Diabetes after pregnancy prevention trials: Systematic review for core outcome set development.

Diabetes prevention intervention studies in women with previous gestational diabetes have increased, but no consensus exists on core outcomes to support comparisons and synthesis of findings. We aimed to systematically catalogue outcomes in diabetes after pregnancy prevention interventions with the goal of developing a core outcome set. Embase, Medline, Cochrane Library, Cochrane Pregnancy and Childbirth Trials Register, and CINAHL were searched from inception to October 2017. Post-partum lifestyle and diabetes screening intervention studies in women with previous gestational diabetes and/or their families were eligible. No limits were placed on intervention type, duration, or location. Two authors independently screened and performed data extraction on outcomes, measurement tools, and relevant study characteristics. We analysed data from 38 studies (29 randomised controlled trials and 9 pre-post intervention evaluations) comprising 12,509 participants. Most publications (80%) occurred between the years 2012 and 2017. Among 172 outcomes, we identified 36 outcome groups and classified them under three domains: health status (body weight, body composition, diabetes risk, cardiometabolic risk, diabetes development, mental health, pregnancy outcomes, and fitness), health behaviours (dietary, physical activity, diabetes screening, behaviour change, and breastfeeding), and intervention processes (implementation). The health status domain contained the most commonly reported outcomes, but measurement tools were very heterogeneous. Despite the recent explosion in diabetes after pregnancy prevention studies, large variation in outcomes and measurement methods exists. Research is needed to define a core outcome set to standardise diabetes after pregnancy prevention interventions. The core outcome set should engage a wide group of stakeholders to identify impactful indicators for future trials.

Synthesis of 5-(1-H or 1-alkyl-5-oxopyrrolidin-3-yl)-8-hydroxy-[1,6]-naphthyridine-7-carboxamide inhibitors of HIV-1 integrase.

HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.

Calcitonin gene-related peptide (CGRP) receptor antagonists: investigations of a pyridinone template.

In our effort to find potent, orally bioavailable CGRP receptor antagonists for the treatment of migraine, a novel series based on a pyridinone template was investigated. After optimizing the privileged structure and the placement of the attached phenyl ring, systematic SAR was carried out on both the N-alkyl and C-5 aryl substituents. Several analogs with good potency and pharmacokinetic profiles were identified.

Alpha-hydroxy amides as a novel class of bradykinin B1 selective antagonists.

Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.

Cyclopropylamino acid amide as a pharmacophoric replacement for 2,3-diaminopyridine. Application to the design of novel bradykinin B1 receptor antagonists.

Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.

9-hydroxyazafluorenes and their use in thrombin inhibitors.

Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.

Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells.

Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.

Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines.

Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

A potent and orally active HIV-1 integrase inhibitor.

A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.

A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells.

Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.

The acceptability of self-collected samples for HPV testing vs. the pap test as alternatives in cervical cancer screening.

OBJECTIVE: To explore the acceptability of the self-collection of samples for human papillomavirus (HPV) testing in comparison with that of the Pap test. METHODS: The study population consisted of 1069 women 20 years and older who were eligible for coverage through the Mexican Institute of Social Security (IMSS). These women were randomly selected among participants in a larger study to evaluate the use of HPV testing as an alternative in cervical cancer screening. All participants provided a self-collected vaginal sample for HPV testing according to explicit instructions and underwent a Pap test. Afterwards, each woman was interviewed about her experience and opinion regarding the two procedures. Acceptability was measured by a calculated score based on discomfort, pain, embarrassment, privacy, perception of personal treatment during the Pap test, and understanding of how to perform the self-sampling method. RESULTS: Ninety-three percent of women experienced sufficient privacy with the Pap test, whereas 98% of women reported that privacy with the self-sampling procedure was acceptable. The Pap test consistently provoked more discomfort, pain, and embarrassment than self-sampling. Sixty-eight percent of the women who indicated a test preference chose self-sampling. Preference for this method was positively associated with monthly household income. Women reported a preference for self-sampling because it is more comfortable (71.2%) and causes less embarrassment (55.8%). CONCLUSIONS: Self-sampling is more acceptable than the Pap test and could improve coverage rates of early detection programs. The incorporation of self-collected samples to detect HPV could encourage participation in screening programs among those women who reject the Pap test because of the necessary pelvic examination.

Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability.

Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.