piperidines and Nasopharyngitis

Psoriasis and psoriatic arthritis (PsA) are inflammatory immune-mediated conditions which can cause considerable disability and reduced quality of life. Management can be complex as clinical heterogeneity may lead to different treatment pathways. Tofacitinib is a novel, oral Janus Kinase (JAK) inhibitor with proven efficacy in rheumatoid arthritis. Areas covered: This review analyzes recent studies of tofacitinib in psoriatic disease treatment. The relevant literature was identified using clinicaltrials.gov, PubMed, and Google Scholar. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase-III studies, and received FDA and EMA approval. Tofacitinib was superior to placebo for the treatment of moderate-to-severe plaque psoriasis in the OPT Pivotal 1 and 2, OPT Retreatment studies, but FDA approval was declined for this indication based on issues of clinical efficacy and long-term safety. Expert commentary: Tofacitinib is an important oral drug for the treatment of PsA. However, the long-term safety data require further evaluation. Tofacitinib and other JAK inhibitors show potential to broaden the treatment options in PsA and other inflammatory conditions.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Clinical Trials as Topic; Drug Approval; Humans; Janus Kinases; Nasopharyngitis; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

This randomized, double-blind, phase III study evaluated the efficacy and safety of once-daily treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg once daily or 250 mg twice daily), in Japanese patients with type 2 diabetes. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to the end of treatment (week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the end of treatment (week 24) was 0.16 (0.072)% in alogliptin alone, -0.49 (0.049)% in alogliptin/metformin once daily, and -0.60 (0.049)% in alogliptin/metformin twice daily. The LS mean difference in HbA1c change from baseline between alogliptin/metformin once daily and alogliptin alone (alogliptin/metformin once daily minus alogliptin alone) was -0.65% (95% confidence interval [CI] -0.821, -0.480) and between alogliptin/metformin once daily and twice daily (once daily minus twice daily) was 0.11% (95% CI -0.026, 0.247). The overall frequency of adverse events was similar among the groups. This study showed that the efficacy of alogliptin/metformin once daily was superior to alogliptin alone and non-inferior to alogliptin/metformin twice daily, and that alogliptin/metformin once daily was safe and well tolerated in Japanese patients with type 2 diabetes.

Topics: Acute Disease; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Metformin; Middle Aged; Nasopharyngitis; Pancreatitis; Piperidines; Treatment Outcome; Uracil

A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR.. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+).. At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%).. No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoproteins E; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Edema; Female; Genotype; Humans; Hypoglycemic Agents; Indans; Intelligence Tests; Interview, Psychological; Male; Middle Aged; Nasopharyngitis; Piperidines; PPAR gamma; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Topics: Anemia; Creatinine; Drug Administration Schedule; Drug Interactions; Exanthema; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Heart Rate; Humans; Hypertension; Indazoles; Leukopenia; Mutation; Myelodysplastic Syndromes; Nasopharyngitis; Nausea; Ovarian Neoplasms; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia; Transaminases; Vomiting