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Quality assessments of placebo controlled trials of beta blockers for migraine…………………………………………………………………………………………………………… 433 Evidence Table 18 order 500 mg cyklokapron free shipping symptoms you may be pregnant. Randomized controlled trials of beta blockers for bleeding esophageal varices…………………………………………………………………………………………………………… cyklokapron 500 mg visa medications via g-tube. cheap 500 mg cyklokapron with amex medicine vial caps. cheap 500 mg cyklokapron overnight delivery treatment statistics. Quality assessments of randomized controlled trials of beta blockers for bleeding esophageal varices………………………………………………………………………………………………. Adverse events in head-to-head trials of beta blockers for hypertension…………... Safety of all head-to-head trials of beta blockers………………………………………493 The medical literature relating to this topic is scanned periodically. Prior versions of this report can be accessed at the DERP website. Beta blockers Page 2 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Head-to-head controlled trials Walle Head-to- Patients of either sex, more than 21 years of Cardiiovascular diseases, such as angina pectoris, secondary 1994 head age, with mild to moderate hypertension hypertension, grade II or III AV block, heart failure, or a history of Crossover (diastolic blood pressure in the range of 95 myocardial infarction (within 12 months); cerebrovascular ischemia: Fair Double blind to 110 mmHg) were eligible for the study. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Head-to-head controlled trials Walle Run-in: 4-wk, SB, placebo No Psychologic General Well-Being Mean age: 58 y/o, 1994 (PGWB) index 43. Atenolol Minor Symptom Evaluation (MSE) Ethinicity: NR 100 mg x 6 weeks profile Washout: NR Sundar Wash-out period: 2 weeks between NR Quality of life questionnaire (5-point Age, Ethnicity: NR 1991 the interventions scale) Gender: 100% male -the sense of well being and satisfaction atenolol (ate): 100mg per day with life propranolol (pro): 80mg per day -the physical state -the enotional state duration of treatment: 4 weeks -intellectual functions -ability to perform in social roles -sexual life Beta blockers Page 4 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Head-to-head controlled trials Walle mean weight: 76kg NR/NR/60 2/0/58 Metoprolol CR vs. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Head-to-head controlled trials Walle Clinical Overall AEs: no differences (data NR) meto vs. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Head-to-head controlled trials Steiner Head-to- The patients were required to have been Patients could not have major concomitant medical or mental problems 1990 head diagnosed with mild-to-moderate essential or significant changes in living conditions (e. Beta blockers Page 7 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Head-to-head controlled trials Steiner placebo run-in for 3-5 weeks No Four-point scale in the Symptom Check Age, Ethnicity: NR 1990 titration for 1-4 weeks (lowering of List-90-R (SCL) (by patients) Gender: 100% male DBP by at least 10 mmHg or to Psychological General Well-Being 90mmHg or less) (PGWB) Index (by patients and spouses maintenance for 4 weeks or significant others) Insomnia Symptom Questionnaire Propranolol 80-240mg per day Sexual Function Questionnaire for male (mean=133. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Head-to-head controlled trials Steiner NR 489/360/344 27/1/151 Propranolol vs. Atenolol 1990 (179 for pro PGWB Index (patients) and ate) pro: 73 -Global, anxiety, depressed mood, positive well-being, ate: 78 general health vitality: NS -Self-control: -0. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Head-to-head controlled trials Steiner Reported by pro(%) vs. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Head-to-head controlled trials Dahlof Head-to- Patients with either sex with mild to 1. The patient had not followed the instructions to fill in and return the 1988 head moderate primary hypertension, either newly questionnaire on 3 occasions during the run-in period Crossover diagnosed or previously treated with 2. The diastolic blood pressure <90mmHg or >105mmHg monoterapy 3. Any serious concomitant illness or drug abuse which can interfere with the treatment 10. Unwillingness to participate in the study Blumenthal Head-to- Participants were eligible for the study if they NR 1988 head had resting diastolic blood pressures that exposure were within 90 to 110 mmHg on four design separate occassions, using a random zero unclear device, during a 2-week screening interval before testing. Subjects did not take any antihypertensive medication for at least 6 weeks before the screening and were free of any significant disease other than hypertension. Beta blockers Page 11 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Head-to-head controlled trials Dahlof placebo run-in: 2 weeks NR MSE-profile mean age: 54. Duration: 2 weeks Beta blockers Page 12 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Head-to-head controlled trials Dahlof Duration of hypertension: 3. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Head-to-head controlled trials Dahlof Beta-blocker Subjective symptoms- 2(2. Beta blockers Page 14 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Head-to-head controlled trials Buhler Head-to- Patients with a diastolic blood pressure Patients were on other antihypertensive drugs, had contraindications 1986 head (DBP) of 100-120 mmHg (Korotkoff V) om for beta-blocker therapy, severe disease, or who were known for their Crossover the seated position poor compliance. Placebo-controlled trials Oberman, 1990 Placebo- 21-65 years old; between 110 and 160% History of myocardial infarction, stroke, or asthma, or a serum Wassertheil-Smoller, controlled ideal weight (Metropolitan Life Insurance creatinine level of 177 mmol/d or greater, insulin-dependent diabetes, 1991 Height-Weight Tables); diastolic BP at allergy to thiazides or beta-blockers, pregnancy, or likelihood of Wassertheil-Smoller, baseline of 90-100 mm Hg difficulty in complying with the interventions 1992 United States Trial of Antihypertensive Interventions and Management (TAIM) Fair quality Beta blockers Page 15 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Head-to-head controlled trials Buhler Wash-out period: 2 weeks NR self-assessment questionnaire 86 (82. Then, if DBP> 95mmHg, increase to: bis Ethinicity: NR 20mg or ate 100mg. Placebo-controlled trials Oberman, 1990 Atenolol (ate) 50 mg Dietary interventions Life Satisfaction Scale Per protocol analysis Wassertheil-Smoller, Chlorthalidone (chl) 25 mg 1) Usual Diet Physical Complaints Inventory (n=697) 1991 Placebo (pla) 2) Low sodium (goal of 52 Symptoms Checklist Mean age=49 Wassertheil-Smoller, mmol/d for participants 56% male 1992 weighing 50 kg or less to 68% white United States 100 mmol/d for those weighing 92 kg) + high Trial of Antihypertensive potassium (goal: 62 Interventions and mmol/d to 115 mmol/d) Management (TAIM) 3) Weight loss group (goal: 4. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Head-to-head controlled trials Buhler 10 were not available for the crossover 138/134/116 12/0/104 Baseline:bis/ baseline:ate (all NS) 1986 comparison because of: intercurrent headache- 20:7/ 19:9 disease (n=1), BP response deemed tiredness- 17:20/ 17:13 unsatisfactory by the investigator (n=3), Nervousness- 17:10/ 10:8 and unwanted effects (n=6). Sleep problems- 18:11/ 15:10 Cold extremities- 14:13/ 16:12 Sweating- 12:9/ 11:11 Tingling sensations- 12:6/ 9:5 Feeling of weakness- 11:6/ 5:7 Dizziness- 11:3/ 8:7 Joint pain- 9:9/ 6:8 Depressed mood- 12:11/ 9:5 Sex problems- 5:7/ 6:4 Placebo-controlled trials Oberman, 1990 Previous dug treatment = 66. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Head-to-head controlled trials Buhler self- Baseline:bis / baseline:ate (number), all NS bis (1): dizziness 1986 assessment headache- 20:7/ 19:9 ate (5): diarrhea, skin rash, asthmatic questionnaire tiredness- 17:20/ 17:13 bronchitis, vertigo, headache Nervousness- 17:10/ 10:8 Sleep problems- 18:11/ 15:10 Cold extremities- 14:13/ 16:12 Sweating- 12:9/ 11:11 Tingling sensations- 12:6/ 9:5 Feeling of weakness- 11:6/ 5:7 Dizziness- 11:3/ 8:7 Joint pain- 9:9/ 6:8 Depressed mood- 12:11/ 9:5 Sex problems- 5:7/ 6:4 Placebo-controlled trials Oberman, 1990 NR NR NR Wassertheil-Smoller, 1991 Wassertheil-Smoller, 1992 United States Trial of Antihypertensive Interventions and Management (TAIM) Fair quality Beta blockers Page 18 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Placebo-controlled trials Perez-Stable, 2000 Placebo- Patients with mild hypertension, defined as Concomitant use of insulin, bronchodilators, antidepressants or controlled an average diastolic blood pressure antihypertensive medications within 1 month of screening; coronary Fair quality between 90 and 104 mm Hg on three artery disease, vascular heart disease, renal insufficiency, readings taken during each of two screening cerebrovascular disease, and secondary causes of hypertension visits 2 weeks apart; aged 18-59 Beta blockers Page 19 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Placebo-controlled trials Perez-Stable, 2000 Propranolol (pro) 80-400 mg daily NR Cognitive Function Test Battery Age: Pro=4; Pla=45 (n=156) Stimulus Evaluation/Response % male: Pro=67; Fair quality Placebo (pla) (n=156) Selection Pla=66 Continuous Performance Task(CPT) % White: Pro=76; Digit Symbol Substitution Task(DSST) Pla=71 California Veral Learning Test(CVLT) Psychological Measures Center for Epidemiological Studies Depression Scale(CES-D) Beck Depression Inventory(BDI) Beta blockers Page 20 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Placebo-controlled trials Perez-Stable, 2000 Current smokers: Pro=10%; Pla=11% nr/nr/312 NR/NR/203 Mean changes in: Current daily drinkers of alcohol: Selection reaction time(ms): pro=(-3); pla=(-10) Fair quality Pro=11%; Pla=12% CPT Mean DBP: Pro=96; Pla=96 Reaction time(ms): pro=12; pla=6 Mean SBP: Pro=140=Pla=141 Correct responses: pro=0; pla=0 Commission errors: pro=(-1); pla=(-1) Omission errors: pro=0. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Placebo-controlled trials Perez-Stable, 2000 NR NR NR Fair quality Beta blockers Page 22 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Year Study Country design Eligibility criteria Exclusion criteria Placebo-controlled trials Anonymous, 1977 Placebo- Mild hypertension Secondary hypertension; already on antihypertensive treatment; Greenberg, 1984 controlled Men and women; aged 35-64; with mild cardiac failure; MI or stroke within previous 3 months, angina; Anonymous, 1985 Single blind hypertension (diastolic BP 90-109 mm Hg, intermittent claudication; diabetes; gout; asthma; other serious Miall, 1987 together with systolic pressure below 200 disease; pregnancy Anonymous, 1988a mm Hg) Anonymous, 1988b Anonymous, 1992 Lever, 1993 UK Medical Research Council (MRC) Fair quality Head-to-head controlled trials Brixius Head-to- Male out-patients aged (40-55) w/ newly Patients with history of DM, alcohol and/or drug abuse, major 2007 head diagnosed or existing mild (stage I; SBP 140- cardiovasuclar and non-cardiovascular diseases, or those receiving 159 mmHg and DBP 90-99 mmHg) essential concomitant treatment related ot hypertension and/or ED. Also in a stable, monogamous heterosexual partnership for at least 6 months and to have no symptoms of sexual disfunction, even if taking beta-blockers or diuretics. Beta blockers Page 23 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Author Allowed other Age Year Interventions (drug, regimen, medications/ Method of outcome assessment and Gender Country duration) interventions timing of assessment Ethnicity Placebo-controlled trials Anonymous, 1977 Propranolol (pro) up to 320 mg daily Methydopa Data for terminating events (e. Ethnicity: NR Group B: metropolol succinate 95 mg daily x 12 weeks, once daily placebo x 2 weeks, nebivolol (neb) 5 mg daily X 12 weeks Beta blockers Page 24 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Randomized controlled trials of beta blockers for hypertension Number Number Author screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Placebo-controlled trials Anonymous, 1977 (Mean values for men/women) 515,000 nr/nr/17,354 # events/rate per 1000 patient years Greenberg, 1984 Body weight(kg): pro=81/70; pla=81/70 screened/46, analyzed Strokes: pro=42/1. Randomized controlled trials of beta blockers for hypertension Author Method of Year adverse effects Withdrawals due to adverse events (%, Country assessment? Adverse effects reported adverse n/enrolled n) Placebo-controlled trials Anonymous, 1977 NR NR # patients/% Greenberg, 1984 Impaired glucose tolerance: Anonymous, 1985 pro=43/0.

Gabapentin in the treatment of fibromyalgia: a randomized generic cyklokapron 500 mg otc medications used for fibromyalgia, double-blind effective cyklokapron 500 mg symptoms pulmonary embolism, placebo-controlled cyklokapron 500mg mastercard treatment gonorrhea, multicenter trial 500 mg cyklokapron with visa symptoms vaginal yeast infection. Citalopram in patients with fibromyalgia--a randomized, double-blind, placebo-controlled study. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Drugs for fibromyalgia 55 of 86 Final Original Report Drug Effectiveness Review Project 81. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE, Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Giordano N, Geraci S, Santacroce C, Mattii G, Battisti E, Gennari C. Efficacy and tolerability of paroxetine in patients with fibromyalgia syndrome: A single-blind study. A randomized, controlled, trial of controlled release paroxetine in fibromyalgia. Guidelines on the management of fibromyalgia syndrome - a systematic review. Affective pain modulation in fibromyalgia, somatoform pain disorder, back pain, and healthy controls. Arnold LM, Crofford LJ, Martin SA, Young JP, Sharma U. The effect of anxiety and depression on improvements in pain in a randomized, controlled trial of pregabalin for treatment of fibromyalgia. History of depressive and/or anxiety disorders as a predictor of treatment response: a post hoc analysis of a 12-week, randomized, double- blind, placebo-controlled trial of paroxetine controlled release in patients with fibromyalgia. Treatment response to pregabalin in fibromyalgia pain: effect of patient baseline characteristics. Drugs for fibromyalgia 56 of 86 Final Original Report Drug Effectiveness Review Project Appendix A. The American College of Rheumatology 1990 criteria for a1 the classification of fibromyalgia 1. Pain is considered widespread when all the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain, (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. Pain in 11 of 18 tender point sites on digital palpitation Definition. Pain on digital palpitation, must be present in at least 11 of the following 18 tender point sites: Occiput: bilateral, at the suboccipital muscle insertions. Low cervical: bilateral, at the anterior aspects of the intertransverse spaces C5-C7. Trapezius: bilateral, at the midpoint of the upper border. Supraspinatus: bilateral, at origins, above the scapula spine near the medial border. Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions of upper surfaces. Lateral epicondyle: bilateral, 2 cm distal to the epicondyles. Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle. Greater trochanter: bilateral, posterior to the trochanteric prominence. Knee: bilateral, at the medial fat pad proximal to the joint line Digital palpation should be performed with an approximate force of 4 kg. For a tender point to be considered “positive” the subject must state that the palpation was “painful”. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia. Drugs for fibromyalgia 57 of 86 Final Original Report Drug Effectiveness Review Project The figure specifies tender point locations for the 1990 classification criteria for fibromyalgia 1 (The Three Graces after Baron Jean-Baptiste Regnault, 1793, Louvre Museum, Paris. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Drugs for fibromyalgia 58 of 86 Final Original Report Drug Effectiveness Review Project Appendix B. Glossary This glossary defines terms as they are used in reports produced by the Drug Effectiveness Review Project. Some definitions may vary slightly from other published definitions. Absolute risk: The probability or chance that a person will have a medical event. It is the ratio of the number of people who have a medical event divided by all of the people who could have the event because of their medical condition. Add-on therapy: An additional treatment used in conjunction with the primary or initial treatment. Adherence: Following the course of treatment proscribed by a study protocol. Adverse drug reaction: An adverse effect specifically associated with a drug. Adverse event: A harmful or undesirable outcome that occurs during or after the use of a drug or intervention but is not necessarily caused by it. Adverse effect: An adverse event for which the causal relation between the intervention and the event is at least a reasonable possibility. Active-control trial: A trial comparing a drug in a particular class or group with a drug outside of that class or group. Allocation concealment: The process by which the person determining randomization is blinded to a study participant’s group allocation. Applicability: see External Validity Before-after study: A type nonrandomized study where data are collected before and after patients receive an intervention. Before-after studies can have a single arm or can include a control group. Bias: A systematic error or deviation in results or inferences from the truth. Several types of bias can appear in published trials, including selection bias, performance bias, detection bias, and reporting bias. Bioequivalence: Drug products that contain the same compound in the same amount that meet current official standards, that, when administered to the same person in the same dosage regimen result in equivalent concentrations of drug in blood and tissue. Black box warning: A type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects.

Nevirapine versus atazanavir/ritonavir purchase cyklokapron 500mg with mastercard symptoms 7 days past ovulation, each combined with tenofovir diso- proxil fumarate/emtricitabine cheap 500mg cyklokapron free shipping treatment for depression, in antiretroviral-naive HIV-1 patients: the ARTEN Trial order cyklokapron 500mg amex medicine 3605 v. Comparison of once-daily atazanavir with efavirenz purchase cyklokapron 500 mg amex medicine quinidine, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. Efavirenz plus zidovudine and lamivudine, efavirenz plus indi- navir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Analysis of hepatic events within the 2NN study: controlling for ethnicity and CD4+ count at initiation of nevirapine therapy. Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Swaminathan S, Padmapriyadarsini C, Venkatesan P, et al. Efficacy and safety of once-daily nevirapine- or efavirenz- based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial. Characterization of genotypic and phenotypic changes in HIV-1- infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies. Lipid Levels and Changes in Body Fat Distribution in Treatment-Naive, HIV- 1-Infected Adults Treated With Rilpivirine or Efavirenz for 96 Weeks in the ECHO and THRIVE Trials. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. Nevirapine or efavirenz combined with two nucleoside reverse transcriptase inhibitors compared to HAART: a meta-analysis of randomized clinical trials. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. Impact of the background regimen on virologic response to etravirine: pooled 48-week analysis of DUET-1 and -2. Virologic, immunologic, clinical, safety, and resistance out- comes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. TMC278 25mg QD has no effect on corrected QT interval in a study in HIV-negative volunteers. Transmission of drug-resistant HIV-1 is stabilizing in Europe. TMC278 long acting – a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. Dose escalation or immediate full dose when switching from efavirenz to nevirapine-based highly active antiretroviral therapy in HIV-1-infected individuals? Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA Cohort Study. Clin Infect Dis 2008; Wolf E, Koegl C, Theobald T, et al. Nevirapine-associated hepatotoxicity: no increased risk for females or high CD4 count in a single-centre HIV cohort. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse tran- scriptase inhibitor plasma concentrations in HIV-infected patients. Clinical efficacy of antiretroviral combination therapy based on pro- tease inhibitors or NNRTIs: indirect comparison of controlled trials. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. If the protease is inhibited and proteolytic splicing prevented, non-infectious virus particles will result. With the knowledge of the molecular structure of the protease encoded by the virus, the first protease inhibitors were designed in the early nineties; these agents were modified in such a way that they fit exactly into the active site of the HIV protease (Youle 2007). Since 1995, protease inhibitors have revolutionized the treatment of HIV infection. At least three large studies with clinical endpoints demonstrated the efficacy of indinavir, ritonavir and saquinavir (Hammer 1997, Cameron 1998, Stellbrink 2000). Although PIs were at first criticized for their high pill burden and side effects (see below), they remain an essential component of antiretroviral therapies. With growing knowledge of the mitochondrial toxicity of nucleoside analogs and through the 6. Overview of antiretroviral agents 91 introduction of easier-to-take PIs, this class of drugs is currently experiencing a renaissance – today, even PI-only regimens are being investigated. Boosted PI combinations are more effective than unboosted. There three widely used boosted PIs: atazanavir, darunavir and lopinavir. Current data suggest that the differences are not significant enough to completely rule out any of these agents. Besides gastrointestinal side effects and relatively high pill burden (no STRs avail- able), all PIs used in long-term therapy show tolerability problems – to a greater or lesser extent, all are associated with lipodystrophy and dyslipidemia (Nolan 2003). Other problems include drug interactions, which can sometimes be substantial. Cardiac arrhythmias (Anson 2005) and sexual dysfunction have also been attributed to PIs (Schrooten 2001), although the data does not remain unchallenged (Lallemand 2002). All PIs are inhibitors of the CYP3A4 system and interact with many other drugs (see chapter on Drug Interactions). Ritonavir is the strongest inhibitor, saquinavir proba- bly the weakest. There is a high degree of cross-resistance between protease inhibitors, which was described even before PIs were put on the market (Condra 1995). With darunavir and tipranavir two second-generation PIs are available that are effective even in the presence of several resistance mutations (see below). All PIs must be boostered by the so called pharmacoenhancers, in order to achieve sufficient plasma levels. Ritonavir is a potent inhibitor of the isoenzyme 3A4, a subunit of the cytochrome P450 hepatic enzyme system. Inhibition of these gastrointestinal and hepatic enzymes allows the most important pharmacokinetic parameters of almost all PIs to be significantly increased or “boosted” (Kempf 1997): maximum concentration (Cmax), trough levels (Ctrough or Cmin) and half-life. The interaction between riton- avir and the other PIs simplifies daily regimens by reducing the frequency and number of pills to be taken every day, in many cases independent of food intake. In 2014, cobicistat (Tybost) was approved as a booster for atazanavir and darunavir. Initially, cobicistat was developed for the integrase inhibitor elvitegravir in the fixed- dose combination Stribild that came to market in 2013. PK studies, however, had shown that with cobicistat comparable levels of atazanavir and darunavir can be achieved (Elion 2011, Kakuda 2014). In a double-blind, randomized study on 692 ART-naive patients treated with TDF+FTC+atazanavir, efficacy and tolerability of cobicistat and ritonavir were comparable (Gallant 2013). Based on these data, cobici- stat is now available as pharmacoenhancer for atazanavir and darunavir.

Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients order cyklokapron 500mg on-line medications 4h2. Changes in AIDS-related lymphoma since the era of HAART 500mg cyklokapron fast delivery medicine 0025-7974. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin’s lymphoma cheap cyklokapron 500mg with visa medicine park ok. Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone discount 500mg cyklokapron fast delivery medications54583, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chem- otherapy and lenalidomide alone. JCO 2010, 28:e704-8 Bibas M, Trotta MP, Cozzi-Lepri A, et al. Role of serum free light chains in predicting HIV-associated non-Hodgkin lymphoma and Hodgkin’s lymphoma and its correlation with antiretroviral therapy. Changes in cancer mortality among HIV-infected patients: the Mortalité 2005 Survey. Phase II trial of CHOP plus rituximab in patients with HIV-associated non- Hodgkin’s lymphoma. A clinical, molecular and cytogenetic study of 12 cases of human her- pesvirus 8 associated primary effusion lymphoma in HIV-infected patients. Combined chemotherapy including high-dose methotrex- ate in KSHV/HHV8-associated primary effusion lymphoma. Immunologic recovery in survivors following chemotherapy for AIDS-related non-Hodgkin lymphoma. B-cell stimulatory cytokines and markers of immune activation are ele- vated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma. Plasmablastic lymphoma: a new subcategory of HIV-related NHL. Successful reduced-intensity conditioning allogeneic HSCT for HIV-related primary effusion lymphoma. Primary effusion lymphoma cell lines harbouring human herpesvirus type-8. HHV-8-positive body-cavity-based lymphoma: a novel lymphoma entity. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Rituximab in combination with chemotherapy versus chemotherapy alone in HIV-asso- ciated non-Hodgkin lymphoma: a pooled analysis of 15 prospective studies. Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy. Plasmablastic lymphoma in HIV+ patients: an expanding spectrum. Excessive neurotoxicity with ABVD when combined with protease inhibitor- based antiretroviral therapy in the treatment of AIDS-related Hodgkin lymphoma. Detrimental clinical interaction between ritonavir-boosted protease inhibitors and vinblastine in HIV-infected patients with Hodgkin’s lymphoma. Incidence and risk factors of HIV-related non-Hodgkin’s lymphoma in the era of combi- nation antiretroviral therapy: a European multicohort study. Potential hazard drug-drug interaction between boosted protease inhibitors and vinblastine in HIV patients with Hodgkin’s lymphoma. Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus. The role of tumor histogenesis, FDG-PET, and short course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Low-intensity therapy in adults with Burkitt’s lymphoma. Causes of death in HIV-infected patients from the Cologne-Bonn cohort. Epeldegui M, Breen EC, Hung YP, Boscardin WJ, Detels R, Martínez-Maza O. Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis. Incidence, predictors and significance of severe toxicity in patients with human immunodeficiency virus-associated Hodgkin lymphoma. Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association. Safety and activity of a new intensive short-term chemoim- munotherapy in HIV-positive patients with Burkitt lymphoma. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Molecular histogenesis of plasmablastic lymphoma of the oral cavity. Characteristics of non-Hodgkin lymphoma arising in HIV-infected patients with suppressed HIV replication. Gibson TM, Morton LM, Shiels MS, Clarke CA, Engels EA. Risk of non-Hodgkin lymphoma subtypes in HIV- infected people during the HAART era: a population-based study. B-cell stimulation and prolonged immune deficiency are risk factors for non- Hodgkin’s lymphoma in people with AIDS. Allogeneic hematopoietic cell transplantation in human immunodefi- ciency virus-positive patients with hematologic disorders: a report from the center for international blood and marrow transplant research. Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. No evidence for an early excess incidence of progressive mul- tifocal leukencephalopathy in HIV-infected patients treated with rituximab. Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV- positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study. Successful autologous stem cell transplantation in a severely immuno- compromised patient with relapsed AIDS-related B-cell Lymphoma. AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS-associated Burkitt or Burkitt-like lymphoma: short intensive poly- chemotherapy is feasible and effective. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplan- tation. Nonmyeloablative conditioning followed by transplantation of geneti- cally modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with AIDS. Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin’s lymphoma: AIDS-malig- nancies consortium trial 010. Low-dose compared with standard-dose m-BACOD chemotherapy for non- Hodgkin’s lymphoma associated with HIV infection. Non-Hodgkin lymphoma in HIV-infected patients in the era of HAART.

How I treat while not showing an OS benefit at this time purchase cyklokapron 500 mg visa medications ok for pregnancy, showed a PFS benefit multiple myeloma in younger patients purchase cyklokapron 500mg without a prescription treatment vs cure. High-risk cytogenetics maintenance and that for progression and death is higher in patients and persistent minimal residual disease by multiparameter flow not on maintenance therapy in the CALGB 100104 study buy 500mg cyklokapron with amex treatment 2nd degree burn. The risk cytometry predict unsustained complete response after autolo- of SPM development should be evaluated within the context of the gous stem cell transplantation in multiple myeloma cyklokapron 500 mg for sale medications and mothers milk 2014. European perspec- dations for very-high-risk disease. Therefore, for very-high-risk tive on multiple myeloma treatment strategies: update follow- patients with plasma cell leukemia; t(14;16), del(17p), del(1p), and ing recent congresses. Bergsagel PL, Mateos MV, Gutierrez NC, Rajkumar SV, San bortezomib and lenalidomide maintenance therapy can be considered. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple Summary and future directions myeloma. The treatment of the MM patient has improved over the past 10 6. Consensus years, with median PFS approaching 4 years after autologous recommendations for risk stratification in multiple myeloma: HSCT. New agents based on MM cell metabolic pathways of report of the International Myeloma Workshop Consensus growth and cell development and antibodies that have activity with Panel 2. Combining fluores- treatment of relapsed and refractory disease. Such agents include novel PIs such as marizomib and the oral 8. The molecular PIs ixazomib and oprozomib, the recently Food and Drug Adminis- characterization and clinical management of multiple myeloma tration (FDA)–approved PI carfilzomib, the recently FDA-approved in the post-genome era. IMiD pomalidomide, the deacetylase inhibitors, the novel alkylators 9. A gene expression including bendamustine and melphalan-flufenamide, the spindle signature for high-risk multiple myeloma. Continued improve- monoclonal antibody elotuzumab (anti-CS1), which has activity ment in survival in multiple myeloma and the impact of novel when combined with lenalidomide, dexamethasone, and daratu- agents [abstract]. Activin A, BAFF, CD40, CD56, CD74, CD138, DKK-1, IL-6/R, 11. Thalidomide Hematology 2013 501 in induction treatment increases the very good partial response treatment of multiple myeloma: a clash of philosophies. Optimizing therapy for transplant-eligible initial therapy for newly diagnosed multiple myeloma. J Clin patients with newly diagnosed multiple myeloma. Minimal residual plus dexamethasone is superior to vincristine plus doxorubicin disease assessed by multiparameter flow cytometry in multiple plus dexamethasone as induction treatment prior to autologous myeloma: impact on outcome in the Medical Research Council stem-cell transplantation in newly diagnosed multiple my- Myeloma IX Study. Lenalidomide with multiple myeloma: sequential improvement of response plus high-dose dexamethasone versus lenalidomide plus low- and achievement of complete response are associated with dose dexamethasone as initial therapy for newly diagnosed longer survival. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bort- prognostic factor in patients with multiple myeloma treated ezomib induction and maintenance treatment in patients with with high-dose therapy: long-term analysis of the IFM 99-02 newly diagnosed multiple myeloma: results of the randomized and 99-04 Trials. Bortezomib with surrogate for extended survival in multiple myeloma. Single versus double tion therapy after, double autologous stem-cell transplantation autologous stem-cell transplantation for multiple myeloma. Once- versus twice- autologous peripheral blood stem cell transplantation in mul- weekly bortezomib induction therapy with CyBorD in newly tiple myeloma: up-front or rescue treatment? Boccadoro M, Cavallo F, Gay F, Di Raimondo F, Nagler A, tients with newly diagnosed multiple myeloma. A phase 1/2 study (MEL200) plus lenalidomide maintenance or no maintenance of carfilzomib in combination with lenalidomide and low-dose in newly diagnosed multiple myeloma (MM) patients. J Clin dexamethasone as a frontline treatment for multiple myeloma. Carfilzomib, cyclophos- lenalidomide-dexamethasone vs autologous transplant in newly phamide and dexamethasone (CCd) for newly diagnosed mul- diagnosed myeloma: a phase 3 trial. Clin Lymphoma Myeloma tiple myeloma (MM) patients [abstract]. A phase 1/2 study of autologous plus reduced intensity allogeneic transplantation in weekly MLN9708, an investigational oral proteasome inhibitor, the upfront management of multiple myeloma: meta-analysis of in combination with lenalidomide and dexamethasone in pa- trials with biological assignment. Randomized, multi- bortezomib, thalidomide, and dexamethasone in patients with center, phase 2 study (EVOLUTION) of combinations of autografted myeloma. Bortezomib-thalidomide- mide in previously untreated multiple myeloma. Long-term outcomes of transplantation in patients with newly diagnosed multiple previously untreated myeloma patients: responses to induction myeloma. Bortezomib, lenalido- risk stratification model can help to direct the use of novel mide, and dexamethasone (VRD) consolidation and lenalido- treatments. Approach to the updated results of the IFM 2008 phase II VRD intensive 502 American Society of Hematology program [abstract]. Thalidomide plus maintenance after stem-cell transplantation for multiple my- dexamethasone as a maintenance therapy after autologous eloma. Consolidation with VTd free survival in multiple myeloma. A randomized phase 3 stem cell transplantation in multiple myeloma. Superiority of bortezomib, multiple myeloma: a Nordic Myeloma Study Group random- thalidomide, and dexamethasone (VTD) as induction pretrans- ized phase III trial. Part I: the role of maintenance therapy in patients PETHEMA/GEM study. Available at after stem-cell transplantation for multiple myeloma. Maintenance therapy to lenalidomide and the incidence of second primary malignan- with thalidomide improves survival in patients with multiple cies (SPM) in the phase III study of lenalidomide versus myeloma. Thalidomide transplant (ASCT) for multiple myeloma (MM) CALGB (Alli- arm of Total Therapy 2 improves complete remission duration ance) ECOG BMTCTN. Subcutaneous versus ized phase 3 study on the effect of thalidomide combined with intravenous administration of bortezomib in patients with adriamycin, dexamethasone, and high-dose melphalan, fol- relapsed multiple myeloma: a randomised, phase 3, non- lowed by thalidomide maintenance in patients with multiple inferiority study. Randomized trial of lenalidomide, bortezomib, dexamethasone 48. The role of vs high-dose treatment with SCT in MM patients up to age 65 maintenance thalidomide therapy in multiple myeloma: (DFCI 10-106) (IFM DFCI 2009). Available from: http:// MRC Myeloma IX results and meta-analysis. Study to compare VMP with HDM followed by VRD consoli- 49. Consolidation dation and lenalidomide maintenance in patients with newly therapy with low-dose thalidomide and prednisolone prolongs diagnosed multiple myeloma (EMN 2) (HO95). Stem cell transplant with lenalidomide maintenance in patients 2009;27(11):1788-1793. New strategies in the treatment of autologous haemopoietic stem-cell transplantation in patients multiple myeloma.

Three trials assessed the efficacy and safety of bupropion compared with sertraline cheap cyklokapron 500 mg line abro oil treatment, one assessed bupropion compared with paroxetine proven cyklokapron 500 mg medicine for uti, and one assessed bupropion compared with fluoxetine discount cyklokapron 500mg with mastercard medicine 2355. The weighted mean differences of CGI-S and HAM-A scores did not differ significantly between bupropion and SSRIs 500 mg cyklokapron amex treatment 6th feb. However, the authors could not pool data on HAM-D and CGI-S because of lack of data. Bupropion compared with escitalopram A fair pooled data analysis of two identically designed RCTs assessed the comparative efficacy 42 of bupropion XL (300-450 mg/d), escitalopram (10-20 mg/d), and placebo. Both studies lasted 8 weeks and enrolled a total of 830 patients. No differences in efficacy could be detected between the two active treatments (HAM-D, CGI-I, CGI-S, HAD). After 8 weeks, 43 percent of patients on bupropion XL, 45 percent on escitalopram, and 34 percent on placebo achieved remission. Response rates were 62 percent, 65 percent, and 52 percent, respectively. Bupropion compared with fluoxetine A fair, 6-week study compared the efficacy of bupropion (225-450 mg/d) and fluoxetine (20-80 109 mg/d) in 123 patients with moderate to severe depression. Results presented no significant differences in efficacy measures (changes of HAM-D, HAM-A, CGI-S, CGI-I scores). Response rates were similar for Second-generation antidepressants 30 of 190 Final Update 5 Report Drug Effectiveness Review Project both drugs (bupropion, 62. Adverse events did not differ significantly between treatment groups. Another fair, 8-week RCT compared efficacy and sexual side effects of bupropion SR 110 (150-400 mg/d), fluoxetine (20-60 mg/d), and placebo in 456 outpatients with MDD. Results showed no statistically significant differences in efficacy. At endpoint, bupropion SR had more remitters than fluoxetine (47% compared with 40%). Bupropion SR also showed significantly fewer sexual side effects than fluoxetine throughout the study. Beginning at week 1 until endpoint, significantly more fluoxetine-treated patients than bupropion SR-treated patients (P<0. Bupropion compared with paroxetine One fair RCT examined the efficacy of bupropion SR (100-300 mg/d) and paroxetine (10-40 111, 112 mg/d) in 100 outpatients ages 60 years or older (range 60-88 years) over 6 