Annals of Pharmacotherapy

Thirty-seven patients admitted for labor induction and presenting with unfavorable cervical features were randomized in a single-blind fashion to receive either 3 mg of prostaglandin E₂ in an intravaginal gel or a 2-mg dose in a vaginal suppository. With the aid of previously reported placebo data, the intent was to compare the two dosage forms in terms of their ability to promote cervical ripening, and to see which dosage form was more effective in terms of influencing the overall incidence of cesarean section. The two groups showed a comparable improvement (α = 0.05) in cervical condition over that of the placebo group, with the mean Bishop score increasing by 2.0 points in the gel group, 2.5 points in the suppository group, and 0.7 points in the placebo group. As the suppository contained a lower dose of drug than the gel, the data support the concept that the type of drug vehicle and dosage form are important variables affecting product performance. No statistically significant difference in the incidence of cesarean section was noted between the two groups or between either group and placebo. This may be attributable to the small sample size and the relatively high proportion of women diagnosed as having cephalopelvic disproportion/failure to progress. Additional studies are warranted.

An 83-year-old patient developed agranulocytosis following six months of enalapril 10 mg/d. The patient also had received verapamil for three years. Upon discontinuation of both drugs the white blood cell count was rapidly restored. Cases of agranulocytosis due to angiotensin-converting enzyme inhibitors, mainly captopril, have been previously described. We could, however, find no single case associated with verapamil. This, and the very long exposure of the patient to verapamil, support the assumption that this life-threatening complication might have been caused by enalapril.

The purpose of this study was to evaluate the effect of age on lidocaine absorption and metabolism after application to the oropharynx and vocal cords in a manner similar to preparation for flexible fiberoptic bronchoscopy. Five healthy volunteers were studied in each of two age groups: from 25 to 37 and 60 to 68 years of age. Each volunteer had a total of lidocaine 300 mg administered as a gargle, gel, or directly to the vocal cords. Blood samples and expectorant were collected to determine concentrations of lidocaine and its metabolites, monoethylglycinxylidide (MEGX) and glycinxylidide (GX). No differences in peak plasma lidocaine concentrations, 2.09±1.28 μmol/L(1 μg/mL = 4.27 μmol/L) in young subjects, and 2.35 ±0.85 μmol/L in young-elderly subjects, or lidocaine AUC were seen between the two age groups. Lidocaine recovered in expectorant ranged from 96 to 168 mg. This study suggests that, over the age range studied, increased age does not impair lidocaine absorption from the oropharynx or lidocaine metabolism when topical lidocaine is used during flexible fiberoptic bronchoscopy.

Labetalol hydrochloride (HCl) is an effective antihypertensive drug. It is available in a tablet dosage form, which may be difficult to administer to geriatric and pediatric patients. The tablets can be suspended in various liquid vehicles, but its stability under these conditions is unknown. The objective of our study was to determine the stability of labetalol HCl in five liquid vehicles, in both plastic and glass prescription bottles, over a four-week period at room temperature and under refrigeration. Labetalol HCl tablets (Trandate, Glaxo) were triturated, and suspended in distilled water, simple syrup, apple juice, grape juice, and orange juice to approximate concentrations of 7–10 mg/mL. After filtration, the liquids were stored in five amber, plastic prescription bottles, and five amber, glass prescription bottles at 4°C and 23°C. The samples were collected at 0, 24, and 72 hours, and 1. 2, and 4 weeks after initiation of the study. Labetalol HCl was measured by an HPLC method. Because there was no substantial change in labetalol HCl concentration during the study period, the tablet dosage form can be reformulated, stored, and administered to elderly or pediatric patients as a liquid dosage form.

Vomiting is one of the most distressing adverse effects of cancer chemotherapy. Metoclopramide by continuous infusion (400 μg/kg/h after a loading dose of 2.5 mg/kg) is a novel administration method for optimizing efficacy. A two-year-old boy developed urinary retention on three occasions, once accompanied by priapism and slurred speech, while receiving a continuous infusion. This was reversed by procyclidine, suggesting that it may have been a dystonic reaction.

We report a case of hypervagotonia manifested by idioventricular rhythm in a healthy, athletic man who participated in a Phase I study of an investigational calcium-channel blocker. Upon breaking the study's double-blind study code, it was discovered that the subject had received placebo. We discuss this unusual finding and the implications of including athletic subjects in safety/tolerance studies.

