Martin Steinhoff

Textbook of atopic dermatitis

1. Clinical Manifestations 2. Genetic Dissection 3. Pathogenesis 4. Spidermal Barrier Dysfunction 5. _Staphylococcus aureus_ 6. The Role of Viruses 7. The Role of Fungi 8. The Role of Food Allergens 9. The Role of Inhalant Allergens 10. Itch: Pathophysiology and Treatment 11. Psychosomatic Aspects 12. Quality of Life 13. General Management of Patients 14. Mode of Action of Glucocorticosteroids 15. Clinical Aspects of Glucocorticosteroids 16. Phototherapy 17. Antihistamines 18. Systemic Immunomodulation 19. Topical Calcineurin Inhibitors 20. Possible Clinical Associations with Bronchial Asthma 21. Experimental Therapies

Serlopitant for the treatment of chronic pruritus: Results of a randomized, multicenter, placebo-controlled phase 2 clinical trial

Background: The substance P/neurokinin 1 receptor pathway is critical in chronic pruritus; anecdotal evidence suggests that antagonism of this pathway can reduce chronic itch. Objective: To assess the safety and efficacy of the substance P/neurokinin 1 receptor antagonist serlopitant in treating chronic pruritus. Methods: Eligible patients with severe chronic pruritus who were refractory to antihistamines or topical steroids were randomized to serlopitant, 0.25, 1, or 5 mg, or to placebo, administered once daily for 6 weeks as monotherapy or with midpotency steroids and emollients. The primary efficacy end point was percentage change in visual analog scale pruritus score from baseline. Results: Serlopitant treatment resulted in a dose‐dependent decrease in pruritus. The mean percentage decreases from baseline visual analog scale pruritus scores were statistically significantly larger with the 1‐ and 5‐mg doses of serlopitant (P = .022 and P = .013, respectively) than with placebo at week 6. No significant safety or tolerability differences were detected among the groups. Limitations: The sample size was insufficient for subgroup analyses of the efficacy of serlopitant for chronic pruritus on the basis of underlying conditions. Conclusions: Serlopitant, 1 mg and 5 mg daily, was associated with a statistically significant reduction in chronic pruritus and was well tolerated (NCT01951274).

Involvement of TRPV1 and TDAG8 in Pruriception Associated with Noxious Acidosis

Itch and pain are closely related but are distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether acid (protons) can evoke itch like other algogens by spatial contrast activation of single nociceptors. Here, we report that (i) citric acid (0.2 mol/L) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin, (ii) acidified buffer elevated intracellular calcium levels in dorsal root ganglion pruriceptors, and (iii) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1, but neither ASIC3 nor TRPA1, is involved in the acidic citrate-induced scratching response. Furthermore, one of the proton-sensing G-protein-coupled receptors, TDAG8, was highly (∼71%) expressed in Nppb+ dorsal root ganglion pruriceptors. Itch induced by acidic citrate, but not α-methyl-5-hydroxytryptamine, chloroquine, compound 48/80, or bile acid, was markedly decreased in TDAG8-/- mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, protons could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.