piperidines and Influenza--Human

Adults frequently develop eustachian tube dysfunction and middle ear pressure (MEP) abnormalities during natural and experimental influenza and human rhinovirus (HRV) infections. Oral rimantadine treatment did not reduce the otologic manifestations of experimental influenza in adults or natural influenza in children. However, intranasal zanamivir and oral oseltamivir significantly reduced MEP abnormalities during experimental influenza in adults, and oseltamivir treatment appears to reduce the likelihood of otitis media in children with acute influenza. Investigational anti-HRV agents, including intranasal tremacamra, intranasal AG7088, and oral pleconaril, warrant study in this regard. Depending on the virus, early antiviral therapy has the potential to impact the risk of otitis media following respiratory tract infections.

Topics: Acetamides; Adult; Anti-Bacterial Agents; Antiviral Agents; Child; Child, Preschool; Clinical Trials as Topic; Eustachian Tube; Guanidines; Humans; Infant; Influenza A virus; Influenza B virus; Influenza, Human; Interferon-beta; Oseltamivir; Otitis Media; Otitis Media with Effusion; Picornaviridae Infections; Piperidines; Pressure; Pyrans; Pyridazines; Respiratory Tract Infections; Rhinovirus; Rimantadine; Sialic Acids; Superinfection; Virus Replication; Zanamivir

To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity.. We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens).. In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively).. Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses.. NCT01359150, NCT00413699.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Influenza Vaccines; Influenza, Human; Male; Methotrexate; Middle Aged; Piperidines; Pneumococcal Infections; Pneumococcal Vaccines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Young Adult

Topics: Adenine; Adolescent; Adult; Aged; Female; Follow-Up Studies; Humans; Influenza Vaccines; Influenza, Human; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Treatment Outcome

We have developed a series of N(2) -(1-(substituted-aryl)piperidin-4-yl)-N(6) -mesityl-9H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti-HIV-1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in Madin-Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus.

Topics: Animals; Antiviral Agents; Dogs; HIV Infections; HIV-1; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Madin Darby Canine Kidney Cells; Piperidines; Purines

We have recently discovered that inflammatory monocytes recruited to lymph nodes in response to vaccine-induced inflammation can function as potent negative regulators of both humoral and cell-mediated immune responses to vaccination. Monocyte depletion or migration blockade can significantly amplify both antibody titers and cellular immune responses to vaccination with several different antigens in mouse models. Thus, we hypothesized that the use of small molecule CCR2 inhibitors to block monocyte migration into lymph nodes may represent a broadly effective means of amplifying vaccine immunity. To address this question, the role of CCR2 in monocyte recruitment to vaccine draining lymph nodes was initially explored in CCR2-/- mice. Next, a small molecule antagonist of CCR2 (RS102895) was evaluated in mouse vaccination models. Initial studies revealed that a single intraperitoneal dose of RS102895 failed to effectively block monocyte recruitment following vaccination. Pharmacokinetic analysis of RS102895 revealed a short half-life (approximately 1h), and suggested that a multi-dose treatment regimen would be more effective. We found that administration of RS102895 every 6 h resulted in consistent plasma levels of 20 ng/ml or greater, which effectively blocked monocyte migration to lymph nodes following vaccination. Moreover, administration of RS102895 with concurrent vaccination markedly enhanced vaccine responses following immunization against the influenza antigen HA1. We concluded that administration of small molecule CCR2 antagonists such as RS102895 in the immediate post-vaccine period could be used as a novel means of significantly enhancing vaccine immunity.

Topics: Animals; Benzoxazines; Cell Movement; Drug Dosage Calculations; Half-Life; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Cellular; Influenza Vaccines; Influenza, Human; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Models, Animal; Monocytes; Piperidines; Receptors, CCR2

To investigate the antiviral effect of the flavonoid compound flavopiridol on influenza A virus and explore its antiviral mechanism.. The A549 or Madin-Darby canine kidney (MDCK) cells were infected with influenza A virus A/WSN/33 and treated with flavopiridol. The viral proteins were determined by immunolotting and immunofluorescence. The virus titer was measured by plaque assay. To verify whether the activity of host RNA polymerase II was affected by flavopiridol, the phosphorylation status of RNA polymerase II CTD domain was analyzed by immunoblotting with phosphor-specific antibody. The amount of viral mRNA, vRNA and cRNA was measured by reverse transcription and PCR.. The amount of viral proteins was significantly decreased and the titer of virus was greatly reduced in cells treated with flavopiridol. Further analysis showed that the phosphorylation of Ser-2 in the heptad repeat of the CTD domain in RNA polymerase II was decreased in falvopiridol treated cell. This result indicated that the transcription elongation activity of RNA pol II was impaired upon treatment with flavopiridol. Then we found that the amount of viral vRNA was significantly decreased in flavopiridol treated cells while only moderate decrease of mRNA was observed and almost no reduction of cRNA was detected.. Flavopiridol can greatly suppress the replication of influenza virus. We propose that the inhibition of the transcription elongation activity of host RNA polymerase II would cause the decrease of viral mRNA transcription.

Topics: Animals; Antiviral Agents; Cell Line; Flavonoids; Humans; Influenza A virus; Influenza, Human; Piperidines; Protein Kinase Inhibitors; Virus Replication

After 9 days of risperidone therapy (2-6 mg/day), a 24-year-old schizophrenic female patient developed a leucopenia with neutropenia < 1000/mm3. A few days after starting the neuroleptic treatment, she suffered from a cold, without fever. All immunological tests performed yielded negative results except for influenza B virus. The cessation of the risperidone therapy was followed within 48 h by a normalisation of the WBC differential count. Therefore, in the absence of a rechallenge with risperidone for ethical reasons, it cannot be excluded that risperidone represents at least a partial cause of the observed neutropenia.

Topics: Adult; Antipsychotic Agents; Cold Temperature; Female; Humans; Influenza, Human; Isoxazoles; Neutropenia; Piperidines; Risperidone; Schizophrenia