Annals of Pharmacotherapy

This study was conducted to evaluate the safety of esmolol in 114 patients treated with thrombolytic therapy for acute myocardial infarction who also had relative contraindications to beta-blockade, and the predictive value of patient tolerance to esmolol and subsequent patient tolerance of oral beta-blocker therapy.

One hundred and fourteen patients with myocardial infarction documented by enzyme concentrations and electrocardiographic changes who also had relative contraindications to beta-blockade.

Esmolol was initiated during acute myocardial infarction for myocardial ischemia (n=88), hypertension (n=13), or supraventricular tachycardia (n=13). Relative contraindications to beta-blocker therapy included either active signs/symptoms of left ventricular dysfunction or a history of congestive heart failure (n=40), a history of chronic obstructive pulmonary disease or asthma (n=31), bradycardia (HR <60 beats/min; n=18), peripheral vascular disease (n=15), or hypotension (systolic BP <100 mm Hg; n=14).

During initial esmolol dose titration, 69 patients tolerated 300 μg/kg/min, 12 patients tolerated 200 μg/kg/min, 17 patients tolerated 100 μg/kg/min, and 16 patients tolerated 50 μg/kg/min. Twenty-eight patients (25 percent) developed dose-limiting adverse effects during esmolol maintenance infusions. Sixteen patients required esmolol dose reduction and 12 required esmolol discontinuation. Adverse effects reversed within 30–45 minutes following dose reduction or discontinuation. The 86 patients who tolerated esmolol infusions without dose reduction or drug discontinuation were subsequently treated with oral beta-blockers. Eleven of these patients (13 percent) developed adverse effects requiring oral beta-blocker discontinuation. Nine of these patients had tolerated only 50 μg/kg/min of esmolol, and the other 2 patients had tolerated only 100 μg/kg/min.

Esmolol can be used safely in most patients treated with thrombolytic therapy for acute myocardial infarction who have relative contraindications to beta-blockers. Tolerance to higher maintenance doses of esmolol is a good predictor of subsequent outcome with oral beta-blocker therapy.

To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis.

Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam.

Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (V^ss _d), elimination half-life (t_1/2β), clearance (Cl), and area under the curve (AUC_0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam V^ss _d, t_1/2β, Cl, and AUC_0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively.

Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased V^ss _d and t_1/2β in patients with acute appendicitis. An increased V^ss _d also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.

To evaluate the accuracy of response to a request among a sample of drug information centers and to determine the association between accuracy of response and individual center characteristics.

A randomized telephone investigation.

College of Pharmacy drug information center located in a 500-bed tertiary care teaching hospital.

Fifty-nine drug information centers randomly selected from 154 centers that had responded to a survey.

Each center received a telephone request requiring identification of Videx (didanosine), at that time a Phase II investigational product. Each center correctly identifying Videx was presented a patient case and questioned concerning adverse effect management. A written protocol of conversation was followed. Center confidentiality was maintained during data analysis.

The association between correct information regarding Videx and individual drug information center characteristics was evaluated.

Fifty-six evaluable responses were received. Videx was correctly identified by 16 centers (28.6 percent). Two centers (3.6 percent) made an incorrect identification and 38 centers (67.9 percent) could not make an identification. Of the 16 centers correctly identifying Videx, four successfully linked the product with described adverse effects, but none offered therapeutic management recommendations. Factors significantly associated with accurately identifying Videx included possession of a center policy and procedure manual (p=0.011) and on-line searching capability (p=0.021).

These results identify an inconsistency in accuracy of responses among drug information centers. Although standardized operating policies/procedures and on-line searching capability may contribute to increased accuracy, there is clearly a need for enhanced quality assurance efforts.

To evaluate the stability of ondansetron hydrochloride undiluted and mixed in dextrose 5% injection or NaCl 0.9% injection during storage in polypropylene syringes when frozen, refrigerated, or at room temperature.

Batch quantities of ondansetron 0.25, 0.5, 1.0, and 2.0 mg/mL were prepared and individual doses of 10.5 mg were drawn into polypropylene syringes that were stored at −20 °C for up to 3 months, at 4 °C for up to two weeks, or at 22–25 °C for two days, and various combinations of these conditions. At defined sampling times aliquots were withdrawn from syringes, the solution visually inspected, pH measured, and ondansetron concentration determined by HPLC. Drug loss of ≥10 percent of the original content of the solution was considered clinically significant.

The ondansetron concentration in each solution, regardless of storage conditions, remained above 90 percent of the original concentration at each observation time (range 92–107 percent). No changes in color or clarity of any of the solutions were observed, and only slight fluctuations in pH (≤0.05) were noted.

