EP1140076A1 - Use of 5ht3-receptor antagonists for the treatment of chronic fatigue syndrome - Google Patents

Abstract

The invention relates to the use of 5HT3-receptor antagonists for the preparation of a medicine for the treatment of chronic fatigue syndrome.

Description

USE OF 5HT ₃ RECEPTOR ANTAGONISTS FOR THERAPY

OF THE CHRONIC FATIGUE SYNDROME

The present invention relates to a new use for 5HT ₃ receptor antagonists.

CFS, chronic fatigue syndrome or chronic IV fatigue syndrome, was defined as a diagnostic entity in the late 1980s and has been the subject of numerous studies and publications since then.

Particularly problematic with regard to the diagnosis of CFS is the fact that there is a symptom complex of pathological fatigue and fatigue, whereby the symptoms at hand are also to be found at least in part in a number of other internal and psychiatric clinical pictures.

When diagnosing CFS, care must be taken to ensure that there are no symptoms that can be assigned to other clinical pictures.

Basically, the question arises of what fatigue actually is. In general, it is physiologically called a lack of performance, but can also be experienced as listlessness, lack of endurance and physical weakness. Mental fatigue can be divided into poor concentration and memory, lack of interest in activities, and daytime sleepiness.

On the other hand, fatigue is also a natural phenomenon that occurs after physical or psychological stress, which disappears when you rest or sleep. It is therefore important to differentiate between "normal" and "abnormal" Fatigue. It is helpful here that patients suffering from CFS usually suffer from further symptoms that can be used for diagnosis.

Since comparatively short-term fatigue can occur in the course of or after an illness or in the case of severe and persistent exertion, the existence of CFS as a chronic illness can only be concluded in the case of a clinical picture that lasts for at least six months.

In general, the presence of CFS is determined in a patient in whom fatigue cannot be explained medically, even after careful clinical examination. There is general agreement that patients with a defined organic disease should be excluded from the group of CFS patients. With regard to the existence of psychiatric illnesses, there is less agreement regarding a corresponding exclusion. Some researchers believe that depressed and anxious patients should be excluded because they can provide an adequate explanation for fatigue. Other researchers disagree.

Symptoms of chronic mental and physical fatigue, which worsen when active and are often associated with muscle pain, usually occur with CFS. Patients often report that they are efficient for a short period of time, but subsequently experience severe fatigue for hours or days. Other symptoms that are commonly reported include restless sleep, drowsiness, breathlessness, headache, and other symptoms. Depressive phases and anxiety also occur in some of the patients. The diagnosis of CFS is therefore always an exclusion diagnosis.

So far, no effective treatment for the treatment of CFS has been found. Antidepressants are often used for therapy, but the first comprehensive, randomized, placebo-controlled study of antidepressants was negative (Vercoulen, Jan HMM et al., Lancet 1996, 347: 858-61). The subject of the study cited was fluoxetine, with the result that not even patients with accompanying depressive symptoms had a positive result ^• showed a daily dose of 20 mg fluoxetine. This already points to a special ^~ pathogenesis of CFS in contrast to depressive disorders.

Since fluoxetine is a selective serotonin reuptake inhibitor, the cited investigation concludes with the finding that an influence of disturbed serotonin metabolic processes is unlikely to occur in the presence of depression-like symptoms in depressed CFS patients. In this context, reference is made to a further study which relates to serotonin processes in connection with CFS (Yatham L.N. et al., Can. J. Psychiatry 1995, 40, 93-96).

Studies have become known that there is concrete evidence of serotoninergic activity in the brain, as is shown by the significantly increased increase in prolactin in the serum after acute application of D-feufluoroamine in patients with CFS.

Basically, it should be noted that there are no indications of appropriate and effective therapy concepts for the treatment of CFS.

The object of the present invention is therefore to provide compounds which are suitable for the preparation of medicaments for the treatment of CFS.

The present object is achieved by the features of claim 1. Advantageous embodiments of the invention are the subject of the dependent claims.

The present invention is based on the finding that the use of antidepressants which enhance the action of serotonin is not appropriate in CFS, as is also supported by the cited study relating to fluoxetine. First of all, this is a departure from the usual treatment methods, which have essentially focused on the presence of depressive states. It is therefore proposed to use substances that reduce the effect of serotonin, which are channeled through the subset of the so-called 5HT ₃ receptors. According to the invention, the pharmacologically known class of highly specific 5HT ₃ receptor antagonists, which are used, for example, in the treatment of emesis in chemotherapy for cancer, is suitable for this purpose. In an advantageous embodiment of the present invention, the 5HT ₃ receptor antagonists used are alosetron, tropisetron, ondansetron, granisetron, bemesetron or combinations of at least two of the above, very selectively active substances. It is preferred that the amount of active ingredient contained in a dose unit is 2 to 10 mg, an amount of active ingredient of 5 to 8 mg in a dose unit being particularly preferred. A daily dose generally comprises an amount of active ingredient from 2 to 20 mg, particularly preferably an amount of active ingredient from 5 to 16 mg. If necessary, however, the person skilled in the art is also familiar with varying the amount of active ingredient in a dose unit or the amount of the daily dose according to the requirements. The decisive factors for this, such as body weight, general constitution, reaction to the treatment and the like, are constantly monitored by the person skilled in the art in order to be able to react accordingly and, if necessary, to adjust the amount of active ingredient in a dose unit or the daily dose.

