Methotrexate in the management of severe steroid dependent asthma

AIMS: This study was designed to assess the efficacy of low dose methotrexate, 15 mg weekly, as a steroid-sparing agent in asthmatic patients requiring long-term oral prednisone treatment. METHODS: The study was a randomised, double blind, placebo controlled, cross over study of 48 weeks duration. Eleven patients with severe steroid-dependent asthma were included. A successful outcome was defined as a reduction in mean prednisone requirements of 7 mg daily compared to baseline requirements, during active treatment. RESULTS: Two patients were required to be withdrawn owing to methotrexate-related adverse effects. The mean prednisone dose for patients who completed the study was 14.4 mg per day (95% CI; 13.6, 15.1) during active treatment, and 12.9 mg per day (95% CI: 12.2, 13.6) during placebo treatment (NS). Only one patient reduced his individual dose requirements by more than 7 mg per day, whereas in three patients prednisone requirements actually increased during active treatment. There were no significant differences in symptom scores, pulmonary function data, and exacerbations between active and placebo treatments. CONCLUSION: No significant steroid-sparing effect was obtained using low dose methotrexate in this study. This negative outcome may be attributable to the small population of patients studied, low baseline FEV1, and the omission of a steroid minimisation run-in period. Our results highlight the importance of careful patient selection and a painstaking approach in the management of patients with steroid-dependent asthma.     

Hydrophobicity and outer membrane proteins of Shigella dysenteriae type 1 after treatment with subinhibitory concentrations of aminoglycosides

AIMS: We have previously demonstrated that a single dose of oral prednisolone but not single doses of inhaled fluticasone had facilitatory effects on lymphocyte beta2-adrenoceptor (AR) function. To address possible differences in steady-state time-course, the aim of this study was to determine if repeated dosing with inhaled fluticasone would have facilitatory effects on lymphocyte beta2-AR. Plasma cortisol was also evaluated as a measure of systemic bioactivity. METHODS: Ten asthmatic subjects, mean (s.e.mean) age 29 (3) years, FEV1 89 (5) % predicted, were randomised in a double-blind crossover study to receive inhaled placebo (PL), inhaled fluticasone 1000 microg day-1 (F1000) and inhaled fluticasone 2000 microg day-1, each for 4 days and also a single dose of oral prednisolone 50 mg (PRED). Prednisolone was given as open medication. The last dose of study drug was taken at 22.00 h and subjects attended the laboratory at 08.00 h the following day. RESULTS: beta2-AR density (Bmax; fmol/10[6] cells) was significantly increased after PRED compared with PL and inhaled fluticasone. Bmax (geometric mean) after each treatment were: PL 1.51, F1000 1.20, F2000 1.20 and PRED 2.14 (a 1.4 fold difference PRED vs PL; 95% CI 1.05 to 1.95; P < 0.001). There was significant (P < 0.001) suppression of plasma cortisol (nmol l-1) following F2000 and PRED compared with PL: 393.8, F1000 302.1, F2000 205.0 (95% CI F2000 vs PL 58.1 to 319.4) and PRED 87.0 (95% CI PRED vs PL 176.2 to 437.5). The estimated milligram equivalence ratio for adrenal suppression was calculated at 1:11 for fluticasone vs prednisolone. CONCLUSIONS: Repeated dosing with high-dose inhaled fluticasone did not up-regulate lymphocyte beta2-AR as compared with a single dose of oral prednisolone, despite having significantly suppressed early morning plasma cortisol. This study confirms our previous finding of a dissociation in sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte beta2-AR regulation, at least for doses up to 2 mg day-1 of fluticasone.     

Nonsurgical repigmentation therapies in vitiligo. Meta-analysis of the literature

OBJECTIVE: To assess the effectiveness and safety of nonsurgical repigmentation therapies in localized and generalized vitiligo by means of a meta-analysis. DATA SOURCES: Computerized searches of bibliographic databases, a complementary manual literature search, and contacts with researchers and pharmaceutical firms. STUDY SELECTION: Predefined selection criteria were applied to both randomized and nonrandomized controlled trials. DATA EXTRACTION: Two investigators independently assessed the articles for inclusion. When there was a disagreement, a third investigator was consulted. DATA SYNTHESIS: Sixty-three studies were found on therapies for localized vitiligo. Of these, 10 of 11 randomized controlled trials and 29 of 110 patient series were included. One hundred seventeen studies on therapies for generalized vitiligo were found. Of these, 10 of 22 randomized controlled trials and 46 of 231 patient series were included. Among randomized controlled trials on localized vitiligo, the pooled odds ratio vs placebo was significant for topical class 3 corticosteroids (14.32; 95% confidence interval [CI], 2.45-83.72). In the patient series, topical class 3 and class 4 corticosteroids carried the highest mean success rates (56% [95% CI, 50%-62%] and 55% [95% CI, 49%-61%], respectively). Side effects were reported mostly with topical psoralen and intralesional and class 4 corticosteroids. In the randomized controlled trials on generalized vitiligo, the odds ratio vs placebo was significant for oral methoxsalen plus sunlight (23.37; 95% CI, 1.33-409.93), oral psoralen plus sunlight (19.87; 95% CI, 2.37-166.32), and oral trioxsalen plus sunlight (3.75; 95% CI, 1.24-11.29). In the series, the highest mean success rates were achieved with narrowband UV-B (63%; 95% CI, 50%-76%), broadband UV-B (57%; 95% CI, 29%-82%), and oral methoxsalen plus UV-A therapy (51%; 95% CI, 46%-56%). Oral methoxsalen plus UV-A was associated with the highest rates of side effects. No side effects were reported with UV-B therapy. CONCLUSIONS: Class 3 corticosteroids and UV-B therapy are the most effective and safest therapies for localized and for generalized vitiligo, respectively.     

A systematic review on the treatment of giardiasis

To assess the efficacy of treatment of parasitological excretion of cysts and trophozoites and symptoms of patients with giardiasis, a systematic review of published randomized clinical trials was conducted through extensive searches in Medline, Embase and Current Contents from 1966 till 1996 as well as manual reviews of 28 journals. The methodological quality of all trials was assessed by guidelines of the Cochrane Collaboration. Thirty-one trials were included, only one of which had no serious methodological flaws. The mean score of parasitological examination was 4.8 out of a possible 15. There was a considerable effect in cure rate of treatment versus placebo (odds 9.3, 95% CI 4.69-18.4), but all 3 trials in this comparison had serious flaws. Metronidazole treatment over more than 3 days seems to achieve a better parasitological cure rate than other long treatment courses (pooled odds 2.6, 95% 1.7-3.8), but trials are clinically and statistically heterogeneous. Single-dose therapy is as effective as longer treatment courses (pooled odds 0.67, 95% 0.31-1.44). Within the single-dose regimens tinidazole (2 g) reaches a higher parasitological cure rate than other short therapies (pooled odds 55, 95% CI 3.7-8.3) with relatively few side-effects. Placebo-controlled trials with parasitological and clinical outcomes are needed.     

A meta-analytic review of the preventive treatment of recurrences of febrile seizures

OBJECTIVE: To assess the efficacy of various medications in the prevention of recurrent febrile seizures. STUDY DESIGN: A meta-analysis of all published randomized, placebo-controlled trials of the preventive treatment of febrile seizures published in English; 45 articles were found, but only 9 trials were randomized and placebo-controlled--4 using phenobarbital; 3, diazepam; 1, pyridoxine; and 1, phenytoin. In one of the phenobarbital trials, valproate was also compared with placebo. RESULTS: The risk of recurrences was significantly lower in children receiving continuous phenobarbital therapy than placebo (odds ratio 0.54, 95% confidence intervals 0.33 to 0.90, p = 0.017). The odds ratio for recurrences in the valproate group was 0.09, 95% CI 0.01 to 0.78, p = 0.011. No difference in the risk was found for recurrences between children receiving intermittent diazepam and placebo (odds ratio 0.81, 95% CI 0.54 to 1.22, p = 0.31). The risk for recurrences in children receiving pyridoxine or phenytoin did not differ from the risk among children receiving placebo. Four children would have to be treated with valproate (95% CI 2 to 11) or eight children would have to be treated with phenobarbital (95% CI 5 to 27), continuously, to prevent one febrile seizure. CONCLUSIONS: Because both agents found to be effective in prevention of recurrent febrile seizures have known adverse effects, prophylaxis of febrile seizures cannot be recommended.     

Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials

We performed meta-analyses of randomized, control trials to assess the effects of seven analgesic therapies on postoperative pulmonary function after a variety of procedures: epidural opioid, epidural local anesthetic, epidural opioid with local anesthetic, thoracic versus lumbar epidural opioid, intercostal nerve block, wound infiltration with local anesthetic, and intrapleural local anesthetic. Measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), vital capacity (VC), peak expiratory flow rate (PEFR), PaO2, and incidence of atelectasis, pulmonary infection, and pulmonary complications overall were analyzed. Compared with systemic opioids, epidural opioids decreased the incidence of atelectasis (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.33-0.85) and had a weak tendency to reduce the incidence of pulmonary infections (RR 0.53, 95% CI 0.18-1.53) and pulmonary complications overall (RR 0.51, 95% CI 0.20-1.33). Epidural local anesthetics increased PaO2 (difference 4.56 mm Hg, 95% CI 0.058-9.075) and decreased the incidence of pulmonary infections (RR 0.36, 95% CI 0.21-0.65) and pulmonary complications overall (RR 0.58, 95% CI 0.42-0.80) compared with systemic opioids. Intercostal nerve blockade tends to improve pulmonary outcome measures (incidence of atelectasis: RR 0.65, 95% CI 0.27-1.57, incidence of pulmonary complications overall: RR 0.47, 95% CI 0.18-1.22), but these differences did not achieve statistical significance. There were no clinically or statistically significant differences in the surrogate measures of pulmonary function (FEV1, FVC, and PEFR). These analyses support the utility of epidural analgesia for reducing postoperative pulmonary morbidity but do not support the use of surrogate measures of pulmonary outcome as predictors or determinants of pulmonary morbidity in postoperative patients. IMPLICATIONS: When individual trials are unable to produce significant results, it is often because of insufficient patient numbers. It may be impossible for a single institution to study enough patients. Meta-analysis is a useful tool for combining the data from multiple trials to increase the patient numbers. These meta-analyses confirm that postoperative epidural pain control can significantly decrease the incidence of pulmonary morbidity.     

The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction

AIMS: The aims of this investigation were to evaluate the efficacy of regular inhaled beclomethasone in the control of symptoms and lung function with non-asthmatic smoking related obstructive pulmonary disease and to evaluate the relationship between clinical responses to a short course of oral prednisone and longer term outcomes using inhaled steroid. METHODS: The study was a randomised, double blind, placebo controlled, crossover investigation in 18 patients. The active treatment was inhaled beclomethasone 1000 micrograms given twice daily for three months by metered dose inhaler. At the end of each treatment period, patients received oral prednisone 30 mg/day for ten days. The two treatment phases were separated by a one month washout interval. Peak flow rates, symptom scores and "rescue" bronchodilator use were recorded twice daily. Lung function (FEV1, FVC and lung volumes) and bronchial hyperresponsiveness (PC20 methacholine) were measured at monthly visits. The number of exacerbations requiring intervention therapy were also recorded. RESULTS: There were no consistent benefits attributable to beclomethasone. Lung function was not significantly better as a result of active treatment. Sputum production improved but other symptom scores were similar during active and placebo therapy. Three patients exhibited an increase in FEV1 of 15% or more during active treatment but did not do so when oral prednisone was administered immediately after the period of placebo treatment. A further three patients showed an improvement in FEV1 of 15% or more with oral prednisone but failed to improve during treatment with inhaled beclomethasone. The predictive value of the "trial of steroid" was 0% and 81.3% for positive and negative outcomes respectively. CONCLUSIONS: Our results indicate that in non-asthmatic chronic obstructive pulmonary disease inhaled corticosteroid fails to achieve significant improvements in either lung function or symptoms. The response to a "trial of steroid" using oral prednisone is not clinically helpful in selecting the small number of patients who may subsequently benefit from this form of therapy.     

Effects of histamine type 2-receptor antagonists cimetidine and famotidine on left ventricular systolic function in chronic congestive heart failure

Twelve patients with stable congestive heart failure and left ventricular dysfunction were enrolled in a double-blind, randomized crossover trial of famotidine, cimetidine and placebo to determine whether histamine type 2 (H2) antagonists adversely affect left ventricular systolic performance. Two-dimensional echocardiograms were obtained at baseline, after 4 days of oral treatment with standard doses of famotidine and cimetidine, and placebo, and at the conclusion of the trial. The baseline mean ejection fraction was 19 +/- 7%. The changes in ejection fraction were +2 +/- 11% (95% confidence interval [CI] -5 to 9%) with famotidine, +3 +/- 10% (95% CI -3 to 10%) with cimetidine, and -3 +/- 7% (95% CI -8 to 2%) with placebo. There were no significant differences in changes in ejection fraction among the 3 experimental treatments (p = 0.22; analysis of variance). The changes in end-systolic wall stress/volume ratios from baseline were +6 +/- 21% (95% CI -6 to 18%) for famotidine, +8 +/- 29% (95% CI -8 to 25%) for cimetidine, and +2% +/- 29% (95% CI -15 to 18%) for placebo (p = 0.69; analysis of variance). No patient had a worsening of symptoms during therapy. Despite previous reports that H2 antagonists may depress left ventricular systolic function, at standard doses these agents result in no decrease in left ventricular systolic function in patients with chronic congestive heart failure.     

A therapeutic trial of acupuncture in neurogenic bladder of spinal cord injured patients--a preliminary report

This randomized, double-blind, placebo-controlled, four-way crossover study was conducted on an in-clinic basis to assess forearm perfusion after subcutaneous (s.c.) naratriptan and placebo by reserve volume (hyperemic/baseline) and basal forearm blood flow (FBF) measured by strain gauge plethysmography. Nineteen male and female volunteer migraine subjects (International Headache Society criteria) received s.c. naratriptan 1 mg, 5 mg, 10 mg, and placebo on four separate study days outside a migraine attack. FBF was recorded at baseline, at 7-min intervals post-dose up to 1 h (basal) and once after sublingual glyceryl trinitrate administered at 1 h (hyperemic). Vital signs and electrocardiograms were recorded at baseline and 15, 30, 45, and 60 min post-dose. There were no statistically significant differences in reserve volume (hyperemic/baseline) between any dose of s.c. naratriptan and placebo. The naratriptan to placebo ratio was 102% (95% CI: 87-120%; p = 0.789) for 1 mg; 97% (95% CI: 83-114%, p = 0.737) for 5 mg; and 92% (95% CI: 79-108%; p = 0.325) for 10 mg. There were no statistically significant differences in basal FBF for any dose compared to placebo. The naratriptan to placebo ratio was 95% (95% CI: 87-104%; p = 0.263) for 1 mg; 94% (95% CI: 86-102%; p = 0.142) for 5 mg; and 94% (95% CI: 86-103%; p = 0.157) for 10 mg. The percentage of patients reporting adverse events was 53% with placebo, 53% with s.c. naratriptan 1 mg, 89% with 5 mg and 89% with 10 mg. In conclusion, these results suggest that s.c. naratriptan doses similar to and above the oral therapeutic dose equivalent (single oral dose 2.5 mg) have no significant effect on peripheral blood flow as measured by FBF. S.c. naratriptan doses 1 mg, 5 mg, and 10 mg were well tolerated.     

The effectiveness and safety of vaccines against human anthrax: a systematic review

We report on the results of a systematic review of existing controlled clinical trials undertaken to assess the effectiveness and safety of vaccines against human anthrax in relation to disease incidence and side-effects. Two articles retrieved by electronic and hand search fulfilling some of the inclusion criteria underwent a quality assessment by a group of reviewers. Data synthesized from the two trials showed that estimates of overall effectiveness and safety favour treatment (overall odds ratio 0.16; 95% confidence interval 0.07-0.34). The route of inoculation appears to make little difference to the effectiveness of the vaccines; however, one study shows that the incidence and severity of side-effects are significantly higher with the killed vaccine than with the alum-based placebo (overall odds ratio 0.16; 95% confidence interval 2.38-27.17).     

