Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.

OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Submaximal exercise testing in the assessment of interstitial lung disease secondary to systemic sclerosis: reproducibility and correlations of the 6-min walk test.

BACKGROUND: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD). AIM: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters. METHODS: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT. RESULTS: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity. CONCLUSION: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.

Efficacy and tolerability of low-dose transdermal estrogen (Oesclim) in the treatment of menopausal symptoms.

OBJECTIVE: To establish the proportion of symptomatic postmenopausal women who can be satisfactorily maintained on a low HRT dose of 25 microg/day 17-beta-estradiol (Oesclim 25 transdermal patches), after 8 weeks of treatment. STUDY DESIGN AND PATIENTS: This was a multicenter open label non-comparative trial. Treatment was initiated with 25 microg/day dosage, which could be increased to 50pg/day if required after 8 weeks, according to clinical evaluation. Sequential treatment with an oral progestogen was also given for > or = 12 days/month in all non-hysterectomized women. The primary criterion for evaluation of efficacy was the proportion of patients who remained on Oesclim 25 after 8 weeks of treatment in comparison to patients requiring Oesclim 50. RESULTS: Sixty-two patients were included in the study and 60 were treated. 88.3% of treated patients [CI: 78.7-94.9] fulfilled the primary criterion, remaining with the Oesclim 25 dosage after 8 weeks of treatment. All clinical menopausal symptoms showed a decrease from baseline to the end of the study. The mean daily number of vasomotor symptoms decreased from 8.2 (+/- 5.6) at baseline, for the entire treated population, to 1.0 (+/- 2.2) and 1.0 (+/- 1.2) at the end of the study in patients remaining with Oesclim 25 and in those requiring Oesclim 50, respectively. At the interim visit, patients in the Oesclim 50 group had a higher number of symptoms than those maintained on Oesclim 25. The global efficacy of the treatment was evaluated as very effective/effective by 93% of all patients and very good/good by investigators for 91% of their patients. Overall 91% of all patients evaluated the global tolerability as very well/well, while investigators rated it very good/good for 97% of their patients. The vast majority of all patients (93%) were very satisfied/satisfied with the trial treatment, and 90% of them were willing to continue the study drug. CONCLUSION: Oesclim low dose (25microg) hormonal transdermal therapy was efficient in management of climacteric symptoms in this 16-week study. The good acceptance of the treatment was associated with its high efficiency and tolerability.

Assessing time-by-covariate interactions in relative survival models using restrictive cubic spline functions.

BACKGROUND: The Cox model is widely used in the evaluation of prognostic factors in clinical research. However, in population-based studies, which assess long-term survival of unselected populations, relative-survival models are often considered more appropriate. In both approaches, the validity of proportional hazards hypothesis should be evaluated. METHODS: We propose a new method in which restricted cubic spline functions are employed to model time-by-covariate interactions in relative survival analyses. The method allows investigation of the shape of possible dependence of the covariate effect on time without having to specify a particular functional form. Restricted cubic spline functions allow graphing of such time-by-covariate interactions, to test formally the proportional hazards assumption, and also to test the linearity of the time-by-covariate interaction. RESULTS: Application of our new method to assess mortality in colon cancer provides strong evidence against the proportional hazards hypothesis, which is rejected for all prognostic factors. The results corroborate previous analyses of similar data-sets, suggesting the importance of both modelling of non-proportional hazards and relative survival approach. We also demonstrate the advantages of using restricted cubic spline functions for modelling non-proportional hazards in relative-survival analysis. The results provide new insights in the estimated impact of older age and of period of diagnosis. DISCUSSION: Using restricted cubic splines in a relative survival model allows the representation of both simple and complex patterns of changes in relative risks over time, with a single parsimonious model without a priori assumptions about the functional form of these changes.

Efficacy and tolerability of a low-dose of Oesclim (25 mcg daily) in the management of symptomatic menopausal women: a French open-label study.

