摘要:

We evaluated the potential hepatic toxicity of ibuprofen, aspirin, and oxaprozin in 1468 patients with rheumatoid arthritis and osteoarthritis by slightly modifying an algorithm that was developed to evaluate the drug relatedness of renal toxicity associated with therapeutic doses of these agents in the same population. Ibuprofen proved to be the safest of these nonsteroidal antiinflammatory drugs; it was associated with no AST elevation that was considered probably drug related as determined by application of the algorithm to laboratory values and information from case report forms. The frequency of probably drug‐related AST elevations was highest (5%) with aspirin; with oxaprozin, an investigational nonsteroidal antiinflammatory drug, the incidence (3%) fell between that for the other two agents. Thus our findings on the hepatic safety of ibuprofen are consistent with those in the medical literature.Clinical Pharmacology and Therapeutics(1988)43,473–479; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1988.61

年代:1988

数据来源: WILEY

摘要:

The simultaneous disposition of the enantiomers of ibuprofen in synovial fluid and plasma was studied in eight patients with arthritis. Concentrations of the active S‐enantiomer in synovial fluid exceeded those of the R‐enantiomer at all times in all patients with the ratio of S to R concentrations being 2.1 ± 0.3 (mean ± SE). Synovial fluid concentrations fluctuated much less than in plasma and exceeded plasma concentrations from 5.4 ± 0.3 hours for R‐ibuprofen and 5.5 ± 0.6 hours for S‐ibuprofen. Pharmacokinetic analysis suggested that, although the enantiomers diffuse into synovial fluid primarily in the unbound form, there may be significant diffusion of the enantiomers out of synovial fluid in the protein‐bound form in some patients. Interpatient differences in the disposition of the enantiomers of ibuprofen in synovial fluid were evident and may contribute to the interindividual variability in response to treatment with ibuprofen.Clinical Pharmacology and Therapeutics(1988)43,480–487; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.62

年代:1988

数据来源: WILEY

摘要:

Caffeine metabolism is known to be accelerated in cigarette smokers, but the effects of smoking on the kinetics and pattern of metabolism in a daily consumption pattern have not been described. We investigated the effects of tobacco abstinence on the rate and pattern of caffeine metabolism in nine habitual smokers who consumed six cups of coffee per day, each cup containing 2 mg/kg caffeine. Abstinence from smoking for 4 days resulted in a 46% increase in the 24‐hour AUC. Thus, significant, although probably not complete, normalization of the enzyme‐inducing effects of cigarette smoking can be seen after 4 days abstinence. During abstinence, 24‐hour urine ratios of dimethylxanthines to caffeine and mono‐dimethylxanthines to dimethylxanthines were reduced, suggesting that cigarette smoking accelerates both demethylation steps. Other metabolic pathways were unaffected.Clinical Pharmacology and Therapeutics(1988)43,488–491; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1988.63

年代:1988

数据来源: WILEY

摘要:

The effects of four single oral doses of ICI 118,551 (a selective β2‐adrenoceptor blocking agent: doses 10, 20, 50, and 100 mg) have been compared with placebo in five normal, healthy volunteers on some cardiovascular responses to intravenous infusions of dobutamine. Increasing infusions of dobutamine produced reproducible dose‐dependent reductions in systolic time intervals and increases in systolic blood pressures, these responses representing positive inotropic effects of dobutamine. These effects of dobutamine were unaffected 2 hours after administration by 10 mg ICI 118,551 and minimally by 20 mg; the 50 mg dose attenuated the systolic time interval effect whereas the 100 mg dose attenuated further the systolic time interval reduction and also the increase in systolic blood pressure. These results allow a conclusion that at unit doses of 50 mg and above, ICI 118,551 will produce demonstrable effects on β1‐adrenoceptors.Clinical Pharmacology and Therapeutics(1988)43,492–498; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1988.64

年代:1988

数据来源: WILEY

摘要:

A two‐part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three‐stage flecainide infusions of predetermined durations in eight patients. The three‐stage infusions (0.15 ± 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 ± 0.004 mg/kg/min for 60 minutes, and 0.31 ± 0.05 mg/kg/hr for 5 to 47 hours; mean ± SE) resulted in 95% ± 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% ± 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.Clinical Pharmacology and Therapeutics(1988)43,499–508; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1988.65

年代:1988

数据来源: WILEY

摘要:

Recently detoxified men with alcohol dependence (n = 15) and healthy volunteers (n = 14) were administered oral and intravenous imipramine and desipramine. Alcoholics had significantly greater total body clearance of imipramine (0.93 vs. 0.48 L/hr/kg; P<0.05) and desipramine (1.00 vs. 0.62 L/hr/ kg; P<0.05) than did control subjects. Intrinsic clearance of unbound imipramine was greater in the alcoholic group (19.80 vs. 6.56 L/hr/kg; P<0.05), as was the intrinsic clearance of unbound desipramine (14.52 vs. 9.05 L/hr/kg; P<0.05). The mean elimination half‐life for imipramine was significantly decreased in alcoholics (8.7 vs. 19.9 hours after intravenous infusion and 10.9 vs. 19.6 hours after oral administration; P<0.05). The mean elimination half‐life for desipramine was decreased in alcoholics after intravenous infusion (16.5 vs. 22.4 hours; P<0.05). Unbound fractions of drug in plasma were decreased in the alcoholic group for both imipramine and desipramine after both routes of administration. α1‐Acid glycoprotein levels were elevated in the alcoholic group whereas total protein and albumin levels did not differ between groups. These findings suggest that recently detoxified alcoholics may require higher doses of imipramine than do nonalcoholic subjects. Desipramine clearance was affected to a lesser degree than imipramine, suggesting that from a pharmacokinetic standpoint it may be the preferred drug for the treatment of alcoholics with depression. Periodic monitoring of plasma levels may be required for recently abstinent alcoholics treated with antidepressants.Clinical Pharmacology and Therapeutics(1988)43,509–518; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1988.66

年代:1988

数据来源: WILEY

摘要:

Changes in cardiac performance in response to epinephrine administered by graded infusion were assessed by M‐mode echocardiography in normotensive healthy subjects after pretreatment with placebo, the β1‐selective blocker atenolol, or the nonselective β‐blocker propranolol. Epinephrine alone increased heart rate and left ventricular end diastolic dimension and decreased left ventricular end systolic dimension. Left ventricular performance as assessed by fractional shortening and systolic blood pressure/end‐systolic volume (P/V) ratio was also increased. Atenolol pretreatment did not significantly affect the increase in heart rate by epinephrine. However, atenolol did prevent the effects of epinephrine on left ventricular dimensions and left ventricular performance at the lower infusion rates and significantly blunted these effects at the highest infusion rate. After propranolol, epinephrine significantly decreased left ventricular end diastolic dimension despite decreasing heart rate and left ventricular emptying (associated with a high afterload). P/V ratio remained unchanged. These results indicate that β2‐receptors may play a major role in the increase in heart rate caused by epinephrine. In contrast, epinephrine's positive inotropic effect appears to be mediated primarily via β1‐receptors and, at higher concentrations, possibly also through β2‐receptors. The pattern of changes in left ventricular end diastolic dimension suggests that epinephrine increases venous return via both β1and β2‐receptor stimulation and that α‐receptor stimulation (epinephrine after propranolol) may actually decrease venous return.Clinical Pharmacology and Therapeutics(1988)43,519–

ISSN:0009-9236    

DOI:10.1038/clpt.1988.67

年代:1988

数据来源: WILEY

摘要:

A double‐blind, randomized, parallel‐group study compared the analgesic efficacy of a single oral dose of 500 mg diflunisal, 60 mg codeine, 500 mg diflunisal plus 60 mg codeine given as separate agents, and placebo in 161 patients with moderate to severe postoperative pain. Standard subjective measures were used to evaluate analgesia. Eight‐hour sum of pain intensity differences and total pain relief scores for all active treatments were significantly better than were those for placebo(p<0.05). Diflunisal plus codeine performed the best followed by diflunisal, codeine, and placebo. Diflunisal plus codeine was better than placebo from 1½ to 8 hours(p<0.01), better than codeine from 1½ to 6 hours(p<0.05), and better than diflunisal alone from ½ to 1½ hours(p<0.05) for most measures of analgesia. Factorial analysis demonstrated a significant early codeine effect and a significant diflunisal effect throughout. No significant treatment group differences were observed regarding adverse effects. Our data demonstrate that diflunisal plus codeine is generally well tolerated and provides analgesia superior to that of diflunisal or codeine alone in the treatment of moderate to severe postoperative pain.Clinical Pharmacology and Therapeutics(1988)43,529–535; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1988.68

年代:1988

数据来源: WILEY

摘要:

The single‐dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end‐stage renal disease who were on hemodialysis and seven age‐matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half‐life (43.6 vs 27.5 hours) and AUC (9.9 ± 2.1 vs 6.0 ± 1.6 μg · hr/ml) were significantly(p<0.05) increased in the patient population. No significant differences were noted in the maximum rimantidine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end‐stage renal disease but supplemental doses on dialysis days are not required.Clinical Pharmacology and Therapeutics(1988)43,536–541; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.69

年代:1988

数据来源: WILEY

摘要:

Ketorolac tromethamine, an analgesic agent with prostaglandin synthetase–inhibiting activity, is more active than aspirin in vitro in inhibiting collagen– or arachidonic acid–induced platelet aggregation. In this randomized, double‐blind study, 26 volunteers received ketorolac, 30 mg intramuscularly four times a day for 5 days, and placebo, two capsules orally four times a day for at the last 2 study days. The effects of this treatment were compared with those of intramuscular placebo and oral aspirin, two 325 mg capsules, given on the same schedule to eight volunteers. Aspirin at a mean serum concentration of 84 μg/ml did not affect prothrombin time, partial thromboplastin time, platelet count, or bleeding time. Ketorolac produced a modest prolongation of the bleeding time, from 4.9 ±1.1 minutes (mean ± SD) to 7.8 ± 4.0 minutes(p<0.005). Ketorolac did not affect the prothrombin time or partial thromboplastin time but was associated with clinically insignificant change in the platelet count from 303 ± 57 × 103/m3to 277 ± 56 × 103/mm3.Clinical Pharmacology and Therapeutics(1988)43,542–546; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1988.70

年代:1988

数据来源: WILEY