Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Role of the baroreflex in beta 2-sympathomimetic induced tachycardia in male rats.

The aim of the study was to determine whether tachycardia which is associated with the use of beta 2-sympathomimetic tocolytic agents is caused by baroreflex activation or by direct stimulation of cardiac beta-adrenoceptors. In conscious male rats, tachycardiac responses following intravenous injection of hexoprenaline, ritodrine and fenoterol were compared following (i) bilateral sinoaortic denervation (SAD) or (ii) sham-operation, and (iii) ganglionic-blockade using hexamethonium. Dose-ranges were chosen to result in similar reductions in diastolic blood pressure (DAP). Furthermore, following ganglionic blockade, the relative contribution of beta 1-adrenoceptor stimulation was assessed using the selective beta 2-receptor antagonist ICI 118,551. In intact rats, increases in HR induced by all beta-adrenoceptor agonist were comparable. In SAD and ganglion-blocked rats, DAP fell more pronounced at even lower doses. The corresponding increases in HR were approximately 3 times smaller than in intact rats but not different between agents. During ganglionic blockade ICI 118,551 significantly inhibited HR responses to fenoterol and hexoprenaline but not ritodrine. The conclusion is that in intact male rats, baroreflex activation is the major determinant of tachycardia following injection of ritodrine, fenoterol or hexoprenaline. Increasing the beta 2-selectivity of these drugs will not limit the tachycardic effects.

[Decreased fetal movement and a sinusoidal pattern on the cardiotocogram: 2 alarm signals]. / Verminderd leven voelen en een sinusoïdaal patroon op het cardiotocogram: 2 alarmsignalen.

A 24-year-old primigravida was referred at 35 weeks of gestation due to decreased foetal movement. External monitoring demonstrated a sinusoidal foetal heart rate pattern accompanied by late decelerations. A hydropic and severely anaemic infant with clinical signs of thrombocytopenia was delivered by emergency caesarean section. He failed to breath spontaneously and required positive pressure ventilation. Cranial ultrasound and computerised tomography of the brain revealed a massive intraparenchymal haemorrhage. After the infant had died, post mortem studies revealed the presence of maternal antibodies to the human platelet antigen (HPA) 1a which suggested neonatal isoimmune thrombocytopenia as cause of the intracranial haemorrhage. A sinusoidal foetal heart rate pattern is an alarm signal--it is not necessarily significant but is often associated with mortality or serious morbidity and is therefore a reason for quickly investigating the condition of the foetus.

Biopharmaceutical aspects of ritodrine retard in pregnant women.

Biopharmaceutical aspects of the new sustained-release formulation of ritodrine, a tocolytic agent, were studied in 9 patients with preterm labour. A mean bioavailability of 26% (range 22%-32%) was estimated after the 4th day of treatment (steady state). A.U.C.'s from oral administration were found to correlate well with those measured in i.v. therapy in the same patients (r = 0.92; p = 0.0004). It was concluded that differences in bioavailability of ritodrine-retard are small enough to enable clinicians, using this sustained release preparation, to make fair estimations of the oral dosage, needed to replace the initial i.v. treatment.

Testicular feminization syndrome in the neonate.

If we see a young, phenotypically female patient with an XY karyotype, it is of great importance to differentiate between the testicular feminization syndrome and gonadal dysgenesis. Patients with testicular feminization will always have normal testes, which are situated either in the ovarian fossa or in the inguinal canal. Patients with gonadal dysgenesis always have streak gonads. The risk of developing a malignancy in an abnormally located testis is very low, certainly before puberty, whereas the risk for dysgenetic gonads to develop a malignancy is high. Testes in patients with testicular feminization have an important endocrine function in puberty, whereas in gonadal dysgenesis patients they do not. For these reasons, in patients with testicular feminization, one should not remove the testes until the completion of puberty, whereas in patients with gonadal dysgenesis removal should be performed immediately upon recognition of the disorder.