Ulrike Haus

Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia

Objective: To determine the efficacy of a serotonin receptor (5‐HT3) antagonist in the treatment of fibromyalgia (FM) in a prospective, randomized, double‐blind, placebo‐controlled, multicentre trial. Methods: Twenty‐one female patients (age 21–63 years) with FM according to the American College of Rheumatology classification criteria for FM were assigned randomly to either a placebo group or to receive a daily intravenous bolus injection of 5 mg tropisetron for 5 days. Results: In patients receiving tropisetron, the visual analogue scale (VAS) score for pain decreased by 28.9 compared with a decrease of 6.8 in the placebo group [probability (p)=0.063; effect size: 0.794]. Similar results were obtained using a body diagram pain score as a secondary efficacy parameter: mean pain reduction was 27.2 in the tropisetron group, versus 2.8 in the placebo group (p=0.038; effect size: 0.902). Conclusion: 5‐HT3 receptor antagonists provide significant pain relief for a group of FM patients.

Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain

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.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 openlabel 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 S 35% reduction in individual pain scores was 72.4% at day 28. The pressure tolerance of tenderpoints was slightly increased at the end of the treatment period. In addition, significant improvements were observed in the StateTraitAnxietyInventory (STAI), scales of von Zerssen (BfS) and Beck Depression Index (BDI). Functional symptoms were compared with the results from a 10day, randomized, doubleblind 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.

Spectrum of use and tolerability of 5-HT3 receptor antagonists.

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 Parkinsons 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.

Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid.

Bone turnover markers are helpful to diagnose bone metastases. The aim of this study was to evaluate the usefulness of these markers in prostate cancer patients with bone metastases before and during the treatment with zoledronic acid as predictive and monitoring tools of skeletal‐related events (SRE).

Treatment of fibromyalgia with tropisetron – dose and efficacy correlations

Previous studies evaluating the efficacy and tolerance of tropisetron for the treatment of fibromyalgia (FM) used the drug either intravenously or orally, and at different dosage levels ranging from 2 mg to 15 mg daily. The shortest treatment was a single dose and the longest treatment period covered 28 days. A significant reduction of the pain intensity was achieved by using tropisetron 5 mg per day. Apart from the fact that treatment periods were different, the efficacy of oral and intravenous administration did not differ significantly. Tropisetron was well tolerated; but in the 15 mg group in one of the studies, the decrease in pain was less than in the placebo group, however, the frequency of constipation and other gastrointestinal symptoms increased. Furthermore, it was hypothesized that due to the impacts of CYP2D6 activities, a daily dose of tropisetron 2 mg may be efficacious in slow metabolizers only. Although tropisetron proved to be efficacious in a group of fibromyalgia patients, the dose‐response curves cannot yet be explained in a fully satisfactory manner, which may encourage research focusing on possible subgroups of FM.

Granulocyte/macrophage-colony-stimulating-factor plus interleukin-2 plus interferon alpha in the treatment of metastatic renal cell carcinoma: a pilot study.

Abstract Granulocyte/macrophage-colony-stimulating factor (GM-CSF) plays a central role in the differentiation and function of dendritic cells, which are crucial for the elicitation of MHC-restricted T cell responses. Preclinical and the first clinical data provide a rationale for the application of GM-CSF in immunotherapy of cancer. Ten patients with renal cell carcinoma stage IV (Holland/Robson) were treated in this pilot study. Therapy was started with GM-CSF alone (2 weeks). Interleukin (IL-2) and interferon α (IFNα) were added sequentially (3 weeks GM-CSF plus IL-2 or IFNα, 3 weeks GM-CSF plus IL-2 plus IFNα). Therapy was performed on an outpatient basis. The cytokine regimen was evaluated for toxicity, clinical response and immunomodulatory effects [fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells (PBMC), mixed-lymphocyte reaction and cytotoxicity of PBMC]. GM-CSF treatment caused a significant increase in the number of PBMC expressing costimulatory molecules. Addition of IL-2 and IFNα led to an increase in CD3+, CD4+, CD8+ and CD56+ PBMC in week 9. In an autologous mixed-lymphocyte reaction a 2.1-fold increase in T cell proliferation was observed after 2 weeks of GM-CSF treatment, and cytotoxicity assays showed changes in natural-killer- (NK)- and non-NK-mediated cytotoxicity in some patients. Two patients achieved partial remission, one patient had a mixed response. The toxicity of the regimen was mild to moderate with fever, flu-like symptoms and nausea being observed in most patients. Severe organ toxicity was not observed. We conclude that GM-CSF might be useful for immunotherapy of renal cell carcinoma, especially in combination with T-cell-active cytokines. Further studies are warranted.

