Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- 2 1 7~8~8
The Use of Pento~y~hylline
in Treating Multiple Sclero~
The present invention relates to the use of pentoxy-
phylline in treating both intermittently and chroni-
cally progressing forms of multiple sclerosis.
Multiple sclerosis (MS) is one of the most frequent
neurological disorders in our part of the world. It
usually starts in early adulthood and can progress ei-
ther chronically or intermittently. As yet, its exact
development mechanism is not known. However, both a ge-
netic disposion and environmental factors seem to play
a rôle.
Part of the clinical picture of MS are the disseminated
patches of demyelinisation in the central nervous sys-
tem (CNS) of the patient. This demyelinisation spreads
intermittently and unsystematically in the central
nervous system and causes the so-called attacks of
nerve-related defunctionalisation which characterise
the symptomatology of the disease.
In many cases, a new stage of steady progression of the
disease occurs which can be delimited. It is assumed
that other pathomechanisms than the progressive demye-
linisation play a rôle at this late stage.
So far, it was only possible to treat the symptoms of
the disease by administering corticosteroids (1 g/day
i.v. for three days) when attacks accompanied by new
neurological symptoms occurred; said administration
helps reduce the duration of such attacks. Due to the
known, manifold and severe side effects of corticoids,
however, it is not possible to use them for prophylac-
21 76~48
.
tic continous therapy. Moreover, the treatment of pa-
tients who also suffer from other diseases which can be
influenced by corticosteroids such as diabetes melli-
tus, type I, is very difficult and hazardous.
In order to avoid these disadvantages, I have examined
the effectiveness of various groups of drugs.
Studies have shown that a long-term therapy of MS with
immunosuppressants such as azathioprine or cyclosporine
A has no effect on the progression of the disease. The
subcutaneous application of interferon-B, on the other
hand, resulted in a noticeable reduction of attacks.
However, the application of interferon-B is difficult
for the patient to administer, accompanied by numerous
side effects and very costly. In addition, interferon-B
is only effective in patients where initial MS symptoms
are slow to develop.
Therefore, it is the object of the invention to provide
a preparation for the therapy of MS which overcomes the
above-described disadvantages.
The object of the invention is surprisingly achieved by
the use of pentoxyphylline in the treatment of both in-
termittently and chronically progressing forms of MS.
It is a known effect of pentoxyphylline (PTX) that it
has a positive influence on the deformability of eryth-
rocytes and leucocytes. Therefore, it is primarily used
in cases of angiopathy to improve the microcirculation
(Journal of Medicine, Volume 10, No. 5, 1979) or to
treat peripheral arterial circulation disorders and im-
muno-disorders in general. Secondly, it is known that
pentoxyphylline reduces platelet aggregation, promotes
the release of prostacycline I and reduces the rates of
mitosis of lymphomae. Therefore, it is used in the
- 2 1 76~48
-
therapy of lymphomae and to prevent the development of
metastases (Journal of Medicine, Volume 15, No. 5 and
6, 1984). Another indication for using pentoxyphylline
is experimental peritonitis where, when administered,
it reduces abscess formation and fibrin deposits (Arc.
Sog., Volume 120, pages 1141 - 1144, 1985).
It has now been found that, in addition to the indica-
tions previously known, PTX is suitable for treating
multiple sclerosis without any of the side effects that
frequently occur in other forms of therapy.
In the course of an open therapy study, we gained first
experience in treating MS attacks with pentoxyphylline.
It was found that both the intravenous treatment (3 x
200 mg i.v./day for five days) and the oral therapy (3
to 4 x 400 mg/day) resulted in a marked reduction in
attack duration and an extension of the attack-free in-
terval.
The PTX dosage to be used depends on the general state
of health and the weight of the patient. As a rule, it
is 0,01 to 6 g/day, preferably 1 to 3 g/day and most
preferred 1.2 to 2.4 g/day. On the basis of kilograms
bodyweight, the concentrations used are 0.1 to 120
mg/day per kg, preferably 10 to 60 mg/day per kg and
most preferably 12 to 48 mg/day per kg.
It has also been found that, in addition to the appli-
cation of pentoxyphyllin alone, a combination with cor-
ticosteroids in treating acute attacks is indicated due
to a surprising synergistic effect of both substances
when administered jointly.
In addition to other corticosteroids used for thera-
peutic purposes, possible corticosteroids are predni-
son, prednisolon, prednisolon-21-acetate, prednylidene
21 76a~8
A
and methyl prednison. The use of methyl prednisolon is
preferred.
The dosage is 0.01 to 103 mg/day, preferably 10 to 250
mg/day and most preferably 100 to 200 mg/day. Expressed
in mg units per day and kg bodyweight, the dosage is
to 20, preferably 0.1 to 2.5 and most preferably 1
to 2 mg/day per kg.
When combining PTX and corticosteroids for therapy,
dosages corresponding to the most preferred dosages are
preferably prepared, e.g. 1.2 mg/day PTX (16 mg/kg/day
PTX) orally and 500 mg/day methyl prednisolon (7
mg/kg/day, i.v.) for three days. This amount is mark-
edly lower that the dosages so far administered in the
therapy of acute attacks (1 g/day i.v. for three days).
Due to the lower dosages, the risk of a transitory dia-
betic metabolic condition of the kind frequently ob-
served with the dosages used to far is significantly
reduced while the success of the therapy remains iden-
tical.
Of course, any deviations from the dosages specified
here are at the discretion of the physician.
The dosage units both of the neat PTX preparations and
the combinations with corticosteroids may be presented
in the form of tablets, coated tablets, capsules or
sustained-release formulae. When capsules are used, the
capsule material acts as carrier and the contents may
have the form of a powder, gel, emulsion etc. However,
it is particularly advantageous to prepare oral, sub-
lingual and peroral formulations of the active ingre-
dient which contain the calculated amounts of the ac-
tive ingredient together with the desired carrier. It
is also possible to prepare preparations for trans-
dermal or parenteral (i.p., i.v., i.m., subcutaneous)
2176848
-
injection of solutions or crystal suspensions as de-
pository preparation. Preparations for inhalation
(spray preparations) or suppositories may also be used.
All the above-mentioned preparations may be prepared by
known methods.
Any pharmacologically acceptable materials may be used
as carrier materials, excipients and additives.
Possible dosages are 200, 400 and 600, respectively, mg
PTX/tablet, 100 or 300, respectively, mg/PTX ampoule;
and 0.5 to 10 mg/tablet or 10 to 1000 mg/ampoule for
the corticosteroids.
In case of combination preparations, 200 to 300 mg of
PTX and 0.5 to 10 mg of corticoid/tablet or 100 to 150
mg PTX and 10 to 1000 mg corticoid/ampoule are used.
Case examples:
Example 1
A female patient (42 years, weight 64 kg) has been suf-
fering from intermittent MS for eight years. During
previous attacks, she was treated with cortisteroids.
However, this therapy resulted in repeated occurrences
of a psychosis. The patient was admitted to hospital
with brain stem symptoms (double vision, tingling
paraesthesia in the trigeminus sector and coarse nys-
tagmus accompanied by vertigo and nausea). Nuclearspin-
tomography revealed a new patch in the brain stem. A
five-day infusion therapy with PTX (3 x 200 mg/day
i.v.) was carried out. Even the second day, the patient
experienced a significant improvement of the vertigo
and double vision symptomatology. After two days, both
nystagmus and the tendency to fall had disappeared. Af-
- 2176848
_.
ter the infusion therapy, the patient was changed to
oral medication of 3 x 400 mg/day. Since then (six
months), no further attacks have occurred. Before
treatment, the patient suffered from three to four at-
tacks a year.
Example 2
A female patient (45 years, weight 58 kg) has been suf-
fering from MS for three years. So far, mainly sensory
symptoms have occurred which became manifest in un-
pleasant paraesthesia of the extremities. During a new
attack accompanied by excruciating burning sensations
in both legs, the patient was treated with 3 x 400 mg
PTX/day. After only three days, the dysaesthesia which
had often continued for weeks had decreased to a point
where the patient was able to sleep and do day-to-day
housework. Once again, a period of five months has
elapsed without any further attack.
Example 3
In the case of a male patient (36 years, weight 62 kg)
MS was diagnosed two years ago. Since then he had five
light attacks which did not require treatment. Since
the patient suffers from diabetes mellitus, type I, a
steroid therapy would be highly risky. Upon a sudden
deterioration of the vision of the left eye, retro-
bulbar neuritis was diagnosed. An ~m; nation of the
fundus did not reveal any pathological condition. An
i.v. infusion therapy (3 x 300 mg/day) was started
without delay. As early as the next day, the symptoms
had decreased. The patient is able to recognise numbers
and his sight has improved von O.1 to 0.65.
- 21 7~848
. 7
1~ ~
Example 4
In a 48-year-old female patient, intermittent MS was
diagnosed at the age of 36. During the last two years,
there has been a frequent occurrence of attacks affect-
ing the brain stem and the sensory ability. After the
last two attacks, the symptoms did not regress; a re-
sidual condition characterised by slight ataxia and a
spastic gait pattern remained. After another severe at-
tack resulting in a complete loss of vision of the
right eye, we decided to administer pentoxyphylline at
a dosage of 1200 mg (oral) for four weeks in addition
to high dosages of methyl prednisolon (1 g per day i.v.
for three days). Not only was the patient's vision re-
stored almost completely after five days, but also a
significant improvement of the residual symptoms of
previous attacks was observed. At her own request, the
patient has continued the (oral) pentoxyphylline treat-
ment with the above dosage. Since then, eight months
have passed and no new attack has occurred. The other
symptoms have improved significantly both subjectively
and objectively.
Example 5
In a 23-year old female patient MS was diagnosed two
years ago. After several merely sensory attacks, a no-
ticeable hemiparalysis of the left side of the body oc-
curred. The initial high-dosage treatment with methyl
prednisolon (1 g i.v. for 3 days) did not result in a
marked improvement of the symptoms. Therefore, we de-
cided to continue administering methyl prednisolon at a
low oral dosage (100 mg every other day reduced to 20
mg) and to additionally treat her with 1200 mg of pen-
toxyphylline (oral administration). Over the next three
days, a dramatic improvement was observed, and the pa-
tient was able to walk without aid. Due to a pathologic
2 1 7~8~8
~ 8
-
glucose tolerance, the cortison dosage was rapidly re-
duced and the pentoxyphylline dosage continued. The
stabilisation and improvement of the gait pattern con-
tinued. Once again, the patient has requested that the
pentoxyphylline treatment be continued.
