摘要:

A recently developed algorithm for the diagnosis of adverse drug reaction (ADR) was used to investigate the quality of evidence in reported cases of ADRs to 1% gamma benzene hexachloride (GBH), a popular scabicide and pediculicide currently under suspicion as a cause of central nervous system (CNS) toxicity, especially in children. Of the 53 reported cases of alleged toxicity, 37 were associated with lindane insecticide (>1% GBH), which is not a pharmaceutical preparation. Of these 37 cases, 34 scored as definite or probable reactions on the algorithm. Of the 26 reports associated with the drug, 1% GBH, none scored as definite and only 6 as probable ADRs. Of these 6 probable cases, 5 represented inappropriate application or unintended ingestion. The use of rigorous operational criteria, such as those developed in this algorithm, permits a scientifically disciplined assessment of whether or not a drug has been fairly indicted, and also provides valuable clinical information about other aspects of suspected drug toxicity.Clinical Pharmacology and Therapeutics(1980)27, 149–155; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.23

年代:1980

数据来源: WILEY

摘要:

The possibility of an action of propranolol which reduces traffic in the sympathetic nervous system and/or reduces release of norepinephrine at sympathetic nerve endings has been investigated in normal subjects. Plasma norephinephrine was measured in resting supine subjects before and during infusions of sodium nitroprusside which reduced the systolic blood pressure by approximately 10 and later by 20 mm Hg. In 5 subjects these observations were repeated 2 hr after a single 200‐mg oral dose of propranolol and in 3 they were repeated after 2 to 8 wk of propranolol 320 mg twice daily. In the control experiments, plasma norepinephrine increased from 0.22 up to 0.74 ng/ml when the blood pressure was reduced by 17/15 mm Hg. Corresponding figures 2 hr after 200 mg propranolol were an increase of plasma norepinephrine from 0.30 or 0.79 ng/ml with a reduction of blood pressure of 19/15 mm Hg. After long‐term treatment with 640 mg propranolol daily, a similar reduction of pressure with sodium nitroprusside increased plasma norepinephrine from 0.24 to 0.68 ng/ml. There was no significant alteration in the elevation of plasma norepinephrine following blood pressure reduction with nitroprusside after either short‐ or long‐term treatment with propranolol. These experiments do not suggest a significant role for a nervous system effect of propranolol in modifying sympathetic activity.Clinical Pharmacology and Therapeutics(1980)27, 156–164; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1980.24

年代:1980

数据来源: WILEY

摘要:

Six healthy male subjects received phenytoin sodium as 9 100‐mg capsules alone or with aspirin in a randomized, crossover fashion. Aspirin, 975 mg every 6 hr, was started 22 hr before a phenytoin dose and continued for an additional 48 hr during blood sampling. Mean 4‐hr plasma salicylate levels ranged from 104 to 157 μg/ml during the sampling period. Individual mean values for the free fraction of salicylate varied from 0.107 to 0.167. The fraction of free phenytoin in plasma rose from 0.128 ± 0.004 to 0.163 ±0.009 when aspirin was given (p<0.001). Subjects had lower total phenytoin 48‐hr area under the curve (AUC) values when on aspirin (323 ± 36 without and 261 ± 49 μg · hr · ml−1with aspirin; p0.5). Thus, more rapid clearance of total phenytoin probably compensated for salicylate displacement of phenytoin from plasma protein binding sites. Total phenytoin levels for therapeutic monitoring must be interpreted cautiously when patients also receive salicylate.Clinical Pharmacology and Therapeutics(1980)27, 165–169;

ISSN:0009-9236    

DOI:10.1038/clpt.1980.25

年代:1980

数据来源: WILEY

摘要:

In vitro studies have shown that phenytoin (DPH) is displaced from plasma protein binding sites by some drugs. These results have been extrapolated to suggest that, in vivo, this may cause a rise in the free concentration, leading to a greater pharmacologic effect. We examined the effects of aspirin on the levels and kinetics of total serum DPH and free drug as represented by salivary concentrations in 7 healthy subjects. Aspirin induced a decrease (mean, 27.4 ± 3.7%) in total serum DPH concentration but no corresponding change in salivary concentration. During continued aspirin administration, no change was observed in elimination half‐life (½β) of total serum DPH but there was a trend toward reduced ½β in saliva. The ratio of saliva to total serum DPH concentration also increased during this period. These results suggest that displacement of DPH from plasma protein binding sites does not result in an increase in free concentration and thus increased pharmacologic activity, but any previous relationship between total serum concentration and therapeutic effect will no longer hold, as a greater proportion of the total concentration will be in the free form and therapeutically active.Clinical Pharmacology and Therapeutics(1980)27, 170–178; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.26

年代:1980

数据来源: WILEY

摘要:

Procaine hydrolysis in vitro has been studied in whole blood, plasma, and washed erythrocytes. Esterase activity was higher in whole blood than in either diluted plasma or resuspended erythrocytes. Eserine and echothiophate specifically inhibited plasma procaine esterase activity, while acetazolamide blocked hydrolysis of procaine by washed erythrocytes. Kinetic studies in whole blood also identified 2 different enzymes. Procaine esterase activity associated with red blood cells was not impaired in patients with renal failure or hepatic cirrhosis, but procaine half‐life (½) in whole blood of normal subjects was longer after 250 mg acetazolamide.Clinical Pharmacology and Therapeutics(1980)27, 179–183; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.27

年代:1980

数据来源: WILEY

摘要:

The effects of oral cholestyramine 4 gm 8 times daily and spironolactone 300 mg daily, given independently and in combination, on the elimination rate of digitoxin were studied in 6 healthy subjects pretreated with 0.1 or 0.15 mg oral digitoxin daily for 30 days before each intervention. The mean pretreatment digitoxin concentrations for the group ranged from 21 ± 2.9 (SD) ng/ml to 28.5 ± 6.9 ng/ml. The mean control digitoxin half‐life (½) was reduced from 141.6 to 84.4 by treatment with cholestyramine alone. Treatment with spironolactone alone prolonged the mean digitoxin ½ to 192.2 hr. The mean digitoxin ½ after both active drugs was intermediate at 102.9 hr. Spironolactone did not fulfill the expectation from animal studies that it would enhance the clearance of digitoxin by cholestyramine. The prolongation of digitoxin elimination after spironolactone may contraindicate this drug in digitoxin intoxication.Clinical Pharmacology and Therapeutics(1980)27, 184–187; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.28

年代:1980

数据来源: WILEY

摘要:

Eight healthy subjects took single 400‐mg doses of quinidine sulfate in the fasting state, and immediately after a standard breakfast, in a crossover study with at least 1 wk intervening. No other food or liquid was taken for 3 hr after the quinidine. Total and unbound quinidine levels were determined in multiple serum samples and in all urine collected for 48 hr thereafter. Mean systemic availability of quinidine in fasting and postprandial states based on area under the serum concentration curve (19.0/19.1 μg/ml × hr), or on cumulative urinary excretion (85.3/90.8 mg), did not differ. Compared with the fasting state, postprandial doses led to lower peak total serum quinidine levels (1.96/1.73 μg/ml) reached later after the dose (1.47/2.41 hr) and longer absorption half‐life (½) (31.6/37.7 min) but none of these differences was significant. Actual differences were, in fact, considerably greater because of lower protein binding in the fasting (27.5% unbound)/postprandial (23.2%/unbound) state (p<0.05). Peak unbound quinidine levels averaged 34% lower (0.65/0.43 μg/ml, p<0.1), and were reached later (1.26/2.75 hr after dose, p<0.025) in the postprandial trial. Thus, administration of quinidine with a standard breakfast did not influence total systemic availability but slowed the appearance in serum of unbound quinidine, partly due to increased serum protein binding in the postprandial state. This may explain the lower frequency and severity of quinidine‐attributed side effects (nausea, diarrhea, nasal congestion, and palpitations) in the postprandial trial.Clinical Pharmacology and Therapeutics(1980)27, 188–193; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1980.29

年代:1980

数据来源: WILEY

摘要:

Theophylline kinetics after intravenous aminophylline were determined in 5 nonsmoking healthy males before and after allopurinol for 1 wk. There was no significant alteration in theophylline disposition.Clinical Pharmacology and Therapeutics(1980)27, 194–197; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.30

年代:1980

数据来源: WILEY

摘要:

Spironolactone has been reported to diminish the hypoprothrombinemic effect of oral anticoagulants in animals and digitoxin blood levels in man by induction of hepatic enzymes. To evaluate this in man, single oral doses of racemic warfarin, 1.5 mg/kg body weight, with and without 200 mg oral spironolactone daily, were administered to 9 normal subjects. Daily venous blood samples were analyzed for 1‐stage prothrombin activity, hematocrit, and warfarin content. There was a decrease in hypoprothrombinemic effect (p<0.01), an increase in venous hematocrit (p0.5) during warfarin with spironolactone‐induced diuresis over that with warfarin alone. It is concluded that the interaction of warfarin and spironolactone results primarily from the diuresis with consequent concentration of clotting factors and decreased anticoagulant effect.Clinical Pharmacology and Therapeutics(1980)27, 198–201; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1980.31

年代:1980

数据来源: WILEY

摘要:

Tobacco smoking covaried with alcohol consumption in male social drinkers over 15 days of unrestricted alcohol availability. Increased tobacco smoking was associated with alcohol consumption in occasional, moderate, and heavy smokers. Tobacco smoking was not systematically related to marihuana smoking even though both drugs were often smoked at the same time. During ten days of concurrent access to tobacco, alcohol, and marihuana, tobacco smoking continued to covary with alcohol consumption rather than with marihuana smoking. Marihuana smoking appeared to be independent of alcohol consumption patterns.Clinical Pharmacology and Therapeutics(1980)27, 202–209; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.32

年代:1980

数据来源: WILEY