Annals of Pharmacotherapy

To assess the efficacy of using an iodized talc slurry as a sclerosing agent instilled into the pleural space via a 12-French pigtail catheter for controlling malignant pleural effusions.

A prospective study in which patients were followed until their death.

A university-affiliated tertiary-care teaching hospital.

Medical oncology patients admitted with symptomatic malignant pleural effusions were considered for iodized talc pleurodesis.

The control of pleural effusion. Treatment failure was defined as any reaccumulation of fluid in the pleural space.

Fifteen patients were treated for a total of 17 instillations. The median follow-up on all patients until death was 6 months (range 1–20). The most frequent adverse effect in the study group was pleuritic chest pain (60%). The probability of control of effusion, as determined by the method of Kaplan–Meier, was 81% (SEM 9.7%). The cost of preparing 5 g of iodized talc was $4.32 (US).

Iodized talc slurry instilled through a small-bore pigtail catheter is a safe, economical, and effective treatment for malignant pleural effusion.

To present an 8-year (1985–1992) cumulative analysis of the 12 743 calls received by the Medication Information Line for the Elderly (MILE), a consumer-oriented drug information service.

Data on all calls received by MILE were documented using a standard format. Certain calls were selected by the pharmacist for follow-up based on the nature and predicted severity of the inquiry.

MILE is located within the Faculty of Pharmacy of the University of Manitoba and staffed by experienced, practicing pharmacists. Calls were received from the elderly and their care providers. Calls were initially taken on a local Winnipeg line, although in 1987 a toll-free number was made available to rural Manitoba residents.

The majority of the calls received by MILE were from women aged 65 years or older who accessed MILE on their own initiative. Ninety-one percent of the calls were rated as not serious. Only 6% of calls were from outside Winnipeg. Although 94% of the older consumers reported having a regular pharmacist, they commonly never thought of using their pharmacist for inquiries. The drugs cited most often by consumers, nurses, physicians, and dentists were the nonsteroidal antiinflammatory agents, cardiac drugs, diuretics, antihypertensives, benzodiazepines, and antidepressants. The types of inquiries most frequently involved adverse drug reactions, drug interactions, and therapeutic use. The drugs cited and inquiries made by pharmacist callers were more diverse than those of consumers and other healthcare professionals.

Many older drug consumers have medication information needs that are not being met. Since a large proportion of the callers appeared to be self-motivated women, MILE may not be accessing all older consumers in need of information. This analysis also suggests that many older consumers are not aware that the pharmacist is available and capable of providing drug information.

To compare medication adherence calculated from four different data sources including a pill count and self-report obtained during a home medication history, as well as calculations based on refill frequency derived from a provincial prescription claims database (manual and electronic).

Baseline medication adherence was collected as part of a prospective, randomized, controlled study. Mean medication adherence results obtained from the four data sources were compared using repeated-measures ANOVA followed by a Tukey's multiple range test.

A pharmacy consultation service located at an interdisciplinary wellness center for noninstitutionalized elderly.

65 years or older, noninstitutionalized, taking one or more prescribed or nonprescribed medications. Clients would either present to the wellness center or be referred by the Provincial Home Care program.

When calculated from self-report or manual or electronic prescription claims data, mean percent adherence by drug was high and not statistically different (95.8% ± 17.1%, 107.6% ± 40.3%, and 94.6% ± 24.0%, respectively), whereas the pill count adherence was significantly lower at 74.0% ± 41.5% (p < 0.0001).

An unexpected finding was that the pill count technique used in this study of elderly clients using chronic, repeat medications appeared to underestimate medication adherence. Numerous other limitations of pill count, self-report, and a province-wide prescription claims database in estimating medication adherence are presented. When using medication adherence as a process measure, the researcher and practitioner should be aware of the limitations unique to the data source they choose, and interpret data cautiously.

To evaluate the physical and chemical stability of a suspension of mycophenolate mofetil (MMF) prepared in the hospital from commercially available MMF capsules.

Suspensions of MMF were prepared at room temperature and stored at 5, 25, 37, and 45 °C over a period of 50 to 210 days. The contents of MMF and its degradation product, mycophenolic acid, in the suspension were measured at various time points by HPLC.

MMF suspensions were stable (as determined by the presence of ≥90% of the labeled amount) at 45 °C for at least 11 days, at 37 °C for at least 28 days, at 25 °C for at least 28 days, and at 5 °C for at least 210 days. The suspension was also physically stable at 5 °C during the entire test period.

The compounded MMF suspension was stable for at least 11 days at all the temperatures studied and for as long as 210 days at 5 °C. This formulation appears to be clinically acceptable and provides a convenient dosage form for pediatric patients and for adults during the early postoperative period.

To report a case of QT prolongation associated with concomitant cyclobenzaprine and fluoxetine administration followed by torsade de pointes potentiated by droperidol.

A 59-year-old white woman who had been receiving long-term fluoxetine and cyclobenzaprine therapy was admitted for Achilles tendon repair. Baseline QTc was prolonged at 497 msec. Prior to surgery, the patient received droperidol, an agent known to prolong the QT interval. During surgery the patient developed torsade de pointes, which progressed into ventricular fibrillation. On postoperative day 1, after cyclobenzaprine discontinuation, the QTc decreased toward normal (440 msec).

Cyclobenzaprine shares anticholinergic effects, tachycardia, and dysrhythmic potential with the tricyclic antidepressants (TCAs). Fluoxetine is a known inhibitor of the CYP2D6 isoenzyme (along with CYP3A4 and CYP2C) and has been shown to increase TCA serum concentrations. The combination of cyclobenzaprine and fluoxetine resulted in significant QT prolongation in our patient that progressed to torsade de pointes after preoperative droperidol administration. Resolution of QT abnormalities after cyclobenzaprine discontinuation provided further evidence of a drug-induced etiology. Other possible medical and drug-related causes of torsade de pointes are reviewed and ruled out.

Clinicians should be aware of the dysrhythmic potential of cyclobenzaprine and fluoxetine, monitor for other cytochrome P450 inhibitors, and avoid concomitant drugs known to prolong the QT interval.

To determine whether the potentiation of warfarin's anticoagulation effect, which occurred in two patients, was due to an interaction with fenofibrate.

Two patients developed significant potentiation of the anticoagulant effect of warfarin while receiving fenofibrate. In one patient we followed published guidelines to test the potential interaction, including rechallenge twice, and measurements of factors II, V, and VII and liver enzymes to ensure the authenticity of the interaction. We confirmed the interaction by noting that the international normalized ratio (INR) increased with rechallenge, the clotting factor concentrations decreased in concert with the INR, and no other laboratory or clinical factors accounted for this potentiation of the oral anticoagulant affect

We previously developed criteria specifically for determining the strength of inferred causation in reports of drug interactions with oral anticoagulants; these criteria were adapted from previously described principles of causality assessment. Our observations in two patients suggest a “highly probable” potentiating interaction between fenofibrate and warfarin. Our data do not allow us to draw definitive conclusions on a mechanism of interaction, but fenofibrate is an oral antilipemic agent, similar to clofibrate, that has been described as potentiating oral anticoagulants by affecting coagulation factor synthesis, likely by altering receptor synthesis. Our finding of lower concentrations of coagulation factors suggests a similar mechanism for fenofibrate. Recent data suggest that lipid lowering is effective for primary and secondary prevention of cardiac events. One might therefore expect to see an increase in the use of the various lipid-lowering agents in patients who receive long-term anticoagulation. Our results indicate that the potential for an exaggerated anticoagulant effect occurs within 5–10 days in patients treated with fenofibrate who are receiving long-term anticoagulation with warfarin.

Fenofibrate potentiates the effect of warfarin. Serial monitoring of the INR, at least three times per week, is therefore strongly recommended when initiating fenofibrate therapy in patients receiving warfarin.

To review the literature on the use of thrombolytic agents in the pharmacotherapeutic management of acute myocardial infarction (AMI).

English-language clinical trials, reviews, and editorials derived from MEDLINE (January 1966–September 1997) and/or cross-referencing of selected articles.

Articles that were selected best represent the clinical trials researching the role for thrombolytics in the therapy of AMI to improve morbidity and mortality.

AMI is one of the leading causes of mortality in the US. Following supportive data that the most common cause of an AMI is an intracoronary thrombus, clinical investigation has demonstrated that intravenous thrombolytic agents improve survival rates in patients who experience an AMI. Several clinical trials have been conducted to determine whether one thrombolytic agent is superior to others with respect to improving mortality. At present, only the first Global Use of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial has reported any statistically significant difference in mortality rate. In this trial, “front-loaded” alteplase induced a statistically significant (p < 0.001) 1% absolute reduction in 30-day and 1-year mortality compared with streptokinase. This has led to alteplase being the preferred thrombolytic at many US institutions. However, the results of GUSTO-I have been questioned by some on the basis of either study design or clinical significance.

Thrombolytic agents have secured a place in the treatment of AMI due to their well-proven reduction in mortality rates. In general, comparative trials have demonstrated minimal differences in efficacy among these agents. Probably just as important as choosing which thrombolytic agent to use is ensuring that a patient experiencing an AMI is administered thrombolytic therapy unless a contraindication to receive such therapy exists in the patient and/or the patient is a candidate to receive an emergent intracoronary procedure. Trials also indicate that the sooner thrombolytics can be administered, the greater the benefit to the patient.

To review the pharmacokinetics and pharmacodynamics of oral and intravenous azithromycin compared with other macrolide antibiotics, and to evaluate these differences and their relation to clinical effectiveness.

A MEDLINE search (1966–May 1998) was performed to identify applicable English-language clinical, animal, and microbiologic studies pertaining to pharmacokinetic and pharmacodynamic parameters.

Relevant studies concerning microbiology, pharmacokinetics, tissue concentrations, pharmacodynamics, and the clinical effects of these parameters were selected.

The structural modification that distinguishes the azalide antibiotics from the macrolide antibiotics is responsible for the pharmacokinetic and pharmacodynamic behavior of azithromycin, resulting in the high and sustained tissue and intracellular concentrations seen with this agent. Drug delivery to the site of infection by phagocytes and fibroblasts is the hallmark of azithromycin's tissue-directed pharmacodynamics, allowing for convenient once-daily, 5-day regimens for most infections that respond to oral therapy and 7–10 days for more serious infections requiring initial intravenous therapy. Metabolism is via hepatic pathways other than cytochrome P450, thus minimizing the risk of drug interactions.

Compared with other macrolide antibiotics, the unique pharmacokinetic and pharmacodynamic features of azithromycin offer the potential for improved efficacy and safety from drug interactions. These attributes, combined with its once-daily dosing schedule, make azithromycin suitable for the treatment of many types of bacterial infection.

BSPharm PhD, Assistant Professor of Pharmacy Practice and Administration and Neurology, Colleges of Pharmacy and Medicine, The Ohio State University

To provide an overview of key pharmacotherapeutic issues in epilepsy for the woman of childbearing potential.

A MEDLINE search (1966–1997) was done to identify pertinent literature. Chapters in epilepsy textbooks, pregnancy registries, and their respective bibliographies were also evaluated.

All identifiable sources written in English were evaluated.

Epilepsy is a common neurologic disorder. It is estimated that nearly 1 million American women of childbearing age have epilepsy. There are many women's health issues in epilepsy. These include menstrual cycle influences on seizure activity, contraceptive–antiepileptic drug interactions, pharmacokinetic changes during pregnancy, teratogenicity of antiepileptic drugs, breast-feeding, and quality of life. These issues challenge both the woman with epilepsy and the many healthcare providers involved in her care. This article reviews these issues and makes recommendations. It addresses both the first-generation antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, valproic acid) and the newer or second-generation agents (felbamate, gabapentin, lamotrigine, topiramate, tiagabine).

Drug interactions between enzyme-inducing antiepileptic drugs and contraceptives are well documented. Higher doses of oral contraceptives or a second contraceptive method are suggested if epileptic women use an enzyme-inducing antiepileptic drug. Planned pregnancy is highly recommended and counseling before conception is crucial. Prepregnancy counseling should include, but is not limited to, folic acid supplementation, optimal control of seizure activity, monotherapy with the lowest effective antiepileptic drug dose, and medication adherence. Patient information should be provided about the risk of teratogenicity and the importance of prenatal care. Antiepileptic drug dosage adjustments may be necessary and should be based on clinical symptoms, not solely on serum drug concentrations. While the future holds promise for many aforementioned women's issues in epilepsy, many questions remain to be answered.

Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost.

A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency.

Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed.

Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity.

Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis.

Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

To discuss the use of statistical graphics in the analysis of pharmacokinetics and pharmacodynamics data.

Information on graphic techniques and their application was retrieved from a MEDLINE search (January 1980–March 1997) of the English-language literature and bibliographic reviews of review articles and books. Data used to generate plots were extracted from some new drug applications submitted to the Food and Drug Administration and by simulation.

In carrying out data analysis, we should look at data in several ways, construct a number of plots, and do several analyses, letting the results of each step suggest the next. The information from a plot should be relevant to the goals of the analysis. Thus, in choosing a graphic method, it is necessary to match the capabilities of the method to the need in the context of the application. For example, if linear relationships among variables in a set of multidimensional data are relevant, scatter plots such as the pairs plot with smoothing is likely to be more informative than other graphic methods. It is necessary to recognize what kinds of perceived structure are attributable to the data, and what kinds are artifacts of the display technique itself when using graphs for data analysis.

Graphic techniques enable the data analyst to explore data thoroughly, look for patterns and relationships, confirm or disprove the expected, and discover new phenomena. An important element of statistical graphic techniques is flexibility, both in tailoring the analysis to the structure of the data and in responding to patterns that successive steps of analysis uncover. Statistical graphics can and should be used to enhance numeric statistical analyses.

To discuss how literature can be used to educate healthcare practitioners and students about the patient's physical and emotional response to treatment.

A MEDLINE search (January 1975-November 1997) of English-language literature pertinent to using literature in health care was performed. Additional literature was obtained from a search of the New York University Web site on medicine and humanities, biographies of Charlotte Perkins Gilman, and a search of the MLA and INFOTRAC database.

All articles and literature were considered for possible inclusion in this article. Pertinent information, as judged by the author, was selected for discussion.

Literature can pose a wealth of information to the healthcare professional. The short story “The Yellow Wallpaper” is analyzed in this article as one example of how literature portrays the patient's emotional response to disease. This short story describes a 19th-century woman's “descent into madness” and the ineffective treatment attempted by her well-meaning physician husband. The author, Charlotte Perkins Gilman, loosely based the story on her own experience with the respected physician, S Weir Mitchell and his famous rest cure. Some biographical information about Mitchell and Perkins is included, as well as a commentary on the treatment of depression in the 19th century.

Short stories such as “The Yellow Wallpaper,” novels, and other short stories can help to remind the healthcare professional of the subjective nature of even our most proven therapies. As we strive to teach and deliver pharmaceutical care, we can use literature to help us understand the emotional impact of our drug therapies.