Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

Tolvaptan is a vasopressin

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15–50 μM), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil, MK-571, or 10 μM elacridar. Coincubation of tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing tolvaptan concentrations (0.15–50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μM tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites

Not sold here: limited access to legally available syringes at pharmacies in Tijuana, Mexico

<p>Abstract</p> <p>Background</p> <p>Sterile syringe access is a critical component of HIV prevention programs. Although retail pharmacies provide convenient outlets for syringe access, injection drug users (IDUs) may encounter barriers to syringe purchase even where purchase without a prescription is legal. We sought to obtain an objective measure of syringe access in Tijuana, Mexico, where IDUs report being denied or overcharged for syringes at pharmacies.</p> <p>Methods</p> <p>Trained "mystery shoppers" attempted to buy a 1 cc insulin syringe according to a predetermined script at all retail pharmacies in three Tijuana neighborhoods. The same pharmacies were surveyed by telephone regarding their syringe sales policies. Data on purchase attempts were analyzed using basic statistics to obtain an objective measure of syringe access and compared with data on stated sales policies to ascertain consistency.</p> <p>Results</p> <p>Only 46 (28.4%) of 162 syringe purchase attempts were successful. Leading reasons for unsuccessful attempts were being told that the pharmacy didn't sell syringes (35.3%), there were no syringes in stock (31.0%), or a prescription was required (20.7%). Of 136 pharmacies also surveyed by telephone, a majority (88.2%) reported selling syringes but only one-third (32.5%) had a successful mystery shopper purchase; the majority of unsuccessful purchases were attributed to being told the pharmacy didn't sell syringes. There was similar discordance regarding prescription policies: 74 pharmacies said in the telephone survey that they did not require a prescription for syringes, yet 10 of these pharmacies asked the mystery shopper for a prescription.</p> <p>Conclusions</p> <p>IDUs in Tijuana have limited access to syringes through retail pharmacies and policies and practices regarding syringe sales are inconsistent. Reasons for these restrictive and inconsistent practices must be identified and addressed to expand syringe access, reduce syringe sharing and prevent HIV transmission.</p

Vulnerability Factors and Pathways Leading to Underage Entry into Sex Work in two Mexican-US Border Cities

The current wave of interest in human trafficking and the commercial sexual exploitation of children has exposed a lack of knowledge about the vulnerabilities leading to underage entry into sex work. This knowledge is necessary for the development of effective prevention programs to identify girls who are most at-risk, especially in Latin America, a region that is believed to be a large source of persons moved across international borders for the purposes of sexual and labor exploitation. The objective of this study was to explore and increase understanding of the vulnerability factors and pathways leading to underage entry into sex work experienced by women currently engaging in sex work in two cities on the northern border of Mexico. From August 2013 to October 2014, 20 female sex workers (FSWs) with a history of entry into sex work prior to age 18 were recruited for in-depth interviews from a larger time-location sample of female sex workers (FSWs) participating in a quantitative survey in Tijuana and Ciudad Juarez. The median age of entry into sex work was 14 (range 10-17); 12/21 participants reported being forced into sex work and, of these, 7 were transported to another city where they began engaging in sex work. Family dysfunction (e.g., domestic violence between parents, parent drug use, neglect, etc.), sexual and physical abuse, and teen pregnancy were among the key themes that emerged as vulnerabilities to underage entry into sex work. Women’s narratives clearly illustrated that the vulnerabilities and pathways leading to underage entry are manifold, complex, and often intersect with each other. Our findings begin to lay the groundwork for understanding the potential vulnerabilities and pathways leading to underage entry into sex, and may have relevance to Latin America in general. This study also provides a foundation for further research to explore what may mitigate these vulnerabilities as well as creating evidence-based interventions to prevent commercial sexual exploitation of minors in the region

HIV risk behaviours differ by workplace stability among Mexican female sex workers with truck driver clientele

Background. In a study of female sex workers (FSWs) servicing truck driver clients in Mexican border cities, we evaluated differences in HIV/STI risk behaviours determined by workplace. Design and Methods. Our study was cross-sectional and its population comprised 100 FSWs from Nuevo Laredo (US border) and 100 FSWs from Ciudad Hidalgo (Guatemalan border). The main outcome was that the primary place of sex work was unstable in a public place (street, vehicle, gas station, etc.) intead of stable (bar, brothel, and hotel). Logistic regression was used to identify correlates associated with trading sex at unstable workplaces in the last month. Results. Of the FSWs surveyed, 18% reported an unstable workplace. The majority of FSWs surveyed were young (&lt;30 years), single, had &lt;9th grade education, and had worked in the sex trade for a median of 4.9 years. After controlling for study site, FSWs with unstable vs stable workplaces were more likely to have a majority/all truck driver clientele, but were less likely to have visited a gynaecologist in the last year (OR 0.1, 95% CI 0.03-0.4) or ever had an HIV test (OR 0.1, 95% CI 0.06-0.3), and there was a trend towards lower condom use self-efficacy scores (OR 0.8 per unit increase, 95% CI 0.7-1.0). On multivariate regression, unstable workplace was associated with having majority/all truck driver clientele, being surveyed in Nuevo Laredo, and decreased odds of ever having an HIV test. Conclusions. Among Mexican FSWs with truck driver clients, providing safe indoor spaces for sex work may help facilitate public health interventions that improve HIV/STI prevention and reproductive health outcomes

Influence of Peer Support on HIV/STI Prevention and Safety Amongst International Migrant Sex Workers: A Qualitative Study at the Mexico-Guatemala Border

