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Biomedical subjects

P D Kroboth

Publications and source records attributed to P D Kroboth.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1986

Single-dose pharmacokinetics of clomiphene citrate in normal volunteers.

Twenty-four healthy adult female volunteers participated in a randomized, three-phase double-blind crossover trial comparing the single-dose (50 mg) pharmacokinetics of three formulations of clomiphene citrate (CC). Plasma levels of both the Z(cis) and E(trans) isomers of CC, as well as principal metabolites, were determined at periodic intervals; and no differences between formulations were observed. The active Z isomer attained peak blood levels later than the inactive E isomer and was eliminated much more slowly, significant plasma concentrations still being detected up to 1 month after treatment. The results of this study demonstrate that three commercially available formulations of CC are bioequivalent.

Adult↗
PubMed1985

Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction.

The sedative, psychomotor, and memory effects of single oral doses of alprazolam (ALP), lorazepam (LOR), temazepam (TMP), and triazolam (TRZ) were evaluated in women taking oral contraceptives (OCs) and a comparable group of control women. Nine women taking OCs and 11 control women took doses of 1 mg ALP and 2 mg LOR and 10 OC users and 10 control women took 30 mg TMP and 0.5 mg TRZ on two occasions separated by 28 days. Minimal psychomotor impairment was noted after TMP. ALP, LOR, and TRZ produced greater performance impairment in the OC users. Correcting the maximum observed performance decrement for plasma concentration did not account for the differences between OC users and controls. After TMP, there was less sedation during the first 2 hours in OC users, who also had higher plasma TMP clearance. There were no differences in sedation between OC users and controls after ALP, LOR, and TRZ; however, there was less than 50% power to detect a 30% difference. Amnestic effects in OC users and controls did not differ after any of the four drugs. The observed patterns of anterograde amnesia were different, with the earliest and most pronounced recognition failure after TRZ (50% at 1.5 hours), while the LOR effect increased to a maximum (30%) 4 hours after dosing. Our data suggest that differences in benzodiazepine pharmacokinetics between OC users and control women do not account for observed differences in psychomotor impairment. Women taking OCs are more sensitive to the psychomotor effects of single oral doses of benzodiazepines.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Effects of end-stage renal disease and aluminum hydroxide on temazepam kinetics.

The kinetics of temazepam, 30 mg, were evaluated in 11 patients with end-stage renal disease. Age ranged from 18 to 65 years. On two occasions separated by 1 week, single oral 30 mg doses of temazepam were given once with water (TM) and once with 3600 mg aluminum hydroxide gel (TM + AHG). There were no significant differences in the maximum plasma concentration, the time to reach maximum concentration, or elimination rates between TM and TM + AHG dosing. In approximately half the subjects there were secondary temazepam peak concentrations. In the remaining subjects, temazepam elimination was biphasic, with the terminal t1/2 ranging from 11 to 77 hours. There was a lag time before absorption in all subjects. The percent free temazepam in plasma from dialysis subjects ranged from 4.4% to 8.8% (mean = 5.9%). Compared with literature reports of subjects with normal renal function, the maximum plasma concentration was lower and the percent free temazepam was higher in dialysis subjects. When sedation score was plotted against plasma temazepam concentration, there was clockwise hysteresis consistent with tolerance or adaptation to effects of the drug. Thus aluminum hydroxide gel does not affect temazepam absorption. The clinical significance of the low plasma concentrations and high free temazepam fraction in dialysis subjects is uncertain.

Absorption↗
PubMed1985

Effects of end stage renal disease and aluminium hydroxide on triazolam pharmacokinetics.

Triazolam 0.5 mg was administered to 11 dialysis patients and 11 age, weight and sex matched controls. Peak plasma concentrations (Cmax) were higher in control subjects, but there were no other differences between the groups. When dialysis patients took triazolam with 3600 mg aluminum hydroxide suspension, Cmax and AUC were increased into the range observed in control subjects. It appears that triazolam can be used at normal doses in patients with renal dysfunction, without regard to interaction with aluminum hydroxide gel, or to alterations in elimination.

Adolescent↗
PubMed1984

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration.

Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.

Administration, Oral↗
PubMed1984

Severe theophylline toxicity. Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion.

The presenting symptoms, course, and treatment of 10 patients with severe theophylline toxicity (heart rate above 120, multifocal atrial tachycardia or premature ventricular contractions, hypotension, seizures) are described. Theophylline levels at presentation averaged 66 micrograms/ml (range 30 to 180 micrograms/ml). All patients had marked tachycardia; 80 percent had gastrointestinal symptoms, 50 percent were hypotensive, and 20 percent had seizures. A known history of poor compliance or other risk factors to overdosage was present in 60 percent. Of the five patients in whom drug clearances were determined, two had uniform first-order drug elimination. Three had biphasic elimination with an initial period of delayed elimination due to either zero-order kinetics or continued drug absorption. During the first-order elimination period, mean plasma theophylline clearance was 28.0 +/- 4.3 ml per minute with a half-life of 8.2 hours. In the patients with initially delayed elimination, the mean clearance during the slow phase was 9.6 +/- 3.3 ml per minute with an apparent half-life of 31 hours. One patient was treated with charcoal hemoperfusion but the others received conservative management alone; all recovered without permanent sequelae. Propranolol and verapamil were useful in controlling supraventricular tachycardia. It appears that most patients with severe theophylline toxicity can be managed without hemoperfusion, which should be considered only when drug clearance is reduced, and hypotension, tachycardia, ventricular ectopy, or seizures are refractory to conservative measures.

Aged↗
PubMed1984

Use of procainamide in chronic ambulatory peritoneal dialysis: report of a case.

A patient on chronic ambulatory peritoneal dialysis (CAPD) was treated with procainamide for control of ventricular arrhythmias. A procainamide half-life of 11.5 hours was observed, with a dialysis clearance of 6.5 mL/min. The N-acetylprocainamide (NAPA) dialysis clearance was 5.3 mL/min. The CAPD clearance of procainamide and its active metabolite, NAPA, is much lower than that reported for hemodialysis. Procainamide therapy should be initiated with reduced dosages in patients with renal failure.

Acecainide↗
PubMed1984

Triazolam protein binding and correlation with alpha-1 acid glycoprotein concentration.

On two occasions separated by a minimum of 1 wk, plasma was obtained from 12 patients (aged 18 to 73 yr) on dialysis after an overnight fast. Samples were assayed for albumin and alpha 1-acid glycoprotein (AGP) concentrations. 14C-Triazolam was added to each sample to a final concentration of 5 ng/ml. Protein binding was determined by equilibrium dialysis. Unbound triazolam ranged from 6.4% to 15.4% (mean = 10.0%). AGP concentrations ranged from 71.8 to 205.1 mg% (mean = 123.4 mg%). Triazolam binding ratio (bound/unbound concentration) correlated with AGP concentration (r2 = 0.69) but not with albumin concentration, age, or sex. This correlation was verified by adding AGP in varying amounts to control plasma.

Adolescent↗
PubMed1984

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics.

The effects of low-dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low-dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

Administration, Oral↗
PubMed1983

Hearing loss and erythromycin pharmacokinetics in a patient receiving hemodialysis.

A left upper lobe pneumonia developed in a patient who was receiving hemodialysis; he was treated intravenously with 1 g of erythromycin lactobionate every six hours. After five doses, hearing loss was noted; this was later documented by audiogram. Erythromycin serum concentrations as high as 100 mg/L and a half-life more than three times longer than normal were observed. To our knowledge, this represents the first report of reversible hearing loss associated with elevated serum erythromycin concentrations and prolonged serum half-life.

Adolescent↗
PubMed1982

Pharmacokinetics of single-dose erythromycin in normal and alcoholic liver disease subjects.

