摘要:

Clinical Pharmacology and Therapeutics(1991)50,471–486; doi:10.1038/clpt.1991.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.172

年代:1991

数据来源: WILEY

摘要:

Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 ± 0.31 ml/min/kg) on study days 4, 7, and 14 (p<0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 ± 0.56 ml/min/kg) (p<0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 130%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and α1‐acid glycoprotein (r= 0.41), and lorazepam clearance and C‐reactive protein (r= −0.38) were significantly correlated (p<0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r= −0.43 andr= −0.37, respectively). These findings suggest that hepatic oxidative and conjugative metaboHsm increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.Clinical Pharmacology and Therapeutics(1991)50,487–497; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1991.173

年代:1991

数据来源: WILEY

摘要:

The effects of milk and yogurt on the bioavailability of ciprofloxacin were studied in seven healthy volunteers in a randomized crossover trial. After an overnight fast, 500 mg ciprofloxacin was given with 300 ml water, milk, or yogurt. Plasma ciprofloxacin concentrations were significantly (p<0.05) lower during the milk and yogurt phases from ½ to 10 hours; at ½ hour the concentration was reduced by 70% by milk and by 92% by yogurt. Milk reduced the peak plasma concentration by 36% (p<0.05) and yogurt by 47% (p<0.05). The extent of bioavailability, measured as the total area under the plasma concentration‐time curve and 24‐hour urinary excretion of ciprofloxacin, was reduced by 30% to 36% by milk and yogurt (p<0.05). We conclude that the absorption of ciprofloxacin can be reduced by concomitant ingestion of milk or yogurt. To avoid therapeutic failures in infections where the causative organism is only moderately susceptible, ingestion of large amounts of dairy products in liquid form with ciprofloxacin is not recommended.Clinical Pharmacology and Therapeutics(1991)50,498–502; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.174

年代:1991

数据来源: WILEY

摘要:

The effect of food on the pharmacokinetics of didanosine was evaluated in an open two‐way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration‐time curves (AUC0‐∞) were 3902 (1316) and 2083 (922) hr · ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact didanosine when didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0‐∞, and %UR were significantly lower for subjects who received didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half‐life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0‐∞and %UR, was reduced significantly in the presence of food. It is recommended that didanosine be administered under fasting conditions.Clinical Pharmacology and Therapeutics(1991)50,503–507; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1991.175

年代:1991

数据来源: WILEY

摘要:

Caffeine was used as a metabolic probe to screen healthy subjects for their activities of two enzymes, deduced to be CYP1A2 (an inducible cytochrome P450) and xanthine oxidase. A longitudinal study revealed modest effects of caffeine dose, ethanol intake, and time‐of‐day on the CYP1A2 index, without any effect on the xanthine oxidase index. The coefficients of intraindividual variation not accounted for were 5.0% for the xanthine oxidase and 17.2% for the CYP1A2 index. In a population study, both indexes showed a log normal distribution, with CYP1A2 values of most subjects covering a 6.3‐fold range but only a 1.7‐fold range with xanthine oxidase. The CYP1A2 index was 33% decreased in women who used oral contraceptives and substantially increased in cigarette smokers. Neither the CYP1A2 nor the xanthine oxidase index differed between volunteers of Chinese and European extraction. Four of 178 subjects showed unexplained low xanthine oxidase values (i.e., values several standard deviations below the mean).Clinical Pharmacology and Therapeutics(1991)50,508–519; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1991.176

年代:1991

数据来源: WILEY

摘要:

The effects of quinidine on oxidative routes of drug metabolism mediated by different forms of cytochrome P450 were investigated in 10 healthy subjects. Each subject was studied on three different occasions and separately received oral administration of (1) a “cocktail” of nifedipine (5 mg), sparteine sulfate (90 mg), and mephenytoin (100 mg), (2) quinidine sulfate (200 mg), and (3) quinidine sulfate followed by the “cocktail” 1 hour later. Quinidine pretreatment significantly inhibited the aromatization of nifedipine to its major first‐pass pyridine metabolite (M‐0) and prolonged the elimination half‐life of the calcium channel antagonist, both by about 40%. More marked inhibition of metabolism was observed with sparteine, and the formation of dehydrosparteine was abolished. A significant correlation was found between the 0–8—hour urinary ratio and the plasma concentration ratio of sparteine to dehydrosparteine obtained 4 hours after drug administration. No quinidine‐induced changes were observed in the 4‐hydroxylation of mephenytoin. The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs.Clinical Pharmacology and Therapeutics(1991)50,520–528; d

ISSN:0009-9236    

DOI:10.1038/clpt.1991.177

年代:1991

数据来源: WILEY

摘要:

