Annals of Pharmacotherapy

To determine the relationship of inappropriate prescribing in the elderly to health outcomes.

General Medical Clinic of the Durham Veterans Affairs Medical Center.

A total of 208 veterans more than 65 years old who were each taking five or more drugs and participated in a pharmacist intervention trial.

Prescribing appropriateness was assessed by a clinical pharmacist using the medication appropriateness index (MAI). A summed MAI score was calculated, with higher scores indicating less appropriate prescribing. The health outcomes were hospitalization, unscheduled ambulatory or emergency care visits, and blood pressure control.

Bivariate analyses revealed that mean MAI scores at baseline were higher for those with hospital admissions (18.9 vs. 16.9, p = 0.07) and unscheduled ambulatory or emergency care visits (18.8 vs. 16.3, p = 0.05) over the subsequent 12 months than for those without admissions and emergency care visits. MAI scores for antihypertensive medications were higher for patients with inadequate blood pressure control (> 160/90 mm Hg) than for those whose blood pressure was controlled (4.7 vs. 3.1, p = 0.02).

Inappropriate prescribing appeared to be associated with adverse health outcomes. This finding needs to be confirmed in future studies that have larger samples and control for potential confounders.

To test the reliability of drug utilization evaluation (DUE) applied to medications commonly used by the ambulatory elderly.

A DUE model was developed for four domains: (1) justification for use, (2) critical process indicators, (3) complications, and (4) clinical outcomes. DUE criteria specific to use in the elderly were developed for angiotensin-converting enzyme (ACE) inhibitors and histamine₂ (H₂)-antagonists, and consensus was reached by an external expert panel. After pilot testing, two clinical pharmacists independently evaluated these medications, applying the DUE criteria and rating each item as appropriate or inappropriate. Interrater and intrarater reliability was assessed by using κ statistics.

In a sample of 208 ambulatory elderly veterans, 42 (20.2%) were taking an ACE inhibitor and 56 (26.9%) an H₂-antagonist. The interrater agreement for individual domains, represented by κ statistics, were 0.10–0.58 and 0–0.83 for ACE inhibitors and H₂-antagonists, respectively. The κ statistic for overall agreement, which considered ratings from all criteria across all domains, was 0.24 for ACE inhibitors and 0.18 for H₂-antagonists. Intrarater reliability was assessed 3 months later, and κ statistics were 0.61–0.65 (0.49 overall) and 0–0.96 (0.81 overall) for ACE inhibitors and H₂-antagonists, respectively.

Intrarater reliability for DUE was good to excellent. However, interrater reliability exhibited only marginal reproducibility, particularly where evaluators were required to use subjective judgment (i.e., complications, clinical outcomes). DUE may not be a suitable standard for assessing medication appropriateness in ambulatory elderly patients.

To evaluate the reliability of a medication appropriateness index (MAI) modified for elderly outpatients in a non-Veterans Affairs setting.

Reliability study.

General community.

Ten community-dwelling elderly (> 65 y) taking five or more regularly scheduled medications and participating in a university-based health service intervention study.

Interrater reliability of MAI ratings of 65 medications made by two clinical pharmacists for individual items and for an overall summed score was calculated by use of κ statistics and intraclass correlation coefficient.

The interrater agreement for each of the individual MAI items was high for both appropriate and inappropriate ratings and ranged from 80% to 100% (overall κ = 0.64). Overall agreement for the summed score was good (intraclass correlation = 0.80).

The modified MAI is a reliable instrument for evaluation of medication appropriateness in a non-Veterans Affairs, ambulatory, elderly population and may provide pharmacists with a practical and standard method to evaluate patients' drug regimens and identify some potential drug-related problems.

To compare the bioavailability of three generic brands of carbamazepine tablets with that of a proprietary brand in adult patients with epilepsy.

A double-blind, randomized, three-phase crossover study.

A psychiatric facility.

Eighteen patients with epilepsy who had taken carbamazepine at least 5 months before entering the study.

Ten blood specimens from each patient were collected at steady-state. Plasma concentration of carbamazepine was analyzed for pharmacokinetic parameters such as maximum plasma concentration (C_max), mean time to reach maximum concentration (t_max), and mean AUC.

There were no statistically significant differences in these parameters among four brands of carbamazepine. However, when comparing the 90% CI of AUC of three generic brands with that of the proprietary brand, the AUC of two generic brands lay within a range of 80% to 120%. The effects of gender and each brand of carbamazepine on these pharmacokinetic parameters were also analyzed. Breakthrough seizures occurred even though the plasma concentration of carbamazepine was therapeutic.

The bioavailability of two generic brands of carbamazepine tablets (Carmapine and Carzepine) and the proprietary brand (Tegretol) were equivalent in this sample of adult patients with epilepsy.

To determine the stability of fosphenytoin sodium admixtures with NaCl 0.9% injection and dextrose 5% (D5W) injection when stored in glass or polyvinyl chloride (PVC) containers, to evaluate the compatibility of fosphenytoin with 11 other intravenous solutions, and to determine the stability of fosphenytoin repackaged in polypropylene syringes.

Dilutions of fosphenytoin sodium 1, 8, and 20 mg phenytoin sodium equivalents (PE)/mL were prepared in NaCl 0.9%, D5W, and 11 other intravenous fluids. Aliquots of each solution in NaCL 0.9% or D5W were transferred to three glass bottles for storage at 25 °C and 21 PVC bags for storage at 25, 4, or −20 °C Aliquots of each admixture with the other intravenous fluids were transferred to three PVC bags and stored at 25 °C for 7 days. In addition, 63 syringes were filled with fosphenytoin sodium 50 mg PE/mL (undiluted) and stored at 25, 4, or −20 °C. Samples of each solution from the three containers were analyzed for visual compatibility, pH, and fosphenytoin concentration initially and at 0.5, 1, 2, 3, 7, 14, and 30 days during storage at 25 and 4 °C and at 1, 7, 14, and 30 days during storage at–20 °C. Following removal of containers from the freezer, additional samples were obtained after 7 days at 4 or 25 °C, and 7 days at 25 °C, and then 7 days at −20 °C.

No visible precipitation or change in color or clarity was observed in any of the fosphenytoin solutions during the study. The concentration of fosphenytoin at each sampling time remained within 97–104% of initial concentration, regardless of container, concentration, intravenous admixture, or storage temperature.

Fosphenytoin sodium, either undiluted in polypropylene syringes or diluted with NaCl 0.9% or D5W in PVC bags, remains stable for at least 30 days at room temperature, under refrigeration, or frozen. After removal from the freezer, fosphenytoin can be thawed, kept at 4 or 25 °C for 7 days, and then returned to the freezer for another 7 days. Admixtures of fosphenytoin sodium in various other intravenous fluids are stable for at least 7 days at room temperature.

To evaluate the ability of a novel topical antimicrobial gel containing cetrimide, bacitracin, and polymyxin B sulfate to prevent infections of minor wounds.

A clinical trial compared the test preparation with placebo and a povidone iodine antiseptic cream.

Five primary schools in Sydney, Australia, participated in the study over a 6-week spring/summer school term.

Children aged 5–12 years with parental consent were eligible for study participation. Accidental injuries occurring at school were treated in a standardized manner by nurses at each site.

Wounds were evaluated by the medical practitioner after 3 days of topical treatment. The clinical outcome was classified as resolution or suspected infection. If a clinical infection was suspected, the injury was swabbed for microbiologic evaluation. Growth of a dominant microorganism was classified as a microbiologic infection.

Of the 177 injuries treated, there were nine clinical infections. A comparison of these showed a significant difference among treatment groups (p < 0.05). This difference was associated with the test preparation and placebo; the test preparation reduced the incidence of clinical infection from 12.5% to 1.6% (p < 0.05; 95% CI, 0.011 to 0.207). A comparison of microbiologic infections showed no significant differences among treatment groups (p > 0.05).

The novel gel preparation containing cetrimide, bacitracin, and polymyxin B sulfate showed therapeutic action and reduced the incidence of clinical infections in minor accidental wounds. It may be a suitable product for first aid prophylaxis.

To describe the effect of introducing a route conversion program on the prescribing of antimicrobials for the treatment of respiratory tract infections and skin/soft tissue infections in a sample population.

Concurrent, pre- and postintervention study.

Four general internal medicine wards at The Toronto Hospital, a 1170-bed, tertiary care health center in Toronto, Ontario, Canada.

Patients receiving antimicrobial therapy for respiratory tract infections and skin/soft tissue infections.

Written guidelines and education sessions were presented to residents, interns, medical students, and pharmacists responsible for the care of patients admitted to four general internal medicine wards.

Clinical and laboratory parameters related to the status of the infection were monitored prospectively and compared with the course of drug therapy, with consideration of the patient's ability to meet the criteria established in the guidelines. The number of days of intravenous therapy prescribed despite appropriateness of oral therapy was tallied.

Twenty-seven patients (28 infections) were identified for inclusion in the 7-week preliminary audit, and 30 patients (32 infections) were included in the audit after the program, which continued for 5 weeks. Following implementation of the program, the number of days that intravenous therapy was continued despite the appropriateness of oral therapy was reduced from 41% to 26% of the total days of intravenous therapy prescribed.

The program had a positive influence on antimicrobial prescribing behavior in the population studied. Strategies to ensure continued benefit from the program have been developed.

To examine the possible drug interaction between nifedipine and tacrolimus in liver transplant recipients.

A retrospective study was done comparing two groups of liver transplant recipients. The starting time for comparison was the same after transplant. One group (n = 22) consisted of hypertensive patients who were treated with nifedipine; the other group (n = 28) did not receive nifedipine. The two groups were compared over 1 year. The effect of nifedipine on tacrolimus was measured in terms of tacrolimus whole blood trough concentrations, daily tacrolimus dosages, and cumulative tacrolimus dosages at 1, 3, 6, and 12 months. All patient charts were reviewed with regard to concurrent medication that could affect the metabolism of tacrolimus and eventually affect tacrolimus concentrations and dosages.

All required information was retrieved from medical records.

There was a statistically significant difference between daily dosage requirements of tacrolimus at 90 (p = 0.03), 180 (p = 0.004), and 365 (p = 0.0004) days between the nifedipine and no-nifedipine groups. The tacrolimus daily dosage in the nifedipine group was decreased by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage of the no-nifedipine group. Statistically significant differences in cumulative dosages of tacrolimus were observed at 180 (p = 0.02) and 365 (p = 0.003) days between the nifedipine and no-nifedipine groups, with cumulative dosage reduction of 25% and 31% by 6 and 12 months, respectively, in the nifedipine group compared with the no-nifedipine group.

Nifedipine decreased the daily and cumulative dosage requirement of tacrolimus. The interaction observed between nifedipine and tacrolimus is the first reported in humans and is clinically important. As a result of this drug interaction, it is recommended that blood concentrations of tacrolimus be monitored during coadministration of these drugs and that the tacrolimus dosage be adjusted accordingly.

To describe a case of a drug interaction between cyclosporine and quinupristin/dalfopristin (QND).

A patient who had undergone a kidney transplant and was receiving chronic cyclosporine therapy was treated with the investigational streptogramin antibiotic QND. Baseline trough cyclosporine concentrations ranged from 80 to 105 ng/mL. Two and 3 days after initiation of QND therapy, trough cyclosporine concentrations increased to 261 and 291 ng/mL, respectively. Following discontinuation of QND, the cyclosporine blood concentration decreased and the dosage was subsequently increased to the previous regimen.

A patient's cyclosporine blood concentration tripled 3 days after initiating therapy with QND. A one-third reduction in the cyclosporine dosage was required. QND was the most likely cause for the change in cyclosporine blood concentrations, probably due to inhibition of cyclosporine metabolism. This represents the first published case of an interaction between cyclosporine and QND.

Frequent monitoring of cyclosporine concentrations with attention to the need for dosage modification is recommended when initiating or discontinuing QND therapy.

To describe the effects of treatment with the selective serotonin reuptake inhibitor fluvoxamine on three patients with advanced dementia who developed a stereotypic movement disorder.

Three patients in a skilled nursing facility were referred by their primary physicians for psychiatric consultation to assist with the management of stereotypic behaviors. The patients received a standard medical, neurologic, and psychiatric workup for dementia. Two of the patients were diagnosed with dementia of the Alzheimer type and the other patient was diagnosed with vascular dementia. All three patients were started on fluvoxamine 25 mg/d; behaviors were monitored daily by the nursing staff and their primary care physicians and weekly by their psychiatrist using the Abnormal Involuntary Movement Scales. The dosage was titrated upward weekly to a maximum dosage of 150 mg/d.

Two patients showed complete resolution of their stereotypic behaviors by week 6. The third patient showed noticeable improvement with some residual movements after 8 weeks of treatment.

Fluvoxamine appeared effective in the control of stereotypic behaviors in three patients with advanced dementia.

TO report a case of agranulocytosis secondary to spironolactone in a patient with cryptogenic liver disease.

A 58-year-old Hispanic woman with cryptogenic cirrhosis was admitted to University Hospital on October 31, 1995. Laboratory data revealed a leukocyte count of 1.0 × 10³/mm³ and an absolute neutrophil count (ANC) of 10 cells/mm³. Prior to treatment with spironolactone, the leukocyte count was 10.2 × 10³/mm³ and ANC 8400 cells/mm³. Agranulocytosis resolved 5 days following the discontinuation of spironolactone. Results from the bone marrow biopsies before and after treatment with spironolactone suggested that agranulocytosis was caused by the drug's toxic effect on the bone marrow.

Drug-induced agranulocytosis is a serious adverse effect, occurring at a rate of approximately 6.2 cases per million persons each year. In addition to the case reported here, three other reports of agranulocytosis secondary to spironolactone have been published in the literature. Several factors have been identified that may increase a patient's risk for developing agranulocytosis, including increased age, hepatic or renal impairment, drag dosage and duration, and concurrent medications.

Agranulocytosis secondary to spironolactone is a serious potential adverse effect. Patients with risk factors for developing this adverse effect should be closely monitored since early detection and discontinuation of spironolactone can improve prognosis.

TO report two cases of seizures associated with the use of muromonab-CD3.

TWO uremic cadaveric kidney transplant recipients had developed generalized seizures following administration of muromonab-CD3 within the first 2 days after transplantation. Seizures were treated successfully with intravenous phenytoin, and muromonab-CD3 administration was discontinued.

The overall frequency of seizures during muromonab-CD3 administration is 6%. Uremia in patients in the early posttransplant period appears to predispose them to seizures. Seizures that happened to our two uremic patients after transplant suggest that they had been induced by muromonab-CD3 administration. The mechanism of how this could have induced seizures is unknown.

Prophylactic muromonab-CD3 should be used carefully in uremic kidney transplant recipients following surgery. If therapy with muromonab-CD3 is necessary, early hemodialysis should be considered in an effort to lower the risk of seizures.

TO report a case of erythromelalgia in an adolescent patient successfully treated with nitroprusside.

A 15-year-old girl with erythromelalgia resistant to aspirin therapy received an infusion of nitroprusside. The response of the erythromelalgia to nitroprusside was dramatic, with complete pain resolution within 17 hours after the start of therapy. No relapse of erythromelalgia was seen when nitroprusside was discontinued and the patient remained well after 6 months.

This case adds to existing literature substantiating the benefit of nitroprusside for the treatment of erythromelalgia in pediatric patients. Erythromelalgia in children may represent a different disease entity than that seen in adults, which is commonly responsive to aspirin therapy. The pathogenesis of erythromelalgia is unclear and precludes formulating a proposed mechanism by which nitroprusside has benefit in children.

Nitroprusside is valuable for erythromelalgia resistant to aspirin therapy in pediatric patients. Because of unanswered questions regarding the disease, aspirin remains the agent of first choice in all patients with this rare disease.

TO describe a patient with asymptomatic bronchial asthma and hypertension who developed an acute asthma attack after receiving sustained-release verapamil.

A 66-year-old white woman with a 10-year history of hypertension and bronchial asthma was switched from immediate-release verapamil hydrocloride 40 mg tid to sustained-release verapamil 240 mg/d po for better hypertension control. After taking the first tablet, she developed dyspnea, cough, and wheezing. Antiasthmatic medications were prescribed, but the asthma symptoms did not improve. She continued taking verapamil for 6 months, then, on her own, stopped all medications including the sustained-release verapamil, and her asthma symptoms disappeared. On rechallenge she developed severe dyspnea, cough, and wheezing 20 minutes after administration. The asthma resolved within 24 hours following three albuterol inhalations. The next day similar symptoms developed with rechallenge of the same brand of sustained-release verapamil in a 120-mg formulation, and verapamil was discontinued. Six months later she was again prescribed sustained-release verapamil 240 mg in another clinic where the physician was unaware of her previous reaction. Once again, severe dyspnea, cough, and wheezing developed.

On four separate occasions the patient was challenged, advertently or inadvertently, with sustained-release verapamil. Similar symptoms developed after each challenge and resolved after discontinuing this preparation. Although dyspnea associated with verapamil administration has been reported, this is the first report of an elderly asymptomatic asthmatic patient with hypertension who developed an acute asthma attack following sustained-release verapamil administration.

Sustained-release verapamil is thought to be the cause of the asthma attack in this patient because she was not taking any other preparations; the symptoms started with the administration of sustained-release verapamil and were relieved after its discontinuation.

TO estimate the cost-effectiveness of thrombolytic therapy versus no thrombolytic therapy for patients following acute myocardial infarction, focusing on the impact of time to treatment on outcome.

A decision model was developed to assess the benefits, risks, and costs associated with thrombolytic therapy for treatment of acute myocardial infarction compared with standard nonthrombolytic therapy. The model used pooled data from a recent study of nine large randomized, controlled clinical trials and 12-month outcome data from a recently published meta-analysis of thrombolytic therapy trial data. Outcomes were expressed in terms of survival to hospital discharge and survival to 1 year after discharge. The risks of treatment that led to death, morbidity, or added costs were estimated. The model determined excess and marginal costs per death averted to hospital discharge and at 1 year. Results were also estimated in terms of cost per year of life saved. Sensitivity analyses included variations in time to treatment and drug cost.

The marginal cost of thrombolytic therapy per death averted at 1 year was $222 344, or $14 438 per year of life saved. For patients treated within 6 hours of acute myocardial infarction, the marginal cost per death averted was $181 536 at 1 year, or $11 788 per year of life saved.

Thrombolytic therapy is significantly more cost-effective than many other cardiovascular interventions and compares favorably with other forms of medical therapy. Results suggest that shortening the time to treatment has a critical impact on the cost-effectiveness of thrombolytic therapy.

TO provide primary and referring healthcare practitioners with guidelines for the provision of safe and effective anticoagulation management in any venue to standardize and improve quality of care and to permit negotiation for reimbursement from third-party payers.

Data on the current practice of anticoagulation providers and outcomes related to anticoagulation clinic care were obtained through the literature, interviews with anticoagulation providers, and a focus group meeting of anticoagulation clinic stakeholders. This information collation process revealed that an anticoagulation service consists of three separate areas for which guidelines should be developed. Based on the consensus opinions of the committee members, the literature review, and the current practice of anticoagulation services providers, a draft guideline was developed and reviewed by an independent multidisciplinary panel of anticoagulation services providers whose comments were incorporated into the final guideline.

Systematic outpatient anticoagulation services are systems of care designed to coordinate and optimize the delivery of anticoagulation therapy by (1) evaluating patient-specific risks and benefits to determine the appropriateness of therapy; (2) facilitating the management of anticoagulation dosages and prescription pick up or delivery; (3) providing ongoing education of the patient and other caregivers about warfarin and the importance of self-care behavior leading to optimal outcomes; (4) providing continuous systematic monitoring of patients, international normalized ratio results, diet, concomitant drug therapy, and disease states; and (5) communicating with other healthcare practitioners involved in the care of the patient. To create a reproducible framework for the provision of these services, guidelines for structure, process, and outcomes of coordinated outpatient anticoagulation management services were developed. Guidelines for organization and management include (1) qualifications for personnel, (2) supervision, (3) care management and coordination, (4) communication and documentation, and (5) laboratory monitoring. Guidelines for the process of patient care include (6) patient selection and assessment, (7) initiation of therapy, (8) maintenance and management of therapy, (9) patient education, and (10) management and triage of therapy-related and unrelated problems. Guidelines for the evaluation of patient outcomes include (11) organizational components and (12) patient outcomes. The impact of these 12 guidelines on patient care and reimbursement procurement will depend on their implementation and the perceived value of their use.

TO review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, dosage, and administration guidelines for pegaspargase.

A MEDLINE search (1980–1996), a CANCERLIT search (1983–1996), and a CURRENT CONTENTS search (1980–1996) using the terms pegaspargase, PEG-asparaginase, PEG-L-asparaginase, polyethylene glycol L-asparaginase, polyethylene glycol conjugated L-asparaginase, and Oncaspar were conducted.

All articles were considered for possible inclusion in this review. Abstracts were included only when they were judged to add critical information not otherwise available in the medical literature.

L-Asparaginase has been a main component of treatment regimens for acute lymphocytic leukemia. A key limiting factor of L-asparaginase use has been the development of hypersensitivity to the drug. Recently, a polyethylene glycol (PEG) conjugated form of L-asparaginase, pegaspargase, has been made available. PEG modification of L-asparaginase has been shown to alter the tendency of the enzyme to induce an immune response and to extend the half-life of the drug. The majority of patients with hypersensitivity to the native enzyme preparations tolerate pegaspargase without further clinical hypersensitivity. The adverse effect profile of pegaspargase is similar to that of the native forms of L-asparaginase. The recommended dosage of pegaspargase is 2500 IU/m² administered by intramuscular or intravenous injection every 2 weeks in combination with other chemotherapeutic agents.

Pegaspargase is a safe, effective alternative to L-asparaginase in patients who have had clinical hypersensitivity reactions to both Escherichia coli- and Erwinia carotovora-demed L-asparaginase. However, pegaspargase should not be routinely substituted for L-asparaginase.

TO review the literature that compares Zolpidem with triazolam, with an emphasis on efficacy and safety in humans.

Information was retrieved from a MEDLINE search (1983–1996) of the English-language literature using the terms triazolam and zolpidem.

Reports of clinical trials comparing the safety and efficacy of zolpidem and triazolam were included in this review.

Data were evaluated according to study design, efficacy, and adverse effects. Pertinent information was selected and the data synthesized into a review format.

Zolpidem and triazolam have similar pharmacokinetic and pharmacodynamic effects in humans. Clinical trials have shown that usually recommended, equipotent dosages of zolpidem and triazolam do not differ with respect to pharmacokinetics, efficacy, tolerability, residual effects, memory impairment, rebound insomnia, abuse potential, or other adverse effects.

Zolpidem offers no distinct therapeutic advantage over triazolam for the treatment of insomnia.