Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure.

Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50 (bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r = 0.964; p less than 0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.

Docetaxel: a taxoid for the treatment of metastatic breast cancer.

The pharmacology, pharmacokinetics, clinical trials, adverse effects, and dosage and administration of docetaxel are reviewed. Docetaxel, a taxoid for the treatment of metastatic breast cancer, blocks the ability of tumor cells to divide in the M phase of the cell cycle. The drug has demonstrated superior cytotoxic activity in the treatment of a variety of cancers and enhanced activity in combination with other drugs. The pharmacokinetics of docetaxel appear to be linear. There seems to be a large interpatient variation in docetaxel biotransformation rates. Docetaxel has FDA-approved labeling for use in the treatment of patients with locally advanced or metastatic breast cancer whose disease has progressed during anthracycline-based therapy or who have relapsed during anthracycline-based adjuvant therapy. Phase II trials established the drug's role in first-line and second-line treatment of advanced breast cancer and as therapy for anthracycline-resistant advanced breast cancer, and they suggested a role for the agent in combination chemotherapy. The dose-limiting toxicity in all studies has been neutropenia. Other commonly noted adverse effects include mucositis, hypersensitivity reactions, and neuropathy. The recommended dosage for patients with metastatic or locally advanced breast cancer and normal hepatic function is 60-100 mg/m2 i.v. infused over one hour every three weeks. Docetaxel is not recommended for patients with liver metastases or impaired liver function because clearance of the drug is impaired. Docetaxel is effective in the treatment of metastatic and anthracycline-resistant breast cancer and may have a role in combination with other agents and in neoadjuvant and adjuvant therapy.

Pathophysiology and treatment of Wilson's disease.

The pathophysiology, symptomatology, and treatment of Wilson's disease are reviewed, and new approaches to drug management are discussed. Wilson's disease is a rare, autosomal recessive disorder that occurs between the ages of 6 and 60 years. Disturbances in copper metabolism may result in the accumulation of excess copper in the liver, the basal ganglia of the brain (lenticular degeneration), the kidneys, the cornea (Kayser-Fleischer rings), and other tissues. The diagnosis of Wilson's disease is frequently overlooked; nonspecific symptoms and multisystem involvement may mimic other disease states, such as neurologic and psychiatric disorders, and hemolytic anemia. Screening tests for Wilson's disease include 24-hour urinary copper levels, serum ceruloplasmin and copper assays, radioactive uptake of 64Cu, and liver biopsy. Current methods of therapy include the use of a chelating agent--penicillamine or trientine--for initial rapid decoppering. Penicillamine therapy has been associated with many adverse reactions, including worsening of the neurologic symptoms of the patient. Zinc is a useful agent for maintenance therapy. Investigational studies exploring the use of ammonium tetrathiomolybdate for initial rapid decoppering have shown promising results. Unless it is recognized and treated, Wilson's disease can cause severe symptoms and, ultimately, death. Initial rapid decoppering with chelating agents, such as penicillamine and trientine, followed by lifelong maintenance therapy with zinc is the current method of treatment.

Ondansetron--the first of a new class of antiemetic agents.

The chemistry, pharmacokinetics, adverse effects, stability, compatibility, and dosage of ondansetron hydrochloride are described, and clinical studies of the use of ondansetron for the prophylaxis of nausea and vomiting induced by antineoplastic therapy are reviewed. Ondansetron hydrochloride is a specific antagonist of serotonin type 3 (5-HT3) receptors, both in the chemoreceptor trigger zone and in the GI tract. Peak plasma concentrations of ondansetron occur approximately one hour after an oral dose and 6 to 20 minutes after an i.v. dose. The mean elimination half-life is approximately 3.5 hours in healthy volunteers, but it is extended in elderly patients (mean of 7.9 hours). In clinical trials, ondansetron has been shown to provide excellent control of nausea and vomiting in patients treated with cisplatin. Comparisons of ondansetron with metoclopramide in patients treated with various types of chemotherapy have shown better response rates with ondansetron. Ondansetron has also been shown to be effective in controlling nausea and vomiting in patients receiving cyclophosphamide with an anthracycline and in patients receiving combination therapy with cyclophosphamide, methotrexate, and fluorouracil. Adverse effects appear to be mild and include headache, constipation, diarrhea and transient abnormalities in liver function tests. The dose of ondansetron (as the hydrochloride salt) for the prophylaxis of chemotherapy-induced nausea and vomiting in adults is 0.15 mg/kg i.v. every four hours for three doses, beginning 30 minutes before antineoplastic therapy. The efficacy of ondansetron is comparable to that of metoclopramide, and the adverse-effect profile is much less problematic. The cost of ondansetron is much higher than that of metoclopramide; thus its use should be limited to patients at high risk for metoclopramide-induced adverse effects and patients in whom metoclopramide is ineffective.

Corticosteroids in the management of alcoholic hepatitis.

The pathophysiology of alcoholic hepatitis and the use of corticosteroids in the management of alcoholic hepatitis are described. Alcoholic hepatitis is a chronic, progressive, often fatal disease. Symptoms may be absent or may range from mild to severe, with little correlation between clinical and histologic findings. A definitive diagnosis can be made only through histologic examination of the liver. Biochemical liver tests may help in diagnosing or staging alcoholic hepatitis. Prognosis depends on the extent of underlying liver disease, the presence of other complications of liver disease, concomitant disease states, and abstinence from use of alcohol. Therapy has traditionally consisted of supportive care. Corticosteroids have been widely studied in the management of alcoholic hepatitis, but lack of consistency in time to treatment, proportion of female subjects, and disease severity make it difficult to draw conclusions from these studies. Data suggest that corticosteroid therapy may reduce short-term mortality among patients with alcoholic hepatitis who also have hepatic encephalopathy. This beneficial effect depends on the absence of gastrointestinal bleeding. Corticosteroid therapy may be warranted in patients with alcoholic hepatitis with encephalopathy but no gastro-intestinal bleeding. Further trials are needed to assess the long-term benefit of corticosteroids and to determine the optimum dosage.

Pimozide: use in Tourette's syndrome.

The orphan drug pimozide was recently approved for marketing in the U.S. for the treatment of Tourette's syndrome (TS). TS is characterized by recurrent, involuntary motor movements and vocal tics, and is believed to be due to neurochemical dysfunction. Pimozide's receptor selectivity differs from that of haloperidol, the standard agent used for TS. Clinical trials with pimozide demonstrate a positive response for many patients, although superiority over haloperidol has not been demonstrated in general. Pimozide causes annoying side effects in a large percentage of patients and may cause severe side effects (e.g., tardive dyskinesia, cardiovascular toxicity) with prolonged use and/or at higher doses. The long half-life of pimozide allows for once-daily dosing. Pimozide should be reserved for treatment of patients with TS who have not responded to haloperidol or who cannot tolerate haloperidol's adverse effects.

Comparison of famotidine with cimetidine and ranitidine.

The pharmacodynamic, therapeutic, and toxicologic properties of famotidine are evaluated and compared with those of cimetidine and ranitidine. Famotidine, an H2-receptor antagonist with a thiazole nucleus, is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers. A single nocturnal dose of 20 mg is effective in preventing duodenal ulcer relapse. Further studies are required that compare the efficacy of famotidine with cimetidine and ranitidine in the treatment of gastric ulcers and in the prevention of recurrent duodenal ulcers. The overall incidence of adverse effects observed with famotidine appears to be similar to that reported for cimetidine and ranitidine. Like ranitidine, famotidine does not have antiandrogenic effects or substantially inhibit the hepatic metabolism of drugs. Because of its increased antisecretory potency and lack of antiandrogenic effects at higher doses, famotidine may be the H2-receptor antagonist of choice in treating Zollinger-Ellison syndrome. Additional clinical experience, as well as cost and safety factors, will determine the place of famotidine in treating and preventing acid-peptic disorders.

Development and funding of a pharmacy-based investigational drug service.

The development, implementation, and operation of a pharmacy-based investigational drug service (IDS) at a university medical center are described. Before the IDS was established, pharmacy participation in investigational drug research was limited to the preparation of novel dosage forms. Medication errors, improper storage and labeling, and inadequate inventories of investigational drugs were common problems. Stepped-up enforcement by FDA and the National Cancer Institute (NCI) of guidelines for investigational drug control prompted the formation of a multidisciplinary task force, which recommended that the department of pharmaceutical services expand its support of investigational drug studies to include inventory control, record keeping, and clinical services. The IDS is supported by both the hospital and the school of medicine and currently receives 36% of its funding from principal investigator grants and contracts. The IDS coordinates more than 100 study protocols and dispenses more than 4000 doses of investigational drugs annually. The IDS is staffed by 1.0 full-time equivalent (FTE) clinical pharmacist and 0.5 FTE technician. Inventory control and billing functions are performed by a departmental microcomputer system. The IDS has demonstrated a positive gross margin for each of its first two years of operation. Problems associated with the control and use of investigational drugs at this institution have been successfully corrected by the implementation of a pharmacy-based IDS.

Quality assurance program for a hospital investigational-drug service.

The development and implementation of a quality-assurance (QA) program for a pharmacy-based investigational-drug service are described. The objective of the QA program was to assess the quality of the activities in the areas of drug acquisition, inventory control, availability of drug data sheets and dispensing guidelines, provision of a quarterly drug accountability report, and documentation of drug dispensing to patients and decentralized pharmacy areas. The audit criteria were based on hospital policies and procedures and federal regulations for the handling of investigational drugs. Audits of four randomly selected protocols are conducted quarterly by a pharmacist who is not affiliated with the investigational drug service. The results of the first two audits have identified several areas for improvement, including the need for additional pharmacy staff education regarding study protocols, the importance of maintaining complete and accurate drug accountability records by decentralized pharmacists, and the need to provide a centralized source of study protocol information. The QA program has enabled the investigational-drug service to establish and enforce the policies and procedures for the appropriate handling of investigational drugs in this institution.

Investigational drug practices in Michigan hospitals.

All 188 acute-care hospitals in Michigan with licensed pharmacies were surveyed to assess compliance with recommendations of ASHP, FDA, and the Joint Commission on Accreditation of Healthcare Organizations related to investigational drug use; other practice issues related to investigational drugs but not covered in those guidelines were also studied. Pharmacy directors were questioned about their practices for approving, prescribing, procuring, storing, and labeling investigational drugs; preparation, content, and use of investigational drug data sheets; record keeping; personnel issues; and other investigational drug services provided by the pharmacy department. The response rate was 84.5% (159 completed questionnaires returned), but only 44 respondents (27.7%) indicated that investigational drugs were currently used in their institutions. Written investigational drug policies and procedures were available in 116 (73.0%) of the responding pharmacy departments. Respondents currently handling investigational drugs had high rates of adherence for the following practice guidelines: preparation of data sheets (75.0%), storage (97.7%), monitoring of investigational drug use and stock levels (79.5%), and maintaining perpetual inventories (79.5%). Areas with relatively poor adherence rates included pharmacy department preparation of investigational drug patient-information sheets (20.5%), maintaining information within the pharmacy on minimum stock levels (53.9%), mode of shipment (30.8%), time to receive investigational drugs after order placed (38.5%), acceptance of nursing transcriptions of oral orders (56.8%), including "investigational drug" on the dispensing label (55.8%), and approval of data sheets by the investigator and the institutional review board (40.5% and 37.8%, respectively). Pharmacy departments, regardless of hospital size, should improve their adherence to ASHP, FDA, and Joint Commission guidelines for handling investigational drugs.

A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea.

The disruption of the natural flora of the gastrointestinal tract (especially Lactobacillus acidophilus) may occur during antibiotic therapy. This may lead to diarrhea, dehydration, and electrolyte imbalances. It has been suggested that replacement of the lactobacilli with a commercially available product may prevent the diarrhea. The efficacy and safety of prophylactically administered Lactinex (culture of L. acidophilus and L. bulgaricus) was compared with placebo for the prevention of amoxicillin-induced diarrhea in pediatric patients. Lactinex or placebo was administered four times a day for ten days to coincide with the antibiotic therapy. The Lactobacillus preparation did not appear to consistently prevent diarrhea in this patient population. Patients' age, diet, and parental definition of diarrhea were factors that may have influenced the results.