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1. |
The need for an open mind about the treatment of chronic nonmalignant pain |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 367-369
Marcus M Reidenberg,
Russell K Portenoy,
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摘要:
Clinical Pharmacology and Therapeutics(1994)55,367–369; doi:10.1038/clpt.1994.
ISSN:0009-9236
DOI:10.1038/clpt.1994.43
年代:1994
数据来源: WILEY
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2. |
Relationship of electroencephalographic and cardiovascular changes to plasma nicotine levels in tobacco smokers |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 370-377
Chitoshi Kadoya,
Edward F Domino,
Shigeaki Matsuoka,
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摘要:
ObjectiveThe effects of smoking one tobacco or placebo cigarette on the mean change in voltage of the electroencephalogram (EEG), arterial blood pressure, heart, and eye blink rates were correlated with the increase in plasma nicotine, exhaled carbon monoxide, and carboxyhemoglobin levels.MethodsTwenty nonsmokers (age range, 19 to 42 years; mean age ± SE, 27.0 ±1.9 years) and 65 regular tobacco smokers (age range, 20 to 48 years; mean age ± SE, 27.7 ± 0.8 years) were studied about 10 to 12 hours after overnight tobacco deprivation and immediately after inhaling air through a straw or after smoking one of their own brands of cigarettes, respectively.ResultsAn increase of at least 10 ng/ml plasma nicotine was needed to obtain a statistically significant decrease in alpha1and an increase in beta EEG activity. An increase of at least 15 ng/ml plasma nicotine was needed to obtain a statistically significant decrease in delta EEG activity. The mean dominant alpha frequency, heart rate, systolic and diastolic blood pressure, exhaled carbon monoxide, and carboxyhemoglobin levels increased significantly with increasing plasma nicotine concentrations.ConclusionsMeasurement of plasma nicotine levels is especially important to quantify the relationship between tobacco smoking, mean EEG activity, and cardiovascular changes. Nicotine plasma concentrations greater than 10 µg/ml produce consistent and statistically significant changes in brain wave activity. Smaller increments in plasma nicotine produce less consistent EEG changes.Clinical Pharmacology and Therapeutics(1994)55,370–377; doi:10.1038/clpt.
ISSN:0009-9236
DOI:10.1038/clpt.1994.44
年代:1994
数据来源: WILEY
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3. |
Effect of age and gender on tirilazad pharmacokinetics in humans |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 378-384
Laura K Hulst,
Joseph C Fleishaker,
Gary R Peters,
John D Harry,
D Mark Wright,
Penelope Ward,
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摘要:
Tirilazad mesylate pharmacokinetics were assessed in 12 young and 12 elderly volunteers (six men and six women per age group). Subjects received single 10‐minute intravenous infusions of 1.5 mg/kg and 3.0 mg/kg tirilazad mesylate. Plasma tirilazad mesylate concentrations were determined by HPLC. The were no significant dose effects on clearance, but half‐life increased with dose because of assay insensitivity at the lower dose. Mean half‐lives were 16.3 ± 15.5 and 21.4 ± 12.6 hours for young and elderly subjects, respectively, at the 3.0 mg/kg dose. At the same dose, mean tirilazad mesylate systemic clearance was 0.630 ± 0.254 and 0.428 ± 0.090 L/hr/kg, respectively. The decreased clearance in elderly volunteers was primarily attributable to a lower clearance in elderly women relative to young women. The small effect of age on tirilazad clearance is likely to have minimum clinical impact. Tirilazad clearance was approximately 40% higher in young women than in young men. The clinical importance of this observation is unknown.Clinical Pharmacology and Therapeutics(1994)55,378–384; doi:10.1038/
ISSN:0009-9236
DOI:10.1038/clpt.1994.45
年代:1994
数据来源: WILEY
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4. |
Absence of effect of ranitidine on blood alcohol concentrations when taken morning, midday, or evening with or without food |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 385-391
