A pilot study: effects of decreasing serum insulin with diazoxide on vitamin D levels in obese women with polycystic ovary syndrome.

INTRODUCTION: We conducted a pilot project to test the hypothesis that decreasing insulin concentrations with diazoxide would affect parameters of vitamin D in obese women with and without polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Eight obese women with PCOS and nine matched controls participated in the study. Diazoxide was administered orally 100 mg three times daily for 10 days, and parameters of vitamin D were measured at baseline and end-of-study. RESULTS: At baseline, women with polycystic ovary syndrome had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than controls. After treatment with diazoxide, there were no significant changes in vitamin D parameters when PCOS and control women were evaluated separately. Diazoxide exhibited differential effects on 25(OH)D concentrations in PCOS as compared with normal women (P for interaction=0.045), and serum 25(OH)D levels converged after diazoxide treatment. CONCLUSIONS: Obese women with PCOS had significantly lower serum 25(OH)D levels at baseline than age- and body mass index-matched controls. Short-term administration with diazoxide seemed to have differential effects on 25(OH)D levels in PCOS as compared with control women. Further studies are necessary to confirm this finding.

Effects of Beta-Blocker Titration on Glucose Homeostasis in Heart Failure.

BACKGROUND: Abnormal glucose metabolism and insulin resistance have been associated with heart failure incidence, severity, and mortality. Metabolic parameters such as hepatic glucose production may be altered by beta-adrenoceptor antagonists in patients with heart failure. OBJECTIVE: This study evaluated the effects of metoprolol or carvedilol up-titration on fasting glucose, insulin resistance and beta(2)-mediated glucose production in patients with chronic heart failure. METHODS: This was a prospective, randomized, active comparator study in 15 patients with AHA/ACC Stage C systolic dysfunction HF stable on medical therapy. Participants were randomized to metoprolol 25mg daily or carvedilol 3.125mg twice daily. Metoprolol was titrated to a target of 200mg daily, and carvedilol was titrated to 25mg twice daily over 8weeks. Insulin resistance as assessed by the homeostatic model, and terbutaline-induced glucose production (AUC(0-180)), were assessed at baseline and at 4 subsequent beta-blocker titration visits over 8 weeks. RESULTS: In all 15 patients, terbutaline-induced glucose AUC(0-180) decreased (p=0.0006) as beta-blocker doses increased. A significant reduction in glucose AUC(0-180) compared to baseline was only noted in patients taking metoprolol at 100mg daily (-2424.6 [95% CI -372.6 to -4478.4] mg/dL*min) and 200mg daily (-2437.2 [95% CI -15.1 to -4604.4] mg/dL*min), and not observed in those taking carvedilol. After beta-blocker titration, fasting glucose concentrations for the metoprolol and carvedilol groups were 86.9 (95% CI 89.8-101.6) mg/dL and 95.7 (95% CI 89.8-101.6) mg/dL, respectively (p=0.0273), adjusted for baseline values. There was no significant difference between metoprolol and carvedilol on insulin resistance. CONCLUSION: Increasing doses of beta-blockers are associated with decreased in beta2-mediated glucose production in heart failure. Metoprolol, but not carvedilol, decreases hepatic glucose production at commonly used heart failure doses.

Educational Outcomes Resulting From Restructuring a Scholarship Course for Doctor of Pharmacy Students.

Objective. To compare educational outcomes between two iterations of a scholarship and research course for Doctor of Pharmacy (PharmD) students at Virginia Commonwealth University's School of Pharmacy. Methods. The first iteration of a course intended to teach pharmacy students the knowledge and skills necessary to design and conduct research involved lectures and application exercises, including limited guided questions about different aspects of the research process. In the fall of 2015, multiple structured activities and accompanying grading rubrics, each designed around the structure and content of a section of a research proposal, were introduced to the course to supplement lectures. Both iterations of the course culminated with students submitting a research proposal. After establishing interrater reliability, faculty members graded a random sample of 20 research proposals, 10 from each version of the course, and section-specific and overall proposal scores were compared. Results. In the proposals submitted after the course revisions, significant improvements in three areas were identified: the overall score, the section-specific scores for research hypothesis/specific aims, and institutional review board (IRB) discussion/informed consent. Nominal, though not statistically significant, improvements were observed in other sections. Conclusion. Additional research is needed regarding the best instructional strategies to reinforce data analysis and statistical testing knowledge and skills in PharmD students. Overall, our findings support the hypothesis that a more formalized, guided approach for teaching research methods improves learning outcomes for PharmD students.