The substances used according to the invention for the production of the medicament, 5HT ₃ receptor antagonists, are preferably oral or intravenous

Dosage form processed in order to offer possible variations in the application and to be able to ensure the most gentle possible administration for the respective patient.

The present invention is explained in more detail below on the basis of exemplary embodiments. These exemplary embodiments serve to explain and in no way limit the scope of the present invention.

To check the effectiveness of the therapeutic approach according to the invention, two patient groups of ten patients each were treated with tropisetron and ondansetron, respectively.

In the previous diagnosis, the Chronic Fatigue Syndrome (CFS) was narrowed down based on classification criteria, based on those of the Centers of Disease Control and Prevention in Atlanta in the version revised in 1994 (Fukuda K. et al., Ann Intern Med 1994; 121: 953-1959). The assessment was based on a clinically confirmed, aetiologically unclear, persistent or recurrent exhaustion (duration> 6 months) that was new or could be used for a limited period of time (does not already exist for life) It is not the result of an ongoing overload, which does not improve significantly through rest, which leads to a significant reduction in the previous level of activity in training and work as well as in the social and personal area. The prerequisite is that the occurrence of 4 or more of the following symptoms, all of which must have persisted or recurrent for at least 6 consecutive months of the disease and must not have preceded exhaustion. The symptoms are:

- Short-term memory or concentration limitations that are severe enough to cause a substantial reduction in previous activity levels

Sore throat (non-purulent pharyngitis)

- Painful neck and armpit lymph nodes

- Muscle pain

- Arthralgia

- New quality headache

- no rest through sleep

- Worsening of condition for more than 24 hours after exertion.

Such an exclusion diagnosis allows a patient group to be narrowed down according to the preceding criteria, the prevalence of which is approximately 3% and the complaints cannot be named otherwise for diagnosis. With

The group of patients treated with tropisetron received the active ingredient in the form of a capsule with an active ingredient amount of 5 mg / dose unit, the daily dose also being 5 mg. The second group of patients received the active substance ondansetron in tablet form, one dose unit containing 8 mg of active substance and the daily dose consisting of two dose units twice, i.e. 16 mg daily.

The 5HT ₃ receptor antagonists were administered over a period of 15 days. During the study period, patients were tested for the following ^"listed parameters:

- MARDS; Days O and 15

- VAS (visual analog scale) fatigue / exhaustion; Days 0, 8 and 15

- VAS performance; Days 0, 8 and 15

- Daily documentation of both VAS by the patient himself

- accompanying symptoms; Days 0, 8 and 15

- performance in the course; Day 15

- final assessment by doctor and patient; Day 15

The main changes under therapy were visualized

Analog scales were recorded, which documented the extent of the abnormal fatigue / exhaustion and the reduction in performance. Here, the subjectively invented state with regard to fatigue / fatigue or performance was marked on a one-dimensional scale, which covers a range from 0 to 100, where 0 stands for normal fatigue / fatigue or performance and 100 for the greatest fatigue / fatigue or for 100% reduction in performance.

Regarding the two visual analog scales, a significant improvement of more than 35% was found in a third of the patients. This affected both patient groups equally. If one also takes into account the patients who reported a noticeable improvement, the response rate is approx. 66%.

The studies carried out clearly show that a significant improvement occurred in about a third of the patients with the main symptoms of CFS, exhaustion and reduced performance, with a further third feeling at least a slight improvement in the symptoms. This is a very clinical point of view Significant therapeutic success, especially against the background that other therapeutic approaches have proven to be practically ineffective.

Another important indication for the therapy of CFS on the effectiveness of the proposed therapy is the fact that in the experiments described and described above, a significant improvement in the patient's condition could already be observed within the examination period of 15 days, which in view of the Persistence of the observed symptoms is extremely surprising, since the diagnosed symptoms had to be present for more than 6 months by definition.

The effect of the substances tropisetron and ondansetron used in the study on the inhibition of the 5HT ₃ receptor as the highly specific principle of action common to the two substances is based on the fact that these two compounds differ considerably in their chemical structure and are the only thing in common in the presence of a structural element is in the form of an indole ring.

Claims

Expectations 1. Use of 5HT ₃ receptor antagonists for the manufacture of a medicament for the treatment of CFS (Chronic Fatigue Syndrome). 2. Use according to claim 1, characterized, that as 5HT ₃ receptor antagonists alosetron, tropisetron, ondansetron, Granisetron, Bemesetron or combinations of at least two of the above substances can be used. 3. Use according to claim 1 or 2, characterized, that the amount of active ingredient contained in a dose unit is 2 to 10 mg, in particular 5 to 8 mg. 4. Use according to one of the preceding claims, characterized, that a daily dose comprises an amount of active ingredient from 2 to 20 mg, in particular an amount of active ingredient from 5 to 16 mg. 5. Use according to one of the preceding claims, characterized, that the drug is manufactured in an oral or intravenous dosage form.