Paroxetine Controlled Release for Premenstrual Dysphoric Disorder: Remission Analysis Following a Randomized, Double-Blind, Placebo-Controlled Trial

Objective: To compare the efficacy and safety of paroxetine controlled release (CR) (12.5 mg/day or 25 mg/day) versus placebo in premenstrual dysphoric disorder (PMDD).Method: A double-blind, randomized, placebo-controlled trial was conducted over 3 menstrual cycles in women aged 18-45 years with confirmed DSM-IV PMDD in 47 outpatient centers across the United States and Canada from November 1999 to January 2002. The primary efficacy measure was the visual analog scale (VAS)-Mood, which is the mean of 4 core symptoms: irritability, tension, depressed mood, and affective lability.Results: A statistically significant difference was observed in favor of paroxetine CR 25 mg versus placebo on the VAS-Mood (adjusted mean difference = -12.58 mm, 95% CI = -18.40 to -6.76; p < .001) and for paroxetine CR 12.5 mg versus placebo (adjusted mean difference = -7.51 mm, 95% CI = -13.40 to -1.62; p = .013). Paroxetine CR was generally well tolerated.Conclusion: Paroxetine CR doses of 12.5 mg/day and 25 mg/day are effective in treating PMDD and are well tolerated.     

Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder

CONTEXT: Paroxetine controlled release (CR) is approved for the treatment of major depressive disorder (MDD) in the dosage range of 25 to 62.5 mg daily. However, lower daily doses (12.5 mg and 25 mg) of this formulation have not been investigated in the treatment of MDD. If the 12.5-mg and 25-mg doses are found to be efficacious, these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD. OBJECTIVE: To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States. PARTICIPANTS: 447 adult (> or = 18 years of age) outpatients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression (HAM-D) score of at least 20 comprised the intent-to-treat study population (mean age = 38.8 years; 58.4% female; 75.6% white). INTERVENTION: Eligible patients completing a 1-week single-blind placebo run-in period were randomly assigned to receive once-a-day study medication (paroxetine CR 12.5 mg [N = 156], paroxetine CR 25 mg [N = 154], or placebo [N = 149]) in an 8-week, double-blind, parallel cell comparison. MAIN OUTCOME MEASURES: The primary efficacy measure was the change from baseline to study endpoint (week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions (CGI) Severity of Illness scale (CGI-S). The proportion of patients considered at study endpoint to be in response (CGI-Improvement score of 1 or 2) or in remission (HAM-D < or = 7) in the 3 treatment groups was also compared. Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety observations were made by assessing the proportion of patients who had adverse experiences, including laboratory and electrocardiographic abnormalities, during the treatment period. RESULTS: The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects (change in HAM-D score) from baseline to study endpoint (LOCF: p = .038, 95% CI = -3.38 to -0.09 and p = .005, 95% CI = -4.06 to -0.74, respectively). Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D (p = .011, 95% CI = -0.57 to -0.07) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group. However, LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg (p = .018, 95% CI = -0.61 to -0.06) and 25-mg (p < .001, 95% CI = -0.78 to -0.22) treatment groups. Significantly more patients in the 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response (CGI-Improvement score of 1 or 2, p = .035, OR = 1.68, 95% CI = 1.04 to 2.73) as well as for remission (HAM-D score 相似文献   

Zolmitriptan, a 5-HT1B/1D receptor agonist for the acute oral treatment of migraine: a multicentre, dose-range finding study

Zolmitriptan is a selective 5-HT_1B/1D receptor agonist for acute oral imgraine theraphy. This randomized, placebo|controlled, parallel-grup study investigated the efficacy and tolerability of oral zolmitriptan (5, 10, 15 and 20 mg) in the tretment of single acute migraine attacks. Of 1181 patients randomized, 840 were evaluable for the primary efficacy analysis. Headache response rates (a reduction in headache intensity from severe or moderate at baseline to mild or no pain at 2 hours post-treatment) were similaracross the zolmitriptan dose groups (66%, 71%, 69% and 77% for 5 mg, 10 mg, 15 mg and 20 mg, respectively) and were significantly higher than that for placebo (19%; all groups P < 0.001). A headache response was reponse was reposted at 1 hour by 40-50% of zolmitriptan recipients (16% placebo). At 2 hours post dose,39-47% of zolmitriptan-treated patients were pain-free, compared with 1% of placebo recipients. Headache recurrence occurred in 21-29% (upper 95% CI 37.1) of zolmitriptan-treated patients and in 65% (95% CI 38.3, 85.8) of placebo recipients. Zolmitriptan was well tolerated at each dose. The most commonly reported adverse events were asthenia, dizziness, paraesthesia and feelings of heaviness. Mostadverse events were of mildor moderate intensity and were efficacy and tolerability profile, the dose response data suggest that lower doses would also offer significant efficacy.     

Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial

PURPOSE: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebo-controlled, crossover study in patients with epilepsy. METHODS: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill. RESULTS: The mean dose-corrected LTG concentration after placebo treatment was 84%[95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, -20-61%) when shifting from oral contraceptives to placebo. CONCLUSIONS: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).     

Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review

This review discusses the efficacy and safety in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of intravenous immunoglobulin and compares this treatment with plasma exchange and prednisolone. We searched publications from 1985 onwards for randomised controlled studies examining the effects of intravenous immunoglobulin in patients with this immune-mediated neuromuscular disorder. Six trials, with 170 patients in total, were judged eligible. A significantly higher proportion of patients improved in disability within a month after the start of treatment with intravenous immunoglobulin than with placebo (relative risk 3.17 [95% CI 1.74 to 5.75]). During this period, intravenous immunoglobulin has similar efficacy to plasma exchange and oral prednisolone; therefore which of these treatments should be the first choice is currently uncertain. An algorithm on treatment approaches for CIDP is proposed.     

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.     

Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study

INTRODUCTION: The transdermal patch (20 microg ethinylestradiol+150 microg norelgestromin daily) and the vaginal ring (15 microg ethinylestradiol+120 microg etonogestrel daily) are new contraceptives, designed to deliver a low dose of hormones, suggesting a low exposure. However, few data are available about their risk of venous thrombosis. The objective was to investigate the effect of the patch, the ring, and an oral contraceptive (30 microg ethinylestradiol+150 microg levonorgestrel daily) on activated protein C sensitivity ratio (APC-sr) and on sex hormone-binding globulin (SHBG) levels in plasma. MATERIALS AND METHODS: After a two month wash-out, 13 volunteers were randomly assigned to either the patch followed by the oral contraceptive or vice versa, or the ring followed by the oral contraceptive or vice versa. All treatments lasted two cycles and were separated by a wash-out of two cycles. APC-sr and SHBG levels were determined on day 18-21 of the second cycle of the wash-out and of each treatment period. RESULTS: Compared to the oral contraceptive, both the patch and the ring led to higher APC resistance (mean difference APC-sr 1.1; 95% CI 0.67-1.52 and 0.55; 95% CI 0.11-1.00, respectively) and higher SHBG levels (mean difference 210 nmol/l; 95% CI 134-286 and 148 nmol/l; 95% CI 48-248, respectively). CONCLUSION: The activity of the protein C system in plasma was impaired more by contraceptive patch and vaginal ring than by an oral contraceptive containing the second generation progestagen levonorgestrel.     

Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy

PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.     

Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation

Compared to second generation, the use of third generation oral contraceptives has been associated with an increased risk of venous thrombosis especially in women with the factor V Leiden mutation. To find an explanation for these risk differences we investigated the effects of desogestrel- and levonorgestrel-containing oral contraceptives as well as their progestagens separately on the coagulation system in the absence or presence of the factor V Leiden mutation. In a single center, double blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second generation (30 microg ethinylestradiol/150 microg levonorgestrel) or a third generation (30 microg ethinylestradiol/150 microg desogestrel) oral contraceptive. After two cycles of use and a wash-out period of 2 menstrual cycles, the participants received the corresponding progestagen-only preparation containing 150 microg levonorgestrel or 150 microg desogestrel. In plasmas of the participating women fragment 1+2, factor V, VII, VIII, IX, X and XI were determined. Both combined oral contraceptives induced a decrease in factor V, whereas the levels of all other coagulant parameters increased. However, in women without the factor V Leiden mutation the effects of desogestrel-containing preparations were significantly different compared to levonorgestrel-containing oral contraceptives for factor V (-8.0; 95% CI -13.4 to -2.6), factor VII (26.8; 95% CI 15.5 to 38.0) and factor IX (-9.6; 95% CI -16.2 to -3.2). When these women used progestagen-only pills, a differential effect between desogestrel and levonorgestrel was only found for factor IX (-6.5; 95% CI -11.4 to -1.5). In carriers of the factor V Leiden mutation desogestrel-containing oral contraceptives induced more pronounced changes in factor V (-14.2; 95% CI -22.4 to -6.0) and factor VII (36.1; 95% CI 19.7 to 52.6) compared to levonorgestrel-containing oral contraceptives. Comparing desogestrel- and levonorgestrel-only, only for factor V a differential effect was found in these women (-9.5; 95% CI -18.3 to -0.6). It appears that desogestrel-containing oral contraceptives have a more pronounced effect on the coagulation system than levonorgestrel-containing oral contraceptives which may be explained by a less effective compensation of the thrombotic effect of ethinylestradiol by desogestrel.     

Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial

This study aims to establish the relative effectiveness and safety of low molecular weight heparin in elderly patients with venous thrombosis in order to find an alternative to oral anticoagulant therapy with less bleeding complications in the long-term treatment of deep venous thrombosis (DVT). One hundred consecutive elderly patients (>75 years old) with venographically demonstrated proximal DVT were included in a randomized trial. All patients were treated for ten days with adjusted doses of intravenous heparin. Informed consent was obtained and on the eight day, patients were randomly allocated to receive acenocoumarol (INR 2.0-3.0) or subcutaneous enoxaparin (4000 anti-Xa units once a day) for three months. All patients were followed-up clinically and venographically for a one year period. The results were analyzed with Fisher's exact test or chi-square test as appropriate. During the treatment and surveillance period, 6 of the 50 patients (12%) who received acenocoumarol and 8 of the 50 patients (16%) who received enoxaparin had new episodes of venous thromboembolism confirmed by objective testing (p = 0.6; 95% CI for the difference: -19.5 to 11.5). Hemorrhagic complications occurred in six of the 50 patients (12%) who received acenocoumarol and in one (2%) of those on enoxaparin (p = 0.1; 95% CI for the difference: -1.8 to 21.8). Vertebral fractures developed in 2 patients (4%) in the enoxaparin group (p = 0.5; 95% CI for the difference: -11.4 to 3.4). These results show that fixed dose enoxaparin seems to be effective and safe in the long-term treatment of proximal DVT in the elderly. In comparison with oral anticoagulants, the findings are inconclusive due to the wide confidence intervals for differences between outcomes, however they suggest that the former may have less bleeding complications with similar efficacy.     

A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence

OBJECTIVE: Problems related to illegal amphetamine use have become a major public health issue in many developed countries. To date, evidence on the effectiveness of psychosocial treatments has remained modest, and no pharmacotherapy has proven effective for amphetamine dependence. METHOD: Individuals meeting DSM-IV criteria for intravenous amphetamine dependence (N=53) were randomly assigned to receive aripiprazole (15 mg/day), slow-release methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely due to unexpected results of interim analysis. An intention-to-treat analysis was used. The primary outcome measure was the proportion of amphetamine-positive urine samples. RESULTS: Patients allocated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (odds ratio=3.77, 95% CI=1.55-9.18), whereas patients who received methylphenidate had significantly fewer amphetamine-positive urine samples than patients who had received placebo (odds ratio=0.46, 95% CI=0.26-0.81). CONCLUSIONS: Methylphenidate is an effective treatment for reducing intravenous drug use in patients with severe amphetamine dependence.     

Trial of subtherapeutic pergolide in de novo Parkinson's disease.

The effect of pergolide 25 mug twice daily on levodopa initiation was assessed in a randomized, placebo-controlled, parallel group, double-blind multicenter trial in 106 untreated early Parkinson's disease patients. The primary endpoint of mean time until levodopa was 520 days (95% confidence interval [CI], 422-618 days) for pergolide versus 434 days (95% CI, 358-609 days) for placebo. However, this increase of 86 days for pergolide was not statistically significant. The wash-in effect of pergolide was significant at 6 weeks (change in mean Unified Parkinson's Disease Rating Scale [UPDRS] 2 and 3 was -0.1 [95% CI, -1.4 to 1.3] for pergolide vs. 2.2 [95% CI, 1.1-3.3] for placebo). At termination, the change from baseline in mean UPDRS 2 and 3 score was 11.4 (95% CI, 8.8-14) for pergolide and 14.6 (95% CI, 12-17.2) for placebo (P=0.08). There was no significant change in UPDRS 2 and 3 for the 83 patients achieving the planned 4-week washout at termination (pergolide 1.2 [95% CI, -0.8 to 3.2] vs. placebo 0.0 [95% CI, -1.6 to 1.6]. Adverse events were infrequent and occurred equally for pergolide and placebo. The study shows no evidence of a neuroprotective effect but indicates a mild symptomatic benefit from pergolide at a dose normally considered subtherapeutic.     