We investigated the effects of the adenosine antagonist caffeine on the hemodynamic response to dipyridamole infusion (0.4 mg/kg for 4 minutes). According to a randomized, placebo‐controlled double‐blind protocol, eight normotensive volunteers each participated in five tests: placebo after placebo, dipyridamole after placebo, and dipyridamole after 1, 2, and 4 mg/kg caffeine. Infusion of caffeine alone (4 mg/kg) induced an increase in mean arterial pressure of 6.1 ± 0.5 mm Hg versus 1.5 ± 0.9 mm Hg after placebo (p<0.05). Infusion of dipyridamole alone exerted a characteristic hemodynamic response with an increase in systolic blood pressure (+ 8.4 ± 2.4 mm Hg), pulse pressure (+ 7.0 ± 2.4 mm Hg), heart rate (+ 25.7 ± 3.8 beats/min) and calculated rate‐pressure product (+ 3419 mm Hg × beats per minute), all being significantly different from the changes induced by placebo. Caffeine induced a dose‐dependent attenuation of the response to dipyridamole, with a significant negative correlation between the dose of caffeine on the one hand (0, 1, 2, and 4 mg/kg) and the dipyridamole‐induced increments in systolic blood pressure (r= −0.53), pulse pressure (r= −0.50), heart rate (r= −0.95), and rate‐pressure product (r= −0.93) on the other hand. We conclude that caffeine attenuates the hemodynamic response to dipyridamole infusion in humans in a dose‐dependent fashion. Because of the widespread use of caffeine, this pharmacologic interaction may be of clinical importance, for example, in the diagnostic use of dipyridamole in thallium‐201 myocardial imaging.Clinical Pharmacology and Therapeutics(1991)50,529

ISSN:0009-9236    

DOI:10.1038/clpt.1991.178

年代:1991

数据来源: WILEY

摘要:

The effects of fish oil and naloxone on blood pressure, catecholamines, and endorphins during the cold pressor test were evaluated in a randomized, double‐blind, placebo‐controlled, two‐way crossover trial of normotensive and medication‐free hypertensive men (n= 13 each). Subjects were given 5 gm ω‐3 fatty acids per day or placebo for 30 days with a 1‐month washout between interventions. The cold pressor test (hand in ice water for 5 minutes) was done at the end of the treatment periods. Intravenous naloxone (10 mg) or placebo was given before the cold pressor test. Fish oil‐treated, normotensive, or hypertensive groups had similar changes in blood pressure, plasma catecholamine levels, and β‐endorphins during the cold pressor test, but naloxone treatment was associated with fivefold and tenfold increases in plasma epinephrine and Cortisol levels, respectively. Naloxone may modulate sympathomedullary discharge through blockade of endorphin activity. It is unlikely that endorphins are involved in the blood pressure increase during the cold pressor test or that fish oil alters this response.Clinical Pharmacology and Therapeutics(1991)50,538–546; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.179

年代:1991

数据来源: WILEY

摘要:

Plasma homocysteine levels were determined in patients who participated in a randomized, double‐blind placebo‐controlled trial of folate supplementation (1 mg/day) during methotrexate therapy for rheumatoid arthritis. Plasma and red blood cell folate levels before methotrexate therapy were significantly negatively correlated with homocysteine levels. Homocysteine levels were not significantly correlated with the initial C1index (an assay that measures the folate status of blood mononuclear cells) or the C1index during methotrexate therapy. There was no significant difference in homocysteine levels between pre‐treatment and levels drawn at 3 or 6 months. Initial homocysteine levels were predictive of toxicities, such as gastrointestinal intolerance and elevations of liver enzymes in the placebo group. There was no significant correlation between occurrence of toxicity and initial homocysteine levels in the folic acid‐supplemented group. Homocysteine levels were not predictive of the efficacy of methotrexate therapy. We conclude that plasma homocysteine levels are correlated with plasma and red blood cell folate levels before methotrexate therapy but is not correlated with folate status in blood mononuclear cells.Clinical Pharmacology and Therapeutics(1991)50,547–556; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1991.180

年代:1991

数据来源: WILEY

摘要:

The physiologic and potential pharmacologic roles of atrial natriuretic factor in congestive heart failure have remained confusing. We have evaluated the hemodynamic responses to human atrial natriuretic factor [ANF (102‐126)] given as bolus intravenous doses of 2.0 or 4.5 µg/kg to 12 patients with congestive heart failure. Responses were monitored with pulmonary and systemic arterial catheters in place. By 30 minutes after 4.5 µg/kg ANF (n= 6), heart rate decreased from 97 ± 16 to 91 ± 15 beats/min, right atrial pressure from 14 ± 4 to 12 ± 3 mm Hg, and pulmonary capillary wedge pressure from 33 ± 3 to 23 ± 2 mm Hg (allp<0.05); responses persisted for 120 minutes. Mean arterial pressure, cardiac index, stroke volume index, and pulmonic and systemic vascular resistances did not change significantly. The 2.0 µg/kg ANF dose produced similar responses, but only heart rate and right atrial pressure decreased significantly. No clinically important side effects were noted. High‐dose ANF bolus doses can be administered simply and safely and improve hemodynamic parameters in chronic heart failure. Therefore ANF does have pharmacologic activity in heart failure and may have therapeutic potential.Clinical Pharmacology and Therapeutics(1991)50,557–563; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1991.181

年代:1991

数据来源: WILEY