10-mg Group Research Articles

Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women

The aim of this study was to determine the effect of DRIs on hot flash symptoms in menopausal women. This was a randomized, double-blind, placebo-controlled trial of menopausal women, aged 38 to 60 years, who experienced 4 to 14 hot flashes per day. After a 1-week run-in period, a total of 190 menopausal women were randomized to receive a placebo or 40 or 60 mg/day of a DRI for 12 weeks. The primary outcome was the mean changes from baseline to week 12 in the frequency of hot flashes recorded in the participant diary. The secondary outcomes included changes in quality of life and hormonal profiles. A total of 147 women (77%) completed the study. It was found that 40 and 60 mg of DRI improved hot flash frequency and severity equally. At 8 weeks hot flash frequency was reduced by 43% in the 40-mg DRI group and by 41% in the 60-mg DRI group, compared with 32% in the placebo group (P = not significant vs placebo). The corresponding numbers for 12 weeks were 52%, 51%, and 39%, respectively (P = 0.07 and 0.09 vs placebo). When comparing the two treatment groups with the placebo group, there were significant reductions in mean daily hot flash frequency. The supplement (either 40 or 60 mg) reduced hot flash frequency by 43% at 8 weeks (P = 0.1) and 52% at 12 weeks (P = 0.048) but did not cause any significant changes in endogenous sex hormones or thyroid hormones. Menopausal quality of life improved in all three groups, although there were no statistically significant differences between groups. DRI supplementation may be an effective and acceptable alternative to hormone treatment for menopausal hot flashes.

Evaluation of clinical dosage of gatifloxacin for respiratory tract infections in elderly patients based on pharmacokinetics/pharmacodynamics (PK/PD)

The efficacy and safety of gatifloxacin (GFLX) was evaluated for elderly patients with respiratory infections. Each patient received one-half (100 mg b.i.d.) or one-quarter (100 mg q.d.) of the conventional dosage of 200 mg b.i.d., after a tentative clinical dosage for GFLX was estimated based on the patient's age and body weight. The subjects were 34 patients aged 65 years or older with mild to moderate acute bronchitis, pneumonia, or chronic respiratory tract infections. The serum concentration of GFLX was measured for each patient, and population and pharmacokinetic (PPK) analysis was performed, using the Bayesian method, to calculate the AUC and maximum drug concentration (Cmax). The overall efficacy rate of GFLX for 33 patients was 87.9% (29/33 patients). GFLX was effective for 75.0% (6/8 patients) in the 100-mg dosage group and 92.0% (23/25 patients) in the 200-mg dosage group. The clinical efficacy was 90.0% (9/10 patients) for acute bronchitis, 86.7% (13/15 patients) for pneumonia, and 87.5% (7/8 patients) for chronic respiratory tract infections. The bacterial eradication rate was 85.7% (12/14 patients). No adverse events or laboratory abnormalities were observed. The AUC values were 11.2-37.5 microg.h/ml and 12.7-111 microg.h/ml for the 100-mg and 200-mg dosage groups, respectively, and the Cmax values were 1.28-3.02 microg/ml and 0.72-6.35 microg/ml, respectively, for the two groups. These results suggest that the dosage of GFLX examined in this study is clinically useful in elderly patients aged 65 or older with acute bronchitis, pneumonia, or chronic respiratory tract infections. The results of PPK analysis with the dosage management also support the efficacy of GFLX.

Efficacy and Tolerability of Desvenlafaxine Succinate Treatment for Menopausal Vasomotor Symptoms

To compare efficacy and safety of desvenlafaxine succinate (desvenlafaxine) with placebo for the treatment of vasomotor symptoms. This randomized, double-blind, placebo-controlled trial enrolled 707 healthy, postmenopausal women experiencing 50 or more moderate-to-severe hot flushes per week. Participants randomly received desvenlafaxine 50, 100, 150, or 200 mg or placebo daily. Trial duration was 52 weeks. Primary outcomes were change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12. Six hundred twenty women with an average of 11 moderate-to-severe hot flushes per day at baseline completed at least one on-therapy evaluation for primary efficacy end points; 519 participants completed 12 weeks of treatment, and 368 completed the study. Desvenlafaxine 100 mg/d achieved a significantly greater reduction compared with placebo in average daily number of hot flushes at weeks 4 (P=.013) and 12 (P=.005), reaching a 64% decrease from baseline at week 12, and the 75% responder rate was significantly higher for desvenlafaxine 100 mg (50%) compared with placebo (29%; P=.003; number needed to treat=4.7) at week 12. Average daily severity of hot flushes was significantly lower in the desvenlafaxine 100-mg group compared with placebo at week 12 (P=.020). Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo-treated women during the first week of therapy only. Desvenlafaxine is an effective nonhormonal treatment for vasomotor symptoms in postmenopausal women. Its tolerability profile is consistent with that of other serotonin-norepinephrine reuptake inhibitors. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00421031 I.

Pregnancy-Associated Plasma Protein-A Elevation in Patients With Acute Coronary Syndrome and Subsequent Atorvastatin Therapy

Pregnancy-associated plasma protein-A (PAPP-A) was associated with atherosclerotic plaque vulnerability, whereas statin therapy was associated with increased plaque stability. Eighty-six patients presenting with clinical indications (non-ST-elevation myocardial infarction, unstable angina, and stable angina) for invasive coronary angiography and subsequent verified coronary artery disease (CAD) were randomly assigned in a double-blind manner to atorvastatin 10 or 80 mg/day. PAPP-A, high-sensitivity C-reactive protein (hs-CRP), and lipids were measured at baseline (before statin therapy) and at 1 and 6 months. PAPP-A was significantly increased in 35 patients with acute coronary syndrome (ACS) compared with 51 patients with stable CAD (p <0.001). Patients randomly assigned to atorvastatin 10 mg did not show a significant decrease in PAPP-A from baseline at 1 or 6 months. Patients treated with atorvastatin 80 mg showed a significant decrease at 1 month compared with baseline, but not at 6 months. hs-CRP was not significantly different between the ACS and stable CAD groups. Patients receiving atorvastatin 10 mg showed no hs-CRP decrease at 1 or 6 months, whereas it significantly decreased in the 80-mg group at 6 months, but not at 1 month. In conclusion, PAPP-A significantly increased in patients with ACS compared with those with stable coronary disease. High-dose atorvastatin significantly decreased PAPP-A at 1 month and hs-CRP at 6 months in patients with verified CAD. Low-dose atorvastatin did not produce this effect.

A Double‐Blind, Dose Comparison Study of Topiramate for Prophylaxis of Basilar‐Type Migraine in Children: A Pilot Study

Basilar-type migraine (BM) is the most common migraine "variant," representing 3-19% of migraine in children.BMis characterized by attacks of dizziness, vertigo, visual disturbances, ataxia, and/or diplopia, followed by migraine headache. The objective of this study is to assess the efficacy and safety of topiramate for prophylaxis of BM in children and adolescents (6-18 years). Outpatient, double-blind, parallel-group, dose comparison study with 2 phases: prerandomization (screening/washout and 4-week prospective baseline) and 12-week double blind (titration and maintenance). Following consent and assent, subjects with BMs, as defined by the International Classification of Headache Disorders (second edition), and > or =4 migraines/month were randomized to receive either 25 mg per day or 100 mg per day of topiramate in a 1 : 1 ratio. Fourteen children (4 boys, 10 girls) completed the double-blind phase (7 in the 25-mg group and 7 in the 100-mg group). During the prospective baseline, the mean headache frequency of the combined group "all migraines" per month was 4.5/month (25 mg) and 4.8/month (100 mg). Average duration of migraine was 5.5 hours (25 mg) and 5.0 hours (100 mg) and average mean pain (5-point faces scale) was 3.3 for both (25 mg 100 mg). The reduction in median monthly migraine rate during the double-blind treatment phase relative to baseline was 2.9 (64.4%) and 3.6 (75.0%) for the 25-mg and 100-mg topiramate-treated groups, respectively (P < .001). The reduction in median monthly BM rate during the double-blind treatment phase relative to baseline was 2.5 (74.24%) and 2.3 (82.8%) for the 25-mg and 100-mg topiramate-treated groups, respectively. The overall reduction in BM attacks reduced from 2.84/month to 0.59/month (79.2%; P < .0042). Overall, 86% of patients responded with a greater than 50% reduction in migraine frequency (100%, 25 mg and 71%, 100 mg). Mean reduction in migraine duration was 18 minutes (25 mg) and 89 minutes (100 mg). There was no significant difference in migraine severity between the 2 groups. Parent Global Assessment was "very much" or "much improved" in 6 of 7 (25 mg) and 3 of 7 (100 mg) patients. Migraine disability as measured by PedMidas reduced from moderate to no disability (P < .001). There were no serious adverse events. Preventive therapy with topiramate resulted in reducing the overall migraine frequency and the frequency of attacks of BM at both 25 mg and 100 mg doses relative to the historical baseline and prospective baseline periods. The 2 treatment groups resulted in comparable outcomes.

