摘要:

Five healthy men were passively exposed under pre‐ and postplacebo controlled conditions to sidestream smoke from four and 16 standard marijuana cigarettes (2.8% delta‐9‐tetrahydrocannabinol [Δ‐9‐THC]) for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16‐cigarette exposure conditions were similar to those observed after active smoking of one 2.8% Δ‐9‐THC marijuana cigarette. Effects after the four‐cigarette condition were less pronounced. Concurrent physiologic measurements showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of Δ‐9‐THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16‐cigarette condition. With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs, urines positive per subject under the four‐ and 16‐cigarette passive exposure conditions were 4.6 ± 2.2 and 35.2 ± 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 ± 0.8, respectively, for the EMIT 100 assay. From the results of these studies, caution is clearly indicated for individuals who might be substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting marijuana screening data.Clinical Pharmacology and Therapeutics(1986)40,

ISSN:0009-9236    

DOI:10.1038/clpt.1986.171

年代:1986

数据来源: WILEY

摘要:

The influence of age on the responsiveness of dorsal hand vein α‐receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein α‐receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.Clinical Pharmacology and Therapeutics(1986)40,257–260; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.172

年代:1986

数据来源: WILEY

摘要:

The active and major metabolite of nortriptyline (NT),E‐10‐hydroxynortriptyline (E‐10‐OH‐NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% ± 9.9%. Of the given dose, 51.2% ± 8.7% was recovered as conjugated E‐10‐OH‐NT and 23.9% ± 4.3% was recovered as unchanged compound. The plasma t1/2of E‐10‐OH‐NT was 8.0 ± 1.2 hours and total plasma clearance was 47.5 ± 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose‐dependent elimination. The mean apparent volume of distribution was 7.7 ± 2.1 L/kg. Single oral doses of 50 mg E‐10‐OH‐NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P<0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E‐10‐OH‐NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E‐10‐OH‐NT call for further phase I studies.Clinical Pharmacology and Therape

ISSN:0009-9236    

DOI:10.1038/clpt.1986.173

年代:1986

数据来源: WILEY

摘要:

The pharmacodynamic effects of single oral doses of atenolol (100 mg), labetalol (300 mg), and propranolol (80 mg) were compared with those of placebo in a randomized, double‐blind, Latin square design in 12 patients with hypertension. Atenolol and propranolol both significantly reduced cardiac output (−0.55 vs. −0.31 L/min) and heart rate (−8.0 vs. −6.6 bpm), whereas labetalol had no effect on either parameter (− 0.08 L/min; +1.0 bpm). Labetalol significantly reduced vascular resistance (− 339 dynes · cm/sec5), but atenolol and propranolol did not (147 vs. 62 dynes · cm/sec5). Only labetalol significantly reduced the systolic (−15.3 mm Hg), diastolic (−11.5 mm Hg), and mean blood pressures (−12.8 mm Hg). Atenolol significantly reduced only diastolic blood pressure (−5.20 mm Hg), whereas propranolol failed to lower these parameters significantly. These data indicate that the hemodynamic profile of labetalol differs from that of selective and nonselective β‐blockers. Labetalol lowered blood pressure primarily by reducing vascular resistance, whereas reductions in heart rate and cardiac output were the predominant effects of atenolol and propranolol.Clinical Pharmacology and Therapeutics(1986)40,268–2

ISSN:0009-9236    

DOI:10.1038/clpt.1986.174

年代:1986

数据来源: WILEY

摘要:

The plasma protein binding of disopyramide (D) was determined in seven patients with cirrhosis, six with nephrotic syndrome, and seven healthy subjects. Plasma samples containing concentrations of 0.2 to 12.0 μg/ml were ultrafiltered and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1 to 6 μg/ml were significantly (P<0.01) greater in patients with cirrhosis than in healthy subjects. No difference was observed between patients with nephrotic syndrome and healthy subjects. The free fraction at D 3 μg/ml correlated better with α1‐acid glycoprotein (r = −0.77) than with albumin (r = −0.46). Patients with cirrhosis had significantly (P<0.01) lower capacity constants as compared with the other two study groups. There was a significant (P<0.01) correlation between capacity constant and α1‐acid glycoprotein (r = 0.71). Our results suggest that the D therapeutic range measured as the total plasma concentration in cirrhosis, but not in nephrosis, should be approximately 50% lower than previously believed.Clinical Pharmacology and Therapeutics(1986)40,274–280; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1986.175

年代:1986

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1986)40,280–280; doi:10.1038/clpt.1986.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.176

年代:1986

数据来源: WILEY

摘要:

The pharmacokinetics of the antiviral drug 9‐[2‐hydroxy‐l‐(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2of 0.23 hours and terminal t1/2of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 μg/ml and<0.25 to 0.63 fJig/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.Clinical Pharmacology and Therapeutics(1986)40,281–286; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1986.177

年代:1986

数据来源: WILEY

摘要:

6‐Mercaptopurine (6MP) pharmacokinetics and red blood cell 6‐thioguanine nucleotide (TGN) concentrations were studied in 19 children receiving remission maintenance treatment for lymphoblastic leukemia. There was a high interpatient variation in all the pharmacokinetic parameters measured. The pharmacokinetic parameters measured in two children who subsequently had relapses were within the 95% confidence limits of the 17 other children. There was no difference in 6MP pharmacokinetic parameters with respect to neutropenia either after or before the study. The children who developed neutropenia 10 to 19 days after study had significantly higher TGN concentrations (U = 8; P<0.001) and had spent a longer time receiving reduced 6MP dosage in the 12 weeks before the study (U = 19.5; P<0.025). TGN concentrations are a better index of a child's ability to form active cytotoxic metabolites than 6MP dose or plasma concentrations.Clinical Pharmacology and Therapeutics(1986)40,287–292; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1986.178

年代:1986

数据来源: WILEY

摘要:

Sixty‐three outpatients with chronic insomnia were treated for 3 weeks under double‐blind conditions with either brotizolam (n = 29) at a dose of 0.25 mg or 0.5 mg or placebo (n = 34). A 3‐day placebo period preceded and followed the double‐blind treatment phase. Brotizolam consistently produced significantly more sleep improvement than placebo but also more adverse effects. In those patients switched abruptly from brotizolam to placebo, rebound insomnia was observed, being most marked at the first post‐brotizolam placebo night.Clinical Pharmacology and Therapeutics(1986)40,293–299; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1986.179

年代:1986

数据来源: WILEY

摘要:

Antibody coating of resealed drug carrier erythrocytes may be useful for drug targeting to the reticuloendothelial system. We have investigated the survival in the circulation of anti‐Rh antibody (IgG anti‐D)–coated autologous erythrocytes loaded with gentamicin by hypoosmotic dialysis. Five subjects were injected with 15.2 ± 0.4 ml and five additional subjects with 62.8 ± 1.5 ml carrier cells. Survival of the cells was monitored by intraerythrocytic gentamicin concentration in blood. In the first subject group initial t1/2was 0.21 ± 0.06 hours and terminal t1/2was 1.71 ± 0.36 hours. In the second group initial t1/2was 0.59 ± 0.21 hours followed by a slow phase with a t1/2of 89 ± 28 hours. Results indicate that rapid drug delivery to the reticuloendothelial system by antibody—sensitized carrier erythrocytes is possible, but small volumes of erythrocytes seem more efficient.Clinical Pharmacology and Therapeutics(1986)40,300–303; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1986.180

年代:1986

数据来源: WILEY