Joseph A. Barone

Domperidone: A Peripherally Acting Dopamine2-Receptor Antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of domperidone in the treatment of gastrointestinal motility disorders and emesis. DATA SOURCES: MEDLINE and Excerpta Medica online databases were searched to identify published reports. STUDY SELECTION: Domperidone has been marketed worldwide outside the US since 1978, and extensive clinical data for this drug are available. This review focuses on the clinical experience from controlled studies of domperidone in the treatment of motility disorders, particularly diabetic gastroparesis. Also, case reports are used in summarizing safety. The control comparator groups included placebo or other prokinetic drugs (metoclopramide and cisapride). Controlled clinical trials of domperidones efficacy and safety as an antiemetic are also briefly examined. Although a variety of domperidone dosage forms have been marketed, data generated from trials using the 10-mg tablet are highlighted because this is the only dosage form available in Canada and is under investigation in the US. DATA EXTRACTION: Because symptoms do not correlate with objective measures of gastrointestinal motility and they are the primary reason that patients with motility disorders seek treatment, the primary outcome extracted from the clinical studies was symptomatic response to treatment. Safety and efficacy between domperidone and placebo, metoclopramide, or cisapride were compared. DATA SYNTHESIS: Domperidone, a peripheral dopamine2-receptor antagonist, regulates the motility of gastric and small intestinal smooth muscle and has been shown to have some effects on the motor function of the esophagus. It also has antiemetic activity as a result of blockade of dopamine receptors in the chemoreceptor trigger zone. In controlled clinical trials, domperidone provided better relief of symptoms (anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, distension) than placebo in patients with symptoms of diabetic gastropathy; symptomatic improvement was similar with domperidone and metoclopramide or cisapride. Domperidone also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because very little domperidone crosses the blood–brain barrier, reports of central nervous system adverse effects, such as dystonic reactions, are rare. CONCLUSIONS: Domperidone is a unique gastrokinetic and antiemetic drug. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide. In the management of diabetic gastropathy, domperidones antiemetic activity distinguishes it from cisapride.

Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers.

The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59% that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.

Trends in blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988-2004.

Objectives The objectives of this study were to examine the trends in the prevalence of type 2 diabetic patients with comorbid hypertension and blood pressure (BP) control rates in the United States and determine factors associated with these outcomes. Methods We used data from National Health and Nutrition Examination Surveys (NHANES) III (1988–1994) and NHANES 1999–2004, a cross-sectional sample of the noninstitutionalized US populations. Type 2 diabetic patients were identified as patients at least 30 years of age with physician-diagnosed diabetes who were taking insulin or oral antidiabetic drugs to manage the condition. A diagnosis of hypertension was based on physician diagnosis, treatment with antihypertensive medications, or BP at least 140/90 mmHg. BP control was defined as diabetic patients who maintained BP <130/80 mmHg. Logistic regression was used to estimate risks of high BP, and odds of high BP treatment and control rates, after adjusting for demographic and clinical risk factors. Results The age-adjusted prevalence of diabetic patients and those with hypertension increased significantly from 5.8 to 7.1% and 3.9 to 4.7%, respectively, from NHANES III to NHANES 1999–2004. Among diabetic patients with hypertension, patients who were treated with medication or lifestyle or behavioral modification therapy have increased significantly from 76.5 to 87.8% during the observation period. The proportion of patients who controlled BP increased from 15.9 to 29.6%, but 70% of patients still did not meet the target BP goal. Conclusion Aggressive public health efforts are needed to improve BP control in type 2 diabetic patients with hypertension.