Stephen Toon,
Azhar Z Khan,
Beverly I Holt,
Francis G P Mullins,
Stephen J Langley,
Malcolm M Rowland,
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摘要:
ObjectiveTo investigate the effects of multiple dosing with ranitidine (300 mg four times a day) on the absorption of a moderate dose of alcohol (0.5 gm · kg−1), consumed postprandially or on an empty stomach at different times of day, and to investigate if coadministration of ranitidine affects psychomotor function.MethodsTwo double‐blind, randomized, two‐way crossover, and placebo‐controlled studies were performed in a university research establishment. Study subjects were 36 (18 in each study) normal, healthy, nonalcoholic men aged from 25 to 48 years. Subjects received either 300 mg ranitidine four times a day or placebo for 8 days with oral alcohol (0.5 gm · kg−1) in the morning on day 4, at midday on day 6, and in the evening on day 8. Alcohol was consumed 45 minutes after standard meals and 30 minutes after ranitidine in the first study; it was consumed on an empty stomach 30 minutes after ranitidine in the second study.ResultsMaximum blood alcohol concentrations, area under the blood alcohol concentration–time curve, and time to maximum concentration were not significantly different during ranitidine coadministration compared with coadministration of placebo. This result held true for each time of day and for fed and fasting states. Similarly, ranitidine had no detectable effect on any of the results from tests of psychomotor function.ConclusionIrrespective of the time of day, ranitidine has no statistically or clinically significant effects on blood alcohol profiles.Clinical Pharmacology and Therapeutics(1994)55,385–391; doi:10.1
ISSN:0009-9236
DOI:10.1038/clpt.1994.46
年代:1994
数据来源: WILEY
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5. |
Lithium pharmacokinetics in the obese |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 392-398
Robert A Reiss,
Curtis E Haas,
Shyam D Karki,
Barry Gumbiner,
Stephen L Welle,
Stanley W Carson,
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摘要:
IntroductionThe purpose of this study was to investigate the disposition of lithium in obese subjects compared with the disposition in normal weight volunteers.MethodsTen obese volunteers (weight, 110.2 ± 28.6 kg) were compared with eight evaluable normal weight volunteers (weight, 63.1 ± 6.6 kg). Oral lithium citrate (31.4 mEq) was administered and blood samples were obtained over a 48‐hour period. Creatinine clearance (CLCR) was determined from a 12‐hour urine collection. Total body water was determined by the deuterium oxide dilution method.ResultsThe clearance of lithium (CLLi) for the obese group was significantly greater than that for the control group (33.9 ± 7.0 ml/min versus 23.0 ± 6.2 ml/min;p= 0.005). The steady‐state volume of distribution (Vss) for the obese group was significantly less than that for the control group (0.42 ± 0.09 L/kg versus 0.66 ± 0.16 L/kg;p= 0.001). For the combined group, Vsswas significantly correlated with ideal body weight and fat free mass but not with total body weight. The CLLiwas significantly correlated with total body weight, but not with CLCR.ConclusionsThe pharmacokinetic properties of lithium were significantly different for the obese subjects compared with those the normal weight control subjects. At steady state there is a direct proportionality between CLLiand the dose required to achieve a given serum lithium concentration, therefore the results of this study suggest that obese patients may require larger lithium maintenance doses than nonobese patients.Clinical Pharmacology and Therapeutics(1994)55,392–398; doi:10.103
ISSN:0009-9236
DOI:10.1038/clpt.1994.47
年代:1994
数据来源: WILEY
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6. |
Polymorphic debrisoquin metabolism in a turkish population |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 399-401
Atila Bozkurt,
Nursabah E Basci,
Askin Isimer,
Ahmet Sayal,
S Oguz Kayaalp,
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摘要:
