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Biomedical subjects

F J Kroboth

Publications and source records attributed to F J Kroboth.

At least 19 recordsLinked to original sources
PubMed2000

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.

Aged↗
PubMed1999

Alprazolam increases dehydroepiandrosterone concentrations.

The gamma-aminobutyric acid (GABA) agonist alprazolam is known to decrease adrenocorticotropic hormone and cortisol concentrations. Dehydroepiandrosterone (DHEA) is secreted synchronously with cortisol by the adrenal glands and demonstrates diurnal variation. The major objective of this study was to determine whether alprazolam affects concentrations of DHEA and DHEA-S, the sulfated metabolite. In vitro studies have demonstrated that DHEA-S, and perhaps DHEA, have GABA antagonistic activity. Another objective was to determine whether DHEA-S and/or DHEA concentrations are related to psychomotor impairment after alprazolam. Thirty-eight healthy volunteers (25 young men, aged 22-35, and 13 elderly men, aged 65-75) received a single intravenous dose of alprazolam 2 mg/2 min (part 1). Fifteen young and 13 elderly men responded to alprazolam and agreed to participate in part 2 of the study, which was a crossover of placebo and alprazolam infusion to plateau for 9 hours. Plasma samples at 0, 1, 4, and 7 hours were assayed for steroid concentrations. Alprazolam produced (1) significant increases in DHEA concentrations at 7 hours in both young and elderly men; (2) significant decreases in cortisol concentrations; and (3) no change in DHEA-S concentrations. The relationship between psychomotor decrement and DHEA concentrations at 7 hours after alprazolam 2 mg/2 min was described by a u-shaped curve (p < 0.0047). Both the linear and quadratic components of the equations for the tests were significant (p < 0.002). These results suggest that alprazolam modulates peripheral concentrations of DHEA and that DHEA and/or DHEA-S may have an in vivo role in modulating GABA receptor-mediated responses.

Adult↗
PubMed1998

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.

Aged↗
PubMed1997

Alprazolam in young and elderly men: sensitivity and tolerance to psychomotor, sedative and memory effects.

This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22-35) and 13 elderly (ages 65-75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and elimination t[1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC50 values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Median t[1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.

Adult↗
PubMed1996

Didactic value of the clinical evaluation exercise. Missed opportunities.

The clinical evaluation exercise (CEX), a direct observation of trainees' clinical skills, is a common method of house officer evaluation. During our studies of its reliability, the extent of the CEX's didactic value surfaced. This brief report describes the amount of information passed from the evaluator to the house officer in 73 CEXs. On average, evaluators made eight teaching points in postexamination sessions. However, there were as many points recorded on the CEX forms that evaluators never mentioned. In a subset of CEXs carried out with two observers present, agreement in the teaching points presented to the house officer within the pairs witnessing the same examination was 18%. Positive feedback constituted 9% to 12% of the points presented. Our observations suggest that the more systematic feedback mechanisms may enhance the didactic value of the CEX.

Clinical Competence↗
PubMed1996

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.

Adult↗
PubMed1995

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)

Administration, Oral↗
PubMed1995

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)

Adolescent↗
PubMed1995

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.

Administration, Oral↗
PubMed1993

Design and pharmacodynamic evaluation of novel dual release formulations of triazolam.

Triazolam is an effective hypnotic that can cause amnesia and psychomotor performance decrements, particularly after a 0.5 mg dose. Previous pharmacodynamic studies suggested a relationship between these effects and triazolam plasma concentration. A novel dual release bilayer tablet was designed to mimic the onset of action of a 0.25 mg dose and to maintain the duration of a 0.5 mg dose without the side effects associated with the 0.5 mg dose. The immediate release component of the bilayer tablet contained 0.25 mg triazolam while the sustained release component contained 0.15 mg triazolam. Two prototype formulations of the bilayer tablet, differing in rate of release in the sustained release component, were tested against a conventional 0.5 mg triazolam compressed tablet and placebo in a single-dose, double-blind, four-way crossover study in healthy male subjects. Triazolam plasma concentration time profile was obtained over 12 hours following single administration of each treatment. Effects of triazolam on central nervous system function were evaluated using psychomotor performance tests, immediate and delayed recall tests and rating of sedation. The triazolam plasma concentrations were not significantly different among the active drug treatments, although the dual release tablets did give the expected profiles. There were significant differences in triazolam effects on memory and psychomotor performance. The slowest releasing dual-release tablet showed significantly less psychomotor impairment and memory deficit than the conventional tablet. There was no difference in sedation among the active drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

The intravenous pyelogram in acute pyelonephritis.

In a cohort of 67 otherwise healthy patients with acute pyelonephritis that was severe enough to warrant hospitalization and uroradiography, 8% had a genitourinary abnormality that influenced management. Consequently, over 90% of patients had studies that did not alter their care. In an attempt to identify clinical clues that might increase specificity without compromising sensitivity of the intravenous pyelogram in acute pyelonephritis, only the fever curve was statistically useful. Confined to patients who were febrile through 72 hours of appropriate antibiotic treatment, the yield of urography in demonstrating anomalies of immediate clinical significance rose from 8% to 36%. The likelihood of an acutely important abnormality was also increased fivefold in both diabetic patients and patients with a urinary pathogen other than ampicillin-sensitive Escherichia coli, but small numbers precluded statistical significance. Bacteremia was common (27%), but not helpful other than in confirming the microbiological diagnosis. Nonacute structural abnormalities were present in 43% of the patients, three to nine times more frequently than in reported cases without upper tract infection.

Acute Disease↗
PubMed1987

Pyoderma gangrenosum with myelofibrosis.

Pyoderma gangrenosum is a papulovesicular skin disorder commonly associated with underlying systemic disease, but rarely with the myeloproliferative syndromes. A case of rapidly progressive pyoderma is cited in a 77-year-old white man who had no other evidence of disease aside from macrocytic anemia. Bone marrow biopsy revealed proliferation of fibroblasts and a dense reticulin network consistent with myelofibrosis. Response of the pyoderma to steroid therapy was dramatic. Although pyoderma gangrenosum is more commonly associated with inflammatory bowel disease and rheumatoid arthritis, this is the fifth reported case of its coexistence with idiopathic myelofibrosis.

Aged↗
PubMed1984

Pneumonia caused by Pittsburgh pneumonia agent: radiologic manifestations.

Using an objective scoring system, chest radiographs were reviewed in 23 cases of pneumonia due to the Pittsburgh pneumonia agent (PPA, Tatlockia micdadei, Legionella micdadei), including six cases of pneumonia with simultaneous isolation of PPA and L pneumophila (Legionnaires' disease). Infiltrates were typically segmental to lobar; nodular infiltrates were noted in three cases. Spread to additional lobes after presentation occurred in four of 17 PPA infections. Pneumonia caused by both PPA and L pneumophila was unusually severe, with involvement of all lobes occurring in four of six cases, compared with one of 17 cases of PPA infection (p less than 0.02). Radiographic severity did not correlate with underlying disease, immune status, or outcome. The majority of patients receiving erythromycin demonstrated objective radiologic improvement. In a patient population that included nonimmunosuppressed patients, nodule formation and rapid radiologic progression were not found to be characteristic of PPA pneumonia.

Aged↗