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The pharmacology, pharmacokinetics, efficacy and safety of ivabradine are reviewed. Ivabradine is an oral medication that directly and selectively inhibits the hyperpolarization-activated cyclic-nucleotide gated funny (If) current in the sinoatrial node resulting in heart rate reduction. It has a plasma elimination half-life of 6 hours and is administered twice daily. Ivabradine is extensively metabolized by cytochrome P450 3A4, and its metabolism is affected by inducers and inhibitors of the 3A4 enzyme. Studies in patients with heart failure indicate that ivabradine improves surrogate markers such as exercise tolerance. The results of (1) phase III trial demonstrated ivabradine significantly reduced heart failure hospitalizations but had no effect on mortality. Ivabradine has been extensively evaluated for coronary artery disease wherein (2) large trials was shown to have no mortality benefit. Ivabradine has been associated with improved symptoms in stable chronic angina pectoris. Ivabradine has been evaluated for other cardiovascular conditions including tachycardias of various natures, arrhythmia prevention postcardiac surgery, in acute coronary syndrome, and for heart rate control during coronary computed tomography angiogram. The most common adverse events reported in clinical trials were bradycardia, new-onset atrial fibrillation, and phosphenes. Ivabradine, a novel cardiac medication, has been studied in numerous cardiac conditions. It is only currently approved in the United States to reduce hospitalizations for systolic heart failure. The role of this medication in other conditions has not been fully elucidated.

Continuous i.v. milrinone infusions are used to treat patients with acute decompensated heart failure.[1][1] It is conceivable that patients receiving i.v. milrinone may also be treated for infection, making it necessary to administer milrinone and i.v. antibiotics through the same i.v. line.

Pulmonary arterial hypertension is a devastating disease. Before the 1990s, when pharmacologic treatment was finally approved, only supportive therapy was available, consisting of anticoagulation, digoxin, diuretics, and supplemental oxygen. Calcium channel blocker therapy was also an option, but only a small percentage of patients respond to it. However, starting with epoprostenol in 1996, the number of drugs approved to treat pulmonary arterial hypertension increased. Three distinct classes of drugs were developed based on the pathophysiology of the disease: the prostanoids, endothelin-1 receptor antagonists, and phosphodiesterase type 5 inhibitors. The prostanoids are administered either parenterally or by inhalation to replace the lack of prostacyclin within the pulmonary arterial vasculature. The endothelin-1 receptor antagonists were the first class of oral drugs to be developed, but drug interactions and adverse effects are prominent with this class. The phosphodiesterase type 5 inhibitors increase the second messenger cyclic guanosine monophosphate (GMP) that is induced by nitric oxide stimulation. All of the drugs within these three classes are distinct in and of themselves, and their clinical use requires in-depth knowledge of pulmonary arterial hypertension and its pathophysiology. Because these drugs have different mechanisms of action, combination therapy has shown promise in patients with severe disease, although data are still lacking. This article should serve as a practical guide for clinicians who encounter patients with pulmonary arterial hypertension and the drugs used for the treatment of this devastating disease.

Purpose: To evaluate and discuss the role of specific types of abdominal surgery (SURG) before radical radiation therapy as a risk factor for late rectal toxicity in prostate cancer patients. Methods: Results concerning questionnaire-based scored late bleeding and faecal incontinence in 718 patients with a complete follow-up of 36 months were analysed, focusing on the impact of specific pre-radiotherapy abdominal/pelvic surgery procedures. Patients were accrued in the prospective study AIROPROS 0102. Different types of surgery (rectum-sigma resection, kidney resection, cholecystectomy or appendectomy) were considered as covariates together with a number of different parameters previously found to be predictive of late toxicity and including clinical as well as dosimetric parameters. Univariate (UVA) and multivariate (MVA) logistic analyses were carried out. Results: In total 69/718 patients were previously submitted to one or more surgical procedures, mostly cholecystectomy (n = 21) and appendectomy (n = 27). Actuarial incidences of G2–G3 and G3 bleeding were 52 (7.2%) and 24 (3.3%) respectively; 19 (2.6%) chronic incontinence events were registered. Results: Cholecystectomy was found to be highly correlated with late rectal bleeding at UVA: OR = 4.3 and p = 0.006 for G2–G3 and OR = 5.4 and p = 0.01 for G3. Considering MVA (including dosimetric and clinical factors), G2–G3 bleeding was significantly correlated to cholecystectomy (OR = 6.5, p = 0.002), V75Gy (OR = 1.074, p = 0.003) and secondarily with appendectomy (OR = 2.7, p = 0.10), presence of acute radioinduced rectal bleeding (OR = 1.70, p = 0.21) and androgen deprivation (OR = 0.67, p = 0.25). Results: Appendectomy (OR = 5.9, p = 0.004) and cholecystectomy (OR = 5.5, p = 0.016) were very strong predictors of G3 bleeding with V75Gy playing a less significant role (OR = 1.037, p = 0.26). Conversely, no specific surgery was correlated with actuarial or chronic incontinence. Conclusions: This analysis highlights previous SURG as the best predictor of late rectal bleeding. Among the different types of abdominal surgery, cholecystectomy and appendectomy play the major role, especially for severe late bleeding.

BACKGROUND: Limited data are available regarding adverse bleeding events associated with antithrombotic agents incorrectly dosed based on renal function in patients receiving percutaneous coronary intervention (PCI). OBJECTIVE: To compare the incidence of bleeding during their hospital stay in patients with reduced renal function receiving incorrect doses of bivalirudin or eptifibatide to the incidence of correct doses, based on manufacturer recommendations; secondary objectives were to determine the incidence of correct dosing based on manufacturer recommendations and the incidence of TIMI (Thrombolysis in Myocardial Infarction) major bleeding. METHODS: A chart review over a 32-month period showed that patients with reduced renal function who received either eptifibatide or bivalirudin during PCI were evaluated for correct dosing based on manufacturer recommendations, bleeding incidence according to the TIMI criteria, and extent of bleeding according to the TIMI and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria. RESULTS: One hundred ninety patients met inclusion criteria, 56 who received eptifibatide and 134 who received bivalirudin. Eptifibatide was dosed incorrectly in 64% of the patients. Patients receiving incorrectly dosed compared to correctly dosed eptifibatide experienced significantly more bleeding (64% vs 35%, respectively, p = 0.04), a greater extent of bleeding based on the TIMI and GUSTO criteria (p = 0.03 and p = 0.009, respectively), and had more TIMI major bleeding (19% vs 5%, respectively). Bivalirudin was dosed incorrectly in 28% of the patients. Patients receiving incorrectly dosed compared to correctly dosed bivalirudin experienced a significantly greater extent of bleeding based on the GUSTO criteria (p = 0.01). There was no significant difference between the incidence of bleeding (37% vs 21%, respectively; p = 0.06), extent of bleeding based on the TIMI criteria (p = 0.058), or incidence of TIMI major bleeding (5% vs 3%). CONCLUSIONS: Patients receiving incorrectly dosed eptifibatide and bivalirudin are susceptible to adverse bleeding events. The occurrence of incorrect dosing offers an opportunity for pharmacist-driven institutional improvement.

