Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5-HT3 receptor antagonists are a novel therapy for patients suffering from fibromyalgia, although the optimal duration of treatment is still unclear. The objective of this phase II study was to evaluate whether prolonging treatment with tropisetron to 4 weeks is tolerable and correlated with an improved clinical benefit. Thirty female patients with fibromyalgia received oral tropisetron (5 mg) daily for 28 days in an open-label fashion. Treatment resulted in significantly decreased pain as measured by visual analog scale (VAS), with a mean reduction of 59.7% and an absolute median change of -25.0 from baseline to day 28 (p<0.0001). A similar, significant reduction of 55.7% and absolute median change of -31.0 was observed in the painscore (p<0.0001). The response rate with patients showing a > or = 35% reduction in individual pain scores was 72.4% at day 28. The pressure tolerance of tender-points was slightly increased at the end of the treatment period. In addition, significant improvements were observed in the State-Trait-Anxiety-Inventory (STAI), scales of von Zerssen (Bf-S) and Beck Depression Index (BDI). Functional symptoms were compared with the results from a 10-day, randomized, double-blind phase III study of tropisetron in 418 fibromyalgia patients. In both studies several functional symptoms such as sleep disturbances and dizziness improved significantly (p<0.05). In the 28 days study, the number and extent of improvement in functional symptoms was increased compared with the shorter trial. Tolerability and safety of tropisetron was good, and typically for 5-HT3-receptor antagonists, gastrointestinal symptoms and headache were the most frequently reported events. In conclusion, 28 days treatment of fibromyalgia patients with 5 mg tropisetron resulted in significant pain reduction, which was most pronounced after 10 days with a further reduction up to day 28. Psychometric tests showed significant improvements in depression and anxiety state scores, while functional symptoms improved with extended tropisetron treatment.
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PMID:Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain. 1102 33

The observed effects on the symptoms of fibromyalgia of daily oral administration of 5 mg of the 5-HT3 receptor antagonist, tropisetron, for 10 days, could be maintained or exceeded with intravenous administration of only 2 mg of the formulation. Following a single i.v. injection of 2 mg tropisetron, a more rapid and profound reduction in pain was achieved than with 5 mg oral tropisetron per day. In individual cases, patients who had previously experienced no reduction in pain from 10 days of 5 mg oral tropisetron daily responded to i.v. therapy. A more favourable and persistent effect on pain, combined with a simultaneous significant improvement in various vegetative and functional symptoms was achieved with five days treatment with 2 mg tropisetron i.v. per day. The results outlined and the possibility for rapid improvements with drug treatment of fibromyalgia should be confirmed in randomised, placebo controlled trials.
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PMID:Results of the intravenous administration of tropisetron in fibromyalgia patients. 1102 34

A prospective, randomized, placebo-controlled, multicenter, double-blind trial in fibromyalgia patients demonstrated that peroral daily treatment with 5 mg tropisetron for 10 days produced a significant reduction in pain and other symptoms. The aim of the present study was to determine whether intravenous administration of 2 mg tropisetron daily for a limited period of time would produce quicker and more favorable results. In the first cohort 18 fibromyalgia patients received a single intravenous injection of 2 mg tropisetron. In the second cohort 24 fibromyalgia patients were treated with 2 mg intravenous tropisetron daily for 5 days. Pain intensity was measured with the visual analog scale and the pain score. Pain at tender and control points (dolorimeter) as well as 17 ancillary symptoms before and after treatment were evaluated. Pain intensity was followed-up by means of a patient diary until recurrence. Dolorimetry revealed that a single intravenous injection of 2 mg tropisetron significantly reduced pain and enhanced pain threshold. These effects, however, lasted for only a few days. Of 18 patients in the first cohort, only three showed no response to therapy. Of the 24 patients in the second cohort, 23 showed pain reduction when 2 mg tropisetron was administered daily for 5 days. Pain relief lasted for 2 weeks to 2 months in 20 of these patients. Two patients stopped filling in the pain diary. Twelve ancillary symptoms such as sleep disturbances, fatigue, morning stiffness were also significantly improved by the latter treatment. In the global assessment 16 out of 24 patients showed significant improvement and seven showed slight improvement. Only one patient experienced no improvement. Tolerability was good. In conclusion, intravenous injection of 2 mg of the 5-hydroxytryptamine3 receptor antagonist tropisetron once daily for 5 days produced a longer-lasting therapeutic effect on fibromyalgia symptoms than did peroral daily treatment with 5 mg of this drug. The results achieved are currently being evaluated in a randomized, placebo-controlled, double-blind trial.
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PMID:Fibromyalgia treatment with intravenous tropisetron administration. 1144 69