Safety and Symptom Improvement With Esomeprazole in Adolescents With Gastroesophageal Reflux Disease

The primary objective was to assess the safety of esomeprazole 20 or 40 mg once daily in adolescents with clinically diagnosed gastroesophageal reflux disease (GERD). A secondary aim was to assess changes in GERD symptoms after esomeprazole therapy. In this multicenter, randomized, double-blind study, adolescents ages 12 to 17 years inclusive received esomeprazole 20 or 40 mg once daily for 8 weeks. Adverse events and changes in clinical parameters (eg, physical examination, laboratory measurements) were evaluated to assess safety. Patients or their parents or guardians scored symptom severity daily, and investigators scored overall GERD symptom severity every 2 weeks using a 4-point scale. In the 148 adolescents with safety data, treatment-related and non-treatment-related adverse events were reported by 75% and 78% of patients in the esomeprazole 20- and 40-mg groups, respectively. Twenty-two patients (14.9%) experienced adverse events that were considered related to treatment; the most common were headache (8%, 12/148), abdominal pain (3%, 4/148), nausea (2%, 3/148), and diarrhea (2%, 3/148). No serious adverse events or clinically important findings in other safety assessments were observed. At baseline, 68% (100/147) had heartburn, 63% (93/147) had epigastric pain, 57% (84/147) had acid regurgitation, and 15% (22/147) had vomiting symptoms. Symptom scores decreased significantly in both the esomeprazole 20-mg and 40-mg groups by the final study week (P < 0.0001). Investigators rated 63.1% (94/149) of the patients as having moderate or severe symptoms at baseline; at the final visit, this percentage decreased significantly to 9.3% (13/140; P < .0001). In adolescent patients with GERD, esomeprazole 20 or 40 mg daily for 8 weeks was well tolerated, and GERD-related symptoms were significantly reduced from baseline values in both groups.

Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: A 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients

Background: The S-enantiomer of citalopram (escitalopram) is the active moiety linked to the anti-depressant effects associated with citalopram (the racemate). For escitalopram to be approved for the treatment of depression in Europe, findings from clinical trials of escitalopram are required to match previous results from studies of the racemate, citalopram. Objective: The aim of this study was to compare the efficacy and tolerability of escitalopram and citalopram in outpatients with major depressive disorder (MDD). Methods: This prospective, randomized, double-blind, active-controlled study was conducted at 8 psychiatric outpatient clinics in the Federation of Russia. Adult outpatients aged 25 to 45 years with MDD and a total score >25 on the Montgomery-Asberg Depression Rating Scale (MADRS) were eligible. Patients were randomly assigned to receive 6 weeks of treatment with fixed daily doses of escitalopram 10 rag, citalopram 10 rag, or citalopram 20 rag. Efficacy assessments were made at weeks 0 (baseline), 1, 4, and 6 (study end or last observation carried forward). The primary efficacy parameter was the change from baseline in MADRS total score. Secondary measures were the change from baseline in MADRS total score in a subgroup of severely depressed patients (baseline MADRS total score, >35), MADRS core depression subscale score, and Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I) scores; and the proportions of patients classified as responders and remitters at study end. Tolerability was assessed using adverse events (AEs) recorded by the investigator. Results: Of 330 assessable randomized patients, 8 withdrew, including 7 who withdrew consent and 1 who withdrew due to recurrence of a preexisting event. Thus, 322 patients were included in the assessment (mean age, 35 years; 41.6% male; all white; escitalopram 10 rag, 108 patients; citalopram 10 rag, 106; citalopram 20 rag, 108). At study end, the mean (SE) change from baseline in MADRS total score was significantly greater in the escitalopram arm than in the 10- and 20-rag citalopram arms (-28.70 [0.78] vs -20.11 [0.80] and -25.19 [0.78]; both, P < 0.001). Improvements were more marked in the severely depressed subgroup (-30.33 [0.95] vs -20.87 [0.99] and -26.34 [0.91]). Changes in the CGI-S and CGI-I scores and the rates of response and remission were significantly greater in the escitalopram group compared with those in the citalopram 10- and 20-rag groups (CGI-S: -2.60 [0.10] vs -1.61 [0.10] and -2.05 [0.10]; CGI-I: +1.58 [0.09] vs +2.35 [0.10] and +1.80 [0.09]; response: 95.4% vs 44.3% and 83.3%; remission: 89.8% vs 25.5% and 50.9% [all, P < 0.001]). Mean (SE) changes from baseline in core depression subscale score were -19.00 (0.59), -13.00 (0.60), and -16.52 (0.58) with escitalopram, citalopram 10 rag, and citalopram 20 mg, respectively. The prevalence of AEs was significantly lower in the escitalopram group (7) compared with the citalopram groups (16 and 19 in the 10- and 20-mg groups, respectively; both, P < 0.05). Nausea (2 [1.9%], 5 [4.7%], and 7 [6.5%] patients in the escitalopram and citalopram 10- and 20-mg groups, respectively) and headache (1 [0.9%], 2 [1.9%], and 4 [3.7%]) were the most frequently reported AEs. Conclusions: The results from this study suggest that escitalopram 10 mg was more effective than citalopram 10 and 20 mg at 6 weeks in these adult outpatients with MDD. All treatments were well tolerated. (Clin Ther. 2007;29:2319-2332) Copyright © 2007 Excerpta Medica, Inc.