weeks. The majority of patients were white (bupropion SR: 98%, paroxetine: 90%) and female (bupropion SR: 54%, paroxetine: 60%) and had not used antidepressants for the current episode before enrollment (bupropion SR 83%; paroxetine 88%). The overall loss to follow-up was 16 percent with no significant difference between treatment groups. Statistical LOCF analysis showed that efficacy in any outcome measure did not differ significantly between treatment groups. Response rates (≥ 50% reduction in HAM-D scores) were similar in both groups (bupropion SR 71%; paroxetine 77%). Both treatment groups improved significantly in quality-of-life scales (Quality- of-Life in Depression Scale [QLDS], Short Form-36 Health Survey [SF-36]) between baseline and endpoint (P<0. Bupropion compared with sertraline A fair, 16-week trial assessed efficacy and tolerability of bupropion SR (100-300 mg/d) and 113 sertraline (50-200 mg/d) in outpatients (N=248) with moderate to severe depression. Intention- to-treat analysis with a LOCF method was used to assess main outcome measures. Efficacy measures (changes of scores on HAM-D, HAM-A, CGI-S, CGI-I) did not differ significantly by treatment group. The article did not report on response or remission rates. Some adverse events (nausea, diarrhea, somnolence, sweating) were significantly higher among sertraline-treated patients (P<0. Discontinuation rates because of sexual adverse events were also significantly higher in the sertraline group (13. Two fair-rated RCTs compared the incidence of sexual dysfunction in 360 and 364 patients with MDD during 8 weeks of treatment with bupropion SR (150-400 mg/d), sertraline 114, 115 (50-200 mg/d), or placebo. Outcome measures were efficacy (HAM-D, CGI) and sexual dysfunction as assessed by investigators using DSM-IV definitions for sexual dysfunction disorders. Intention-to-treat analyses reported no significant differences in any efficacy measures between bupropion SR and sertraline at endpoints. During the studies, sertraline showed more sexual adverse events than bupropion at various time points. However, in one trial overall satisfaction with sexual function did not differ 114 significantly between the bupropion and the sertraline group at endpoint. In the other study, beginning at day 21 until the end of the study, the overall satisfaction with sexual function was 115 significantly higher in the bupropion group than in the sertraline group (P<0. Second-generation antidepressants 31 of 190 Final Update 5 Report Drug Effectiveness Review Project Nefazodone compared with fluoxetine Three studies with identical protocols examined the effects of antidepressive treatment with 116-118 either nefazodone or fluoxetine on sleep in outpatients with MDD. Data from these trials 118 were pooled into one analysis. A total of 125 patients with MDD and sleep disturbance were enrolled for 8 weeks. Effects on sleep were measured by the Hamilton Depression Rating Scale (HADRS) Sleep Disturbance Factor, Inventory for Depressive Symptomatology-Clinician Related (IDS-C), Inventory for Depressive Symptomatology-Self-Rated (IDS-SR), and EEG measurements. Nefazodone significantly improved sleep quality as assessed by clinician ratings and self- reported evaluations (P<0. Nefazodone and fluoxetine were equally effective in reducing depressive symptoms (changes in HAM-D scores). Response rates for depression were 47 percent for nefazodone and 45 percent for fluoxetine. Nefazodone compared with paroxetine Another fair, multi-national study enrolled 206 moderately depressed patients to an 8-week, 119, 120 acute-phase trial comparing nefazodone (200-600 mg/d) to paroxetine (20-40 mg/d). Patients who responded to acute treatment were enrolled in an open-label continuation phase 120 (N=108) from w eek 8 to month 6. Both groups showed significant improvements from baseline HAM-A, HAM-D, and MADRS scores in the acute phase without significant differences between study groups. Clinical improvement was either maintained or improved during the open-label continuation phase without significant differences between groups. Nefazodone compared with sertraline A fair, multicenter European study assessed the efficacy and tolerability of nefazodone (100-600 121 mg/d) and sertraline. One hundred-sixty outpatients with moderate to severe depression were enrolled in this 6-week trial. Intention-to-treat results did not show significant differences in efficacy between treatment groups. Response rates were similar (nefazodone 59%, sertraline 57%). Additional outcome measures assessed by questionnaire were sexual function and satisfaction under antidepressant treatment. Overall satisfaction with sexual function was significantly higher in the nefazodone group (P<0. Among men, 67 percent in the sertraline group and 19 percent in the nefazodone group reported difficulty with ejaculation (P<0. Other adverse events did not differ significantly between the two groups.

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