Pain is perceived, transmitted, processed and modulated within an extensive network of neurotransmitters and hormones. Despite increasing knowledge about the biologic principles, even on the molecular level, the more we learn about the precise mechanisms of their interactions the more questions arise. It is also pertinent to remember that clinical scientists studying pain modulating pharmacologic agents always have to consider possible placebo effects [57-61]. Most of our knowledge regarding the function of neurotransmitter systems in the CNS has been provided by animal studies. Thus we cannot be sure that they have exactly parallel counterparts in humans. For instance, animal studies suggest an inverse relationship between brain and spinal cord concentrations of substance P. If these observations are converted to an interpretation of human fibromyalgia, low brain-tissue levels of both serotonin and substance P should be expected, while spinal cord serotonin concentrations would be low and spinal cord substance P would be high [1]. There is good evidence that 5-HT, its receptors, and their interactions with other neurotransmitters are essential for nociception and antinociception. The activities of 5-HT receptors can be studied by agonist and in humans especially by antagonist use. But even with a direct spinal application of selective agonists and antagonists, observations may still be confounded by (1) dose, as there can be a dose-dependent activation of different receptor subtypes; (2) type of nociceptive tests (e.g., thermal versus pressure versus chemical models), which may have differences in the way they are regulated; and (3) influences due to effects on temperature, blood flow or motor function. With this potential for variability, it is perhaps not surprising that there is some variability in the results of studies reporting on the effects of various 5-HT agonists and antagonists on nociceptive transmission within the spinal cord [62]. For instance, different 5-HT3 receptor densities could exist in various neuronal systems, one density type being completely inhibited at low concentrations, and the others only at higher concentrations of 5-HT3 receptor antagonists, thus resulting in contrary effects. Finally, the "endogeneous 5-HT tone" may greatly influence agonist and antagonist action. Considering this complexity of serotonin-mediated reactions, it is not surprising that treatment of pain by 5-HT3 receptor antagonists appears to yield inconsistent results. As fibromyalgia is now regarded as a pain amplification syndrome with a broad variety of additional nonpain symptoms, the interrelations are complicated even more. Fibromyalgia associated symptoms (e.g., fatigue, insomnia, and irritable bowel syndrome) can be modulated by 5-HT3 receptor antagonists. From the data evaluated so far, there is evidence that 5-HT3 receptor antagonists provide significant benefit in some fibromyalgia patients. In our practice, the data justify a careful application in clinical use according to the study results. The dosage, route of application, long term adverse reactions and duration of therapy still need to be studied in greater detail. Recently reported adverse events from therapy of irritable bowel syndrome with alosetron [63-67] provide a note for caution before hastily using 5-HT3 receptor antagonists without more studies. One can surmise that, much as the biochemistry of depression has been elucidated by the development of the SSRIs, a greater understanding of the role of 5-HT3 receptor antagonists in treating fibromyalgia patients may provide some insights into disease mechanisms of this enigmatic disorder.
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PMID:Current experience with 5-HT3 receptor antagonists in fibromyalgia. 1212 20

It is well known that the 5-HT3 receptor tropisetron shows a bell-shaped dose-response curve in the treatment of pain associated with fibromyalgia. The best results are achieved with a daily oral dose of 5 mg for 10 days. Dosages of 10 and 15 mg per day have a much weaker effect. If tropisetron is administered by intravenous injection, a regimen of 5 mg per day over 5 days will suffice to reduce pain substantially. An open study of selected cases revealed that 2 mg of tropisetron daily for 5 days also yielded satisfactory pain reduction, whereas this was not observed in a placebo-controlled double-blind study. We therefore investigated which factors might be responsible for the different effects of the drug. Judging from the above-mentioned studies, the effect of a minimum dosage of tropisetron could be assumed to be partly attributable to the different half-life periods. This is supported by the markedly different rates of constipation, a characteristic side effect of the drug, reported by the two studies.
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PMID:Do cytochrome enzymes influence the therapeutic effect of tropisetron in fibromyalgia? 1295 40

Modern management of fibromyalgia (FM) requires a holistic approach, which includes nonpharmacologic strategies (both exercise and behavioral strategies) and pharmacologic treatment. Despite only partial effects in some patients, tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal antiinflammatory drugs, analgesics and opioids are in use. The use of antiepileptic drugs and antispasticity agents is mainly supported by anecdotal data. Three other classes of agents are currently thought to have useful potentials. N-methyl-D-aspartate-(NMDA-)mediated neurotransmission may play an important role in mediating wind-up and related phenomena in pain pathways. Recent studies have demonstrated that NMDA receptor antagonists improve pain symptoms in FM. But a poor side effect profile represents a significant problem. Cerebrospinal fluid substance P concentrations are significantly elevated in FM patients, but the analgesic potential of neurokinin-1 (NK1) receptor antagonists did not meet early expectations. Tropisetron, a 5-HT3 receptor antagonist, was tested in a multicenter, double-blind, randomized, placebo-controlled trial including 403 patients. In those receiving 5 mg tropisetron, 39.2% fulfilled the response criterion (pain reduction 35%) as compared to 26.2% in the placebo group (p=0.033). On 10 and 15 mg, the responder rates were smaller and statistically not significant. A total of 78 responders to therapy were followed up for 12 months. After the end of treatment, pain intensity rose within one month in all 4 groups. Patients having received 5 or 10 mg showed a less pronounced increase in pain. In addition, even 12 months after stopping treatment, pain was still markedly below baseline levels in the 5 and 10 mg groups.
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PMID:[What's new in the therapy of fibromyalgia?]. 1464 17

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.
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PMID:Physiology and pathophysiology of the 5-HT3 receptor. 1551 4

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.
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PMID:Spectrum of use and tolerability of 5-HT3 receptor antagonists. 1551 6

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.
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PMID:Analgesic effects of 5-HT3 receptor antagonists. 1551 7

In 223 fibromyalgia (FM) patients in a rheumatology practice, a follow-up postal survey was carried out 0.5-2 years after a 5-day intravenous (i.v.) treatment with 5 mg of the 5-HT3 receptor antagonist tropisetron daily on the effect of this treatment. 121 patients returned the completed questionnaire. After subtraction of 22 undeliverable questionnaires, this represented 60.2% of patients contacted for whom an assessment of the tropisetron treatment was possible. A good to very good effect of the treatment on the pain was reported by 45% of the patients, and only 25% reported an unsatisfactory effect. The effect of tropisetron IV lasted between one day and 12 weeks (mean 8.6 +/- 13.6 d). Sleep and general condition were also assessed as good or very good by almost half of the patients. The tolerance of tropisetron was generally good. In comparison with the current treatment and the best treatment with other drugs ever received, tropisetron was rated as more efficacious in almost half of the cases, though an unsatisfactory effect of tropisetron compared to other treatments was reported in 30% of the cases. Considered in comparison to less or at most equally efficacious alternatives, according to this open respective study, IV tropisetron treatment represents a promising option for the treatment of FM even though the study design incorporated many imponderables. Particularly the question of whether the success of treatment can be improved further with a longer lasting treatment or a selection of the patients still needs to be settled.
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PMID:Intravenous treatment of fibromyalgia with the 5-HT3 receptor antagonist tropisetron in a rheumatological practice. 1551 20


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