Annals of Pharmacotherapy

Urinary incontinence is a common, though often hidden, medical problem among the elderly. Urinary continence requires integrity of the neural, muscular, and hormonal systems. Five distinct types of urinary incontinence can be distinguished based on patient symptoms. A variety of factors can impair continence, including aging, environmental barriers, and medications. Both pharmacological and nonpharmacological measures are useful in the treatment of incontinence.

Sulbactam/ampicillin is a combination of a beta-lactamase inhibitor with minimal intrinsic antibacterial activity (sulbactam sodium), and an aminopenicillin (ampicillin sodium). The addition of sulbactam to ampicillin has no effect on the chemical stability of ampicillin in aqueous solution, and the administration guidelines of the combination are the same as for ampicillin alone. Sulbactam acts primarily by irreversible inactivation of beta-lactamases from most beta-lactamase-producing organisms. The pharmacokinetics of sulbactam are similar to those of ampicillin with an elimination half-life of about one hour in most patients. One difference is that serum and tissue concentrations of sulbactam are usually twice those of ampicillin, at equivalent doses. The sulbactam/ampicillin combination has been approved for the treatment of adults with intraabdominal, skin and skin structure, and gynecological infections due to beta-lactamase-producing bacteria such as Staphylococcus aureus, Escherichia coli, and species of Klebsiella and Bacteroides. Clinical studies to date have also shown the combination to be effective for the treatment of meningitis, pneumonia, gonorrhea, epiglottitis, urinary tract infections, cervical adenitis, and as prophylaxis for abdominal and gynecological surgeries. Many of these studies, however, have included small numbers of patients and/or had design flaws. Adverse effects have been minor with most being attributed to the ampicillin component. Sulbactam/ampicillin compares favorably with other antibiotic regimens in terms of acquisition costs and ease of administration.

Lovastatin is the first 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor approved for the treatment of primary hypercholesterolemia. It is indicated as adjunctive therapy to dietary control and should be initiated at 20 mg/d in the evening. With higher dosages, twice-daily dosing is preferred, particularly when the dosage reaches the maximum recommended 80 mg/d. Compared with other drugs available, lovastatin has been shown to have good efficacy and a low incidence of side effects. Limited pharmacokinetic information available from the manufacturer reports absorption ∼ 30 percent, protein binding > 95 percent, and a dual pathway for elimination through both urine (10 percent) and feces (83 percent). The drug has been clinically tested versus placebo and in combination with other cholesterol-lowering drugs. Lovastatin is effective in lowering total cholesterol and low-density lipoprotein cholesterol by 25–30 percent, with nonfamilial (hypercholesterolemic) patients responding better than those with the familial form of the disease. One percent of lovastatin patients have discontinued therapy because of intolerable side effects. The most common complaints are flatulence and diarrhea; more severe abnormalities include elevation of liver enzymes and an unclear propensity for producing lens opacities. The monthly cost to a patient taking 20 mg/d is approximately $44. Although the drug should be added to hospital formularies, long-term safety experience and competition from other HMG-CoA reductase inhibitors will determine lovastatin's final therapeutic role.

Previous studies have documented potentially adverse effects of diuretics and beta-blocking agents on plasma lipid profiles. This study was designed to establish the effects on lipid profiles of the angiotensin-converting enzyme inhibitors lisinopril and enalapril, alone and in combination with hydrochlorothiazide (HCTZ), the calcium-channel blocker nitrendipine, HCTZ, and hydralazine. After a two-week, single-blind, placebo phase, 77 patients with essential hypertension were given active agent as monotherapy in a double-blind fashion for 8–20 weeks. The dose of each agent was titrated to achieve diastolic blood pressure <90 mm Hg. At the end of placebo and treatment phases, plasma was analyzed for triglycerides, total cholesterol, and high- (HDL), and low-density lipoprotein (LDL) cholesterol. Overall, few changes in lipid contents were noted. Total cholesterol decreased during therapy with hydralazine but increased in patients receiving the combination of lisinopril and HCTZ. HDL cholesterol was depressed in those taking HCTZ alone and in combination with lisinopril. LDL cholesterol was lowered during therapy with hydralazine but was otherwise unaffected by all other agents. None of the agents evaluated significantly affected triglyceride concentrations. Thus, monotherapy with lisinopril, enalapril, and nitrendipine do not affect plasma lipid concentrations. Hydralazine lowers total and LDL cholesterol. If these findings are confirmed in trials with larger numbers of patients, these effects on lipid profiles may influence choice of agent in the therapy of essential hypertension.

