ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03986.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Therapeutic drug monitoring (TDM) is practiced for a number of frequently used drugs in infants and children. It is believed that monitoring drug levels will increase the probability of a therapeutic response and minimize the probability of adverse drug sequelae. Dose adjustments are based on measured drug levels interpreted relative to published therapeutic ranges which may or may not reflect the true relationship with either therapeutic or adverse effects. Potential errors derive from many sources, some amenable to solutions based on current knowledge, others awaiting improved understanding of the causes and consequences of unreliable therapeutic ranges.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03987.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03988.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The authors compared the outcome of 208 smokers treated with fixed‐dose transdermal nicotine (n = 69), tapered‐dose transdermal nicotine (n = 71), or Buspirone (n = 68). At baseline, there were no significant differences among the three treatment groups with regard to age, gender, educational level, duration of smoking, number of cigarettes smoked per day, concomitant disease states or drug use, or Fagerstrom score. All smokers participated in a behavior modification program. Fixed‐dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 6 weeks. Tapered‐dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 4 weeks, 14 mg/day for 4 weeks and 7 mg/day for 4 weeks. Both transdermal nicotine regimens were initiated on the evening before the attempted quit date. Buspirone was started 21 days before the quit attempt and continued for 7 days after the quit attempt. Buspirone was initiated at 5 mg TID for 7 days and then 10 mg TID for 21 days. Smoking cessation was assessed by patient diaries and random plasma thiocyanate determinations. Dropouts for any reason were considered treatment failures. Quit rates were as shown in the Table I. Discontinuation of treatment for perceived side effects and dropouts for all reasons were not significantly different among the treatment groups. The authors conclude that fixed‐dose transdermal nicotine, tapered‐dose transdermal nicotine, and buspirone are associated with similar efficacy and safety when combined with behavior modification in smokin

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03989.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The analgesic efficacy of single oral doses of drinkable diclofenac dispersible 50 mg was compared with that of Ibuprofen 400 mg and placebo in a randomized, double‐blind, parallel‐group trial in 257 adult patients (245 valid for efficacy) with severe postoperative pain after extraction of an impacted lower third molar. In this study, pain intensity (on a 100‐mm visual analog scale) and pain relief from baseline (using a jive‐point verbal rating scale) were assessed serially during an observation period of 6 hours. Intake of rescue analgesic was permitted in case of insufficient therapeutic effect; however at least 1 hour should have elapsed after test drug consumption. On the main efficacy variable, namely, reduction in the pain intensity score, both diclofenac dispersible (n = 83) and ibuprofen (n = 80) were statistically significantly(P<.01)superior to placebo (n = 82) starting at 20 and 40 minutes, respectively, after drug intake. The active medications were also significantly(P<.01)better than placebo for the secondary efficacy parameters viz. summed pain relief scores over 6 hours (TOTPAR‐6); frequency of remedication with a rescue analgesic in the three treatment groups (diclofenac, 24%; ibuprofen, 28%; placebo, 65%); mean time to remedication; and global evaluation. All the treatments were well tolerated. Thus assay sensitivity of this trial (ibuprofen significantly better than placebo) has been demonstrated; in addition, diclofenac as a dispersible formulation has been shown to be an effective analgesic for the treatment of post‐surgical

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03990.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Once‐daily diltiazem hydrochloride, CARDIZEM® CD (diltiazem CD) 300 mg, was evaluated for safety, efficacy, and the relationship between peak and trough antihypertensive ejects in a multicenter, placebo‐controlled, parallel design trial. After a 4‐ to 6‐week placebo baseline period, 111 patients with essential hypertension were randomized to receive placebo or diltiazem CD for a 4‐week treatment period. Diltiazem CD 300 mg lowered supine diastolic and systolic blood pressure at trough significantly more than placebo (‐7.5 mm Hg vs. −1.3 mm Hg, P =0.0001 and −6.4 mm Hg vs. 0.5 mm Hg, P =0.0051, respectively). Supine blood pressure was also measured hourly from 6 to 10 hours after the dose to assess peak effect and trough/peak ratios. Using the largest residual drug effect of−6.3 mm Hg at 6 hours as peak and the 24−hour residual drug effect of−5.9 mm Hg as trough, the trough/peak ratio was estimated to be 71%, with a lower one‐sided 95% confidence limit of 50%. The precision of the trough/peak ratio is estimated by the lower confidence limit of 50%, which establishes the trough/peak ratio as statistically ≥ 50%. No statistically significant differences in supine DBP were noted between the peak effect hours, indicating a plateau of the peak antihypertensive effect from 6 to 10 hours post‐dose. Diltiazem CD therapy was well tolerated, with no serious treatment‐related adverse events reported during the trial and no patients discontinuing the trial due to a treatment‐related adverse event. This trial demonstrates diltiazem CD 300 mg is a safe and effective therapy when administered once daily for the tre

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03991.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The crossover trial has an intuitive appeal to clinicians because each patient is used as his own control Thus, between‐subject variability of symptoms is eliminated. However, this study design suffers from the bias of treatment‐by‐period interaction. If, for example, the effect of the first treatment period carries on into the next one, then it influences the response to the latter period (carryover effect). A second problem is, that the standard approach (Hills‐Armitage analysis) for interaction has a low sensitivity. An alternative method that looks at the performance of the separate treatment groups and not, as the standard approach, at the means of the groups is presented. This alternative approach does have more sensitivity than the standard in the common clinical situation where there is interaction in just one of the treatment groups. This study shows that this is so. However, the standard approach is more sensitive in the case of two‐group interaction. One approach supplements

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03992.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Standard curves and validation points for high‐performance liquid chromatography (HPLC) determination of four drugs (carbamazepine and phenytoin at therapeutic drug monitoring concentrations and deuterium labeled carbamazepine and phenytoin at tracer dose concentrations) were computed using standard least squares linear regressions analysis and six alternative regression techniques (weighted 1/x, 1/y, 1/x2, 1/y2least squares linear, log/log least squares linear, and robust). The coefficient of determination (R2) and the coefficient of prediction (R2pred) values for standard curves and the computed values for validation points did not differ significantly among the seven methods. The lower limit of quantitation (LLQ) values obtained with all six of the alternative regression methods were significantly (P<.01) lower than the LLQ values obtained with least squares linear regression analysis. The lowest LLQ values were obtained with 1/x2and 1/y2weighting and were threefold to tenfold less than the values obtained with unweighted least squares linear regression analysis (P<.001). The authors conclude that alternative regression analysis techniques (especially 1/x2and 1/y2weighting) offer significant advantages for clinical pharmacology studies when concentration values being measured by HPLC are near the LLQ of the method determined by unweighted least squares linear regression analysis. In other situations, alternative forms of regression analysis had no significant advantages in our stud

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03993.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Serotonin receptor (5‐HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5‐HT3receptor antagonists also have antiemetic activity in ipecac‐induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5‐HT3receptor antagonist, on ipecac‐induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5‐hydroxyindoleacetic acid (5‐HIAA) excretion in healthy men. In separate randomized, placebo‐controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac‐induced emesis in both groups. In dogs, zatosetron inhibited ipecac‐induced emesis in a dose‐dependent manner with a 100‐μg/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5‐HIAA/creatinine ratio (mg/g) or 5‐HIAA excretion rate (μg/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac‐induced emesis in healthy men, as has been shown previously with other 5‐HT3receptor antagonists in chemotherapy‐induced emesis in cancer patients. We did not observe the increase of urinary 5‐HIAA in our study with ipecac‐induced emesis, however, as has been described previously in cisplatin‐induced emesis. Our study indicates that ipecac‐induced emesis may be a useful model for testing 5‐HT3receptor antagonists fo

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03994.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Administration of antibiotics by the inhalational route has become part of standard protocols for treatment of and prophylaxis for Pseudomonal pneumonias in patients with cystic fibrosis. For tobramycin, however, limited data are available on the aerosol absorption patterns, and no absolute bioavailability data for tobramycin exist. The purpose of this study was to measure the absolute bioavailability and systemic absorption characteristics of tobramycin when administered in high doses by a nebulizer. Multiple serum concentrations of tobramycin were measured after administration of an intravenous dose (mean, 2.9 mg/kg every 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inhalational doses were superimposed over the “tail” of a steady‐state intravenous dose to improve the sensitivity of the assay procedure (Abbott‐TDX). Absolute bioavailability (F) was determined from AUC ratios normalized for dose. Model‐independent pharmacokinetic parameters (volume of distribution [Vss] and total clearance [CLt]) were determined for each subject. Absorption characteristics (absorption rate constant [Ka] and mean absorption time [MAT]) were assessed after calculation of the cumulative fraction of drug absorbed, amount of bioavailable drug, and percent remaining to be absorbed per unit time using the Loo‐Riegelman method. Three men and three women completed the study, and all received concurrent doses of ceftazidime. Mean absolute bioavailability (± standard deviation) was 9.13% (± 3.82), and the rate of absorption into the systemic circulation was consistent with a zero‐order model profile for all subjects. Mean absorption time values reflected a wide degree of subject variability and ranged from approximately 15 to 150 minutes. The authors conclude that there is limited uptake of tobramycin into the systemic circulation when administered by nebulizer aerosol into the lungs even in high doses. Absorption of tobramycin from the alveolar space into the pulmonary vasculature appears to be rate limited, but this may be characteristic for adults with cystic fibrosis. The authors also conclude that high doses of tobramycin administered by aerosolized nebulizer in these patients would contribute little to the risk of toxicity because of the poor systemic upta

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb03995.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY