Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

BACKGROUND AND PURPOSE: Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H(3) receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H(4) receptor) to influence vestibular system function, using a selective H(4) receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH: RT-PCR was used to assess the presence of H(4) receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H(4) receptor modulation in the rat vestibular system. KEY RESULTS: The transcripts of H(4) and H(3) receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H(4) receptor agonist 4-methylhistamine. Thioperamide, a H(3) /H(4) receptor antagonist, exerted effects similar to those of H(3) and H(4) receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H(4) receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS: H(4) receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H(4) receptors as pharmacological targets for the treatment of vestibular disorders.

Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Recently, completed phase III studies demonstrated a survival benefit for a fixed number of cycles of docetaxel-containing chemotherapy treatment of androgen-independent prostate cancer (AIPC). Management of patients who respond well to initial chemotherapy for AIPC remains ill-defined. We previously reported that in a select group of such patients, retreatment with the same regimen was feasible and was associated with quality of life gains. Here, we report that multiple cycles of such intermittent chemotherapy are feasible. We prospectively tested intermittent chemotherapy in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1) (22% of the 37 patients who were initially treated with this regimen). Chemotherapy was suspended until a rise in PSA > or =50% and 1 ng ml(-1). The median duration of the first treatment holiday was 20 weeks (13-74 weeks) and all patients retained sensitivity to retreatment. Four patients were eligible for a second chemotherapy holiday, and the median duration was 21 weeks (17-28 weeks). Two patients elected to take a third chemotherapy holiday, which lasted 10 and 28 weeks. The median time to treatment failure was 26.5 months (95% CI 23.6-29.4 months), and the median survival is 41 months (95% CI 33.7-48.3 months). Multiple cycles of intermittent chemotherapy interrupted by clinically meaningful treatment holidays are feasible in a subset of AIPC patients treated with this docetaxel-containing regimen. Intermittent chemotherapy for AIPC is feasible and deserves further study.

Imatinib mesylate and zoledronic acid in androgen-independent prostate cancer.

OBJECTIVES: To determine the safety and efficacy of zoledronic acid (Zometa) combined with imatinib mesylate (Gleevec) in patients with bone pain due to androgen-independent prostate cancer. METHODS: Fifteen patients were treated with zoledronic acid 4 mg intravenously every 28 days and imatinib mesylate 400 mg/day. The pain response, defined as a 2-point reduction in the Present Pain Intensity Scale or normalization if the initial score was 1, was the primary endpoint. Secondary endpoints included palliative response, prostate-specific antigen response, measurable disease response, time to progression, impact on quality of life, decrease in markers of bone turnover, and tolerability of the drug combination. RESULTS: The study was stopped early because of a lack of activity. No palliative or clinical activity was detected for the combination, and no prostate-specific antigen responses were observed. The median time to progression was 4 weeks (95% confidence interval 3 to 5), and the median duration of treatment was 8 weeks (range 1.6 to 16.7). The median overall survival was 54 weeks (95% confidence interval 18 to 90). Therapy was associated with a reduction in urine N-telopeptides and a trend toward a reduction in serum osteocalcin, but no change occurred in bone-specific alkaline phosphatase. CONCLUSIONS: In this patient population, imatinib mesylate and zoledronic acid produced no prostate-specific antigen responses and had no palliative or clinical activity.

Intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Intermittent use of chemotherapy for androgen-independent prostate cancer (AIPC) instead of treatment until disease progression may reduce toxicity. We prospectively tested this approach in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1). Chemotherapy was suspended until a rise in PSA>/=50% and 1 ng ml(-1). The median duration of treatment holiday was 20 weeks (13-43+weeks) and all patients retained sensitivity to re-treatment. Chemotherapy holiday was associated with an improvement of fatigue (P=0.05). Intermittent chemotherapy for AIPC is feasible and deserves further study.