Analysis of Physiology Theory Question Papers for Competency-Based Medical Education Implementation in Gujarat: A Pilot Study.

Introduction Theory question papers form an important part of assessment in medical education. As per the Competency-Based Medical Education (CBME) guidelines 2019, questions should test higher levels of cognition. This pilot study analyzes 60 question papers from different universities in Gujarat for their construct and content validity. The aim was to analyze the quality of physiology question papers from various medical universities in Gujarat to gain insights into assessment quality and its alignment with the CBME guidelines. The objectives were twofold: to evaluate the "construct validity" and "content validity" of these physiology theory question papers over the past three years according to the CBME standards. Methods An observational study using a cross-sectional records-based approach was carried out, evaluating 60 summative exam question papers in physiology from eight different universities of Gujarat for their construct and content validity. Using Bloom's taxonomy, the learning level of the cognitive domain for the questions asked was assessed. The findings compared and displayed a sample of papers. Results A total of 1842 questions were analyzed from the 60 question papers of eight different universities of the Gujarat state. The study found that the questions asked for different levels of cognition in Bloom's taxonomy, i.e., remember, understand, apply, analyze, evaluate, and create, were 560 (30.40%), 434 (23.26%), 222 (12.05%), 118 (6.41%), 94 (5.10%), and 0.00%, respectively. A total of 414 (22.48%) questions did not have any verb, so they did not fit into any level of Bloom's taxonomy. The majority of questions (1773, 96.25%) were asked from the core competencies, while a small percentage (69, 3.75%) of questions were asked from the non-core competencies of physiology. Conclusion The majority of questions in the summative question papers in physiology were of level "remember" and "understand" as per Bloom's taxonomy. Of the questions, 26% did not have any verb. There is a need to incorporate more questions testing higher levels of cognition and to use blueprints by universities. Faculty training is also necessary to bring about course correction.

Influencing Appropriate Statin Use in a Charity Care Primary Clinic.

According to the American College of Cardiology/American Heart Association (ACC/AHA) new cholesterol management guidelines in 2019, statin regimen was prescribed to only about 46.4% and 30% of diabetes (DM) patients and patients with atherosclerotic cardiovascular disease (ASCVD), respectively. Atherosclerotic cardiovascular disease accounts for most deaths and disabilities in North America. This study argues that a systematic approach to identifying targeted interventions to adhere to the statin regimen for ASCVD is sparse in previous studies. This study seeks to address the research gap. Besides, the study argues that the statin regimen could improve cholesterol management with the enablers of pharmacy, providers, electronic medical records (E.M.R.), and patients. It paves the way for future research on cardiovascular and statin regimens from different perspectives. Current study has adopted the Qualitative observation method. Accordingly, the study approached the charity care primary clinic serving a large population in the northeastern part of the United States, which constitutes the project's setting. The facility has 51 internal medicine residents. The facility has E.H.R., which is used by the clinical staff. Besides, providers use electronic medication prescribing (E-Scribe). Four PDSA cycles were run in six months. Here, the interventions were intensified during each subsequent cycle. The interventions were then incorporated into routine clinical practice. Based on the observation, the study found a 25% relative improvement by six months based on the baseline data of the appropriate intensity statin prescription for patients with ASCVD or DM by medical resident trainees in our single-center primary care clinic. A total of 77% of cardiovascular disease patients were found to be on an appropriate statin dose at baseline. On the other hand, the proportion of patients with DM who were on proper dose statin was 80.4%. According to the study's findings, PDSA could result in a faster uptake and support of the ACC/AHA guidelines. Evidence indicates that overmedication of persons at low risk and time constraints are some of the most significant impediments to the greater use of prescription medications. Proactive panel management can help improve statins' use by ensuring they are used appropriately.

Determination of doravirine in human plasma using liquid-liquid extraction and HPLC-MS/MS.

Aim: A method to quantitate doravirine (MK-1439) in human plasma has been developed to support human clinical trials designed to evaluate the safety, pharmacokinetics and efficacy of the compound. Methodology & results: The analyte was extracted using liquid-liquid extraction, separated on a reverse phase HPLC column, and detected on an API-4000 mass spectrometer using a Turbo-Ion spray source in positive ionization mode coupled with multiple reaction monitoring mode was used for quantification. The dynamic range for the assay was 0.02-10 ng/ml using 100 µl of human plasma. Conclusion: The assay was found to be sensitive, selective and reproducible and applied to support the doravirine clinical development program.

