mk-0524 and Pruritus

There are many factors that increase the risk of cardiovascular disease, and a prominent factor among these is dyslipidemia. The following literature review focuses on the use of niacin therapy in order to treat dyslipidemia and how to control the associated "niacin flush." The associated studies gathered are reviews and randomized control trials. They were obtained by using electronic searches. Certain keywords took precedence, and articles focusing on niacin therapy were chosen. Recent research has found promising insight into more effective prevention of the niacin-mediated flush through a selective antagonist for the prostaglandin D2 receptor, laropiprant. Aspirin (or NSAIDs) also provide some prevention for flushing, although recent studies have shown that it is not as effective as laropiprant. There is a need for further research in order to come to a clear conclusion regarding combined therapies of aspirin and laropiprant pretreatment, as well as exact dosage requirements.

Topics: Aspirin; Dose-Response Relationship, Drug; Dyslipidemias; Humans; Hypolipidemic Agents; Indoles; Niacin; Pruritus

Niacin commonly causes cutaneous flushing, which is partially alleviated by laropiprant, a selective antagonist of prostaglandin D2 at the DP1 receptor. Here we report an unusually high incidence of exanthematous eruption associated with the use of the extended-release (ER) niacin/laropiprant combination treatment in Hong Kong Chinese patients.. Among 201 patients treated with ER niacin/laropiprant 1000/20 mg over 7 days to assess flushing symptoms and 166 of the patients who continued the treatment for 12 weeks (doubling the dose after 4 weeks), 28 patients (14%) developed a highly pruritic cutaneous eruption at a mean of 5 days after starting the treatment or 4 days after increasing the dose. This resolved over several days after drug withdrawal with symptomatic treatment. Compared with the subjects who completed 12-weeks treatment uneventfully, those who developed cutaneous eruption were older, had significantly lower body weight, were taking background lipid-lowering treatment more frequently and had greater flushing responses in the first few days of treatment.. The relationship of the exanthematous eruption with lower body weight and the increase in dosage suggests a pharmacokinetic effect that may be related to increased exposure to niacin or its metabolites and provoked by inhibition of the DP1 receptor with laropiprant, as we have not seen this rash with niacin used alone. This may suggest that the southern Chinese population may have some genetic predisposition; as such, a high frequency of exanthematous reactions has not been reported in other populations.

Topics: Adult; Aged; Anti-Inflammatory Agents; Biopsy; Body Weight; Drug Combinations; Drug Eruptions; Exanthema; Female; Histamine Antagonists; Hong Kong; Humans; Indoles; Male; Middle Aged; Niacin; Pruritus; Skin; Vitamins

Prostaglandin D(2) (PGD(2)) is known to have antipruritic activity by suppressing histamine release. However, agents that can topically induce PGD(2) for itch relief are not well established. The antimycotic sertaconazole nitrate (STZ) has been shown to exhibit anti-itch properties; however, the mechanism for this activity has not been elucidated. STZ mitigated degranulation of RBL-2H3 (rat basophilic leukemia) mast cells induced by compound 48/80, a pruritogenic agent known to promote the release of histamine, and augmented PGD(2) production in mast cells and macrophages. Addition of exogenous PGD(2) abrogated compound 48/80-induced degranulation by acting through the prostanoid D receptor 1 (DP1). STZ induced p38 mitogen-activated protein kinase (MAPK) phosphorylation in mast cells and a pharmacological inhibitor of p38 MAPK, SB203580, resulted in the attenuation of PGD(2) levels. Finally, in a murine model of pruritus, the scratching behavior induced by compound 48/80 was mitigated by topical application of STZ. This effect was reversed by the addition of the cyclooxygenase inhibitor, ibuprofen, or a DP1 receptor antagonist (MK0524). Collectively, these results suggest that STZ mediates its anti-itch effects by boosting the antipruritic agent, PGD(2), by the activation of the p38-MAPK pathway. This is the first report to demonstrate a promising approach to topically induce PGD(2) for improving pruritus.

Topics: Administration, Topical; Animals; Antifungal Agents; Cell Degranulation; Cell Line; Drug Interactions; Histamine; Imidazoles; Indoles; Macrophages; Mast Cells; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; p38 Mitogen-Activated Protein Kinases; Prostaglandin D2; Pruritus; Rats; Receptors, Prostaglandin; Thiophenes