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1. |
Gene therapy: A new approach for the treatment of genetic disorders |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 1-11
Denis Cournoyer,
Maurizio Scarpa,
Stephen N Jones,
Kateri A Moore,
John W Belmont,
C Thomas Caskey,
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摘要:
Clinical Pharmacology and Therapeutics(1990)47,1–11; doi:10.1038/clpt.1990
ISSN:0009-9236
DOI:10.1038/clpt.1990.1
年代:1990
数据来源: WILEY
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2. |
Morphine and metabolite behavior after different routes of morphine administration: Demonstration of the importance of the active metabolite morphine‐6‐glucuronide |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 12-19
Richard Osborne,
Simon Joel,
Duncan Trew,
Maurice Slevin,
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摘要:
The pharmacokinetic parameters of morphine, morphine‐6‐glucuronide, and morphine‐3‐glucuronide were studied after single‐dose morphine administration by five different routes. The quantitative significance of the active metabolite morphine‐6‐glucuronide was assessed, and the effects of novel dosing forms on morphine metabolism and distribution were examined. After administration of intravenous morphine the morphine‐6‐glucuronide plasma AUC exceeded that of morphine. After administration of oral morphine very low morphine levels were observed—the morphine‐6‐glucuronide plasma AUC exceeded that of morphine by a factor of 9:1. Sublingual, buccal, and sustained‐release buccal morphine tablet administration resulted in delayed absorption, with attenuation and delay of peak morphine and metabolite levels. Morphine bioavailability and morphine glucuronide production were not altered.Clinical Pharmacology and Therapeutics(1990)47,12
ISSN:0009-9236
DOI:10.1038/clpt.1990.2
年代:1990
数据来源: WILEY
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3. |
Interactions in the renal and biliary elimination of digoxin: Stereoselective difference between quinine and quinidine |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 20-26
Ann Hedman,
Bo Angelin,
Annie Arvidsson,
Rune Dahlqvist,
Bengt Nilsson,
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摘要:
The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady‐state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within‐subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady‐state biliary clearance of digoxin from control value 134 ± 57 ml/min (mean ± SD) to 87 ± 39 ml/min during treatment with quinine (p<0.05) and from 95 ± 24 to 55 ± 27 ml/min during treatment with quinidine (p<0.01;n= 4). Quinidine reduced the renal clearance of digoxin (155 ± 26 versus 110 ± 21 ml/min) (p<0.05;n= 4), whereas quinine had no such effect (177 ± 40 versus 185 ± 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.Clinical Pharmacology and Therapeutics(1990)47,20–26; doi:10
ISSN:0009-9236
DOI:10.1038/clpt.1990.3
年代:1990
数据来源: WILEY
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4. |
Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: Relationship to the presence of immunoidentified cytochrome P‐450IID1 |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 27-35
Örjan Mortimer,
Kerstin Persson,
Margarita G Ladona,
David Spalding,
Urs M Zanger,
Urs A Meyer,
Anders Rane,
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摘要:
We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n= 10) and poor metabolizers (n= 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P‐450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). TheO‐demethylation of codeine was highly correlated with theO‐demethylation of dextromethorphan (r= 0.90). TheN‐demethylation of codeine was catalyzed at a considerably higher rate than theO‐demethylation. TheN‐demethylation toO‐demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate ofO‐demethylation of codeine (r= 0.95) and of dextromethorphan (r= 0.88) in the extensive metabolizers. The comeasurement of theO‐demethylation andN‐demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P‐450IID1.Clinical Pharmacology and Therapeutics(1990)47,27–35;
ISSN:0009-9236
DOI:10.1038/clpt.1990.4
年代:1990
数据来源: WILEY
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5. |
Disposition of a murine monoclonal antibody vinca conjugate (KS1/4‐DAVLB) in patients with adenocarcinomas |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 36-41
Dennis Schneck,
Fred Butler,
William Dugan,
Donna Littrell,
Bruce Petersen,