Chronic Sheehan's Syndrome - A Differential to be Considered in Clinical Practice in Women with a History of Postpartum Hemorrhage.

Sheehan's syndrome is hypopituitarism due to pituitary gland necrosis resulting from hemorrhagic shock during pregnancy. It is a rare complication with varied manifestations and a considerable delay in diagnosis. We describe the case of a 36-year-old female with eight years of non-specific symptoms of generalized myalgias and intense fatigue managed symptomatically all these years. Further clinical assessment revealed amenorrhea and agalactia ongoing for several years without a clinical diagnosis. A good history and physical led to the diagnosis during a routine outpatient visit. She had significant improvement noted following the commencement of treatment. Previous case reports describe cases being diagnosed after one or other complications from long-term panhypopituitarism. Through this case, we want to illustrate that undiagnosed Sheehan's syndrome is associated with long-term morbidity, and there should be a high index of suspicion for it to be diagnosed during a routine clinical visit and thus prevent complications before a diagnosis can be made. It is essential to create awareness, especially in developed countries like the United States, where it has received less attention over the last few years.

Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ∼40% for AUC0-24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P<0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n=4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years.

Effects of multiple doses of clarithromycin on the pharmacokinetics of laropiprant in healthy subjects.

Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open-labeled, randomized, 2-period cross-over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7-day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC0-∞ and Cmax of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in Tmax (P= 0.543) or apparent terminal half-life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first-pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.

Pharmacokinetics of laropiprant and glucuronide metabolite in patients with severe renal insufficiency.

Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m(2) and >80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.

Absorption, metabolism, and excretion of [(14)C]MK-0524, a prostaglandin D(2) receptor antagonist, in humans.

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [(14)C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 microCi). [(14)C]MK-0524 was absorbed rapidly, with plasma C(max) achieved 1 to 1.5 h postdose. The major route of excretion of radioactivity was via the feces, with 68% of the administered dose recovered in feces. Urinary excretion averaged 22% of the administered dose, for a total excretion recovery of approximately 90%. The majority of the dose was excreted within 96 h following dosing. Parent compound was the primary radioactive component circulating in plasma, comprising 42 to 72% of the total radioactivity in plasma for up to 12 h. The only other radioactive component detected in plasma was M2, the acyl glucuronic acid conjugate of the parent compound. The major radioactive component in urine was M2, representing 64% of the total radioactivity. Minor metabolites included hydroxylated epimers (M1/M4) and their glucuronic acid conjugates, which occurred in the urine as urea adducts, formed presumably during storage of samples. Fecal radioactivity profiles mainly comprised the parent compound, originating from unabsorbed parent and/or hydrolyzed glucuronic acid conjugate of the parent compound. Therefore, in humans, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces.

Determination of a prostaglandin D2 antagonist and its acyl glucuronide metabolite in human plasma by high performance liquid chromatography with tandem mass spectrometric detection--a lack of MS/MS selectivity between a glucuronide conjugate and a phase I metabolite.

A method for the determination of a prostaglandin D(2) receptor antagonist (I, a compound being evaluated for the prevention of niacin induced flushing) and its acyl glucuronide metabolite (II) in human plasma is presented. The method utilized high performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection using an atmospheric pressure chemical ionization (APCI) interface operated in the positive ionization mode. The product ion was a radical cation generated via a homolytic bond cleavage. A chemical analog of the drug was used as internal standard (III). The acyl glucuronide metabolite (II) was detected using the same precursor-to-product ion transition used for the parent compound after chromatographic separation of I and II. Drug and metabolite were extracted using semi-automated, 96-well format solid phase extraction (SPE), and chromatography was performed using a reverse phase analytical column with an isocratic mobile phase. The chromatographic retention factor (k') of II was found to be highly sensitive to mobile phase formic acid concentration. An adjustment in mobile phase formic acid concentration improved the chromatographic separation between II and a mono-hydroxylated metabolite after an unexpected lack of MS/MS selectivity between the two molecules was observed. The dependence of retention factor on formic acid concentration (k' increased as formic acid concentration decreased) was thought to indicate polar interactions between II and the stationary phase. The stability of II in spiked human plasma was determined. The rate of hydrolysis back to parent compound was relatively low (approximately 0.1 and 0.5% per hour at room temperature and 4 degrees C, respectively) indicating that significant changes in analyte concentrations did not occur during sample processing. The concentration range of the assay was 10-2500 ng/mL for both drug and glucuronide metabolite.

Potential for interactions between caspofungin and nelfinavir or rifampin.

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24h) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24h) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.