Ondansetron 2 mg/mL undiluted, or at concentrations of 0.25, 0.5, or 1 mg/mL, mixed in dextrose 5% injection or NaCl 0.9% injection was determined to be stable when stored in polypropylene syringes for each storage condition at all time points studied, including the maximum for each: three months at −20 °C, followed by 14 days at 4 °C, and by 48 hours at 22–25 °C.

To determine if published drug use evaluation (DUE) criteria for inpatients could be modified to describe and evaluate drug therapy in outpatients.

Retrospective review of drug profiles and diagnostic codes in outpatients included in the Iowa Medicaid Management Information System database.

Criteria specifying clinical indication, process indicators, complications, and outcomes were modified from existing inpatient DUE criteria for ciprofloxacin. The Iowa Medicaid database provided demographics, drug profiles, and diagnostic codes for outpatients prescribed ciprofloxacin between March 1 and March 15, 1993.

539 patients were evaluated. Mean (±SD) age was 62.1 ± 23.8 years; 70.9 percent were women, 44.9 percent were nursing home patients who received lower doses (p=0.04). Of 146 patients (27.1 percent) with infection-related International Classification of Diseases-Clinical Modification, 9th Revision (ICD-9CM) codes, 43.8 percent did not meet indication for use criteria, 15.8 percent met criteria, and 40.4 percent were equivocal/other. Process indicators in 539 patients revealed that 2.4 percent were <18 years old and potential interactions existed for theophylline (9.3 percent), iron (9.7 percent), warfarin (4.8 percent), sucralfate (2.2 percent). Two patients (0.4 percent) received prenatal vitamins. Dosage and duration of therapy could not be linked to disease severity. Complications of therapy were not evaluable. Outcomes were assessed indirectly by using concurrent antibiotic histories. These histories showed that patients received a mean 2.7 ± 2.4 (median 2, range 1–16) ciprofloxacin prescriptions during the study period. There was frequent concurrent use of antibiotics, and 29 percent of prescriptions were preceded or followed by additional quinolone therapy within 30 days.

Evaluating appropriateness of therapy with this methodology is feasible if validated ICD-9CM codes are reported consistently in sufficient numbers of patients. Low levels of reporting of relevant disease codes require that large numbers of patients be screened to use this method effectively. Descriptive use data are readily obtained. Data obtained by this method indicated several apparent deficiencies in ciprofloxacin therapy.

To report a case of chronic, nonproductive cough secondary to the angiotensin-converting enzyme (ACE) inhibitor quinapril, with complete resolution after switching to another ACE inhibitor, fosinopril.

All relevant articles from January 1985 through February 1993 were identified, primarily through MEDLINE search and review of pertinent articles' bibliographies.

A 68-year-old woman developed a dry, irritating cough within one month of starting quinapril therapy for the treatment of essential hypertension. The patient was a nonsmoker with no respiratory illnesses. The cough continued for the duration of therapy with quinapril. One month after changing to fosinopril therapy, the patient reported complete resolution of the cough. She remains cough-free to date.

Cough induced by ACE inhibitors is a frequently documented adverse effect. It is severe enough to require discontinuation of therapy in 1–10 percent of patients. The cough is considered to be a class-related adverse effect with cross-reactions between ACE inhibitors routinely reported. At this time, changing to another ACE inhibitor or additive therapy with nonsteroidal antiinflammatory drugs is not recommended. Discontinuation of the ACE inhibitor results in rapid alleviation of the cough, although this is not always necessary, as most patients may experience a cessation or decrease in cough. We report a case of cough following the administration of quinapril, with complete resolution after changing to the alternative ACE inhibitor fosinopril in a patient with essential hypertension.

Cough has been encountered commonly after the administration of ACE inhibitors. Frequency of cough is variable and although this complication has been described as a class effect, patients with a persistent, severe ACE inhibitor-induced cough may benefit from a trial of fosinopril therapy. This may be particularly useful in patients unable to tolerate an alternative class of antihypertensive agents.

To report a case of reversible vancomycin-associated neutropenia occurring during long-term therapy with vancomycin using weight and age-adjusted dosing.

