 mg
daily to 320 mg daily;
sotalol (Betapace, ~3erlex), dogage range from 30 mg daily to
3~20 mg daily; and
timolol (Blocadren), dosage range from 1 mg daily to 60 mg
daily;
(f) nitrates such as
sodium nitroprusside, intravenous dogage range from 1 mg daily
to loO mg daily;
21~0107
113
;c,~cnrhi~r~ s-mononitrate, dosage range from lO mg daLly lO0 mg
dally;
1RoAnrhi~ dinitrate, dosage range from 2 mg daily to 240 mg
daily; and
E.lct~;n~ releage trin;~ro~lycerin, dosage range from l mg
daily to 540 mg daily;
(g~ calcium ~nt~^n1atc such as
diltiazem (Cardizem or Cardizem SR), dosage range from lO mg
daily to 360 mg daily;
ver, 1 (Calan or Calan SR), dosage range from lO mg to 480
mg;
nifedipine (Procardia), dosage range from 3 mg daily to 180 mg
daily;
nifedipine (Procardia Xr,), dosage range from 3 mg daily to 90
mg daily;
nicardipine (Cardene), dosage range from 6 mg daily to 120 mg
daily;
i~3r~ ;n~. (Dy~laC~rc), dogage range from 0.5 mg daily to 20 mg
daily;
;r~n~ (~orva!7c, Pizer Labg Divigion), dosage range from
O.s mg daily to lD mg daily; and
f~ln~r;nf~ (Plend~l, Merck ~ Co.), dosage range from 0.5 mg
daily to 20 mg daily;
~ h) N,N~-dimethylthiourea, i-lL~av~l-vus, i-lL~ - lAr, sub-
~ t,nf.~l~c or oral dogage range from 5 mg/kg daily to 100 mg/kg
daily;
(i) N-2-mercaptopropionylglycine, i~ a~ ud, i--~ lAr,
~ h~l tAn~ or oral dogage range from 5 mg/kg daily to lO0
mg/kg daily;
(j) deferoxamine mesylate, ill~.av,,ll~,ug or ~ hr--tAn.~nllc dosage
range from 1 mg/kg daily to S0 mg/kg daily;
(k) ebselen, dosage range from s mg/kg daily to 1 gm/kg
daily;
(l) taurine, docage range ~rom l mg/kg daily to lO0 mg/kg
daily;
(m) fibrinolytic c~-h~t~n~c including
str~rtnkin~ce, intravenoug dogage range from lS0,000 I.U. to
l.S million I.U. over one hour;
urokinase, i~La~ u~ dogage range from 300, 000 I.U. to 3
,~ . 2~90107
114
millio~ I.U. over one hour;
acylated streptokinage-rlAr-;~ lex ~anigtreplase), intra-
venous dosage range from 3 I.U. to 30 I.~. over two minutes:
and
Ll ' nAnt tissue rlA 'nnrJon activator l:~lt~rlAce, rt-PA),
il LL.-Y~u~ dosage range from 10 mg to 100 mg over a four hour
period;
(n) heparin, i~ Ye~ s or ~-.hr~ltAn~m~q dosage range 10,000
units/day to 25,000 units/day;
(o) aspirin, dosage range from 50 mg daily to 1. 5 gm daily;
(p) An~;~tl~n~;n converting enzyme ;nhih;tnrR ;nrl~lr1;nrJ
captopril (Capoten), dosage range from 2.5 mg daily to 300 mg
daily;
enalapril (VaRotec), do3age range from 0.25 mg daily to 40 mg
daily;
foAinopril (~onopril), dosage ra~ge from 1 mg daily to 60 mg
. daily;
-. l;Rinnrr;l (~eDtril), doDage range from 0.5 mg daily to 40 mg
daily;
ramipril (Al tace), dosage range from 0 . 25 mg daily to 10 mg
daily;
rguinapril (Accupril, Parke-Davis), dosage range from 1 mg
daily to 80 mg daily;
quinapril/hydrochlornth;A7;c~ ' 'nAt;nn~ (Accuretic, Parke-
Davis), dosage range from 2 mg ~-;nRrr;l and 1.25 mg hydro-
chlornth;A7;rl~ daily to 80 mg quinapril and 125 mg hydro-
chlorothiazide daily; and
benazepril (Lotensin, CIBA phArr-c~t~r~ dosage range from
o.1 mg daily to 80 mg daily.
The following illustrate specific f~ lAt;nnl~ according to
the present invention.