A pilot study using nabilone for symptomatic treatment in Huntington's disease

Pilot study of nabilone in Huntington's disease (HD). Double‐blind, placebo‐controlled, cross‐over study of nabilone versus placebo. Primary outcome, Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Secondary measures: UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI). 44 randomized patients received either nabilone (1 or 2 mg) followed by placebo (n = 22), or placebo followed by nabilone (n = 22). Recruiting was straightforward. Nabilone safe and well tolerated, no psychotic episodes. Assessment of either dose of nabilone versus placebo showed a treatment difference of 0.86 (95% CI: ?1.8 to 3.52) for total motor score; 1.68 (95% CI: 0.44 to 2.92) for chorea; 3.57 (95% CI: ?3.41 to 10.55) for UHDRS cognition; 4.01 (95% CI: ?0.11 to 8.13) for UHDRS behavior, and 6.43 (95% CI: 0.2 to 12.66) for the NPI. Larger longer RCT of nabilone in HD is feasible and warranted. © 2009 Movement Disorder Society     

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.     

Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed-effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.51-4.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.29-0.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings.     

Extended-release epidural morphine (DepoDur): review and safety analysis

Extended-release epidural morphine (EREM) provides effective postoperative analgesia for 48 h following injection. It is administered as a single bolus into the lumbar epidural space, and is indicated for lower abdominal and lower extremity surgery associated with moderate-to-severe pain. While its efficacy has been well documented in randomized controlled trials, the safety and clinically appropriate dosing are less well defined. A meta-analysis approach was used to assess the adverse effects of EREM (n = 801) in comparison with intravenous opioids and standard epidural morphine. EREM 15 mg or greater was associated with a trend towards a higher incidence of hypoventilation (odds ratio: 0.48; 95% confidence interval [CI]: 0.21-1.09; p = 0.081; number-needed-to-treat [NNT] = 14) compared with placebo. The incidence of pruritus was significantly higher for all EREM doses compared with both placebo (p = 0.004) and standard epidural morphine (p = 0.03). Vomiting was also increased with EREM 15 mg or greater compared with placebo (odds ratio: 0.40; 95% CI: 0.18-0.89; p = 0.02; NNT = 5). A multimodal analgesic regime is recommended to permit the use of lower EREM doses, thus reducing the risk for adverse effects including respiratory depression. Prophylactic time-contingent antiemetics are also recommended when EREM is used.     

Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised,placebo-controlled trial

To investigate the effect of postmenopausal oral and transdermal hormone therapy on plasma levels of C-reactive protein (CRP), we performed a randomised, double-blind, double-dummy, placebo-controlled, 15-month study. One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo (n = 49), or transdermal 17beta-oestradiol (E(2)) 50 micro g (tE(2) group, n = 33), or oral E(2) 1 mg (oE(2) group, n = 37), or oral E(2) 1 mg combined with gestodene 25 micro g (oE(2) + G group, n = 33) for thirteen 28-day treatment cycles, followed by four cycles placebo for each group. Data were collected at baseline and in cycles 4, 13 and 17. In cycle 13, CRP was significantly increased in the oE(2) group compared to placebo (P = 0.004). The median percentage change from baseline versus placebo was +75% (P <0.001). In cycle 17, significantly lower values were observed in the oE(2) group compared to cycle 13 and to the placebo group (-49%, P <0.001). There were no significant changes versus placebo in the other groups. In conclusion, oral E(2) significantly increased CRP levels. This change was larger than the increase found during oral E(2) + G. Transdermal E(2) did not affect CRP levels.     

Dose finding, placebo-controlled study of oral almotriptan in the acute treatment of migraine.

OBJECTIVE: To assess the efficacy and tolerability of oral almotriptan, a selective serotonin receptor (5-HT1B/1D) agonist, when used at different doses in the treatment of acute migraine. METHODS: This was a placebo controlled, double-blind, parallel-group, dose-finding study. Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2, 6.25, 12.5, or 25 mg at the onset of moderate or severe pain. Patients graded pain intensity on a 4-point verbal scale from 0 (no pain) to 3 (severe pain) and recorded adverse events. The primary efficacy variable was headache response at 2 hours. Data were analyzed on an intent-to-treat basis. RESULTS: Nine hundred and three patients were randomized, and 742 were included in the evaluation of the efficacy and tolerability. Headache response at 2 hours was 32.5% with placebo, and 30%, 56.3%, 58.5%, and 66.5% with almotriptan 2, 6.25, 12.5, and 25 mg doses (p < 0.05 for 6.25, 12.5, and 25 mg vs placebo). A dose-dependent decrease in the incidence of migraine-associated symptoms and the need for escape medication was observed. The incidence of adverse events with the almotriptan 2-mg, 6.25-mg, and 12.5-mg groups was comparable to that with the placebo group. CONCLUSION: Almotriptan 12.5 mg demonstrated the most favorable ratio between efficacy and tolerability, offering equivalent efficacy and better tolerability compared with the 25 mg dose. The minimum effective dose of almotriptan was 6.25 mg.     

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.