The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials

BACKGROUND: In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed. METHOD: Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day) or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data. RESULTS: Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6-16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p < or = .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms. CONCLUSION: Risperidone produced significantly (p < or = .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents.     

A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team

BACKGROUND: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. METHOD: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. RESULTS: The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated. CONCLUSIONS: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.     

Effect of psychotherapy on the course of Crohn''s disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn''s disease. German Study Group on Psychosocial Intervention in Crohn''s Disease

OBJECTIVES: To determine whether a combination of ciprofloxacin hydrochloride and metronidazole hydrochloride would be as effective or more effective than a combination of gentamicin sulfate and metronidazole hydrochloride for preventing infection in patients with penetrating abdominal trauma, to evaluate the factors associated with increased risk of infection, and to determine the serum peak and trough levels of gentamicin with the dosage regimen of 2.5 mg/kg every 12 hours. DESIGN: Randomized double-blind study. SETTING: Level I trauma center. PATIENTS: Eighty-four patients with penetrating intra-abdominal injuries (gunshot wound, 69; stab wound, 15) thought to require laparotomy. INTERVENTIONS: The patients were randomized during treatment in the emergency department to be given a combination of ciprofloxacin hydrochloride, 400 mg every 12 hours, and metronidazole hydrochloride, 500 mg every 6 hours, or a combination of gentamicin sulfate, 2.5 mg/kg every 12 hours, and metronidazole hydrochloride, 500 mg every 6 hours. RESULTS: Of 68 patients with intra-abdominal injuries who could be observed for at least 48 hours after laparotomy, posttraumatic infections developed in 12 (18%), and nosocomial infections developed in 6 (9%). The incidence of posttraumatic infections in patients who were given gentamicin and metronidazole (5/33 [15%]) was not significantly lower than the incidence in patients who were given ciprofloxacin and metronidazole (7 of 35 [20%]; P=.75). The presence of any infection increased the mean+/-SD length of hospital stay from 8.7+/-3.5 days to 23.3+/-10.9 days and increased the mean+/-SD hospital charges from $24 507+/-$9860 to $104920+/-$49083 (P<.001). Univariate analysis showed the factors most significantly associated with infection were as follows: (1) the use of blood transfusions (P<.001), (2) the penetrating abdominal trauma index of 35 or more (P<.002), (3) injury to the colon requiring a colostomy (P=.004), and (4) a trauma score of less than 12 (P<.02). Multivariate analysis showed the only significant factor was the receipt of blood transfusions (F=10.165; P<.005). CONCLUSIONS: Ciprofloxacin and gentamicin, each in combination with metronidazole, were equivalent in their ability to prevent infections after penetrating abdominal trauma; other factors, especially the receipt of blood transfusions, had much more effect on the incidence of infection. Infection greatly increases the length of hospital stay and hospital charges. The use of an increased dosing regimen of 2.5 mg/kg every 12 hours of gentamicin sulfate was effective at obtaining a therapeutic peak serum concentration.     

Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial

CONTEXT: Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years. DESIGN: Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995. SETTING AND PARTICIPANTS: Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers. INTERVENTION: Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks. MAIN OUTCOME MEASURES: Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels. RESULTS: A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels. CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.     

Phase-IV multicentre clinical study of risperidone in the treatment of outpatients with schizophrenia. The RIS-CAN-3 Study Group

OBJECTIVE: Since most clinical trials of atypical antipsychotics have been conducted in hospitalized patients, a Phase-IV, multicentre, 8-week, open-label, flexible-dose study was performed to assess the efficacy and safety of risperidone in outpatients with schizophrenia. METHOD: Three hundred and thirty patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) diagnosis of schizophrenia were enrolled at 61 Canadian sites. Upon trial entry, the patients had their neuroleptic and antiparkinsonian drugs discontinued, and treatment with risperidone was initiated at a dose of 2 mg daily, then increased by 2 mg daily on each of the 2 following days until the initial target dose of 6 mg daily was reached on day 3. No further titration was allowed until day 14, after which the dose could be increased or decreased. RESULTS: During the stabilization phase (days 14-56), the dose was unchanged in 44% of the patients, increased in 24%, decreased in 23%, and titrated both up and down in 9% of the patients. In the efficacy-evaluable population (n = 292), treatment with risperidone produced substantial (-26.4) and significant (P = 0.0001) improvement in the total Positive and Negative Syndrome Scale (PANSS) score. At the end of the study (week 8), 85% of patients were classified as clinically improved according to an a priori definition (that is, 20% or more decrease from baseline in total PANSS score). On their last study visit, 75% of patients reported their experience with risperidone as better than their previous neuroleptic therapy. Risperidone was generally well tolerated. The adverse events reported by more than 5% of the patients were insomnia, nausea, headache, somnolence, dizziness, fatigue, anxiety, vomiting, and ejaculation disorder. Seventy-four percent of the reported treatment-related adverse events were recorded during the first 2 weeks of the trial, possibly because of the discontinuation of prior neuroleptic and antiparkinsonian drugs followed by immediate upward titration of risperidone. However, only 8.5% of adverse events were reported to have occurred during week 3, and only 0.8% of adverse events were reported for week 8. Risperidone treatment produced significant improvements over baseline in the incidence and severity of extrapyramidal symptoms (EPS). A slight but statistically significant increase in body weight was observed. CONCLUSIONS: The results of this open-label, Phase-IV trial in a large population of outpatients with schizophrenia found that risperidone was superior to the neuroleptics that patients had previously taken in terms of efficacy and severity of EPS. Our results suggest the use of risperidone at lower doses in outpatients with schizophrenia.     

Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial

CONTEXT: Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to be minimal or absent. OBJECTIVE: To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM). DESIGN: Double-blind, randomized, placebo-controlled, parallel trial. SETTING: Sixty-two sites in the United States. PARTICIPANTS: A total of 569 male and female volunteers with type 2 DM. INTERVENTION: After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n = 377) or placebo (n = 192) for 12 weeks. MAIN OUTCOME MEASURES: Change from baseline in glucose and hemoglobin A1c (HbA1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries. RESULTS: After 12 weeks, mean (+/-SE) HbA1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5% 0.1% vs 9.3%+/-0.1% and 7.0+/-0.1 mmol/L [126+/-2 mg/dL] vs 9.3+/-0.2 mmol/L [168+/-4 mg/ dL], respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P= .004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P=.003), general health (+0.27; P=.01), sleep (+0.26; P=.04), depression (+0.25; P=.05), disorientation and detachment (+0.23; P= .05), and vitality (+0.22; P=.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses = $24 vs $115 per worker per month; P<.001), fewer bed-days (losses = $1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses = $2660 vs $4275 per 1000 person-days; P=.01). CONCLUSIONS: Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.     

Survey on the pharmacodynamics of the new antipsychotic risperidone

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50: 0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50: 0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056-0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4-10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and alpha-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.     

Use of atypical neuroleptics in child and adolescent psychiatry

BACKGROUND: This article reviews the published clinical experience with atypical neuroleptics in children and adolescents. METHOD: A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug. RESULTS: We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder. CONCLUSION: The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.     

Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study

OBJECTIVE: To investigate the short-term safety and efficacy of risperidone in the treatment of children and adolescents with pervasive developmental disorders. METHOD: This was a 12-week, prospective, systematic, open-label trial that included 18 subjects (15 boys and 3 girls) with a mean age of 10.2 +/- 3.7 years. The sample included 11 subjects with autistic disorder, 3 with Asperger's disorder, 1 with childhood disintegrative disorder, and 3 with pervasive developmental disorder not otherwise specified. Fourteen subjects had comorbid mental retardation. Behavioral ratings were obtained during two baseline visits and again after 12 weeks of risperidone treatment. RESULTS: The optimal dose of risperidone for the 18 subjects was 1.8 +/- 1.0 mg/day. On the basis of the global improvement item of the Clinical Global Impression Scale, 12 of 18 subjects were considered responders. Significant improvement was seen in measures of interfering repetitive behavior, aggression and impulsivity, and some elements of impaired social relatedness. The most common side effect was weight gain (range 10 to 35 lb). CONCLUSIONS: These preliminary results suggest that risperidone may be effective for improving interfering behavioral symptoms in some children and adolescents with pervasive developmental disorders. Double-blind, placebo-controlled studies are needed before definitive statements of safety and efficacy can be made.     

Normalization of acquired QT prolongation in humans by intravenous potassium

BACKGROUND: QT interval prolongation and dispersion have been implicated in serious arrhythmias in congestive heart failure (CHF) and the congenital and drug-induced long-QT syndromes (LQTS). In a subset of the congenital LQTS, infusion of potassium can correct QT abnormalities, consistent with in vitro increases in outward currents such as I(Kr) or I(Kl) when extracellular potassium concentration ([K+]o) is increased. Furthermore, increasing [K+]o decreases the potency of I(Kr)-blocking drugs in vitro. The purpose of this study was to test the hypothesis that increasing [K+]o corrects QT abnormalities in CHF and in subjects treated with quinidine. METHODS AND RESULTS: KCl (maximum, 40 mEq) was infused into (1) 12 healthy subjects treated with quinidine sulfate (5 doses of 300 mg/5 h) or placebo and (2) 8 CHF patients and age-matched normal control subjects. Mean [K+] increased from 4 to 4.2 mEq/L to 4.7 to 5.2 mEq/L. Potassium infusion significantly reversed QTUc prolongation, especially in the precordial leads (quinidine, 590+/-79 to 479+/-35 [+/-SD] ms(1/2), P<.001; CHF, 521+/-110 to 431+/-47 ms(1/2), P<.05). There was no effect in either control group. Similarly, potassium decreased QTUc dispersion (quinidine, 210+/-62 to 130+/-75 ms(1/2), P<.01; CHF, 132+/-68 to 84+/-35 ms(1/2), P=.07) and was without effect in the control subjects. QT morphological abnormalities, including U waves and bifid T waves, were reversed by potassium. CONCLUSIONS: Potentially arrhythmogenic QT abnormalities during quinidine treatment and in CHF can be nearly normalized by modest elevation of serum potassium.     

Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group

BACKGROUND: Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors. METHODS: The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. RESULTS: After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P<.001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P=.25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02 mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL]; P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. CONCLUSIONS: Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels.     

Early inpatient rehabilitation after elective hip and knee arthroplasty

CONTEXT: Inpatient rehabilitation after elective hip and knee arthroplasty is often necessary for patients who cannot function at home soon after surgery, but how soon after surgery inpatient rehabilitation can be initiated has not been studied. OBJECTIVE: To test the hypothesis that high-risk patients undergoing elective hip and knee arthroplasty would incur less total cost and experience more rapid functional improvement if inpatient rehabilitation began on postoperative day 3 rather than day 7, without adverse consequences to the patients. DESIGN: Randomized controlled trial conducted from 1994 to 1996. SETTING: Tertiary care center. PARTICIPANTS: A total of 86 patients undergoing elective hip or knee arthroplasty and who met the following criteria for being high risk: 70 years of age or older and living alone, 70 years of age or older with 2 or more comorbid conditions, or any age with 3 or more comorbid conditions. Of the 86 patients, 71 completed the study. INTERVENTIONS: Random assignment to begin inpatient rehabilitation on postoperative day 3 vs postoperative day 7. MAIN OUTCOME MEASURES: Total length of stay and cost from orthopedic and rehabilitation hospital admissions, functional performance in hospitals using a subset of the functional independence measure, and 4-month follow-up assessment using the RAND 36-item health survey I and the functional status index. RESULTS: Patients who completed the study and began inpatient rehabilitation on postoperative day 3 exhibited shorter mean (+/-SD) total length of stay (11.7+/-2.3 days vs 14.5+/-1.9, P<.001), lower mean (+/-SD) total cost ($25891+/-$3648 vs $27762+/-$3626, P<.03), more rapid attainment of short-term functional milestones between days 6 and 10 (36.2+/-14.4 m ambulated vs 21.4+/-13.3 m, P<.001; 4.8+/-0.8 mean transfer functional independence measure score vs 4.3+/-0.7, P<.01), and equivalent functional outcome at 4-month follow-up. CONCLUSION: These data showed that high-risk individuals were able to tolerate early intensive rehabilitation, and this intervention yielded faster attainment of short-term functional milestones in fewer days using less total cost.     

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.     

Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy

BACKGROUND: Fluctuations in lipid and lipoprotein levels are encountered quite often in hyperlipidemic patients. We examined the possibility that lipid and lipoprotein levels fluctuate due to the different effects of estrogen and progestogen in postmenopausal hyperlipidemic women receiving combined hormonal replacement therapy. METHODS: In an open-label study conducted during 3 consecutive hormonal cycles (3 months), levels of fasting total cholesterol, triglycerides, and low (LDLC)- and high-density lipoprotein cholesterol (HDLC) were determined in 36 postmenopausal hyperlipidemic women on day 13 of conjugated equine estrogen (1.25 mg/d) therapy and on day 25 after 12 days of receiving estrogen plus medroxyprogesterone acetate (5 mg/d). RESULTS: While receiving estrogen and combined therapies, means +/- SD total cholesterol levels increased from 6.50 +/- 0.97 mmol/L (251 +/- 37 mg/dL) to 6.88 +/- 1.42 mmol/L (266 +/- 54 mg/dL) (P<.001); LDLC levels, from 4.05 +/- 1.14 mmol/L (156 +/- 44 mg/dL) to 4.62 +/- 1.36 mmol/L (178 +/- 52 mg/dL) (P<.001). Mean +/- SD HDLC cholesterol levels decreased from 1.44 +/- 0.32 mmol/L (55 +/- 12 mg/dL) to 1.29 +/- 0.28 mmol/L (50 +/- 10 mg/dL) (P<.001); triglyceride levels, from 2.23 +/- 1.03 mmol/L (197 +/- 91 mg/dL) to 2.06 +/- 1.04 mmol/L (182 +/- 92 mg/dL) (P<.001). CONCLUSIONS: Hyperlipidemic postmenopausal women receiving combined sequential estrogen and progestogen replacement therapy demonstrate very significant fluctuations in their lipid and lipoprotein levels. These fluctuations depend on the hormonal phase, ie, estrogen alone or combined with progestogen.     

Influence of nitric oxide in the chronic phase of two-kidney, one clip renovascular hypertension

Chronic two-kidney, one clip (2K1C) renovascular hypertension is characterized by a largely angiotensin-independent elevated blood pressure (BP). We hypothesized that the long-term effect of hypertension would compromise endothelium-derived nitric oxide (NO) and diminish its influence in controlling renal perfusion. We determined the influence of endothelium-derived NO on renal hemodynamics and the angiotensin-NO interaction regulation of renal perfusion in rats with chronic 2K1C hypertension. Renal blood flow (RBF) was measured by radioactive microspheres in rats with either early-phase (4 weeks after clipping, n=7) or chronic-phase (13 to 16 weeks after clipping, n=7) 2K1C hypertension. The systemic and renal response to NO synthesis inhibition was determined with 10 mg/kg body wt N omega-nitro-L-arginine methyl ester (L-NAME). In rats with early-phase 2K1C hypertension, BP was 149+/-3 mm Hg, which increased by 42+/-3 mm Hg with L-NAME (P<.001). L-NAME decreased RBF by 20% (P<.02) and 17% (P<.005) and increased renal vascular resistance (RVR) by 58% (P<.005) and 62% (P<.02) in the nonclipped and clipped kidneys, respectively. In rats with chronic 2K1C hypertension, BP was 166+/-3 mm Hg, and L-NAME increased this by 35+/-6 mm Hg (P<.001). In the nonclipped and clipped kidneys of chronic 2K1C hypertensive rats, L-NAME decreased RBF by 20% (P<.01) and 17% (P<.01) and increased RVR by 51% (P<.005) and 60% (P<.02), respectively. There were no differences in L-NAME-induced changes between early- and chronic-phase 2K1C hypertensive rats. Next, we treated seven chronic-phase 2K1C hypertensive rats with 10 mg/kg body wt losartan, which reduced BP by only 7.7% (P<.005). After losartan, L-NAME increased BP by 41+/-3 mm Hg (P<.001), decreased RBF to the nonclipped kidney by 44% (P<.05), and increased RVR by 110% (P<.005); the decrease in RBF was significantly greater compared with untreated chronic-phase controls (P<.05). In the clipped kidney, L-NAME decreased RBF by 26% (P<.05) and increased RVR by 76% (P <.05). Thus, angiotensin blockade did not attenuate the systemic or renal vasoconstriction to L-NAME. Our results suggest that in both early and chronic phases of 2K1C hypertension, NO contributes significant dilator tone to buffer the hypertension and maintains perfusion of both kidneys by counterbalancing angiotensin-independent vasoconstriction.     

A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department

STUDY OBJECTIVE: To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated. SETTING: Sixteen emergency departments in the United States. POPULATION: Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose. INTERVENTIONS: Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered. MEASUREMENTS AND MAIN RESULTS: Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ. CONCLUSION: Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.     

Benefit of active compression-decompression cardiopulmonary resuscitation as a prehospital advanced cardiac life support. A randomized multicenter study

OBJECTIVES: We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemia during patch-off hours in patients with stable angina pectoris receiving a beta-adrenergic blocking agent or calcium antagonist, or both. BACKGROUND: The current recommendations for the use of intermittent TD-NTG may be associated with the occurrence of rebound ischemia. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, crossover trial with three study periods. Tolerability to TD-NTG was assessed in Period I. Seventy-two patients were assigned to receive either double-blind transdermal placebo or maximally tolerated TD-NTG for 2 weeks (Period II) and were then crossed over to the alternative treatment for another 2 weeks (Period III). The patients were instructed to apply medication daily at 8 AM, to remove it at 10 PM and to note symptoms and sublingual nitroglycerin (SL-NTG) use in a diary. The occurrence of ischemia was assessed from patient-perceived angina, symptom-limited exercise treadmill test (ETT) and 48-h ambulatory electrocardiographic (AECG) monitoring. RESULTS: Transdermal NTG (0.2 to 0.4 mg/h) significantly reduced the magnitude of ST segment depression at angina onset during ETT compared with placebo. Total angina frequency was not significantly different between TD-NTG (mean [+/-SD] 3.2 +/- 4.2) and placebo (3.3 +/- 5.2). During patch-off hours, angina frequency increased with TD-NTG (1.1 +/- 2.1) compared with placebo (0.7 +/- 1.6) (p = 0.03). Similar trends for an increase in ischemia after TD-NTG were also observed from AECG analyses. Specifically, ischemia frequency tended to be lower during patch-off hours for placebo than with TD-NTG (0.05 +/- 0.09 vs. 0.08 +/- 0.20 episodes/h, respectively, p = 0.08), even though frequency of ischemia tended to be higher during patch-on hours for placebo than with TD-NTG (0.12 +/- 0.19 vs. 0.07 +/- 0.15 episodes/h, respectively, p = 0.11). During placebo, ischemia frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with a 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia. CONCLUSIONS: An increase in ischemia frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by a corresponding trend for AECG ischemia to increase during these same hours.     

Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial

CONTEXT: Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients. OBJECTIVE: To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997. SETTING: Sixteen US outpatient clinical centers. PARTICIPANTS: A total of 229 subjects were randomized. INTERVENTION: A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study. MAIN OUTCOME MEASURES: The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events. RESULTS: One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group). CONCLUSIONS: Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.     

Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependence

BACKGROUND: Posttraumatic stress disorder (PTSD) often co-occurs with alcohol dependence, yet little is known about treatment of this comorbidity. The serotonin selective reuptake inhibitors have been shown preliminarily to be effective in decreasing symptoms of PTSD but have not been studied in individuals with comorbid alcohol dependence. This is of particular interest as the SSRIs also have a modest effect in decreasing alcohol consumption. METHOD: In this preliminary trial, nine subjects with comorbid PTSD and alcohol dependence were treated in an open-label trial with sertraline for a 12-week period. Symptoms of PTSD and depression were monitored monthly with the Impact of Event Scale and the Hamilton Rating Scale for Depression (HAM-D). Alcohol consumption was monitored by a self-report instrument (Time-Line Follow-Back). RESULTS: There were significant decreases in all three symptom clusters of PTSD measured by overall PTSD symptom scores (p < or = .001) and in HAM-D scores (p < or = .001) during the follow-up period. Days of abstinence increased and average number of drinks decreased during the follow-up period. Four subjects claimed total abstinence during the follow-up period. CONCLUSION: While limited by small sample size and the open-label, nonblinded study design, this study suggests that sertraline may be useful in the treatment of PTSD complicated by alcoholism. The medication was well tolerated and subjects showed improvement in PTSD symptoms as well as decreased alcohol consumption. A controlled trial of sertraline in this population would be of interest.     

A 2-year study of sertraline in the treatment of obsessive-compulsive disorder

The present study investigated the tolerability, safety profile, and anti-obsessional efficacy of sertraline, a selective serotonin reuptake inhibitor, during long-term treatment of patients with obsessive-compulsive disorder (OCD). Fifty-nine OCD patients who had completed a 1 year double-blind, fixed dose study comparing sertraline and placebo subsequently entered a 1-year open extension. Among the 51 patients who had been treated with sertraline during the double-blind phase, the mean total duration of sertraline treatment was 690 days. Only treatment responders who completed the 52-week double-blind treatment phase were permitted to enter the open extension. The higher rate (p < 0.02) of sertraline patients (51 out of 241) than of placebo patients (eight out of 84), who responded to treatment and entered the open-label phase is therefore consistent with the greater mean improvement observed in the sertraline group during double-blind treatment. Placebo responders differed from sertraline responders in that they were less impaired at baseline of the double-blind study [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) of 18.5 versus 23.4] and they exhibited less improvement during double-blind treatment (-6.1 versus -11.4). In the open-label phase all patients received sertraline at a starting dose of 50 mg once a day, titrated in 50 mg increments to a maximum dose of 200 mg according to clinical response. At end-point the mean Y-BOCS score for all patients decreased by a further 3.6 points. Patients previously treated with placebo showed greater improvement after being switched to sertraline than those who received continued sertraline treatment. Patients who completed the study and received 2 full years of sertraline treatment (n = 38) exhibited a mean improvement of 15.6 points using the Y-BOCS. Sertraline was well tolerated during both the double-blind phase and the open extension, and the incidence of adverse experiences was generally reduced during the second year of treatment. Three patients discontinued open treatment because of adverse experiences. Long-term sertraline treatment did not appear to be associated with the emergence, increased incidence, or increased severity of adverse experiences or clinically significant abnormalities in laboratory tests, vital signs, or the electrocardiogram. The study supports the long-term safety and tolerability of sertraline over a 2-year treatment course and the sustained efficacy of sertraline in patients with OCD.