The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

<p>Abstract</p> <p>Background</p> <p>Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.</p> <p>Methods</p> <p>DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.</p> <p>Results</p> <p>HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P ≤ 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P ≤ 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P ≤ 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.</p> <p>Conclusions</p> <p>Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.</p

The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study.

BACKGROUND: Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda. METHODS: HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures. RESULTS: During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more. CONCLUSION: Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes. TRIAL REGISTRATION: CRYPTOPRO [ISRCTN 76481529 ], November 2004

Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure

<p>Abstract</p> <p>Background</p> <p>Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation.</p> <p>Methods</p> <p>Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end.</p> <p>Results</p> <p>Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression.</p> <p>Conclusions</p> <p>Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.</p

Simultaneous angiotensin receptor blockade and glucagon-like peptide-1 receptor activation ameliorate albuminuria in obese insulin-resistant rats.

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (Ualb V) in the following groups: (a) untreated, lean LETO (n&nbsp;=&nbsp;7), (b) untreated, obese OLETF (n&nbsp;=&nbsp;9), (c) OLETF&nbsp;+&nbsp;angiotensin receptor blocker (ARB; 10&nbsp;mg olmesartan/kg/d; n&nbsp;=&nbsp;9), (d) OLETF&nbsp;+&nbsp;GLP-1 mimetic (EXE; 10&nbsp;µg exenatide/kg/d; n&nbsp;=&nbsp;7) and (e) OLETF&nbsp;+&nbsp;ARB +exenatide (Combo; n&nbsp;=&nbsp;6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, Ualb V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced Ualb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity

Amylin: Pharmacology, Physiology, and Clinical Potential

Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin's major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents

Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans.

BACKGROUND: Data from retrospective studies have suggested that there may be an interaction between fluconazole and nevirapine, increasing nevirapine concentrations and potentially leading to hepatotoxicity. METHODS: This study was nested within a large double-blind placebo-controlled study designed to determine if primary prophylaxis with fluconazole (200 mg three times per week) could reduce cryptococcal disease [CRYPTOPRO (ISRCTN 76481529)] in HIV-infected adults in rural south-western Uganda. Detailed pharmacokinetic studies were performed on 49 participants (22 on placebo and 27 on fluconazole) who had been on fluconazole or placebo with nevirapine for > or =4 weeks. RESULTS: The geometric mean pre-dose concentrations of nevirapine were 3865 ng/mL [95% confidence interval (95% CI) 3452-4758 ng/mL] and 5141 ng/mL (95% CI 4760-6595 ng/mL) (P = 0.009) in the placebo and fluconazole arms, respectively. The change in the peak nevirapine concentration in plasma (C(max)) was also higher in the fluconazole arm compared with the placebo arm [median 6546 (95% CI 6040-7974) versus 5126 (95% CI 4739-5773) ng/mL, P = 0.012]. Fluconazole increased the nevirapine area under the curve (AUC) from 0 to 8 h by 29% [geometric mean AUC(0-8) 46 135 (95% CI 42 432-57 173) versus 35 871 (95% CI 32 808-41 372) ng.h/mL, P = 0.016]. In the larger cohort from which the participants were drawn, co-administration of fluconazole did not increase the risk of hepatotoxicity. CONCLUSIONS: Fluconazole led to significant increases in nevirapine exposure, but was not associated with evidence of increased hepatotoxicity

Pregnancy in HIV clinical trials in Sub Saharan Africa: failure of consent or contraception?

OBJECTIVE: Higher than expected pregnancy rates have been observed in HIV related clinical trials in Sub-Saharan Africa. We designed a qualitative study to explore the factors contributing to high pregnancy rates among participants in two HIV clinical trials in Sub-Saharan Africa. METHODS: Female and male participants enrolled in one of two clinical HIV trials in south-west Uganda were approached. The trials were a phase III microbicide efficacy trial among HIV negative women using vaginal gel (MDP); and a trial of primary prevention prophylaxis for invasive cryptococcal disease using fluconazole among HIV infected men and women in Uganda (CRYPTOPRO). 14 focus group discussions and 8 in-depth interviews were conducted with HIV positive and negative women and their male partners over a six month period. Areas explored were their experiences about why and when one should get pregnant, factors affecting use of contraceptives, HIV status disclosure and trial product use. RESULTS: All respondents acknowledged being advised of the importance of avoiding pregnancy during the trial. Factors reported to contribute to pregnancy included; trust that the investigational product (oral capsules/vaginal gel) would not harm the baby, need for children, side effects that led to inconsistent contraceptive use, low acceptance of condom use among male partners. Attitudes towards getting pregnant are fluid within couples over time and the trials often last for more than a year. Researchers need to account for high pregnancy rates in their sample size calculations, and consider lesser used female initiated contraceptive options e.g. diaphragm or female condoms. In long clinical trials where there is a high fetal or maternal risk due to investigational product, researchers and ethics committees should consider a review of participants contraceptive needs/pregnancy desire review after a fixed period, as need for children, partners and health status of participants may alter over time