A 2-year-old boy was started on vancomycin therapy for presumed endocarditis resulting from his ventriculoseptal defect. After 18 days of treatment, neutropenia with an absolute neutrophil count (ANC) of 990 × 10⁶ cells/L was noted. The neutropenia progressed over the next 3 days and reached a nadir concentration of 459 × 10⁶ cells/L. Vancomycin therapy was discontinued after 17 days (antibiotic day 20). A rise in the ANC occurred within 2 days of discontinuation. An improved ANC of 1672 × 10⁶ cells/L occurred within 5 days. Vancomycin serum concentrations remained within an acceptable range: a peak of 30 μg/mL and a trough of 9 μg/mL.

Case reports in the literature of vancomycin-associated neutropenia in adults were briefly reviewed and compared. The onset and resolution and mechanism of vancomycin-induced neutropenia were studied. The potential relationship between vancomycin, weight-, and age-adjusted dosing and the occurrence of neutropenia in our pediatric patient was postulated.

Vancomycin is identified as a possible cause of drug-induced neutropenia. More data are needed that clearly indicate vancomycin as the offending agent in children. The vancomycin-induced neutropenia is believed to be immunologically based and independent of drug concentrations.

To report two cases in which patients were reputed to have exhibited thrombocytopenia secondary to the histamine-receptor blocking agent ranitidine. Evaluation and the associated time frame of events failed to confirm these observations.

Two case studies.

Ranitidine was ordered as part of the therapeutic course of two patients admitted to the medicine service. The development of thrombocytopenia in both patients was attributed to this agent and it was discontinued. In addition to ranitidine, both patients received several other agents with greater potential to cause thrombocytopenia, and had a time course of development of the adverse effect that would not support ranitidine as the offending agent. Both patients required histamine-receptor antagonists at some point following their discontinuation and, based on the available evidence, the pharmacy suggested that these agents be restarted. In neither case did restarting the histamine-receptor antagonist lead to recurrence of thrombocytopenia.

Although ranitidine can cause thrombocytopenia, the reported incidence is very low. Spontaneous reporting of adverse effects is essential in establishing a true pattern of safety for a drug. However, reports need to be scrutinized before they are rolled into the collective intelligence. Overzealous or incomplete reporting will lead to cautions that are either unnecessary or, because they deny people necessary treatment, dangerous.

To report a case of erythema multiforme and hypersensitivity myocarditis caused by ampicillin.

A 13-year-old boy was treated with ampicillin and gentamicin because of suspected septicemia. Medications were discontinued when erythema multiforme and congestive heart failure caused by myocarditis occurred. The patient was treated with methylprednisolone and gradually improved. Macrophage-migration inhibition (MIF) test with ampicillin was positive.

After most infections causing erythema multiforme and myocarditis were ruled out, a drug-induced allergic reaction was suspected. Positive MIF test for ampicillin showed sensitization of the patient's lymphocytes to ampicillin.

Hypersensitivity myocarditis is a rare and dangerous manifestation of allergy to penicillins.

To report a serious drug interaction possibly occurring with the monoamine oxidase inhibitor phenelzine and the selective serotonin reuptake inhibitor sertraline.

A 61-year-old woman with treatment-refractory major depressive disorder was being treated unsuccessfully with lithium, phenelzine, thioridazine, and doxepin. Sertraline 100 mg/d was added to the patient's therapy. Within three hours of ingesting the first dose, the patient experienced a dramatic increase in her temperature, pulse, and respirations along with labile blood pressure, and symptoms of rigidity, diaphoresis, shivering, and decreased sensorium. The patient was transported to the emergency room and treated with diazepam 10 mg iv, followed by midazolam 10 mg iv for control of rigidity. She was also intubated. The patient then experienced precipitous falls in her blood pressure and respiratory rate. Ice packs combined with a cooling blanket and dantrolene 80 mg iv were administered to control fever and rigidity, respectively. She had an initial working diagnosis of neuroleptic malignant syndrome, which was later changed to serotonin syndrome. Dantrolene was continued for 72 hours at which time the patient was extubated and transferred to a psychiatric unit.

Selective serotonin reuptake inhibitor antidepressants should not be combined with monoamine oxidase inhibitor antidepressants because of the risk of serotonin syndrome.

To review the pharmacology, biopharmaceutics/pharmacokinetics, clinical efficacy, adverse effects, and therapeutic considerations regarding the use of tacrine in patients with Alzheimer's disease.

Data from the scientific and professional literature were analyzed, interpreted, and summarized. Citations were obtained by performing a MEDLINE search using the following indexing terms: tacrine, tetrahydroaminoacridine, and Alzheimer's drug therapy. Data also were obtained from a summary of the New Drug Application (Summary Basis of Approval of Cognex) and from the approved product labeling.

Studies in Alzheimer's disease have been plagued by methodologic inconsistencies and deficiencies. Only efficacy studies subsequent to the Food and Drug Administration's (FDA) issuance of recommendations for studies in Alzheimer's disease (1991) were used. Therefore, only double-blind, placebo-controlled, parallel design studies of at least three-month's duration using the Alzheimer's Disease Assessment Scale-Cognitive Subscale and the Clinical Interview-Based Impression of Change as efficacy parameters were included.

Trials were assessed according to the criteria listed above. Results were evaluated on the basis of both completed patients and last observation carried forward models.

Tacrine is a cholinesterase inhibitor that increases the availability of acetylcholine in muscarinic neurons. It has a mean bioavailability after oral administration of about 17 percent and an elimination half-life of approximately three hours. Although drug interactions are poorly studied, tacrine is metabolized by isoenzyme P-450IA2 and may interact with other drugs metabolized by this isoenzyme. Tacrine has been shown to have efficacy in mildly to moderately impaired Alzheimer's patients on both psychometric testing and a clinician's structured interview. Although efficacious, its effects are not dramatic, and it does not affect the ultimate course of the disease. Adverse effects are frequent, and significantly elevated hepatic transaminase concentrations may occur in approximately 25 percent of patients.

Tacrine is the first drug approved by the FDA for treatment of Alzheimer's disease. Although it may improve psychometric test scores in mild to moderately impaired patients, it is not a panacea and does not affect the course of the disease. Patients must be monitored closely for elevated transaminase, cholinergic adverse effects, and interactions with drugs metabolized through P-450IA2.

To review the effects of plasminogen activators (tissue plasminogen activator, streptokinase, and anistreplase) on fibrinogen and thrombin, platelets, complement, blood rheology, and neutrophils.

A MEDLINE search, as well as a review of recent scientific abstracts, was conducted to identify pertinent literature.

Focus was placed on studies conducted in humans. However, many in vitro studies have been performed to fully elucidate the effect of plasminogen activators on different aspects of hemostasis and on the fibrinolytic and immune systems.

Data from in vitro, human, and animal studies were evaluated.

There is a discrepancy between 9O-minute patency and mortality in acute myocardial infarction patients treated with thrombolytic drugs. This could be caused, in part, by other hematologic and immunologic effects of thrombolytic drugs. Though the emphasis of clinical trials has been infarct-related artery patency, left ventricular function, and mortality, some studies have evaluated the effect of thrombolytic agents on fibrinogen and thrombin, platelets, blood rheology, complement, and neutrophils. This review discusses the alteration of systemic hematologic and immunologic parameters by thrombolytic drugs and the possible clinical implications of these effects.

Although the interactions between thrombolytic drugs, hemostasis, and the fibrinolytic and immune systems are complex and still not fully understood, it appears that these drugs differ in their effects on these systems. A greater understanding of these properties and their clinical implications may ultimately enhance the care and outcome of acute myocardial infarction patients treated with thrombolytic therapy.

To provide an overview of the efficacy and adverse effects associated with once-daily administration of aminoglycosides.

An extensive MEDLINE search and review of journals was conducted to identify information for this review.

Aminoglycosides alone or in combination with beta-lactams are commonly used for their activity against gram-negative microorganisms. Numerous studies have been performed comparing efficacy and toxicity of once-daily administration of aminoglycosides with multiple-daily dosing. Two studies have found a significant difference in clinical efficacy between once-daily and multiple-daily dosing of aminoglycosides. Several studies have observed a lower incidence of toxicity with once-daily than multiple-daily dosing, but others have found no difference.

Review of the literature suggests that once-daily administration of aminoglycosides may be as safe and effective as multiple-daily dosing regimens for the treatment of certain infections caused by gram-negative bacteria.

To update readers on the pharmacotherapeutic management of cryptosporidiosis in patientswith AIDS.

A MEDLINE search was used to identify pertinent literature. Additionally, programs and abstracts from the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy; the 1st International Conference on Macrolides, Azalides, and Streptogramins; the 93rd American Society for Microbiology Meeting; and the 6th and 7th International Conferenceson AIDS were used.

Available data from in vitro, animal, and human experiments were reviewed.

Intestinal cryptosporidiosis in patients with AIDS can be a life-threatening opportunistic infection. However, there can be significant variability in disease expression, including spontaneous remission. Supportive care with hydration and nutritional supplementation remains a hallmark of therapy. Unfortunately, there is no proven specific pharmacotherapy of cryptosporidiosis in patients with AIDS. Numerous agents have been analyzed for in vitro activity and efficacy in experimental animal models and actual human cases of the infection, including paromomycin, azithromycin, c1arithromycin, octreotide, hyperimmune bovine colostrum, bovine transfer factor, and many others. Because limited numbers of controlled trials have been conducted with potential therapeutic agents, the majority of the information to date is preliminary in nature.

Despite the availability of some evolving and potentially promising treatment modalities, further controlled clinical trials are necessary to evaluate the role of pharmacotherapy for intestinal cryptosporidiosis in patients with AIDS.

To summarize and evaluate the literature regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms.

A literature search of articles from January 1966 to July 1993 using MEDLINE, EM-Base, and Current Concepts/Life Sciences, as well as bibliographies of relevant articles.

All identified original and review publications regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms were reviewed. Emphasis was placed on original studies published since 1975.

Data from published research were extracted and evaluated according to study design, sample size, dosing regimen, outcome measures, and treatment efficacy and safety.

Infantile spasms constitute a rare epileptic syndrome with a poor long-term prognosis for normal intellectual development. The spasms are characterized by a brief symmetric contraction of the muscles of the neck, trunk, and/or extremities, often occurring in a series of 2 to more than 100 spasms during a single episode. The disorder is age-specific, with the peak onset of symptoms occurring between 2 and 8 months of age. Spasms of no identifiable cause in infants with normal development prior to the onset of infantile spasms are classified as cryptogenic or idiopathic, whereas those with an identifiable cause are classified as symptomatic. Long-term prognosis is best in cryptogenic cases, with 30–70 percent attaining normal intellect compared with 5–19 percent in symptomatic cases. The etiology and pathophysiology are not well understood. Recent theory postulates that infantile spasms may be caused by an excess of corticotropin-releasing hormone activity during infancy. The suspected association between the whole-cell pertussis vaccine and infantile spasms is coincidental. Few well-designed, prospective, controlled clinical trials for the treatment of infantile spasms have been conducted.

Standard anticonvulsants such as phenytoin, the barbiturates, carbamazepine, and the succinimides have been ineffective. Of the anticonvulsants, only the benzodiazepines, valproic acid, and vigabatrin have shown efficacy in reducing spasm frequency and severity. Hormonal therapy with adrenocorticotropic hormone (ACTH) and/or prednisone has been the most frequently studied treatment modality and appears to be the most effective. Hormonal therapy achieves complete spasm control in 50?75 percent of infants within four weeks of initiation. Opinions differ regarding the relative efficacy between ACTH and prednisone, the need for early initiation of hormonal treatment, and the benefits of high dosages of ACTH (>40 units/d). No treatment has been shown conclusively to improve the long-term intellectual development of these infants. Neurosurgery may be the treatment of choice in select cases when a localized central nervous system abnormality can be demonstrated. Well-designed, blind, prospective clinical trials are needed to answer definitively many lingering questions regarding the treatment of infantile spasms.

To describe a formulary antiulcer agent prescribing program developed as the result of a drug use evaluation (DUE). Program implementation, methods. cost impact, and results of a follow-up DUE are provided.

The institution is a 51 OOO-bed correctional system consisting of 40 separate units each containing an ambulatory care clinic. Medication orders are transmitted via mainframe computer system to one of four pharmacies, which collectively dispense an average of 4000 medication orders (30 days' supply) per day.

Results from the antiulcer agent (cimetidine, ranitidine, sucralfate) DUE revealed that the agents studied were prescribed in dosages and durations exceeding criteria developed by the Pharmacy and Therapeutics Committee. A program designed to reduce dosages to maintenance therapy after eight weeks at treatment dosage was developed by the Pharmacy and Therapeutics Committee with staff physician input. Antiulcer agent use and expenditures were followed and a follow-up DUE was completed seven months after program implementation. Antacid use and frequency of upper gastrointestinal studies that were ordered were followed.

The follow-up DUE showed the mean daily dosage for prescribed histamine₂-receptor antagonists decreased (Cimetidine from 694 to 454 mg, ranitidine from 280 to 183 mg) and the mean duration of therapy decreased from 14 to 10 months. The percentage of patients with potentially significant drug interactions decreased from 14.2 to 6.5 percent. The mean number of antiulcer agents dosage units dispensed per month decreased by 24461 units, resulting in a projected annual savings of $327 273. There were no identifiable clinically important changes in the use of antacid products or prescribing of upper gastrointestinal studies.

A cost-savings program sponsored by the pharmacy and therapeutics committee decreased costs, corrected prescribing to more closely meet preset criteria, and produced no discernable unfavorable effect on patient care.