摘要:

The current enthusiasm for biologic approaches to psychiatric problems stems from the practical applications of clinical psychopharmacology. Effective drugs led to more efficient and humane treatment of patients with such disorders. Still, our present drugs leave much to be desired. As we have learned more about how they may ameliorate various types of mental disorders, we generate hypotheses about the possible causes of the disorders we treat. Thus we try to lift ourselves by our bootstraps; drugs generate hypotheses that one hopes will lead to better drugs. Although at times progress seems to be agonizingly slow, if we consider the great progress of the past 35 years one cannot be less than enthusiastic about the prospects for the next three decades. It has been my good fortune to have been connected closely with the developments of the past, a few of which have been discussed in this personal odyssey. It will be the good fortune of my younger colleagues to see the future realization of many of our hopes for better treatment and understanding of psychiatric disorders.Clinical Pharmacology and Therapeutics(1988)44, 123–127; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.125

年代:1988

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1988)44, 127–127; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.126

年代:1988

数据来源: WILEY

摘要:

The pharmacokinetics of intravenous morphine were determined in three groups (0 to ½, 2 to 4, and 6 years) of children and related to the respiratory rate, arterial PCO2, and postoperative analgesia. With respect to pharmacokinetics, children seem to mature very early, because in patients aged 5 to 6 months corresponding parameters similar to those in adults were encountered. The two youngest patients (11 days and 2.4 months) diverged clearly from the others. Their mean plasma clearance of morphine was 5.2 ml/min/kg and volume of the central compartment was 0.36 L/kg. In the other patients the clearance ranged from 25.8 to 75.6 ml/min/kg and volume of central compartment from 0.67 to 2.07 L/kg, respectively. The mean analgetic concentration of morphine was 26.2 μg/L in the youngest group and 3.8 μg/L in the other patients. The effect of morphine on respiration was similar in all groups and did not differ from that of adults. The respiratory depressant effect of morphine in the two youngest patients was not analyzed.Clinical Pharmacology and Therapeutics(1988)44, 128–136; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1988.127

年代:1988

数据来源: WILEY

摘要:

To compare the relative merits of two different administration regimens, tyramine was administered intravenously in ascending doses to 12 healthy subjects to raise systolic blood pressure slightly more than 30 mm Hg. Six subjects received tyramine by bolus injection and six other subjects received tyramine by infusion. The bolus dose of tyramine needed was 4.34 ±1.51 mg (X± SD) and the infusion rate needed was 1.11 ± 0.33 mg/min. Four blood pressure response patterns to continuous tyramine infusion were observed. Because different units were measured for the quantity of tyramine administered, the between‐subject variance estimate to within‐subject variance estimate ratios were calculated. The two techniques had equivalent consistency. With the bolus method, in contrast to the infusion procedure, the dose‐response relationship was obvious in most subjects. Therefore the bolus method was judged to be more useful than the infusion method.Clinical Pharmacology and Therapeutics(1988)44, 137–144; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1988.128

年代:1988

数据来源: WILEY

摘要:

The maturation of the different pathways of caffeine metabolism was studied during infancy. The group of children (n = 14) consisted of four premature newborn infants and 10 older infants who received caffeine citrate solution. Caffeine and 11 of its metabolites were measured by HPLC. Total demethylation andN3‐ andN7‐demethylation increase exponentially with postnatal age; the plateau is reached by 120 days and accounts for 58.6%, 90.5%, and 79.3%, respectively.N1‐demethylation shows no variation with postnatal age. It is suggested thatN3‐demethylation is more important in young infants than in adults and that maturation ofN1‐demethylation occurs later than 19 months of age. 8‐Hydroxylation is mature as early as 1 month of age and may be higher in infants than in adults. Acetylation is not mature before at least 1 year of age. Differences in maturation rate of acetylation may be related in part to genetic acetylator status.Clinical Pharmacology and Therapeutics(1988)44, 145–151; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1988.129

年代:1988

数据来源: WILEY

摘要:

The degree of interindividual and intraindividual variability in acetylator activity was investigated with caffeine used as a probe of enzyme activity. Acetylator phenotype and relativeN‐acetyltransferase activity were estimated in 46 subjects by measuring the urinary ratio of two metabolites, AFMU/1‐MX, after a single 300 mg oral dose of caffeine on five separate occasions. Thirty homozygous slow (rr) and 15 heterozygous rapid (Rr) acetylators were identified. The degree of interindividual variability in acetylator activity was observed to be a mean of 32% (range 27% to 36%) and 20% (range 11% to 29%) in the rr and Rr groups, respectively. The mean intraindividual variation on repetitive measurement was 19% (range 6% to 49%) in the rr and 14% (range 7% to 24%) in the Rr acetylator group. Four subjects had apparent changes in acetylator activity with time such that they were unable to be assigned to any one acetylator group. Two of these four subjects exhibited apparent homozygous rapid acetylator activity intermittently during the 5‐week trial. This variability may explain, in part, some of the high degree of patient variability observed in the toxicity, efficacy, and drug‐related disease associated with acetylated drugs and environmental toxins.Clinical Pharmacology and Therapeutics(1988)44, 152–157; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1988.130

