Influence of Insurance Status and Demographic Features on Recognition of Symptomatic and Asymptomatic Gonorrhea Cases.

A random sample of individuals diagnosed as having gonorrhea from 2009 to 2013 were interviewed. Demographic and clinical features for asymptomatic and symptomatic individuals were examined to elucidate trends in medical care. Age, race, and sexually transmitted disease history had no association with the absence of symptoms (e.g., infection found by screening), whereas insurance coverage did for women.

H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.

We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)-/- mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE-/- mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.

Role of ambulatory blood pressure monitoring in hypertension and diabetes.

The prevalence of hypertension and diabetes are both rising in the USA and around the globe. The treatment of hypertension in the ambulatory setting begins with proper blood pressure measurement, and often the involvement of home blood pressure monitoring. If the diagnosis of hypertension is confirmed, then education on lifestyle modifications is the foundation to reaching blood pressure goals. If it is unclear, then ambulatory blood pressure monitoring should be performed to properly evaluate daily trends in blood pressure. The National Institute for Health and Clinical excellence (NICE) recommends 24-hour ambulatory blood pressure evaluation in all newly diagnosed patients with hypertension. The much-anticipated JNC 2013, while not likely to endorse this approach, will likely recommend an office goal systolic blood pressure of less than 140 mmHg in patients with diabetes as do the most recent American Diabetes Association clinical practice guidelines. All new guidelines are derived from a critical evidence based evaluation of the available data.

Blood pressure targets for patients with diabetes or kidney disease.

The most recent scientific guideline statements from foundations and societies dealing with diabetes and kidney disease argue for blood pressure (BP) goals lower than 130/80 mm Hg, but whether the evidence from properly done clinical trials supports this BP level remains questionable. A review of all the evidence suggests that almost all of the data come from retrospective data analyses of randomized cardiovascular and chronic kidney disease (CKD) trials. Meta-analyses of all clinical trials to date demonstrate that reducing BP reduces risk for stroke and coronary heart disease, but none have achieved a mean BP goal of less than 130/80 mm Hg. In fact, only two prospective trials achieved a BP lower than 130/80 mm Hg in people with type 2 diabetes, as did three trials in advanced proteinuric CKD. Of these, one of the two diabetes trials showed a benefit for overall cardiovascular risk reduction, and two of the three kidney disease trials showed a benefit on slowing of advanced CKD. Of note, however, these two trials in CKD had baseline average proteinuria rates of more than 500 mg/day. No benefit of a lower BP was seen in microalbuminuric CKD. Therefore, the totality of the prospective randomized trial evidence indicates that a BP less than 130/80 mm Hg is not defensible to slow nephropathy progression unless proteinuria levels are at least 500 mg/day, and it does not reduce overall cardiovascular events in diabetes. Stroke benefit was uniformly seen at BP levels less than 130/80 mm Hg, however. Therefore, newer guidelines are emerging that state that the BP goal for most people is lower than 140/90 mm Hg with level IA or IB evidence, and that levels lower than 130/80 mm Hg are defensible only if advanced proteinuric CKD is present or stroke risk is very high (i.e., history of prior stroke or several risk factors for stroke, including hypertension, smoking, diabetes mellitus, dyslipidemia).

Quantification of the transporter substrate fexofenadine in cell lysates by liquid chromatography/tandem mass spectrometry.

Drug-drug interactions at transporters present a significant and under-investigated clinical problem. Investigations of specific transporter functions and screening for potential drug-drug interactions, both in vitro and especially in vivo, will require validated experimental probes. Fexofenadine, an approved, well-tolerated drug, is a promising probe for studies of membrane transporter function. Although fexofenadine pharmacokinetics are known to be controlled by transporters, the contributions of individual transporters have not been defined. We have developed a rapid, specific, and sensitive analytical method for quantitation of fexofenadine to support this work. This liquid chromatography/tandem mass spectrometry (LC/MS/MS) method quantifies fexofenadine in cell lysates from in vitro studies using cetirizine as the internal standard. Cell lysates were prepared for analysis by acetonitrile precipitation. Analytes were then separated by gradient reversed-phase chromatography and analyzed by tandem mass spectrometry using the m/z 502.17/466.2 transition for fexofenadine and m/z 389.02/201.1 for cetirizine. The method exhibited a linear dynamic range of 1-500 ng/mL for fexofenadine in cell lysates. The lower limit of quantification was 1 ng/mL with a relative standard deviation of less than 5%. Intra- and inter-day precision and accuracy were within the limits presented in the FDA guidelines for bioanalysis. We also will validate this method to support not only the quantification of fexofenadine, but also other probe drugs for drug-drug interaction studies. This method for quantification will facilitate the use of fexofenadine as a probe drug for characterization of transporter activity.

In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma.

The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches. Among these drugs, 30 were extensively validated as mono-therapeutic agents and 9 in 14 various combinations in vitro. Two drugs, auranofin, a thioredoxin reductase inhibitor, and ganetespib, an HSP90 inhibitor, were predicted to have anti-cancer activities in silico and were confirmed active across a panel of genetically diverse EWS cells. When given in combination, the survival rate in vivo was superior compared to auranofin or ganetespib alone. Importantly, extensive formulations, dose tolerance, and pharmacokinetics studies demonstrated that auranofin requires alternative delivery routes to achieve therapeutically effective levels of the gold compound. These combined screening approaches provide a rapid means to identify new treatment options for patients with a rare and often-fatal disease.

