The Health Care Sector Response to Intimate Partner Violence in Kenya: Exploring Health Care Providers' Perceptions of Care for Victims.

Intimate partner violence (IPV) is prevalent in Kenya, yet few studies have examined the role of health care providers (HCPs) in addressing IPV. Interviews with 18 Kenyan HCPs explored how they recognize and support IPV victims, including barriers to care. HCPs most commonly see victims of physical abuse. Medical responses to victims included counseling, treatment, and referrals, although rural HCPs reported fewer available services than in urban settings. HCPs attributed the limited response to IPV victims to unclear laws and fragmented care, especially in a culture where IPV remains largely unspoken and underreported. These results underscore the need for increased training on IPV assessment and response for HCPs in Kenya, with emphasis on standardized care guidelines for victims.

Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.

Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.

Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists.

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.

HIV risks and seroprevalence among Mexican American injection drug users in California.

Latinos in the United States are an ethnically diverse group disproportionately affected by HIV/AIDS. We describe HIV seroprevalence, HIV risk behaviors and utilization of health services among Mexican American injection drug users (IDUs) in California (n = 286) and compare them to White (n = 830) and African American (n = 314) IDUs. Study participants were recruited from syringe exchange programs (n = 24) in California. HIV seroprevalence among Mexican Americans (0.5%) was dramatically lower than Whites (5%) and African Americans (8%). Mexican Americans reported fewer sex-related risks than Whites and African Americans though injection-related risks remained high. Compared to Whites, Mexican Americans were more likely to participate in drug treatment during a 6 month period (AOR 1.5, 95% CI 1.1, 2.0) but less likely to receive any health care (AOR 0.6, 95% CI 0.5, 0.8). Exploring cultural and structural factors among Mexican American IDUs may offer new insights into how to maintain low rates of HIV seroprevalence and reduce barriers to health care utilization.

HIV prevalence and risk among heterosexual methamphetamine injectors in California.

This study funded by Centers for Disease Control compares HIV prevalence and risk behavior among heterosexual methamphetamine (n = 428) and nonmethamphetamine (n = 878) injectors in California, USA, during 2001-2003. While HIV was not highly prevalent among methamphetamine injectors (3%), sexual and injection risk behaviors were highly prevalent (ranging from 21% to 72%). In multivariate analyses, methamphetamine injectors had higher odds than nonmethamphetamine injectors of unprotected vaginal intercourse and sex with five or more sexual partners in the past 6 months and of distributive and receptive syringe sharing in the past 30 days. There was no significant difference in HIV sero-status by methamphetamine use. Suggestions are made for designing HIV prevention programs. The study's limitations are noted.

Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.

Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists.

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.

AAV2/8 Anti-angiogenic Gene Therapy Using Single-Chain Antibodies Inhibits Murine Choroidal Neovascularization.

While anti-angiogenic therapies for wet age-related macular degeneration (AMD) are effective for many patients, they require multiple injections and are expensive and prone to complications. Gene therapy could be an elegant solution for this problem by providing a long-term source of anti-angiogenic proteins after a single administration. Another potential issue with current therapeutic proteins containing a fragment crystallizable (Fc) domain (such as whole antibodies like bevacizumab) is the induction of an unwanted immune response. In wet AMD, a low level of inflammation is already present, so to avoid exacerbation of disease by the therapeutic protein, we propose single-chain fragment variable (scFv) antibodies, which lack the Fc domain, as a safer alternative. To investigate the feasibility of this, anti-vascular endothelial growth factor (VEGF)-blocking antibodies in two formats were produced and tested in vitro and in vivo. The scFv transgene was then cloned into an adeno-associated virus (AAV) vector. A therapeutic effect in a mouse model of choroidal neovascularization (CNV) was demonstrated with antibodies in both scFv and immunoglobulin G1 (IgG1) formats (p < 0.04). Importantly, the scFv anti-VEGF antibody expressed from an AAV vector also had a significant beneficial effect (p = 0.02), providing valuable preclinical data for future translation to the clinic.

Injecting drug use and community-associated methicillin-resistant Staphylococcus aureus infection.

To demonstrate that injecting drug use is a major risk factor of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection and injecting drug users may be a reservoir of CA-MRSA infection in our community, we conducted a matched case-control study. Cases were CA-MRSA-infected patients at University of California, Davis, Medical Center, Sacramento, CA, from December 1, 2003, to May 31, 2004. Two control groups were community-associated methicillin-susceptible S. aureus (CA-MSSA)-infected patients and a randomly selected uninfected patient group in the same hospital. Controls were matched to cases by age and isolate culture date. One hundred twenty-seven CA-MSSA patients and 381 randomly selected uninfected controls were selected to match the 127 CA-MRSA cases. The adjusted odds ratio of injecting drug use compared with the CA-MSSA group was 2.11 (95% confidence interval [CI], 1.1-4.3) and 4.09 (95% CI, 2.2-7.5) compared with the uninfected group. We suggest that injecting drug use is a significant risk factor for CA-MRSA infection, which could contribute to the increasing prevalence of CA-MRSA in an urban community.

Approval of syringe exchange programs in California: results from a local approach to HIV prevention.

OBJECTIVES: We studied the effect of local approval of syringe exchange programs in California (through Assembly AB136) on program availability and performance. METHODS: We determined the number of active syringe exchange programs in California by conducting Internet searches and obtaining information from the state and from local programs. To track changes in program availability and performance between 2000 and 2002, we interviewed 24 program directors annually for 3 years about program characteristics, syringe exchange policies, law enforcement contact, and other issues. We conducted multivariate analyses to determine whether AB136 approval status was associated with changes in performance. RESULTS: Fifteen local governments (13 counties and 2 cities) enacted the new law by 2002, and operating syringe exchange programs increased from 24 to 35. The proportion of these programs that were not locally approved declined from 54% to 40%. No new approved programs were started in high-need counties. Total syringes exchanged increased by more than 1 million per year, average annual budgets increased by more than 50%, and police harassment of the program volunteers, clients, and operators declined. Improvements at approved syringe exchange programs accounted for these changes. CONCLUSIONS: Statewide approval and funding appears necessary to further syringe exchange availability in California.

Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR).

The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure-activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.

(D)-2-tert-Butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid: synthesis and incorporation into the growth hormone secretagogues.

The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.

Design, synthesis, and structure-activity relationships of piperidine and dehydropiperidine carboxylic acids as novel, potent dual PPARalpha/gamma agonists.

Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.

Tetrazole based amides as growth hormone secretagogues.

A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.

Optimization of 1H-tetrazole-1-alkanenitriles as potent orally bioavailable growth hormone secretagogues.

1H-tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.

Design and synthesis of tetrazole-based growth hormone secretagogue: the SAR studies of the O-benzyl serine side chain.

The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).

Discovery of a tetrazole-based growth hormone secretagogue: 4-(hydroxybutyl)carbamic acid 2-{5-[1-(2-amino-2-methylpropionylamino)-2- benzyloxyethyl]tetrazol-1-yl}ethyl ester (BMS-317180).

A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.

Examination of the association between syringe exchange program (SEP) dispensation policy and SEP client-level syringe coverage among injection drug users.

AIM: To determine whether syringe exchange programs' (SEPs) dispensation policy is associated with syringe coverage among SEP clients. DESIGN: Cross-sectional samples of SEPs and their clients. SETTING: SEPs in California, USA. PARTICIPANTS: Twenty-four SEPs and their injection drug using (IDU) clients (n = 1576). MEASUREMENTS: Clients were classified as having adequate syringe coverage if they received at least as many syringes from the SEP as their self-reported injections in the last 30 days. SEPs were classified based on their syringe dispensation policy. Dispensation schemes ranging from least restrictive to most are: unlimited needs-based distribution; unlimited one-for-one exchange plus a few additional syringes; per visit limited one-for-one plus a few additional syringes; unlimited one-for-one exchange; and per visit limited one-for-one exchange. FINDINGS: Adequate syringe coverage among SEP clients by dispensation policy is as follows: unlimited needs-based distribution = 61%; unlimited one-for-one plus = 50%; limited one-for-one plus = 41%; unlimited one-for-one = 42%; and limited one-for-one = 26%. In multivariate analysis, adequate syringe coverage was significantly higher for all dispensation policies compared to per visit limited one-for-one exchange. Using propensity scoring methods, we compared syringe coverage by dispensation policies while controlling for client-level differences. Providing additional syringes above one-for-one exchange (50% versus 38%, P = 0.009) and unlimited exchange (42% versus 27%, P = 0.05) generally resulted in more clients having adequate syringe coverage compared to one-for-one exchange and per visit limits. CONCLUSION: Providing less restrictive syringe dispensation is associated with increased prevalence of adequate syringe coverage among clients. SEPs should adopt syringe dispensation policies that provide IDUs sufficient syringes to attain adequate syringe coverage.

Higher syringe coverage is associated with lower odds of HIV risk and does not increase unsafe syringe disposal among syringe exchange program clients.

OBJECTIVE: To determine if adequate syringe coverage --"one shot for one syringe"--among syringe exchange program (SEP) clients is associated with injection-related HIV risk behaviors and syringe disposal. DESIGN: HIV risk assessments with 1577 injection drug users (IDUs) recruited from 24 SEPs in California between 2001 and 2003. Individual syringe coverage was calculated as a proportion of syringes retained from SEP visits to total number of injections in the last 30 days. RESULTS: Participants were divided into four groups based on syringe coverage: <50%, 50-99%, 100-149%, and 150% or more. In multivariate logistic regression, SEP clients with less than 50% syringe coverage had significantly higher odds of reporting receptive syringe sharing in the last 30 days (adjusted odds ratio [AOR]=2.3; 95% confidence interval [CI]=1.4, 3.6) and those with 150% or more coverage had lower odds of reporting receptive syringe sharing (AOR=0.5; 95%CI=0.3, 0.8) as compared to SEP clients with adequate syringe coverage of 100-149%. Similar associations were observed for other main outcomes of distributive syringe sharing and syringe re-use. No differences in safe syringe disposal were observed by syringe coverage. CONCLUSIONS: Individual syringe coverage is strongly associated with safer injection behaviors without impacting syringe disposal among SEP clients. Syringe coverage is a useful measure for determining if IDUs are obtaining sufficient syringes to lower HIV risk.