Annals of Pharmacotherapy

To assess the impact of treatment with zidovudine plus lamivudine or zalcitabine on health-related quality of life (HRQOL) in patients with HIV.

HRQOL assessments were conducted as part of a double-blind, randomized, 24-week (extended to 52 wk) efficacy and safety study. The Medical Outcomes Study HIV Health Survey (MOS-HIV), which assesses 10 physical and psychological domains of HRQOL, was self-administered by patients at baseline and at weeks 16, 32, 52, or at treatment discontinuation.

Twenty-one outpatient centers in the US, Canada, and Puerto Rico.

The study enrolled 254 HIV-positive patients (CD4+ 100–300 cells/mm³); 206 patients completed the MOS-HIV at baseline and at least once during treatment. Post hoc analyses stratified patients into two subgroups: AIDS (CD4+ <200 cells/mm³) and non-AIDS (CD4+ ≥200 cells/mm³).

Patients received zidovudine 200 mg three times daily plus one of the following: lamivudine 150 mg twice daily, lamivudine 300 mg twice daily, or zalcitabine 0.75 mg three times daily.

Change in MOS-HIV scores from baseline to last completed questionnaire.

Following an average of 36 weeks of treatment, there were statistically significant differences across treatment groups in mean change scores on the physical functioning, role functioning, and vitality scales, with stable or increased (improved) scores in the zidovudine plus lamivudine 150 mg group and decreased scores in the zidovudine plus zalcitabine and zidovudine plus lamivudine 300 mg groups for most scales. Post hoc analyses found that in the non-AIDS subgroup, only the zidovudine plus lamivudine 150 mg group had increases in mean MOS-HIV scores (on 8 of 10 scales); in the AIDS subgroup, all but two MOS-HIV scores (in the zidovudine plus zalcitabine group) decreased in all three treatment groups.

These results suggest that, of the three combination therapies studied, zidovudine plus lamivudine 150 mg was most likely to maintain or improve HRQOL in HIV-positive patients.

To evaluate concomitant prescribing of tranquilizers and hypnotics in antidepressant treatment with particular focus on the relationship to drug class in patients prescribed antidepressant treatment for depressive disorders.

Repeated cross-sectional surveys of Swedish physicians in ambulatory care from 1991 to 1996, including specialty practices. The participation rate was 65–70%.

Tranquilizers and hypnotics were prescribed in 36.1% of the visits in which the intention was to treat depression. Concomitant prescribing increased with the patient's age for all antidepressant drug classes. Women received more concomitant prescriptions than men when treated with nonselective monoamine-reuptake inhibitors (NSMRI), mainly tricyclic compounds. Psychiatrists prescribed more concomitant tranquilizers and hypnotics than other physicians, and general practitioners fewer, when treating depression with selective serotonin-reuptake inhibitors (SSRIs), mainly citalopram. A logistic regression model showed that the risk for concomitant prescribing was higher when an NSMRI was prescribed than with other antidepressants.

Concomitant prescribing of tranquilizers and hypnotics was common among antidepressant-treated patients. The most plausible reasons for the high rate of concomitant prescribing were the symptoms of the depression itself and/or the common comorbidity with anxiety disorders seen in this group of patients. The results of this study indicate that the concern about increased tranquilizer and hypnotic use among patients treated with SSRIs suggested in other studies seems to be unfounded in Sweden.

To assess the cost-effectiveness of abciximab therapy versus traditional practice in high-risk patients receiving percutaneous transluminal coronary angioplasty (PTCA) from a Canadian hospital perspective.

A predictive decision analytic model using published clinical and economic evaluations, as well as costs of medical care in Canada.

High-risk PTCA patients as defined by the Evaluation of c7E3 for Prevention of Ischemic Complications trial and the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina trial.

Two treatment strategies were compared: (1) abciximab 0.25 mg/kg intravenous bolus 10 minutes prior to PTCA followed by abciximab 10 4μg/min intravenous infusion for 12 hours after the procedure, and (2) no abciximab adjunctive therapy at the time of PTCA. Both treatment strategies were combined with intravenous heparin up to 100 units/kg bolus pre-PTCA followed by bolus doses for 1 hour after PTCA per the protocol. Cumulative outcomes were considered up to 6 months after initial PTCA.

At 6 months, 29% of the patients in the abciximab treatment arm compared with 33% in the no abciximab arm achieved one of the primary events. The most common adverse event experienced was major bleeding at 4% in the abciximab treatment arm versus 1.6% in the no abciximab arm. The average cost per patient for each strategy was $3261 Can ($1 Can = $0.686 US) (abciximab arm) versus $2073 Can (no abciximab arm), resulting in an incremental cost-effectiveness ratio of $29 700 Can per event-free patient. In univariate sensitivity analyses, the only controllable factor that changed the results of the cost-effectiveness outcome was the cost of abciximab.

Although the use of abciximab as an adjunct to PTCA results in a reduction in event rates in high-risk patients compared with traditional treatment, there is an increased cost associated with this strategy.

To report a possible case of leukocytoclastic vasculitis associated with clarithromycin therapy.

