Scandinavian journal of rheumatology. Supplement最新文献

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.

Current research suggests an involvement of 5-HT3 receptors in peripheral and central perception and processing of pain as well as in inflammation. Tropisetron and other selective 5-HT3 receptor antagonists have been used successfully for pain reduction and treatment of related symptoms in patients diagnosed with fibromyalgia. This article proposes a concept of the underlying pathophysiology and mechanisms of action of 5-HT3 receptor antagonists in the context of the relevant clinical data on their application in patients with rheumatic disease.

Background: There is no known disease-modifying therapy for progressive systemic sclerosis.

Objectives: It was shown that a patient with secondary fibromyalgia syndrome for whom the development of systemic sclerosis was suspected because of a Raynaud's phenomenon and the presence of SCL-70 antibodies in the serum had experienced a clear pain reduction under treatment with tropisteron, which is the reason why this drug was also used with established systemic sclerosis.

Method: Two patients with progressive systemic sclerosis and positive SCL-70 antibodies were treated for 6 weeks with 5 mg tropisetron daily. Both patients had clear skin symptoms, functional impairments of the locomotor system, and a secondary fibromyalgia syndrome. The skin score and joint motion were checked before, during, and after treatment. In addition, the patients filled in the visual analog scale for pain at these times. At the end of the 6 weeks, the patients showed a clear improvement of the skin score and the movability of various joints as well as a clear reduction of pain. The medication was well-tolerated. Constipation developed in the patients; it could be controlled with laxatives. Follow-up questioning of the patients after 3 months showed that their condition had remained stable.

Conclusion: Two patients with progressive systemic sclerosis showed an improvement of various symptoms under a blockade of the 5-HT3 receptors via tropisetron. The long-lasting effect pointed to immunomodulation. The two cases give cause for clarifying this by means of clinical studies, which should also investigate the question of dosage (possibly 5 mg tropisetron twice daily).

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet provide a homogenous conception of the significance of 5-HT3 receptors in all investigated fields; in nociception, for example, contradictory observations are still inadequately explained and complicated by bell-shaped dose-response curves. Further elucidation and better understanding of the serotonergic neuronal network remains a task for the next decade.

Unlabelled: The use of local tropisetron injections improved the treatment of tendinopathies considerably, with the effect being comparable to the topical application of local anaesthetics combined with depot corticosteroids. On the other hand, local injection of prilocaine alone exerted a shorter and weaker effect on the condition.

Objectives: After it had been proven that systemic application of the 5-HT3 receptor antagonist tropisetron exerts an analgesic effect on musculoskeletal pain in fibromyalgia, we investigated the efficacy of the substance in tendinopathies and myofascial pain syndromes.

Results: Local injections of tropisetron as a treatment for trigger points in myofascial pain syndrome also brought about rapid and prolonged relief in the majority of cases. The analgesic effect was far superior to the action of local anaesthetics.

Conclusion: The present findings indicate that the analgesic action of the 5-HT3 receptor antagonist tropisetron sets in rapidly and lasts for a long time. Various mechanisms are under discussion to explain the long duration of the effect. Tropisetron not only has an analgesic but probably also an antiphlogistic effect which can be attributed to the inhibited release of substance P and other neuropeptides from the nociceptors and the blocked release of phlogistic substances from macrophages, monocytes etc.

Several lines of research indicate that serotonin (5-hydroxytryptamine, 5-HT) and 5-HT receptors may play a part in the pathogenesis of chronic inflammatory rheumatic conditions like rheumatoid arthritis (RA) and scleroderma/progressive systemic sclerosis (PSS). In this paper, case reports on two patients with RA who were successfully treated with 5-HT3 receptor antagonist tropisetron were presented. Short-term oral tropisetron (5-10 mg/d) induced either remission of RA or improvement in RA-related symptoms, which lasted for several weeks or months after the treatment was discontinued. Interestingly, tropisetron was effective in a patient with refractory rheumatoid vasculitis, which is a severe complication that requires high-dose glucocorticoids in most cases. The beneficial effect of 5-HT3 receptor antagonists in RA and PSS suggests that this class of drugs may have potential in the treatment of chronic inflammatory rheumatic conditions. Double blind, placebo-controlled studies are urgently needed to confirm the efficacy and tolerance of 5-HT3 receptor antagonists in larger cohorts of patients.