Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TITLE OF THE INVENTION
COMBINATION THERAPY FOR HIV INFECTION
s
FIELD OF THE INVENTION
The combination in this invention is useful in the inhibition
of HIV protease, the inhibition of HIV reverse transcriptase, the
treatment of infection by HIV and in the treatment of AIDS and/or ARC
10 (i.e., AIDS related complex), either as compounds, ph~nrqrP~ lly
acceptable salts or esters (when a~ UIJIid~), ph~nmsl~.elltin~l
composition ingredients, whether or not in combination with other
antivirals, anti-infectives, immnnnmodulators, an~ibiotics or vaccines.
Methods of treating AIDS, methods of preventing infection by HIV, and
15 methods of treating infection by HIV are also disclosed.
BACKGROUND OF THE INVENTION
A l~lluvillls rl~PcignqtPd human immunodeficiency virus
(HIV) is the etiological agent of the complex disease that includes
20 progressive destruction of the immune system (acquired immune
deficiency syndrome; AIDS) and degeneration of the central and
peripheral nervous system. This virus was previously known as LAV,
HTLV-III, or ARV. A common feature of retrovirus replication is the
extensive post-tr:~n~fion:~l processmg of precursor polyproteins by a
2s virally encoded protease to generate mature viral proteins required for
virus assembly and fimction. Inhibition of this processing prevents the
production of normally infectious virus. For example, Kohl, N.E. et
al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), ~lPnnnnctr~tPd that genetic
inactivation of the HIV encoded protease resulted in the production of
30 immature, non-infectious virus particles. These results indicate that
J inhibition of the HIV protease ~ ,enls a viable method for the
treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a ~1
gene in one open reading frame [Ratner, L. et al., Nature, 313, 277
(1985)]. Amino acid sequence homology provides evidence that the PQl
wo 96/00068 PCr/USg~/07690 ~
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sequence encodes reverse transcriptase, an endonuclease and an HIV
protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M.D. et al.,
s Science, 231, 1567 (1986); Pearl, L.H. et al., Nafure, 329, 351 (1987)].
The compound disclosed and referred to as "Compound J"
in EPO 541,168, which published on May 12, 1993, is a potent inhibitor
of HIV protease and is useful in the prevention of infection by HIV, the
treatment of infection by HIV and the treatrnent of AIDS or ARC,
without signific~nr side effects or toxicity.
¢~f N~ OH
N ~ ' ~NH OH
t-Bu-NH ~O
C~ .d J ~J~
One ~ub~ lidl and persistent problem in the treatment of
AIDS has been the ability of the HIV virus to develop resistance to the
individual 11,~ ;f. agents employed to treat the disease. To solve
this problem, a combination therapy for AIDS has been discovered by
applicants.
Applicants ~lemnn~tr~te that the combination of compoumds
of this invention is an effective inhibitor of HIV protease.
In the present invention, applicants co-administer a potent
HIV protease inhibitor, such as Compound J, or other chemical entities,
with a non-nucleoside HIV reverse L~ s.~ se inhibitor such as
30 nevarapine or an oc-anilinophenyl~ret:~mi~l~ (i.e., oc-APA) derivative.
Optionally, a third ~:o111po~ which is a nucleoside inhibitor of HIV
reverse ~ s~ ~se, such as AZT, ddl or ddC, is added to the
cnmhin~tion. This co111l,h1dlion therapy is a method to enhance the
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;Liv~e~ in treating AIDS and to preclude the development of
resistance to the individual ~I,eldl ~ulic agents.
SUMMARY OF THE INVENTION
The instant invention involves a combination of
compounds, which is Compound J and a non-nucleoside HIV reverse
l,~ls~ ,Lase inhibitor selected from nevarapine or an a-APA
lC derivative, and, optionally, a nucleoside inhibitor of HIV reverse
transcriptase selected from AZT, ddl or ddC,
or a ph~nn~relltic~lly acceptable salt or ester thereof.
In one embodiment of the invention is the col"l,i"alion
which is Compound J and nc~dl~llJille.
In a class is the combination which is Compound J and an
a-APA derivative.
In a subclass is the combination wherein the a-APA
derivative is R89439.
In a second subclass is the combination wherein the
a-APA derivative is R18893.
Illustrative of the invention is the ~;u~ubiulalion which is
Compound J, nevarapine and the nucleoside inhibitor of HIV reverse
s~ ldse.
Further illustrating the invention is the c-"~ ;on
wherein the the nucleoside inhibitor of HIV reverse l,~ls~ .~se is
AZT.
Exemplifying the invention is a method of inhihiting HIV
protease, cu",~risiulg ~ lli";~ i"g to a suitable mammal in need of
such treatment an effective amount of the colllbilldlioll.
An example of the invention is a method of inhibiting HIV
reverse ~,~,s.;li~a~e, comprising ~ uliulg to a suitable mammal in
need of such treatment an effective amount of the combination.
An illustration of the invention is a method of preventing
infection of HIV, or of treating infection by HIV, or of treating AIDS
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or ARC, comprising ~mini~tPring to a suitable mammal in need of such
treatment an effective arnount of the combination.
More specifically illustrating the invention is a
~ha.",A~ icAl composition useful for inhibiting HIV protease,
CUI~ illg an effective amount of the combination, and a
phArmA~ ellticAlly acceptable carrier.
Specifically exemplifying the invention is a phAllll~l eIII;f~A1
composition useful for inhibiting HIV reverse L.~ls~ L~se, Cu~ illg
an effective amount of the combination, and a pharmaceutically
acceptable carrier.
A further example is a pharmaceutical composition useful
for preventing or treating infection of HIV, or for treating AIDS or
ARC, co---~ i--g an effective amount of the combination and a
phArmAcellti~.Ally acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
This invention is c~nrern~d with the crmhinAtion of certain
compolmds, orl-llA""~ ;rAlly acceptable salts thereof, in the
inhibition of HIV protease, the inhibition of HIV reverse Ll~lsc.i~ se,
the prevention or treatment of infection by HIV and im the treatment of
the resulting acquired immune deficiency syndrome (AIDS). The
combination is defined as follows:
Compound J and a non-nucleoside inhibitor of HIV reverse
transcriptase selected from nevarapine and an o-APA derivative, or
ph:lrmA~cllti~Ally acceptable salts thereof.
The HIV protease inhibitor Cornpound J is ~y..Ll.e~ d by
30 the protocol of EP 0 541 168, published 12 May 1993. Compound J is
N-(2(R)-hydroxy- I (S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-
(4-(3-pyridylmethyl)-2(S)-N'-(t-butyl-carboxamido)-~il,e- A i11YI))-
P~IIIAIIr~III;~IP or phArmA( e.llti~ Ally acceptable salt thereof.
Nevarapine is I l-cyclopropyl-5,1 1-dihydro-4-methyl-6H-
dipyrido[3,2-b:2',3'-e][ l ,4~diazepin-6-one,
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H3C H~O
~N~
Nevarapine
Nevarapine is synthesized by the procedure described in Hargrave, K.D.
et al., J. Med. Chem., 34, 2231 -2241 (1991) and Klunder, K.D. et al., J.
Med. C~lem.,35, 1887-1897 (1992).
a-APA derivatives are oc-anilinophenylacetarnide
derivatives of the forrnula:
R2
~NNH
Cl H R
o~-APA derivative
wherein Rl is methoxy, nitro or C(0)-CH3 and R2 is hydrogen or
methyl. Of particular interest in the instant combimation are the o~-APA
derivatives R89439 and R18893. R89439 is the a-APA derivative
wherein Rl is C(0)-CH3 and R2 is methyl. R18893 is the a-APA
derivative wherein Rl is nitro and R2 is hydrogen. o-APA derivatives
are made by the procedure described in PCT patent application,
lnr~rn:~tirm~l Publication No. W092/00952, published 23 January 1992.
The ph~rrns~rellti~lly acceptable salts of the present
invention (in the forrn of water- or oil-soluble or dispersible products)
include the conventional non-toxic salts or the ~lual~lllaly arnmoniurn
salts which are forrned, e.g., from inorganic or organic acids or bases.
Exarnples of such acid addition salts include acetate, adipate, alginate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,
.
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camphorate, camphorsulfonate, cyclopelll~lelJ,ul)ionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
glycerophosphate, h(~nni~nlf~t~ heptanoate, h~Y~nn~fe, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyeth~nesnlfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,
pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succimate, tartrate, thiocyanate, tosylate, and lln~lrr~no~t~ Base salts
1C include ammonium salts, alkali metal salts such as sodium and potassium
salts, alkaline earth metal salts such as calcium and m~gnf sinm salts,
salts with organic bases such as dicyclohexylamine salts, N-methyl-D-
glll~:lmin~, and salts with amino acids such as arginine, Iysine, and so
forth. Also, the basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl, propyl,
and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl
halides like benzyl and phenethyl bromides and others. Other
ph~ rellfi~ :llly acceptable salts include the sulfate salt ethanolate and
sulfate salts.
The pll;~"l,~r~ ic:~lly acceptable salts of the combination of
the instant invention include the eoll,billation wherein one of the
imdividual Cullll)o~ is im the form of a ph:lrrn~lreutic:~lly acceptable
salt, or the combination wherein all of the individual components are in
the form of pl"~""~ e,llic~lly acceptable salts, or a ph~rm~renfit~liy
acceptable salt of the combined l;Ulll~lOllelll:j (i.e., a salt of the
~;c,lllbillalion). In one embodiment of the present invention, the sulfate
salt of the combination is utilized.
The ph~rm~rentic~lly acceptable esters in the present
invention refer to non-toxic esters, preferably the alkyl esters such as
methyl, ethyl, propyl, isopropyl, butyl, i.sobutyl or pentyl esters, of
which the methyl ester is preferred. However, other esters such as
phenyl-Cl 5 alkyl may be employed if desired.
~ WO 96/00068 PCT/US9~/07690
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Esterification of alcohols, such as Compound J of the
present invention, is performed by a variety of conventional
5 procedures, including reacting the alcohol group with the ~lu~lulJfldl~
anhydride, carboxylic acid or acid chloride. These reactions, as well as
other methods of e."~lirlcdlion of alcohols, are readily apparent to the
skilled artisan.
Reaction of the alcohol with the app.ulu.;ate anhydride is
o carried out in the presence of an acylation catalyst, such as 4-DMAP (4-
dimethylaminopyridine, also known as N,N-dimethylaminopyridine),
pyridine, or l,~-bis[dimethylamino]napthalene.
Reaction of the alcohol with the appropriate carboxylic acid
is carried out in the presence of a dehydrating agent and, optionally, an
acylation catalyst. The dehydrating agent, which serves to drive the
reaction by the removal of water is selected from dicyclohexylcarbo-
dii~nide (DCC), 1-[3-dimethylalllhlu,uluyyl]-3-ethylcarbodiimide (EDC)
or other water soluble dehydrating agents.
Altematively, reaction of the alcohol with al~,uluplidle
20 carboxylic acid can also result in esterification, if performed instead in
the presence of trifluoroacetic anhydride, and, optionally, pyridine. A
further variant is reacting the alcohol with appropriate carboxylic acid
in the presence of N,N-carbonyl-liimi~1~7r-le with pyridine.
Reaction of the alcohol with the acid chloride is carried out
25 with an acylation catalyst, such as 4-DMAP or pyridine.
Selective e~i~lir~ lion of Compound J is performed by a
variety of methods known to the skilled artisan. In one method, the
alcohol is first esterified with a trichloroethyl derivative (e.g., mono-
trichloroethyl succinate). After chromatographic isolation of the
30 preferred ester, reductive elimination of the tricholoroethyl group is
carried out by reaction with _inc dust in acetic acid. Alternatively,
another method of selective esterification is the hydrolysis of the bis-
ester.
The co."billdlion of compounds of the present invention is
useful in the inhibition of HIV protease, the inhibition of HIV reverse
WO 96/00068 PCrlUS95/07690
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transcriptase, the prevention or treatment of infection by human
immunodeficiency virus (HIV) and the treatment of cnn~e-l--Pnt
5 pathological conditions such as AIDS. Treating AIDS or preventing or
treating infection by HIV is defined as including, but not limited to,
treating a wide range of states of HIV infection: AIDS, ARC, both
sy~ OlllaLic and asymptomatic. and actual or potential exposure to
HIV. For example, the compounds of this invention are useful in
10 treating infection by HIV after suspected past exposure to HIV by e.g.,
blood transfusion, exchange of body fluids, bites, acriflrrlt~l needle
stick, or exposure to patient blood during surgery.
For these purposes, the combinations of the present
invention may be adrninistered orally, parenterally (including
15 sllhcnt~ ollc injections, intravenous, intr~m-lccul~r, intrasternal
injection or imfusion terhni(lues), by inhalation spray, or rectally, in
dosage unit formulations cnnt:~ining conventional non-toxic
ph"""~ ir~lly acceptable carriers, adjuvants and vehicles.
Thus, in accordance with the present invention there is
further provided a method of treating and a ph~rm~relltin~l composition
for treating HIV infection and AIDS. The treatment involves
lhlg to a patient in need of such treatrnent a ph~rm~entir~l
composition Co~ g a ~hdllllac~u~ical carrier and a Lh~,la~u~ically
effective amount of each compound in the ~;olllbillalion of the present
2s invention.
These ph:lrm~rellti~ l compositions may be in the form of
orally-~lmini~tr~hle suspensions or tablets; nasal sprays; steril
injectable preparations, for example, as sterile injectable aqueous or
oleaginous suspensions or suppositories.
In accordance with the method of the present invention, the
mdividual components of the combination can be ~ministered
separately at different times during the course of therapy or
concurrently in divided or single combination forms. For exarnple, in a
two-culll~ colllbilldlion which is the HIV protease inhibitor,
Compound J, and the non-nucleoside HIV reverse transcriptase
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inhibitor, nevarapine, treatment with nevarapine can commence prior
to, subsequent to or concurrent with commencement of treatment with
5 Compound J. The instant invention is therefore to be understood as
embracing all such regimes of simlllt~nrous or alternating treatment and
the term "~minictrring" is to be interpreted accordingly.
When :~lminictered orally as a suspension, these
compositions are prepared according to trchni(llles well-known in the
o art of ph~rm~relltir~l formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners/flavoring agents known in the art. As immr(li:~tr release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosrh~te, starch, m~lgnPcillm stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents and
lubricants known in the art.
When ~llllilli~i~ ..,d by nasal aerosol or inhalation, these
compositions are prepared according to terhniqll~c well-known in the
2c art of ph~rm~celltir~l formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluulucdlbolls, and/or
other solubilizing or dispersing agents known in the art.
The injectable solutions or suspensions may be fnrmlll~ltrd
25 according to known art, using suitable non-toxic, parenterally-
acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water,
Ringer's solution or isotonic sodium chloride solution, or suitable
dispersing or wetting and sllcrrn~ling agents, such as sterile, bland, fixed
oils, including synthetic mono- or diglycerides, and fatty acids,
3c including oleic acid.
When rcctally ~ d in the form of suppositories,
these compositions may be prepared by mixing the drug with a suitable
non-irritatirlg excipient, such as cocoa butter, synthetic glyceride esters
or polyethylene glycols, which are solid at ordinary lellllueldlul~s, but
liquidify and/or dissolve in the rectal cavity to release the drug.
WO 96/00068 PCI/US9~/07690
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The compounds of this invention can be a~lmini~tt-red to
humans in the dosage ranges specific for each compound. Compound J,
5 or a ph~rm~celltir~lly acceptable salt thereof, is administered orally in a
dosage range between about 40 mg and about 4000 mg per day, divided
into between one and four doses per day. Nevarapine, or a
ph~ lly acceptable salt thereof, is ~lrlmini~tPrcd orally at a
dosage range between about 12 mg per day and about 500 mg per day,
o given in a single dose per day. The o~-APA derivatives, and in
particular, R89439 and R18893, or pha~ ic~lly acceptable salts
thereof, are :~lmini~tPred orally at a dosage range between about 100
mg per day and about 1000 mg per day, divided into between one and 3
doses per day. It will be understood, however, that the specific dose
15 level and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of
action of that compound, the age, body weight, general health, sex, diet,
mode and time of ad.llil-istla~ion, rate of excretion, drug combination,
20 the .severity of the particular condition, and the host undergoing
therapy.
The combination of the present invention can also be
combined with an optional third antiviral component which is a
mlrlPn~i-lP inhibitor of HIV reverse llalls~ J~se. For example, the
25 cul,ll,hla~ion of this invention may be effectively ~ rlc;d~ whether
at periods of pre-exposure and/or past exposure, in c-~mhin~tion with
effective amounts of the AIDS antivirals AZT, ddl or ddC, known to
those of ordimary skill in the art.
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TABLE I
Antivirals
Drug Name ~l~nllfacturer !nriir~irln
ddl Bristol-Myers AIDS, ARC
Dideoxyinosine (New York, NY)
ddC Hoffman-LaRoche AIDS, ARC
Dideoxycytidine (Nutley, NJ)
Zidovudine, AZT Burroughs-Wellcome AIDS, adv, ARC,
(Research Triangle pediatric AIDS,
Park) Kaposi's sarcoma,
as~ ,l,.",-~;r HIV
infection, less severe
HIV disease, neuro-
logical involvement, in
GullllJilldlion with other
therapies
AZT is synthesized by the methods of J.P. Horwitz et al., J.
25 Org. Chem., 29, 2076 (1964); R.P. Glinski et al., J. Org. Chem., 38,
4299 (1973); and C.K. Chu et al., Tetrahedron Letters, 29, 5349
(1988). Application of AZT as a therapeutic drug in the treatment of
AIDS is disclosed in U.S. Patent No. 4,724,232.
The compound ddC is ~ylllhe~i~ed by the methods of J.P.
30 Horwitz et al., J. Org. Chem., 32, 817 (1967); R. Marumoto and M.
Honjo, Chem. Pharm. Bull., 22, 128 (1974); and T-S. Lin et al., J. Med.
Chem., 30, 440 (1987). Application of ddC as a therapeutic drug in the
treatment of AIDS is disclosed in U.S. Patent Nos. 4,879,277 and
5,028,595.
WO 96100068 rcrlU59~107690
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The compound ddl is synthesized by the methods of U.S.
Patent No. 5,011,774; and V. Bhat et al., Synthetic Commun., 22(10),
1481-86 (1992). Application of ddl as a therapeutic drug in the
treatment of AIDS is disclosed in U.S. Patent No. 5,254,539.
Preferred col.lb;lla~ions are sim~lt~nl~ous or alternating
treatments of an inhibitor of HIV protease and a non-nucleoside
inhibitor of HIV reverse Lldlls~ JlnSe. An optional third component in
lC the instant combination is a mlcleosi(l~ inhibitor of HIV reverselldns~ se, suzh as AZT, ddC or ddl. These col--bi--ations may have
synergistic effects on limiting the spread of HIV. Thus, the present
invention includes cwllbi l~Llions of the HIV protease inhibitor
Compound J, with a non-nucleoside HIV reverse transciptase inhibitor
selected from nevarapine or oc-APA and a nucleoside HIV reverse
lldll~ ,ldse inhibitor selected from AZT, ddl or ddC.
EXAMPLE 1
2c Protocol for pharmacokinetic evaluation of combination therapy with
onlv nevarapine
This is a fixed-sequence, r~n~c mi7e-1, two-period, parallel
protocol to measure the effect of nevarapine on the phalmacokinetics
and safety and tolerability of Compound J, an HIV- I protease inhibitor
25 in seronegative patients. The pharmacokinetics and safety of a single
600 mg oral dose of Compound J is measured at baseline (Period I) and
agaim (Period II) following adllLi-li.lldtion of nevarapine at 400 mg once
a day (or a placebo instead of nevarapine) for six days. The study
design is outlined in detail in the Table. Plasma c~"" ~ ,,I;on of
30 Compound J is d~l~,.lllilled at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours folIowing the dose. Laboratory safety is measured at
predose and 12 hours after Compound J on Day 1.
Total plasma clearance of Compound J is calculated as the
dose divided by the total area under the plasma concentration-time
curve from zero to infinity. l'he apparent half-life is estimated from
WO 96/00068 PCT/US95107690
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the slope of the terminal phase fitted to the log plasma concentration-
time curve by the method of least squares. The concentration of
5 Compound J in plasma or plasma filtrate is d~ Pilled by analysis on
HPLC, monitored for absorbance at 220 nm.
TABLE 2
10 Period I (day O)
Period I (day I )- Compound J single 600 mg dose
Compound J plasma profile (12 h)
pharmacokinetics
Period l-to-II- interim nevarapine 400 mg once each day
treatment (days 2-7)
FXAMPLE 2
Protocol for combination therapv with only nc~ala~Jille
In this protocol to show the antiviral activity of one
regimen of Compound J given with nevarapine in HlV-seronegative
25 subjects, Compound J is ~ elcd at a dose of 600 mg four times a
day and nevarapine is ~,i",i~ lGd at 400 mg once a day. Antiviral
activity is measured before and during c~-rnhin~2tinn therapy by
Illf.5.~111illg serum levels of the HIV p24 antigen, serum levels of HIV
RNA, and CD4 Iymphocyte counts.
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EXAMPLE 3
5 Protocol for pharmocokinetic evaluation of cnmhins~tinn therapy with
only c~-APA
This is a protocol to show effects of an o~-APA derivative
on plasma concentration profile of Compound J in HlV-seronegative
subjects. It is a fixed-sequence, randomi~ed, two-period, parallel
o protocol. The pharmacokinetics and safety of a single 600 mg oral dose
of Compound J is measured at baseline (Period 1) and again (Period II)
following adllli"i~L.~lion of the a-APA derivative at doses ranging from
25 mg up to S00 mg from between one and three times a day (or a
placebo instead of the oc-APA derivative) for six days.
EXAMPLE 4
Protocol for colnhination therapv with only a-APA
In this protocol to show the antiviral activity of one
20 regimen of Compound J given with an a-APA derivative in HIV-
selulle~a~ive subjects, Compound J is ;l.l,.,i..;~l~.l"d at a dose of 600 mg
four times a day and the c~-APA dtfiva~iv~ is ~ ..,d at doses
ranging from 25 mg up to S00 mg from between one and three times a
day. Antiviral activity is measured before and during combination
25 therapy by measuring serum levels of the HIV p24 antigen, serum levels
of HIV RNA, and CD4 Iymphocyte counts.
While the foregoing specification teaches the principles of
30 the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the invention
r.l .nn. ..p~cceS all of the usual variations, adaptions, or modifications, as
come within the scope of the following claims and its equivalents.