Effect of Intensive Lipid Lowering with Atorvastatin on Renal Function in Patients with Coronary Heart Disease

Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. Mean estimated GFR at baseline was 65.6 +/- 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 +/- 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 +/- 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 +/- 0.14 ml/min per 1.73 m2 with 80 mg (P < 0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to > or = 60 ml/min per 1.73 m2 in significantly more patients and declined to < 60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.

The Effects of KW-3902, an Adenosine A1-Receptor Antagonist,on Diuresis and Renal Function in Patients With Acute Decompensated Heart Failure and Renal Impairment or Diuretic Resistance

This study sought to evaluate the dose-dependent effects of adenosine A1-receptor blockade on diuresis and renal function in patients with acute decompensated heart failure (ADHF) and renal impairment or diuretic resistance. Intravenous loop diuretics are the mainstay of therapy for patients with ADHF. Treatment, however, may be complicated by diuretic resistance and/or worsening renal function. We carried out a pair of randomized, double-blind, placebo-controlled, proof-of-concept studies in 2 clinically challenging ADHF populations. In the ADHF protocol, 146 patients with volume overload and an estimated creatinine clearance (CrCl) of 20 to 80 ml/min were randomized to placebo or 1 of 4 doses of KW-3902 (rolofylline) infused over 2 h daily for up to 3 days. On day 1, KW-3902 monotherapy increased urine output during the first 6 h (445, 531, 631, and 570 ml in the 2.5-, 15-, 30-, and 60-mg groups, respectively) compared with placebo (374 ml; p = 0.02). On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo (p = 0.04). By day 4 or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo (p = 0.10). In the diuretic-resistant protocol, 35 patients with an average CrCl of 34 ml/min were randomized to a single infusion of placebo, 10, 30, or 60 mg of KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and estimated CrCl with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902. In patients with ADHF and volume overload, KW-3902, an adenosine A1-receptor antagonist, enhances the response to loop diuretics and may have a renal protective effect.

Desvenlafaxine succinate (DVS) efficacy for the relief of vasomotor symptoms (VMS) associated with menopause: a double-blind, placebo-controlled trial

