Lothar Färber

Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo.

Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. In vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C(4) (LTC(4)), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS.

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.

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.