The literature has been examined to assess the optimal prophylactic antimicrobial regimen for patients undergoing coronary bypass surgery. Antimicrobial surgical prophylaxis should be based on the two main potential pathogens, Staphylococcus epidermidis and S. aureus. It is unclear whether the prophylactic use of antimicrobials can or should be guided by in vitro antimicrobial susceptibility testing; data from well-performed clinical trials should be evaluated. The data fail to demonstrate consistently a significant difference within the cephalosporin class of antimicrobials with regard to prevention of infectious complications. Although it does not reach statistical difference, the trend with respect to efficacy appears to be cefuroxime, then cefamandole, and then cefazolin. The lack of significant difference among antimicrobials suggests an institution-individualized approach to the selection of the optimal antimicrobial for prophylaxis. For our facilities we recommend the following regimen: cefazolin sodium 1–2 g iv q8h for two days. There are not enough data at this time to recommend less than two days of antimicrobial prophylaxis for this type of surgery. In addition, aminoglycosides provide no added benefit when added to cephalosporins.

Colony-stimulating factors (CSFs) are hematopoietic growth hormones that stimulate the production, maturation, and function of white blood cells. The best studied are granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF), both of which can be produced by recombinant DNA technology. Clinical indications for these agents include bone marrow failure secondary to administration of chemotherapeutic drugs or radiation, bone marrow transplantation, and a variety of congenital or iatrogenic neutropenias. Toxicity in usual clinical doses is mild, and consists mainly of bone pain and constitutional symptoms such as fever, headache, and myalgias. Interleukin-2 (IL-2) is a lymphokine that stimulates that multiplication of several types of killer cells. These cells can recognize and destroy foreign substances, such as tumors, without destroying normal cells. Major applications of IL-2 include treatment of patients with renal cell carcinoma, in whom the overall objective response rate is 15–30 percent, and malignant melanoma with response rates of about 18 percent. Combination therapy with other biologics and conventional cytotoxic drugs may increase IL-2's efficacy against these tumors. Toxicity is generally severe, but reversible. Hemodynamic toxicity, consisting of hypotension, edema, weight gain, and decreased renal function, is most characteristic. Suggestions are given for pharmacologic management of these and other IL-2 toxicities.

Quinapril is a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. The drug undergoes hepatic hydrolysis into its major active diacid metabolite, quinaprilat, and two minor inactive metabolites. On a weight basis quinaprilat is three times as potent an ACE inhibitor as quinapril. Approximately 60 percent of an oral dose of quinapril is absorbed. In contrast with captopril, the absorption of quinapril is unaffected by food. Peak serum concentrations of quinapril and quinaprilat are achieved within one and two hours, respectively. Approximately 61 percent of an orally administered dose is excreted in the urine, principally as quinaprilat. The elimination half-life of quinaprilat is three hours, but is prolonged up to 11 hours in patients with renal dysfunction. Quinapril dose reduction is recommended in patients with a creatinine clearance of 0.50 mL/sec or less. In the elderly the elimination of quinaprilat is reduced and correlates well with renal function. In patients with cirrhosis the hydrolysis of quinapril to quinaprilat is impaired resulting in lower plasma quinaprilat concentrations and up to a two-fold increase in quinapril half-life. Quinaprilat has a strong binding capacity to tissue ACE allowing for once-daily dosing. The recommended starting dose for quinapril is 20 mg/d. The nature and incidence of adverse reactions to quinapril are similar to those of enalapril and captopril. Quinapril's antihypertensive efficacy is equal to that of captopril and enalapril. A small number of patients with congestive heart failure (CHF) have been treated with quinapril. Preliminary data indicate that quinapril is an equally effective therapeutic alternative to presently available ACE inhibitors in the treatment of CHF. Quinapril, a second-generation ACE inhibitor, has not been shown to offer significant clinical advantage over enalapril. In formulary evaluations quinapril may be considered therapeutically equivalent to enalapril.

Because of its in vitro activity in leukemic cell lines and Phase I studies of acute leukemia, Phase II and III clinical trials with idarubicin hydrochloride were conducted in patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. In the Phase III comparative trials between the combinations of idarubicin and cytarabine and daunorubicin hydrochloride and cytarabine, the idarubicin/cytarabine combination resulted in significantly greater complete remission rates and longer overall survival in two of three studies conducted in the US. As a result, the Food and Drug Administration approved intravenous idarubicin with a Class 1A rating in September 1990 for use in combination with other antileukemic drugs (e.g., cytarabine) for the treatment of acute myelogenous leukemia in adults. The recommended dose of idarubicin is 12 mg/m² daily for three days by slow intravenous injection in combination with cytarabine. Although idarubicin causes myelosuppression similar to that described with daunorubicin, the incidence of cardiotoxicity in animal models is lower. Idarubicin also has the advantage of oral administration, but the oral formulation of the drug remains investigational. The use of idarubicin in pediatric patients also remains to be established.

