piperidines and Abortion--Spontaneous

GSK2245035, a small molecule Toll-like Receptor 7 (TLR7) agonist developed for immunomodulatory treatment for allergic airways disease, aimed to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type I interferons (IFNs). GSK2245035 demonstrated selectivity for potent release of type I IFNs compared to TNF-α and IL-6, with dose dependent increases in the interferon inducible chemokine, IP-10, in the nasal compartment. Implantation and parturition require pro-inflammatory processes including IFNs, Interferon Stimulated Genes, TNFα and IP-10 while pregnancy requires immune regulation to maintain maternal fetal immune tolerance, and recombinant type I IFNs induced abortions in monkeys. Due to its mechanism of action, GSK2245035 was studied at pharmacologically and clinically relevant doses in a monkey pregnancy model. Monkeys received 0, 3 or 30 ng/kg/week GSK2245035 intranasally once weekly, from Day 20 postcoitum through Day 63 postpartum. Although systemic IFN-α and IP-10 levels were approximately 14.8 or 40 -fold (respectively) above predose levels at 3 or 30 ng/kg/week, respectively, there were no effects on pregnancy and infant outcome. Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-α and decreased infant anti-KLH IgM and IgG titers following KLH immunization at ≥3 ng/kg/week, relative to controls. Potentially, lower IFN-α and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function.

Topics: Abortion, Spontaneous; Adenine; Administration, Intranasal; Animals; Asthma; Chemokine CXCL10; Disease Models, Animal; Female; Humans; Interferon-alpha; Macaca fascicularis; Piperidines; Pregnancy; Pregnancy Complications; Toll-Like Receptor 7

The objective of this prospective multicenter study was to determine whether cisapride is associated with increased risk of malformations, spontaneous abortions, or decreased birthweight when used during pregnancy. Cases were paired for age, smoking, and alcohol consumption with controls exposed to nonteratogens, as well as with disease-paired controls. One hundred and twenty-nine pregnant women were exposed to cisapride during pregnancy, including 88 during the period of fetal organogenesis. There were no differences in maternal history, birthweight, gestational age at delivery, and rates of livebirths, spontaneous or therapeutic abortions, fetal distress, and major or minor malformations among groups. It is concluded that exposure to cisapride during pregnancy is not associated with a major increased risk of malformations or spontaneous abortions or with decreased birthweight.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Birth Weight; Case-Control Studies; Cisapride; Cohort Studies; Female; Gastrointestinal Agents; Humans; Infant, Newborn; Piperidines; Pregnancy; Pregnancy Complications; Prospective Studies; Risk Factors

The antifertility activity of piperine was investigated in pregnant mice when given by various routes of administration and at different periods of gestation. Piperine effectively inhibited implantation, produced abortion and delayed labor when it was given from day 2 through 5, day 8 through 12 and day 15 until labor, respectively. At the same dose level which interrupts pregnancy, piperine did not affect the estrous cycle. Neither uterotropic, antiestrogenic nor antiprogestational property was observed. Additionally, piperine also inhibited uterine contraction both in vivo and in vitro. These results suggested that the antifertility activity of piperine did not operate through any hormonal actions or uterotonic activity.

Topics: Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Spontaneous; Alkaloids; Animals; Benzodioxoles; Chemical Phenomena; Chemistry; Depression, Chemical; Embryo Implantation; Embryo Implantation, Delayed; Female; Fetal Death; In Vitro Techniques; Litter Size; Mice; Mice, Inbred Strains; Piperidines; Polyunsaturated Alkamides; Pregnancy; Pregnancy, Prolonged; Uterine Contraction