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1. |
Benefits, risks, and costs of prescription drugs: A scientific basis for evaluating policy options |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 111-119
Geoffrey M Anderson,
Walter O Spitzer,
Milton C Weinstein,
Elaine Wang,
James L Blackburn,
Ulf Bergman,
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摘要:
Clinical Pharmacology and Therapeutics(1990)48,111–119; doi:10.1038/clpt.1990.1
ISSN:0009-9236
DOI:10.1038/clpt.1990.125
年代:1990
数据来源: WILEY
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2. |
The erythromycin breath test as a predictor of cyclosporine blood levels |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 120-129
Paul B Watkins,
Ted A Hamilton,
Thomas M Annesley,
Charles N Ellis,
Joseph C Kolars,
John J Voorhees,
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摘要:
The daily dose of cyclosporine required to attain a desired blood level can vary greatly among patients. Because elimination of cyclosporine depends on its metabolism in the liver by an enzyme (cytochrome P‐450IIIA) that also demethylates erythromycin, we reasoned that the ability of patients to demethylate a test dose of erythromycin might be useful in estimating their appropriate daily doses of cyclosporine. Accordingly, the [14C‐N‐methyl] erythromycin breath test was administered to 32 patients before they received 3.0, 5.0, or 7.5 mg/kg/day cyclosporine to treat psoriasis. We found that a simple mathematical equation incorporating just the14CO2production, the age of the patient, and the daily dose of cyclosporine accounted for almost 80% (R2= 0.78) of the interpatient variability in cyclosporine blood levels we observed. Our data indicate that P‐450IIIA activity largely accounts for the relationship between dose of cyclosporine and blood levels for an individual patient. We conclude that the erythromycin breath test may be a convenient guide for cyclosporine dosing.Clinical Pharmacology and Therapeutics(1990)48,120–129; doi:10.1038/clp
ISSN:0009-9236
DOI:10.1038/clpt.1990.126
年代:1990
数据来源: WILEY
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3. |
Imipenem pharmacokinetics in patients with burns |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 130-137
Bradley A Boucher,
William L Hickerson,
David A Kuhl,
Anne Marie Bombassaro,
George S Jaresko,
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摘要:
The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem‐cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24‐hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two‐compartment model provided a superior fit to the data compared with a one‐compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p>0.05). Combined mean (±SD) parameter estimates for the two dosing periods were as follows: Vc, 0.11 ± 0.06 L/kg; Vss, 0.22 ± 0.06 L/kg; CL, 12.5 ± 3.6 L/hr/1.73 m2; t½α, 0.18 ± 0.13 hr; t½β, 1.12 ± 0.44 hr. Mean clearance in two patients with creatinine clearance values>150 ml/min/1.73 m2was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists. Measured creatinine clearance values may be useful in estimating imipenem clearance clinically.Clinical Pharmacology and Therapeutics(1990)48,130–137; doi:1
ISSN:0009-9236
DOI:10.1038/clpt.1990.127
年代:1990
数据来源: WILEY
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4. |
Dopamine clearance in critically ill infants and children: Effect of age and organ system dysfunction |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 138-147
Daniel A Notterman,
Bruce M Greenwald,
Frank Moran,
Ann DiMaio‐hunter,
Linda Metakis,
Marcus M Reidenberg,
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摘要:
To learn if there are age‐related differences in the pharmacokinetic behavior of dopamine, plasma dopamine clearance was determined in 27 acutely ill infants and children who were receiving a continuous intravenous infusion of the drug. Steady‐state clearance was calculated from dopamine concentration in arterial blood. Dopamine clearance was 60.7 ± 28.1 ml/kg/min. The age of the patient exerted an effect on clearance of dopamine (r= − 0.63;p<0.05), and dopamine clearance was nearly twice as rapid in children younger than 2 years as it was in older children (82.3 ± 27.7 ml/kg/min versus 45.9 ± 17.0 mg/kg/min). Conjugated bilirubin exerted an age‐independent effect on clearance of dopamine; clearance was 44.8 ± 28.6 ml/kg/min in children with abnormal conjugated bilirubin (≥0.9 mg/dl) and 70.1 ± 2.56 ml/kg/min in children with normal conjugated bilirubin (<0.9 mg/dl). Clearance was lowest (29.8 ± 5.7 ml/kg/min) in the four children who had both hepatic and renal dysfunction. Age is an important determinant of dopamine clearance, explaining in part the clinical observation that infants and young children require higher infusion rates.Clinical Pharmacology and Therapeutics(1990)48,138–147; doi:10.
ISSN:0009-9236
DOI:10.1038/clpt.1990.128
年代:1990
数据来源: WILEY
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5. |
Inactivation of heparin during extracorporeal circulation in infants |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 148-154
Thomas P Green,
Barbara Isham‐Schopf,
Richard J Irmiter,
Clark Smith,
Donald L Uden,
Robin H Steinhorn,
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摘要:
Heparin anticoagulation is necessary to prevent clotting during procedures involving the extracorporeal circulation of blood. Our preliminary observations suggested that heparin was inactivated in the extracorporeal circuit during extracorporeal membrane oxygenation. We tested this hypothesis by comparing heparin pharmacokinetics in five infants during extracorporeal circulation with kinetics, respectively determined in each patient and in the isolated circuit immediately after discontinuation of the procedure. Heparin clearance was 1.6 ± 0.5 ml/kg/min in the patient and 2.1 ± 0.8 ml/kg/min in the separated circuit. In each patient, the total of heparin clearances in the patient and circuit, 3.7 ± 1.0 ml/kg/min, was virtually identical with the heparin clearance during the procedure, 3.8 ± 1.9 ml/kg/min (r= 0.94,p<0.01). We conclude that more than one half of the heparin administered to infants during extracorporeal membrane oxygenation is eliminated by the extracorporeal circuit itself or by blood components in the circuit. These data explain the relatively large heparin doses needed to maintain anticoagulation in infants during extracorporeal circulation. In light of these findings, a reexamination of the normal mechanisms of elimination of heparin activity appears to be warranted.Clinical Pharmacology and Therapeutics(1990)48,148–154; doi:10.1038/clpt.19
ISSN:0009-9236
DOI:10.1038/clpt.1990.129
年代:1990
数据来源: WILEY
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6. |
Serum concentrations and effects of (±)‐nicardipine compared with nifedipine in a population of healthy subjects |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 155-160
Hervé C Porchet,
Pierre Dayer,
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摘要:
The dihydropyridine calcium antagonist (±)‐nicardipine shares some of the pharmacologic properties of the dihydropyridine prototype nifedipine. To compare them, serum concentrations and cardiovascular effects of 10 mg nifedipine and 20 mg (±)‐nicardipine were evaluated at 1, 2, and 3 hours after oral intake in a randomized, crossover, single‐blind study involving 79 healthy volunteers. (±)‐Nicardipine serum concentrations were much lower than those of nifedipine, indicating a greater hepatic first‐pass metabolism of (±)‐nicardipine. There was a significant correlation between serum concentrations of both drugs. The frequency distributions of nifedipine and (±)‐nicardipine AUC(0–3), heart rate increase, and mean arterial pressure decrease showed no bimodality. This does not confirm the proposed polymorphism of nifedipine oxidation. Concentration‐effect plots indicate that (±)‐nicardipine is more potent than nifedipine but shows comparable efficacy in blood pressure reduction.Clinical Pharmacology and Therapeutics(1990)48155–16
ISSN:0009-9236
DOI:10.1038/clpt.1990.130
年代:1990
数据来源: WILEY
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7. |
Population pharmacokinetics of zidovudine |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 161-167
Steven R Gitterman,
George L Drusano,
Merrill J Egorin,
Harold C Standiford,
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摘要:
The epidemic of human immunodeficiency virus infection has forced an unprecedented acceleration of drug development. The lack of effective therapy at present against many of the infectious complications of acquired immunodeficiency syndrome (AIDS) has forced the rapid clinical introduction of new agents. Population pharmacokinetic models are particularly attractive as a means of assessing drug disposition in cohorts different from those studied during necessarily abbreviated phase I trials. We have used the population pharmacokinetics model as implemented by the computer program NONMEM to study the distribution of zidovudine in a large number of patients who have AIDS‐related complex and who are therefore at an earlier stage of immunosuppression than subjects in other studies. We confirm a clearance of drug identical to that seen by traditional methods but a larger volume of distribution than estimated previously in patients with AIDS. Possible reasons for this discrepancy and the use of this method in the development of antiretroviral therapy are discussed.Clinical Pharmacology and Therapeutics(1990)48,161–167; doi:10.1038/clpt.1990
ISSN:0009-9236
DOI:10.1038/clpt.1990.131
年代:1990