Objective To develop pharmacist practice standards, pharmacy preceptor standards, and objectives for students completing advanced practice community pharmacy rotations. Setting Ohio. Practice Description Pharmacy schools and community pharmacies that serve as advanced practice rotation sites. Practice Innovation Developed standards for preceptors and objectives for student experiences. Interventions Focus groups that included both community pharmacists and pharmacy faculty collaborated on defining key standards for advanced community pharmacy rotations. Main Outcome Measure Not applicable. Results Three main documents were produced in this initiative, and these are provided as appendices to this article. Professional and patient care guidelines for preceptors define minimum standards for these role models. Expectations of pharmacists as preceptors provide insights for managing this student–teacher relationship, which is fundamentally different from the more common employer–employee and coworker relationships found in pharmacies of all types. Objectives for student experiences during advanced practice community pharmacy rotations present core expectations in clinical, dispensing, patient education, wellness, and drug information areas. Conclusion Through this collaboration, Ohio colleges of pharmacy developed a partnership with practitioners in community settings that should enhance the Ohio experiential educational program for student pharmacists. Use of the established guidelines will help educators and practitioners achieve their shared vision for advanced practice community pharmacy rotations and promote high-quality patient care.

A 23-year-old male presented from a nursing home with hypotension, tachycardia, diaphoresis and electrocardiographic evidence of right ventricular strain that was confirmed by echocardiography. His differential diagnosis included sepsis and pulmonary embolism. A high-resolution computed tomography scan demonstrated no pulmonary emboli but did demonstrate multiple bilateral pulmonary nodules. Upon questioning he admitted to injecting a long-acting narcotic that had been manually macerated, dissolved in saline, and injected through an indwelling intravenous line. Lung biopsy findings were consistent with cellulose-induced perivascular granulomatosis. Cellulose granulomatosis can be seen in patients who inject medications designed for oral use and should be considered in patients who present with acute pulmonary hypertension.

OBJECTIVE: To review the evidence for statin secondary prevention of coronary artery disease in patients with near-optimal or optimal low-density lipoprotein cholesterol (LDL-C). DATA SOURCES: A MEDLINE search (1966-October 2003) was conducted using the search terms HMG-CoA reductase inhibitor, statins, coronary disease, post-myocardial infarction, and average cholesterol. DATA SYNTHESIS: Secondary prevention trials enrolling subjects with near-optimal (CONCLUSIONS: Statin secondary prevention of coronary artery disease in patients near goal LDL-C is controversial, but recent trial results show promise.

OBJECTIVE To determine whether rate control is a viable initial treatment approach in persistent atrial fibrillation (AF) through the evaluation of recently completed trials comparing rate and rhythm control. DATA SOURCES Biomedical literature was obtained through MEDLINE (1966—December 2003) and the Iowa database. STUDY SELECTION AND DATA EXTRACTION Articles identified from the biomedical literature search were reviewed and included if deemed relevant. DATA SYNTHESIS Currently available data suggest that rate control is not inferior to rhythm control in patients with persistent AF with respect to mortality. Rate control also reduces hospitalizations and the occurrence of proarrhythmias. No significant difference was observed between treatments with respect to thromboembolism and strokes. CONCLUSIONS Due to the increased incidence of hospitalizations and antiarrhythmic adverse effects associated with rhythm control, rate control is a reasonable first-line strategy in the treatment of recurrent AF, especially in elderly patients who are asymptomatic or mildly symptomatic. Further studies are needed to clearly define the role of rate control in younger patients.

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST—segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. β -Adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy for vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

OBJECTIVE: To review published reports on the pharmacology and clinical use of dofetilide in the management of cardiac dysrhythmias. DATA SOURCES: A MEDLINE search (January 1966–June 1999) was performed using dofetilide and UK-68,798 as key words. English-language articles were identified, and the references of these articles were used to further identify pertinent articles. STUDY SELECTION: All acquired studies and reviews discussing the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of dofetilide were reviewed. DATA EXTRACTION: Articles were selected based on quality of review of the pharmacology and clinical use of dofetilide. Given the paucity of data on the clinical pharmacology and use of dofetilide, most articles obtained were used, including abstracts when full reports were not available. DATA SYNTHESIS: Dofetilide is a relatively specific class III antiarrhythmic agent. It increases action potential duration and effective refractory period without impacting conduction velocity. These actions of dofetilide are explained by its ability to inhibit the rapid component of the delayed, outward-rectifying potassium current, thus blocking the efflux of potassium during repolarization. Introductory investigations suggest that dofetilide may be of use in treating and preventing atrial dysrhythmias such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. Dofetilide may also have a role in preventing ventricular tachycardia from occurring. Some data also suggest that dofetilide may improve the morbidity of heart failure patients. Currently, the most troublesome adverse effect of dofetilide is its propensity to induce ventricular proarrhythmias, especially torsade de pointes. CONCLUSIONS: Based on the data currently available, dofetilide should have a role in the pharmacotherapy of cardiac dysrhythmias, especially those of atrial origin. More data on its efficacy and tolerability are needed, however, to fully delineate dofetilide's role amid currently available antiarrhythmic agents.

OBJECTIVE: To review the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SOURCES: A MEDLINE search (1980–1995) using the term syncope and cross-referencing selected articles. STUDY SELECTION: Articles selected were those considered to assist in providing the reader with a basic introduction to the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SYNTHESIS: Syncope is a common disorder with many different etiologies. The patient's history and physical examination are extremely important in making the diagnosis. The recent availability of head-upright tilt testing and electrophysiologic studies of the myocardium have helped define the etiology in many patients in whom an etiology would not have been found in the past. When the cause of syncope has been diagnosed, the appropriate therapy to prevent future attacks will be defined in many instances. One form of syncope, known as neurocardiogenic syncope, can be difficult to treat. Recent trials have suggested the use of beta-blockers, fludrocortisone, disopyramide, or selective serotonin reuptake inhibitors may be helpful in some patients.

OBJECTIVE: To review the scientific literature on the pharmacology and clinical uses of abciximab. DATA SOURCES: MEDLINE, Index Medicus, and bibliographic literature searches of English-language articles pertaining to abciximab, 7E3, m7E3, and c7E3 were performed. Eli Lilly also provided unpublished results of the Evaluation of 7E3 for the Prevention of Ischemic Complications trial. DATA SELECTION: The selection of data presented focused on controlled trials using abciximab at doses currently approved by the Food and Drug Administration. DATA SYNTHESIS: Abciximab is a humanized chimeric Fab fragment of 7E3.7E3 is a murine antibody directed against the integrin glycoprotein IIb/IIIa receptor (GPIIb/IIIa) located on platelets. These receptors play an integral part in platelet aggregation by allowing fibrinogen to bind to them and interconnect platelets. When administered intravenously, abciximab binds to GPIIb/IIIa and hinders platelet aggregation. Bleeding times and activated clotting times are increased and the platelets' response to adenosine diphosphate is reduced with the use of abciximab. Clinical trials have indicated that abciximab can reduce the incidence of abrupt closure and restenosis associated with percutaneous transluminal coronary angioplasty (PTCA) performed in high-risk patients. Clinical trials also suggest that abciximab may have a role in the treatment of unstable angina and the acute therapy of myocardial infarctions. Complications associated with abciximab include bleeding and thrombocytopenia. The thrombocytopenia is likely related to immunologic mechanisms. In addition, the production of antimurine antibodies has been demonstrated with abciximab use. Abciximab is currently approved for the prevention of abrupt coronary closure associated with PTCA in patients at high risk for this event. CONCLUSIONS: Abciximab is effective in preventing platelet aggregation and has been proven to be of clinical benefit in selected high-risk patients receiving PTCA.

Objective: To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h. Design: Randomized, controlled, crossover, prospective, open-label trial. Setting: Medical college-affiliated hospital. Participants: Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg. Interventions: Volunteers received, in random order, tobramycin sulfate 2 mg/kg iv on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast). Main Outcome Measures: Primary endpoints were area under the time–concentration curve (AUC), time to reach maximum concentration (tmax), and maximum concentration (Cmax). Secondary endpoints were elimination rate constant (ke), clearance (Cl), and half-life (t1/2). Results: Six volunteers successfully completed the trial. The tmax values observed following fast CRIS and ivpb were 28 ± 8 and 32 ± 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the tmax associated with slow CRIS (44 ± 7 min). The Cmax values observed following ivpb (11.2 ± 1.5 mg/L) and slow CRIS (10.9 ± 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 ± 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 ± 4.8 and 31.2 ± 3.8 mg/L•h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 ± 4.3 mg/L•h). No significant difference in ke (fast CRIS 0.32 ± 0.03 h-1; slow CRIS 0.33 ± 0.04 h-1; ivpb 0.34 ± 0.0 h-1) was observed among any of the methods. Conclusions: CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher Cmax, but the tmax values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed tmax, but the Cmax values of slow CRIS and ivpb were not statistically different.

Purpose To prospectively evaluate long-term late rectal bleeding (lrb) and faecal incontinence (linc) after high-dose radiotherapy (RT) for prostate cancer in the AIROPROS 0102 population, and to assess clinical/dosimetric risk factors. Materials and methods Questionnaires of 515 patients with G0 baseline incontinence and bleeding scores (follow-up ⩾6years) were analysed. Correlations between lrb/linc and many clinical and dosimetric parameters were investigated by univariate and multivariate logistic analyses. The correlation between lrb/linc and symptoms during the first 3years after RT was also investigated. Results Of 515 patients lrb G1, G2 and G3 was found in 32 (6.1%), 2 (0.4%) and 3 (0.6%) patients while linc G1, G2 and G3 was detected in 50 (9.7%), 3 (0.6%) and 3 (0.6%), respectively. The prevalence of G2–G3 lrb events was significantly reduced compared to the first 3-years (1% vs 2.7%, p =0.016) ⩾G1 lrb was significantly associated with V75Gy (OR=1.07). In multivariate analysis, ⩾G1 linc was associated with V40Gy (OR=1.015), use of antihypertensive medication (OR=0.38), abdominal surgery before RT (OR=4.7), haemorrhoids (OR=2.6), and G2–G3 acute faecal incontinence (OR=4.4), a nomogram to predict the risk of long-term ⩾G1 linc was proposed. Importantly, the prevalence of ⩾G1 linc was significantly correlated with the mean incontinence score during the first 3years after RT (OR=16.3). Conclusions Long-term (median: 7years) rectal symptoms are prevalently mild and strongly correlated with moderate/severe events occurring in the first 3years after RT. Linc was associated with several risk factors.

The aim of this study was to develop a model exploiting artificial neural networks (ANNs) to correlate dosimetric and clinical variables with late rectal bleeding in prostate cancer patients undergoing radical radiotherapy and to compare the ANN results with those of a standard logistic regression (LR) analysis. 718 men included in the AIROPROS 0102 trial were analyzed. This multicenter protocol was characterized by the prospective evaluation of rectal toxicity, with a minimum follow-up of 36 months. Radiotherapy doses were between 70 and 80 Gy. Information was recorded for comorbidity, previous abdominal surgery, use of drugs and hormonal therapy. For each patient, a rectal dose–volume histogram (DVH) of the whole treatment was recorded and the equivalent uniform dose (EUD) evaluated as an effective descriptor of the whole DVH. Late rectal bleeding of grade ≥ 2 was considered to define positive events in this study (52 of 718 patients). The overall population was split into training and verification sets, both of which were involved in model instruction, and a test set, used to evaluate the predictive power of the model with independent data. Fourfold cross-validation was also used to provide realistic results for the full dataset. The LR was performed on the same data. Five variables were selected to predict late rectal bleeding: EUD, abdominal surgery, presence of hemorrhoids, use of anticoagulants and androgen deprivation. Following a receiver operating characteristic analysis of the independent test set, the areas under the curves (AUCs) were 0.704 and 0.655 for ANN and LR, respectively. When evaluated with cross-validation, the AUC was 0.714 for ANN and 0.636 for LR, which differed at a significance level of p = 0.03. When a practical discrimination threshold was selected, ANN could classify data with sensitivity and specificity both equal to 68.0%, whereas these values were 61.5% for LR. These data provide reasonable evidence that results obtained with ANNs are superior to those achieved with LR when predicting late radiotherapy-related rectal bleeding. The future introduction of patient-related personal characteristics, such as gene expression profiles, might improve the predictive power of statistical classifiers. More refined morphological aspects of the dose distribution, such as dose surface mapping, might also enhance the overall performance of ANN-based predictive models.

OBJECTIVE: To review published reports of adverse effects associated with single- and multiple-dose activated charcoal therapy, and to formulate recommendations for safe use of activated charcoal therapy. DATA SOURCES: A manual search of Index Medicus from 1970 to December 1993 was conducted for English language articles; bibliographies of the resultant articles were also scanned. STUDY SELECTION: Cases were included if they were described in full detail, resulted in significant morbidity or mortality, and uniquely contributed to the formulation of recommendations for safe use of activated charcoal therapy. DATA SYNTHESIS: The major causes of morbidity and mortality secondary to activated charcoal therapy are aspiration of charcoal, gastrointestinal obstruction, and fluid and electrolyte abnormalities. Aspirations have occurred as a result of a number of circumstances that may be avoided. These include use in patients with unprotected airways, use of excessive charcoal dose, administration of inappropriately diluted charcoal, and administration of charcoal in the field. Gastrointestinal obstruction has occurred when multiple doses of activated charcoal have been administered without a cathartic and in cases in which a cathartic was administered if the patient had impaired peristalsis. Fluid and electrolyte abnormalities have occurred secondary to excessive cathartic administration. CONCLUSIONS: Activated charcoal therapy should be used judiciously so that related morbidity and mortality can be prevented. Adequate consideration for the patient's airway protection capability is necessary. Judicious dosing of charcoal and concomitant cathartic therapy, along with adequate monitoring of fluid and electrolyte status, abdominal physical assessment, and clinical condition are all vital to the safe use of activated charcoal therapy.

Intravenous conivaptan infusions have been used in decompensated heart failure patients with severe hyponatremia.[1][1] Such patients are often receiving other i.v. medications, but compatibility data are limited.[2][2],[3][3] This investigation studied the compatibility of conivaptan with four

Purpose Development of user-friendly tools for the prediction of single-patient probability of late rectal toxicity after conformal radiotherapy for prostate cancer. Methods and Materials This multicenter protocol was characterized by the prospective evaluation of rectal toxicity through self-assessed questionnaires (minimum follow-up, 36 months) by 718 adult men in the AIROPROS 0102 trial. Doses were between 70 and 80 Gy. Nomograms were created based on multivariable logistic regression analysis. Three endpoints were considered: G2 to G3 late rectal bleeding (52/718 events), G3 late rectal bleeding (24/718 events), and G2 to G3 late fecal incontinence (LINC, 19/718 events). Results Inputs for the nomogram for G2 to G3 late rectal bleeding estimation were as follows: presence of abdominal surgery before RT, percentage volume of rectum receiving >75 Gy (V75Gy), and nomogram-based estimation of the probability of G2 to G3 acute gastrointestinal toxicity (continuous variable, which was estimated using a previously published nomogram). G3 late rectal bleeding estimation was based on abdominal surgery before RT, V75Gy, and NOMACU. Prediction of G2 to G3 late fecal incontinence was based on abdominal surgery before RT, presence of hemorrhoids, use of antihypertensive medications (protective factor), and percentage volume of rectum receiving >40 Gy. Conclusions We developed and internally validated the first set of nomograms available in the literature for the prediction of radio-induced toxicity in prostate cancer patients. Calculations included dosimetric as well as clinical variables to help radiation oncologists predict late rectal morbidity, thus introducing the possibility of RT plan corrections to better tailor treatment to the patient’s characteristics, to avoid unnecessary worsening of quality of life, and to provide support to the patient in selecting the best therapeutic approach.

Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlled-release tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area-under-the-curve at steady state (AUCss) were observed, the oral clearance of pentoxifylline among the smokers (.22 +/- .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 +/- 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite 1-(5-hydroxy-hexyl)-3,7-dimethylxanthine (MI), the maximum concentration and AUCss of the smokers were significantly decreased when compared with the nonsmokers. The AUCss of the smokers was 1438 +/- 819 ng.hour/mL and of the nonsmokers was 2864 +/- 1375 ng.hour/mL (P < .02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces MI plasma concentrations.

Intravenous metoprolol tartrate is commonly used to reduce morbidity and mortality in the acute treatment of myocardial infarction in hemodynamically stable patients, especially in the presence of hypertension.[1][1] Such patients are often receiving other intravenous medications by continuous

A 66 year-old woman with no history of renal or liver disease presented with progressive asthenia and diffuse myalgia. She cited 5 months history of mild hyperlipidemia under treatment with rosuvastatin (10 mg/day). Clinical examination documented both an increase in liver size and proximal muscle weakness, with difficulty in raising arms above the head. Blood tests showed the presence of renal, liver and muscle failure, with no evidence of virological, immunological or haematological diseases. Rosuvastatin treatment was stopped and blood values normalised within five days; but because of an increase in cholesterol plasma levels, rosuvastatin (10 mg/day) was restarted. Two days later, the patient returned to our observation due to the development of asthenia and muscle weakness, with an increase in creatine phosphokinase, 12,165 U/l. Rosuvastatin was discontinued and replaced with pravastatin (40 mg/day) with a complete resolution of clinical and laboratory findings in about six days. Our patient was taking rosuvastatin, warfarin and telmisartan, which are metabolised by CYP2C9; we therefore hypothesised that the rosuvastatin-induced rhabdomyolysis was probably by CYP2C9 enzyme saturation.

Purpose Hepatic steatosis is frequently observed in subjects with metabolic syndrome (MS). In type 2 diabetics, it is independently associated with cardiovascular diseases. In order to confirm and extend this finding, a large group of patients with risk factors for atherosclerosis was studied. Methods Carotid atherosclerosis was investigated by echo-Doppler, and hepatic steatosis by ultrasound and transaminase values. Strict exclusion criteria were chosen in order to avoid secondary forms of fatty liver and interference on transaminase values. Results Among 970 enrolled patients, about 20% were diabetics, half had MS and 76% presented echographic hepatic steatosis. In multivariate analyses, fatty liver and MS were associated with carotid atherosclerosis [odds ratio (95% confidence intervals) 2.15 (1.27–3.63) and 1.72 (1.12–2.64), respectively], whereas HOMA index was not. Aspartate aminotransferase and alanine aminotransferase were not independently associated with carotid atherosclerosis, whereas gamma-glutamyl transferase showed a link with atherosclerosis beyond MS and steatosis presence. The analyses of the 780 non diabetics recruited showed similar results. Conclusions The results of the present study demonstrate that hepatic steatosis measured by echography is associated with carotid atherosclerosis in a large population mostly carrying cardiovascular or metabolic risk factors, independently of MS, cardiovascular diseases, diabetes mellitus and/or insulin resistance.

Assessing the predictors of late rectal toxicity after high-dose conformal radiotherapy for prostate cancer.One thousand one hundred thirty-two patients entered a prospective observational multicentric study; late rectal toxicity was evaluated by a self-reported questionnaire. Results concerning bleeding and faecal incontinence of 718/1132 patients with a complete follow-up at 36 months were analysed. The correlation between a number of clinical-dosimetric parameters and moderate/severe toxicity was investigated by univariate and multivariate logistic analyses.Fifty-two (7.2%) and 57/718 (7.9%) patients were scored as moderate/severe bleeders and faecal incontinents, respectively; 19/57 incontinent patients showed persistent incontinence at 36 months. Bleeding was mainly correlated with V75 Gy while severe bleeding was mainly correlated with the previous abdominal/pelvic surgery; a different rectal dose-volume relationship in the two groups of patients (with/without surgery) was found. Moderate/severe acute toxicity was weakly correlated to late bleeding. The best predictor of faecal incontinence was acute toxicity (OR=4 and 7 for chronic and actuarial incontinence, respectively).The application of rectal dose-volume constraints limited the incidence of rectal bleeding. The risk of bleeding may be further reduced by limiting V75 Gy5% and, in the case of patients previously submitted to abdominal/pelvic surgery, V70 Gy15-20%. Faecal incontinence seems to be mainly a consequential effect after acute toxicity.

The Lp(a) is a low density lipoprotein produced by the liver and it seems to be related to vascular diseases. There is a large individual variability of Lp(a) in the blood levels in the different subjects. The mechanism of the Lp(a) in the pathogenesis of atherosclerosis is not completely clear. There are a lot of different hypotheses and, one of these, is based on the structural analogy of apo(a) with plasminogen. According to current knowledge, it seems that there is a strong relationship between Lp(a) levels and coronary artery disease. Instead, there are still doubts about the real relationship between Lp(a) and stroke. Furthermore, Lp(a) levels seems to be influenced by some other cardiovascular risk factors: fibrinogen, cigarette smoke, and other. Actually, the dosage of the protein is not very useful in clinical practice.

Purpose To predict acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) and Subjective Objective Signs Management and Analysis/Late Effect of Normal Tissue (SOMA/LENT) toxicities of the lower gastrointestinal (LGI) syndrome in patients with prostate cancer undergoing three-dimensional conformal radiotherapy using a tool (nomogram) that takes into account clinical and dosimetric variables that proved to be significant in the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0102 trial. Methods and Materials Acute rectal toxicity was scored in 1,132 patients by using both the RTOG/EORTC scoring system and a 10-item self-assessed questionnaire. Correlation between clinical variables/dose–volume histogram constraints and rectal toxicity was investigated by means of multivariate logistic analyses. Multivariate logistic analyses results were used to create nomograms predicting the symptoms of acute LGI syndrome. Results Mean rectal dose was a strong predictor of Grade 2–3 RTOG/EORTC acute LGI toxicity (p = 0.0004; odds ratio (OR) = 1.035), together with hemorrhoids (p = 0.02; OR = 1.51), use of anticoagulants/antiaggregants (p = 0.02; OR = 0.63), and androgen deprivation (AD) (p = 0.04; OR = 0.65). Diabetes (p = 0.34; OR = 1.28) and pelvic node irradiation (p = 0.11; OR = 1.56) were significant variables to adjust toxicity prediction. Bleeding was related to hemorrhoids (p = 0.02; OR = 173), AD (p = 0.17; OR = 0.67), and mean rectal dose (p = 0.009; OR = 1.024). Stool frequency was related to seminal vesicle irradiation (p = 0.07; OR = 6.46), AD administered for more than 3 months (p = 0.002; OR = 0.32), and the percent volume of rectum receiving more than 60 Gy (V60Gy) V60 (p = 0.02; OR = 1.02). Severe fecal incontinence depended on seminal vesicle irradiation (p = 0.14; OR = 4.5) and V70 (p = 0.033; OR = 1.029). Conclusions To the best of our knowledge, this work presents the first set of nomograms available in the literature specific to symptoms of LGI syndrome and provides clinicians with a tailored probability of the specific outcome. Validation of the tool is in progress.

Purpose: To find predictors for rectal and intestinal acute toxicity in patients with prostate cancer treated with ≥70 Gy conformal radiotherapy. Methods and Materials: Between July 2002 and March 2004, 1,132 patients were entered into a cooperative study (AIROPROS01-02). Toxicity was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale and by considering the changes (before and after treatment) of the scores of a self-administered questionnaire on rectal/intestinal toxicity. The correlation with a number of parameters was assessed by univariate and multivariate analyses. Concerning the questionnaire, only moderate/severe complications were considered. Results: Of 1,132 patients, 1,123 were evaluable. Of these patients, 375, 265, and 28 had Grade 1, 2, and 3 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity, respectively. The mean rectal dose was the most predictive parameter (p = 0.0004; odds ratio, 1.035) for Grade 2 or worse toxicity, and the use of anticoagulants/antiaggregants (p = 0.02; odds ratio, 0.63) and hormonal therapy (p = 0.04, odds ratio, 0.65) were protective. The questionnaire-based scoring revealed that a greater mean rectal dose was associated with a greater risk of bleeding; larger irradiated volumes were associated with frequency, tenesmus, incontinence, and bleeding; hormonal therapy was protective against frequency and tenesmus; hemorrhoids were associated with a greater risk of tenesmus and bleeding; and diabetes associated highly with diarrhea. Conclusion: The mean rectal dose correlated with acute rectal/intestinal toxicity in three-dimensional conformal radiotherapy for prostate cancer, and hormonal therapy and the use of anticoagulants/antiaggregants were protective. According to the moderate/severe injury scores on the self-assessed questionnaire, several clinical and dose–volume parameters were independently predictive for particular symptoms.

Aims and background The National Working Group on Prostate Radiotherapy of AIRO (Associazione Italiana Radioterapia Oncologica, Italian Association of Radiotherapeutic Oncology) was established in March 2001. A retrospective multicenter survey was performed to analyze the patterns of care for prostate cancer patients treated with postoperative radiotherapy following radical prostatectomy in Italy with regard to the year 2000. Materials and methods A structured questionnaire was mailed to 47 Italian radiotherapy centers to assess patient accrual in the postoperative setting in the interval comprised between period January-December 2000. Numbers of patients treated for different stages, specific prognostic factors indicating the need for adjuvant radiotherapy, fractionation schedules and prescription doses were acquired as well as other clinically important factors such as radiotherapy timing and the use of hormone therapy. More technical features of the treatment, such as patient positioning, mode of simulation, typical field setup and dose prescription criteria were also included in the questionnaire. Results The questionnaire was returned by 24 radiotherapy Institutions (51%) with a total number of 470 patients treated postoperatively in the year 2000. An average of about 20 patients were enrolled by each radiotherapy center. The age range was 45-81 years. Radiotherapy was delivered within 6 months of radical prostatectomy in 297 patients (65.4%) (mean, 3.4 months). In 157 (34.6%), the treatment was delivered as a salvage approach for biochemical or micro-macroscopic recurrence. Most of patients had locally advanced stage disease (pT3-pT4) (76%). Unfavorable prognostic factors, such as positive margins, capsular invasion, Gleason pattern score Conclusions The study confirmed that important risk factors for recurrences are present in a significant percentage of patients treated by radical prostatectomy. The number of patients that would benefit from adjuvant radiotherapy is therefore potentially very large. Future prospective studies should be conducted to assess and to clarify the respective roles of adjuvant and salvage radiotherapy in prostate cancer patients.

Flunarizine and cinnarizine have been well documented to cause EPS. Other CCBs, on rare occasions, also have been reported to cause EPS. Theoretical explanations for these events include the inhibition of calcium influx into striatal cells and direct dopaminergic antagonistic properties. In addition, the chemical structures of flunarizine and cinnarizine, which are related to neuroleptics, may explain the relatively greater incidence of EPS with these agents. Suggested risk factors for acquiring EPS with flunarizine or cinnarizine use appear to be age, although experience with using these agents in younger patients is limited, and a family history of tremors and/or Parkinson's disease. The onset and type of presentation is unpredictable and, in most instances, discontinuation of the medication relieves the symptoms within a few days to months. Pharmacologic management of EPS with continued use of the offending agent generally has not been of clinical benefit. In conclusion, patients receiving CCBs, particularly flunarizine and cinnarizine, should be monitored for EPS.

OBJECTIVE: To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. DATA SOURCES: A MEDLINE search (1966–December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. DATA SYNTHESIS: Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C–lowering effect of statin medications by an additional 15–20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. CONCLUSIONS: Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.

OBJECTIVE: To review the primary literature describing the pharmacology and clinical uses of bivalirudin. DATA SOURCES: A MEDLINE search (January 1966–May 2001) was conducted that used bivalirudin, hirulog, and direct thrombin inhibitor as key words. References from retrieved articles and unpublished information acquired from the manufacturer and the Internet were also used. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, and clinical efficacy of bivalirudin were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the pharmacology and clinical use of bivalirudin. Given the paucity of data pertaining to the clinical use of bivalirudin, most articles were used, including abstracts and communications with the manufacturer. DATA SYNTHESIS: Bivalirudin is a direct thrombin inhibitor that inactivates both unbound and fibrin-bound thrombin. Bivalirudin rapidly induces anticoagulation and has a relatively short duration of action. Bivalirudin displays linear kinetics and is primarily eliminated renally. Bivalirudin was proven effective in preventing postprocedural ischemic complications in patients with unstable or postinfarction angina who received percutaneous transluminal coronary angioplasty (PTCA). Yet, further investigations that include less critically ill patients and use the current clinical practice of administering glycoprotein IIb/IIIa antagonists and/or inserting intracoronary stents are needed to fully evaluate its efficacy. Bivalirudin has also induced early patency in patients with myocardial infarction in combination with streptokinase, but its use with newer thrombolytics needs to be studied. Bivalirudin has been used in patients with immunologically mediated, heparin-induced thrombocytopenia (HIT) without complications. Bleeding is the major adverse effect and occurs more commonly in patients with renal dysfunction. CONCLUSIONS: At present, bivalirudin is worthy of consideration in patients requiring PTCA who have HIT. Advocating the routine use of bivalirudin in patients experiencing an acute coronary syndrome or HIT is premature.

Control of hyperphosphatemia in renal failure is often difficult to achieve. Although calcium-containing phosphate binders have become the preferred phosphate binders, many patients require the addition of an aluminum-containing phosphate binder (APB). Enhanced aluminum absorption has been noted when APBs are administered with citrate-containing products such as citrate/citric acid solution (CCA). Alternative phosphate binders such as calcium acetate may also increase aluminum absorption. This study investigated the effect of CCAs on aluminum absorption when aluminum antacids (APBs) were administered concurrently and 2 hours apart. The effects of the alternative alkalinizing agent sodium bicarbonate and the alternate phosphate binding agent calcium acetate on aluminum absorption were also studied. During five 2-day phases, ten normal volunteers randomly received three times daily with standardized meals aluminum hydroxide alone and concurrently with NaHCO3, calcium acetate, CCA, or with CCA 2 hours postprandially. Twenty-four hour urines were collected on the second day of each phase and aluminum excretion was determined using inductively coupled plasma emission spectroscopy. Urine aluminum excretion was statistically significantly (P

OBJECTIVE: To evaluate evidence supporting the use of spironolactone in managing congestive heart failure. DATA SOURCES: Literature accessed through MEDLINE (January 1966–December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure. DATA SYNTHESIS: Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure. RESULTS: Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure. CONCLUSIONS: Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.

OBJECTIVE: To describe a hypertensive reaction induced by concurrent use of selegiline and dopamine. CASE SUMMARY: A 75-year-old critically ill white man who was receiving selegiline 5 mg twice daily for Parkinson's disease was initiated on an intravenous dopamine infusion for decreased urine output and hypotension. Within minutes of starting the dopamine infusion, the patient's systolic blood pressure increased from 105 to 228 mm Hg. Similar reactions occurred during two subsequent rechallenges. DISCUSSION: Since monoamine oxidase is involved in the metabolism of catecholamines, selegiline may have affected the metabolism of the dopamine administered to the patient. Although selegiline is known to be a monoamine oxidase inhibitor specific for type B, evidence exists stating that selegiline may not be as specific as previously thought. CONCLUSIONS: Dopamine should be used cautiously, if at all, in patients who are chronically receiving selegiline or who have received selegiline within the prior two weeks.

Chronic lymphocytic leukemia (CLL) is recognized as a heterogeneous disease.[1][1] Although the clinical staging systems (Rai et al[2][2] and Binet et al[3][3]) provide useful methods of assessing patient prognosis, they do not provide an understanding of the basis of the heterogeneity. CLL cells

The aim of this study was to evaluate long-term clinical follow-up and echocardiographic data on pregnant patients with mitral stenosis who underwent percutaneous mitral valvuloplasty (PMV) in our center and the development of their infants. PMV has proven to be an effective alternative to treat pregnant patients with mitral stenosis. However, long-term outcome of these patients, as well as the potential harmful effects caused by radiation on their infants, still awaits to be determined. From January 1988 to February 1999, 30 pregnant women (mean gestational duration, 24.95 +/- 5.59 weeks) underwent PMV. Twenty-three (77%) were subsequently followed by a medical interview during 5.33 +/- 3.12 years. Clinical variables such as NYHA functional class (FC), the need of a repeat PMV or surgical procedure, the presence of embolic events, and mortality rate were evaluated during follow-up. Mitral valve area, mean transmitral gradient, and the presence of mitral regurgitation were also assessed by Doppler echocardiography. Clinical data on the development of the infants were obtained from the assistant pediatricians. All patients were in NYHA FC III or IV before the procedure. During follow-up, 91% of them were in FC I and II. Two patients (9%) who had remained in FC III underwent a repeat successful PMV; no further surgery was required. There were no embolic events or death related to the procedure. Echocardiography showed an initial increase in mitral valve area from 1.14 +/- 0.22 cm(2) to 2.01 +/- 0.21 cm+/- (P0.0001). During long-term follow-up, it decreased to a mean of 1.75 +/- 0.24 cm(2) (P0. 0001). Initial transmitral valve gradient decreased from 17.73 +/- 4. 56 mm Hg to 5.91 +/- 1.80 mm Hg (P = 0.0001) and 8.95 +/- 3.58 (P = 0.002) during long-term follow-up. Twenty one children (96%), aged 4. 91 +/- 2.8 years, showed normal growth and development, and no clinical abnormalities were observed. These favorable long-term results suggests PVM to be the procedure of choice to treat pregnant women with mitral stenosis who remain in FC III or IV despite adequate medical therapy. No harmful effects due to the use of radiation were observed in the children.

The effect of aluminum hydroxide gel on quinidine gluconate bioavailability was studied in eight nonsmoking healthy male volunteers. Subjects were randomized to receive quinidine gluconate 648 mg with and without 30 mL of aluminum hydroxide gel. The mean area under the concentration-time curve (AUC) (23.11 ±5.21 mg•h/L), time to reach maximum concentration (tmax) (3.13 ± 0.64 h), maximum serum concentration (1.44 ±0.41 mg/L), and elimination rate constant (0.069 ±0.010−h) observed during the control phase of the trial did not differ significantly (p>0.05) from values obtained during the coadministration of aluminum hydroxide with quinidine gluconate (23.91 ±4.48 mg•h/L, 4.13 ±2.12 h, 1.53 ±0.34 mg/L, and 0.077 ±0.013−h, respectively). There was considerable individual variation in AUC with one subject demonstrating an increase of 35 percent and one subject demonstrating a decrease of 18 percent. There was a trend toward aluminum hydroxide delaying tmax with only one subject experiencing an earlier tmax, with the coadministration of aluminum hydroxide. The results of this single-dose trial suggest that, although statistically the concurrent administration of aluminum hydroxide gel with quinidine gluconate does not significantly alter the extent of quinidine absorption, clinically significant individual variations may occasionally occur.

OBJECTIVE: To review the literature on the use of thrombolytic agents in the pharmacotherapeutic management of acute myocardial infarction (AMI). DATA SOURCE: English-language clinical trials, reviews, and editorials derived from MEDLINE (January 1966–September 1997) and/or cross-referencing of selected articles. STUDY SELECTION: Articles that were selected best represent the clinical trials researching the role for thrombolytics in the therapy of AMI to improve morbidity and mortality. DATA SYNTHESIS: 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. CONCLUSIONS: 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.

Macrolide antibiotics appear to be able to enhance the oral bioavailability of digoxin by altering the gastrointestinal flora that metabolize digoxin to less active dihydro metabolites, thus leading to increased serum digoxin concentrations and possible digoxin toxicity in select patients stabilized on digoxin therapy. This interaction may be of clinical importance in up to 10% of the population. Currently, the orally administered erythromycin, clarithromycin, and roxithromycin have been implicated. Although realistically this interaction may be encountered rarely, when it does occur, it can be of clinical significance. Addendum Following acceptance of this manuscript, two additional reports of a digoxin–clarithromycin drug interaction have been published. Nawarskas et al.28 described clarithromycin-induced digoxin toxicity (digoxin-induced ST segment changes, non-sustained ventricular tachycardia, and a digoxin concentration of 4.4 ng/mL) due to 3 days of clarithromycin 500 mg bid in a 78-year-old woman stabilized on oral digoxin 0.25 mg/d. Laberge and Martineau29 observed a clinical presentation suggestive of digoxin toxicity and an elevated digoxin concentration of 3.9 ng/mL in a 78-year-old man stabilized on digoxin 0.25 mg/d who had received 4 days of clarithromycin 250 mg bid.

Initial trials hint that HMG-CoA reductase inhibitors may have a role in preventing or retarding the progression of AGAS. Whether the potential of HMG-CoA reductase inhibitors to prevent AGAS is due to their lipid-lowering effect, immunomodulating properties, or a combination of both is also not completely known at present. Further study is needed to fully identify their mode of preventing AGAS and, more important, to determine their usefulness and role in preventing AGAS, especially since concurrent HMG-CoA reductase inhibitor use with cyclosporine is not innocuous. Potential for a pharmacokinetic drug interaction, which results in an elevation of HMG-CoA reductase inhibitor concentrations, exists when these two agents are used together, thus increasing the potential for the HMG-CoA reductase inhibitor to cause musculoskeletal complications. When such combination therapy is used, the likelihood of this interaction can be reduced by prescribing the HMG-CoA reductase inhibitor conservatively--using the smallest effective dose and increasing the daily dosage slowly. Although the risk of musculoskeletal toxicity exists at any HMG-CoA reductase inhibitor dosage, most patients should be able to tolerate daily dosages of up to 20 mg of lovastatin, 10 mg of simvastatin, and 40 mg of pravastatin. Patients also need to be made aware of and monitored for musculoskeletal symptoms suggestive of myositis and/or myalgias. In addition, the avoidance of elevated cyclosporine concentrations and when practical, monitoring of HMG-CoA reductase inhibitor concentrations are recommended.

Although it appears that adenosine would be theoretically useful in the emergent therapy of theophylline toxicity, published clinical data supporting the efficacy and safety of using adenosine for such a situation are currently lacking. The use of adenosine also is not without some risk. In addition, the use of adenosine infusions can be relatively expensive. Until more clinical evidence can be obtained, the routine use of adenosine in the treatment of acute theophylline ingestion cannot be recommended.

Multiple fresh specimens from 59 nonsmall cell carcinomas of the lung, 38 carcinomas of the gastric tract and 55 carcinomas of the colon and rectum were analyzed by deoxyribonucleic acid (DNA) flow cytometry (FC) after radical resection to evaluate tumor ploidy as an independent prognostic factor. The minimum follow-up period was five years (range of five to ten years). Aneuploidy was observed in 98.0 percent of carcinomas of the lung, in 70.9 percent of carcinomas of the colon and rectum and in 63.1 percent of carcinomas of the gastric tract. FC DNA heterogeneity, in terms of different number of DNA stem lines or different DNA indices between core and periphery, or both, was found in 50.0 percent of carcinomas of the lung, 47.0 percent of carcinomas of the colon and rectum and in 34.5 percent of carcinomas of the gastric tract. A diploid pattern was more frequently observed in less advanced stages of the gastrointestinal tract. By univariate analysis (Kaplan-Meier), patients with carcinoma of the lung with hypodiploid or hypertetraploid peaks, or both, and aneuploid gastric tumors had poorer prognosis. These differences were only marginally significant. Cox analysis demonstrated that the single most important prognostic variable for predicting the overall survival rate was the stage of disease. Tumor DNA content can be considered a marker of advanced stages, particularly in tumors of the gastrointestinal tract, but there is no evidence that it is an independent prognostic variable able to predict long term survival in patients who have been radically resected.

Simvastatin is a methyl analogue of lovastatin and acts as an HMG-CoA reductase inhibitor effective in the treatment of hypercholesterolaemia. Like lovastatin, it is an inactive hydrophobic lactone prodrug which is metabolised in vivo to several more polar, pharmacologically active compounds, most notably the corresponding hydroxy acid form, simvastatin acid. HPLC techniques have been developed to assay simvastatin and its metabolites. In addition, a pharmacodynamic assay has been developed that measures HMG-CoA reductase inhibitory activity. This latter assay may be more applicable to clinical situations since simvastatin is not active, while its metabolites are. Simvastatin is well absorbed from the gastrointestinal tract but is highly extracted by the liver and only 7% of the dose reaches the general circulation intact. The peak inhibition of HMG-CoA reductase activity occurs within 2 to 4 hours. Increasing the dose of simvastatin from 5 to 120 mg increases the pharmacological activity in a linear fashion. The several metabolites tend to remain within the liver and the intestines (via biliary excretion). Some gastrointestinal reabsorption of metabolites may occur. Simvastatin is eliminated mainly in the faeces due to biliary excretion but only a small percentage of the dose is found in the stool in the form of the parent compound or simvastatin acid. Since simvastatin is metabolised by the cytochrome P450 system, a potential for drug interactions exists. Elevated HMG-CoA reductase inhibitory activity has been observed when simvastatin was administered concurrently with cyclosporin, possibly increasing the risk of myopathy and subsequent rhabdomyolysis which are associated with simvastatin use. Simvastatin has also been shown to potentiate the effects of warfarin [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To review the literature investigating the use of fish oil in preventing restenosis postangioplasty (RPA). DATA SOURCES: An Index Medicus and bibliographic search of the English-language literature pertaining to the use of fish oil in preventing RPA. The key terms used were fish oil, angioplasty, and eicosapentaenoic acid. STUDY SELECTION AND DATA EXTRACTION: The results of all trials, including abstracts, that were obtained are reviewed and critiqued. DATA SYNTHESIS: Restenosis of a coronary vessel at the site of angioplasty occurs 30–40 percent of the time. Because fish oil has been theorized to prevent atherosclerosis and because atherosclerotic-like processes are theorized to be involved in RPA restenosis, fish oil has been studied to determine whether it can prevent RPA. Results of such trials have been mixed. Some have observed a reduction in the number of patients with angiographic or clinical evidence of restenosis. Two trials have failed to observe such an effect. Reasons for the differences are unknown. Possible explanations include differences in study design, endpoint parameters, definition of restenosis, and dosing methods of the fish oil. Bleeding was not of significant concern in any of the trials, even when fish oil was combined with antiplatelet therapy. CONCLUSIONS: Fish oil may be considered for use in patients to prevent RPA. It probably should be continued for only six months following the procedure. Current data suggest that at least 3 g/d of eicosapentaenoic acid and 1 g/d of docosahexaenoic acid should be used. If possible, therapy should be started as soon as it is known that angioplasty will be performed or at least as soon as possible following the procedure. Many patients may not be able to tolerate fish oil because of its gastrointestinal effects.

The authors describe the different kinds of meteoropathies, pointing out how these disorders are becoming ever more frequent in countries belonging to the consumer and welfare society due to the progressive lowering of body resistance and immunologic responses. These "unfavourable meteosyndromes", as meteoropathies should be called, develop when wave disturbances arrive, and are more manifest and persistent in subjects with neurologic disturbances, i.e. in the presence of anxiety, stress, hypertension, coronary artery disease, arthropathy, hyperthyroidism, etc. The different moments in which meteoropathies are more frequent and the possible therapies are also discussed.

The action of the transcutaneous application of propranolol using modulated sinusoidal current iontophoresis was studied. When this way of administration is used, the drug, while maintaining its negative chronotropic effect, loses the negative inotropic one. Investigations were performed on 58 men aged 32 to 62 who underwent an aortocoronary bypass for myocardial ischemia. Thirty-four patients had already had myocardial infarction. The drug reduced the heart rate and increased cardiac contractility. Moreover, the study showed that only the levogyral isomer of propranolol (the only active one) passes through the skin.