SK76696A3 - Pentoxifyllin allone or in combination with corticosteroid - Google Patents

Abstract

The invention concerns the use of pentoxifyllin in the treatment of the stepwise advancing or chronically progressing form of multiple sclerosis. This use can be implemented alone or in combination with corticosteroids. The dose is 0.01 to 6.0 g/day, irrespective of the presence of corticosteroids.

Description

Pentoxyfylline alone or in combination with a corticosteroid

Technical field

The invention relates to ammonium pentoxyphylline or in combination with a corticosteroid for the preparation of a medicament for the treatment of multiple sclerosis.

BACKGROUND OF THE INVENTION

Multiple Sclerosis (SM) is one of the most common nerve diseases in our latitudes. It starts mostly at the age of early adolescence and can occur chronically progressively or in gradual impacts (attacks, relapses). The exact mechanism of its formation is not yet known. Genetic predisposition and the environment appear to have some impact.

A known pattern of disease is scattered foci of marrow disruption in the patient's central nervous system (CNS). This demyelination spreads in non-systemic shocks in the CNS and leads to nerve-mediated so-called. attacks (outages) that characterize the symptomatics of the disease.

In many cases, there is a curable new stage of sustained disease progression. Pathomechanisms other than progressive demyelination are believed to play a role at this late stage.

Until now, this disease can only be treated symptomatically when it occurs with impacts (attacks) with new neurological symptoms by administering corticosteroids (1 g / day i.v. for three days), resulting in a shorter impact time. However, due to the known numerous and difficult side effects of corticosteroids, preventive continuous therapy cannot be performed. In addition, this treatment is very difficult and risky in patients suffering from other corticosteroid-susceptible diseases such as type 1 diabetes mellitus.

To circumvent these disadvantages, the efficacy of different classes of drugs has been investigated.

Studies of long-term therapy of SM with immunosuppressive agents such as Azathioprine or Cyclosporin A have shown that these agents had no effect on the course of the disease. In contrast, subcutaneous administration of Interferon-beta for the first time showed a marked reduction in attacks. However, the administration of Interferon-beta is difficult for the patient to use due to the many side effects and very high cost. In addition, Interferon-beta works only in patients with mild initial symptoms of SM.

The task is to find a preparation for SM therapy which overcomes the above-mentioned disadvantages.

Surprisingly, this problem has been solved using Pentoxifylline.

SUMMARY OF THE INVENTION

The present invention relates to pentoxyylline alone or in combination b with a corticoeteroid for the preparation of a medicament for the treatment of an acute or chronically progressive form of multiple sclerosis.

Pentoxifylline (PTX) is known to positively affect the formability of erythrocytes and leukocytes. It is therefore mainly used to improve microcirculation in angiopathies (J. of Medicine, Vol. 10, No. 5, 1979) or generally in peripheral arterial vascular disorders and immune disorders. Pentoxifylline is known to reduce platelet aggregation (platelets), promote the release of prostacyclin I, and reduce the number of lymphoma mitoses. It is therefore used to prevent the formation of metastases and in the treatment of lymphomas (J. of Medicine, vol. 15, no. 5 and 6, 1984). Another indication for the use of Pentoxifylline is experimental peritonitis in which its administration leads to markedly less abscess formation and fibrin deposition (Are. Sog., Vol. 120, pp. 1141-4, 1985).

It has now been found that PTX, in addition to the hitherto known indications, is also suitable for the treatment of multiple sclerosis without the side effects that often occur with other therapies.

In one open-label therapeutic study, it was possible to gain first experience in treating SM attacks with Pentoxifylline. There was a marked reduction in the duration of the attack as well as an increase in the interval without attacks, both for intravenous administration (3 x 200 mg i.v./day for 5 days) and oral therapy (3 to 4 x 400 mg / day).

Λ

The individual dose of Pentoxifylline used depends on the general condition and weight of the patient. It is generally 0.01 to 6 g / day, preferably 1-3 g / day, and most preferably 1.2 - 2.4 g / day. The concentrations used in relation to body weight are 0.1 to 120 mg / kg per day, preferably 10 - 60 mg / kg per day, and most preferably 12 - 48 mg / kg per day.

In addition, it has been found that, in addition to the administration of Pentoxifylline alone, the combination with corticosteroids can be unexpectedly indicated in the treatment of acute attacks, due to the surprising synergistic effects of the two agents when co-administered.

Among the corticosteroids in addition to other therapeutically used agents, prednisone, prednisolone, prednisolone-21-acetate, prednylidene and methylprednisone are particularly suitable. Preferably methylprednisolone is used.

The dose is from 0.01 to 10 ³ mg / day, preferably 10-250 mg / day, and .najvýhodnejšie 100-200 mg / day. In units per day and kilogram of body weight, it is 10 ⁴ - 20, preferably 0.1 - 2.5, and most preferably 1-2 mg / kg per day.

When combining PTX with corticosteroids, dosages corresponding to the most preferred dosage, such as e.g. 1.2 mg / day PTX (16 mg / kg and day PTX) orally and 500 mg / day methylprednisolone (7 mg / kg and day i.v.) for 3 days. This amount is clearly below the dosage used so far in the treatment of acute attacks (1 g / day i.v. for 3 days).

Lower doses with the same outcome of therapy significantly reduce the risk of a transient level of diabetic metabolism, which is often observed at previously used doses.

Naturally, the physician may deviate from the doses provided herein in individual assessments.

Dosage units of pure PTX preparations, as well as combinations with corticosteroids, can be in the form of tablets, dragees, capsules, or retard formulations, where, when using capsules, the capsule material assumes the function of a carrier, and the contents can be e.g. powder, gel, emulsion, etc. It is particularly advantageous to prepare an oral, sublingual and oral formulation with the active ingredient containing a calculated amount of the active ingredient together with the desired carrier. It is also possible to make preparations for transdermal or parenteral (i.p.,

i.v., i.m., subcutaneously) injections of solutions or crystalline suspensions as depot preparations. Inhalation preparations (spray preparations) and lace are also applicable. All of the above preparations are made according to known procedures.

All pharmacologically customary materials are used as carrier materials, excipients and additives.

The possible dose (dose) is 200, 400, or 600 mg PTX / tablet, or 100, respectively. 300 mg PTX / ampoule; corticosteroids 0.5 - 10 mg / tablet or 10 - 1000 mg / ampoule.

In the case of combination preparations, 200-300 mg PTX and 0.5-10 mg corticoid / tablet or 100-150 mg PTX and 10-1000 mg corticoid / ampoule are used.

Examples

Example 1:

The patient (42 years, 64 kg of body weight) was ill with a sudden progressive SM disease eight years ago. It has been treated with corticosteroids during previous impacts (attacks), but this has already led to psychosis several times. The patient was admitted with symptomatology of the brainstem (double vision, trigeminal paraesthesia and gross nystagmus with vertigo and nausea). In nuclear spin tomography a new plaque appeared in the brainstem. PTX infusion therapy (3 x 200 mg / day i.v.) was performed. Already on the second day, the patient experienced a clear improvement in the symptoms of vertigo and double vision. After two days, nystagmus and vertigo tendency were not clinically detectable. The patient was switched from infusion therapy to oral medication 3 x 400 mg / day. Prior to this therapy, the patient regularly had 3-4 attacks (attacks) per year.

Example 2:

The patient (45 years, 58 kg of body weight) was ill with SM three years ago. Up to now, there have been predominantly symptoms of sensitivity, which have resulted in particularly unpleasant limb paresthesia. During a new attack with a tormenting burning sensation on both legs, the patient was treated with a dose of 400 mg PTX / day. The dysesthesia that had lasted for several weeks had been reduced so much after three days that the patient could get up again and do her daily housework. Again, there is a 5-month observation period during which no problems have occurred so far.

Example 3:

In one patient (36 years, 62 kg body weight), SM is known for two years. Since then, he has had five attacks that were not very pronounced and did not need treatment. Because the patient is suffering from type 1 diabetes mellitus, steroid therapy is very risky. Retrobulbar neuritis has been diagnosed with sudden impairment of left eye vision. Fundoscopy (observation of the eye background) was inconspicuous. An IV infusion therapy with PTX (3 x 300 mg / day) was started immediately. Already the next day the symptoms subsided, the patient again recognizes the numbers and the visa improved from 0.1 to 0.65.

Example 4:

In a 48-year-old female patient, she was diagnosed with suddenly progressing MS at 36 years of age. In the last two years there have been accumulations of attacks affecting sensitivity and brainstem. Symptomatics have always been unsatisfactorily returned to their original state after the last two attacks, leaving residual conditions with slight ataxia and a picture of spastic gait. After a severe attack with complete loss of the right eye visa (vision) again, we decided to give Pentoxifylline at a dose of 1200 mg orally for weeks over a high dose of methylprednisolone (1 g / day, i.v. for 3 days). Thus, within five days, not only the visa of the affected eye was nearly completely returned, but the residual symptoms of past attacks were also clearly improved. The patient continued to take Pentoxifylline (orally) at the above doses at her own desire and there was no renewed attack within 8 months. Other symptoms have also improved objectively and objectively.

Example 5:

In a 23-year-old female patient suffering from SM for two years, the left half of her body became paralyzed for the first time after a purely sensitive attack. Initial high-dose treatment with methylprednisolone (1 g i.v. for 3 days) did not result in any significant improvement in symptoms. Therefore, we decided to continue to give oral methylprednisolone at a lower dose (100 mg, reduced to 20 mg every other day), if this was to be administered to the patient 1200 mg of Pentoxifylline orally, thereby dramatically improving and restoring the ability to walk without tools over the next 3 days. . Then, based on pathological glucose tolerance, the cortisone dose was reduced very rapidly while maintaining the dosage of Pentoxifylline. In this way it was possible to maintain the acquired stability and improvement of the gait image, and again in this case the patient would like further treatment with Pentoxifylline.

Claims (1)

Use of pentoxyphylline alone or in combination with a corticoeteroid for the preparation of a medicament for the treatment of an acute * or chronically progressive form of multiple sclerosis.