Steven J. Adelman

In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein.

Estrogens with some bulky alkyl substituents in both the 2- and 4-positions have been synthesized and evaluated for the ability to inhibit the in vitro oxidation of low density lipoprotein as determined by the thiobarbituric reactive substances method. The present compounds with bulky groups in either the 2- or the 4-position (but not both the 2- and 4-) were especially effective as antioxidants, having IC50 values lower than either estradiol or probucol; however, they do not bind to the estrogen receptor with any great affinities (RBA < 0.1 versus estradiol). This separation of antioxidant efficacy from estrogenicity may allow these compounds to serve as useful probes for ascertaining the relative importance of these effects in the cardioprotective role played by estrogens.

A conjugated equine estrogen with differential effects on uterine weight and plasma cholesterol in the rat

OBJECTIVE Our purpose was to determine the effect of Premarin (conjugated estrogens) and three of its component estrogens on uterine weight and plasma cholesterol concentrations in surgically menopausal female rats. STUDY DESIGN A randomized trial of Premarin and three component estrogens--estrone sulfate, 17 alpha-estradiol sulfate, and 17 alpha-dihydroequilenin sulfate--in female rats after oophorectomy. RESULTS High-dose Premarin and high- and middle-dose estrone sulfate significantly increased uterine weight relative to untreated controls (high-dose Premarin, 243.34 +/- 0.15 mg; high-dose estrone sulfate, 376.1 +/- 9.36 mg; middle-dose estrone sulfate, 249.0 +/- 6.34 mg; untreated controls, 124.63 +/- 3.17 mg; for all, p < 0.05). 17 alpha-Dihydroequilenin sulfate had no effect on uterine weight relative to controls. All 17 alpha-dihydroequilenin sulfate doses markedly reduced total plasma cholesterol concentrations versus controls (34.02 +/- 3.44 mg/dl, 32.49 +/- 1.08 mg/dl, and 71.55 +/- 5.16 mg/dl vs 90.44 +/- 1.06 mg/dl; for all, p < 0.02). 17 alpha-Dihydroequilenin sulfate had a more pronounced effect on low- or very-low-density lipoprotein cholesterol than total plasma cholesterol or high-density lipoprotein cholesterol concentrations. CONCLUSIONS 17 alpha-Dihydroequilenin sulfate reduced total plasma cholesterol concentrations without inducing uterine growth in rats after oophorectomy.

Effects of 17α-dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys

Abstract OBJECTIVES: Our purpose was to determine the effects of 17α-dihydroequilenin on plasma lipid and lipoprotein, glucose, and insulin concentrations; coronary artery vasomotor function; and reproductive organ and mammary gland proliferation in atherosclerotic male and female rhesus macaques. STUDY DESIGN: Fifty adult female and 33 adult male rhesus macaques were randomized to treatment by lifetime dietary cholesterol exposure and ratio of total plasma cholesterol to high-density lipoprotein cholesterol. The female treatment groups were intact female controls ( n = 9), ovariectomized controls ( n = 16), ovariectomized plus 0.3 mg/kg/day 17 α -dihydroequilenin ( n = 17) and ovariectomized plus subcutaneous estradiol ( n = 7). The male treatment groups were control ( n = 16) and 1.25 mg/kg/day 17 α -dihydroequilenin ( n = 17). Treatment lasted 5 weeks. Longitudinal assessments of plasma lipid and lipoprotein and glucose and insulin concentrations were performed. Coronary artery vasomotor function was assessed by quantitative coronary angiography 1 week after initiation of treatment. Morphologic and immunohistochemical assessments of proliferation index values of reproductive organs and mammary glands were done at necropsy. RESULTS: 17α-Dihydroequilenin prevented endothelium-dependent vasoconstriction in males ( p p α -Dihydroequilenin treatment increased plasma apolipoprotein A-1 concentrations ( p p α -Dihydroequilenin had no other effects on plasma lipid and lipoprotein concentrations in either males or females. It had no trophic effects on uterus, endometrium, or breast. There was no effect on either prostatic or testicular weight. CONCLUSION: 17α-Dihydroequilenin may represent a single-agent hormone therapy for reduction of ischemic heart disease risk for both menopausal women and men. It has no apparent trophic effects on reproductive organs or mammary glands of female and male rhesus macaques. (Am J Obstet Gynecol 1996;175:341-51.)

Control of chronic inflammation with pathway selective estrogen receptor ligands.

The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.

Determination of 17α-dihydroequilenin in rat, rabbit and monkey plasma by high-performance liquid chromatography with fluorimetric detection

A high-performance liquid chromatographic (HPLC) method with fluorescence detection for the determination of total (unconjugated and conjugated) 71α-dihydroequilenin in male and female rat rabbit and male rhesus monkey plasma is described here. Plasma sample preparation involved hydrolysis with enzyme (Glusulase), addition of internal standard (14β-equilenin) and solvent extraction. The extracts were chromatographed on a C6, 5-μm reversed-phase HPLC column and detection was accomplished with a fluorescence detector operated at an excitation wavelength of 210 nm and an emission wavelength of 370 nm. The assay was linear over a range of 2.5 to 100 ng/ml in male and female rat plasma, and 5 to 500 ng/ml in female rabbit and male and female monkey plasma. The method was specific, accurate and reproducible (percent differences <14.5; coefficients of variation <9.5%) in all matrices examined. The applicability of this method was successfully tested by quantifying total plasma concentrations of 17α-dihydroequilenin in ovariectomized female rats, ovariectomized female rabbits and a normal female rhesus monkey receiving 2.0, 8.3 and 0.1 mg/kg, respectively, of 17α-dihydroequilenin sulfate intragastrically.

Future therapies for the prevention and treatment of venous and arterial thrombosis

The incidence of thrombosis as a complication of invasive surgery, in cancer patients, as a cause or complication of stroke, acute myocardial infarction (AMI), thrombolysis, unstable angina (UA) or angioplasty is substantial. To better serve this patient population in the prevention and prophylaxis of thrombosis, new types of anticoagulant drugs are under development by the pharmaceutical industry. The goal of these efforts are orally-active anticoagulants with specificity and pharmacokinetic properties that could translate into better control of anticoagulation and thrombosis and less bleading liability compared to the currently used anticoagulants: heparin, the low molecular weight heparins and warfarin. Various approaches for which there is a great deal of activity include: tissue factor/Factor VIIa inhibitors, Factor Xa inhibitors, thrombin inhibitors, glycoprotein IIb/IIIa antagonists. There is also interest in Factor IXa inhibitors, thrombin receptor antagonists and inhibitors of plasminogen activator inhibitor-1.

Meeting Highlights: Cardiovascular & Renal: The Scientific Conference on the Correlation of Clinical Syndromes of Atherosclerosis with Lesion Morphologies as seen by Pathology and Imaging Techniques: January 19–21, 1995, Lake Buena Vista, Florida, USA

The scientific conference on the correlation of clinical syndromes of atherosclerosis with lesion morphologies as seen by pathology and imaging techniques was an excellent summation of current knowledge of the role and impact of atherosclerosis and vascular dysfunction in a variety of disease states. A number of the most respected researchers in the field of atherosclerosis were present and discussed topics such as coronary artery atherosclerosis, carotid atherosclerosis, aortic atherosclerosis and femoral/iliac atherosclerosis. These discussions included the correlation of diseases of the different vascular beds, the clinical syndromes associated with the different sites, and the current status and utility of imaging techniques. In summary, atherosclerosis appears to play the major role in coronary artery disease (including unstable angina), stroke (both embolic and haemorrhagic), aortic aneurysm and peripheral vascular disease. Additionally, atherosclerosis appears to play a significant role in instance...