piperidines and Virus-Diseases

The single-dose effects of the cytochrome P-450 inhibitors erythromycin and ketoconazole on the steady-state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1-receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open-label, placebo-controlled, two-way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half-life was approximately 45 and 44 hours, respectively. In both studies, mean steady-state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P-450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P-450 system is minimal.

Topics: Administration, Intranasal; Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Biological Availability; Bradycardia; Cross-Over Studies; Drug Interactions; Electrocardiography; Erythromycin; Headache; Heart Block; Histamine H1 Antagonists; Humans; Ketoconazole; Male; Middle Aged; Piperidines; Rhinitis; Time Factors; Virus Diseases

As there are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with JAK inhibitors, the observed elevated risk may be a result of an off-target effect. Computational approaches combined with in vitro studies can be used to predict and validate the potential for an approved drug to interact with additional (often unwanted) targets and identify potential safety-related concerns. Potential off-targets of the JAK inhibitors baricitinib and tofacitinib were identified using two established machine learning approaches based on ligand similarity. The identified targets related to thrombosis or viral infection/reactivation were subsequently validated using in vitro assays. Inhibitory activity was identified for four drug-target pairs (PDE10A [baricitinib], TRPM6 [tofacitinib], PKN2 [baricitinib, tofacitinib]). Previously unknown off-target interactions of the two JAK inhibitors were identified. As the proposed pharmacological effects of these interactions include attenuation of pulmonary vascular remodeling, modulation of HCV response, and hypomagnesemia, the newly identified off-target interactions cannot explain an increased risk of thrombosis or viral infection/reactivation. While further evidence is required to explain both the elevated thrombosis and viral infection/reactivation risk, our results add to the evidence that these JAK inhibitors are promiscuous binders and highlight the potential for repurposing.

Topics: Antirheumatic Agents; Azetidines; Humans; Janus Kinase Inhibitors; Machine Learning; Phosphoric Diester Hydrolases; Piperidines; Purines; Pyrazoles; Pyrimidines; Sulfonamides; Thrombosis; Virus Diseases

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Red-Cell Aplasia, Pure; Steroids; Virus Diseases

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Bacterial Infections; Case-Control Studies; Enzyme Inhibitors; Female; Humans; Invasive Fungal Infections; Italy; Lymphoproliferative Disorders; Male; Middle Aged; Molecular Targeted Therapy; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Purines; Quinazolinones; Retrospective Studies; Risk Factors; Virus Diseases

Topics: Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Azetidines; Gene Regulatory Networks; Humans; Janus Kinases; Methotrexate; Models, Statistical; Piperidines; Prednisolone; Purines; Pyrazoles; Pyrimidines; Rituximab; Signal Transduction; STAT Transcription Factors; Sulfonamides; Virus Diseases

The purpose of this study was to investigate the influence of chronic virus- related liver disease severity on propofol requirements.. In this study, 48 male patients with chronic hepatitis B infection were divided into three groups according to Child-Turcotte-Pugh classification of liver function (groups A, B, and C with mild, moderate and severe liver disease, respectively). After intubation, propofol concentration was adjusted by ± 0.3 μg/mL increments to maintain bispectral index in the range of 40-60. Target propofol concentrations at anesthesia initiation, pre-intubation and pre-incision were recorded.. The initial concentration used in group C was significantly lower than that used in group A or B (p<0.05), whereas no difference was observed between groups A and B. At pre-intubation, the actual required concentration of propofol increased significantly (3.2 μg/mL) in group A (p<0.05), which lead to significant differences between the groups (p<0.05). At pre-incision, the requirements for propofol decreased significantly in both groups A and B (3.0 μg/mL and 2.7 μg/mL, respectively) compared with those at pre-intubation (p<0.05), and were significantly different for all three groups (p<0.05), with group C demonstrating the lowest requirement (2.2 μg/mL). The required concentrations of propofol at pre-incision were similar to those at induction.. In this study, propofol requirements administered by target-controlled infusion to maintain similar depths of hypnosis were shown to depend on the severity of chronic virus-related liver dysfunction. In other words, patients with the most severe liver dysfunction required the least amount of propofol.

Topics: Adult; Anesthesia; Anesthetics, Intravenous; Chronic Disease; Electroencephalography; Hepatitis B, Chronic; Humans; Liver Diseases; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Virus Diseases

Topics: Acute Disease; Bacterial Infections; Butyrates; Child; Child, Preschool; Diarrhea, Infantile; Enteritis; Gastroenteritis; Gastrointestinal Agents; Humans; Infant; Infant, Newborn; Piperidines; Virus Diseases

Topics: Biomedical Research; Colchicine; Colectomy; Colitis; Colitis, Ulcerative; Colonic Diseases; Colonic Diseases, Functional; Crohn Disease; Diabetic Neuropathies; Diarrhea; Diphenoxylate; Diverticulitis; Diverticulitis, Colonic; Drug Therapy; Dysentery; Dysentery, Amebic; Enteritis; Gastroenteritis; Humans; Piperidines; Postgastrectomy Syndromes; Postoperative Complications; Toxicology; Virus Diseases