fluvoxamine and Pruritus

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

The contribution of serotonin and noradrenaline to the modulation of pruriceptive processing was evaluated by administrating antidepressants or noradrenaline reuptake inhibitors. The pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of scratching behavior by chloroquine, a representative pruritogen, indicating the involvement of serotonin and/or noradrenaline in the modulation of pruriceptive processing. By contrast, the single administration of noradrenaline reuptake inhibitor such as atomoxetine and nisoxetine or serotonin reuptake inhibitor such as fluvoxamine and escitalopram had little effect on chloroquine-induced scratching, whereas the induction of scratching behavior by chloroquine was significantly ameliorated by co-administration of serotonin reuptake inhibitors and noradrenaline reuptake inhibitors. These results indicate that the simultaneous increases of serotonin and noradrenaline elicit the attenuating effect on pruriceptive processing induced by acute itch, and may also play a crucial role in the descending itch inhibitory system.

Topics: Animals; Citalopram; Drug Interactions; Fluvoxamine; Male; Mice; Mice, Inbred C57BL; Norepinephrine; Pruritus; Serotonin

Chronic pruritus is difficult to treat and requires the evaluation of new therapeutic modalities. We initiated an open-labelled, two-arm prospective, proof-of-concept study applying two selective serotonin re-uptake inhibitors on a long-term basis. Paroxetine and fluvoxamine were tested in a total of 72 pruritic patients (27 men, 45 women, age range 28-88 years, mean age 59.2 years). The reduction in pruritus was evaluated by analysis of visual analogue scores and determination of the maximal antipruritic effect (maximal percentual reduction in pruritus). Forty-nine of 72 patients (68.0%) experienced a weak (n=9), good (n=16) or very good (n=24) antipruritic effect. Statistical analysis proved the efficacy of paroxetine and fluvoxamine with no significant difference. The best response was observed in patients with pruritus due to atopic dermatitis, systemic lymphoma and solid carcinoma. Chronic scratch lesions healed completely in 14/31 patients and partially in 17/31 patients. Adverse drug effects were observed in 70.8% of patients, resulting in discontinuation of treatment in 18 patients. These results support previous reports of high antipruritic potency of selective serotonin re-uptake inhibitors, which are a good alternative treatment modality in chronic pruritus. This should be confirmed in future double-blind studies.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Chronic Disease; Dermatitis, Atopic; Female; Fluvoxamine; Humans; Lymphoma; Male; Middle Aged; Paroxetine; Prospective Studies; Pruritus; Selective Serotonin Reuptake Inhibitors