年代:1988

数据来源: WILEY

摘要:

The pharmacokinetics and safety of high‐dose oral acyclovir for suppression of cytomegalovirus disease were evaluated in 12 patients undergoing renal transplantation. A 12‐week course beginning 24 hours before transplantation was administered in doses of 800 to 3200 mg/day based on renal function. Acyclovir plasma concentrations were measured by RIA on posttransplant days 1 or 2 and 5, 6, or 7. Mean peak and trough concentrations on days 5, 6, or 7 were 25 and 18 μmol/L, respectively. The pharmacokinetic model predicted acyclovir concentrations with a precision of 4.1 μmol/L and bias of —1.19 μmol/L. Estimates of individual pharmacokinetic parameters were consistent with literature and a priori values. Two of six adverse events were attributable to acyclovir; both resolved with dose modification. The dosage adjustment scheme and pharmacokinetic model performed well, allowing us to safely administer high‐dose oral acyclovir immediately after renal transplantation. We are proceeding with a placebo‐controlled study to assess efficacy for suppression of posttransplant cytomegalovirus disease.Clinical Pharmacology and Therapeutics(1988)44, 158–163; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1988.131

年代:1988

数据来源: WILEY

摘要:

The effect of three cycles of high‐dose cisplatin (40 mg/m2day for 5 days) on renal tubular function was evaluated in 30 patients. A significant impairment of proximal tubular salt and water reabsorption rates was observed, but also distal tubular function seemed to be affected. These changes were also present 6 months after termination of treatment. Sodium and magnesium clearance increased significantly during treatment. Magnesium clearance normalized shortly after treatment but sodium clearance was significantly elevated 6 months after treatment. Proteinuria, albuminuria, and amino aciduria, together with an increase of β2‐microglobulin andN‐acetyl‐β‐D‐glucosaminidase (NAG) excretion rates, were observed during each treatment cycle. A good correlation was registered between the increase in urinary excretion rates of protein, NAG, and magnesium and the decrease in proximal tubular salt and water reabsorption during cisplatin administration.Clinical Pharmacology and Therapeutics(1988)44, 164–172; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1988.132

年代:1988

数据来源: WILEY

摘要:

We assessed blood pressure (BP) and heart rate (HR) responses in a double‐blind, randomized study comparing cilazapril, a long‐acting, nonsulfhydryl‐group converting enzyme inhibitor, with placebo in 18 patients with mild to moderate (sitting diastolic BP, 95 to 114 mm Hg) essential hypertension. The BP and HR parameters were evaluated at rest (casual, 24 hours after administration), during treadmill exercise testing (Bruce protocol), and with 24‐hour noninvasive ambulatory BP monitoring. These assessments were made after a 4‐week drug washout period and after 8 to 12 weeks of therapy. After 8 weeks of therapy with cilazapril (mean dose 3.6 ± 0.9 mg/day), casual BP decreased 19/11 mm Hg (p<0.01), whereas placebo lowered BP by 4/5 mm Hg (difference not significant) compared with the baseline period. The casual HR was modestly (7 beats/min) but significantly (p<0.05) lowered by cilazapril monotherapy. Exercise BP was reduced by cilazapril (reduction at peak HR, 23/11 ± 10/5 mm Hg;p<0.05), and exercise HR was unchanged. Compared with baseline, the duration of exercise was improved with cilazapril but not with placebo (1.0 minute vs − 0.2 minute;p<0.05). Twenty‐four‐hour mean, awake, and sleep BPs were reduced with cilazapril with the most impressive reduction occurring during the awake period (19/12 mm Hg;p<0.01). These data demonstrate that cilazapril lowers casual, exercise, and ambulatory BP with a modest but significant improvement in exercise time. Thus cilazapril may be particularly effective in the physically active hypertensive patient.Clinical Pharmacology and Therapeutics(1988)44, 173–178; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.133

年代:1988

数据来源: WILEY

摘要:

Prostaglandin E2is uterotonic. Trimoprostil, a prostaglandin E2analog, is a gastric antisecretory and cytoprotective agent. The effects of single doses of 0, 0.125, 0.75, and 3.0 mg trimoprostil on intrauterine pressure were measured in a double‐blind, crossover study in eight surgically sterile women. The 3 mg dose was not tolerated because of abdominal cramps. The other doses caused a dose‐related increase in resting uterine tone and peak pressure with peak effect occurring between 30 and 60 minutes after administration with a duration of about 120 minutes. No effects on the frequency of uterine contractions occurred. Peak mean tone increased from 11.0 to 71.2 mm Hg (p<0.01) and peak pressure from 24.6 to 125.1 mm Hg (p<0.01) after placebo compared with the 1.5 mg dose. Adverse reactions included abdominal pain that correlated with an increase in intrauterine pressure and tone.Clinical Pharmacology and Therapeutics(1988)44, 179–185; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1988.134

年代:1988

数据来源: WILEY