Birgitte Hjort Guldhammer

A Partial Estrogen Receptor Agonist With Strong Antiatherogenic Properties Without Noticeable Effect on Reproductive Tissue in Cholesterol-Fed Female and Male Rabbits

Estrogen replacement therapy retards the development of cardiovascular disease and osteoporosis in postmenopausal women. However, long-term unopposed use increases the risk of cancer in endometrium and possibly in breast. The racemic compound ormeloxifene, widely used in India as an antifertility agent, is a partial estrogen receptor agonist with antiosteoporotic properties. The present study was undertaken to investigate the effect of the L-enantiomer (levormeloxifene) and the d-enantiomer (d-ormeloxifene) on the development of atherosclerosis. In a short-term experiment (6 weeks), 4 x 10 ovariectomized female rabbits were fed a 0.25% cholesterol-enriched diet and the effect on plasma cholesterol levels was studied. In a long-term experiment (13 weeks), 4 x 15 ovariectomized female and 4 x 15 shamoperated male rabbits were maintained at a similar plasma cholesterol level of 25 mmol/L and the effect on undamaged and balloon-injured arterial wall was studied. In both experiments, the rabbits were treated with levormeloxifene, d-ormeloxifene, 17 beta-estradiol, or placebo, respectively. In the short-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced plasma cholesterol by 30% compared with the placebo group. In the long-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced atherosclerosis by 50% in the undamaged arterial wall of both female and male rabbits. Because these rabbits were cholesterol-clamped, the antiatherogenic effect was not mediated via plasma cholesterol lowering. Like estrogen, levormeloxifene did not inhibit atherosclerosis in the endothelium-denuded site of aorta. The antiatherogenic effects of levormeloxifene were thus similar to those of estrogen, but produced in the absence of any noticeable estrogenic effect on uterine or testicular tissue.

Transport of Insulin Across Rabbit Nasal Mucosa In Vitro Induced by Didecanoyl-L-α-Phosphatidylcholine

To investigate the short-term effects of didecanoyl-L-α-phosphatidylcholine on the nasal mucosa and the mechanism by which didecanoyl-L-α-phosphatidylcholine enhances the nasal absorption of insulin, an in vitro model was developed. The mucosa from the posterior part of the rabbit nasal septum was mounted in an Ussing chamber and incubated in bicarbonate Ringer solution at 37°C. Potential difference, transmucosal conductance, and unidirectional tracer fluxes were measured across an exposed tissue area of 0.44 cm2. Morphological and physiological examinations revealed a typical respiratory epithelium containing amiloride-sensitive Na+ channels and diphenylamine-2-carboxylate–sensitive Cl− channels. Spontaneous potential difference (10.8 ± 0.4 mV [n = 50]; serosa positive) and transmucosal conductance (10.5 ± 0.4 mS/cm2 [n = 50]) were stable for several hours. Mucosal addition of 0.1–0.5% didecanoyl-L-α-phosphatidylcholine increased transmucosal conductance (by 43–53%) and decreased potential difference (to 0–2 mV) to new steady-state values within 10–15 min. Control unidirectional rate constants for permeation of sucrose, polyethylene glycol 4000, and insulin were low and varied according to the molecular size. After addition of didecanoyl-L-α-phosphatidylcholine, unidirectional rate constants for the three compounds all increased 3- to 5.5-fold. The didecanoyl-L-α-phosphatidylcholine effects on potential difference and transmucosal conductance were reversible after a recovery period of at least 40 min when didecanoyl-L-α-phosphatidylcholine had been applied to the mucosal side for 15 min. The results suggest that didecanoyl-L-α-phosphatidylcholine may increase the transepithelial absorption of insulin by facilitating a paracellular passage through a reversible opening of tight junctions.

Benign Prostatic Hypertrophy

IN BRIEF: Benign prostatic hypertrophy is one of the common complaints of older men who visit their primary care physicians. Nonoperative therapy, such as drug therapy or lifestyle modification, is aimed primarily at reducing bothersome lower urinary tract symptoms and preventing serious morbidity such as urinary retention and renal function impairment. As more men reach advanced age, it becomes crucial for the primary care physician to be aware of the epidemiology, pathophysiology, natural history, clinical presentation, and therapeutic modalities available for the treatment of clinically significant cases.