To compare the efficacy of DVS with placebo in the treatment of menopausal VMS. 12-week, multicenter, randomized, double-blind, placebo-controlled trial with dose titration and tapering. Efficacy was evaluated at 4 and 12 weeks. Postmenopausal women with ≥50 moderate-to-severe hot flushes (HFs) per week received placebo or DVS 100 or 150 mg, titrated up from 50 mg/d during week 1 and tapered down at the end of the study. Efficacy endpoints were analyzed using ANCOVA and included reduction from baseline (BL) in the average daily number and severity of moderate-to-severe HFs, reduction in number of nighttime awakenings, 75% responder analysis, and time to reach ≥50% decrease in number of HFs from BL. Safety data are presented elsewhere. Of the 458 subjects randomly assigned to DVS or placebo, 436 were included in the efficacy evaluation for primary endpoints. There were no significant differences between groups for demographic and BL characteristics. All groups had a significant decrease from BL in the number of moderate-to-severe HFs at all time points. Both DVS dose groups had significant reductions in number of HFs compared with placebo at weeks 4 and 12 (all comparisons P≤0.012). The DVS 100-mg and 150-mg groups achieved 65.4% and 66.6% reductions from BL in the number of HFs at week 12, respectively, compared with a 50.8% reduction in the placebo group. All groups had significant decreases from BL in HF severity at all time points; both DVS dose groups had a significantly greater decrease than placebo at weeks 4 and 12 (all comparisons P<0.001). The proportion of subjects with ≥75% reduction from BL in number of HFs was significantly higher at week 12 in the DVS 100-mg (50%) and DVS 150-mg (53%) groups compared with placebo (29%; all comparisons P<0.001). The median time to reach a 50% reduction from BL in the number of HFs was significantly shorter with both DVS doses (100 mg, 7 days; 150 mg, 8 days) compared with placebo (25 days; both comparisons, P<0.001). Both DVS dose groups had significantly greater reductions from BL in the number of nighttime awakenings due to HFs compared with placebo at weeks 4 and 12 (all comparisons P≤0.048) DVS is an effective non-hormonal treatment for VMS and nighttime awakenings associated with menopause and has a rapid onset of action at both 100 and 150 mg doses.

Pharmacokinetics and tolerability of rabeprazole sodium in subjects aged 12 to 16 years with gastroesophageal reflux disease: An open-label, single- and multiple-dose study

Objective: This study was conducted to characterize the pharmacokinetic and safety profile of rabeprazole sodium tablets in children and adolescents with gastroesophageal reflux disease (GERD). Methods: This was a multicenter, open-label, single- and multiple-dose study in subjects aged 12 to 16 years with GERD. Subjects were stratified by age (12-<14 years and 14–16 years) and were randomized to receive oral rabeprazole 10 or 20 mg/d over 5 or 7 days (to accommodate weekends). The pharmacokinetic parameters calculated included C max, T max, AUC, t 1/2, and apparent oral clearance (day 5/7 only). Blood samples for pharmacokinetic determinations were obtained on study days 1, 2, and 5 (or 7) and at discharge on day 6 (or 8). Safety assessments, including adverse events (AEs), were performed at all study visits. Results: Twenty-four subjects were enrolled in the study (12 in each dose group); they were predominantly white, had a mean age of 14.2 years, and had a mean body mass index of 24.3 kg/m 2 (the 90th percentile for adolescents of this age in the United States). Mean age and weight did not differ significantly between the 2 dose groups. On day 1, C max was significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group ( P = 0.024); on day 5/7, both AUC and C max were significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group ( P = 0.005 and P = 0.007, respectively). Within-period comparisons for both groups indicated that the AUC and C max for rabeprazole and its thioether metabolite did not differ significantly from day 1 to day 5/7. In addition, the T max and t 1/2 were relatively unchanged from day 1 to day 5/7 in both dose groups. Treatment-emergent signs and symptoms occurred in 11 subjects, 6 in the 10-mg group and 5 in the 20-mg group. The most frequently reported AEs were headache and nausea (16.7% and 8.3%, respectively). No statistically significant differences were observed between dose groups in terms of the number of subjects with AEs. Conclusions: Rabeprazole 10 and 20 mg were well tolerated in these children and adolescents with GERD. The results of the pharmacokinetic analyses of single and multiple oral doses indicated no apparent accumulation of rabeprazole or its thioether metabolite with the 10-mg dose. There was, however, a suggestion of accumulation with multiple dosing of rabeprazole 20 mg, which requires confirmation in larger studies.

Soy isoflavone supplementation and fasting serum glucose and lipid profile among postmenopausal Chinese women

