TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload.

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-alpha are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-alpha with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-alpha inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-alpha antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-alpha has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.

Inflammation, proinflammatory mediators and myocardial ischemia-reperfusion Injury.

Ischemic myocardium must be reperfused to terminate the ischemic event; otherwise the entire myocardium involved in the area at risk will not survive. However, there is a cost to reperfusion that may offset the intended clinical benefits of minimizing infarct size, postischemic endothelial and microvascular damage, blood flow defects, and contractile dysfunction. There are many contributors to this reperfusion injury. Targeting only one factor in the complex web of reperfusion injury is not effective because the untargeted mechanisms induce injury. An integrated strategy of reducing reperfusion injury in the catheterization laboratory involves controlling both the conditions and the composition of the reperfusate. Mechanical interventions such as gradually restoring blood flow or applying postconditioning may be used independently in or conjunction with various cardioprotective pharmaceuticals in an integrated strategy of reperfusion therapeutics to reduce postischemic injury.

Pramlintide in the treatment of type 1 and type 2 diabetes mellitus.

BACKGROUND: Amylin is a 37-amino acid peptide neurohormone that is cosecreted with insulin from the pancreatic beta cells in response to meals. It lowers serum glucose by decreasing glucagon release, slowing gastric emptying, and decreasing food intake. Pramlintide, a synthetic amylin analogue, is approved by the US Food and Drug Administration for use with mealtime insulin in patients with type 1 diabetes and patients with type 2 diabetes who are using mealtime insulin only or the combination of insulin and metformin and/or a sulfonylurea. OBJECTIVE: This article reviews the available literature on pramlintide with respect to its mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy in type 1 and type 2 diabetes, safety and tolerability, dosing, contraindications, and drug interactions. METHODS: MEDLINE (1966-April 2005), Iowa Drug Information Service (1966-April 2005), and International Pharmaceutical Abstracts (1970-April 2005) were searched for clinical trials and therapeutic reviews published in the English language. The search terms were pramlintide and amylin. The bibliographies of identified articles were reviewed for additional references. All relevant studies were included in the review. RESULTS: Six studies, ranging in duration from 4 to 52 weeks, examined the effect of administering pramlintide with premeal insulin in patients with type 1 diabetes. In these trials, pramlintide 120 to 270 microg/d reduced glycosylated hemoglobin (HbA(1c)) by 0.1 % to 0.67%, 1-hour postprandial glucose (PPG) by 4.4 to 7 mmol/L, and 2-hour PPG by 3.6 to 4.8 mmol/L. Five studies, also ranging from 4 to 52 weeks' duration, examined the effect of administering premeal pramlintide in patients with type 2 diabetes. In these trials, pramlintide 90 to 450 microg/d reduced HbA(1c) by 0.3% to 0.62%, 1-hour PPG by 4.8 mmol/L, and 2-hour PPG by 3.4 mmol/L. The principal adverse events reported in clinical trials were nausea and hypoglycemia. The incidence of hypoglycemia in the first 4 weeks of therapy was 2 to 4 times greater with pramlintide compared with placebo; thus, the manufacturer recommends reducing the dose of premeal insulin by 50% when starting pramlintide. Close monitoring of blood glucose levels is recommended when initiating pramlintide therapy. CONCLUSIONS: Use of pramlintide in addition to insulin in patients with type 1 and type 2 diabetes was associated with modest reductions in HbA(1c). The primary adverse effects of pramlintide therapy were nausea and hypoglycemia.

Age-related androgen deficiency and type 2 diabetes.

There is a higher prevalence of low testosterone levels in males with type 2 diabetes compared to those without. Additionally, there is evidence that low testosterone levels may predict the development of type 2 diabetes. Symptoms of hypogonadism include decreased libido, decreased bone mineral density (BMD), and decreased lean muscle mass. The majority of the published cases in men with diabetes were attributed to age-related idiopathic hypogonadotropic hypogonadism. This paper reviews the link between type 2 diabetes and age-related hypogonadism and the treatment options for hypogonadism. Pharmacists who provide care for males with diabetes should be aware of the increased incidence of hypogonadism, know how to screen for it, and be able to recommend appropriate therapy.