数据来源: WILEY
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8. |
Glucocorticoids suppress levels of immunoreactive bradykinin in inflamed tissue as evaluated by microdialysis probes |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 168-178
Kenneth M Hargreaves,
Ann Costello,
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摘要:
Although circulating bradykinin increases during surgery, concentrations remain unknown in the biologically relevant compartment, the inflamed tissue. We have developed a new method, using microdialysis probes, for collecting tissue samples of immunoreactive bradykinin in both postoperative patients and rats injected with carrageenan. In vitro studies determined optimal flow rate, that dialysate levels of immunoreactive bradykinin were linearly related to external concentrations, and that the probes do not activate bradykinin synthesis. In oral surgery patients, tissue levels of immunoreactive bradykinin peaked approximately 3 hours after surgery. Preoperative administration of methylprednisolone (125 mg) reduced immunoreactive bradykinin levels by 62% (p<0.001) compared with placebo. Comparison of bradykinin levels to concurrent pain revealed a counterclockwise hysteresis, suggesting a delay between peak levels of bradykinin in the effect compartment and pain. In rats, dexamethasone suppressed tissue levels of immunoreactive bradykinin. The glucocorticoid suppression was dependent on de novo protein synthesis. Microdialysis appears to be a novel and useful method for measuring the peripheral release of bradykinin and, possibly, other inflammatory mediators.Clinical Pharmacology and Therapeutics(1990)48,168–178; doi:10.1038/clpt.1990.1
ISSN:0009-9236
DOI:10.1038/clpt.1990.132
年代:1990
数据来源: WILEY
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9. |
Hemodynamic effects of atrial natriuretic factor in young and elderly subjects |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 179-188
Tim L T A Jansen,
Adriaan C I T L Tan,
Paul Smits,
Theo Boo,
Theo J Benraad,
Theo Thien,
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摘要:
Because levels of plasma atrial natriuretic factor (ANF) increase with advancing age, a diminished hemodynamic responsiveness to ANF in the elderly has been hypothesized in the literature. Therefore hemodynamic effects after two infusion rates (0.25 and 2.0 μg/min) of atrial natriuretic factor (99‐126) were investigated in young (n= 8) and elderly (n= 9) volunteers in a double‐blind, randomized, and placebo‐controlled protocol. After low‐rate infusion, ANF concentrations increased to the upper normal range, and only minor effects were observed. In contrast, high‐rate infusion resulted in a decrease in blood pressure and forearm vascular resistance, whereas an increase in heart rate was observed in both groups. Between young and elderly subjects, a significant difference was observed in the ANF‐induced decrease in systolic blood pressure (mean ± SD, − 4% ± 4% versus − 12% ± 7%,p<0.05) and mean arterial pressure (− 6% ± 5% versus −11% ± 4%,p<0.05) during the high rate infusion. When compared with the concentrations of the young subjects, the ANF concentrations reached at both ANF dosages were higher in the elderly subjects; this was the result of a diminished ANF clearance in the elderly subjects. After correction of the changes of systolic blood pressure and mean arterial pressure for the higher ANF levels reached within this elderly group, no difference between young and elderly subjects remained. We conclude that a diminished cardiovascular responsiveness to ANF with advancing age could not be demonstrated. In contrast, the high‐rate infusion of ANF induced an increased hemodynamic response in the elderly subjects, but this seems to be the result of the higher ANF levels reached within this group.Clinical Pharmacology and Therapeutics(1990)48,179–
ISSN:0009-9236
DOI:10.1038/clpt.1990.133
年代:1990
数据来源: WILEY
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10. |
Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans |
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Clinical Pharmacology&Therapeutics,
Volume 48,
Issue 2,
1990,
Page 189-194
William S Harris,
Carlos A Dujovne,
Klaus Bergmann,
James Neal,
Jack Akester,
Sheryl L Windsor,
Douglas Greene,
Zee Look,
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摘要:
A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082,N‐(2,4‐difluorophenyl)‐N‐(4‐neopentylbenzyl)‐N‐(n‐heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single‐blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study.Clinical Pharmacology and Therapeutics(1990)48,189–194; doi:1
ISSN:0009-9236
DOI:10.1038/clpt.1990.134
年代:1990
数据来源: WILEY
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