Veralipride versus conjugated oestrogens: a double-blind study in the management of menopausal hot flushes

A double-blind, randomized study was carried out in 43 women, who had undergone spontaneous menopause at least 6 months earlier, to compare the effectiveness and tolerance of veralipride with that of a conjugated oestrogens preparation in the control of hot flushes. Twenty-one women received 100 mg veralipride per day and 22 were due to receive 1.25 mg per day of the hormone preparation over a period of 20 days but 3 women in the oestrogen group discontinued the trial without giving any reason. The number, duration and severity of hot flushes were assessed and scored at the start of the trial and during treatment. Statistical analysis of the results showed marked relief with both preparations but no significant difference between them in terms of effectiveness or tolerance. Veralipride, however, appeared to provide better control in patients who had complained of severe hot flushes initially.     

The safety of veralipride

The perimenopausal period, from 1 to 4 years, is characterised by vasomotor symptoms, or hot flushes, and other effects due a deficit of estrogens. Approximately 85% of women have hot flushes for 1 year and 25 – 50% continue for up to 5 years. The cause of hot flushes has been linked to dysfunction of the thermoregulatory centre caused by estrogen withdrawal. One proposal for the aetiology of hot flushes is that the thermoregulatory zone is shifted downward in patients who experience hot flushes. Estrogen withdrawal creates a change of the central opioid system and a thermoregulatory instability. Estrogen and/or progestin replacement is the treatment of choice for this distressing symptom. However, steroid replacement may be associated with risks and complications, and is limited in some subjects by well-known contraindications. Veralipride, a synthetic benzamide derivative with antidopaminergic action, is effective in reducing the frequency and severity of hot flushes associated with menopausal hypoestrogenism, gaining interest as a non-hormonal treatment for climacteric flushing. In recent years, extrapyramidal disorders associated with veralipride therapy have been reported and are often due to drug misuse. Adverse effects include acute dyskinesia or Parkinsonism, which may occur after many months of treatment. An association between adverse effects and mistake of administration has been described. This article discusses available data on the benefits and risks of veralipride therapy for menopausal symptoms.     

The safety of veralipride

The perimenopausal period, from 1 to 4 years, is characterised by vasomotor symptoms, or hot flushes, and other effects due a deficit of estrogens. Approximately 85% of women have hot flushes for 1 year and 25 - 50% continue for up to 5 years. The cause of hot flushes has been linked to dysfunction of the thermoregulatory centre caused by estrogen withdrawal. One proposal for the aetiology of hot flushes is that the thermoregulatory zone is shifted downward in patients who experience hot flushes. Estrogen withdrawal creates a change of the central opioid system and a thermoregulatory instability. Estrogen and/or progestin replacement is the treatment of choice for this distressing symptom. However, steroid replacement may be associated with risks and complications, and is limited in some subjects by well-known contraindications. Veralipride, a synthetic benzamide derivative with antidopaminergic action, is effective in reducing the frequency and severity of hot flushes associated with menopausal hypoestrogenism, gaining interest as a non-hormonal treatment for climacteric flushing. In recent years, extrapyramidal disorders associated with veralipride therapy have been reported and are often due to drug misuse. Adverse effects include acute dyskinesia or Parkinsonism, which may occur after many months of treatment. An association between adverse effects and mistake of administration has been described. This article discusses available data on the benefits and risks of veralipride therapy for menopausal symptoms.     

Pregnancy and progeny after long-term contraceptive treatment with low-dose progestogens

Summary

Sixteen women who had used a low-dose progestogen-only oral contraceptive preparation (‘Exluton’), containing 0.5?mg. lynestrenol per tablet, for periods of at least a year were studied. All had normal pregnancies after discontinuing the preparation and gave birth to healthy infants: 11 girls and 5 boys. No complications were found at subsequent routine examinations of the infants.     

A comparative double-blind study of loprazolam, 1 mg and 2 mg,versus placebo in anxiety-induced insomnia

Summary

A double-blind trial was carried out in 40 anxious in-patients with insomnia to compare the hypnotic effectiveness and tolerance of loprazolam, 1?mg and 2?mg, versus placebo. Groups of 10 patients received one or other dose of loprazolam or placebo for 7 nights and then placebo for the following 3 nights. Sleep quality and morning residual efiects were assessed each morning during the 10-day trial period by means of a sleep questionnaire. The results showed that I?mg loprazolam was superior to placebo but less effective than 2?mg loprazolam. No side-effects were reported at either dose level.     

A double-blind study of piretanide in the treatment of hypertension

Summary

A double-blind trial was carried out in three parallel groups of patients with mild to moderate hypertension to assess the efficacy and tolerance of piretanide given as a single dose of 3?mg, 6?mg or 12?mg per day over a period of 12 weeks. Active drug treatment in the 90 patients studied was preceded and followed by 2-week periods on placebo. The results showed that although all three groups had significant reductions in systolic and diastolic blood pressures, both at rest and standing, compared with initial levels. the decrease was significantly greater in the two higher dosage groups. Pulse and respiratory rates also decreased and body weight was reduced slightly. The biochemical and haematological parameters in all three groups showed no clinically relevant changes during treatment with piretanide. Minor side-effects definitely or probably associated with piretanide treatment were observed in all three groups but were generally mild and did not interfere with treatment. Only 1 of the 9 patients who withdrew prematurely from the trial did so because of lack of effect, I patient withdrew because of side-effects and the other 6 patients who dropped out for drug-related reasons did so because the antihypertensive effects were too marked at the 6?mg (3 patients) or 12?mg (3 patients) per day dosage level.     

Double-blind comparison of meptazinol (200 mg) and dextropropoxyphene/paracetamol in a multi-centre,general practice setting

Summary

A multi-centre, double-blind, double-dummy trial was carried out in general practice to compare the effectiveness and tolerance of oral meptazinol with dextropropoxyphene/paracetamol in patients with acute or chronic painful conditions. Patients received doses of 400?mg meptazinol or 65?mg dextropropoxyphene plus 650?mg paracetamol every 3 to 6 hours as required up to a maximum of 4 doses per day over a period of 14 days. No significant difference in analgesic efficacy, as assessed by the patients on a visual analogue pain rating scale, was found between the two treatments. The results are discussed in terms of the benefit/risk ratio of polypharmic and single compound drugs.     

Labetalol in the difficult hypertensive patient in general practice

Summary

An open study was carried out in general practice to assess the effectiveness and tolerance of labetalol in the treatment of 53 difficult hypertensive patients, most of whom had failed to respond to previous hypotensive therapy. The results showed that in the 49 patients receiving treatment for more than 3 months good blood pressure control was readily achieved, and with labetalol alone in all but 6 of them. The majority were controlled on doses ranging from 300 to 600?mg per day. Treatment was discontinued in 3 patients because of severe side-effects. Mild, tolerable side-effects, similar to those found with beta-adrenergic blocking agents, were reported by 35 patients.     

Bromocriptine in depression

Summary

A double-blind trial was carried out in 9 patients with endogenous depression to compare the effectiveness of bromocriptine (15?mg per day, 4 patients) with that of imipramine (75?mg per day, 5 patients) over a period of 10 weeks. The results of assessments using the Hamilton Rating Scale for Depression showed that both drugs produced comparable reduction in mean scores and there was no significant difference between the two treatment groups. Fewer patients had anticholinergic type side-effects on bromocriptine although some had transient nausea.

Bromocriptine

imipramine

depression     

Single daily dose treatment of anxiety with clobazam: A double-blind study versus normal multipledose treatment with diazepam

Summary

A double-blind trial was carried out in 45 anxious out-patients to compare the effectiveness and tolerance of clobazam and diazepam. The severity of each patient's symptoms was assessed before, during and at the end of the trial period using the Hamilton Anxiety Rating Scale, and a note kept of any side-effects. The results showed that a single daily dose of 20?mg clobazam was equally as effective as 5?mg diazepam 3-times daily. Clobazam, however, produced considerably fewer side-effects than diazepam, especially drowsiness.     

Glipizide in the treatment of maturity-onset diabetes: a multi-centre,out-patient study

Summary

A multi-centre clinical assessment was carried out in 592 diabetic patients to study the efficacy and tolerance of glipizide under normal out-patient conditions. Of the total group, 347 patients were maturity-onset diabetics who had received no previous treatment or only dietary control. The other 245 patients had previously received treatment with other hypoglycaemic agents, including insulin in 23 cases. Mean initial dosage was 7.5?mg glipizide per day and this increased over the 3-month period of the study to 10.1?mg in the total group (9.3?mg in new patients). Mean post-prandial blood glucose levels and glycosuria fell rapidly during the first week and then continued to decrease slowly. Changes in mean body weight were somewhat erratic during the trial and at 12 weeks there was an apparent mean increase of] kg. After allowing for dropouts, analysis of the results showed that 96.7% of the new patient group and 90.5% of the total group were satisfactorily controlled and maintained on glipizide. Patient tolerance was good, and only 28 (4.7%) patients complained of side-effects, almost half of which related to mild, transient hypoglycaemia.     

The Relative Merits of a Slow-Release and a Standard Iron Preparation during Pregnancy

Summary

A comprehensive study was carried out in 248 pregnant women between a once-daily slow-release preparation of ferrous sulphate/folic acid (105?mg. elemental iron) and a twice-daily standard tablet preparation of ferrous fumarate/folic acid (80?mg. elemental iron per day). The slow-release iron preparation led to significantly higher serum levels at the end of pregnancy and to marginally higher haemoglobin levels. The incidence of gastro-intestinal side-effects caused by this preparation, however, was significantly higher.     

Primary dose-dependent pharmacokinetic study of veralipride

A dose-dependent pharmacokinetic study of veralipride (a new post-menopausal "hot flushes" regulator) was developed in humans after oral solution administration (100, 150, 200, and 250 mg). In most cases, two maxima of plasma drug concentrations occurred, probably due to a double intestinal site of absorption. From model independent pharmacokinetic parameters, it can be concluded that a linearity in the tested range doses exists.     

Treatment strategies for hot flushes

Background: Vasomotor symptoms are the most common complaints for which menopausal women seek medical care. Eighty per cent of all menopausal women will have hot flushes and night sweats, and of these 9% will have severe symptoms impacting their quality of life. Ideally, treatment should target the group most severely afflicted, and options for treatment should be tailored to each woman, since, for most women, vasomotor symptoms spontaneously resolve in 3 – 5 years. Recommendation at this time is for the shortest duration of therapy, which means that episodic review of therapy is indicated. Objective: To review the latest literature investigating therapies for vasomotor symptoms and to discuss their effectiveness with emphasis on placebo-controlled, randomized clinical trials. Methods: A literature search in PubMed for ‘vasomotor symptoms’, ‘menopause symptoms’, ‘hot flushes’, ‘hot flashes’ and ‘night sweats’ from 2003 to the present was performed. Conclusions: Estrogen remains the gold standard for treating vasomotor symptoms. As investigations into the physiology of hot flushes continue, centrally active drugs (selective serotonin or norepinephrine-serotonin reuptake inhibitors and gabapentin) have increased in use. The benefit from dietary herbal supplements is still inconclusive; however, recent studies have shown some mild response to soy and black cohosh.     

Number needed to treat and costs per responder among biologic treatments for moderate-to-severe psoriasis: a network meta-analysis

Background: The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response.

Objectives: To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA-approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder.

Methods: The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs, were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually.

Results: Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300?mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150?mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300?mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150?mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90.

Conclusion: The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments.     

The contraceptive effects of a new low-dose combination type oral contraceptive

Summary

A study was carried out in 9 women volunteers to investigate the central and peripheral effects of a low-dosage oral contraceptive combination of 0.75?mg lynestrenol plus 0.0375?mg ethinyl oestradiol given for 22 days per cycle over a period of 6 cycles. The results of assessments of a number of hormonal, vaginal and cervical parameters showed that this combination has a two-fold effect: a central effect on the pituitary and a peripheral effect on the ovaries and on endometrial development. The findings of an effect on cervical mucus, as with higher dose combinations, were not sufficiently consistent to warrant a claim for a cervical barrier. The preparation appeared to be well tolerated but there was a high incidence of irregular bleeding in the first treatment cycle. In most of the women, however, this had corrected itself by the second cycle.     

A controlled comparison of dipyrone and paracetamol in post-episiotomy pain

Summary

A double-blind, placebo-controlled trial was carried out in 299 patients suffering from post-episiotomy pain to compare the analgesic effectiveness and tolerance of single doses of 500?mg dipyrone and 500?mg paracetamol. Assessments of pain relief over a 6-hour period showed that dipyrone produced significantly better results than placebo within half an hour of intake mid maintained this superiority throughout the 6 hours. It also afforded consistently better pain relief than paracetamol and was significantly more effective at the 6-hour assessment. Side-effects were few and mild.     

A multi-centre general practice trial of a Dindolol/clopamide combination (‘Viskaldix’) in essential hypertension

Summary

A large, open, multi-centre study was carried out in general practice to evaluate the effectiveness and tolerance of a combination of 10?mg pindolol plus 5?mg clopamide, in single tablet form, in the treatment of patients with essential hypertension. Computer analysis of the records of 8989 patients who completed the 8-weeks' study period showed that treatment with the combination product, in a dosage of 1 tablet daily in 83 % of the patients, resulted in excellent blood pressure control in the majority (75 %) of cases, irrespective of age or previous antihypertensive treatment, and was particularly effective in those with mild to moderate hypertension who had previously not received any therapy. Side-effects were generally not troublesome and only 8.3 % of patients stopped treatment for this reason. The most commonly reported side-effects were dizziness, nausea, tiredness and headache.     

Comparative trial of an antihistamine,mequitazine, and placebo

Summary

Forty patients suffering from a dermatological condition suitable for treatment with an antihistamine were studied in a double-blind randomized trial to compare the effectiveness and tolerance of mequitazine and placebo. Over a period of 2 weeks, patients received either 5?mg mequitazine twice daily or placebo. Where justified, patients were also given concomitant topical treatment but only with a hydrating cream or ichthyol paste. Patientsl overall response to treatment was significantly better in the mequitazine group, whether the results were analyzed for all patients or those receiving just the trial drugs without topical treatment. Few side-effects were reported and there was no significant difference between the levels of drowsiness experienced with mequitazine compared with placebo.