An 83-year-old white woman was prescribed clarithromycin for pneumonia. Six days after her initial presentation, she developed lesions on her palms. Clarithromycin was discontinued at that time. The following day she developed purpuric eccymotic nonblanching lesions that primarily appeared on the lower extremities, buttocks, and abdomen. Colonoscopy revealed generalized erythema and edema of the bowel mucosa. Gastroscopy revealed duodenitis and gastritis, but no bleeding or ulceration. Skin biopsy of the lesions was compatible with leukocytoclastic vasculitis. Renal function was not affected, although hematuria was noted. All symptoms resolved after drug withdrawal and a short course of corticosteroids.

Searches were performed on MEDLINE, Embase, International Pharmaceutical Abstracts, and major adverse drug reaction databases to identify reports and articles discussing clarithromycin- and macrolide-induced leukocytoclastic vasculitis.

Leukocytoclastic vasculitis is one category of drug hypersensitivity reactions characterized by distinctive patterns of perivascular inflammation. The case described here is consistent with the diagnosis of leukocytoclastic vasculitis, and is similar to the other single published case report associated with clarithromycin.

Leukocytoclastic vasculitis induced by clarithromycin is a rare but serious potential adverse effect.

To describe the occurrence of extravasation in two patients receiving low-dose dopamine infusions.

Intravenous dopamine was infused peripherally (in the antecubital fossa) to two patients in the cardiac intensive care unit in an attempt to enhance renal blood perfusion and urine output. Dopamine extravasation occurred in both patients while the low dose (<3 μg/kg/min) was infused. Significant local tissue injury was observed in both patients.

Dopamine infusion can cause tissue ischemia or necrosis secondary to vasospasm and extravasation. Most of the case reports in the literature have occurred when relatively high doses of dopamine were infused. Only one reported extravasation-induced injury with low-dose dopamine. Although low-dose dopamine has a vasodilatory effect in selected tissues, high concentrations achieved locally as a result of extravasation can still cause severe vasoconstriction and ischemic tissue injury.

Low-dose dopamine therapy should be administered with similar precautions as high-dose dopamine. A central intravenous access should be placed for dopamine infusion whenever possible. If this approach is not feasible, dopamine should be infused only peripherally through a long intravenous catheter into a large vein. A 5-cm angiocatheter that is 20 gauge or larger is recommended for peripheral dopamine infusion in our institution. The infusion site should be inspected frequently for early detection of extravasation, and changed to a central or a peripherally inserted central catheter as soon as possible, especially in patients at high risk for extravasation.

To report a case of methemoglobinemia in a patient receiving dapsone for prophylaxis of Pneumocystis carinii pneumonia (PCP).

A 69-year-old white woman was hospitalized to rule out sepsis. Two years prior to this admission, the patient received an orthotopic liver transplant after which she required hemodialysis three times weekly. Because of intolerance to trimethoprim/ sulfamethoxazole and aerosolized pentamidine, she was prescribed dapsone therapy on hospital day 13, that was continued for 11 days. On hospital day 45 the patient received a cadaveric kidney transplant, and dialysis treatments were scheduled only as needed. One week after the transplant, dapsone therapy was resumed. Nine days into this course of dapsone, the patient developed dyspnea and oxygen desaturation of unknown etiology. The patient was evaluated for and diagnosed with methemoglobinemia. She received two doses of intravenous methylene blue and one dose of oral activated charcoal due to fluctuating methemoglobin concentrations.

The elimination of dapsone is not completely understood. Several case reports of dapsone-induced methemoglobinemia are present in the literature. Most have occurred in patients who have accidentally or deliberately overdosed. Cases of methemoglobinemia in patients receiving therapeutic doses of dapsone are discussed.

The growing numbers of immunosuppressed patients due to transplantation or HIV may result in increased dapsone use for the prevention of PCP. Clinicians should be aware of the adverse effects associated with dapsone therapy, and patients with dyspnea and hypoxemia of unclear etiology should be evaluated for methemoglobinemia.

To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach.

A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts.

AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions.

By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.

To review the pathophysiology, epidemiology, treatment, and prophylaxis of disseminated Mycobacterium avium complex (MAC) infection in HIV-infected individuals.

A MEDLINE (January 1966–July 1997) and AIDSLINE (January 1980–July 1997) search of basic science articles pertinent to the MAC infection in HIV-infected patients.

All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion.

The organism, epidemiology, and pathophysiology of disseminated MAC are discussed for background. A review of clinical trials for the treatment and prophylaxis of disseminated MAC are presented, along with unresolved issues concerning these topics.

The incidence of disseminated MAC has increased dramatically with the AIDS epidemic. The infection can lead to increased morbidity and mortality in HIV-infected patients. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50/mm³.

To review the pharmacology and pharmacokinetics of glucosamine and critically evaluate currently available literature regarding its safety and efficacy.

A MEDLINE search was conducted between January 1965 and May 1997. Key words used in the search were osteoarthritis, osteoarthrosis, gonarthrosis, and glucosamine. In addition, references cited in articles obtained from the MEDLINE search were reviewed for additional literature.

All articles were considered for inclusion in the review. Articles were excluded from critical evaluation for lack of randomization, lack of a control group, 30 or fewer study participants, inconsistent treatment regimen, incomplete dosing information, or incomplete reporting of results.

Osteoarthritis affects approximately 12% of the US population; the incidence increases with increasing age. Currently used pharmacologic treatments, including acetaminophen and nonsteroidal antiinflammatory drugs, do not slow or reverse the degenerative process in osteoarthritis. Glucosamine has recently received a great deal of attention from the public as a potential treatment of osteoarthritis, prompting healthcare professionals to investigate its clinical usefulness and potential for adverse effects. The drug has been proposed to stop and possibly reverse the degenerative process in osteoarthritis. Following absorption of an oral dose, glucosamine is incorporated into plasma proteins during first-pass metabolism, resulting in 26% bioavailability. Unbound glucosamine is concentrated in the articular cartilage. Each of the three critically evaluated studies reported a decrease in the symptoms of osteoarthritis (e.g., decreased Lequesne index, decreased pain severity, increased range of motion) for the glucosamine group, which was greater than that obtained in the control group. Flaws in study design, however, prevent the use of these results in modifying current clinical practice. Reported short-term adverse effects include mild gastrointestinal problems, drowsiness, skin reactions, and headache.

Improvement in the symptoms of osteoarthritis associated with the use of glucosamine has been observed in clinical trials; however, those trials have flaws in design and data analysis. Further research needs to be conducted before glucosamine can be recommended as a treatment for osteoarthritis.

To characterize the usefulness of glucosamine sulfate in the treatment of patients with osteoarthritis (OA).

Pertinent citations were identified via a MEDLINE search (January 1975–March 1997). Only trials available in the English language involving human subjects, OA, and glucosamine sulfate were selected for review.

OA is the most common form of arthritis and represents a major cause of morbidity and disability in the elderly. The main symptom of OA is pain and most of the commonly prescribed medications (e.g, acetaminophen, nonsteroidal antiinflammatory drugs) have been targeted at relieving the pain. Some of these medications have serious adverse effects and do not necessarily change the natural course of the disease. Glucosamine sulfate, a nutritional supplement, has recently emerged as an alternative treatment option for patients with OA. The beneficial effects of this chondroprotective agent have been reported to reverse or at least stop the progression of the disease without inducing serious adverse effects. Limited data from short-term human trials suggest that glucosamine sulfate administered orally, intravenously, intramuscularly, and intraarticularly may produce a gradual and progressive reduction in joint pain and tenderness, as well as improved range of motion and walking speed. Results of the trials have also shown that glucosamine has produced consistent benefits (>50% overall improvement in symptom scores) in patients with OA and that, in some cases, it may be equal or superior to ibuprofen in controlling symptoms.

There is evidence that glucosamine sulfate may provide pain relief, reduce tenderness, and improve mobility in patients with OA. Most of the current data, however, are derived from the European and Asian literature and there are no studies supporting the use of this agent in the US. The studies published to date have been done in small numbers of patients; adequate long-term trials examining the safety, efficacy, and optimal dosage requirements of glucosamine sulfate are lacking. Most of the available clinical data are difficult to interpret due to serious deficiencies in study design. Furthermore, studies evaluating the appropriate place of glucosamine sulfate in the therapeutic armamentarium of OA remain to be done.

To compare the characteristics and clinical efficacy of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) in the treatment of deep-vein thrombosis (DVT). Adverse effects, dosing, and cost issues are also discussed.

A MEDLINE search (January 1984–October 1997) was used to identify pertinent French and English literature, including clinical trials and reviews on LMWHs and their use in DVT.

Trials comparing dalteparin, enoxaparin, tinzaparin, and nadroparin with UFH were selected. As studies were numerous, only randomized trials including more than 50 patients were reviewed. Moreover, all patients studied had a first episode of symptomatic DVT confirmed by objective tests (i.e., venography, duplex ultrasonography, impedance plethysmography). Clinical efficacy and safety of LMWHs were assessed in these trials.

Results pertaining to venographic assessment, recurrent thromboembolism, total mortality, and bleeding complications were extracted from the selected studies.

Compared with UFH, LMWHs have a longer plasma half-life, better subcutaneous bioavailability, more predictable anticoagulant response, and require less intense laboratory monitoring. Most trials demonstrate comparable effects on thrombus extension and incidence of recurrent thromboembolism. Compared with UFH, LMWHs do not alter total mortality. Although animal trials predict a lower hemorrhagic potential for LMWHs, the incidence of bleeding complications is generally similar to that observed with UFH. Outpatient management of DVT with LMWHs has shown comparable safety and efficacy with inpatient UFH use but a shorter hospital stay.

Because LMWHs are as safe and as effective as UFH, and because of their more convenient method of administration, they can be considered valuable alternatives for the treatment of DVT. Savings generated by less intensive laboratory monitoring and the possibility of early hospital discharge and outpatient therapy may outweigh the higher acquisition cost of LMWHs.