4-amino-2-metl~ r~ ylacetic acid 1 gm
t butylated-hydroxytoluene 200 mg
allopurinol 200 mg
p_: 'n~h-~n7~;~ acid 20 gm
2 ~ 7
115
tert-hutylhydror"uinone 1 gm
l ~qr~rh;-;~ 5: it~ t~ 100 mg
4_A~inrrh.onylacetic acid 10 gm
2,6-di-tert-butyl-4-~2'-thenoyl]phenol 500 mg
raptopril 2 0 0 mg
E~Lample 25
~ Jse of agents previously r"rrJn; ~ as having general
Anti-;nfl r~ry propertieg and as possibly having 7c~f~l1n~
in r1;n;r:~lly treating chronic ~nfl trTy diseases of vary-
ing origin, but which at present remain under investigation
can be improved by use of a . _ t~nrl comprising from about
1 gm to about 20 gm of at least one primary therapeutic agent
q;n~ a primary amine ben :oic acid derivative having a
r~ r weight of from about 100 to about 1,400 Dalton~3, and
nr~;nnill 1y at lea6t one sllhst~nre selected from tho6e noted
ahove in section (v) through section (ix), and an agent
previously r~rrrn;7~d ag having general anti-;nfl nry
properties and as possibly having usefulnegs in clinically
treating chronic ;nfli tnry di8ea8eg of varying origin, but
which at present remain under inv~qt;r~tinn~ such as, for
example,
(a) tilomisole (WY-18,251, NSC-310,663), dosage range from
0.1 mg/kg daily to 100 mg/kg dailyi
(1~) tei~idap, dosage range from 0.1 mg/kg daily to 1oo mg/kg
daily;
(c) 1- [ (4-chlorophenyl) methyl3 -2-methyl-5- (o~uinolinyl-
methoxy)-lH-indole-3-acetic acid, dogage range from 0.1 mg/kg
daily to 100 mg/kg dailyi
(d) t~r~ 1in, dosage range from 0.1 mg/kg daily to loO mg/kg
daily;
(e) scalaradial, dosage range from o 1 mg/kg daily to 100
mg/kg daily;
(f) neutral macrolide of ~ rlll;l~ formula C" H6, NO~, H,O
derived from st~entrmvrf~q ~ q ~o. 9993 ~FR506),
do6age range from o.s mg/kg daily to 5D mg/kg daily;
(g) tirilazad mesylate (U-74006F), i~ 6 v,~ u~ dosage range
from o.15 mg/kg/hr to 15 mg/kg/hr;
21 ~0~07
116
th) derivative of t;r;lA7~ in which the sterold portion of
the chemical ~LLU~_~U/ e: has been replaced with the t, ' ~ hy
chroman portion of d-~ tocopherol ~U78517F, Upjohn3, intraven-
ous dosage range from 150 ,ug/kg/hr to 1~ mg/kg/hr;
(i) pentoxifylline (Poechst-Roussell phAr~ t; rAl c), intra-
venous, il-L~ lAr or ~ .... c dosage range from 1
mg/kg daily to 100 mg/kg;
(; ~ indoxole, dosage range from 0 . S mg/kg daily to 50 mg/kg
daily;
(k) h; ,y~vl, dosage range from 0.5 mg/kg daily to 50
mg/kg daily;
(13 fl ;7~ , dosage range from 0.5 mg/kg daily to 50 mg/kg
daily;
~m) rh~n;~nn~, iLlLLCL~_ vuu~ i lAr, gllhrlltAnrn-lc or
oral dosage range from 25 mg/kg daily to 1 gm/kg daily;
(n) ehselen, il~ oUs, illL~ crlllAr, s-lh~rllti~n~n-lR or oral
dosage range from 5 mg/kg daily to 500 mg/kg daily;
~o) hucolome, dosage range from Z00 mg daily to 2 gm daily;
(p) sodium 2-[~1-(2-oxocyclopen~ylmethyl~phenyllpropionate
dihy-drate, dosage range from o.l mg/kg daily to 25 mg/kg
daily;
(q) qi~r~tnflAvone, dosage range ~rom 50 mg/kg daily to 1 gm
daily;
(r) rirci l inl, dosage range from 50 mg/kg daily to 1 gm
daily;
(s) hypoiaetin-8-gl--rnoi~, dosage range from 50 mg/kg daily
to 1 gm dailyi
(t) hypolaetin, dosage range from 50 mg/kg daily to 1 gm
daily;
(u) oroxindin, dosage range from 50 mg/kg daily to 1 gm
daily;
(V) rluerre~tAr;etin-7-r~ rncir~ dosage range from 50 mg/kg
daily to 1 gm daily;
(w) gossypin, dosage range from 50 mg/kg daily to 1 gm daily;
(x) hih;fnl;n, dosage range from 50 mg/kg daily to 1 gm
daily;
(y) gossypetin, dosage range from 50 mg/kg daily to 1 gm
daily; ~
~z) leuco ~ nidol, dosage range from 50 mg/kg daily to 1 jm
~190107
117
daily;
(a') ind~,y~ufe-~, dosage range from o.S mg/kg daily to 50 mg/kg
daily;
(b') crude extract of MAn~ vill~ Yelutina, dosage range from
So mg/kg daily to 1 gm/kg daily;
(c' ) 1- ~3- (naphth-2-ylmethoYy)phenyl] -1- ~thiazol-2-yl)propyl
methyl ether, dosage range from 1 mg/kg daily to 100 mg/kg
daily;
(d' ) epirizole, dosage range from 5 mg/kg daily to 150 mg/kg
daily;
(e') DL-2-(4-hexyloYyphenyl)glycine octyl e3ter, dosage range
from 25 mg daily to 500 mg daily;
(f') DL-2-~4-(5.5-dimethylheYyloxy)phenyl]glycine octyl ester,
dosage range from 25 mg daily to 500 mg daily;
(g~ Y;~nm, dosage range from 0.1 mg/kg daily to 50 mg/kg
daily;
(h') kojic acid, dosage range from 0.1 mg/kg daily to 50 mg/kg
daily;
(i' ) 2- (2-hydroxy-4-methylphenyl) ---;n~-thi~7~ hydrochloride,
dosage range from 0.1 mg/kg daily to 50 mg/kg daily;
(~ ~ ) 2- (p-bL~ , ' yl) -9-dimethylaminopropyl-9H-imioazo ~1, 2-
I:r]-benzimidazole, dosage range from 0.1 mg/kg daily to sO
mg/kg dailyi
. (k' ) l,.:ll~y~ufen, dosage range from O .1 mg/kg daily to 50
mg/kg dailyi
(1') flunoxaprofen, dosage range from o.1 mg/kg daily to so
mg/kg daily;
(m' ) ~ z~ , dosage range from O .1 mg/kg daily to 100
mg/kg daily;
(n~ ) mi~oprostol, dosage range from 10 ~Lg/k daily to 1 mg/kg
daily;
(o' ) 6-methoYy-2-naphthylacetic acid, dosage range from
mg/kg daily to 100 mg/kg daily;
(p' ) niflumic acid, dosage range from 250 mg daily to 5 gm
daily;
(q~) clidanac, dosage range from 0.1 mg/kg daily to 100 mg/kg
daily;
(r~) prs)~ in, dosage range from o.s mg/kg daily to 200
mg/kg dailyi
~ 219~10~
118
(s') 4-(2-chlorophenyl~-2-[2-(4-lsohutylphenyl~ethyl]-6,9-
dimethyl-6~1-thieno[3,2-f] tl,2,43triazolo[4,3a] [1,4]~1iA7~.r;n,o
(Y-24180~, dosage range from lO fLg/kg daily to 10 mg/kg daily;
(t'~ I _ hAcnn~, i L~ lAr, i~-LL~-.yll~.vial, intra-
lesional or oral dosage range from 1 mg daily to 200 mg daily,
or Al t~rnAt~ day dosing;
(u'~ ~ll ' hAqnn~ 21-acetate, i lAr, intrasynovial,
~ntrAll~q~nnA- or oral dosage range from l mg daily to 200 mg
daily, or ~l t~rnAt~o day dosing; and
(v~ paramet_asone disodium p~ ~hdLe,; lAr, intra-
synovial, ;ntrAl~sinnAl or oral dosage range from l mg daily
to 200 mg daily, or Al t~rnAt ~ day dosing.
The following ~ qtrAte specific fl lAtinnq according to
the present invention.
4_: 'nnrh~nylacetic acid, pntAqRi salt 1 gm
~J-acetylcysteine 1 gm
tenidap 10 mg
4-amino-2-metl~.,Ay~ oic acid 20 gm
d-o-tocopheryl g.l~-rinAt,. 3,000
neutral l---rnl i~ of m~ -llAr formula
C<< ~9 N0l, H,0 derived from
Stre~ nmv~q t,~ .iic
No. 9993 (F~506~ 3.5 gm
4_~minnrh~nylacetiC acid lS gm
probucol 6 oo mg
tilomisole 2 gm
~ithout further .~ hnrAr; nn the foregoing will so fully il-
lustrate my invention that otherg may, by applying current or
future knowledge, adapt the same for uge under varioUG condi-
tions of service.
