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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 325 records · Page 18Linked to original sources
PubMed1983

Pharmacokinetic properties of benzodiazepine hypnotics.

The kinetic properties of three benzodiazepine hypnotics are reviewed. Flurazepam serves as a precursor for at least two rapidly appearing and rapidly cleared metabolites that may contribute to sleep induction and are nonaccumulating. The final metabolite of flurazepam (N-desalkylflurazepam), however, has a long half-life and accumulates during repeated dosage. Temazepam has a relatively slow rate of absorption and an intermediate half-life in the range of 10 to 20 hours. Triazolam has an intermediate rate of absorption; due to its ultrashort half-life (1.5 to 5 hours), triazolam is a non-accumulating hypnotic. Taken together with sleep laboratory studies and clinical trials, knowledge of the kinetic profile of benzodiazepine hypnotics can assist in evaluating their clinical benefits and disadvantages.

Absorption↗
PubMed1983

Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen.

The influence of obesity on the distribution or clearance of lorazepam and oxazepam, two benzodiazepines biotransformed by glucuronide conjugation, was studied in a series of obese subjects (mean weight 113 kg; mean percent IBW 179%) and healthy controls of normal body habitus matched for age and sex. Overweight subjects and controls received 2 to 3 mg of lorazepam intravenously or 30 mg of oxazepam orally. Absolute Vd in obese compared to control subjects was increased for both lorazepam (131 vs. 77 L, p less than 0.001) and oxazepam (97 vs. 38 L, p less than 0.001). When normalized to body weight, Vd/kg was similar for both drugs. Total metabolic clearance was similarly increased in the obese cohort for lorazepam (102 vs. 63 ml/min, p less than 0.005) and oxazepam (157 vs. 50 ml/min, p less than 0.001). Again, when normalized to body weight, clearance per kilogram was similar for both drugs. Since both Vd and clearance increased with body weight, elimination half-life (dependent on both Vd and clearance) was not significantly different in obese subjects (lorazepam 16.5 vs. 14.9 hr; oxazepam 7.7 vs. 8.9 hr). A random subgroup of obese and control subjects received a single intravenous dose of acetaminophen, also biotransformed by conjugation. Acetaminophen clearance was significantly correlated with that of lorazepam (r = 0.59, p less than 0.01) and oxazepam (r = 0.87, p less than 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p less than 0.01). Thus obesity is associated with enhanced capacity for biotransformation of drugs via glucuronide conjugation. conjugating capacity increases in proportion to TBW and is consistent among drugs biotransformed by this mechanism.

Acetaminophen↗
PubMed1983

Pharmacokinetics of alprazolam.

The metabolic profile and human pharmacokinetics of alprazolam, a benzodiazepine of unique chemical structure, are discussed. Alprazolam's pharmacokinetics may be altered by age and sex, body weight, and concurrent treatment with cimetidine. The unique structure of alprazolam may be associated with a wider range of biologic activity than is seen with other benzodiazepines.

Age Factors↗
PubMed1983

Pharmacokinetics of benzodiazepines and psychostimulants in children.

The pharmacokinetics of benzodiazepines and psychostimulants are reviewed and an overview of the kinetic principles relevant to the utilization of these drugs in infancy and childhood is provided. Newborns and premature infants can metabolize and eliminate diazepam, although the parent drug has a longer half-life and decreased rate of biotransformation to its primary metabolites than in older children and adults. The newborn's capacity to carry on metabolic processes involved in the biotransformation of diazepam, including hydroxylation, demethylation, and glucuronide conjugation, is also limited before 5 months of age; after this time hepatic enzymes develop to adult capacity. Kinetic studies of psychostimulants in childhood indicate that methylphenidate is metabolized in the child as it is in the adult. The drug appears to be rapidly metabolized to ritalinic acid and the half-life seems to be relatively short. Volumes of distribution appear to be relatively large, suggesting extensive distribution of the drug to body tissues. Neither diazepam nor methylphenidate is without the potential for toxicity, which increases with dosage. The authors conclude that advancements in the technical capacity for obtaining and analyzing microsamples of blood as well as the use of noninvasive urinary studies will make future research in children possible.

Adolescent↗
PubMed1983

In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.

Factors influencing the rate and extent of benzodiazepine uptake into cerebrospinal fluid (CSF), peripheral tissue distribution and electroencephalographic (EEG) effects were evaluated in a model utilizing anesthetized male cats. A single (0.25-10 mg/kg) dose of the following eight benzodiazepines was administered i.v.: diazepam, desmethyldiazepam, midazolam, lorazepam, alprazolam, triazolam, flunitrazepam and clobazam. Multiple samples were simultaneously drawn from arterial blood and cisternal CSF over the next 4 hr and the EEG was continuously monitored. Concentrations of benzodiazepines in plasma and CSF samples were measured by electron-capture gas-liquid chromatography and plasma protein binding determined by equilibrium dialysis. Physicochemical properties of lipophilicity of each benzodiazepine were determined by measurement of the octanol/buffer partition ratio at physiologic pH and by the high-pressure liquid chromatographic (HPLC) retention on a reverse-phase C18 column at neutral pH. Disappearance of all benzodiazepines from plasma was consistent with a linear sum of two or three exponential terms. After correction for individual differences in protein binding, volume of distribution (Vd) of unbound drug was highly correlated with HPLC retention (r = 0.91), but not significantly related to octanol/buffer partition coefficient. Diazepam and midazolam, having the longest HPLC retention also had the largest unbound Vd. All benzodiazepines rapidly entered CSF, with peak concentrations usually attained within 15 min of dosage. More lipophilic drugs tended to enter CSF most rapidly, but associations of entry rate and in vitro lipophilicity were not significant. After distribution equilibrium was attained, disappearance of benzodiazepines from both plasma and CSF occurred in parallel. Equilibrium CSF/total plasma concentration ratios of all drugs were much less than unity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Some current treatment options for symptoms of anxiety.

The psychologic (i.e., psychotherapeutic or behavioral) and pharmacologic approaches available for the treatment of anxiety are reviewed. Accurate diagnosis and consideration of patient characteristics are essential in choosing among the numerous treatment options. Nonpharmacologic methods are generally the first treatment choice in situational and nonincapacitating anxiety. When anxiety is severe and prolonged, adjunctive drug treatment is appropriate, with antidepressants for phobic and panic states and anxiolytics for generalized anxiety disorder and mixed anxiety and depression. Benzodiazepines are currently the anxiolytics of choice; newer nonbenzodiazepine compounds may provide increased safety.

Aged↗
PubMed1983

Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) vs. conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine.

Fourteen healthy volunteers received a single i.v. dose of antipyrine (1.2 g) on two occasions, once before and once during cimetidine treatment (300 mg every 6 hr). In a similar manner, 8 subjects received diazepam (10 mg), 11 subjects received acetaminophen (650 mg) and 8 subjects received lorazepam (2 mg), all by the i.v. route, once before and once during cimetidine coadministration. Pharmacokinetic analysis indicated increased antipyrine elimination T1/2 during cimetidine treatment (16.7 vs. 10.9 hr; P less than .001) on the basis of decreased total metabolic clearance (0.46 vs. 0.72 ml/min/kg; P less than .001). Likewise, diazepam T1/2 was increased (58 vs. 39 hr; P less than .01) during cimetidine treatment due to decreased total metabolic clearance (0.42 vs. 0.30 ml/min/kg; P less than .01). In contrast, cimetidine did not alter T1/2 or the clearance of lorazepam (T1/2, 16.8 vs. 15.3 hr; clearance, 1.03 vs 1.07 ml/min/kg) or acetaminophen (T1/2, 2.66 vs. 2.60 hr; clearance, 4.8 vs. 4.5 ml/min/kg), both drugs which undergo conjugative biotransformation. In an animal model used to assess the effect of cimetidine on acetaminophen toxicity, the LD50 of acetaminophen alone in Charles River CD-1 mice was 480 mg/kg (95% confidence interval: 436-528 mg/kg). With simultaneous 75 mg/kg of cimetidine treatment, the LD50 for acetaminophen was significantly increased (P less than .05) to 1020 mg/kg (95% confidence interval: 962-1081 mg/kg). Thus, cimetidine slows the metabolic clearance of antipyrine and diazepam, drugs biotransformed by hepatic oxidation, but does not alter the kinetics of acetaminophen or lorazepam, both metabolized by conjugation. Cimetidine may decrease the toxicity of high-dose acetaminophen by preventing formation of the hepatotoxic oxidative metabolites, although having no effect on conjugation of acetaminophen which yields nontoxic metabolites that are subsequently cleared from the body.

Acetaminophen↗
PubMed1983

Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex.

Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.

Administration, Oral↗
PubMed1982

Clobazam kinetics: intrasubject variability and effect of food on adsorption.

The kinetics of single 20-mg oral doses of clobazam was determined on two occasions in 12 healthy male volunteers. Clobazam was given in the fasting state on one occasion and following a standard breakfast on another. Compared with the fasting state, administration of clobazam with food reduced mean peak plasma concentrations (465 vs. 333 ng/ml, P less than 0.01), and prolonged the time to reach peak concentration (1.7 vs. 2.5 hours after dosage, P less than 0.1). Total area under the curve nor the extent of formation of desmethylclobazam, the major metabolite. Clobazam AUC and elimination half-life each were highly correlated within subjects between the two trials (r = 0.97 and 0.95, respectively). Thus, administration of clobazam with food slows the rate of clobazam absorption but does not alter the completeness of absorption. The rate of drug elimination is highly replicable upon repeated administration clobazam to the same individual.

Adult↗
PubMed1982

Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam.

Ten healthy volunteers received single 2-mg doses of lorazepam on five occasions in random sequence. Modes of administration were: A, intravenous injection; B, deltoid intramuscular injection; C, oral tablets in the fasting state; D, sublingual dosage of oral tablets in the fasting state; and E, sublingual dosage of specially formulated tablets in the fasting state. Kinetic variables were determined from multiple plasma lorazepam concentrations measured during 48 hr postdose. After intravenous lorazepam, mean (+/- SE) values were: elimination half-life (t 1/2 beta), 12.9 (+/- 0.8) hr; volume of distribution, 1.3 (+/- 0.07) liters/kg; total clearance, 1.21 (+/- 0.1) ml/min/kg. Absorption of intramuscular lorazepam was rapid. Peak plasma levels were reached at 1.15 hr after dosage, with absorption half-life averaging 14.2 (+/- 4.7) min. Absorption or oral and sublingual lorazepam tended to be less rapid than intramuscular injection, although differences were not significant. Times of peak concentration were 2.37, 2.35, and 2.25 hr postdose for trials C,D, and E, respectively; values of absorption half-life were 32.5, 28.5, and 28.7 min. Absolute systemic availability for trials B, C, D, and E averaged 95.9, 99.8, 94.1, and 98.2%, respectively; none of these differed significantly from 100%. Values of t1/2 beta were highly replicable within individuals regardless of the administration route. Thus, sublingual lorazepam is completely absorbed and is a suitable administration route in clinical practice.

Administration, Oral↗
PubMed1982

Prolongation of drug half-life due to obesity: studies of desmethyldiazepam (clorazepate).

Desmethyldiazepam pharmacokinetics were determined after oral administration of its precursor, clorazepate, to 12 obese subjects (mean weight: 105.4 kg; mean percent ideal body weight: 170%) who were matched for age, sex, and smoking habits with 12 normal controls (66.5 kg; percent ideal body weight: 103.3%). After an overnight fast, a single 15-mg clorazepate capsule, equivalent to 10.3 mg of desmethyldiazepam, was administered. Multiple plasma samples drawn 10-42 days postdose were analyzed for desmethyldiazepam by electron-capture GLC. Obese subjects compared to controls had a prolonged desmethyldiazepam elimination half-life (t1/2) (154.1 hr versus 57.1 hr; p less than 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (Vd) was greatly increased in the obese (158.8 liters versus 63.3 liters; p less than 0.001). The value of Vd remained greater even after correction for body weight (1.52 liter/kg versus 0.94 liter/kg; p less than 0.005). However, clearance of desmethyldiazepam was not different between groups (13.2 ml/min in obese versus 13.4 ml/min in controls). The percent ideal body weight was highly correlated with Vd (r = 0.82), as was total body weight (r = 0.86). The value of t1/2 was correlated highly with Vd (r = 0.89) but only weakly with clearance (r = -0.38). Therefore, the large increase in the desmethyldiazepam t1/2 value seen in obese subjects is predominantly due to the disproportionate distribution of this lipid-soluble drug into body fat as opposed to lean tissue. The contribution of clearance to desmethyldiazepam t1/2 was of much less importance than was Vd in this obese study population.

Adult↗
PubMed1982

Steady-state plasma desmethyldiazepam during long-term clorazepate use: effects of antacids.

The effect of antacid on steady-state plasma desmethyldiazepam (DMDZ) concentrations during long-term treatment with clorazepate dipotassium (CZP) was evaluated in 10 subjects. Each took 7.5 mg CZP nightly for 30 consecutive nights divided into three 10-day treatments given in random sequence as follows: (1) 7.5 mg CZP nightly with no antacid, (2) CZP nightly for 30 ml Maalox, and (3) CZP nightly with Maalox with an additional 30 ml Maalox three times daily. The overall mean steady-state DMDZ plasma level, measured during the last 3 days of each treatment condition, was 175 ng/ml. Within-day means ranged from 159 to 202 ng/ml and were not influenced by treatment condition, time, or trial sequence. DMDZ washout after termination of the 30-day trial was slow, proceeding with a half-life of 75 hr (range, 63 to 109 hr). Thus, Maalox does not alter steady-state DMDZ levels during long-term CZP therapy.

Adult↗