Natural progesterone and antihypertensive action.

In a placebo controlled, double blind crossover study natural progesterone was given by mouth, in increasing doses, to six men and four postmenopausal women with mild to moderate hypertension who were not receiving any other antihypertensive drugs. When compared with values recorded before treatment and during administration of placebo progesterone caused a significant reduction in blood pressure, suggesting that progesterone has an antihypertensive action rather than a hypertensive one as has been previously thought. This possible protective effect of progesterone should be investigated further.     

Progesterone and the premenstrual syndrome: a double blind crossover trial.

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos''s menstrual distress questionnaire, Beck et al''s depression inventory, Spielberger et al''s state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.     

Duration of luteal support (DOLS) with progesterone pessaries to improve the success rates in assisted conception: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Luteal phase support has been shown by a meta analysis of prospective randomised studies, to be beneficial in establishing a pregnancy after IVF. The optimal length of treatment is unresolved at present and it remains unclear how long to treat women receiving luteal supplementation. It has been used for as little as 2 weeks and for as long as 12 weeks of gestation. OBJECTIVE: To conduct a prospective randomised double blind study to investigate the effect of the duration of luteal support with progesterone in IVF cycles. Trial design: Following 2 weeks of standard treatment and a positive biochemical pregnancy test, this randomised control trial will allocate women to a supplementary 8 weeks of treatment of vaginal progesterone or 8 weeks of placebo. Eligibility: All women presenting to the Hewitt Centre for Reproductive Medicine, Liverpool Women's NHS Foundation Trust, for assisted conception with a positive biochemical pregnancy test at 2 weeks post embryo transfer are eligible to enter the trial. Primary outcome measure:The primary outcome measure is the proportion of all randomised women that continue successfully to a viable pregnancy (at least one fetus with FHR >100 beats minute) on transabdominal / transvaginal ultrasound at 10 weeks post embryo transfer / 12 weeks gestation (i.e. at the end of 8 weeks supplementary trial treatment).     

Induction of remissions of insulin-dependent diabetes by cyclosporin

The effect of cyclosporine was evaluated in a double blind placebo controlled trial in 122 recent onset insulin-dependent diabetics. A significantly higher incidence of complete remissions was observed in patients treated with cyclosporine than in those receiving placebo (respectively 24 and 5.8%). The effect was still more clear-cut in patients having presented the highest cyclosporine blood level (37%). These results which have been obtained with modest toxicity demonstrate that cyclosporine induces remission of insulin-dependent diabetes and prompt to set up new controlled trials to evaluate the duration of the effect obtained and the potential risks of the treatment.     

Controlled study of withdrawal symptoms and rebound anxiety after six week course of diazepam for generalised anxiety.

A group of patients suffering from anxiety, as assessed by general practitioners and psychologists using research criteria for generalised anxiety, were treated with either diazepam or placebo double blind for six weeks. This active treatment period was preceded by a one week single blind placebo "wash in" period and followed by a two week single blind placebo "wash out" period. The results suggest that diazepam can produce rebound anxiety and withdrawal symptoms when used in moderate doses and for what has previously been regarded as a safe length of time. If replicated these results have implications for the therapeutic use of benzodiazepines.     

Treatment of the restless legs syndrome with carbamazepine: a double blind study.

One hundred and seventy four patients suffering from the restless legs syndrome were examined in a double blind, between patient, placebo controlled study in general practice for five weeks to investigate the effects of carbamazepine and placebo on the syndrome. The syndrome was more common among middle aged women with relatively low systolic blood pressure. The median haemoglobin concentration was about average for the population, but the severity of the symptoms seemed to increase with decreasing concentrations of haemoglobin. Both placebo and carbamazepine showed a significant therapeutic effect (p less than 0.01). Carbamazepine was significantly more effective than placebo (p less than or equal to 0.03). The significant therapeutic effect of placebo in restless legs showed that only double blind controlled trials can confirm the efficacy of suggested treatments.     

胃食管反流病中安慰剂反应率的相关研究

目的：对胃食管反流病（GERD）随机对照试验中的安慰剂反应率进行Meta分析并研究影响该反应率的因素。方法：检索EMBASE,CochraneControlledTrialRegister和Medline数据库中公开发表的关于双盲、随机、安慰荆对照治疗GERD的英文文献,所有文献均包括质子泵抑制剂／H2受体阻滞剂,治疗时间至少为2周。对文献试验数据进行Meta分析,绘制森林图,同时绘制漏斗图检查发表偏倚。结果：纳入24个研究,共包括8917名患者。有效治疗的反应率与安慰剂反应率相比的OR为3．70（95％CI：2．77～4．95）。所有的安慰剂反应率为18．84％（2．93％-47．05％）。运用质子泵抑制剂治疗的患者与H：受体阻滞剂治疗者相比,安慰剂反应率明显降低（14．50％vs．24．68％,P=0．05）。糜烂性食管炎患者的安慰剂反应率与非糜烂性食管炎者相比略低,两者差异无显著性（P〉0．05）。结论：在GERD随机对照试验中,安慰剂反应率确实存在。该反应率降低与质子泵抑制剂的运用相关,而与腐蚀性食管炎的存在与否无关。     

Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people.

OBJECTIVE--To assess quantitatively the efficacy of quinine (as quinine sulphate) compared with placebo in the treatment of nocturnal leg cramps. DESIGN--A meta-analysis of six randomised, double blind, crossover trials. SETTING--Randomised trials that were available as of April 1994. SUBJECTS--A total of 107 general ambulatory patients who suffered from regular nocturnal leg cramps from six clinical trials. RESULTS--Data from individual patients were used to calculate point estimates and 95% confidence intervals for each of the outcome measures reported by these studies. Treatment with quinine resulted in a significant reduction in the number of cramps for a four week period compared with placebo (8.83 fewer cramps; 95% confidence interval 4.16 to 13.49). Treatment with quinine reduced the number of nights with cramps by 27.4% (24.0% to 30.8%) compared with placebo. Treatment did not produce a significant change in the severity or duration of individual nocturnal leg cramps. Side effects were uncommon. CONCLUSIONS--The results indicate that quinine can prevent nocturnal leg cramps in general ambulatory populations. Given the possible serious side effects of treatment with quinine, the benefits and risks in patients taking this drug should be closely monitored.     

Sequential parallel comparison design for “gold standard” noninferiority trials with a prespecified margin

Three‐arm noninferiority trials (involving an experimental treatment, a reference treatment, and a placebo)—called the “gold standard” noninferiority trials—are conducted in patients with mental disorders whenever feasible, but often fail to show superiority of the experimental treatment and/or the reference treatment over the placebo. One possible reason is that some of the patients receiving the placebo show apparent improvement in the clinical condition. An approach to addressing this problem is the use of the sequential parallel comparison design (SPCD). Nonetheless, the SPCD has not yet been discussed in relation to gold standard noninferiority trials. In this article, our aim was to develop a hypothesis‐testing method and its corresponding sample size calculation method for gold standard noninferiority trials with the SPCD. In a simulation, we show that the proposed hypothesis‐testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy.     

Moderate potassium chloride supplementation in essential hypertension: is it additive to moderate sodium restriction?

Twenty patients with mild or moderate essential hypertension and not receiving any drug treatment, who had been moderately restricting their sodium intake to around 70 mmol(mEq) a day for at least one month and whose mean blood pressure was then 163/103 mm Hg, were entered into a double blind, randomised crossover study to compare one month''s treatment with slow release potassium chloride tablets (64 mmol potassium chloride a day) with one month''s treatment with a matching placebo. Mean (SEM) urinary sodium excretion on entry to the study was 68 (6.8) mmol/24 h. Mean urinary potassium excretion increased from 67 (6.9) mmol(mEq)/24 h with placebo to 117 (4.6) mmol/24 h with potassium chloride. Supine and standing systolic and diastolic blood pressures did not change significantly with potassium chloride supplementation when compared with pressures while receiving placebo or before randomisation. In patients who are able moderately to restrict their sodium intake doubling potassium as a chloride salt has little or no effect on blood pressure.     

Lack of effect of oral magnesium on high blood pressure: a double blind study.

Seventeen unselected patients with mild to moderate essential hypertension and whose average supine blood pressure after two months'' observation with no treatment was 154/100 mm Hg were entered into a double blind randomised crossover study of one month''s treatment with magnesium aspartate (15 mmol magnesium/day) and treatment with placebo for a further month. This preparation of magnesium was well tolerated and did not cause diarrhoea. Despite a significant increase in plasma magnesium concentration and a significant increase in urinary excretion of magnesium while taking magnesium aspartate there was no fall in blood pressure compared with either treatment with placebo or values before treatment. The results provide no evidence for a role of dietary magnesium in the regulation of high blood pressure and are contrary to recent speculations.     

Peppermint oil in irritable bowel syndrome

In a literature search 16 clinical trials investigating 180-200 mg enteric-coated peppermint oil (PO) in irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651 patients enrolled were identified. Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods, five had a randomized double blind parallel group design and two were open labeled studies. Placebo served in 12 and anticholinergics in three studies as comparator. Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range 10-52%) for placebo. The three studies versus smooth muscle relaxants did not show differences between treatments hinting for equivalence of treatments. Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI effects like heartburn and anal/perianal burning or discomfort sensations, whereas the anticholinergics caused dry mouth and blurred vision. Anticholinergics and 5HT3/4-ant/agonists do not offer superior improvement rates, placebo responses cover the range as in PO trials. Taking into account the currently available drug treatments for IBS PO (1-2 capsules t.i.d. over 24 weeks) may be the drug of first choice in IBS patients with non-serious constipation or diarrhea to alleviate general symptoms and to improve quality of life.     

Suppression of uterine activity and abortion by inhibition of prostaglandin synthesis

The premise has been examined that the evolution of uterine activity, provoked by progesterone(P)-deficiency and consequent prostaglandin(PG)-dominance, can be suppressed in patients by inhibiting PG-synthesis. In 20 midtrimester pregnant women P-deficiency, evolution of intrauterine pressure (IUP), oxytocin response (OR) and abortion had been induced by the hypertonic saline technique and the changes in P and E2 levels and in IUP and OR measured sequentially. According to a "double blind" protocol, 10 volunteers received placebo, while another 10 were treated during 14 hours with 1050 mg naproxen, an inhibitor of PG-synthesis. Significant decrease in plasma progesterone (P 0.001) and estradiol 17Beta (P 0.02) preceding clinical progress in abortion demonstrated that hypertonic saline suppressed the endocrine function of the fetoplacental unit in both groups of patients. In spite of a 40% reduction in the P-levels of the experimental group (at a time when the controls aborted) the evolution of IUP, OR and abortion in the naproxen treated had been delayed by about 30 hours. This significant delay in all the measured parameters (P 0.001) is evidence that inhibition of PG-synthesis prevents the endogenous activation of the uterus in patients, as it does in animal "models".     

Is there a place in the United Kingdom for intensive antacid treatment for chronic peptic ulceration?

Sixty nine patients with chronic duodenal or juxtapyloric ulceration were studied in a prospective double blind randomised trial to compare the efficacy of antacid and placebo at high (30 ml seven times daily) and low (10 ml as required) doses. After four weeks ulcers had healed in 12 out of 18 patients (67%) receiving "low dose" antacid compared with in six out of 17 patients (35%) receiving low dose placebo; ulcers had also healed in six out of 19 patients (32%) receiving "high dose" antacid compared with in two out of 15 patients (13%) receiving high dose placebo. Overall, the effect of antacid was superior to that of placebo in healing ulcers (p less than 0.05) and the effect of low dose treatment was superior to that of high dose treatment (p less than 0.01). There were no significant differences between antacid and placebo at eight weeks. Antacid was better than placebo in relieving pain, but the difference was not significant. Poor compliance and high incidence of diarrhoea made high dose antacid an impractical treatment. Low dose antacid was associated with a significantly better rate of healing than high dose antacid and was far better tolerated. This low dosage of antacid should be considered to be an active treatment in trials of ulcer healing.     

Impact of gestrinone on the course of asymptomatic endometriosis.

A new drug, gestrinone, was subjected to the first double blind, randomised placebo controlled trial of any treatment of endometriosis. The disease deteriorated in eight (47%) of the 17 patients prescribed placebo (95% confidence limits 23% and 71%) compared with none of the 18 patients prescribed gestrinone (p = 0.002). There was a difference in elimination of the endometriosis in the gestrinone group compared with placebo but this was not statistically significant (p = 0.057). There was a significant difference in improvement of the disease in the gestrinone group compared with placebo (p = 0.004), confirming that gestrinone is an effective treatment of endometriosis. Endometriosis deteriorates in at least 23% of patients; as it is impossible to predict in whom this will happen, treatment appears to be warranted in all cases.     

Effect of magnesium lactate dihydrate and calcium lactate monohydrate on 20-km cycling time trial performance

Manufacturers of supplements containing magnesium lactate dihydrate and calcium lactate monohydrate claim improved athletic performance. Although energy can be produced through the lactate shuttle system, there is limited evidence to suggest that substantial quantities are available for human movement during exercise. The purpose of this study was to evaluate the effectiveness of lactate as a performance-enhancing substance. Nine recreational to competitive cyclists (VO2max = 52.46 ± 11.8) completed 3 simulated 20-km time trials conducted on a Velotron. The first trial was used as a familiarization trial, and the last 2 trials were counterbalanced ergogenic aid/placebo trials. To eliminate the possibility of bias, the study was conducted double blind. Dependent measures (time, mean power, heart rate [HR], and ratings of perceived exertion) for the 3 trials were compared using repeated measures analysis of variance (p = 0.05). There were no significant differences between placebo and ergogenic aid in measures of time (38.78 ± 5.87 minutes vs. 39.07 ± 6.00 minutes; p = 0.212), mean power (236.40 ± 74.8 W vs. 232.81 ± 76.12 W; p = 0.342), and HR (167.36 ± 10.11 minutes vs. 163.70 ± 13.07 minutes; p = 0.092). Ratings of perceived exertion for the placebo trial were significantly higher in relation to the ergogenic aid trial (15.97 ± 0.72 vs. 15.70 ± 0.85; p = 0.039). Although not significant, times during the placebo trials were faster in relation to the ergogenic aid trials. Ratings of perceived exertion were significantly higher in the placebo trials, which could reflect the trend toward faster times. Supplementation of magnesium lactate dihydrate and calcium lactate monohydrate does not appear to significantly improve times during a simulated 20-km time trial and therefore should not be recommended for use as an ergogenic aid.     

Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review

ObjectiveTo evaluate the efficacy of progesterone and progestogens in the management of premenstrual syndrome.DesignSystematic review of published randomised, placebo controlled trials.ResultsOverall standardised mean difference for all trials that assessed efficacy of progesterone (by both routes of administration) was −0.028 (95% confidence interval −0.017 to −0.040). The odds ratio was 1.05 (1.03 to 1.08) in favour of progesterone, indicating no clinically important difference between progesterone and placebo. For progestogens the overall standardised mean was −0.036 (−0.014 to −0.060), which corresponds to an odds ratio of 1.07 (1.03 to 1.11) showing a statistically, but not clinically, significant improvement for women taking progestogens.ConclusionThe evidence from these meta-analyses does not support the use of progesterone or progestogens in the management of premenstrual syndrome.

What is already known on this topic

The premenstrual syndrome affects about 1.5 million women in the United KingdomThere are numerous treatment options, progesterone being one of the most strongly advocatedProgesterone and progestogens are among the most widely prescribed treatments for premenstrual syndrome in the United Kingdom and the United States

What this study adds

There is no evidence to support the claimed efficacy of progesterone in the management of premenstrual syndromeThere is insufficient evidence to make a definitive statement about progestogens, but current evidence suggests that they are not likely to be effective     

A clinician's guide for conducting randomized trials in individual patients.

In determining optimal treatment for a patient conventional trials of therapy are susceptible to bias. Large-scale randomized trials can provide only a partial guide and have not been or cannot be carried out for most clinical disorders. However, randomized controlled trials (RCTs) in individual patients (N of 1 RCTs) may in some circumstances provide a solution to this dilemma. In an N of 1 RCT a patient undergoes pairs of treatment periods (one period of each pair with the active drug and one with matched placebo, assigned at random); both the patient and the clinician are blind to allocation, and treatment targets are monitored. N of 1 RCTs are useful for chronic, stable conditions for which the proposed treatment, which has a rapid onset of action and ceases to act soon after it is discontinued, has shown promise in an open trial of therapy. The monitoring of treatment targets usually includes quantitative measurement of the patient''s symptoms with the use of simple patient diaries or questionnaires. Pairs of treatment periods are continued until effectiveness is proved or refuted. The cooperation of a pharmacy is required for the preparation of matching placebos and conduct of the trial. Formal statistical analysis may be helpful for interpreting the results. The practical approach presented in this paper allows clinicians to conduct their own N of 1 RCTs.     

Antihirsutism activity of Fennel (fruits of Foeniculum vulgare) extract. A double-blind placebo controlled study.

Idiopathic hirsutism is defined as the occurrence of excessive male pattern hair growth in women who have a normal ovulatory menstrual cycle and normal levels of serum androgens. It may be a disorder of peripheral androgen metabolism. In this study we evaluated the clinical response of idiopathic hirsutism to topical Fennel extract. Fennel, Foeniculum vulgare, is a plant, which has been used as an estrogenic agent. The ethanolic extract of Fennel was obtained by using a soxhlete apparatus. In a double blind study, 38 patients were treated with creams containing 1%, 2% of Fennel extract and placebo. Hair diameter was measured and rate of growth was considered. The efficacy of treatment with the cream containing 2% Fennel is better than the cream containing 1% Fennel and these two were more potent than placebo. The mean values of hair diameter reduction was 7.8%, 18.3% and -0.5% for patients receiving the creams containing 1%, 2% and 0% (placebo) respectively.