Cisapride: A Gastrointestinal Prokinetic Drug:

OBJECTIVE: To summarize the pharmacology, pharmacokinetics, efficacy, and safety of cisapride, and to evaluate its potential therapeutic role. DATA SOURCES: A computerized search of the MEDLINE database was used to identify English-language publications of cisapride data in humans. The MEDLINE search was supplemented by review article bibliographies. There was no attempt to limit the search to a specific gastrointestinal motility disorder. STUDY SELECTION: The MEDLINE search alone identified 165 citations. Because of the volume of available human cisapride data, the focus of the efficacy section is on complete published reports of controlled clinical studies. Abstracts and uncontrolled data are discussed only when other information is unavailable to address important aspects. DATA EXTRACTION: Information regarding study design, study population, results, and safety was recorded from each publication. The placebo response to gastrointestinal complaints in patients with motility disorders is high. Therefore, objective evidence of improvement was emphasized when documentation was available. DATA SYNTHESIS: Cisapride stimulates the motility of smooth muscle lining the esophagus, stomach, small intestine, and colon, and increases the tone of gut sphincters in vitro and in vivo. In controlled investigations, cisapride was superior to placebo in relieving symptoms associated with reflux esophagitis, nonulcer dyspepsia, and gastroparesis. Similar symptom and healing effects were observed with cisapride and histamine (H)2-antagonists in reflux esophagitis. Cisapride was either equal to or superior to metoclopramidein relieving reflux symptoms. However, metoclopramide was associated with significantly more central nervous system adverse effects. Cisapride was well tolerated, with adverse effects limited primarily to the gastrointestinal tract. CONCLUSIONS: Cisapride represents an attractive alternative to metoclopramidefor the treatment of a variety of motility disorders. Because it addresses a primary underlying cause of reflux esophagitis, cisapride may also prove to be an effective alternative to acid suppressants in the management of this disorder.

Food Interaction and Steady-State Pharmacokinetics of Itraconazole Oral Solution in Healthy Volunteers

Study Objectives. To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) solution under multiple‐dose to steady‐state conditions, and to determine the pharmacokinetics of ITR solution at steady state.

Factors related to physicians' adoption of electronic prescribing: results from a national survey.

Electronic prescribing (E-RX) is a component of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). The objective of this study was to identify factors related to physicians’ adoption of E-RX for outpatients. This study employed an electronic survey of US physicians who subscribe to the Physicians Online Internet service. Electronic prescribers were compared to traditional prescribers in terms of demographics, practice type and location, technology use, and beliefs about E-RX. A total of 1104 physicians responded, 19% of whom prescribed electronically. Electronic prescribers were more likely to be generalists practicing in academic or publicly funded centers, have fewer years in practice, and work in technology-equipped offices. They also held different beliefs versus traditional prescribers in terms of E-RX limitations and its potential to improve medication safety and prescribing efficiency. In addition to financial incentives established by MMA, adoption can be stimulated by improvements in the technology and on organizational commitment.

Essential Components of a Faculty Development Program for Pharmacy Practice Faculty

Prospective, ongoing faculty development programs are important in the initial orientation and short- and long-term development of faculty in higher education. Pharmacy practice faculty are likely to benefit from a comprehensive faculty development program due to the complex nature of their positions, incomplete training in select areas, and multiple demands on their time. The need for faculty development programs is supported by the increased need for pharmacy practice faculty due to the increased number of colleges and schools of pharmacy, expanding enrollment in existing colleges and schools, and loss of existing senior faculty to retirement or other opportunities within or outside the academy. This White Paper describes a comprehensive faculty development program that is designed to enhance the satisfaction, retention, and productivity of new and existing pharmacy practice faculty. A comprehensive faculty development program will facilitate growth throughout a faculty members career in pertinent areas. The structure of such a program includes an orientation program to provide an overview of responsibilities and abilities, a mentoring program to provide one-on-one guidance from a mentor, and a sustained faculty development program to provide targeted development based on individual and career needs. The content areas to be covered in each component include the institution (e.g., culture, structure, roles, responsibilities), student-related activities, teaching abilities, scholarship and research abilities, practice abilities and the practice site, and professional abilities (e.g., leadership, career planning, balancing responsibilities). A general framework for a comprehensive pharmacy practice faculty development program is provided to guide each college, school, department, and division in the design and delivery of a program that meets the needs and desires of the institution and its faculty.Prospective, ongoing faculty development programs are important in the initial orientation and short‐ and long‐term development of faculty in higher education. Pharmacy practice faculty are likely to benefit from a comprehensive faculty development program due to the complex nature of their positions, incomplete training in select areas, and multiple demands on their time. The need for faculty development programs is supported by the increased need for pharmacy practice faculty due to the increased number of colleges and schools of pharmacy, expanding enrollment in existing colleges and schools, and loss of existing senior faculty to retirement or other opportunities within or outside the academy. This White Paper describes a comprehensive faculty development program that is designed to enhance the satisfaction, retention, and productivity of new and existing pharmacy practice faculty. A comprehensive faculty development program will facilitate growth throughout a faculty members career in pertinent areas. The structure of such a program includes an orientation program to provide an overview of responsibilities and abilities, a mentoring program to provide one‐on‐one guidance from a mentor, and a sustained faculty development program to provide targeted development based on individual and career needs. The content areas to be covered in each component include the institution (e.g., culture, structure, roles, responsibilities), student‐related activities, teaching abilities, scholarship and research abilities, practice abilities and the practice site, and professional abilities (e.g., leadership, career planning, balancing responsibilities). A general framework for a comprehensive pharmacy practice faculty development program is provided to guide each college, school, department, and division in the design and delivery of a program that meets the needs and desires of the institution and its faculty.