Research in women and special populations.

The American College of Clinical Pharmacy charged a Task Force on Research in Special Populations to review, update, and broaden its 1993 White Paper on Women as Research Subjects. Participants of the task force included pharmacy clinicians and investigators in the field. This resulting White Paper, Research in Women and Special Populations, discusses the current concepts regarding the conduct of research in women, as well as in special populations such as children, elderly, minorities, cognitively impaired, and other vulnerable populations (e.g., prisoners and refugees). For each specific population, the barriers to research participation, current guidelines and regulations, and available recommendations to address these barriers are discussed. The participation in research by these populations requires addressing special social and ethical challenges. Clinical pharmacy researchers should be cognizant of these guidelines and be an advocate for the inclusion and the rights of women and special populations in research participation.

Learning Activities to Build Population Health Management Skills for Pharmacy Students.

Objective. To describe the implementation and evaluation of population health management learning activities in a second-year Doctor of Pharmacy (PharmD) course. Methods. Population health learning sessions were implemented in a step-wise manner: population needs assessment activity to identify priority programs for implementation given a specific patient population; didactic materials to introduce program evaluation foundational knowledge; program evaluation design activity to evaluate implemented programs using the Centers for Disease Control and Prevention's Program Evaluation Framework; and evaluation of program outcome data. Students' self-rated abilities (grouped into Bloom's Taxonomy classifications) and perceptions before and after program evaluation activities were assessed. Qualitative analyses evaluated student feedback on learning sessions. Results. Students' self-rated abilities for all Bloom's classifications increased after the learning sessions. Student perceptions on importance of program evaluation also improved (from 71% reporting "agree" or "strongly agree" pre-activities to 79% post-activities). Students found the application to case scenarios and the opportunity to integrate each component of program evaluation into a complete process useful. Conclusion. Step-wise population health management learning sessions were implemented, culminating in skill-based program evaluation activities. The activities improved students' self-rated abilities and perceptions regarding program evaluation. Areas for improvement for the learning sessions were also identified and will inform future instructional design.

Glucose intolerance in polycystic ovary syndrome--a position statement of the Androgen Excess Society.

OBJECTIVES: Women with polycystic ovarian syndrome (PCOS) are at increased risk for developing glucose intolerance and type 2 diabetes mellitus (DM). Recommendations for the timing and method of screening have varied. The purpose of this statement is to determine the optimal screening method, timing of screening, and treatment modalities for impaired glucose tolerance (IGT) among women with PCOS. PARTICIPANTS: The expert panel was appointed by the Androgen Excess Society (AES) to review the literature and make recommendations based on the available evidence. Meetings were open, and there was no funding for the panel. EVIDENCE: A systematic review was conducted of the published, peer-reviewed medical literature using MEDLINE to identify studies that addressed the prevalence, risk factors, testing, and treatment for IGT in both adults and adolescents with PCOS. Unpublished data were not considered. CONSENSUS PROCESS: The panel held meetings to review the literature and draft the statement as a committee. The AES board members reviewed and critiqued the manuscript, and changes were made based on their comments. CONCLUSIONS: The panel recommends that all patients with PCOS be screened for IGT with a 2-h oral glucose tolerance test. A few members of the AES board recommend alternatively screening women with PCOS for IGT and type 2 DM using an oral glucose tolerance test only in patients with a body mass index of 30 kg/m2 or greater or in lean patients with additional risk factors. Patients with normal glucose tolerance should be rescreened at least once every 2 yr, or more frequently if additional risk factors are identified. Those with IGT should be screened annually for development of type 2 DM. PCOS patients with IGT should be treated with intensive lifestyle modification and weight loss and considered for treatment with insulin-sensitizing agents.

Cardiovascular risk reduction.

A case on cardiovascular risk reduction is presented. Multiple cardiovascular risks (dyslipidemia, hypertension, and diabetes) are addressed. Management of the metabolic syndrome and appropriate testing for the newer cardiovascular marker, C-reactive protein, are also discussed. The case emphasizes the importance of patient education about chronic disease states, which are often asymptomatic.

Metabolic Effects of a Commonly Used Combined Hormonal Oral Contraceptive in Women With and Without Polycystic Ovary Syndrome.