Long-term effects of soy-derived isoflavones on lipids remain uncertain, and few data are available on their effects on glycemic control. We examined the effects of isolated soy germ isoflavones on the changes in fasting glucose (FG) and lipids. A double-blind, randomized, placebo-controlled trial was conducted in 203 postmenopausal Chinese women aged 48 to 62 years. They were randomly assigned to receive daily doses of 500 mg calcium, and 0 mg isoflavones (placebo, n=67), 40 mg isoflavones (n=68), and 80 mg isoflavones (n=68). Serum FG, triglycerides, high-density lipoprotein, low-density lipoprotein, total cholesterol, and lipoprotein cholesterol were measured at baseline and 1 year after treatment. The primary data analysis was performed on the 203 randomized women according to the intent-to-treat principle. The last value carried forward was used for any missing data at follow-up. We observed moderate but significant favorable effects of soy isoflavones on the changes (P=0.012) and percentage of changes (P=0.031) in FG (analysis of variance). The 1-year mean (SD) differences of FG changes were -5.2 (-9.4 to -1.0) mg/dL (P=0.010) and -3.3 (-7.5 to 0.9) mg/dL (P=0.18) in the 40- and 80-mg isoflavone groups compared with the placebo group. We also noted a significant interaction between the treatment and baseline FG on the changes in FG (P=0.004). The isoflavone effects were much more significant in women with baseline FG 100 mg/dL or more than in those with FG less than 90 mg/dL. We observed little effect of soy isoflavones on changes in serum lipids among the treatment groups. One-year of soy isoflavone supplementation might have a favorable effect on FG in women, but has no significant effect on serum lipids.

Desvenlafaxine succinate (DVS), a novel serotonin and norepinephrine reuptake inhibitor, improves mood and menopausal symptoms in women with hot flushes (HFs) associated with menopause

To determine whether DVS, an effective non-hormonal treatment for HFs and night sweats, improves mood disturbances and other menopausal symptoms in a placebo-controlled trial of menopausal women with moderate-to-severe vasomotor symptoms (VMS). Twelve-week multicenter, randomized, double-blind, placebo-controlled trial with dose titration. Postmenopausal women with ≥50 moderate-to-severe HFs/week were randomly assigned to placebo or DVS 100 or 150 mg. Mood and climacteric symptoms were assessed by the Profile of Mood States (POMS) and the Greene Climacteric Scale (GCS), respectively, completed at baseline (BL) and weeks 4 and 12. Responses were analyzed using analysis of covariance with treatment and study site as factors and BL value as a covariate. A total of 459 subjects (DVS n = 300, placebo n = 149) completed questionnaires at BL and were included in the analysis. There were no significant differences between groups for demographic and BL characteristics. There were significant decreases from BL in POMS Total Mood Disturbances (TMD) scores at weeks 4 and 12 in all groups. Both DVS groups showed significantly greater improvement from baseline in TMD scores compared with placebo at weeks 4 (DVS 100 mg, P<0.001; DVS 150 mg, P=0.041) and 12 (DVS 100 mg, P<0.001; DVS 150 mg, P=0.045). The DVS 100-mg group had significant decreases compared with placebo in 4 of 6 POMS subscale scores (week 12, all comparisons, P<0.005). The DVS 150-mg group had significant reductions compared with placebo in 3 of 6 POMS subscale scores. All groups had a significant decrease from BL in GCS total scores at both time points. Improvement in the GCS total score was significantly greater for the DVS 100-mg and DVS 150-mg groups compared with placebo at weeks 4 and 12 (all comparisons, P≤0.001). DVS 100 mg significantly improved all subscale scores, except somatic symptoms, compared with placebo (week 12, all comparisons, P<0.03); DVS 150 mg significantly improved all subscale scores, except somatic symptoms and sexual interest (week 12, all comparisons, P≤0.001). DVS, an effective non-hormonal therapy for HFs, improves mood and climacteric symptoms in women with moderate-to-severe VMS. These data further support DVS 100 mg as the appropriate therapeutic dose.

Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, D-dimer, urinary 11-dehydrothromboxane B(2) (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress D-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.

Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users

A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans. The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose. Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory. Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Delta(9)-tetrahydrocannabinnol pharmacokinetics. Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.

Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures?

Background: Complex regional pain syndrome type I is treated symptomatically. A protective effect of vitamin C (ascorbic acid) has been reported previously. A dose-response study was designed to evaluate its effect in patients with wrist fractures. Methods: In a double-blind, prospective, multicenter trial, 416 patients with 427 wrist fractures were randomly allocated to treatment with placebo or treatment with 200, 500, or 1500 mg of vitamin C daily for fifty days. The effect of gender, age, fracture type, and cast-related complaints on the occurrence of complex regional pain syndrome was analyzed. Results: Three hundred and seventeen patients with 328 fractures were randomized to receive vitamin C, and ninety-nine patients with ninety-nine fractures were randomized to receive a placebo. The prevalence of complex regional pain syndrome was 2.4% (eight of 328) in the vitamin C group and 10.1% (ten of ninety-nine) in the placebo group (p = 0.002); all of the affected patients were elderly women. Analysis of the different doses of vitamin C showed that the prevalence of complex regional pain syndrome was 4.2% (four of ninety-six) in the 200-mg group (relative risk, 0.41; 95% confidence interval, 0.13 to 1.27), 1.8% (two of 114) in the 500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.77), and 1.7% (two of 118) in the 1500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.75). Early cast-related complaints predicted the development of complex regional pain syndrome (relative risk, 5.35; 95% confidence interval, 2.13 to 13.42). Conclusions: Vitamin C reduces the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures?

