摘要:

Clinical Pharmacology and Therapeutics(1991)49, 605; doi:10.1038/clpt.1991.75

ISSN:0009-9236    

DOI:10.1038/clpt.1991.75

年代:1991

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1991)49, 606–608; doi:10.1038/clpt.1991.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.76

年代:1991

数据来源: WILEY

摘要:

The formation of three oxidative metabolites of imipramine,N‐desmethylimipramine (desipramine), 2‐hydroxyimipramine, and 10‐hydroxyimipramine was studied in microsomes of an extensive metabolizer liver (KDL 26) and of a poor metabolizer liver (KDL 31) and in a homogenate of COS‐1 cells in which the P450IID6 complementary deoxyribonucleic acid had been expressed. The following data support the role of P450IID6 in the 2‐hydroxylation of imipramine: (1) The formation of 2‐hydroxyimipramine was reduced to less than 20% of the control value when microsomes were incubated with serum containing inhibitory antibodies against P450IID6 (anti‐LKM1), whereas no effect was seen with regard to formation of desipramine and 10‐hydroxyimipramine, (2) quinidine and levomepromazine were potent competitive inhibitors of 2‐hydroxylation of imipramine (ki≈ 70 nmol/L, and ki≈ 1 µmol/L, respectively) but had no effect onN‐demethylation and 10‐hydroxylation, and (3) in the COS‐1 cell, homogenate, 10‐hydroxyimipramine, 2‐hydroxyimipramine, and desipramine were formed at rates of 48, 164, and 256 pmol per hour per milligram of homogenate protein, respectively. The P450 isozymes that are responsible forN‐demethylation and 10‐hydroxylation of imipramine have not yet been identified.Clinical Pharmacology and Therapeutics(1991)

ISSN:0009-9236    

DOI:10.1038/clpt.1991.77

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics and concentration‐response relationships of intravenous esmolol were investigated in 20 children undergoing indicated cardiac electrophysiologic testing. A loading dose of 600 μg/kg was infused for 2 minutes. An infusion of esmolol was initiated and dosage was titrated until β‐blockade occurred. Serial esmolol blood samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following parameter estimates (mean ± SD): volume of distribution at steady state, 2.0 ± 1.4 L/kg; total body clearance, 321.2 ± 238.8 ml/kg/min; and terminal elimination half‐life, 4.5 ±2.1 minutes. There was a significant correlation between mean esmolol concentrations and mean percentage of reductions of mean arterial pressures and heart rates at each sample time(p<0.001). The doses of esmolol required for β‐blockade (mean ± SD, 535 ± 180 μg/kg/min) in children were considerably higher than those typically used in adults. Esmolol should prove useful in children in the acute management of cardiac arrhythmias and hypertension.Clinical Pharmacology and Therapeutics(1991)49, 618–623; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1991.78

年代:1991

数据来源: WILEY

摘要:

The oxidation of sparteine and mephenytoin was examined in a group of subjects living in Greenland: 300 in East Greenland and 171 in West Greenland. The distributions of the ratio between the chromatographic peak areas of S‐ and R‐mephenytoin in the urine, the S/R ratio was clearly bimodal in both populations. Thus 9.3% of the East Greenlanders had S/R ratios of 0.9 or more and were phenotyped as poor metabolizers of mephenytoin. In the West Greenlanders, 2.9% of the sample had S/R ratios of 0.90 or more and were accordingly phenotyped as poor metabolizers. The intraethnic difference with regard to the frequency of the mephenytoin poor metabolizer is probably attributable in part to a much higher proportion of admixed Caucasian genes in the West Greenlanders than in the East Greenlanders. In both the East and the West Greenlanders, the sparteine metabolic ratio displayed marked interindividual differences without a clear bimodal distribution. Poor metabolizers arbitrarily defined as subjects with an metabolic ratio of 20 or more made up 3.3% of the East Greenlanders and 2.3% of the West Greenlanders, but the difference between the two groups was not statistically significant.Clinical Pharmacology and Therapeutics(1991)49, 624–631; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.79

年代:1991

数据来源: WILEY

摘要:

D‐Xylose absorption was studied in 12 patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS‐related complex who had had diarrhea for more than 8 weeks, averaged an 11% (range, 3% to 21%) body weight loss during the previous 6 months, and had had negative stool examinations for enteric pathogens. Patients were evaluated by duodenal aspiration and biopsy and received both 25 gm oral and 10 gm intravenous doses of D‐xylose. Kinetic analysis of D‐xylose absorption was characterized by an absorption rate constant (ka) and a rate constant (ko) reflecting nonabsorptive loss. Extent of D‐xylose absorption averaged 18.4% ± 9.3% (±SD) in the 12 patients (normal>60%). Percentage of weight loss during the previous 6 months was negatively correlated with ka(r = ‐0.69;p= 0.018) in the 11 patients in whom this parameter was reduced but was not correlated with either koor extent of D‐xylose absorption. In these patients with human immunodeficiency virus enteropathy, kawas reduced out of proportion to the minor histologic changes present in the duodenal biopsy specimens.Clinical Pharmacology and Therapeutics(1991)49, 632–640; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1991.80

年代:1991

数据来源: WILEY

摘要:

The bioavailability of five capsules of cyclandelate that are commercially available in Japan was determined in ten healthy volunteers by measuring mandelic acid (a main metabolite of cyclandelate) excreted in the urine. Bioinequivalence among the five capsules was demonstrated. The relative cumulative excretion of mandelic acid of the most poorly bioavailable capsule was 38% of the most highly bioavailable capsule. The effect of food on the bioavailability of these two capsules was investigated by use of two different kinds of food, one containing fat and one containing high carbohydrates but very low fat. The bioavailability of the two capsules was increased when subjects consumed both types of food before drug administration, although there was a greater effect on bioavailability with food containing fat. This suggests that the absorption of cyclandelate was incomplete in fasting subjects, even from the capsule with the highest bioavailability. Bioinequivalence between the two capsules remained after postprandial drug administration.Clinical Pharmacology and Therapeutics(1991)49, 641–647; doi:10.1038/clpt.1991.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.81

年代:1991

数据来源: WILEY

摘要:

The use of two caffeine metabolite ratios for acetylator phenotyping was validated by demonstrating concordance with two sulfamethazine tests in 178 unrelated healthy subjects. The caffeine metabolites used for this purpose were 5‐acetylamino‐6‐amino‐3‐methyluracil (AAMU), 1‐methylxanthine (1X), and 1‐methylurate (1U). The ratio AAMU/(AAMU + 1X + 1U), referred to as molar ratio orN‐acetyltransferase, was compared with the ratio AAMU/1X. The results indicated that, for screening purposes, the acetylator phenotype can be determined by analysis of a 6‐hour urine sample after a cup of coffee or strong tea or a can of caffeine‐containing soft drink. The ratio AAMU/1X is the ratio of choice for the study of subjects in whom variability of xanthine oxidase can be neglected; use of the ratio AAMU/(AAMU + 1X + 1U) appears appropriate for special purposes. Gender, ethnic origin, habitual or moderate consumption of coffee, tea, soft drinks, or ethanol, or cigarette smoking have little if any effect on the caffeine tests for acetylator phenotyping.Clinical Pharmacology and Therapeutics(1991)49, 648–657; do

ISSN:0009-9236    

DOI:10.1038/clpt.1991.82

年代:1991

数据来源: WILEY

摘要:

Systemic β‐blockade after single doses of ophthalmic β‐blockers (one drop in each eye) was investigated in healthy volunteers in two randomized, double‐blind, crossover, placebo‐controlled studies. β‐Blockade was evaluated by displacement of the bronchodilator (specific airway conductance), positive chronotropic (heart rate), and tremorogenic (finger tremor amplitude) dose‐response curve for inhaled isoproterenol. In study 1, 0.5% betaxolol, 0.6% metipranolol, and 0.5% timolol were tested in 16 subjects. Compared with placebo, all β‐blockers resulted in a significant systemic β‐blockade(p>0.05); the increasing order of potency was betaxolol, metipranolol, and timolol. In study 2, 2% butylamino‐phenoxy‐propanol‐acetate (BPPA; a noncardioselective but topically oculoselective drug) and 1% timolol were investigated in 12 subjects. Placebo and BPPA showed no differences(p>0.05), whereas timolol resulted in a significant β‐blockade(p<0.05). Topical oculoselectivity is an important aspect of drug safety of β‐blocking eyedrops. Measure of tremor is appropriate to evaluate β2‐blockade.Clinical Pharmacology and Therapeutics(1991)4

ISSN:0009-9236    

DOI:10.1038/clpt.1991.83

年代:1991

数据来源: WILEY

摘要:

Potential systemic effects of the racemic carbonic anhydrase inhibitor MK‐927 and its S‐enantiomer, sezolamide hydrochloride, after topical ocular administration were investigated in a double‐masked, randomized, placebo‐controlled study in 16 healthy volunteers. A controlled diet was started 4 days before initiation of treatment and continued throughout the study. For 14 days six volunteers received bilaterally one drop of 2% MK‐927 (1.2 mg) q.i.d., six received one drop of 1.8% sezolamide (1.1 mg) q.i.d., and four received the common vehicle q.i.d. Blood and urine electrolytes and acid‐base profiles were measured before and on days 1, 7, and 14 of treatment, and 24‐hour urine samples were collected daily. All values were compared with those on the pretreatment day. Taking the circadian variations of the parameters into account, no significant treatment effect was observed in either the daily profiles or the 14‐day cumulative sodium, potassium, and citrate excretions. Because the usual variability of the measured biologic parameters has been reduced markedly by the stringent requirements of this study, it can be concluded that the induction of clinically significant metabolic changes by topically administered MK‐927 or sezolamide is unlikely.Clinical Pharmacology and Therapeutics(1991)49, 665–673; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1991.84

年代:1991

数据来源: WILEY