Thomas Stratz

The T102C Polymorphism of the 5-HT2A-Receptor Gene in Fibromyalgia

Based on a possible involvement of serotonergic dysfunction in the pathophysiology of fibromyalgia (FM) and on preliminary reports of a possible genetically driven vulnerability for this disorder we investigated the silent T102C polymorphism of the 5-HT2A-receptor gene in 168 FM patients and 115 healthy controls. Our results showed a significantly different genotype distribution in FM patients with a decrease in T/T and an increase in both T/C and C/C genotypes as compared to the control population (Fishers Exact test, two-sided, P = 0.008). However, the increase in allele-C102 frequency felt short of significance (P = 0.07). Correlation of genotypes to clinical parameters revealed no influences on age of onset, duration of disease or psychopathological symptoms, measured with the Beck Depression Inventory and the symptom checklist SCL-90-R. In contrast to that the pain score, being a self reported information on pain severity, was significantly higher in patients of the T/T genotype (Mann-Whitney U test, P = 0.028). This suggests that the T102-allele might be involved in the complex circuits of nociception. However, the T102C polymorphism is not directly involved in the aetiology of FM but might be in linkage dysequilibrium with the true functional variant, which has to be unravelled.

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.

Antiinflammatory effects of 5‐HT3 receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes

There is evidence from both human and animal research that 5‐hydroxytryptamine (5‐HT)3 receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects have not yet been investigated in detail. Therefore, the antiinflammatory effects of tropisetron and ondansetron were investigated in human monocytes. In human monocytes, both lipopolysaccharide (LPS)‐stimulated tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β secretion were dose‐dependently inhibited by tropisetron starting at a concentration of 5 μg/mL and reaching maximal levels at 25 μg/mL (IC50: 32 μg/mL and 12 μg/mL, respectively). LPS‐induced IL‐6 and PGE2 release was only slightly inhibited at high doses, whereas LPS‐induced release of IL‐8 and matrix metalloprotease (MMP)‐9 was not affected. In conclusion, our data show that the binding of tropisetron to 5‐HT3 receptors results in antiinflammatory effects through inhibition of TNF‐α/IL‐1β, which might explain the antiphlogistic effects of 5‐HT3 antagonists.

Expression of 5‐HT3A receptors in cells of the immune system

There is evidence from both human and animal research that 5‐hydroxytryptamine3 (5‐HT3) receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects including the expression of 5‐HT3 receptors in cells of the immune system have not yet been investigated in detail. Therefore, we investigated the expression of the 5‐HT3A receptor in primary human monocytes, chondrocytes, T‐cells, dendritic cells, and synovial tissue. We found that 5‐HT3A receptors are expressed in monocytes, chondrocytes, T‐cells, and synovial tissue but not in dendritic cells. Our data show that 5‐HT3A receptors are widely expressed in cells of the immune system and that they might play an important role in inflammatory events and in the observed antiphlogistic effects of 5‐HT3 receptor antagonists.

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.

New Treatment Options Using 5-HT3 Receptor Antagonists in Rheumatic Diseases

In vitro studies have shown that a blockade of 5-HT3 receptors brings about a reduction of tumor necrosis factor, IL-1 beta, IL-2, IL-6 as well as a decrease in prostaglandins. Clinical trials have provided evidence of pain reduction in a subgroup of fibromyalgia syndrome and, moreover, have demonstrated that tropisetron injected locally for insertion tendinoses and myofascial syndromes with associated trigger points leads to an alleviation of pain that is comparable to injections with the combination of corticosteroids and local anesthetics. The effects achieved by intra-articular injections in cases of osteoarthritis and rheumatoid arthritis paralleled those exerted by intraarticular injection of corticosteroids. In addition, the positive effects produced by systemically administered tropisetron on scleroderma need to be considered since they suggest that this therapeutic principle can also be applied systemically in immunologic processes.

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.

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.

Microheterogeneity of acute phase proteins in patients with clinically active and clinically nonactive osteoarthritis.

SummaryMicroheterogeneity of two acute phase glycoproteins, α-1-acid glycoprotein (AGP) and α-1-antichymotryspin (ACT), concentrations of AGP, ACT, and C-reactive protein (CRP), and levels of three cytokines: interleukin 1 β (IL-1-β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were determined in 61 serum samples and 7 synovial fluids (SFs) obtained from patients (n=61) with osteoarthritis. Using affinity immunoelectrophoresis with concanavalin A (conA), a significant decrease in the reactivity of AGP and ACT with this lectin was found in patients with clinically active osteoarthritis when compared to those with clinically nonactive disease (p<0.001 and p<0.05, respectively). There was no increase in the concentration of AGP, ACT, and C-reactive protein (CRP) in the sera examined. In particular, no increase in the serum level of these proteins was found in the patients with clinically active disease. Low concentrations of IL-6 and TNF-α were found in most sera and SFs examined. In 6 out of 7 SFs available, IL-6 concentrations were higher than in the respective serum samples but for TNF-α the same could be shown in one case only. Low concentrations of IL-1-β were found in 4 serum samples obtained from patients with clinically active osteoarthritis and in no SF specimen studied. In the entire group, serum level of TNF-α correlated weakly with the AGP and ACT reactivity coefficients with conA (r=0.3634, p<0.005 and r=0.3324, p<0.02, respectively).Our findings suggest that there are changes in the microheterogeneity of acute phase glycoproteins in some patients with osteoarthritis similar to those observed in rheumatoid arthritis and other chronic inflammations. Possible mechanisms of the involvement of cytokines in the regulation of glycosylation of acute phase glycoproteins in osteoarthritis are discussed.

Treatment of tendopathies with tropisetron

Abstract. A comparison between a local anesthetic drug and the 5-hydroxytryptamine 3 (5-HT3) receptor antagonist tropisetron in treating tendopathies or periarthropathies revealed that tropisetron has a longer effect on resting pain and pain on movement than the local anesthetic drug. The most likely explanation for this effect probably is a blocking of stimulated 5-HT3 receptors at the nociceptors in conjunction with an inhibited release of substance P and other neurokines because of this blockage. Further studies will have to show whether the action of tropisetron in tendopathies is as favorable as that of corticosteroids.