Complex regional pain syndrome type I is treated symptomatically. A protective effect of vitamin C (ascorbic acid) has been reported previously. A dose-response study was designed to evaluate its effect in patients with wrist fractures. In a double-blind, prospective, multicenter trial, 416 patients with 427 wrist fractures were randomly allocated to treatment with placebo or treatment with 200, 500, or 1500 mg of vitamin C daily for fifty days. The effect of gender, age, fracture type, and cast-related complaints on the occurrence of complex regional pain syndrome was analyzed. Three hundred and seventeen patients with 328 fractures were randomized to receive vitamin C, and ninety-nine patients with ninety-nine fractures were randomized to receive a placebo. The prevalence of complex regional pain syndrome was 2.4% (eight of 328) in the vitamin C group and 10.1% (ten of ninety-nine) in the placebo group (p=0.002); all of the affected patients were elderly women. Analysis of the different doses of vitamin C showed that the prevalence of complex regional pain syndrome was 4.2% (four of ninety-six) in the 200-mg group (relative risk, 0.41; 95% confidence interval, 0.13 to 1.27), 1.8% (two of 114) in the 500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.77), and 1.7% (two of 118) in the 1500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.75). Early cast-related complaints predicted the development of complex regional pain syndrome (relative risk, 5.35; 95% confidence interval, 2.13 to 13.42). Vitamin C reduces the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended.

Effects of the Progesterone Receptor Modulator VA2914 in a Continuous Low Dose on the Hypothalamic-Pituitary-Ovarian Axis and Endometrium in Normal Women: A Prospective, Randomized, Placebo-Controlled Trial

Progestin-only pills, the main hormonal alternative to ethinyl estradiol-containing pills in women bearing vascular risk factors, are poorly tolerated due to irregular bleeding. In contrast, progesterone receptor modulators can inhibit ovulation, alter endometrial receptivity, and improve cycle control. We evaluated the effects of a new progesterone receptor modulator, VA2914, administered continuously for 3 months, on ovulation and endometrial maturation. Forty-six normal women were included in a prospective, placebo-controlled, randomized trial, conducted in four referral centers. VA2914 (2.5, 5, or 10 mg/d) was administered continuously for 84 d. Pelvic ultrasound (treatment d 67 and 77), hormonal monitoring (FSH, LH, estradiol, and progesterone on treatment d 59, 63, 67, 70, 74, 77, 80, and 84), and endometrial biopsy (treatment d 77) were performed. Ovulation inhibition was assessed by the absence of progesterone values above 3 ng/ml at any time during treatment month 3. Anovulation was observed in 81.8% women in the 5-mg group and 80% in the 10-mg group, and amenorrhea occurred in 81.2 and 90% of cases in the 5- and 10-mg groups. We did not detect any cases of endometrial hyperplasia despite estradiol levels that remained in the physiological follicular phase range throughout treatment cycle 3. Continuous low-dose VA2914 can induce amenorrhea and inhibit ovulation without down-regulating estradiol levels or inducing endometrial hyperplasia in normal women. Long-term studies with a larger population are required to confirm the contraceptive efficacy of this regimen.

Phase 1A Safety Assessment of Intravenous Amitriptyline

The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.

Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes

ABSTRACTObjective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP‑4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100 mg daily was evaluated as a once-daily (100 mg once-daily) or twice-daily (50 mg twice-daily) dosing regimen.Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100 mg once-daily, or sitagliptin 50 mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.Results: Mean baseline HbA1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤ 7%. After 12 weeks, treatment with all doses of sitagliptin significantly ( p < 0.05) reduced HbA1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2 mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly ( p < 0.05) reduced by –14.0 to –22.6 mg/dL with all doses of sitagliptin relative to placebo. HOMA‑β was significantly ( p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA‑IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100 mg once-daily and 50 mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100 mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100 mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.