Overview of clinical trials of hydergine in dementia

OBJECTIVE: To assess the overall effect of Hydergine (a combination drug called ergoloid mesylates) on patients with possible dementia and to investigate potential moderators of an effect. DATA SOURCES: MEDLINE, EMBASE, and two proprietary databases were searched for reports of clinical trials. STUDY SELECTION: Included were randomized, placebo-controlled, double-blind, parallel-group trials in subjects with symptoms consistent with dementia performed with specified outcome instruments and sufficient statistical information to calculate effect sizes. Forty-seven (31%) of 151 trials reviewed met selection criteria. DATA EXTRACTION: Potential moderating variables were extracted from each trial: sample size, inpatient-outpatient status, trial duration, age, gender, medication dose, publication year, and diagnostic grouping. Outcome measures were extracted with their associated statistics. DATA SYNTHESIS: The overall combined treatment effects ("adjusted d") for three types of outcome measures were calculated. Overall, Hydergine was more effective than placebo as assessed by comprehensive ratings (d = 0.47; 95% confidence interval [CI], 0.38 to 0.56; P = .0001), clinical global ratings (d = 0.56; 95% CI, 0.44 to 0.68; P = .0001), and combined neuropsychological measures (d = 0.27; 95% CI, 0.22 to 0.32; P = .0001). Inpatient status, daily doses of 4 mg or more, and vascular dementia were generally associated with larger effects. The effect in patients with possible Alzheimer's dementia was significant only for combined neuropsychological measures in five trials (d = 0.30; 95% CI, 0.16 to 0.44; P = .0001; and with a dose-response, P = .001). CONCLUSIONS: Overall, ergoloid mesylates were more effective than placebo. However, the effect in patients with possible Alzheimer's dementia was very modest at best. The dose-response relation suggests that potentially effective doses may be higher than the currently approved. The circumstances of the efficacy of Hydergine remain inadequately defined.     

Pulsed-field gel electrophoresis is more efficient than ribotyping and random amplified polymorphic DNA analysis in discrimination of Pasteurella haemolytica strains

OBJECTIVE: Factors such as size of hyphema, intraocular pressure, initial visual acuity, and use of steroids or antifibrinolytic drugs may be associated with the likelihood of rebleeding in traumatic hyphema. The association of the visual outcome with secondary hemorrhage has been questioned. DESIGN: Randomized, placebo-controlled, clinical trial. PARTICIPANTS: Two hundred and thirty-eight patients who had hyphema develop after blunt trauma. INTERVENTION: Eighty patients received oral tranexamic acid, 80 patients received placebo, and 78 patients received oral prednisolone. MAIN OUTCOME MEASURES: Secondary hemorrhage and vision at the time of discharge from the hospital were measured. RESULTS: Rebleeding occurred in 43 (18%) of the patients and was prevented significantly by oral tranexamic acid compared with the placebo (odds ratios [OR] = 0.39; 95% confidence interval [CI], 0.17, 0.89). Occurrence of secondary hemorrhage had weak associations with initial high intraocular pressure (OR = 2.7; 95% CI, 0.99, 7.3) and initial visual acuity of 6/60 or less (OR = 1.8; 95% CI, 0.9, 3.7). Secondary hemorrhage had no statistical association with age, gender, oral prednisolone, size of hyphema, and retinal damage. Visual acuity of 6/60 or less at the time of discharge was significantly associated with rebleeding (OR = 10.5; 95% CI, 3.7, 29.2), initial visual acuity of 6/60 or less (OR = 9.9; 95% CI, 2.8, 38.0), retinal damage (OR = 14.6; 95% CI, 3.8, 55.8), and male gender (OR = 6.5; 95% CI, 1.4, 31.9). Final visual acuity had no significant statistical association with age, use of oral prednisolone or tranexamic acid, and size of hyphema. CONCLUSIONS: High intraocular pressure and low vision at the time of first examination may be associated with increased chance of rebleeding. Retinal damage, secondary hemorrhage, male gender, and initial poor vision are associated with a worse visual outcome in patients with traumatic hyphema.     

Survival analysis of two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex in AIDS

OBJECTIVES: Rifabutin prophylaxis has been shown to significantly decrease the incidence of Mycobacterium avium complex (MAC) bacteremia in two randomized controlled clinical trials, but a survival benefit has not been observed. An analysis of complete follow-up of these patients through August 1992 was performed to assess subsequent survival, because although follow-up in the previous trials was limited at the time of initial analysis, the analysis did suggest that a survival benefit might be emerging. METHODS: Data from 1146 AIDS patients with CD4+ counts < or = 200 x 10(6)/l enrolled at 73 US and Canadian sites in two clinical trials of MAC prophylaxis were analyzed using Cox proportional hazards analysis with rifabutin use modeled as a time-dependent covariate, taking into account the initial randomized double-blind phase of the trials and the subsequent open-label phase of follow-up of those patients. Survival from date of enrollment was analyzed. Other covariates adjusted for in the analysis were CD4+ lymphocytes count, Karnofsky performance score and hospitalization for opportunistic complications of AIDS. RESULTS: Patients who received open-label rifabutin may have had a better prognosis than those who did not, based on Karnofsky score and occurrence of opportunistic disease. Adjusting for these variables and for use of rifabutin as time-dependent covariates, the relative hazard (RH) of dying while receiving rifabutin prophylaxis was 0.74 for the entire cohort [95% confidence interval (CI), 0.60-0.91; P < 0.004]. For patients with an enrollment CD4+ count < or = 50 x 10(6)/l (n = 655), the RH was 0.75 (95% CI, 0.58-0.98), and for patients with an enrollment CD4+ count of > 50 x 10(6)/l (n = 491), the RH was 0.69 (95% CI, 0.49-0.99). CONCLUSIONS: An analysis of the combined double-blind and open-label follow-up of two clinical trials of rifabutin prophylaxis for MAC supports the suggestion of the double-blind study that rifabutin improves survival of AIDS patients.     

The new antiepileptic drugs: a systematic review of their efficacy and tolerability

PURPOSE: Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as "add-on" treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability. METHODS: Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a > or = 50% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIs; 50% responders) or 99% CIs; side effects) were calculated. RESULTS: Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53-3.43); LTG, 2.32 (1.47-3.68); TGB, 3.03 (2.01-4.58); TPM, 4.07 (2.87-5.78); VGB, 3.67 (2.44-5.51); and ZNS, 2.7 (1.36-4.47). ORs for discontinuation were GBP, 1.36 (0.75-2.49); LTG, 1.19 (0.79-1.79); TGB, 1.81 (1.21-2.70); TPM, 2.56 (1.64-4.00); VGB, 2.58 (126-5.27); and ZNS, 4.23 (1.71-10.49). CONCLUSIONS: We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.     

Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain--a meta-analysis

The objective of this study was to quantify the analgesic efficacy of paracetamol and its combination with codeine or caffeine through a systematic overview and meta-analysis of relevant randomized controlled trials (RCTs). Systematic retrieval of relevant clinical trials was carried out using computerized searches, historical searches and communication with manufacturers. The results of RCTs were pooled to estimate (i) the difference in percentage improvement of total pain relief (TOTPAR%) and the sum of pain intensity difference (SPID%); (ii) the proportions of patients obtaining moderate to excellent pain relief relative to placebo (ResRR) and (iii) the ratio of patients requiring analgesic re-medication (RemRR). Head-to-head comparisons were also undertaken for paracetamol versus its combination with codeine or caffeine. A total of 80 RCT reports describing 103 placebo comparisons and 26 head-to-head comparisons were identified. The total pain relief score in the single dose studies increased by 38 percentage points for paracetamol and by 24 points for placebo. The difference (d) in TOTPAR% between the two was highly significant (d = 14, 95% CI: 12, 16). For the difference in SPID%, d = 12, 95% CI: 11, 13. Patients were more than twice as likely to obtain moderate to excellent pain relief on paracetamol than on placebo (ResRR = 2.39, 95% CI: 1.89, 3.02), and less likely to require re-medication (RemRR = 0.78, 95% CI: 0.69, 0.88). There was no significant (P > 0.05) dose-response relationship. The analgesic efficacy of paracetamol 600 mg was enhanced with the addition of codeine 60 mg (using TOTPAR% as outcome) in both indirect and head-to-head comparisons. SPID%, but not ResRR and RemRR, data supported this conclusion. Much weaker effects were observed with the caffeine combination. Adverse effects were mild. Surprisingly, drowsiness was seen more often with paracetamol and paracetamol-codeine combinations than with placebo. The relative risks (95% CI) were 1.83 (1.29, 2.59) and 2.39 (1.58, 3.57), respectively. In conclusion paracetamol is an effective analgesic for post-surgical pain. Caffeine adds little to the analgesic effect of paracetamol. However, there is some evidence that codeine 60 mg adds to the analgesic effects of paracetamol 600 mg, using pain relief or pain intensity scores as outcomes, but this is not necessarily translated into an increase in number of patients who obtain moderate to excellent pain relief.     