Debrisoquin hydroxylation polymorphism was studied in 326 unrelated healthy Turkish volunteers. Debrisoquin sulfate (10 mg) was administered to subjects, and debrisoquin and 4‐hydroxydebrisoquin were determined in the 0‐ to 8‐hour urine samples. Debrisoquin oxidation was polymorphic, with 11 subjects (3.37%; 95% confidence interval, 1.69% to 6.07%) phenotyped as poor metabolizers. The metabolic ratio between debrisoquin and 4‐hydroxydebrisoquine in 8‐hour urine samples ranged from 0.02 in extensive metabolizers to 263.8 in poor metabolizers. The proportion of poor metabolizers was found to be in the range observed in the other white populations studied.Clinical Pharmacology and Therapeutics(1994)55,399–401; doi:10.1038/
ISSN:0009-9236
DOI:10.1038/clpt.1994.48
年代:1994
数据来源: WILEY
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7. |
Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: Coincidence with plasma clearance and breath test |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 402-411
Karl Ludwig Rost,
Ivar Roots,
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摘要:
BackgroundOmeprazole has previously been shown to induce hepatic cytochrome P4501A2 activity, as evidenced by an accelerated N‐3‐demethylation in the13C‐[N‐3‐methyl]‐caffeine breath test. In this study we investigated whether the inducing potency of omeprazole can be quantified by the determination of urinary caffeine metabolite ratios, which are based on the urinary excretion of N‐3‐demethylated metabolites. These data were also compared with changes in plasma clearance.MethodsTwelve healthy volunteers were phenotyped as extensive metabolizers of S‐mephenytoin and received seven daily doses of 40 mg omeprazole; eight of these were also treated with 120 mg/day. Moreover, six poor metabolizers were treated with 40 mg/day omeprazole. Three different urinary caffeine metabolite ratios were evaluated from urine samples collected between 5 and 8 hours after caffeine intake.ResultsThe extensive metabolizers had a slight and nonsignificant acceleration between 7.8% and 17.0% after 40 mg omeprazole by the urinary ratios. However, treatment with 120 mg/day led to highly significant increases ranging from 25.0% to 32.1% (p<0.002) in this group. Poor metabolizers responded with the highest increases of 40.2% to 41.2%. There was a good correlation between these parameters and the caffeine breath test, as well as the plasma caffeine clearance.ConclusionThe study showed an equivalent caffeine N‐3‐demethylation activity by all evaluation methods. The three urinary caffeine metabolite ratios sampled at the convenient interval of 5 to 8 hours after administration showed the dependence of CYP1A2 induction by omeprazole on the dose and genetic trait of S‐mephenytoin hydroxylase.Clinical Pharmacology and Therapeutics(1994)55,402–411
ISSN:0009-9236
DOI:10.1038/clpt.1994.49
年代:1994
数据来源: WILEY
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8. |
Genetic basis for differences in debrisoquin polymorphism between a spanish and other white populations |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 412-417
José A G Agúndez,
Carmen Martínez,
María C Ledesma,
Margarita G Ladona,
José M Ladero,
Julio Benítez,
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摘要:
The debrisoquin hydroxylation polymorphism is an autosomic recessive trait of the cytochrome P450IID6, an enzyme involved in drug metabolism, that affects 5% to 10% of white subjects. The genetic basis of this polymorphism was studied in 258 unrelated Spanish white subjects. The results revealed that about 5% of the subjects were homozygous for mutant alleles and that about 1% of the subjects carried alleles that suggestedCYP2D6gene duplication. The extensive metabolizers who were homozygous for the wild‐type allele had higher metabolic ratio than the heterozygous extensive metabolizers, indicating a gene‐dose effect for the wild type allele. TheCYP2D6allele frequencies indicate a reduced frequency for theCYP2D6(B)allele and a higher frequency for the wild‐type allele compared with other white populations. This is also reflected in an increased frequency of the subjects who were homozygous for the wild‐type allele among extensive metabolizers. We conclude that the sameCTP2D6mutations are present in Spaniards and other white subjects. Nevertheless, the frequencies of such mutations are different in our population. This implies that a high number of Spanish subjects may behave differently than other white subjects in the effect of drugs metabolized by the CYP2D6 enzyme.Clinical Pharmacology and Therapeutics(1994)55,412–417; doi:10.1038/cl