Angiotensin-Converting Enzyme Inhibitors: A Comparative Review

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensin-converting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention. The ACE inhibitors, therefore, are capable of lowering blood pressure primarily by promoting vasodilitation and reducing intravascular fluid volume. Captopril, the first orally active, commercially available ACE inhibitor, is a sulfhydryl-containing compound. Captopril was followed by the introduction of enalapril and lisinopril, two non-sulfhydryl ACE inhibitors. The pharmacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively short duration of action, whereas enalapril and lisinopril have slower onset and relatively long duration of action. Captopril is an active ACE inhibitor in its orally absorbable parent form. In contrast, enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of activity. Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces. Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remaining parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension. In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure, and pulmonary artery pressure. These drugs may produce improvement in cardiac output and stroke volume and, with chronic administration, may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefit as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status. Although only captopril and enalapril are currently approved by the Food and Drug Administration for the treatment of CHF, early data with lisinopril suggest beneficial effects comparable to those of captopril. Several unapproved, experimental uses for ACE inhibitors have recently been reported and include treatment of proteinuria, scleroderma renal crisis, idiopathic edema, Raynauds syndrome, and hypertensive emergency. The ACE inhibitors as a group are generally effective and well tolerated in most patients, although the adverse effect profile may vary somewhat among individual agents.

Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model.

The effects of multiple-dose activated charcoal administration on the absorption of orally administered salicylate were evaluated in a simulated overdose model. Thirteen adult volunteers were each given 24 81-mg aspirin tablets during a control phase, and during three randomized treatment periods the volunteers received 50 g activated charcoal for one, two, or three doses (separated by four hours). The control phase and treatment periods were separated by a one-week interval. Urine was collected for 48 hours to determine percent total salicylate excretion. Ten subjects completed all four phases of the study. Mean +/- SD percent recovery of salicylate from urine was: control, 91.0 +/- 6.12; one-dose charcoal, 68.3 +/- 12.46; two-dose charcoal, 65.9 +/- 13.48; and three-dose charcoal, 49.2 +/- 12.48. Each charcoal treatment significantly lowered the absorption of aspirin as compared with the control (P less than .01). There was no significant difference between one-dose and two-dose charcoal regimens. There was a statistically significant decrease in salicylate absorption with the three-dose charcoal regimen as compared to one-dose and two-dose regimens (P less than .01). We conclude that activated charcoal is effective in inhibiting absorption of orally administered salicylate, in a small-dose aspirin ingestion model, with a three-dose multiple charcoal regimen being superior to either single-dose or two-dose regimens.

Factors contributing to trends in prescription drug expenditures

Between 1970 and 1995, national prescription drug expenditures and Medicaid drug expenditures increased proportionately less than did total health care expenditures and total Medicaid expenditures, respectively, although they increased to a greater extent than did expenditures in other sectors of the economy. General inflation, which cannot be controlled by health care policy, has been the major factor contributing to the growth in national prescription drug expenditures. Other contributors were population growth, increases in per capita prescription use, increases in per-prescription intensity (ie, real drug expenditures), and the fact that prescription drug prices exceeded general inflation. Medicaid drug expenditures have increased mainly because of growth in the number of drug recipients, increases in prescription drug prices, and economy-wide inflation.