Use of transverse microradiography to quantify mineral loss by erosion in bovine enamel

BACKGROUND: A double blind, placebo controlled study was undertaken to determine the effects of 104 weeks of intermittent cyclical etidronate therapy on bone mineral density (BMD) in patients undergoing long-term oral corticosteroid therapy. METHODS: Forty nine patients of mean age 59 years on long-term (> 6 months) corticosteroid treatment were randomised to receive either 400 mg/day etidronate or placebo for 14 days followed in both groups by calcium (equivalent to 97 mg elemental Ca/day) with vitamin D (400 IU) for 76 days. The cycle was repeated a total of eight times over a period of two years. Dual energy x ray absorptiometry (DEXA) measurements of the lumbar spine and hip BMD and biochemical bone marker analyses were performed at baseline and every six months. RESULTS: Twenty six patients (10 men) received cyclical etidronate and 23 (nine men) received placebo. The mean (SD) dose of corticosteroid (prednisone or equivalent) at baseline in the etidronate group was 8 (4) mg/day and in the placebo group was 7 (4) mg/day. Most of the patients (43%) suffered from asthma. Forty one patients completed the study (22 in the etidronate group and 19 in the placebo group). All had a low BMD at entry and with treatment a significant difference was observed between groups in the mean (SE) percentage change from baseline in lumbar spine BMD at week 104 of 4.5 (1.65)% (p = 0.007) with a 95% confidence interval (CI) of 1.12 to 7.87%. No clinically or statistically significant treatment differences were observed at the hip or with bone markers. The incidence of adverse events was similar in the two groups. CONCLUSIONS: The results show that intermittent cyclical etidronate therapy with calcium and vitamin D supplementation significantly increases lumbar spine BMD in patients with osteoporosis resulting from long-term treatment with corticosteroids.     

Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials

CONTEXT: Aspirin has been widely used to prevent myocardial infarction and ischemic stroke but some studies have suggested it increases risk of hemorrhagic stroke. OBJECTIVE: To estimate the risk of hemorrhagic stroke associated with aspirin treatment. DATA SOURCES: Studies were retrieved using MEDLINE (search terms, aspirin, cerebrovascular disorders, and stroke), bibliographies of the articles retrieved, and the authors' reference files. STUDY SELECTION: All trials published in English-language journals before July 1997 in which participants were randomized to aspirin or a control treatment for at least 1 month and in which the incidence of stroke subtype was reported. DATA EXTRACTION: Information on country of origin, sample size, duration, study design, aspirin dosage, participant characteristics, and outcomes was abstracted independently by 2 authors who used a standardized protocol. DATA SYNTHESIS: Data from 16 trials with 55462 participants and 108 hemorrhagic stroke cases were analyzed. The mean dosage of aspirin was 273 mg/d and mean duration of treatment was 37 months. Aspirin use was associated with an absolute risk reduction in myocardial infarction of 137 events per 10000 persons (95% confidence interval [CI], 107-167; P<.001) and in ischemic stroke, a reduction of 39 events per 10000 persons (95% CI, 17-61; P<.001). However, aspirin treatment was also associated with an absolute risk increase in hemorrhagic stroke of 12 events per 10000 persons (95% CI, 5-20; P<.001). This risk did not differ by participant or study design characteristics. CONCLUSIONS: These results indicate that aspirin therapy increases the risk of hemorrhagic stroke. However, the overall benefit of aspirin use on myocardial infarction and ischemic stroke may outweigh its adverse effects on risk of hemorrhagic stroke in most populations.     

Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results. METHODS AND RESULTS: A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patient. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87). CONCLUSIONS: Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.     

Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study

OBJECTIVE: To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid. DESIGN: A 4-year prospective study. SETTING: Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands. PATIENTS: The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study. INTERVENTION: During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily. RESULTS: Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups. CONCLUSIONS: Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients.