CH710163A2 - Bupropion used to treat multiple sclerosis. - Google Patents

Abstract

The invention relates to bupropion or a pharmaceutically acceptable salt thereof for use in the treatment of multiple sclerosis and to a corresponding pharmaceutical composition.

Description

The present invention relates to a novel pharmaceutical use of bupropion.

description

Multiple sclerosis (MS) is a disease that has been documented for centuries. It is currently one of the most common neurological diseases with considerable effects on the patient and socio-medical importance. Current attempts at treatment are of the immunosuppressive type or symptomatic type, with the current pharmacological treatment attempts being inadequate. In the context of the present invention, therapy or treatment is intended to mean the improvement or lack of deterioration in a condition.

The substance bupropion Bupropion has the following structure:

(S) shape (top) and (R) shape (bottom)

[0004] Bupropion is usually present as a 1: 1 mixture of stereoisomers. The most common salt form is bupropion hydrochloride.

C13H18CINO (bupropion), Mr = 239.74g / mol, CAS no: 34911-55-2 / 34841-39-9 C13H18CINO. HCl (bupropion hydrochloride), Mr = 276.20g / mol, CAS-No: 31677- 93-7

(RS) -1- (3-chlorophenyl) -2-tert-butylamino-propan-1-one (IUPAC) Mp 233-234 ° C

Bupropion (formerly: amfebutamone) is a frequently prescribed antidepressant from the group of phenethylamines or their subgroup of amphetamines and amphetamine derivatives. Bupropion works by selective inhibition of reuptake and thus indirect activation of certain receptor systems. It creates complex clinical symptoms. Withdrawal symptoms may occur when you stop. Bupropion is currently approved for the treatment of depressive illness. Other indications include smoking cessation, and off label mitigating the side effects of antidepressants, weight loss, and ADHD.

Pharmacodynamics

It is currently well known that buproprion acts in the receptor systems of dopamine and norepinephrine, as the adrenergic related system. The structure is similar to other catecholaminergic substances. It acts as a reuptake inhibitor in these receptor systems. In addition, a lower reuptake block compared to the serotonergic system is known. An effect on MS cannot be derived from these receptor systems, rather the opposite. For purely receptor-specific considerations, bupropion should be harmful and not beneficial in MS, which is also reflected in the fact that the administration of bupropion is not considered indicated in the presence of MS. There are case studies about the worsening of MS when bupropion was administered in the presence of MS, but these were repeatedly put into perspective. (Bürge, Ball, Chataway: CNS Demyelinization after treatment with Bupropion, The Internet Journal of Neurology 2008 Volume 10 Number 2).

Certain enantiomers are believed to have a stronger effect, although this has not been proven with certainty. In the invention, the term bupropion explicitly includes the mixture of enantiomers and the individual isomers. The preferred salt of bupropion is the hydrochloride, but the disclosure is not limited to this, but rather includes all physiologically acceptable salts of bupropion.

Pharmacokinetics

Bupropion taken orally has a high bioavailability of more than 85%. There are various release characteristics from 2 hours to 12 hours depending on the pharmaceutical preparation. In the invention, all release characteristics are explicitly taken into account. There are currently two isomers. As far as is currently known, both are pharmacologically active. However, all enantiomers are explicitly taken into account within the invention.

Multiple sclerosis or disseminated encephalomyelitis

Somatic diseases are categorized according to ICD 10. The definition of the diseases and the symptoms are explicitly defined in the present application according to this diagnostic system. The current invention relates explicitly to the disease definitions of this categorization system.

In general, multiple sclerosis (MS) is a chronic inflammatory disease of the medullary sheaths of the human nervous system. These demyelinating foci are the characteristic signs and can cause any form of psychiatric neurological symptoms, as they can occur at any point in the nervous system (brain, spinal cord and peripheral nerves).

An etiology has not yet been found. From infection hypotheses to nutritional hypotheses, all etiological images are still being discussed.

There are various forms of MS. This invention explicitly includes all currently described forms and all other forms of MS with typical symptoms. The currently described symptom groups of MS are relapsing-remitting and primarily or secondarily progressive.

Since it is a disease that can affect any part of the nervous system, there are all kinds of symptoms. This is why MS is also known as the “chameleon of neurology”.

The most frequent initial symptoms are visual disturbances, paresthesias, numbness or tingling sensations. Foci in the brain stem can lead to eye movement disorders, swallowing disorders, dizziness, as well as impaired movement coordination (ataxia) and speech disorders (dysarthria). The Charcot triad is the symptom complex of intention tremor, nystagmus and chanting language that occurs in demyelinating foci in the area of the upper cerebellar stalk. When the motor system is affected, symptoms of paralysis occur, whereby the patient's ability to move may be additionally restricted by an abnormal sudden increase in muscle tone (spasticity). If vegetative centers and tracts are affected, disorders of the control of the bladder and bowel function and sexual dysfunction can occur. In very many patients, increased physical and psychological fatigue occurs over time. Not to be neglected are severe cognitive impairments and psychiatric disorders such as depression. Symptoms similar to dementia can develop.

The diagnosis is first made on the basis of the clinic, but then using imaging methods and laboratory tests (liquor diagnostics).

The current therapy is based on immunomodulation due to beta globulins or immunosupressants. In addition, symptomatic therapies such as antidepressants, antispastics or pain relievers were used.

The current view on MS and the use of bupropion is that it is not a therapy option, as there are supposedly case reports of exacerbation of MS symptoms.

In certain cases, the use of bupropion in fatigue has been discussed. However, this would be rejected due to the alleged problem of worsening symptoms.

The completely surprising therapy option arose due to the failure to observe a contraindication in a patient. The patient presented as a psychiatrist did not indicate the existing MS in the anamnestic investigation. Because of the depressive symptoms, bupropion was prescribed in high doses (300 mg / d). However, when the check-up was called, the patient stated that she had MS. However, it came as a complete surprise not only to an improvement in the depressive symptoms, which was to be expected. The gait disorders, speech disorders and visual disorders not shown by her had improved significantly within four weeks after an initially seen deterioration. Why the patient did not stop taking the substance or did not see a doctor remains unclear.

It was clearly shown, however, that the neurological and psychiatric symptoms were improved in a clearly stable manner. An MR examination after 3 months showed a decrease in the medullary lesions rather than a deterioration.

[0023] These results could be verified in three further patients.

When bupropion was administered, surprising improvements were found in the following areas: Weight loss Improving physical activity, Fatigue was perceived considerably less Gait ataxia was noticeably reduced Speech disorders improved Visual disturbances and eye pain improved Sensation of pain throughout the body Paresthesia Signs of paralysis Swallowing disorders and respiratory disorders Sexual function and erectile function Bowel and bladder functions could be controlled much better again.

The invention therefore relates to the therapy of the symptoms of multiple sclerosis with stabilization or improvement of the individual symptoms by administration of bupropion.

The medication can be administered in any pharmaceutical form. Be it

Oral: retarded, unretarded, retarded and unretarded mixed, or intravenously, nasally, pulmonarily or dermally as a dermal patch.

The substance can be administered in any salt form. Physiologically well tolerated salts, such as the hydrochloride, are preferred.

The dosage is between 0.5 mg per day up to 1200 mg per day in exceptional cases.

Examples

Retard capsule

In the following preparation examples, the specified active ingredients are each compressed with the auxiliary substances and compressed to form a prolonged-release tablet:

Auxiliaries: Lactosum Monohydricum, Antioxidant E321, Bupropion Hydrochloride Medical Application Example

[0032] The examples are used as exemplary possibilities for treating MS. Daily administration of 300 mg of retraded bupropion hydrochloride results in a clear improvement in the condition. In the patients, there was a reduction and stagnation of gait ataxia, fatigue, bladder weakness, visual insecurity and sexual dysfunction. Thus, overall there was a considerable improvement in the clinical picture.

Ingestion of 150 mg non-delayed bupropion.

After another standardized evaluation after four weeks of intake there was an improvement in the patient with regard to the reduction and stagnation of the weight loss and a weight gain of 2 kg at a height of 166 cm and previously 50 kg. An improvement in walking difficulties, spasticity and joint rigidity, a clear improvement in the use of painkillers with a reduction in the use of opiates. The reduced ability to articulate improved and the extremely slurred speech improved significantly. Thus, overall there was a considerable improvement in the clinical picture.

Claims (3)

1. Bupropion or a physiologically acceptable salt thereof for use in the treatment of multiple sclerosis. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising bupropion or a physiologically acceptable one thereof. 3. Pharmaceutical composition according to claim 2, characterized in that the physiologically acceptable salt is bupropion hydrochloride.