BACKGROUND: Data on combined hormonal oral contraceptives' (OCs) effects on metabolic changes in women with polycystic ovary syndrome (PCOS) have been conflicting and were predominantly based on OCs with cyproterone acetate (unavailable in the United States) Most studies did not include normal women as controls. We compared metabolic changes before and after an OC commonly used in the United States between women with and without PCOS. METHODS: Ten PCOS and 20 control women took ethinyl estradiol 35 µg and norgestimate 0.18/0.215/0.25 mg. Fasting glucose and insulin, area-under-the-curve (AUC) glucose and insulin, insulin sensitivity (homeostatic model assessment of insulin sensitivity index [HOMA-ISI] and Matsuda index), insulinogenic index (Δinsulin0-30 minutes/Δglucose0-30 minutes), blood pressure, and lipids were evaluated at baseline and after three cycles of OC. RESULTS: At baseline, PCOS women had lower insulin sensitivity (Matsuda index p = 0.0093, HOMA-ISI p = 0.0397), higher fasting insulin (p = 0.0495), fasting glucose (p = 0.0393), AUC insulin (p = 0.0023), and triglycerides (p = 0.0044) versus controls. Baseline AUC glucose did not differ between PCOS women and controls. After 3 months of OC use, glucose tolerance worsened in PCOS women versus controls (p = 0.0468). Higher baseline androgens were predictive of worsened glucose tolerance, and a reduction of AUC insulin during OC use. The insulinogenic index significantly decreased in PCOS women (p < 0.01), while fasting insulin and insulin resistance significantly worsened in control women. CONCLUSION: Women with PCOS exhibited worsened glucose tolerance (demonstrated by AUC glucose) after 3 months of a commonly used OC compared with control women. Larger studies with longer follow-up should confirm these findings.

Effect on Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator during Weight Loss in Obese Women with and without Polycystic Ovary Syndrome.

Background. A deficiency of D-chiro-inositol-inositolphosphoglycan mediator (DCI-IPG) may contribute to insulin resistance in polycystic ovary syndrome (PCOS). Whether the relationship between impaired DCI-IPG release and insulin resistance is specific to PCOS rather than obesity is unknown. We assessed insulin-released DCI-IPG and its relationship to insulin sensitivity at baseline and after weight loss in obese women with and without PCOS. Methods. Obese PCOS (n = 16) and normal (n = 15) women underwent 8 weeks of a hypocaloric diet. The Matsuda index, area under the curve DCI-IPG (AUCDCI-IPG), AUCinsulin, and AUCDCI-IPG/AUCinsulin were measured during a 2 hr OGTT at baseline and 8 weeks. Results. PCOS women had lower AUCDCI-IPG/AUCinsulin at baseline and a significant relationship between AUCDCI-IPG/AUCinsulin and Matsuda index (p = 0.0003), which was not present in controls. Weight loss was similar between PCOS (-4.08 kg) and normal women (-4.29 kg, p = 0.6281). Weight loss in PCOS women did not change the relationship between AUCDCI-IPG/AUCinsulin and Matsuda index (p = 0.0100), and this relationship remained absent in control women. Conclusion. The association between AUCDCI-IPG/AUCinsulin and insulin sensitivity was only found in PCOS but not in normal women, and this relationship was unaffected by weight loss. DCI and its messenger may contribute to insulin resistance in PCOS independent of obesity.

Raspberry Leaf and Hypoglycemia in Gestational Diabetes Mellitus.

BACKGROUND: Raspberry leaf is commonly consumed by pregnant women. Hypoglycemic effects have been documented with other species within the plant family. Whether raspberry leaf affects glycemic control in gestational diabetes mellitus (GDM) is unknown. CASE: A 38-year-old nulliparous woman with GDM developed hypoglycemia requiring lowered insulin dose after consuming raspberry leaf tea at 32 weeks of gestation. The temporal relationship was confirmed by the patient's self-withdrawal and reintroduction of the herb. Fetal surveillance and growth were reassuring. A cesarean delivery was performed at 39 weeks of gestation. The neonate did not experience hypoglycemia or other complications. Placental biopsy revealed normal findings. CONCLUSION: Consumption of raspberry leaf may lead to reduced insulin requirements in GDM. Women with GDM should be cautioned about its use and their glucose levels more closely monitored.

The role of variants regulating metformin transport and action in women with polycystic ovary syndrome.

AIMS: Variants in genes encoding metformin transport proteins and the ATM gene are associated with metformin response. We hypothesized that these gene variants contribute to variable metformin treatment response in polycystic ovary syndrome. MATERIALS & METHODS: The discovery cohort (n = 38) was studied in an open-label study. Results were replicated in two additional cohorts (n = 26 and n = 131). Response was assessed after 3-6 months of treatment with metformin extended-release 1500-2000 mg/day. RESULTS: The rs683369 variant was associated with less weight loss in the discovery cohort (p = 0.003), but these results were not replicated (p = 0.8). There were no differences in glucose parameters, testosterone levels or ovulatory frequency as a function of genotype. CONCLUSION: Variants in organic ion transporters do not explain the variable metformin response in polycystic ovary syndrome.