OBJECTIVE: To establish the proportion of symptomatic postmenopausal women, whose HRT treatment is initiated on Oesclim 25, who can be satisfactorily maintained on this low dose after two months. STUDY DESIGN AND PATIENTS: This was an open-label, multicentre, non-comparative, four-month treatment study. Treatment was initiated with Oesclim 25 (17 beta-oestradiol transdermal patch, 25 mcg/day). Dosage could be increased to Oesclim 50 if required after two months, according to clinical evaluation. Sequential treatment with an oral progestagen was also given for > or = 12 days/month in all non-hysterectomised women. A total of 1465 women were included in the study. RESULTS: 82.3% (CI: 80.1-84.4) of patients remained on Oesclim 25 across the whole study. The mean number of hot flushes was reduced similarly by 93% and 94% at month 4 in the Oesclim 25 group and Oesclim 50 group, respectively. However, at month 2 the decrease in hot flushes and other menopausal symptoms was less marked until the dose was adjusted, in patients switching to Oesclim 50. In a global evaluation, 97.5% of the investigators and 95.7% of the patients rated the overall efficacy of the treatment as good/very good. Overall, treatment initiated at a low dose was well tolerated throughout the study, with a trend showing Oesclim 25 as being better tolerated than Oesclim 50. CONCLUSION: Oesclim low dose (25 mcg) can effectively reduce symptoms in most postmenopausal women with a very satisfactory level of tolerability. The risk/benefit ratio observed is probably one key reason for good patient compliance.

Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group.

OBJECTIVE: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms. STUDY DESIGN: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch. RESULTS: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P <.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups. CONCLUSION: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio.

Efficacy and acceptability of tadenan (Pygeum africanum extract) in the treatment of benign prostatic hyperplasia (BPH): a multicentre trial in central Europe.

Pygeum africanum extract is available as Tadenan in many countries, including those in central and eastern Europe, for the treatment of mild to moderate BPH. Its efficacy and acceptability have been demonstrated in numerous open and placebo-controlled studies in large populations. The present open three-centre efficacy and safety study was conducted according to common protocol at urology clinics in the Czech and Slovak Republics and in Poland, in order to confirm the therapeutic profile of Pygeum africanum in conditions of daily practice, using International Prostate Symptom Score (IPSS) and flowmetry assessments. Men aged 50-75 years and in compliance with the selection criteria (including IPSS > or = 12, quality of life (QoL) score > or = 3, and maximum urinary flow < or = 15 ml/s) were first examined then recalled after two weeks during which no treatment was provided (washout and check of stability). If still compliant, they were entered at this point into a two-month period of treatment with Pygeum africanum extract 50 mg twice daily. There followed a further one-month period without treatment, the objective being to evaluate the persistence of any effects observed during the previous two months of Pygeum africanum administration. The primary efficacy parameter investigated was IPSS; the other efficacy parameters were QoL, nocturnal frequency, maximum urinary flow, average urinary flow, post-voiding residual volume and prostatic volume, after one and two months of Pygeum africanum treatment and one month after stopping treatment. A total of 85 patients were evenly distributed between the three centres and completed the entire study. At inclusion their mean IPSS was 16.17, QoL was 3.60 and nocturia was 2.6 times per night. The changes in subjective scores, IPSS and QoL after the two-month treatment period were highly statistically significant with mean improvements of 40% and 31%, respectively. Nocturnal frequency was reduced by 32% and the mean reduction was again highly statistically significant. Mean maximum urinary flow, average urinary flow and urine volume were also statistically significantly improved, but the modest improvement in post-voiding volume did not reach statistical significance. The improvements, which exceeded those observed with placebo in earlier studies, were maintained after one month without treatment indicating an interesting persistence of clinically useful activity. Prostatic volume and quality of sexual life remained unchanged throughout. No treatment-related adverse effects were observed. In conclusion, under conditions of daily practice, Pygeum africanum extract induces significant improvement in IPSS and uroflowmetry parameters. These positive effects are accompanied by a very satisfactory safety profile with the overall result of a substantial improvement in QoL.

Drawbacks of selection methods for synchronous cell growth: simulation techniques.

Investigations of Koch & Schaecter's (1962) model for the fission of a bacterium were carried out to resolve some conflict in the findings due to Takahasi et al. (1968) and Marr et al. (1969). A computer simulation procedure was used to reexamine the work of Takahasi et al. Our results confirm their findings that a simple formulation of Koch & Schaecter's model predicts a synchronous growth curve which fits the data reasonably well. This contrasts with the predictions of a poor fit given by the complex formulations of Marr et al. However, there is a disagreement between our results and those obtained by Takahasi et al. It involves a relationship between independence of the life length of daughter and mother cells and the degree of synchrony in growth. The practical implications of the simulation results are that selection methods are unlikely to give perfect synchrony.