Six normal males and eight male subjects with alcoholic liver disease (ALD) and ascites were given a single 500-mg dose of erythromycin base. Twelve serum samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after dosing and assayed microbiologically for erythromycin concentration. Absorption was characterized by a zero-order model for both groups. ALD subjects demonstrated a shorter lag time (2.0 versus 3.0 h), an earlier peak (4.6 versus 6.3 h, P less than 0.05), and higher peak concentrations (2.04 versus 1.50 micrograms/ml) than normal subjects. Previously unreported biphasic elimination kinetics after oral dosing were observed in five and four ALD subjects. In the ALD group, the mean half lives for the first (alpha) and terminal (beta) phases were 1.6 and 4.5 h, respectively, and in normal subjects, were 1.3 and 6.6 h. The difference in alpha between groups was significant, P less than 0.05. The clinical significance of this finding for ALD patients receiving prolonged courses of erythromycin is discussed.

Absorption↗
PubMedDate not supplied

Mechanism for the interaction between triazolam and cimetidine.

Four normal volunteers each received three intraduodenal infusions of 0.5 mg triazolam solutions. Three treatments were: a pH 2.3 solution in which 47 per cent of the dose had hydrolysed to form a triazolo-benzophenone (TB); a pH 6.0 solution containing negligible TB; the pH 6.0 solution administered during cimetidine treatment (1200 mg day-1). TB was stable in serum and only very low TB serum concentrations were observed from the pH 2.3 treatment. No difference was observed in any triazolam pharmacokinetic parameter between the pH 6.0 and the pH 2.3 treatments. Cimetidine increased the triazolam AUC infinity and Cmax by 54 and 35 per cent, respectively. These results indicate that TB undergoes extensive presystemic conversion to triazolam and the triazolam-cimetidine interaction occurs primarily through a reduction in triazolam clearance.

Adult↗
PubMedDate not supplied

New drug evaluations. Triazolam.

Triazolam is a sedative/hypnotic triazolobenzodiazepine, structurally related to alprazolam. Recently, it has been approved for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Triazolam is metabolized with a half-life of 1.5-5.0 hours. Its one active metabolite, which appears in low concentrations and is inactivated rapidly, is not thought to contribute to its pharmacologic activity. Triazolam has been shown to decrease sleep latency and the number of nocturnal awakenings while increasing total sleep time in patients with insomnia. Sleep electroencephalogram studies show that triazolam has no effect on delta-sleep (Stages 3 and 4) and has variable effects on rapid-eye-movement sleep. Nighttime administration of triazolam increases daytime alertness in insomniacs and improves or has no effect on performance. The reported side effects are similar to those of other benzodiazepines and include drowsiness, dizziness, and dry mouth. The recommended dosage of triazolam is 0.25-0.5 mg hs. A reduced initial dose of 0.125 mg should be used in geriatric patients.

Animals↗
PubMedDate not supplied

Incidence of next-day anterograde amnesia caused by flurazepam hydrochloride and triazolam.

The incidence of next-day anterograde amnesia was evaluated in hospitalized patients who received flurazepam hydrochloride or triazolam. A blinded observer assessed memory and daytime drowsiness in 154 patients after the bedtime ingestion of flurazepam hydrochloride (n = 54), triazolam (n = 49), or no hypnotic drug (n = 51). The hypnotic agents were administered before midnight. At approximately 0800 the next morning, the patients were shown a picture of an object on colored construction paper and asked to remember it as well as the color of the background. Both the observer and patient assessed drowsiness using the Stanford Sleepiness Scale. The observer also made a note of the items on the patient's breakfast tray. Patients were then revisited at 1100 and asked to recall the object in the picture, the color of the background, and at least three items from their breakfast tray. Ten of the 54 patients in the flurazepam group failed to recall all three items compared with only two in the triazolam group and two in the control group. The 14 patients who experienced memory impairment were significantly more drowsy at 0800 than those who were able to recall the items. Next-day anterograde amnesia occurred more frequently in patients who received flurazepam hydrochloride than in those who received triazolam or no hypnotic drug. This effect may be related to the next-day drowsiness caused by flurazepam and its slowly eliminated active metabolite.

Adult↗