Mechanism of poly(acrylic acid) acceleration of antithrombin inhibition of thrombin: implications for the design of novel heparin mimics.

The bridging mechanism of antithrombin inhibition of thrombin is a dominant mechanism contributing a massive approximately 2500-fold acceleration in the reaction rate and is also a key reason for the clinical usage of heparin. Our recent study of the antithrombin-activating properties of a carboxylic acid-based polymer, poly(acrylic acid) (PAA), demonstrated a surprisingly high acceleration in thrombin inhibition (Monien, B. H.; Desai, U. R. J. Med. Chem. 2005, 48, 1269). To better understand this interesting phenomenon, we have studied the mechanism of PAA-dependent acceleration in antithrombin inhibition of thrombin. Competitive binding studies with low-affinity heparin and a heparin tetrasaccharide suggest that PAA binds antithrombin in both the pentasaccharide- and the extended heparin-binding sites, and these results are corroborated by molecular modeling. The salt-dependence of the K(D) of the PAA-antithrombin interaction shows the formation of five ionic interactions. In contrast, the contribution of nonionic forces is miniscule, resulting in an interaction that is significantly weaker than that observed for heparins. A bell-shaped profile of the observed rate constant for antithrombin inhibition of thrombin as a function of PAA concentration was observed, suggesting that inhibition proceeds through the "bridging" mechanism. The knowledge gained in this mechanistic study highlights important rules for the rational design of orally available heparin mimics.

Multiple cardiovascular considerations in a 76-year-old man.

A 76-year-old man with a history of myocardial infarction, Type 2 diabetes, hypertension, hypercholesterolemia, and heart failure presents with muscle pain and spasm. A number of medication-related problems are identified by the pharmacist. Prioritization of medication-related problems and therapeutic recommendations are provided. The medication-related problems described in this case reinforce the need for establishing individualized action plans and avoiding making too many changes in medication regimens at one time. In addition, the issue of nonpharmacological causes of symptoms can be overlooked when focusing on medication-induced illness.

Sequential compression device compliance in postoperative obstetrics and gynecology patients.

OBJECTIVE: To assess the association of patient and nursing education on sequential compression device compliance in patients who have undergone major obstetric or benign gynecologic procedures. METHODS: We performed a prospective observational study on all English-speaking patients who underwent cesarean delivery or benign gynecologic surgery and were prescribed to wear sequential compression devices postoperatively at a university medical center. The 4-month study was divided into 1-month segments. The first month consisted of baseline observations of compliance. The second month was comprised of structured patient education, the third month involved nursing education, and the final month included both interventions. Observations were made twice daily. All educational interventions and observations were performed by two coauthors. A patient was noted to be compliant if she was ambulating, sitting, or lying in bed with sequential compression devices applied, tubing attached, and the machine powered on. RESULTS: A total of 859 observations was recorded for 228 patients. The number of hospitalization days ranged from 1 to 13 (mean 2.40 days, median 2 days). There was no difference in compliance among the months with 141 of 230 (61.3%), 106 of 194 (54.6%), 155 of 277 (56.0%), and 95 of 158 (60.1%) compliance for each consecutive month (P=.44). Noncompliance increased with each successive postoperative day (odds ratio 1.18 per day, 95% confidence interval 1.07-1.30). The most common patient-stated reason for noncompliance was "the nurse said I don't need them anymore" (82/362 observations [22.6%]). Overall, cesarean delivery was associated with the lowest rate of compliance when compared with gynecologic surgeries (272/519 [52.4%] compared with 225/340 [66.2%], P<.001). CONCLUSION: Compliance with postoperative use of sequential compression devices is approximately 58% and did not improve with patient or nursing educational interventions. LEVEL OF EVIDENCE: III.

Effect of Renin-Angiotensin system inhibition on cardiovascular events in older hypertensive patients with metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS. MATERIALS/METHODS: We used the Cardiovascular Health Study, a prospective cohort study of individuals>65years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events. RESULTS: ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR=0.658, 95 % C.I. [0.436-0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017-0.952] and [0.321-0.875]). CONCLUSIONS: ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

Persistence with oral contraceptive pills versus metformin in women with polycystic ovary syndrome.

OBJECTIVE: We studied patient persistence with oral contraceptive pills (OCPs) compared to metformin for treatment of polycystic ovary syndrome (PCOS) in an urban university clinic population. METHODS: We conducted a retrospective cohort study of women with PCOS who were treated in our specialty clinic between 2004 and 2006. All women with the diagnosis of PCOS, defined as oligomenorrhea or amenorrhea in conjunction with clinical or biochemical evidence of hyperandrogenism, with exclusion of other causes, were included in the study. We abstracted data on demographic characteristics, medical history, anthropometrical measures, desire for pregnancy, prescribed treatment, and patient report of persistence with treatment at 3, 6, and 12 months. The primary outcome measure was persistence with prescribed treatment. RESULTS: One hundred nineteen subjects were included in the study. Demographic and anthropometrical characteristics were similar between the groups. At 3 months, 57.1% were persistent with OCPs, and 57.8% were persistent with metformin (p=0.93). At 6 months, the percentages dropped to 38.1% with OCPs and 43.9% with metformin (p=0.46). At 12 months, only 21.7% continued with OCPs compared to 31.2% with metformin (p=0.19). Subjects were significantly more likely to be persistent with either OCPs or metformin at 3 months compared to either 6 or 12 months (p<0.01). CONCLUSIONS: Women with PCOS showed similar persistence rates with OCPs compared to metformin. Persistence with either treatment precipitously decreases over time and is modest at 12 months.

Comparison of different metabolic syndrome definitions and risks of incident cardiovascular events in the elderly.

The metabolic syndrome is associated with increased cardiovascular risk, and its prevalence increases with age. Various definitions of the metabolic syndrome exist, but whether some definitions are more predictive of future cardiovascular events in the elderly is unclear. We compared the risk of incident cardiovascular events in elderly individuals at least 65 years old from the Cardiovascular Health Study with and without the metabolic syndrome as defined by the European Group for the Study of Insulin Resistance (EGIR), National Cholesterol Education Program (NCEP)/American Heart Association (AHA), American Association of Clinical Endocrinologists, International Diabetes Federation (IDF), and modified World Health Organization (WHO) criteria (n = 3390). Participants were without baseline diabetes or cardiovascular disease. Except for EGIR, all definitions of the metabolic syndrome were significantly associated with increased risk of incident cardiovascular (coronary or cerebrovascular) events. Adjusted hazard ratios (HRs) for risk of incident cardiovascular events as defined by the modified WHO, NCEP/AHA, American Association of Clinical Endocrinologists, and IDF criteria ranged from 1.153 (P = .045) for NCEP/AHA to 1.314 (P < .001) for IDF, with 95% confidence interval (CI) ranging from 1.003 to 1.503. Adjusted HR for EGIR was 1.087 (95% CI, 0.908-1.301; P = .362). Similarly, all definitions of the metabolic syndrome were significantly associated with incident coronary events except for the EGIR definition. Only the modified WHO definition was associated with increased risk for cerebrovascular events (adjusted HR, 1.301; 95% CI, 1.038-1.631; P = .022). Although all metabolic syndrome definitions except EGIR were associated with total cardiovascular events and coronary events, only the modified WHO definition was also associated with risk of cerebrovascular events.

Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome.

The interactive nature of the 8th Annual Meeting of the Androgen Excess and PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.

Total and high-molecular weight adiponectin in women with the polycystic ovary syndrome.

Adiponectin, an adipokine with antidiabetic properties, forms multimers; and the high-molecular weight (HMW) form most closely correlates with insulin sensitivity (S(i)). Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared with healthy controls and that HMW adiponectin correlates with testosterone and S(i). A cross-sectional study involving 13 women with PCOS and 13 age- and body mass index-matched healthy controls was performed. Waist-to-hip ratios (WHRs), glucose, insulin, sex hormone-binding globulin, total testosterone, and total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from sex hormone-binding globulin and total testosterone, and S(i) was determined using a frequently sampled intravenous glucose tolerance test. The study's primary outcomes were differences in total and HMW adiponectin between women with PCOS and healthy control women. Total adiponectin (P < .01), HMW adiponectin (P < .01), and the ratio of HMW to total adiponectin (P = .03) were lower in women with PCOS compared with healthy women. Total and HMW adiponectin levels correlated inversely with WHR (P < .01) and free testosterone (P < .01) and positively with S(i) (P < .001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of S(i). Women with PCOS have lower total and HMW adiponectin levels compared with healthy women. High-molecular weight adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.