The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent, and vidarabine as an antiviral. Unlike vidarabine, fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, and chronic lymphocytic leukemia (CLL). Unfortunately, the doses required to achieve adequate response in the acute leukemias (>75mg/m²) were above the maximum tolerated dose, resulting in intolerable granulocytopenia, thrombocytopenia, and a life-threatening neurotoxic syndrome. In CLL, however, the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available, but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15–40 mg/m²/d for five consecutive days include somnolence, metabolic acidosis, confusion, fatigue, nausea, vomiting, increase in serum creatinine and aminotransferase concentrations, and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.

This article reviews the chemistry, pharmacology, spectrum of activity, pharmacokinetics, clinical efficacy in leprosy and Mycobacterium avium complex (MAC) infection, adverse effects, drug interactions, and special considerations of clofazimine. The drug is active in vivo against M. leprae and in vitro against MAC. In addition, it possesses antiinflammatory and immunosuppressive properties. Clinical studies support the efficacy of clofazimine as a part of multidrug therapy in treating leprosy. It also appears to reduce the incidence and severity of erythema nodosum leprosum reactions that often occur during the treatment of leprosy. Efficacy in treating MAC infection in patients with AIDS is not well documented, despite the use of clofazimine in combination with other agents. A few patients have responded symptomatically and by clearing their mycobacteremia, although there is no evidence that mortality is reduced. Clofazimine is well tolerated, at least when doses ≤100 mg/d are used. Adverse reactions include discoloration of the skin, self-limiting gastrointestinal intolerance, severe and life-threatening abdominal pain and organ damage due to clofazimine crystal deposition, and asymptomatic discoloration of the eye. Clofazimine should be considered for formulary inclusion.

Beta-adrenergic receptor agonists and antagonists are among the most widely used classes of agents in the US today. Heterogeneity in pharmacologic response among humans exists. This article reviews the influence of age on lymphocyte beta₂-adrenergic receptor responses. Evidence obtained in humans indicates that beta-adrenergic receptor numbers on peripheral blood cells may differ, although the direction of the change is not consistent among laboratories. Drug-induced regulation of receptors either up or down appears to be similar among age groups. The affinity of beta-adrenoceptor binding sites for isoproterenol decreases with aging. Events distal to the receptor recognition site itself exhibit age-related differences, presumably due to a decrease in the coupling of beta-adrenoceptors to adenylate cyclase. Mechanisms of decreased catecholamine responsiveness during aging remain to be defined. The precise definition of these alterations may contribute useful insights into the changes that occur with aging in response to catecholamines, other hormones, and neurotransmitters.

Bacterial meningitis continues to be a cause of substantial morbidity in infants and children. Hearing impairment is the most common sequela of this disease. Corticosteroids have been used in an attempt to reduce the incidence of meningitis-induced hearing loss. Some studies have demonstrated a decrease in the incidence of hearing impairment in patients treated with cefuroxime plus dexamethasone compared with cefuroxime alone. Similar data are lacking for other frequently used antibiotics. Based on these studies, the use of dexamethasone should be considered in infants and children greater than two months of age with suspected bacterial meningitis. Critical issues including the timing of steroid initiation in relation to antibiotic therapy and the appropriate antibiotic-corticosteroid regimen must be addressed. Studies should be performed to define the exact role of corticosteroids in the treatment of bacterial meningitis. Until additional data are available, we recommend the use of dexamethasone in pediatric patients older than two months of age with bacterial meningitis.

Cost differences between antibiotic dosing frequencies were studied at Robert Wood Johnson University Hospital. Developing a complete cost profile between antibiotic alternatives is difficult because of role separation within the hospital. To present a more complete profile, the study analyzed the incremental costs associated with the hospital pharmacy and nursing staffs regarding various dosing frequencies, including different iv admixture and administration methods. Results showed that administration of an antibiotic dose costs approximately $3.35 based on labor and material costs associated with admixture and administration. An average of 4.6 minutes/dose saves nurses up to 23 minutes for each patient who receives an antibiotic dosed once rather than six times daily over a 24-hour period. Costs of administration and admixture should be considered in comparisons of combination therapy with monotherapy when deciding between two therapeutically equivalent alternatives.