Ron Bowsher,
Allyn DeLong,
Susan Dorrbecker,
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摘要:
The pharmacokinetics of a murine monoclonal antibody vinca conjugate (KS1/4‐DAVLB) was investigated in 13 patients with adenocarcinomas who received single intravenous doses ranging from 40 to 250 mg/m2and in three patients who were administered 1.5 mg/kg every 48 to 72 hours for up to 15 doses. Five patients in the single‐dose study also received 100 μCi of [3H]‐KS1/4‐DAVLB. Overall mean values for the pharmacokinetic variables were as follows: elimination half‐life, 31.5 hours; distribution volume, 4.43 L; and clearance, 0.09 L/hr. KS1/4‐DAVLB demonstrated linear elimination kinetics in both the single‐ and multiple‐dose studies. Significant concentrations of KS1/4‐DAVLB were noted in a pleural effusion. Ten percent of the radioactive dose was recovered in the urine and 20% in the feces over a 5‐day period. Small molecular weight vinca species were detected in the feces but not in the serum.Clinical Pharmacology and Therapeutics(1990)47,36–41;
ISSN:0009-9236
DOI:10.1038/clpt.1990.5
年代:1990
数据来源: WILEY
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6. |
Simulation and evaluation of nicotine intake during passive smoking: Cotinine measurements in body fluids of nonsmokers given intravenous infusions of nicotine |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 42-49
Margareta Curvall,
Eeva Kazemi Vala,
Curt R Enzell,
John Wahren,
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摘要:
The technique of monitoring cotinine concentrations in body fluids as a means of measuring nicotine intake during passive smoking has been evaluated in two studies, both of which used intravenous infusion to simulate nicotine intake. In the first study, nicotine and cotinine were given separately, for 1 hour in four different intravenous doses (3.2, 15.4, 30.9, and 61.7 nmol/min) to each nonsmoker. In the second study, nicotine and cotinine were infused for 4 hours; each subject received five different doses of nicotine (1.5, 3.1, 6.2, 10.8, and 15.4 nmol/min) and one of cotinine (10.8 nmol/min). The concentration of cotinine was constant in both plasma and saliva from 1 to 4 hours after the nicotine infusion; the plateau levels of cotinine were found to be linearly and directly related to the nicotine intake. The ratio of salivary to plasma cotinine was 1:1.27. A linear relationship was also found between nicotine and cotinine infusion rates and the AUC values for cotinine. The fraction metabolized to cotinine was found to be about 0.5. The results from these studies show that: (1) there is a linear relationship between the plateau concentration of cotinine and the amount of nicotine infused over a period of 1 up to 4 hours; (2) salivary cotinine provides the same information on nicotine intake as does plasma cotinine; and (3) single measurements of either plasma or salivary cotinine concentrations at 1 to 4 hours after the exposure could be used to predict the nicotine intake during 1 to 4 hours of environmental tobacco smoke exposure.Clinical Pharmacology and Therapeutics(1990)47,42–49; doi:10.1038/clpt.1990
ISSN:0009-9236
DOI:10.1038/clpt.1990.6
年代:1990
数据来源: WILEY
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7. |
Pharmacokinetics and disposition of the lipid‐lowering drug acifran in normal subjects and in patients with renal failure |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 50-56
Mitchell N Cayen,
Eckhardt S Ferdinandi,
David R Hicks,
Ramona Gonzalez,
Luc Cosyns,
Jean Dubuc,
Michael Kraml,
K David G Edwards,
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摘要:
The pharmacokinetics and metabolic fate of the antihyperlipidemic drug acifran were assessed after a single oral dose of the14C‐labeled drug to healthy male volunteers. Peak serum acifran and radioactivity concentrations were attained 1 to 2 hours after dosing, and the drug was eliminated with a half‐life of 1.6 hours. Virtually all of the recovered dose was excreted in the urine. All of the serum and urinary radioactivity was caused by unconjugated acifran. In patients with moderate chronic renal failure, the binding of acifran to plasma proteins was decreased, and the plasma concentrations of total and unbound drug were greater than those of healthy subjects. Renal failure substantially reduced the plasma and renal clearance of total and particularly of unbound acifran, moderately reduced its volume of distribution, and increased its elimination half‐life from 1.4 to 1.7 hours to 5.7 hours. The results show that acifran is very well absorbed, is rapidly eliminated, is excreted in the urine, and does not undergo any detectable biotransformation in healthy human subjects.Clinical Pharmacology and Therapeutics(1990)47,50–56; doi:10.1038/clp
ISSN:0009-9236
DOI:10.1038/clpt.1990.7
年代:1990
数据来源: WILEY
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8. |
Pharmacoepidemiology of the effect of caffeine on blood pressure |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 57-60
Dan S Sharp,
Neal L Benowitz,
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摘要:
In experimental studies, caffeine increases blood pressure in caffeine‐naive or nontolerant individuals, but not in regular caffeine consumers. Using an epidemiologic approach, we examined the hypothesis that serum‐caffeine concentration would be positively associated with blood pressure in infrequent (but not habitual) caffeine users in a group of bus drivers. Infrequent and habitual users of caffeine showed no differences in systolic or diastolic blood pressures when there is no measurable caffeine in the serum. However, at serum concentrations of caffeine typical of those achieved after one to two cups of coffee, infrequent users demonstrated greater systolic and diastolic pressures, averaging +5.3 mm Hg and +3.6 mm Hg, respectively, compared with habitual users. The magnitude of difference remained after adjustment for age, body mass index, race, sex, and tobacco and alcohol use. These elevations are large enough to exaggerate the prevalence of hypertension, if such assessments are based on cross‐sectional surveys that fail to assess both proximate caffeine consumption and usual caffeine consumption habits.Clinical Pharmacology and Therapeutics(1990)47,57–60; doi:10.1038/clp
ISSN:0009-9236
DOI:10.1038/clpt.1990.8
年代:1990
数据来源: WILEY
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9. |
Lack of an effect of age on the response to clonidine |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 61-67
Catherine E Klein,
John G Gerber,
Alan S Nies,
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摘要:
The plasma concentration and appearance rate of norepinephrine are increased in the elderly. A hypothesis to explain this observation is that the elderly have a diminished response of the α2‐adrenoreceptor in the brainstem that modulates peripheral sympathetic tone. To evaluate the effect of age on α2‐adrenoreceptor function, we studied 12 healthy elderly subjects and 12 healthy young volunteers and compared the decrease in plasma norepinephrine and blood pressure in response to increasing doses of orally administered clonidine. We found that, for the same plasma clonidine concentration, the blood pressure and plasma norepinephrine concentration fell equivalently in both groups. These data imply that the increased plasma norepinephrine and the elevated blood pressure in the healthy elderly population do not appear to be secondary to a decrease in α2‐adrenergic response to an agonist in the central nervous system.Clinical Pharmacology and Therapeutics(1990)47,61–67; doi:10.1038/
ISSN:0009-9236
DOI:10.1038/clpt.1990.9
年代:1990
数据来源: WILEY
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10. |
Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women |
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Clinical Pharmacology&Therapeutics,
Volume 47,
Issue 1,
1990,
Page 68-72
Timothy J Connelly,
Tsuen Ih Ruo,
Marilynn C Frederiksen,
Arthur J Atkinson,
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摘要:
Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 ± 0.3 gm/dl (± SD) in pregnant subjects, compared with 4.4 ± 0.3 gm/dl in control subjects (p<1 × 10−6), and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 ± 1.0) than in nonpregnant (N = 3.3 ± 0.4) subjects, but binding affinity (Ka) averaged only 227 ± 69 (mol/L)−1in pregnant subjects, compared with 303 ± 44 (mol/L)−1in control subjects (F2,17= 4.26;p= 0.032). At a theophylline plasma concentration of 10 μg/ml, the combined effects of hypoalbuminemia and loweredKawould reduce theophylline binding to 31% ± 3% in pregnant women, compared to 39% ± 3% in nonpregnant control subjects (p<1 × 10−5). Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy‐associated decrease in theophylline binding.Clinical Pharmacology and Therapeutics(1990)47,68–72;
ISSN:0009-9236
DOI:10.1038/clpt.1990.10
年代:1990
数据来源: WILEY
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