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Biomedical subjects

P D Kroboth

Publications and source records attributed to P D Kroboth.

At least 19 recordsLinked to original sources
PubMed1992

Alprazolam in end-stage renal disease. II. Pharmacodynamics.

The sensitivity to the psychomotor and memory effects of alprazolam was evaluated in 12 normal subjects and 12 dialysis patients (seven patients receiving hemodialysis and five patients receiving continuous ambulatory peritoneal dialysis). Subjects received a single oral dose of 0.5 mg alprazolam, 2 mg alprazolam, and placebo in a double-blind, placebo-controlled, balanced, three-way crossover study with a Latin square design. After administration of the test drug, blood was obtained for alprazolam concentration and protein-binding determinations, and psychomotor performance, memory, and sedation were assessed. The maximum psychomotor impairment corrected for free alprazolam concentration was 5.0%, 8.2%, and 10.1% per nanogram per milliliter in normal subjects, patients receiving hemodialysis, and patients receiving continuous ambulatory peritoneal dialysis, respectively (p less than 0.01), after administration of 2 mg alprazolam. Free alprazolam concentrations at which 50% of maximum effect is elicited for psychomotor impairment were 10, 7.40, and 5.31 ng/ml in normal subjects, patients receiving hemodialysis, and patients receiving continuous ambulatory peritoneal dialysis, respectively. The maximum memory impairment corrected for the maximum free alprazolam concentration was 4.4%, 7.2%, and 8.9% per nanogram per milliliter, respectively (p less than 0.09), after administration of 2 mg alprazolam. Thus our group of patients receiving dialysis showed enhanced sensitivity to some psychomotor and memory effects of alprazolam.

Adult↗
PubMed1991

New high-performance liquid chromatographic method for the determination of alprazolam and its metabolites in serum: instability of 4-hydroxyalprazolam.

A high-performance liquid chromatographic method was developed for the determination of alprazolam (ALP) and its active metabolites, alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) in human serum. During assay development, the instability of 4OH was revealed. Factors affecting stability of 4OH were then investigated. In this report, the assay methodology for the determination of ALP and AOH, the instability of 4OH, subsequent interference of 4OH breakdown products with AOH quantification, and factors affecting 4OH stability are described. The clinical significance of our findings are reported.

Alprazolam↗
PubMed1991

Alprazolam in end-stage renal disease: I. Pharmacokinetics.

In a double-blind, randomized, placebo-controlled study, the pharmacokinetics of alprazolam and its active metabolite, alpha-hydroxyalprazolam, were determined in 12 normal subjects and 12 dialysis patients [7 hemodialysis (HD) patients and 5 continuous ambulatory peritoneal dialysis (CAPD) patients]. Blood samples were collected over 48 hours after alprazolam 0.5 mg and alprazolam 2 mg administration. Alprazolam and alpha-hydroxyalprazolam concentrations and alprazolam free fraction were determined. The pharmacokinetics of alprazolam were similar in normal subjects and HD patients with the exception of higher free fraction in HD patients. Differences were detected, however, in the pharmacokinetics of alprazolam in CAPD patients when compared with normal subjects and HD patients. These differences included a higher free fraction and a lower apparent oral clearance and free clearance in CAPD patients than in normal subjects or in HD patients. There was also a tendency for a later Tmax and a longer elimination half-life in CAPD patients than in normal subjects or HD patients. Alpha-hydroxyalprazolam concentrations were less than 15% of corresponding alprazolam concentrations in normal subjects and dialysis patients. Thus, end-stage renal disease is associated with changes in absorption, distribution, and/or elimination of alprazolam.

Adult↗
PubMed1991

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects.

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing.

Previous studies have suggested that elderly men eliminate alprazolam more slowly than young adults. This study in the elderly was designed to determine whether a change in pharmacokinetics influences the response to alprazolam during multiple dose regimens. In addition, the study was designed to determine alprazolam pharmacokinetics and the degree to which its hydroxymetabolites accumulate, the degree of psychomotor impairment, and whether tolerance to impairment and sedation develops during three different multiple dose regimens. Twenty-six subjects completed this study. The subjects were randomized into one of three treatment groups: 0.25 mg q8h, 0.5 mg q8h, and 2 mg q12h. Subjects remained in the clinic for 8 days (day -2-day 5). Day 0 was used as a drug free testing day to establish baseline scores for sedation, digit symbol substitution (DSS), card sorting (CS) tasks, and two computer tests. Subjects received the drug according to schedule on days 1 through 4, with day 5 as the washout day. Blood samples were assayed for alprazolam, alpha-hydroxyalprazolam and 4-hydroxyalprazolam. Alpha-hydroxyalprazolam concentrations were below assay detection limits in all subjects in the 0.25 and 0.5 mg q8h groups and less than or equal to 2.6 ng/ml in the 2 mg q12h group. When detectable, 4-hydroxyalprazolam concentrations were less than 10% of the corresponding alprazolam concentration. Mean alprazolam oral clearance values in the three treatment groups ranged between 0.54 and 0.62 ml/min/kg and half-lives were in excess of 21 h. Degree of sedation and impairment was dose related. Sedation and impairment was not higher on day 4 despite concentrations 2-3 times as great as on day 1, indicating development of tolerance. Subjects were not, however, back to baseline level of performance on day 4.

Aged↗
PubMed1989

Pharmacokinetics of the newer benzodiazepines.

The assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performance liquid chromatography with ultraviolet detection, gas chromatography-mass spectrometry, radioassay and radioreceptor assay. The method used frequently is the highly sensitive and specific electron-capture gas-liquid chromatography. Other methods are associated with limitations. The triazolo- and imidazolebenzodiazepines differ structurally from the 'classical' benzodiazepines such as diazepam, and offer distinct differences in pharmacological activity and in time-course of effect. Alprazolam and triazolam, both 1,4-triazolobenzodiazepines, have high affinities for the benzodiazepine receptor as do midazolam and loprazolam, which are 1,4-imidazolebenzodiazepines. Absorption is characteristically rapid, with peak alprazolam and triazolam concentrations occurring within 1 hour after oral administration. Sublingual administration results in peak alprazolam and triazolam concentrations that are higher and occur earlier than with the oral route. The volume of distribution of alprazolam and triazolam is approximately 1L. Alprazolam is 70% bound to plasma proteins and the extent of binding is independent of concentration. Similarly, triazolam is approximately 85% bound to plasma proteins, variability in binding being explained by variations in alpha 1-acid glycoprotein concentration. The 1,4-triazolo ring prevents the oxidative metabolism of the classical benzodiazepines which results in formation of active metabolites with long elimination half-lives. Alprazolam is extensively metabolised: 29 metabolites have been identified in the urine, and its major metabolite, alpha-hydroxyalprazolam, has pharmacological activity. alpha-Hydroxyalprazolam and 4-hydroxyalprazolam are detectable in plasma in amounts which account for less than 10% of the administered dose. Mean alprazolam elimination half-life in healthy adult subjects ranges from 9.5 to 12 hours; liver disease prolongs alprazolam elimination, but renal insufficiency does not. Triazolam also undergoes oxidation and subsequent glucuronidation. alpha-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and alpha-4-hydroxytriazolam have been identified in plasma and urine. The elimination half-life of triazolam ranges between 1.8 and 5.9 hours, while that of the conjugated metabolites is short, approximately 3.8 hours. Accumulation of triazolam or its metabolites after multiple doses does not occur. Liver disease prolongs triazolam elimination from the body, but renal disease does not.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Tolerance to alprazolam after intravenous bolus and continuous infusion: psychomotor and EEG effects.

A study was undertaken to compare the time course of changes in psychomotor performance and spectral edge (SE) of the EEG and to relate these changes to alprazolam concentrations in a pharmacokinetic/pharmacodynamic tolerance model. Digit symbol substitution (DSS) tests were administered and EEG data were obtained for SE calculation in a four-way crossover study in four normal men. Each treatment consisted of a 2-minute bolus injection followed by an 8-hour infusion. Treatment A, placebo, consisted of a 50% propylene glycol injection followed by a saline infusion. Active drug treatments were: B, 0.5 mg alprazolam plus saline infusion; C, 2.0 mg alprazolam plus saline; and D, 1.0 mg plus 72 micrograms alprazolam/hr for a total dose of 1.576 mg in 8 hours. For both DSS and SE data, three distinct effect-concentration curves result from the three alprazolam treatments, with successive shifts to the right as dose increases. A tolerance rate constant (kt) of 0.15 hr-1 was calculated from the DSS vs. time data during the 8 hour alprazolam infusion. The Hill equation was altered by using kt in an exponential modification of EC50. The resulting tolerance model describes both DSS and SE vs. concentration data from the rapid-injection and continuous-infusion treatments.

Adult↗
PubMed1987

Nighttime dosing of triazolam in patients with liver disease and normal subjects: kinetics and daytime effects.

This study was designed to determine whether the severity of liver dysfunction in cirrhosis affects the kinetics and next-day effects of triazolam after bedtime administration of a single oral dose. Eight patients with biopsy-proven cirrhosis and seven normal subjects matched for age, weight, and sex participated as paid volunteers. The first night was the control night, when no nighttime sedative was administered. The next day, psychomotor testing was performed at 8:30 AM, 2 PM, and 5 PM. Triazolam 0.25 mg was administered at 10:30 PM that evening. Psychomotor testing was repeated on the posttriazolam day in the same manner as on the control day. Blood samples were obtained from a venous catheter at 11 predetermined times in the 14 hours after triazolam administration. Memory testing was also performed. Apparent oral clearance of triazolam was directly related to albumin concentration and indocyanine-green elimination rate constant, and inversely related to partial thromboplastin time expressed as seconds over control. Clearance was 6.69 +/- 2.52 mL/min/kg in the normal subjects and 4.99 +/- 3.14 in the subjects with cirrhosis. There were no significant differences in Cmax between normal subjects (1.43 +/- 0.44 ng/mL) and subjects with cirrhosis (1.62 +/- 0.31 ng/mL) or in tmax (2.0 +/- 1.0 vs 2.5 +/- 1.9 hr) between normal and cirrhosis subjects, respectively. Posttriazolam, cirrhotic subjects took significantly longer to sort cards at 8:30 AM than on the control day. There was a significant correlation between extent of impairment on 8:30 AM card sorting by suit and AUC0-8 (r = 0.687; P = 0.0046).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Pharmacodynamics of triazolam after intravenous administration.

Triazolam pharmacokinetics and effects on sedation, short-term amnesia, and psychomotor performance were evaluated in 25 normal volunteers as part of a safety and tolerance study of intravenous dosing of triazolam. Triazolam kinetics were linear after intravenous administration of doses up to 1.0 mg with no differences among doses in elimination half-life, volume of distribution, or clearance. The hepatic extraction ratio ranged from 0.14 to 0.37, suggesting that triazolam should undergo moderate first-pass metabolism after oral administration. The duration and extent of sedation, decrement in psychomotor performance test scores, and amnesia were dose related, but all subjects returned to baseline alertness and function within eight hours of dosing. The time-course of effects on memory and psychomotor performance were related to triazolam plasma concentration profile using an Emax model for effect and a two-compartment pharmacokinetic model. The probability of a subject being asleep was related to triazolam plasma concentrations using logistic regression. These models indicate that intravenous doses of 0.25 to 0.5 mg triazolam would be effective for use preoperatively for short surgical procedures.

Adult↗
PubMed1987

Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects.

The relationships between alprazolam and metabolite concentrations and CNS effects were determined in a double-blind placebo controlled four-way crossover trial in 16 normal male volunteers. Active drug treatments consisted of 4-day regimens of 4 mg alprazolam PO daily as 2 mg bid., 1 mg qid, and 0.25 mg each hour. On days 1 and 4, the kinetics, sedative and psychomotor effects were evaluated. Plasma concentrations of the 4- and alpha-hydroxy metabolites of alprazolam were less than 10% of unchanged alprazolam levels on both days. Accumulation of these metabolites and alprazolam was dependent on alprazolam half-life (11.6 h). Acute and chronic tolerance to the sedative and psychomotor effects was observed with all active drug treatments. All alprazolam treatments resulted in significantly greater sedation than placebo on days 1 and 4. However, on day 4, sedation was 16-36% less than observed on day 1, despite plasma concentrations 1.4-2.76 times the day 1 concentrations. Sedation from alprazolam was reduced in each successive study phase, suggesting a tolerance which was sustained during the 10-day washout between phases. By day 4, psychomotor performance was not different from placebo, indicating more complete development of tolerance than occurred for the sedative effect. Sedation and psychomotor impairment on day 1 were greatest with 2 mg alprazolam bid. During the initiation of therapy, the patient will likely experience less sedation and psychomotor impairment with smaller, more frequent doses. Since tolerance develops to these effects, the advantage of more frequent dosing regimen dissipates by the 4th day.

Adult↗
PubMed1987

Pentoxifylline in end-stage renal disease.

Little information is available about the clearance of pentoxifylline and its metabolites in renal failure. Consequently, when a dialysis patient required this drug, we started at a low dose and gradually increased the dosage while monitoring the patient for signs or symptoms of toxicity and following plasma concentrations of parent drug and its metabolites. Our patient appeared to develop evidence of drug toxicity after about six days on two-thirds of the usual recommended adult dose of the drug. The pentoxifylline half-life and apparent half-life of metabolite I were both substantially prolonged as compared with data from healthy volunteers. Both accumulated rapidly in plasma. Concentrations of metabolites IV and V were also very high.

Adult↗
PubMed1987

The clinical pharmacist in drug research and development. An academic-industrial center.

The center for Pharmacodynamic Research represents a novel approach to academic-industrial research agreements that may be a useful model for others to pursue. It is designed to take advantage of the strengths of the company and the university in order to enhance the research conducted and to provide benefits to both. At the same time, it takes into account the responsibility of the university to provide graduate education and the need of industry for scientists in the future. The center was only recently established, however, and must be considered work in progress. Although it has been successful to this point, its value will only be established by longevity and productivity. We have every confidence that it will prove to be a valuable experiment.

Drug Industry↗
PubMed1986

Temporal variation in triazolam pharmacokinetics and pharmacodynamics after oral administration.

The effect of time of day of drug administration on triazolam pharmacokinetics was studied in ten healthy men. In a randomized, two-way, crossover investigation, each subject received one 0.5 mg triazolam tablet either in the morning (7 AM) or evening (10 PM). Blood samples were obtained immediately before dosing and at selected times up to 12 hours after dosing. Triazolam plasma concentrations were determined by gas chromatography with electron capture detection. Psychomotor performance tests, including digit symbol substitution, card sorting by suits, and card sorting by fours, were administered, and the subjects' sedation was rated before drug and at two, ten, and 12 hours after drug administration. In addition, anterograde amnesia was assessed by showing objects to subjects two hours after dosing and testing aided and unaided recall at ten hours following administration. Triazolam's apparent elimination half-life after evening administration was significantly longer than after daytime ingestion (3.77 hr vs. 2.94 hr, P less than .05). There was no difference between times of dosing in total oral clearance or apparent volume of distribution. The absorption of triazolam was slower after evening administration, with an absorption half-life of 21.9 vs 13.3 minutes after daytime dosing. Performance decrements were significantly greater two hours after dosing in evening than in the daytime, but anterograde amnesia was more pronounced after daytime dosing. There was no effect on psychomotor performance at ten or 12 hours after administration in daytime or evening. These results indicate temporal variation in triazolam absorption and elimination.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