ISSN:0009-9236
DOI:10.1038/clpt.1994.50
年代:1994
数据来源: WILEY
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9. |
Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 418-426
Steven C Boike,
Martin A Pue,
Martin I Freed,
Patricia R Audet,
Amanda Fairless,
Bernard E Ilson,
Névine Zariffa,
Diane K Jorkasky,
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摘要:
ObjectiveTo characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment.MethodsTwenty‐seven subjects were enrolled in an open‐label parallel‐group study. Eighteen patients had renal impairment (average age [±SD], 49 ± 12 years), and nine subjects were healthy volunteers (average age, 28 ± 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reversed‐phase HPLC. Plasma data were analyzed with use of model‐independent methods.ResultsIn subjects with normal renal function (CLCR>80), the mean maximum plasma concentration of penciclovir was 2.83 µg/ml (range, 1.30 to 3.82 µg/ml) and the mean time to reach maximum concentration was 0.89 hours (range, ½ to 1½ hours). The mean apparent terminal elimination half‐life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCRand between renal clearance and CLCR. Mean area under the plasma concentration–time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function.ConclusionConsideration should be given to modification of the dosing schedule of famciclovir from the usual 8‐hour interval to a 12‐hour interval for patients with moderate renal impairment (CLCR30 to 59 ml/min/1.73 m2) or a 24‐hour interval for patients with severe renal impairment (CLCR<30 ml/min/1.73 m2).Clinical Pharmacology and Therapeutics(1994)55,418–
ISSN:0009-9236
DOI:10.1038/clpt.1994.51
年代:1994
数据来源: WILEY
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10. |
Disposition of drugs in cystic fibrosis. VII. Acetylation of sulfamethoxazole in blood cells: In vitro‐in vivo correlation and characterization of its kinetics of acetylation in lymphocytes |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 4,
1994,
Page 427-433
Renta M Hutabarat,
Arnold L Smith,
Jashvant D Unadkat,
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摘要:
ObjectiveTo determine if acetylation of sulfamethoxazole in blood cells is a surrogate measure of its acetylation in vivo. If it is, to use these cells to determine the mechanism(s) by which acetylation of sulfamethoxazole is enhanced in cystic fibrosis.MethodsSingle‐point sulfamethoxazole acetylation activity in blood cells obtained from patients with cystic fibrosis (n= 6) and control subjects (n= 7) who had previously participated in our in vivo study was determined. The parameters, Vmaxand Km, for acetylation of sulfamethoxazole in lysed lymphocytes obtained from patients with cystic fibrosis (n= 6) and control subjects (n= 5) were also determined.ResultsThe acetylation activity in cystic fibrosis whole blood, lysed erythrocytes, and lysed peripheral blood mononudear cells was significantly (p0.80). The apparent Vmaxfor cystic fibrosis lymphocyte lysate was significantly (p<0.05) greater than that obtained for control lymphocyte lysate (72.99 ± 9.07 versus 60.97 ± 2.26 pmol/mg protein/min), and the apparent Kmwas significantly (p<0.05) lower (0.51 ± 0.07 versus 0.73 ± 0.06 mmol/L).ConclusionBlood cells may be used as surrogate markers to elucidate the mechanism (s) by which acetylation of sulfamethoxazole (catalyzed by the monomorphicN‐acetyltransferase) is enhanced in subjects with cystic fibrosis. Both activation or activation and induction of the monomorphicN‐acetyltransferase should be considered as possible mechanism(s) to explain this phenomenon.Clinical Pharmacology and Therapeutics(1994)55,427–433; doi:10.1038/
ISSN:0009-9236
DOI:10.1038/clpt.1994.52
年代:1994
数据来源: WILEY
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