Jerry W. Taylor

Itraconazole in Antifungal Therapy

OBJECTIVE: This overview compares and contrasts the pharmacotherapy of itraconazole with that of other antifungal agents. DATA SOURCES: Primary literature on itraconazole was identified through a medical literature search from 1976 through 1991. This search included journal articles, abstracts, conference proceedings, and reports of animal and human research published in the English language. STUDY SELECTION: All primary literature was reviewed regardless of the study design or outcome. Literature evaluations of efficacy were ranked using a literature rating scale (Dalen JE, Hirsh J. Arch Intern Med 1986;146:462–72), which was slightly modified to include case reports and observations. DATA EXTRACTION: All data were collected and represented with a primary focus on itraconazoles mechanism of action, pharmacokinetics, clinical efficacy in systemic mycotic infections, drug interactions, and adverse reactions. All articles were referenced in the final data presentation unless grouped data had been accurately reviewed and published. DATA SYNTHESIS: Despite the paucity of controlled comparative trials with itraconazole in patients with deep mycoses, results on efficacy are encouraging. It is still unclear what role itraconazole will have in the prophylaxis of fungal infections in immunocompromised hosts. The favorable pharmacokinetic profile permits once- or twice-daily administration and itraconazole appears to be safe and well tolerated. CONCLUSIONS: Itraconazole should prove to be a useful replacement for ketoconazole on hospital formularies. This recommendation is based on itraconazoles greater apparent safety and efficacy. Reevaluation of this agent will be necessary upon the release of newer imidazoles and triazoles.

Possible intramuscular midazolam-associated cardiorespiratory arrest and death.

Midazolam hydrochloride is commonly used for dental or endoscopic procedures. Although generally considered safe when given intramuscularly, intravenous administration is known to cause respiratory and cardiovascular depression. This report describes the first published case of cardiorespiratory arrest and death associated with intramuscular administration of midazolam. Information regarding midazolam use is reviewed to provide recommendations for safe administration.

Predicting phenytoin dosages using Bayesian feedback: a comparison with other methods.

A Bayesian feedback technique for predicting phenytoin dosage was compared to other dosing methods. Sixty-nine cases were selected on the basis of apparent reliability from 103 medical charts of epileptic patients with multiple phenytoin levels on different dosage regimens. Two published nomograms and a graphical, or computational, technique were compared to the Bayesian technique. Each method was assessed for absolute predictability using measures of bias and precision, i.e., mean percent error and root mean squared percent error, respectively. For a single previous data pair, the Bayesian method was similar to a published nomogram with regard to bias and precision. For multiple data pairs, the graphical or simultaneous equation technique tended to be less biased, but the Bayesian method had better precision. However, none of these differences was statistically significant (p > 0.05). The Bayesian method yielded the lowest percentage of predicted doses that exceeded 110% of the actual dose. The Bayesian method conveniently provides a single method applicable to the use of either single or multiple concentration-dosage data pairs and results in fewer extreme dosing errors.

Evaluation of a Bayesian regression program for predicting warfarin response.

Summary: The ability of a Bayesian regression program (Warfcalc) to predict warfarin response was evaluated retrospectively in 48 inpatients and prospectively in 10 inpatients. The prothrombin ratio (PR) on the last day of inpatient therapy was predicted using zero (naive) to five sequential, daily PR feedbacks. Bias and precision were measured using mean error (ME) and mean absolute error (MAE), respectively. Root mean squared error (RMSE) was used as a combined measure of bias and precision. In the retrospective group, the use of five PR feedbacks yielded the lowest ME, MAE, and RMSE (0.22, 0.30, and 0.45, respectively). The use of two and three daily PR feedbacks resulted in larger prediction errors compared with the use of naive parameters. Further evaluation of the retrospective patient data indicated that deletion of PR feedbacks associated with an activated partial thromboplastin time >100 s and exclusion of metabolic inhibitors in the estimation of warfarin clearance resulted in more reliable predictions (ME = 0.07, MAE = 0.20, RMSE = 0.28). Similarly, deletion of such PR feedbacks and metabolic inhibitors from the prospective data and use of PRs for the first 5 days of therapy yielded ME, MAE, and RMSE values of 0.07,0.21, and 0.27, respectively. The variance for prothrombin complex activity (PCA) as a function of the variance in the prothrombin time (PT) was investigated using Monte Carlo simulation assuming four different random error models for the PT measurements. These error models yielded functions that exhibit a maximum coefficient of variation at PCA values of 40–70%. Thus, the use of PR feedbacks during the first few days of warfarin therapy may yield unreliable predictions unless they are appropriately weighted.

Phenytoin clearances in a compliant population: Description and application

Summary: The saturable elimination kinetics of phenytoin (PHT) makes accurate dosing difficult. A simple equation has been derived to predict dosing requirements if one dose-steady-state serum concentration pair is known [new dose = first dose X Cpss (desired)0.2 x Cpss (achieved)-0.2]. This equation is based on an exponential relation between 177 pairs of PHT clearance and steady-state serum concentrations from 59 compliant patients. To evaluate this population clearance method (PCM), patients were drawn from two independent populations (Minnesota and Iowa, U.S.A.). Predicted doses obtained from PCM were compared with predictions from Bayesian, average Vmax, and average Km methods. The Bayesian method was the most precise and least biased of all methods, under- and overpredicting doses in equal frequency. PCM was biased to produce underpredictions. However, clinically achievable doses can be obtained by consistently rounding the calculated dose upward. The mean underprediction for the Bayesian method was 6 mg, for PCM 46 mg, for average Vmax 21 mg, and for average Km 11 mg. PCM is relatively precise, somewhat biased, and very easy to use.

Enalapril: A New Angiotensin Converting Enzyme Inhibitor

Enalapril maleate is a new angiotensin converting enzyme inhibitor marketed in the U.S. by Merck Sharp and Dohme. It has been demonstrated to actively interfere with the renin-angiotensin-aldosterone system. This is reflected by both hemodynamic (decreased blood pressure) and humoral (increased plasma renin, angiotensin I, and decreased angiotensin II) responses to enalapril therapy. Activity in the kallikrein-bradykinin system is still controversial. Enalapril maleate is a prodrug which is quickly absorbed, hydrolyzed by the liver to the active metabolite enalaprilic acid, and excreted 33 percent in the bile and 61 percent in the urine. The therapeutic dosage range is 10–40 mg/d, maximum of 40 mg, given once or twice daily. The onset and duration of action are dose related. Vertigo and headache have been the most commonly reported side effects. Clinical comparison of enalapril to hydrochlorothiazide, β-adrenergic blockers, and Captopril find it efficacious in the treatment of essential hypertension. Efficacy in treating congestive heart failure and hypertension secondary to renal artery stenosis has also been demonstrated for both angiotensin converting enzyme inhibitors. The overall efficacy and safety of enalapril and Captopril appear equivalent when used at low doses in patients with uncomplicated hypertension.

Warfarin dosage predictions assisted by the analog computer.

This paper describes an analog computer program used to predict warfarin dosages following an initial three daily doses of 10 mg. The program simulates the patients response to warfarin and suggested dosages can be entered into the program daily to predict the dose necessary for the patient. Warfarin dosage predictions were made for 29 patients. There was a statistically significant correlation between predicted prothrombin time (PT) response and actual PT response (p < 0.005) for all predictions made. However, when actual and predicted responses were compared with a paired t test, they were significantly different (p < 0.05). The program described here has been useful for predicting initial warfarin requirements for the majority of patients. Continued research is necessary to identify useful computer methods for predicting warfarin dosages.