Twenty-five courses of oral ciprofloxacin were administered to 16 patients experiencing pulmonary exacerbations of cystic fibrosis in an open, uncontrolled trial of efficacy and tolerance. Patients were treated for 7–35 days and efficacy was evaluated based on changes in clinical score, white blood cell count, quantitative bacteriology of sputum, and pulmonary function tests. Most courses of therapy were associated with a positive response with changes in clinical score and forced expiratory volume in one second being statistically significant (p < 0.05). No side effects to ciprofloxacin were noted. Emergence of bacterial resistance to ciprofloxacin was rare. Ciprofloxacin appears to be effective in patients with cystic fibrosis who are experiencing pulmonary exacerbations associated with susceptible bacterial pathogens.

This investigation evaluated the bioequivalence and efficacy of two sustained-release procainamide products. Ten patients with cardiac arrhythmias were randomized to product A (Procan-SR) or product B (Pronestyl-SR). After nine doses of study medication, plasma procainamide and N-acetylprocainamide concentrations were obtained to determine the area under the concentration versus time curve at steady state (AUC_ss), mean plasma concentration (C_av ^ss), the observed peak plasma concentration (C_max ^ss), the observed trough plasma concentration (C_min ^ss), and the apparent time to achieve C_max ^ss (t_max). The products were compared on a milligram-equivalent (adjusted) basis. Following completion of blood sampling, patients were crossed-over to the alternate product. There was no washout between treatments. After nine doses of the alternate test medications, blood sampling was repeated. Differences in AUC_ss, C_av ^ss, C_max ^ss, t_max, and intradose peak/trough ratios were not statistically significant. Within-group variability in AUC_ss, C_av ^ss C_max ^ss, and t_max was greater with product B, but this trend did not reach statistical significance. Antiarrhythmic efficacy was not significantly different between the two treatments. Although the greater bioequivalence, lesser variability, and the greater number of tablet dosage sizes would favor product A, patients stabilized on a particular brand of sustained-release procainamide should not be switched to another product without careful monitoring. One patient in this study developed nonsustained ventricular tachycardia with low procainamide plasma concentrations after being switched from product A to product B.

The pharmacist is an active member of the cardiopulmonary resuscitation (CPR) team in many hospitals, dispensing medications, maintaining records, providing drug information, calculating doses, and mixing intravenous fluids. We surveyed 135 emergency department nursing directors across the country to assess the methods of and persons responsible for documentation during CPR. Ninety-five (70 percent) completed surveys were returned, showing that documentation was usually done by a nurse (81 percent), by a nurse and pharmacist (9 percent), by a pharmacist (7 percent), or by others (ward clerks, paramedics, or physicians) (3 percent). CPR flowsheets (83 percent), nurses' notes (7 percent), or other methods (10 percent) including notes on paper towels and blackboards are used to record such information in the emergency department. Most respondents were fairly confident (49 percent) or very confident (48 percent) that they could recreate the resuscitative sequence from the information recorded; 2 percent did not have confidence in the reproducibility of the data. Respondents felt that cardiac rhythms (83 percent), drugs and dosages administered (34 percent), and temporal sequence of events (33 percent) could be more accurately recorded during CPR. A majority of respondents (57 percent) felt that an automated recording system would be useful. We conclude that there appears to be considerable variability in the method of documentation of events during CPR in emergency departments throughout the country. Future efforts in emergency care should include the involvement of pharmacists in the development and implementation of a uniform database for use by field and hospital personnel during CPR.

Three methods of estimating inter- and intrasubject variances and coefficients of variation of digoxin renal clearance are discussed and illustrated. All three methods gave essentially the same values for intrasubject variation; two of the methods (II and III), based on two-factor and one-factor analyses of variance, respectively, gave the same estimates of intersubject variation. The preferred method I involves directly calculating variances from the rows and columns of the tabular data, where the rows are repetitive treatments in the same subject and the mean variance represents intrasubject variance; a column represents different subjects' results on a given treatment and the mean of the column variances represents intersubject variance. Problems in attempting to use components of variance are discussed. Intrasubject coefficients of variation of digoxin renal clearance averaged 23.8 percent by method I and ranged from 15.2 to 28.6 percent. Intersubject coefficients of variation averaged 30.5 percent with a range of 17.5–41.8 percent by method I and averaged 42.1 percent with a range of 19.2–49.7 percent by methods II and III.

A 23-year-old woman with asthma developed severe heartburn while using beclomethasone dipropionate. Esophageal candidiasis was diagnosed on endoscopy and confirmed by biopsy. Subsequent studies revealed mild hypogammaglobulinemia and mild impairment of neutrophil candidacidal activity, the significance of which is unknown. Esophageal candidiasis associated with the use of inhaled beclomethasone has not been previously reported.

We present the cases of two patients with short-bowel syndrome who failed to achieve therapeutic cyclosporine serum concentrations on oral drug but were successful on intravenous administration. One patient received cyclosporine after renal transplantation for renal failure secondary to enteric oxalosis; the second received cyclosporine for active Crohn's disease. The rapid bowel transit time was the critical factor in limiting cyclosporine absorption in both cases. In studying oral and intravenous pharmacokinetic profiles, we support a zero-order kinetic model for oral cyclosporine absorption.

Rebound hypertension with a neurological complication occurred during an attempt to substitute transdermal for oral clonidine in a patient with severe hypertension. Published studies have not established an unequivocal correlation between previous oral clonidine dose and the dose of transdermal clonidine required for equally effective antihypertensive therapy. Close observation of blood pressure may be advisable for at least one week following substitution of transdermal for oral clonidine, especially in patients with severe hypertension.

Verapamil has been shown to be effective in the management of supraventricular tachycardia (SVT). However, the utility of verapamil may be limited because of adverse effects, specifically hypotension. Several clinical observations have shown that the intravenous administration of calcium is effective in reversing the myocardial depressant effects of verapamil. We report the case of a patient with SVT and a systolic blood pressure of 80 mm Hg in which the administration of calcium chloride prior to that of verapamil may have negated verapamil-induced hypotension.

This report describes the treatment of resistant gram-negative pneumonitis in a compromised host by the combined use of intravenous and endotracheal tobramycin. The endotracheal administration appeared to have an effect on the serum concentration and elimination rate, necessitating a reduction in the amount of drug given intravenously. The only apparent clinical complication of endotracheal drug administration was transient coughing. The addition of endotracheal aminoglycosides to intravenous antibiotics may be useful in pediatric patients with unresponsive (or other difficult-to-treat) pneumonitis caused by resistant microorganisms. The potential contribution of endotracheal aminoglycosides to the serum level and/or disposition profile must be recognized, and therapeutic drug monitoring guided accordingly when this route of administration is used.

Fifteen cases of presumed cocaine intoxication were evaluated in the emergency room (ER) at a city hospital over a four-day period. This series is unique in that many of these patients were from a similar area of the city, in some cases had the same street address, were regular abusers of cocaine, and presented to the ER with similar symptoms of tachycardia, dilated pupils, marked confusion, bizarre and sometimes violent behavior, psychosis, and hallucinations. Many of these symptoms were present several hours after drug use. Samples of a white powder presumed by the patients to be cocaine were obtained from two patients and analyzed by gas-liquid chromatography. Neither sample contained cocaine, but rather revealed atropine, benzocaine, and procaine. The signs and symptoms of cocaine, amphetamine, and atropine intoxication are reviewed and the problems of drug analysis and differential diagnosis of drug intoxication are discussed.

Two brands of levothyroxine sodium tablets were compared in vivo for bioequivalence in a double-blind, randomized study. The tablets were identical in levothyroxine content. Evaluation was by means of triiodothyronine (uptake), tetraiodothyronine, free thyroxine index, total triiodothyronine by radioimmunoassay, and thyroid-stimulating hormone measurements. No differences in clinical response were found in a study with a high statistical power. It was concluded that the two brands were bioequivalent because of chemical equivalence, use of micronized levothyroxine powder in tablet production with at least one of the brands, and scrupulous attention to quality control during the manufacturing process, all of which contributed to assurance of homogeneity of the products and close adherence (± five percent) to the claimed potency.