Increased aldosterone: mechanism of hypertension in obesity.

The prevalence of both obesity and hypertension are increasing worldwide. Hypertension is a common consequence of obesity. Increased central adiposity is associated with increased aldosterone levels and blood pressure in human beings. A number of small studies have shown an association between obesity-mediated hypertension and mechanisms directly linked to increased levels of aldosterone. These studies have shown a trend toward relatively greater blood pressure reduction using aldosterone-receptor blockers compared with other classes of antihypertensive agents. Other than treatment for weight loss, treatment of hypertension with specific antihypertensive medications that block or reduce aldosterone action are appropriate in obese patients. Further research is needed to understand the exact role of the adipocyte in obesity-mediated hypertension.

Chronic ingestion of H1-antihistamines increase progression of atherosclerosis in apolipoprotein E-/- mice.

Although increased serum histamine levels and H1R expression in the plaque are seen in atherosclerosis, it is not known whether H1R activation is a causative factor in the development of the disease, or is a host defense response to atherogenic signals. In order to elucidate how pharmacological inhibition of histamine receptor 1 (H1R) signaling affects atherogenesis, we administered either cetirizine (1 and 4 mg/kg. b.w) or fexofenadine (10 and 40 mg/kg. b.w) to ApoE-/- mice maintained on a high fat diet for three months. Mice ingesting a low dose of cetirizine or fexofenadine had significantly higher plaque coverage in the aorta and cross-sectional lesion area at the aortic root. Surprisingly, the higher doses of cetirizine or fexofenadine did not enhance atherosclerotic lesion coverage over the controls. The low dose of fexofenadine, but not cetirizine, increased serum LDL cholesterol. Interestingly, the expression of iNOS and eNOS mRNA was increased in aortas of mice on high doses of cetirizine or fexofenadine. This may be a compensatory nitric oxide (NO)-mediated vasodilatory mechanism that accounts for the lack of increase in the progression of atherosclerosis. Although the administration of cetirizine did not alter blood pressure between the groups, there was a positive correlation between blood pressure and lesion/media ratio at the aortic root in mice receiving the low dose of cetirizine. However, this association was not observed in mice treated with the high dose of cetirizine or either doses of fexofenadine. The macrophages or T lymphocytes densities were not altered by low doses of H1-antihistamines, whereas, high doses decreased the number of macrophages but not T lymphocytes. The number of mast cells was decreased only in mice treated with low dose of fexofenadine. These results demonstrate that chronic ingestion of low therapeutic doses of cetirizine or fexofenadine enhance progression of atherosclerosis.

Noninsulin glucose-lowering agents for the treatment of patients on dialysis.

Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose-adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m(2)) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population.

Effects of nebivolol on aortic compliance in patients with diabetes and maximal renin angiotensin system blockade: the EFFORT study.

The beneficial effects of nebivolol on arterial stiffness and endothelial dysfunction are well documented in untreated hypertensive patients and differ from nonvasodilatory ß-blockers. This study tests the hypothesis that the addition of nebivolol in predominantly African American patients with type 2 diabetes already receiving maximally tolerated doses of renin-angiotensin system (RAS) blockers will further improve large artery compliance. Patients with type 2 diabetes and hypertension on maximal RAS blockade (n=70) were randomized to nebivolol or metoprolol succinate daily. Doses were titrated until systolic blood pressure (SBP) was <130 mm Hg. Radial artery applanation tonometry and pulse wave velocity (PWV) analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits at intervals during a 6-month period. Both metoprolol succinate and nebivolol groups demonstrated reductions in brachial SBP (-8.2±4.3 mm Hg [P=.01] and -7.8±3.7 [P=.002], respectively) and aortic DBP (-2.4±1.8 [P=.039] and -4.0±2.9 mm Hg [P=.013], respectively). Aortic SBP decreased in the nebivolol group only (125.3±8 to 121.6±8.2, P=.025). There were no between group differences in aortic SBP, DBP, augmentation index, or PWV reduction. A significant increase in hemoglobin A1c was observed only in the metoprolol group. In patients with well-controlled type 2 diabetes and hypertension treated with maximally tolerated RAS blockade, nebivolol does not offer significant reductions in aortic BP over metoprolol succinate but maintains a stable metabolic profile.

Interaction between Adiponectin and Aldosterone.

More than two thirds of the US population are considered overweight or obese. Adipocytes are now appreciated as important endocrine organs, secreting various factors with hormonal effects. Several different adipokines have been identified, including adiponectin, which is associated with improved insulin sensitivity, a better lipoprotein profile, and lower rates of vascular inflammation and cardiovascular disease. Several studies have identified the renin-angiotensin-aldosterone system as important in the regulation of adiponectin. These studies lay the fundamental groundwork for developing targeted therapies with potential to reduce the burden of obesity-associated diseases, such as the cardiorenal metabolic syndrome.