A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms

OBJECTIVE: Comparison of the effects of treatment of two transdermal therapeutic systems for estrogen replacement therapy with regard to efficacy, tolerability, and acceptance. DESIGN: Open randomized. SETTING: Multicenter. PATIENTS AND INTERVENTIONS: A study population of 104 postmenopausal women was randomized on a 1:1 basis to treatment with one of two estradiol patches, System (Cilag) and Estraderm (Ciba-Geigy). OUTCOME MEASURES: Systolic and diastolic BP, hot flushes, night sweating, fatigue, insomnia, depression, nervousness, headache, vaginal discomfort (efficacy variables); bleeding, dermatological symptoms, comfort and adhesiveness of patch, and other possible causes of discontinuation (tolerability); general evaluation by patient (acceptance). RESULTS: Considering all efficacy variables, 53% of Systen and 46% of Estraderm patients found the therapy satisfactory. Tolerability was somewhat higher in the Systen group. Adhesiveness of the patch was significantly better for Systen. Overall, 79% of Systen patients and 62% of Estraderm patients evaluated treatment as "good" or "very good." The majority of patients in both groups found the patch very comfortable or only slightly obtrusive.     

Differential impact of conventional oral or transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women

OBJECTIVE: To compare the effects on body composition and body weight of tibolone vs two different sequential oral or transdermal oestrogen-progestogen hormone replacement therapies versus no therapy. PATIENTS AND METHODS: One hundred postmenopausal women were assigned to a control group (n = 26), or randomized to 1) tibolone (TIB) 2.5 mg/day (n = 28), 2) oral oestradiol 2 mg/day (PO) plus sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 26), or 3) transdermal oestradiol patch (TTS) releasing 50 micrograms/day plus oral sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 20). Body composition was measured at the base-line and every 6 months for 2 years by DXA (Hologic QDR 1000 W). RESULTS: Total body fat mass increased (P < 0.05) in controls (+3.6 +/- 1.5%) and in TTS treated (+4.7 +/- 2.2%), but not in PO (-1.2 +/- 2.4%) and TIB (-1.6 +/- 2.2%) treated subjects. This increase in total fat mass in controls and TTS treated women was mostly due to an increase in fat mass of the trunk (P < 0.05), but not legs. As a result, a redistribution of body fat to the trunk occurred in controls, TTS and TIB, but not in PO treated women (P < 0.05). Total lean body mass decreased (P < 0.02) in controls (-1.7 +/- 0.7%) and PO (-1.4 +/- 0.6%) but not in TTS (+0.3 +/- 0.8%) and TIB (+0.4 +/- 0.5%) treated subjects. CONCLUSIONS: The menopause is associated with an increase in total body fat and a decline in lean body mass. Oral oestradiol/dydrogesterone and tibolone prevent total body fat changes, whereas transdermal oestradiol/oral dydrogesterone and tibolone prevent the lean mass changes. Furthermore, oral oestradiol/dydrogesterone prevents the shift to a central, android fat distribution.     

Ovarian recovery after total body irradiation and allogeneic bone marrow transplantation: long-term follow up of 79 females

Seventy-nine females undergoing allogeneic BMT following conditioning with total body irradiation (TBI), were prospectively followed between March 1983 and March 1992 with regular gynaecological examinations, including plasma levels of luteinising hormone (LH), follicle stimulating hormone (FSH), 17-beta oestradiol (E2) and pelvic ultrasonography. The end-points of this study were the following: (1) early and late effects of TBI on ovarian function, (2) compliance and results of hormonal replacement therapy (HRT), and (3) predictive events for ovarian recovery. During the first year post-BMT most adult women complained of vasomotor and/or genitourinary tract symptoms. These were associated with decreased E2 and increased LH-FSH plasma levels and a deterioration in their sexual life (94% of sexually active women). Forty-nine adult females were selected to receive systemic hormonal replacement therapy (HRT), consisting of cyclic transdermal oestrogens plus medroxyprogesterone acetate (MPA) or cyclic oral therapy with low doses of conjugated oestrogens and MPA: these patients were selected on the basis of age (< 45 years), absence of medical contraindications or subjective refusal. Compliance and tolerability were overall good: most women (65%) never stopped HRT; this was discontinued in 14 patients for medical reasons and in 3 because of refusal. Forty-three females completed 6 months of HRT: vasomotor symptoms disappeared in 91% of 58 women who previously referred these symptoms. Improvement of genitourinary symptoms was seen both with local and systemic hormonal therapy. However sexual symptoms were reduced in 21 of 26 women (81%) given HRT compared with 8 of 19 (42%) women given local treatment (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Tibolone in the treatment of psychosomatic symptoms in menopause

The purpose of this study was to investigate the value of tibolone in the treatment of psychosomatic symptoms in menopause. Forty-two menopausal women (aged 46-63, mean 53.9) with nightly perspiration, vasomotor flushes, disturbance of libido, dyspnea and other psychosomatic symptoms were assigned to one of two treatment groups for three months: 1st group) 21 users of tibolone; 2nd group) 21 users of placebo. At the end of the trial disturbance of libido was observed in 4 (19.0%) cases tin the 1st group and 11 (52.4%) cases in the 2nd (p < 0.05) and nightly perspiration was observed in 3 cases (14.3%) in the 1st group and 9 cases (42.9%) in the 2nd (p < 0.05). Although vasomotor flushes were observed in only 3 (14.3%) cases in the 1st group and 7 cases (33.3%) in the 2nd group, this difference was not significant (p > 0.05). There was no significant effect of tibolone or placebo in dyspnea, vertigo and headache. From the results it can be concluded that tibolone can have a beneficial effect on some psychosomatic symptoms in postmenopausal women.     

Premedication with promethazine and transdermal scopolamine reduces the incidence of nausea and vomiting after intrathecal morphine

Intrathecal morphine provides effective postoperative pain relief in major orthopaedic surgery. In use, however, is associated with unpleasant side effects like nausea and vomiting. The effect of different premedications on postoperative emetic sequelae induced by intrathecal morphine was studied in a prospective, double blind study. Sixty patients scheduled for arthroplasty surgery of the lower extremity were anaesthetized with spinal anaesthesia with a combination of isobaric bupivacaine 20 mg and morphine 0.3 mg. For premedication the patients were randomised to three groups of equal size. They received either oral diazepam (5-15 mg), oral promethazine (10 mg) or a combination of promethazine and transdermal scopolamine (1.5 mg). Sixty percent of the patients with both promethazine and transdermal scopolamine were totally free from postoperative nausea and vomiting (PONV) symptoms compared to those premedicated with diazepam (40%) or promethazine alone (30%). Promethazine together with transdermal scopolamine reduced significantly the number of patients with vomiting (to 25%) and also vomiting episodes. This combination was also more efficient in reducing the incidence of nausea (to 25%) and nausea episodes than promethazine along (P < 0.05). Combination also reduced the requests for additional pain relief (P < 0.05). PONV occurred in a majority of patients during the first 12 hours of the 24 hour study period and the need for additional analgesics thereafter. The incidence of itching (50-65%) and urinary catheterisation (55-70%) was similar in all groups. In conclusion, the combination of oral promethazine and transdermal scopolamine was most effective in reducing PONV symptoms and also reduced the need for postoperative pain treatment.     

Regional distribution of 5alpha-reductase type 1 and type 2 mRNA along the human epididymis

BACKGROUND AND PURPOSE: In women, symptoms of coronary artery disease are delayed by 10 to 15 years in comparison with men, most likely because of the protective effect of ovarian hormones. This report compares the prevalence and degree of carotid atherosclerosis between 292 premenopausal women and 294 women at 5 to 8 years after menopause. METHODS: Scans were performed in the same laboratory over the same time period for both groups. Intima-media thickness (IMT) was averaged across the common, bulb, and internal carotids. The plaque index summarized degree of focal plaque based on the size and number of plaques throughout both carotid systems. RESULTS: Mean IMT was 0.69 mm for premenopausal women and 0.77 mm for postmenopausal women (P < 0.001). Prevalence of plaque was 25% among premenopausal women and 54% among postmenopausal women (P < 0.001). In both premenopausal and postmenopausal women, risk factors measured before menopause were associated with carotid atherosclerosis. Premenopausal risk factors independently associated with IMT were higher pulse pressure (P < 0.001), triglycerides (P = 0.002), body mass index (P < 0.001), and study group (a surrogate for both age and menopausal status; P < 0.001). Premenopausal risk factors independently associated with focal plaque were ever smoking (P = 0.002), higher pulse pressure (P = 0.028), higher LDL (P = 0.003), age at baseline (P = 0.050), and study group (P < 0.001). CONCLUSIONS: Subclinical carotid atherosclerosis can be observed in middle-aged women. Risk factors measured before menopause are clearly associated with subclinical disease measured both concurrently and at 5 to 8 years after menopause.     

How to stabilize the level of ionized calcium and citrate during plateletpheresis

Felodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (Tl) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.     

Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial

We report the results of a randomized controlled multicentre study on interferon-gamma (IFN-gamma) treatment of systemic sclerosis as determined by skin sclerosis, renal and other organ involvement, global assessment, subjective symptoms and quality of life. Forty-four patients were enrolled into the trial, 27 in the treatment group and 17 in the control group. All patients presented with type I or type II scleroderma. Twenty-nine patients (64%) finished the study. The mean duration of Raynaud's phenomenon and skin sclerosis was 15.3 and 10.8 years, respectively. The skin scores tended to improve in the treatment group (P > 0.05). Mouth aperture increased significantly from 38.5 to 47.7 mm in the treatment group (P < 0.001). Subanalysis of IFN-gamma treated patients with normalized skin sclerosis scores >/=1 showed significant improvement in both skin involvement and subjective symptoms (P < 0.05). Organ involvement improved in eight of 18 treatment patients and in three of 11 control patients. It worsened in three of 18 treatment patients and in four of 11 control patients. One control patient died due to cardiorespiratory failure during the study. No deterioration of renal function occurred during IFN-gamma treatment. There was a significant improvement in quality of life parameters in the control group but not in the treatment group. Plasma levels of neopterin increased significantly during IFN-gamma treatment but not in the control group, whereas N-terminal procollagen III peptide levels did not change in either group. There was a high frequency of mild to moderate influenza-like adverse events during IFN-gamma treatment. Only four of nine drop-out patients, however, experienced symptoms most probably associated with IFN-gamma treatment. We conclude that IFN-gamma therapy has mild beneficial effects on skin sclerosis and disease-associated symptoms in type I and II scleroderma. IFN-gamma treatment was associated with acceptable tolerability and did not induce major renal dysfunction in our patients.     

Urogenital symptoms and their resulting discomfort in non-institutionalized 50-to-75-year-old Dutch women

OBJECTIVE: To determine the prevalence of urogenital symptoms in non-institutionalized Dutch women, aged 50 to 75 years, and the degree of discomfort. DESIGN: Cross-sectional study. SETTING: Nationwide investigation. METHOD: A questionnaire was sent to 2157 non-institutionalized Dutch women aged 50 to 75 years. The survey sample was representative of the female population aged 50 to 75 years with respect to age, marital status, level of education and menopausal age. RESULTS: The usable response was 81.6% (n = 1761). The overall prevalence of vaginal dryness, soreness and dyspareunia was 27%. The prevalence of micturition symptoms, urinary incontinence and recurrent urinary tract infections was 36%. The prevalence estimates for vaginal dryness and urinary incontinence showed a linear decrease with increasing age. Almost half of the symptomatic women reported moderate to severe discomfort. One-third of those affected received medical care. Previous hysterectomy had no effect on the reported prevalence estimates. Hysterectomized women reported moderate to severe complaints more often than non-hysterectomized ones. CONCLUSION: The prevalence of urogenital symptoms in non-institutionalized Dutch women aged 50 to 75 years, was high: 47%. Of these women, 40% to 60% experienced discomfort, but only one-third had sought medical advice. These urogenital problems will probably increase in the coming decades.     

On-demand treatment of gastro-oesophageal reflux symptoms: a comparison of ranitidine 75 mg with cimetidine 200 mg or placebo

AIM: To compare the effects of ranitidine 75 mg with those of either cimetidine 200 mg or placebo given on demand for relief of typical symptoms of gastro-oesophageal reflux disease during a 15-day period. METHODS: A total of 1336 patients (aged > or = 18 years) with heartburn episodes were recruited and randomly assigned to a ranitidine 75 mg, cimetidine 200 mg or placebo group. Depending on the occurrence or persistence of heartburn, treatment was administered as required up to three times daily, with at least 2 h between drug doses. Antacids were allowed as rescue medication if symptoms persisted for at least 2 h after the third medication on any given day. The primary end-point was defined as the proportion of patients with relief of at least 75% of heartburn episodes during the study period (i.e. relief occurring within 2 h after drug ingestion and lasting for at least 5 h). RESULTS: Analysis was performed in an intention-to-treat population comprising 504 subjects in the ranitidine group, 515 in the cimetidine group and 270 in the placebo group. Primary end-point success rates were 41, 38 and 28%, respectively, for the three groups (P < 0.001 for ranitidine vs. placebo, P = 0.274 for ranitidine vs. cimetidine). Ranitidine 75 mg was significantly more effective than placebo in providing overall heartburn relief (P < 0.001). The differences between the ranitidine and cimetidine groups were not significant, except for a greater reduction in heartburn frequency in the ranitidine group at the end of the study period (P < 0.05). Drug dose was lower and less rescue medication was used in the ranitidine group than the placebo group. The three treatment groups did not differ in terms of tolerability. CONCLUSION: On-demand ranitidine 75 mg or cimetidine 200 mg are safe and effective treatment for reflux-related symptoms.     

Effect of oral medroxyprogesterone acetate on menopausal symptoms in patients with endometrial carcinoma

A double-blind cross-over study was performed on 21 patients treated for endometrial carcinomas who had severe menopausal symptoms. The patients were randomized into two groups and received medroxyprogesterone acetate (MPA) 100 mg twice daily per os for 12 weeks and a placebo for 12 weeks. A significantly better effect on hot flushes and sweating was obtained with MPA than with the placebo. On average the maximum effect was achieved by MPA after 4-6 weeks. Six patients had a weight gain of more than 3 kg during the MPA administration, compared with none during the placebo administration. No significant difference was found in the blood pressure increase above 160/90 mmHg between MPA and placebo groups. Patients with endometrial carcinoma may risk exacerbation of their disease by undergoing therapy with exogenous estrogen. In contrast, MPA has been found of value in the treatment of disseminated endometrial carcinomas. In this study oral MPA was effective in the treatment of vasomotor menopausal symptoms and may be an alternative in women for whom estrogens might be hazardous.     

Efficacy and tolerability of moclobemide in comparison with placebo, tricyclic antidepressants, and selective serotonin reuptake inhibitors in elderly depressed patients: a clinical overview

OBJECTIVE: To review the efficacy and safety of moclobemide in comparison with TCAs (for our purposes, "TCAs" will represent tricyclic and tetracyclic antidepressants, including maprotilin and mianserin) and selective serotonin reuptake inhibitors (SSRIs) in elderly depressed patients. METHODS: The efficacy data reviewed were obtained from the following sources: 1) results of published studies in the elderly; 2) data on patients aged > or = 60 years extracted from all available controlled trials in adults (> or = 18 years) in which moclobemide was compared with TCAs or SSRIs; and 3) the adverse events were extracted for patients aged > or = 60 years from the safety data base of all available comparative short-term studies with moclobemide versus TCAs, SSRIs, or placebo and of long-term studies with moclobemide. RESULTS: The data show that moclobemide is an effective antidepressant in depressed patients aged > or = 60 years. The response rate to moclobemide was 50% to 55% in this population. Moclobemide was more effective than placebo and was of similar efficacy to the TCAs and the more recently introduced SSRIs. The tolerability of moclobemide was rated as "very good" or "good" in almost 90% of these patients, which was better than the tolerability of TCAs and similar to that of SSRIs. Patients without any adverse events were more frequently found in the moclobemide group than in those treated with TCAs (P < 0.01) or SSRIs (P < 0.01). Adverse events of the anticholinergic type were more frequent with TCAs than with moclobemide (P < 0.001), and nausea was found 3 times more frequently with SSRIs than with moclobemide (P < 0.01). CONCLUSIONS: Moclobemide is an effective and well-tolerated antidepressant for the treatment of elderly depressed patients.     

Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis

SELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P < 0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%,; P < 0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P < 0.001), nausea/vomiting (2.5% vs 3.4%; P < 0.05) and abdominal pain (2.1% vs 3.6%; P < 0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). The outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.     

Functional GHRH receptor carboxyl terminal isoforms in normal and dwarf (dw) rats

Case records from 219 female patients between 1975 and 1992 who were given long-term prophylaxis (1 year) with nitrofurantoin for the prevention of recurrent urinary infections have been reviewed. Patients' age ranged from 9 to 89 years (median 31-35 years, mode 26-30 years); most (61%) were < 40 years old. The median number of symptomatic episodes in the 12 months immediately before prophylaxis was six (mode 4, mean 6.9). 14.4% of the patients were allergic to an antibiotic, and 23.6% had an imaging abnormality. Three regimens were used: group A (43 patients), 50 mg microcrystalline nitrofurantoin, bd; group B (110 patients), 100 mg macrocrystalline nitrofurantoin (Macrodantin), od; group C (66 patients), 50 mg Macrodantin, od. There were no obvious differences in efficacy between the patient groups (173 assessable patients). The mean incidence of symptomatic episodes decreased 5.4-fold during prophylaxis. Four-fifths of the 43 breakthrough infections (mostly due to Escherichia coli), were caused by nitrofurantoin-sensitive strains. An important finding was that patients with an imaging abnormality responded as well as those with no such abnormalities. In 16% of patients, prophylaxis was not helpful, objectively or subjectively, for no obvious reasons. In most patients where prophylaxis was successful, clinical improvement was maintained for at least 6 months after the end of prophylaxis. Nausea was more common in group A (P < 0.001), as were 'all adverse events'. Of those in group A 25.6% stopped prematurely as a result of an adverse event of any type, compared with 13% of those taking Macrodantin (P < 0.01). Older patients (> 65 years) did not report more adverse events than younger patients. No adverse event was life-threatening. Faecal flora analysis showed neither overgrowth by nitrofurantoin-resistant bacteria nor elimination of sensitive coliforms. Thus, macrocrystalline nitrofurantoin 50 mg at bedtime is appropriate for use in the long-term (12 months) prophylaxis of recurrent urinary infections, in view of its efficacy and favourable safety and tolerability profile. Patients can be managed by their family doctor.     

Is impaired cerebral vasomotor reactivity a predictive factor of stroke in asymptomatic patients?

BACKGROUND AND PURPOSE: Identification of the subgroup of asymptomatic patients with severe internal carotid artery stenosis and high risk of stroke has important clinical implications. Cerebral vasomotor reactivity provides information regarding intracranial hemodynamic features and might have a prognostic value in predicting cerebrovascular ischemic events, especially in patients with carotid stenosis. The aim of our study was to assess the cerebral vasomotor reactivity in asymptomatic patients with carotid stenosis and evaluate its role in stroke occurrence. METHODS: Cerebral vasomotor reactivity was assessed using transcranial Doppler ultrasonology and the Diamox test (intravenous administration of 1.0 g acetazolamide) in 44 asymptomatic patients with severe (> 70%) internal carotid artery stenosis. Patients were followed up prospectively (mean, 2 years). RESULTS: Cerebral vasomotor reactivity was estimated as good (> 40% increase of blood flow velocity in the middle cerebral artery ipsilateral to the carotid stenosis after undergoing the Diamox test) in 23 patients; it was impaired in the other 21. During the follow-up period, the overall annual rate for ipsilateral stokes was 2.3%; it was 7.9% for all ischemic cerebral events. No strokes or transient ischemic attacks occurred in the former group, but there were 7 cerebral ischemic events (2 strokes [1 fatal] and 5 transient ischemic attacks) in the latter group. There was a statistically significant correlation between cerebral ischemic events and impaired cerebral vasomotor reactivity (P = .009). CONCLUSIONS: The data of this preliminary study suggest an important role of impaired cerebral vasomotor reactivity in predicting ischemic cerebral events. Preventive vascular surgery might be considered in this high-risk subgroup of asymptomatic patients with severe carotid stenosis.     

Mood and symptom reporting among middle-aged women: The relationship between menopausal status, hormone replacement therapy, and exercise participation.

Vasomotor, somatic, and psychological symptoms associated with menopause are often treated with hormone replacement therapy (HRT), but the role of nonpharmacological interventions has received little attention. Two studies used the Profile of Mood States (POMS) and Women's Health Questionnaire (WHQ) to examine the effects of exercise among 4 groups of Australian women: premenopausal, perimenopausal, postmenopausal without HRT, and postmenopausal with HRT. Study 1, a comparison of exercisers and nonexercisers, showed that exercisers' moods were significantly more positive than sedentary women's moods, regardless of menopausal state. Exercising women also scored lower on somatic symptoms and memory-concentration difficulties. Study 2 examined the acute effects of aerobic exercise (premenopausal, postmenopausal without HRT, and postmenopausal with HRT) and found significant enhancements in mood and reductions in reported somatic and vasomotor symptoms immediately following an aerobic class. Exercise may assist in the alleviation of some menopausal symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.     

Clinical experience with a 7-day estrogen patch: principles and practice

In the future, hormone replacement therapy (HRT) is likely to become of increasing importance, not only to control short-term climacteric symptoms, but also to protect postmenopausal women from the increasing risk of cardiovascular disease, osteoporosis and other conditions that accompany ovarian failure. This paper reviews the principles and practice associated with HRT, focusing on clinical experience with a new 7-day estrogen matrix patch (Climara). Results from two 11-week placebo-controlled studies, which compared the 7-day patch at two dose levels with 0.625-mg/day oral conjugated equine estrogen, found that both the 0.5- and 0.1-mg estradiol/day patches had a positive effect on climacteric symptoms. Tolerance was good and similar for both patches. Separate studies of skin irritation and adhesion revealed that the 7-day patch was well tolerated and that, although irritation was similar to that associated with Estraderm, adhesion was superior with the 7-day patch. Data on absorption of estradiol from different skin sites indicate that absorption is higher and more consistent from the buttock than from the abdomen, suggesting that choice of application site may require further investigation.     

Acute cystitis in women over 50 years of age. Efficacy of pefloxacin with single dose and norfloxacin for 10 days

This multicentre, open, randomized trial, involving 482 patients and conducted by private practitioners, compared the effectiveness and safety of a single 800 mg dose of pefloxacin and of a 10 days' course of norfloxacin 400 mg bid. in the treatment of uncomplicated acute cystitis in women aged over 50 years. Clinical effectiveness was evaluated on days 17-19 and 28-32 respectively, and bacteriological effectiveness on days 15-17 and 26-28 respectively. The median time taken for the symptoms to disappear was 2 days with pefloxacin and 3 days with norfloxacin (P < 0.001). Irrespective of the nature of cystitis and the patients' age, no significant difference could be found in eradication of the pathogens. Undesirable side-effects were recorded in 7.8 percent of patients under pefloxacin and in 8.8 percent of those under norfloxacin (P = 0.68); gastrointestinal disorders were predominant. The acceptability of treatment, as judged by the patients themselves, was regarded as excellent by 55 percent of women treated with single dose pefloxacin and by 37.6 percent of those treated with norfloxacin (P = 0.001).     

Bioavailability of estradiol from a new matrix and a conventional reservoir-type transdermal therapeutic system

OBJECTIVE: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 micrograms per day of 17 beta-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. RESULTS: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.