A controlled study was conducted to assess the physical compatibility of cimetidine hydrochloride (HCl) and aminophylline and the chemical stability of an admixture of the two medications in dextrose 5% in water (D5W) injection, over 48 hours at room temperature. Three one-liter admixtures were prepared, each containing cimetidine HCl 1200 mg and aminophylline 500 mg in D5W. One liter of only cimetidine HCl 1200 mg in D5W and one liter of only aminophylline 500 mg in D5W served as controls. Samples drawn from the five admixtures and immediately frozen were analyzed for cimetidine and theophylline content at times 0, 1, 6, 24, and 48 hours using high-performance liquid chromatography. Chemical stability of each drug was assessed relative to its time-zero concentration. Samples were also drawn from each test and control solution at every time interval to assess the pH. Admixtures were stored at room temperature out of direct sunlight for the duration of the study, and were visually inspected for color change, turbidity, cloudiness, and precipitation. Recovery of cimetidine and theophylline at all test intervals, pH assessments, and visual inspections of the admixtures showed that cimetidine HCl and aminophylline are both chemically stable and physically compatible for 48 hours at room temperature in one liter of D5W.

The need for a therapeutic drug monitoring service was evaluated in a 150-bed long-term care facility. Thirty blood samples from 28 residents (mean age 87.9 years) were assayed to determine trough drug concentrations. All subjects were examined to determine pharmacodynamic effect. Pharmacokinetic consultations were written for serum drug concentrations outside accepted ranges. Fifty percent (15 of 30) of serum drug levels measured were subtherapeutic; the remaining levels were in the normal therapeutic range. Based on this sample data, it could be concluded that a minimum of 32 percent and as many as 68 percent of serum drug levels would be subtherapeutic following drug analysis in similar nursing home populations. Of 12 consultations, recommendations for seven (58 percent) were accepted by the subject's primary care physicians. Four of the consultations (33 percent) resulted in dosage modifications. These results support the need for further study.

A study was done to determine perceived importance of medication information and the kind of information provided to patients in an outpatient setting. A scale describing 14 points of medication information was used prior to the physician's visit in one study phase and afterwards in the second phase. Results showed that patients perceived all 14 items to be important but rated precautions to observe, drug interactions, and adverse effects most highly. Also, less than half the time was information considered highly important by patients provided by their physicians.

Disparity exists in published recommendations for monitoring of vancomycin serum concentrations. To evaluate the degree of disparity of practice in Illinois, directors of pathology of 202 Illinois hospitals were surveyed to assess their vancomycin monitoring practices. Of the 202 surveys mailed, 82 were returned for a response rate of 41 percent. Most hospitals have 200–500 beds (60 percent) and are nonteaching institutions (72 percent). Two thirds of the hospitals sent vancomycin to an outside laboratory for analysis. Timing of postinfusion (peak) concentrations ranged from 0 minutes following end of infusion to 360 minutes. Approximately one half of the institutions reported a peak therapeutic range of 30–40 mg/L at 30 minutes following end of infusion. A great majority of institutions were consistent in recommended trough range, with 48 of 55 reporting 5–10 mg/L. Although there is some consistency among at least half of the hospitals, there is a great deal of variability among the other half in peak monitoring guidelines.

The publication of scientific research in medical journals is a lengthy process. Submitted manuscripts are often reviewed by two or more outside reviewers who evaluate each manuscript for publication acceptability. The process of manuscript evaluation by an editor-selected reviewer (“peers” or “referees”) is termed “peer review.” One issue involving the peer-review process is the use of blind versus nonblind referees. The purpose of this survey was to determine the percentage of a select group of medicine-related journals that blind their reviewers. We surveyed 114 English language journals. Journal editors were sent a survey that asked two questions: (1) are the referees who review your manuscripts blinded to the identity of the authors? and (2) is the editor blinded to the identity of the authors until after the review of the manuscripts is complete? Ninety-six of 114 (84.2 percent) surveys were returned. Ten journals published invited manuscripts only and were excluded from the survey. Only 18.6 percent (16 of 86) of the journals currently blind referees. None of the journals' editors were blind to the identity of the manuscripts' authors.

Carbocysteine is prescribed for conditions characterized by the accumulation of excessive mucus. Although often described as a mucolytic, its function is probably that of mucoregulation, which results in physical changes in accumulated secretions that are favorable in terms of clearance. The chemistry, pharmacology, pharmacokinetics, clinical applications, and toxicology of carbocysteine are reviewed.

The standard gentamicin dosing recommendations for neonates appear to be inappropriate because they fail to consider the influence of neonatal development on gentamicin pharmacokinetics. Recent reports have emphasized that the standard regimens of 2.5 mg/kg q8–12h produce steady-state trough serum concentrations > 2 μg/ml in up to 91 percent of preterm infants of less than 35 weeks' gestation. A new dosing schedule based on postconceptional age (PCA) was developed to provide a better guideline for initiating and maintaining gentamicin therapy in neonates: PCA greater than 34 weeks, 2.5 mg/kg iv q12h; PCA 28–34 weeks, 2.5 mg/kg iv q16h; PCA less than 28 weeks, 2.5 mg/kg iv q24h. The new dosing schedule reduced the number of neonates with elevated trough concentrations (>2 μg/ml) from 68.4 percent to 33–40 percent. Pharmacokinetic parameters for gentamicin in the various PCA groups were determined. Volume of distribution was constant across age groups (0.5 ± 0.09 L/kg). Elimination rate constants (k_el), half-lives, and clearance rates (Cl) ranged from 0.069 ± 0.02 to 0.14 ± 0.04h⁻¹, 10.71 ± 2.92 to 6.04 ± 1.24 h, and 0.58 ± 0.25 to 0.93 ± 0.24 ml/kg/min, respectively. Significant relationships were found between k_el and Cl and patient age and weight; significant correlations were found between actual and estimated (based on PCA and weight) k_el and Cl. Variability in k_el and Cl estimated was considerable in spite of the correlations. The observed variability stresses again the need for pharmacokinetic monitoring of gentamicin therapy in neonates.

Calcium-channel blocking agents can relieve anginal and chest pain associated with hypermotility of the esophagus. Although calcium-channel antagonists differ in their effects on the esophageal body and the lower esophageal sphincter, reduction of lower esophageal sphincter pressure theoretically could result in gastroesophageal reflux and pain. This pain may be difficult to differentiate from chest pain of cardiac origin. An association between calcium-channel blocking agents and chest pain is speculative at this time. However, the possibility of such an effect should be considered by clinicians in the total management of patients. Future clinical studies are warranted to address the issue of the incidence of such an effect and to define more precisely the potential interrelationship among the calcium-channel antagonists, their efficacy in relieving cardiac pain, and their potential liability in inducing chest pain of noncardiac origin.

A retrospective review of 114 patient charts was conducted at three geographically different hospitals to compare the costs of ceftazidime (CTZ) with the combination of tobramycin and ticarcillin (T/T) in the treatment of hospital-acquired pneumonias and/or septicemias. Variables analyzed to determine the cost of the therapy included duration of treatment, dosage and number of doses administered, side effects, and laboratory tests. Time and motion studies were also performed and the results included in the algorithm. In two of the three hospitals, the computer-calculated cost of CTZ therapy was significantly less than for T/T therapy ($1194 vs. $1668 and $493 vs. $629). In the third hospital there was no significant difference in the costs of the two treatments ($1079 for CTZ vs. $1066 for T/T). The cost of each regimen per patient day followed a similar pattern, with CTZ therapy being significantly less expensive in the same two hospitals. Patients receiving CTZ therapy realized an average cost savings of $29.70 per day at the three institutions. These savings appeared to be due to a reduction in laboratory and administration costs resulting from the decreased frequency of CTZ administration. We conclude that CTZ therapy was less costly than T/T therapy at three geographically different institutions when the cost of supplies, laboratory tests, and personnel time were taken into account.