Influence of tropisetron on the serum substance P levels in fibromyalgia patients

Background: Substance P is found at an elevated level in the cerebrospinal fluid of fibromyalgia (FM) patients. Treatment with tropisetron leads in a subgroup of FM patients to pain reduction. The question arises of whether the substance P level in the serum can be changed by tropisetron treatment. Method: Twenty patients with FM diagnosed according to the ACR criteria were treated for 5 days with a 5 mg tropisetron intravenous (i.v.) bolus injection daily. Before the first injection, 3 h later, and before and 3 h after the last injection, the serum levels of substance P were determined. The determination of this substance was carried out by means of an immunoassay from Assay Design Biotrend, Cologne. To evaluate the success of the tropisetron treatment, patients made a global assessment as ‘clearly better’, ‘better’, ‘unchanged’, or ‘poor’. Patients who answered ‘clearly better’ and ‘better’ were regarded as responders. Results: Of the 20 patients, ten reported a good or very good influence on their pain (responders). In these responders, the means of the serum substance P levels were elevated in comparison with the non‐responders, though the difference was not significant. In responders, the 5‐HT3 receptor antagonist tropisetron produced a significant decrease in the serum substance P levels, while this did not occur in the non‐responders. Conclusion: It is possible that the responders to tropisetron represent a subgroup of FM patients for whom substance P and 5‐HT3 receptors play key roles in the development of the pain symptoms.

Rapid and sustained influence of intravenous zoledronic Acid on course of pain and analgesics consumption in patients with cancer with bone metastases: a multicenter open-label study over 1 year.

BACKGROUND Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcemia. Osteolytic destruction is caused by the activation of osteoclasts by release of tumor-derived stimulating factors. Bisphosphonates are known to inhibit osteoclast function and, therefore, to alleviate the adverse effects of tumor-induced bone resorption. PATIENTS AND METHODS We investigated the effects of zoledronic acid on bone pain and use of analgesic medication in 604 patients with cancer with bone metastases in an openlabel multicenter study over 1 year. Patients were treated with a maximum of 12 infusions (4 mg) every 3 or 4 weeks. RESULTS During treatment, the mean visual analog score value for pain (mm) decreased by 13.9 +/- 32.3 from 37.1 +/- 28.2 to 23.3 +/- 24.2 (P < .0001, t test, intent-to-treat population, n = 410) and the mean analgesic score decreased by 0.56 +/- 1.42 from 1.84 +/- 1.53 to 1.28 +/- 1.63 (P < .0001, t test). A statistically significant reduction in visual analog score pain could be observed within 1 week after initiation of treatment. Application of zoledronic acid was safe and well tolerated. CONCLUSION Treatment with zoledronic acid in patients with cancer with bone metastases in a broad range of tumor types provides substantial benefit in terms of pain relief.

Treatment of Fibromyalgia with Intravenous Application of Tropisetron

Objective: As in a prospective, randomized, placebo-controlled, multicenter, double-blind trial in fibromyalgia [FMS] a significant reduction of pain especially, but of other symptoms as well, could be gained after 10 days of peroral daily treatment with 5 mg tropisetron, the question was evaluated as to whether quicker and better effects could be achieved with intravenous application of 2 mg tropisetron daily for a limited period of time. Methods: In the first cohort, 18 FMS patients received a single bolus intravenous [i.v.] injection of 2 mg tropisetron, in the second cohort 24 FMS patients were treated with 2 mg i.v. bolus injection tropisetron daily for five days. Pain intensity was measured with the visual analog scale and the painscore; pain at the tenderpoints and control points [dolorimeter] was evaluated as well as 17 ancillary symptoms before and after treatment; furthermore, pain intensity was followed up by means of a patient diary, until pain recurrence. Results: Even with a single i.v. injection of 2 mg tropisetron a significant pain reduction as well as an enhancement of the pain threshold provable by dolorimetry could be achieved; however, this lasted only a few days. Three out of these 18 patients did not respond at all to therapy. If 2 mg tropisetron were applied daily for five days, 23 of 24 patients showed a pain reduction, which lasted for two weeks to two months in 20 of these patients. Two patients stopped fillling in the pain diary. Twelve ancillary symptoms such as sleep disturbances, fatigue, morning stiffness, and others, were also significantly improved by the latter treatment. In the global assessment 16 out of 24 patients showed a significant improvement and seven showed a slight improvement of their disease. There was only one patient who did not experience any improvement. Tolerability was good. Conclusion: Intravenous injection of 2 mg of the 5-HT3 receptor antagonist tropisetron once daily for five days can often produce a longer-lasting therapeutic effect on fibromyalgia symptoms. The results achieved are now being evaluated in a randomized, placebo-controlled, double-blind trial.