Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study.

OBJECTIVE AND DESIGN: Most cases of euvolaemic hyponatraemia are associated with elevated plasma levels of AVP. Conivaptan is a high-affinity, nonpeptide vasopressin V(1A)/V(2)-receptor antagonist. We performed a subgroup analysis of a multicentre, randomized, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of intravenous (i.v.) conivaptan for the treatment of euvolaemic hyponatraemia. PATIENTS: Fifty-six euvolaemic patients with serum [Na(+)] of 115 to < 130 mmol/l received conivaptan 40 or 80 mg/day or placebo via continuous i.v. infusion for 4 days. A 20-mg loading dose was administered intravenously over 30 min in the conivaptan groups; the placebo group received a placebo loading dose. MEASUREMENTS: Change in serum [Na(+)], measured by the baseline-adjusted area under the serum [Na(+)]-time curve (AUC), was the primary efficacy parameter. Secondary efficacy measures included the time from the first dose to a confirmed > or = 4 mmol/l increase in serum [Na(+)], total time with serum [Na(+)] > or = 4 mmol/l above baseline, change in serum [Na(+)] from baseline, and number of patients with a confirmed > or = 6 mmol/l increase in serum [Na(+)] or normal [Na(+)]. Safety assessments included adverse events (AE), incidence of overly rapid correction of serum [Na(+)], and changes in vital signs and electrocardiographic and clinical laboratory parameters. RESULTS: During the first 2 days of treatment, and over the entire 4-day treatment period, both conivaptan doses significantly increased the serum [Na(+)] AUC more than placebo (P < 0.01). Conivaptan 40 and 80 mg/day significantly improved all secondary efficacy measures. Conivaptan was generally well tolerated; infusion-site reaction was the most common AE. CONCLUSIONS: In hospitalized patients with euvolaemic hyponatraemia, i.v. conivaptan significantly increased serum [Na(+)] promptly and was well tolerated.

Toxicology review and risk assessment of resorcinol: thyroid effects.

Resorcinol administered at high doses to rodents can disrupt thyroid hormone synthesis and can produce goitrogenic effects. These effects were not seen in a 2-year bioassay at doses of up to 520 mg/kg/day. There are species-specific differences in synthesis, binding, and transport of thyroid hormone that complicate interpretation of goitrogenesis in rodents. Clinical case reports from patients undergoing resorcinol therapy for dermatological indications reveal thyroid side effects when copious amounts of resorcinol-containing ointments are applied to integrity-compromised skin for months to years. Effect levels were greater than 34 mg/kg/day. Occupational epidemiology studies provide no evidence that exposure to resorcinol at levels greater than found in the general environment causes thyroid dysfunction. Studies investigating the relationship between endemic goiter and exposure to "phenolics," including resorcinol, in drinking water do not fulfill accepted scientific criteria for establishing resorcinol as a cause of thyroid disease. Those reports neither quantify exposure levels nor demonstrate dose-response relationships or rule out confounding by the multiple other chemicals present in water supplies, by bacterial contamination of water, or by nutritional factors. A risk assessment comparing potential worst-case exposures to resorcinol through its use in dermatological preparations supports the conclusion that under real-world conditions, human exposures to resorcinol are not expected to cause adverse effects on thyroid function.

Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy.

To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point). After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P < 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5-7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15-20 mg/d. In these resistant macro- and microprolactinomas, the maximal tumor diameter was reduced by 43.7 +/- 3.6% and 22.1 +/- 3.7% and by 59.3 +/- 7.1% and 4.3 +/- 2.1% after CAB and BRC, respectively (P < 0.001). In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion.

Goserelin (Zoladex) or orchiectomy in metastatic prostate cancer? A quality of life and cost-effectiveness analysis.

BACKGROUND: We have today two treatment alternatives (orchiectomy or LHRH-analogue) in metastatic prostate cancer offering the same expectations of survival. This study documents the quality of life (QoL) and cost-effectiveness of these alternatives. PATIENTS AND METHODS: 65 consecutive patients treated at the University Hospital of Tromsø (UHT), Norway, between 1994 and 1999 were registered. At evaluation, 45 patients (LHRH-analogue--15 patients, orchiectomy--30 patients) were alive and included in the QoL-study (EORTC QLQ C-30, QoL 15D). 45 patients were followed-up at the UHT and included in the cost-analysis. Costs were calculated for a 36-month interval and converted to British pounds (1 Pound = 13 NOK). A 5% d.r. was employed. RESULTS: The mean QoL (15D) was 76.4 (orchiectomy) and 72 (LHRH) (0-100 scale). Constipation, urinating problems, fatigue, pain and loss of sexual functioning were the dominant symptoms. The treatment costs per patient treated were 8,895 Pounds (orchiectomy) and 10,937 Pounds (LHRH-analogue). The crossover in cost was located at 25 months. A sensitivity analysis varying discount rate (0-10%), drug charges (25-50% off) and treatment time (12-18 months) did not alter the conclusion. CONCLUSION: Orchiectomy is the treatment of choice when life expectancy is more than two years.

Emergency contraception.

The time has come for emergency contraception. It is highly underused worldwide, and especially in the United States, where patient and physician awareness remain low. There are several highly effective, well-tolerated methods that can be used to prevent undesired pregnancy after unprotected intercourse. This article discusses these methods, their method of action, effectiveness, safety, and tolerability.

Assessment of thyroid function in pesticide formulators.

Thirty male pesticide formulators exposed to the dust and liquid formulation of endosulfan, quinalphos, chlorpyriphos, monocrotophos, lindane, parathion, phorate, and fenvalerate and 20 comparable control subjects from the same area of study were examined for the evaluation of thyroid function tests. The level of TSH was elevated (about 28%) in pesticide formulators as compared to a control group, but the increase was statistically insignificant. Based on the individual TSH measurement, 3 of 30 formulators had isolated elevated levels of TSH and seem to have acquired sub-clinical hypothyroidism; five had TSH values slightly elevated to the upper boarder line (4.03 muIU/ml); and the majority of formulators (N= 22) had TSH values in the normal range varying from 1.29 to 3.9 muIU/ml. Total T3 was suppressed significantly (P< 0.01) in formulators, while marginal decrease (about 7%) was noticed in T4 level. This study indicated thyroid function impairment in few pesticide formulators.