The Interaction of Hydrochlorothiazide with Spirapril: A Novel Ace Inhibitor

In an open-label, randomized trial using a 3 x 3 Latin square design, single doses of 24 mg of the ACE inhibitor spirapril, or 50 mg hydrochlorothiazide, or their combination were given to 18 healthy male volunteers. No alteration in the area under plasma drug concentration curve (AUC), peak plasma level, time to peak level, or elimination half-life was detected for hydrochlorothiazide, spirapril, or its active metabolite, spiraprilat, during combination therapy. It was concluded that there was no significant effect of spirapril on single-dose kinetics of hydrochlorothiazide, nor of hydrochlorothiazide on single-dose kinetics of spirapril. Significant reductions in systolic blood pressure were noted 2--6 h after either spirapril or combination treatment, but no evidence of any synergistic effect of single-dose effects on blood pressure was seen during combination therapy.     

Aromatase inhibitor development for treatment of breast cancer

Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

Difficulties inherent in certifying people with gender dysphoria

This is a first report of the aeromedical implications of an airman undergoing gender transformation. It is clear that during the period of instituting high-dose hormones to undergo sexual transformation appropriate observation periods should be implemented due to the strong effects of these drugs on the psyche.     

The impact of clozapine treatment on serum lipids in chronic schizophrenic patients

The aim of this retrospective study is to determine whether lipid levels rise in neuroleptic-resistant chronic schizophrenic patients during clozapine treatment and if this rise is correlated with a decrease in aggressive and suicidal behavior. Seventy neuroleptic-resistant schizophrenic patients treated with clozapine for at least 6 months were compared with 30 chronic schizophrenic patients treated with classic antipsychotic agents for the same length of time. Data on serum levels of cholesterol and triglycerides and on aggressive and suicidal behavior, as measured by the Overt Aggression Scale (OAS), were collected in both groups before treatment and 6 months later. A significant reduction in aggressive and suicidal behavior was noted in the clozapine-treated group but not in the classical antipsychotic-treated group. Clozapine treatment was associated with an elevation in serum triglyceride level, whereas classic antipsychotic treatment was associated with an increase in serum cholesterol level. We conclude that serum cholesterol level does not play a role in the clozapine-induced attenuation in aggressive and suicidal behavior in neuroleptic-resistant schizophrenic patients, though the accompanying elevation in triglycerides may be relevant to a behavioral effect.     

Intracellular ATP depletion inhibits swelling-induced -[H]aspartate release from primary astrocyte cultures

Volume expansion-sensing outward rectifier (VSOR) anion channel, also referred to as volume-sensitive organic osmolyte-anion channel (VSOAC), appears to be responsible for cell swelling-induced amino acid release in a variety of cells. One prominent feature of the VSOR/VSOAC is that non-hydrolyzed intracellular ATP binding to the channel or an accessory protein is required for its activation. In this study, the effect of intracellular ATP depletion on the swelling-induced release of -[³H]aspartate from rat primary astrocyte cultures due to exposure to either high K⁺ or hypotonic media was studied. When the cells were pretreated for 10 min with a combination of the metabolic inhibitors 2-deoxyglucose and rotenone, 100 mM K⁺ media- or hypotonic media-induced -[³H]aspartate release was completely suppressed. Added separately, each inhibitor showed only partial or no inhibition of -[³H]aspartate release, which correlated with its relative effectiveness in decreasing intracellular ATP levels. These data are consistent with the view that during high [K⁺]_o or hypotonic media-induced swelling of primary astrocyte cultures an ATP-dependent swelling-activated VSOAC channel is responsible for -[³H]aspartate release and close to normal ATP is required for full channel activation.