摘要:

Four methadone‐maintained subjects were given diazepam (0.3 mg/kg) for 9 days. During the dual drug period, the effects and kinetics of methadone and of its major pyrrolidine metabolite were not altered. These findings indicate that, unlike its effects in rodents, diazepam does not inhibit the metabolism of methadone in man.Clinical Pharmacology and Therapeutics(1982)31, 139–143; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1982.22

年代:1982

数据来源: WILEY

摘要:

The induced activity of aryl hydrocarbon hydroxylase (AHH), measured by the metabolism of benzo[a]pyrene to fluorescent products in cultured human lymphocytes, shows a strong seasonal variation. The in vivo metabolism of antipyrine, which is also catalyzed by microsomal cytochrome P‐450‐dependent monooxygenases, has been reported to be correlated with AHH inducibility in human lymphocytes. To determine whether antipyrine metabolism also showed seasonal changes, we measured antipyrine half‐life (t½) in 10 nonsmokers and eight smokers at the two times of the year that correspond to the high and low peaks of inducible AHH activity as measured in lymphocytes. The mean antipyrine t½ determined in all 18 subjects in summer was almost identical to that found in winter (x± SEM = 10.90 ± 0.65 and 10.96 ± 0.78 hr). AHH activity in cultured human lymphocytes from the nonsmoking subjects was determined in control and 3‐methylcholanthrene–induced cells to obtain inducibility ratios of 4.2 ± 0.56 (SEM) in the summer and 1.4 ± 0.14 (SEM) in the winter. These results indicate that the seasonal variation in AHH inducibility in human lymphocytes is not reflected by a corresponding seasonal variation in antipyrine metabolism in vivo.Clinical Pharmacology and Therapeutics(1982)31, 144–150; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1982.23

年代:1982

数据来源: WILEY

摘要:

Thirty‐two healthy men and women, 23 to 78 yr old, received single 650‐mg intravenous doses of acetaminophen and the drug's kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half‐life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetic data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary.Clinical Pharmacology and Therapeutics(1982)31, 151–156; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1982.24

年代:1982

数据来源: WILEY

摘要:

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130‐mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and informer heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first‐pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, “maintenance” patients exhibited steady‐state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 210 ml/min, P half‐life (t½) increased from 3.3 to 11.8 hr, NP t½ increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single‐dose kinetic profile. Changes in the extent of first‐pass elimination of P result in variability in plasma P and NP that may contribute to P‐induced toxicity.Clinical Pharmacology and Therapeutics(1982)31, 157–167; do

ISSN:0009-9236    

DOI:10.1038/clpt.1982.25

年代:1982

数据来源: WILEY

摘要:

The quaternary ammonium antimuscarinic drugs propantheline bromide and clidinium bromide, given orally at the usual therapeutic doses, delayed gastric emptying of a swallowed radiolabeled liquid meal as measured by a gamma camera. Delay of emptying was dose dependent. If an identical meal was given by gastric tube, there was no slowing of emptying by propantheline in the group as a whole. Six subjects who emptied the intubated meal more quickly with placebo had slowed emptying after 30 mg propantheline. In five others, intubation alone slowed gastric emptying while the addition of 30 mg propantheline caused a paradoxical acceleration of gastric emptying. Clidinium bromide, 5 mg, delayed gastric emptying to the same extent as 15 mg propantheline bromide without the marked suppression of salivary secretion induced by the latter.Clinical Pharmacology and Therapeutics(1982)31, 168–174; doi:10.1038/clpt.1982.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.26

年代:1982

数据来源: WILEY

摘要:

Lorazepam, 4 mg, was evaluated in an 18‐night sleep‐laboratory study involving five insomniac subjects. Hypnotic effectiveness and effects on sleep stages and related parameters were assessed. Placebo was given on baseline nights 1 to 4, lorazepam on nights 5 to 11, and placebo was given again on withdrawal nights 12 to 18. Subjective and objective data clearly demonstrated that lorazepam was effective for both inducing and maintaining sleep. Sleep latency was reduced from a baseline value of 34.6 min to 17.9 min (P<0.01) and total wake time was reduced from 75.9 to 38.5 min (P<0.01). On the third and fifth nights of drug withdrawal total wake time rose above baseline levels (termed rebound insomnia) and sleep latency increased by 77% and 60% over baseline (P<0.01). Subjective estimates of daytime anxiety also increased above baseline (rebound anxiety) during the withdrawal period. All subjects experienced severe hangover and varying degrees of impaired functioning during the first 3 days on drug. Three subjects also experienced anterograde amnesia during the day after the first drug night. These side effects diminished in intensity over the course of the study. Our results suggest that while 4 mg lorazepam may be effective in inducing and maintaining sleep, this dose induces clinically significant side effects that are followed by consistent rebound phenomena after withdrawal.Clinical Pharmacology and Therapeutics(1982)31, 175–179; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1982.27

年代:1982

数据来源: WILEY

摘要:

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 with 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.Clinical Pharmacology and Therapeutics(1982)31, 180–183; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1982.28

年代:1982

数据来源: WILEY

摘要:

Thirty‐eight healthy subjects were given single oral doses of debrisoquine and sparteine in a crossover study. The close correlation between urinary metabolic ratios of the two drugs (rs= 0.91; P<0.001) demonstrates that the polymorphic N‐oxidation of sparteine and 4‐hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.Clinical Pharmacology and Therapeutics(1982)31, 184–186; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1982.29

年代:1982

数据来源: WILEY

摘要:

An experimental model was developed to allow extended investigation (up to 3 days) of the kinetics of upper gastrointestinal elimination (including enterohepatic recirculation) of drugs or metabolites in normal subjects under near physiologic conditions. The test drug (100 mg carprofen) was given by mouth or through a triple‐lumen nasogastric tube to the upper duodenum to three normal subjects. The amounts of drug and metabolite passing the gastrointestinal aspiration port for each time interval were calculated from the concentrations measured in the aspirate using dual nonabsorbable markers and continuous sampling and reinfusion of intestinal fluids. Crossover studies without intubation in the same subjects and comparisons to historical controls demonstrated that the intubation procedure did not affect normal kinetic data obtained from conventional blood and urine specimens. The model permits direct comparison of gastrointestinal‐biliary clearance with renal and with total body clearance and is particularly useful in resolving kinetic questions of gastrointestinal‐biliary excretion or recirculation of metabolites when a drug must be taken by mouth. Potential first‐pass phenomena may also be investigated by means of incremental gastrointestinal clearance values.Clinical Pharmacology and Therapeutics(1982)31, 187–194; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1982.30

年代:1982

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1982)31, 195–196; doi:10.1038/clpt.1982.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.31

年代:1982

数据来源: WILEY