Frank J. Kroboth

Correlates and Prevalence of Benzodiazepine Use in Community-Dwelling Elderly

OBJECTIVE: To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older.DESIGN: Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study.PATIENTS/PARTICIPANTS: Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria.MEASUREMENTS AND MAIN RESULTS: Among participants, 511 (9.9%) were taking at least one benzodiazepine, primarily anxiolytics (73%). Benzodiazepines were often prescribed to be taken pro re nata (PRN “as needed”), and 36.5% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2% in benzodiazepine users and 3.3% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7).CONCLUSIONS: One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.

The inter-rater reliability and internal consistency of a clinical evaluation exercise

Objective:To assess the internal consistency and interrater reliability of a clinical evaluation exercise (CEX) format that was designed to be easily utilized, but sufficiently detailed, to achieve uniform recording of the observed examination.Design:A comparison of 128 CEXs conducted for 32 internal medicine interns by full-time faculty. This paper reports alpha coefficients as measures of internal consistency and several measures of inter-rater reliability.Setting:A university internal medicine program. Observations were conducted at the end of the internship year.Participants:Participants were 32 interns and observers were 12 full-time faculty in the department of medicine. The entire intern group was chosen in order to optimize the spectrum of abilities represented. Patients used for the study were recruited by the chief resident from the inpatient medical service based on their ability and willingness to participate.Intervention:Each intern was observed twice and there were two examiners during each CEX. The examiners were given a standardized preparation and used a format developed over five years of previous pilot studies.Measurements and main results:The format appeared to have excellent internal consistency; alpha coefficients ranged from 0.79 to 0.99. However, multiple methods of determining inter-rater reliability yielded similar results; intraclass correlations ranged from 0.23 to 0.50 and generalizability coefficients from a low of 0.00 for the overall rating of the CEX to a high of 0.61 for the physical examination section. Transforming scores to eliminate rater effects and dichotomizing results into pass-fail did not appear to enhance the reliability results.Conclusions:Although the CEX is a valuable didactic tool, its psychometric properties preclude reliable assessment of clinical skills as a one-time observation.

Triazolam pharmacokinetics after intravenous, oral, and sublingual administration

This study was designed to evaluate the relative and absolute bioavailability of triazolam, 0.25 mg, after the administration of the marketed oral tablet and a sublingual prototype wafer; an intravenous dose was used as a reference. Twelve men were evaluated in a three-way crossover study; study days were separated by 1 week. A single dose was administered to each subject at approximately 8 a.m.; serial blood samples were obtained for the determination of triazolam concentration. The fraction absorbed relative to intravenous was 20% higher in the sublingual than in the oral treatment (p = 0.0128); the difference between treatments was greatest in the first 2 hours as indicated by the area under the curve from 0 to 2 hours (p < 0.05). The extraction ratio ranged from 0.05 to 0.25, and the predicted availability after oral administration was 86% with a range of 75 to 95%. In contrast, the observed mean absolute availability was 44% (oral) and 53% (sublingual). A potential explanation for this discrepancy between predicted and observed bioavailability is that after oral administration, a fraction of triazolam may be metabolized by cytochrome P450IIIA4 in the gut wall, with a separate fraction subject to first-pass metabolism in the liver. Although this study was not designed to identify sites of triazolam metabolism, the proposed explanation is consistent with the occurrence of P450IIIA4 in the stomach, small intestine, and liver. Doses administered sublingually avoid first-pass metabolism, producing earlier and higher peak concentrations than do doses administered orally.

Orally administered progesterone enhances sensitivity to triazolam in postmenopausal women

An endogenously formed metabolite of progesterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP) modulates the gamma-aminobutyric acid receptor complex and plays a physiologic role in brain excitability regulation. On the basis of in vitro observations of 3 alpha-OH-5 alpha-DHP-enhanced [3H]flunitrazepam binding, we investigated the potential clinical effect of coadministering oral progesterone and triazolam. Sixteen postmenopausal women were randomly assigned to receive either intravenous triazolam plus oral progesterone 300 mg (TRZPROG) or intravenous triazolam plus oral placebo (TRZ). Triazolam was infused until 0.5 mg was given or until a predetermined maximal response was attained. Pharmacodynamic evaluation included DSST, continuous performance test, hand-eye coordination, short-term memory, and sedation. Effect ratios were calculated as the ratio of area under the effect-time curve to area under the curve (AUC). Variants of the sigmoid Emax model were fit to the data from the three psychomotor performance tests. A triazolam dose of less than 0.5 mg was administered to seven of eight subjects in the TRZPROG and five of eight subjects in the TRZ group, resulting in lower triazolam AUC values for the TRZPROG than for the TRZ group (p = 0.0275). There was clear evidence for a pharmacodynamic interaction. Mean effect ratios for all tests were greater in the TRZPROG group than in the TRZ group (DSST, p = 0.0097; continuous performance test, p = 0.0338; hand-eye coordination, p = 0.0041). The TRZPROG group had lower EC50 values than the TRZ group (DSST, p = 0.0435; continuous performance test, p = 0.0381; hand-eye coordination, p = 0.0154).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral Administration of Micronized Progesterone: A Review and More Experience

Historically, oral progesterone has been regarded clinically ineffective because of its poor absorption and rapid clearance. Recent evidence suggests that an oral micronized form of natural progesterone is readily absorbed, produces luteal phase serum concentrations, provokes an end‐organ response, and has no detrimental effect on the lipoprotein profile. Thus it is considered by many to be an attractive alternative to synthetic progestin. We evaluated the effects of a single oral dose of micronized progesterone 300 mg in eight healthy postmenopausal women. The maximum serum concentration ranged from 15.72–625.98 ng/ml. The extent of absorption increased with increasing age. The reviewed literature and our data indicate considerable intersubject variability in the extent of progesterone absorbed after administration of oral micronized progesterone.

Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men

This study was designed to determine whether differences in alpha-1 acid glycoprotein and free drug concentrations result in an altered response to triazolam. Twelve normal-weight and 12 obese adult male subjects received intravenous doses of triazolam, 0.5 mg, on two occasions separated by 1 week. There was a small difference in the alpha-1 acid glycoprotein concentrations between groups but no difference in free fraction of triazolam. There was a longer terminal half-life (t1/2 beta) in the obese subjects (3.16 +/- 0.87 vs. 3.83 +/- 1.24, p = 0.0098). Overall, week 1 data revealed no difference in effect between normal and obese subjects. However, response data reveal a pattern of increased sensitivity with the second exposure to triazolam. For example, area under the effect curve (AUEC) on all tests was significantly greater in week 2 for both groups of subjects. For a memory test and sedation from 0 to 12 hours, AUEC/free AUC ratios were significantly greater in week 2 for all subjects. The obese had a higher ratio on week 2 than on week 1 for all psychomotor tests and sedation (0 to 4.5 hours; p < 0.05). The results of modeling psychomotor impairment-concentration data pooled by group for each week continue the pattern: week 1 data are similar between the obese and normal-weight subjects. Although EC50 values are up to 15% lower in week 2 for the normal-weight subjects, EC50 values are as much as 66% lower in week 2 for the obese, where a lower EC50 indicates greater sensitivity. Logistic regression of the recognition data is consistent with these results.(ABSTRACT TRUNCATED AT 250 WORDS)

Varicella hepatitis in the immunocompromised adult: a case report and review of the literature

linical infection with the varicella-zoster virus is common, occurring as primary varicella, usually during childhood, and as zoster, following activation of latent virus. Both forms of infection are more severe in the immunocompromised patient. Fulminant hepatic necrosis from acute viral infec- tion is commonly associated with hepatitis B virus (1,2). Herpes simplex virus has been identified in a number of cases of fatal hepatitis in adults (3-18). The pediatric literature is replete with reports of biochemi- cal hepatitis in association with primary varicella, usu- ally subclinical (19-26). In adults, hepatic inflamma- tion may also occur during primary varicella infection, usually in patients with varicella pneumonitis, and is always self-limited (27-31). Aside from these reports, only two other cases of fatal hepatitis caused by the varicella-zoster virus have been reported, one in an immunocompromised child with primary infection (22) and the other in an adult with presumed zoster (32). Our case is the first report of an adult with fatal hepatitis during primary varicella infection.

Hepatic myelopathy Case report with review of the literature

Hepatic myelopathy is a rare complication of hepatic insufficiency, causing progressive spastic paraparesis. There are few reports detailing the clinical and diagnostic aspects of this uncommon cause of neurological deterioration in patients with liver disease. Early recognition of this disorder will become more important as patients with liver disease survive longer due to medical advances, including liver transplantation. We present an additional patient with hepatic myelopathy associated with infantile portal vein thrombosis and review the previous reports of hepatic myelopathy in the English literature.

Influence of DHEA administration on 24-hour cortisol concentrations.

DHEA is marketed and readily available as a daily nutritional supplement to counteract the effects of aging. The effect of DHEA administration on 24-hour plasma cortisol profiles has not been investigated. In this single-blind placebo-controlled crossover study, the effect of DHEA administration on cortisol concentrations was evaluated in healthy older women and men. Once each morning, subjects took either placebo (Days 1 to 7, and 23 to 29) or oral DHEA 200 mg (Days 8 to 22: doses 1 to 15). Twenty-four hour DHEA and cortisol concentrations were measured on Day 1 (placebo), Day 8 (DHEA dose 1), Day 15 (DHEA dose 8), Day 22 (DHEA dose 15), and Day 29 (placebo washout dose 7). DHEA administration resulted in a decrease in plasma cortisol concentrations (mean, peak, and/or AUC) in healthy older women and men. The cortisol-lowering effect of DHEA was more pronounced in women than in men in our study; pairwise differences in concentrations between days showed that relative to Day 1, cortisol was lower on Days 15, 22, and 29 in women (p = 0.0001) and on Day 15 in men (p = 0.002). The mechanism by which DHEA lowers plasma cortisol concentrations merits further investigation.

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA‐S) after single‐ and multiple‐dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA‐S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA‐S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5‐ to 6‐fold in both men and women, and DHEA‐S concentrations increased 5‐fold in men and 21‐fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.