Background Migrant women engaged in precarious employment, such as sex work, frequently face pronounced social isolation alongside other barriers to health and human rights. Although peer support has been identified as a critical HIV and violence prevention intervention for sex workers, little is known about access to peer support or its role in shaping health and social outcomes for migrant sex workers. This article analyses the role of peer support in shaping vulnerability and resilience related to HIV/STI prevention and violence among international migrant sex workers at the Mexico-Guatemala border.&nbsp; Methods This qualitative study is based on 31 semi-structured interviews conducted with international migrant sex workers in the Mexico-Guatemala border communities of Tapachula, Mexico and Tecún Umán and Quetzaltenango, Guatemala. Results Peer support was found to be critical for reducing social isolation; improving access to HIV/STI knowledge, prevention and resources; and mitigating workplace violence, particularly at the initial stages of migration and sex work. Peer support was especially critical for countering social isolation, and peers represented a valuable source of HIV/STI prevention knowledge and resources (e.g., condoms), as well as essential safety supports in the workplace. However, challenges to accessing peer support were noted, including difficulties establishing long-lasting relationships and other forms of social participation due to frequent mobility, as well as tensions among peers within some work environments. Variations in access to peer support related to country of work, work environment, sex work and migration stage, and sex work experience were also identified.&nbsp; Conclusions Results indicate that peer-led and community empowerment interventions represent a promising strategy for promoting the health, safety and human rights of migrant sex workers. Tailored community empowerment interventions addressing the unique migration-related contexts and challenges faced by migrant sex workers should be a focus of future community-based research, alongside promotion of broader structural changes

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH

Differential Effects of Migration and Deportation on HIV Infection among Male and Female Injection Drug Users in Tijuana, Mexico

HIV prevalence is rising, especially among high risk females in Tijuana, Baja California, a Mexico-US border city situated on major migration and drug trafficking routes. We compared factors associated with HIV infection among male and female injection drug users (IDUs) in Tijuana in an effort to inform HIV prevention and treatment programs. IDUs aged ≥18 years were recruited using respondent-driven sampling and underwent testing for HIV, syphilis and structured interviews. Logistic regression identified correlates of HIV infection, stratified by gender. Among 1056 IDUs, most were Mexican-born but 67% were born outside Tijuana. Reasons for moving to Tijuana included deportation from the US (56% for males, 29% for females), and looking for work/better life (34% for females, 15% for males). HIV prevalence was higher in females versus males (10.2% vs. 3.5%, p = 0.001). Among females (N = 158), factors independently associated with higher HIV prevalence included younger age, lifetime syphilis infection and living in Tijuana for longer durations. Among males (N = 898), factors independently associated with higher HIV prevalence were syphilis titers consistent with active infection, being arrested for having ‘track-marks’, having larger numbers of recent injection partners and living in Tijuana for shorter durations. An interaction between gender and number of years lived in Tijuana regressed on HIV infection was significant (p = 0.03). Upon further analysis, deportation from the U.S. explained the association between shorter duration lived in Tijuana and HIV infection among males; odds of HIV infection were four-fold higher among male injectors deported from the US, compared to other males, adjusting for all other significant correlates (p = 0.002). Geographic mobility has a profound influence on Tijuana's evolving HIV epidemic, and its impact is significantly modified by gender. Future studies are needed to elucidate the context of mobility and HIV acquisition in this region, and whether US immigration policies adversely affect HIV risk

Determining Risk for Severe Leptospirosis by Molecular Analysis of Environmental Surface Waters for Pathogenic Leptospira

BACKGROUND: Although previous data indicate that the overall incidence of human leptospirosis in the Peruvian Amazon is similar in urban and rural sites, severe leptospirosis has been observed only in the urban context. As a potential explanation for this epidemiological observation, we tested the hypothesis that concentrations of more virulent Leptospira would be higher in urban than in rural environmental surface waters. METHODS AND FINDINGS: A quantitative real-time PCR assay was used to compare levels of Leptospira in urban and rural environmental surface waters in sites in the Peruvian Amazon region of Iquitos. Molecular taxonomic analysis of a 1,200-bp segment of the leptospiral 16S ribosomal RNA gene was used to identify Leptospira to the species level. Pathogenic Leptospira species were found only in urban slum water sources (Fisher's exact test; p = 0.013). The concentration of pathogen-related Leptospira was higher in urban than rural water sources (~10(3) leptospires/ml versus 0.5 × 10(2) leptospires/ml; F = 8.406, p < 0.05). Identical 16S rRNA gene sequences from Leptospira interrogans serovar Icterohaemorrhagiae were found in urban slum market area gutter water and in human isolates, suggesting a specific mode of transmission from rats to humans. In a prospective, population-based study of patients presenting with acute febrile illness, isolation of L. interrogans-related leptospires from humans was significantly associated with urban acquisition (75% of urban isolates); human isolates of other leptospiral species were associated with rural acquisition (78% of rural isolates) (chi-square analysis; p < 0.01). This distribution of human leptospiral isolates mirrored the distribution of leptospiral 16S ribosomal gene sequences in urban and rural water sources. CONCLUSIONS: Our findings data support the hypothesis that urban severe leptospirosis in the Peruvian Amazon is associated with higher concentrations of more pathogenic leptospires at sites of exposure and transmission. This combined quantitative and molecular taxonomical risk assessment of environmental surface waters is globally applicable for assessing risk for leptospiral infection and severe disease in leptospirosis-endemic regions