Safety of Intravenous Pantoprazole Sodium in Pediatric Patients Aged 1 Month to < 1 Year: A Real-World Retrospective Cohort Study.

OBJECTIVE: To estimate the incidence rates (IR) of prespecified outcomes of interest in pediatric patients (1 month to < 1 year) treated with intravenous (IV) pantoprazole using Optum's longitudinal electronic health records database (Optum Market Clarity) from the United States (US). METHODS: This real-world, non-interventional, retrospective cohort study was conducted from 01 January 2007 to 31 December 2020 in patients who received IV pantoprazole. Premature patients and those weighing < 2.36 kg were excluded. Patients were categorized based on diagnosis of gastroesophageal reflux disease (GERD) and erosive esophagitis (EE) into: Subgroup 1 (GERD and EE), Subgroup 2 (GERD and no EE), and Subgroup 3 (absence of GERD and EE). Overall IRs (per 1000 person-years [PY]) and 95% confidence intervals (CI) of outcomes were estimated (overall and subgroups) and stratified by duration of IV pantoprazole treatment (< 4 days versus ≥ 4 days). RESULTS: Of 1879 eligible patients, none were identified in Subgroup 1; 851 (45.3%) and 1028 (54.7%) patients were identified in Subgroups 2 and 3, respectively. IRs of outcomes of interest ranged from 0.0 to 742.8 per 1000 PY. IRs were highest for vomiting (742.80), diarrhea (377.77), abdominal distension (214.31), hyponatremia (204.99), and hypokalemia (203.49). IRs were comparable between Subgroups 2 and 3. For most outcomes, IRs were higher among patients treated with IV pantoprazole for ≥ 4 days versus those treated for < 4 days. CONCLUSION: These results are consistent with the known safety profile of pantoprazole and emphasize the utility of using real-world data from pediatric populations for assessment of safety outcomes.

The Midazolam RAMPART Study Medical Records Project: A Unique Use of Real-World Data in a Complex Collaborative Partnership to Support a New Drug Application.

INTRODUCTION: This project aimed to retrospectively obtain, review, and extract key safety data from medical records of participants enrolled in RAMPART, the NIH-supported Rapid Anticonvulsant Medication Prior to ARrival Trial of intramuscular midazolam versus intravenous lorazepam for pre-hospital treatment of status epilepticus, to support a US new drug application (NDA) for intramuscular midazolam. METHODS: A collaborative partnership was established between the NDA sponsor, the RAMPART trial lead academic institution, US government agencies, and contract research organizations to retrieve, review, and extract relevant safety data from the medical records of RAMPART participants and summarize those data to include in an NDA submitted to the US Food and Drug Administration (FDA). RESULTS: Key data in the medical records of 890 RAMPART trial participants (1020 enrollments, including 130 repeat enrollments) were reviewed and extracted into a project database. Safety events occurred in 771 (86.6%) participants, and included additional information not collected in the RAMPART trial. This database also enabled subgroup analyses based on medical history and prior/concurrent medications, building upon previous analyses according to age, sex, and race. No previously unrecognized safety patterns were identified, and no association was observed between efficacy and medical history or medication usage. CONCLUSIONS: The use of unstructured real-world retrospective medical record data can effectively support an NDA submission in place of conducting another interventional clinical trial. This retrospective medical records review and extraction of additional safety data contributed to the FDA approval of intramuscular midazolam for the pre-hospital treatment of status epilepticus in 2018. CLINICALTRIALS: GOV: NCT00809146.

A phase 2 pharmacodynamic dose-finding, safety, and efficacy study of dalteparin for pediatric venous thromboembolism treatment in children with and without cancer.

Data from registrational trials of pediatric venous thromboembolism (VTE) treatment are sparse, especially among cancer patients. We conducted a prospective, multicenter, open-label trial (NCT00952380) on dose-finding, safety, and efficacy (measured by 90-day risks of clinically relevant bleeding [CRB] and symptomatic recurrent VTE [srVTE]) of twice-daily subcutaneous dalteparin for acute VTE treatment in patients ≤18 years old. Among 38 patients (cancer, n = 26; noncancer, n = 12), median dalteparin dose requirements per kilogram varied with age but not cancer status. Risks of CRB and srVTE were <4% in cancer and noncancer subgroups. Dalteparin is an important FDA-approved treatment for pediatric VTE, particularly with cancer.

Narrowing feedstock exemptions under the Montreal Protocol has multiple environmental benefits.

The Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal Protocol) can be further strengthened to control ozone-depleting substances and hydrofluorocarbons used as feedstocks to provide additional protection of the stratospheric ozone layer and the climate system while also mitigating plastics pollution. The feedstock exemptions were premised on the assumption that feedstocks presented an insignificant threat to the environment; experience has shown that this is incorrect. Through its adjustment procedures, the Montreal Protocol can narrow the scope of feedstock exemptions to reduce inadvertent and unauthorized emissions while continuing to exempt production of feedstocks for time-limited, essential uses. This upstream approach can be an effective and efficient complement to other efforts to reduce plastic pollution. Existing mechanisms in the Montreal Protocol such as the Assessment Panels and national implementation strategies can guide the choice of environmentally superior substitutes for feedstock-derived plastics. This paper provides a framework for policy makers, industries, and civil society to consider how stronger actions under the Montreal Protocol can complement other chemical and environmental treaties.

Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).

An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study).

BACKGROUND: Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice. OBJECTIVE: The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week. DESIGN: A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016. SETTING: Ten sites in Canada. PATIENTS: A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week. MEASUREMENTS: The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation. METHODS: All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits. RESULTS: Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation. LIMITATIONS: This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d. CONCLUSIONS: Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879618, registered June 13, 2013.

CONTEXTE: La daltéparine sodique, une héparine de faible poids moléculaire, est indiquée pour prévenir la formation de caillots dans le circuit extracorporel durant l'hémodialyse (HD). Pour une séance de dialyse d'une durée maximale de quatre heures, l'étiquette du produit recommande une dose fixe de 5 000 unités internationales (U.I.) administrée en bolus. Cependant, il est possible qu'il puisse être bénéfique d'ajuster la dose en pratique. OBJECTIF: Le but de l'étude PARROT était d'analyser l'innocuité et l'efficacité d'une dose ajustable de daltéparine chez des patients atteints d'insuffisance rénale terminale (IRT) et nécessitant trois à quatre séances d'HD par semaine. TYPE D'ÉTUDE: Il s'agit d'une étude ouverte et multicentrique à traitement unique d'une durée de sept semaines couvrant la période entre octobre 2013 et mars 2016. CADRE: L'étude a eu lieu dans dix centres de dialyse au Canada. SUJETS: L'étude a inclus 152 patients atteints d'IRT et nécessitant trois à quatre séances d'HD par semaine. MESURES: Le résultat principal était la proportion de séances d'HD complétées, non interrompues de manière prématurée en raison d'une anticoagulation inadéquate. MÉTHODOLOGIE: Tous les participants ont initialement reçu 5000 U.I. de daltéparine, dose qui a pu être ajustée lors des séances subséquentes, lorsqu'indiqué par le contexte clinique, à raison d'augmentation ou de réduction de 500 ou 1 000 U.I., sans spécification quant aux doses limites. RÉSULTATS: Les patients ont été suivis sur une période de 256 mois-patients. Pratiquement toutes les séances d'HD évaluables (99,9 %; IC 95 % : 99,7-100) ont été complétées sans coagulation prématurée. La dose de daltéparine a été ajustée pour plus de la moitié (52,3 %) des participants, essentiellement en raison de coagulation ou d'un besoin de procéder à une compression de l'accès vasculaire au-delà de 10 minutes. La dose médiane de daltéparine était de 5 000 U.I. (entre 500 et 13 000 U.I.). Aucune hémorragie majeure n'a été rapportée, mais une hémorragie mineure est survenue dans 2,3 % de toutes les séances d'HD analysées. Aucune bioaccumulation n'a été détectée. LIMITES: Cette étude de courte durée à traitement unique a été conçue pour optimiser le dosage de daltéparine à l'aide d'un schéma de posologie flexible. Elle ne visait pas à évaluer spécifiquement la minimisation de la dose ou à fournir des informations sur l'innocuité à long terme d'une posologie flexible pour la daltéparine. Également, les patients à haut risque d'hémorragie ont été exclus de l'étude, notamment ceux qui prenaient des anticoagulants ou des antiplaquettaires autres qu'une dose quotidienne de moins de 100 mg d'aspirine. CONCLUSION: Dans l'ensemble, un schéma posologique flexible pour la daltéparine sodique a permis de compléter les séances d'HD de façon sécuritaire, en plus de fournir des avantages cliniques par rapport à une dose fixe.

Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. CONCLUSIONS: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures.

OBJECTIVE: Part 1 of this phase III study was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study of caregiver administered diazepam auto-injector (AI) in subjects with acute repetitive seizures (ARS) and demonstrated that diazepam AI was well-tolerated and significantly more effective than placebo AI in delaying the time to next seizure or rescue. Part 2 of this study, presented herein, was an open-label continuation to assess the long-term safety and effectiveness of diazepam AI for the treatment of ARS. METHODS: Of the 234 subjects randomized in part 1, 161 continued into part 2 and were provided open-label diazepam AI. Effectiveness measures were time to next seizure or rescue, number of subsequent rescues by type (rescue medication, emergency room visit, or other medical care), and number of subsequent seizures during the 12-h follow-up period. Safety data (adverse events and respirations <8/min) were also collected. RESULTS: During the open-label part 2 study, 129 subjects were administered a total of 1,380 diazepam AI treatments (median 4.5; range 1-118), of which 1,071 (77.6%) were effective with no subsequent seizure or rescue during the 12-h follow-up period. Median number of subsequent seizures experienced by subjects was one (range 0-20). Of the 1,380 administrations, 79 (5.7%) required use of rescue medication, 18 (1.3%) required a visit to an emergency room, and 6 (0.4%) required other rescue medical care. In most (75%) of subjects with treatment-emergent adverse events (TEAEs), TEAEs were mild or moderate in severity. Commonly reported treatment-related TEAEs were injection-site pain (10.9%), injection-site hemorrhage (7%), and injection-site bruising (6.3%). Although three subjects met the predefined respiratory rate threshold, none were considered clinically significant or reported as AEs. SIGNIFICANCE: Long-term treatment with diazepam AI administered by trained caregivers in an outpatient setting to treat ARS is a safe and effective option. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

A double-blind, randomized, placebo-controlled trial of a diazepam auto-injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures.

PURPOSE: A diazepam auto­injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501). METHODS: In this phase III, randomized, double­blind, parallel­group, placebo­controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2­5, 6­11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. KEY FINDINGS: Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent­to­treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval [CI] 0.34­0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38­2.03) for placebo AI and 2.70 h (95% CI 0.48­11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12­h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment­emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). SIGNIFICANCE: The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well tolerated, with a safety profile similar to placebo.

Maladaptively high and low openness: the case for experiential permeability.

The domain of Openness within the Five-Factor Model (FFM) has received inconsistent support as a source for maladaptive personality functioning, at least when the latter is confined to the disorders of personality included within the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; APA, ). However, an advantage of the FFM relative to the DSM-IV-TR is that the former was developed to provide a reasonably comprehensive description of general personality structure. Rather than suggest that the FFM is inadequate because the DSM-IV-TR lacks much representation of Openness, it might be just as reasonable to suggest that the DSM-IV-TR is inadequate because it lacks an adequate representation of maladaptive variants of both high and low Openness. This article discusses the development and validation of a measure of these maladaptive variants, the Experiential Permeability Inventory.

Using the five-factor model to identify a new personality disorder domain: the case for experiential permeability.

Two studies were conducted to demonstrate that maladaptive aspects of high and low Openness to Experience were related to characterological impairment and that this aspect of personality may define a new domain of personality dysfunction. The 55-item Experiential Permeability Inventory (EPI; containing 4 scales) was developed and demonstrated to have acceptable psychometric properties. Evidence of convergent, discriminant, and incremental validity was provided. These studies provide a methodological framework for identifying and developing aspects of personality dysfunction that can expand the comprehensiveness of the current set of Axis II disorders. Theoretical implications of the EPI are discussed.

Self-esteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicenter, randomized, parallel group, double-blind, placebo controlled study in the United States.

PURPOSE: We assessed the change in confidence, relationships and self-esteem, and its correlation with erectile function in men with ED treated with sildenafil citrate in the first United States based, double-blind, placebo controlled, randomized trial assessed by the validated SEAR. MATERIALS AND METHODS: This 12-week flexible dose (25, 50 or 100 mg) trial determined change scores from baseline to end of treatment for the 5 SEAR components (Sexual Relationship domain, Confidence domain, Self-Esteem subscale [prespecified as the primary end point], Overall Relationship subscale and Overall score), and their correlations with the IIEF and event log data, as well as correlations between SEAR components and a general efficacy question at the end of treatment. RESULTS: Compared with the placebo group (125 patients, mean age +/- SD 55 +/- 13 years, mean years ED 3.8 +/- 4.2), the sildenafil group (128 patients, mean age +/- SD 56 +/- 12, mean years ED 4.6 +/- 4.3) had significantly greater improvements in all 5 SEAR components (p < 0.0001) and all sexual function measures. SEAR component scores showed significant correlations with IIEF Erectile Function domain scores (r range 0.34 to 0.69, p < 0.0001), other IIEF domain scores (p < 0.0001), percentage of successful intercourse attempts (p < 0.0001) and frequency of erection that allowed satisfactory intercourse (p < 0.0001). CONCLUSIONS: In this study of men with ED, sildenafil produced substantial improvements in self-esteem, confidence and relationship satisfaction as measured by SEAR scores, which showed moderate to high positive correlations with IIEF scores.

Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure.

Chronic heart failure (CHF) is an increasingly common cardiovascular disorder. Many patients who have CHF report moderate to marked decreases in the frequency of sexual activity, and up to 75% of patients report erectile dysfunction (ED). There are few controlled clinical data on the efficacy and safety of sildenafil citrate in men who have ED and CHF; thus, we evaluated these parameters in patients who had stable CHF. This was a double-blind, placebo-controlled, flexible-dose study. Men who had ED and stable CHF were randomized to receive sildenafil or placebo for 12 weeks. Primary outcomes were questions 3 and 4 of the International Index of Erectile Function. Secondary outcomes included the 5 functional domains of the International Index of Erectile Function, 2 global efficacy assessment questions, intercourse success rate, the Erectile Dysfunction Inventory of Treatment Satisfaction, and the Life Satisfaction Checklist. By week 12, patients who received sildenafil (n = 60) showed significant improvements on questions 3 and 4 compared with patients who received placebo (n = 72; p <0.002). Larger percentages of patients who received sildenafil reported improved erections (74%) and improved intercourse (68%) compared with patients who received placebo (18% and 16%, respectively). Intercourse success rates were 53% among patients who received sildenafil and 20% among those who received placebo. Patients who received sildenafil were highly satisfied with treatment and their sexual life compared with patients who received placebo. Sixty percent of patients who received sildenafil and 48% of patients who received placebo developed adverse events, including transient headache, facial flushing, respiratory tract infection, and asthenia. The incidence of events related to cardiovascular effects was low. Sildenafil is an effective and well-tolerated management of ED in men who have mild to moderate CHF.

Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial.

BACKGROUND: Erectile dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of sildenafil citrate for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial. METHODS: A total of 568 men (> or =18 years) with ED and hypertension who were taking two or more antihypertensives were randomized to sildenafil (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse. RESULTS: A total of 562 men (mean age, 59 years) took > or =1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events. CONCLUSIONS: Sildenafil was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use of sildenafil in these patients.