Library

Notes: Summary The CIS was undertaken with the aim to evaluate the effects of lipid modifications on angiographic progression and regression of CAD in patients with CAD and hypercholesterolemia. The design included a multicenter randomized, double-blind, parallel, placebo-controlled comparison, with target and safety limits for adjusting the trial medication depending on the LDL cholesterol level (LDL-C) achieved, i.e., up to 40 mg of simvastatin (S) or placebo (P) daily, add-on medication (up to 3 × 4 g Colestyramin), and diet counselling. Male patients, average age 48 (≤ 56) years, were included with angiographic CAD and a screening total cholesterol of 207–350 mg/dl, who were not due to undergo coronary bypass surgery or PTCA, wh did not suffer from serious other disease (e.g., diabetes mellituss), and who had not undergone coronary bypass surgery previously. Results: All baseline variables were comparable in the treatment groups, with 129 patients taking S and 125 taking P. Of these 254 patients 217 had their final study visit and 207 underwent a second angiography after an average treatment time of 2.3 years under an average daily dose of 37 mg S. 205 pairs of films were available for analysis. Vital information was obtained of all patients until closure of the data bank, half a year after the last study angiography. Five deaths occurred within the study period, 12 through March 15, 1995 (S: 1/6, P: 4/6). 37 patients (S: 18, P: 19) discontinued trial drug and protocol. Concomitant CAD medication was comparable in both groups, except lipid-lowering add-on medication which was significantly higher in the P group (38% versus 13%). Significant changes in lipid levels, on treatment, were observed in the S group amounting to a mean difference in LDL-C of −35%, in Apo-Protein B (ApoB) of −30%, in VLDL-C of −37%, and in triglycerides (TG) of −27%, and in HDL-C of +6%, in comparison to the control group; these differences were even greater in 137 fully compliant patients: −41, −36, −39, −31, and +7%, respectively. Progression in the S group was significantly less, as defined by the two primary target criteria: 1) the minimum obstruction diameter (MOD), determined by quantitative coronary angiography (QCA), decreased about five times less in comparison to the control group (S: by −0.017; P: −0.0954 mm), and 2) the standardized visual global change score (GCS) deteriorated almost three times less in the S group (by +0.20) than in the P group (+0.58). Of the secondary target criteria, the mean lumen diameter (QCA) also developed a significant difference (S: −0.20; P: +0.23 mm; P = 0.0006) with a trend toward regression in the S group. The QCA-%-stenosis deteriorated three- to fourtimes less in the S group as compared to the control group (S: by 0.69%; P: by 2.73 %; p = 0.0022), and the number of patients with angiographic progression was nearly halved (S: 30%; P: 56%; P 〈 0.0000). These differences were determined by intention to treat analysis (ITT), and they were obtained in spite of lipid lowering add-on medication in 38% of the P patients; they turned out to be more pronounced in 137 fully compliant patients, in an analysis “as treated”. The mean decrease in LDL-C serum level caused by S was significantly correlated to the decrease in progression, and multivariate regression analysis of both treatment groups identified LDL-C (or ApoB) and TG as independent predictors of progression. Progression appeared to be most pronouncedf in low and medium sized lesions, and the beneficial effect of lipid intervention dominated in lesions with 12–56% QCA stenosis severity. A small fraction of patients who suffered from exercise-induced angina, with ST-segment-depression at the beginning of the study, experienced a significant improvement under S as compared to P treatment. Although the study was not designed to show differences in clinical events, the combined number of all major cardiovascular events tended to be less frequent in the S than in the C group (n.s.), and so did the number of patients with any major adverse event and the absolute number of such events as well as the number of patients with minor adverse experiences and with minor laboratory deviations. Conclusion: In young men, on otherwise full CAD treatment, additional medication with 37 mg simvastatin daily for an average of 2.3 years slowed down angiographic progression of CAD significantly, with a predominant beneficial effect on medium sized coronary lesions. This emerged from the visual as well as the quantitative coronary analysis which gave equivalent and complementing results. By multivariate regression analysis, the inhibitory effect on progression is correlated to the considerable and highly significant difference in LDL-C (or ApoB) and TG effected by simvastatin in comparison to placebo according to the regression equation: ΔMOD [mm] = −0.109 + 0.0003 [TG mg/dl] + 0.0008 [LDL-C mg/dl].

Notes: Summary The existence of β-receptors and their possible contribution to the vascular tone of pial arteries was investigated using the microapplication technique combined with the measurement of vascular diameter. Concentration response curves for (+) and (−)propranolol revealed an identical course with no vascular reaction occurring between 2.5×10−10 and 2.5×10−5 M propranolol. Since both (+) and (−)propranolol were without effect on vascular diameter over a wide concentration range it is concluded that the vascular tone is not influenced by β-receptors under these experimental conditions. The increase in vascular diameter (60%) observed at 2.5×10−4 M (+) and (−)propranolol is supposed to be due to an unspecific effect. Concentration response curves for isoproterenol revealed no vascular reaction between 2.5×10−11 and 2.5×10−8 M, dilations of 4–5% at 2.5×10−7 and 2.5×10−6 M, constrictions of about 5% at 2.5×10−4 and of 3% at 1.25×10−3 M isoproterenol. These weak vascular reactions cannot be explained by reduced biological activity of isoproterenol due to autoxidation during storage. It is concluded that β-receptors are of little or no physiological significance for regulation of the vascular tone of pial arteries.

Notes: Summary In order to evaluate the existence of cholinergic receptors at pial arteries the vasoactive effect of the parasympathomimetic substance carbachol was tested by microapplication into the perivascular space of single pial arteries. Concentration response curves revealed no change in vascular diameter for 10−9 to 10−7 M carbachol. From 10−6 to 10−3 M carbachol dilatations were measured with a maximal reaction at 10−5 M. The carbachol-induced dilatations can be stepwise reduced by ascending pervascular concentrations of atropine thus indicating a competitive antagonism at pial arteries. A cholinergic component influencing pial arterial tone was not found under our experimental conditions since microapplication of atropine (10−9 to 10−4 M) did not induce changes in pial arterial diameter. The dilatation at 10−3 M atropine is believed to be unspecific.

Notes: Abstract PAH secretion (TPAH) was studied in rats at spontaneously occurring glomerular filtration rate (GFR). At saturated transport, TPAH was found to be correlated to GFR. This relationship was also observed at unsaturated transport where TPAH depends upon the PAH concentration in arterial plasma. However, no significant correlation between TPAH and renal PAH load or renal plasma flow rate was found when the effects of GFR were removed by partial correlation analysis. A dependency of TPAH on GFR explains the correlations found between filtration fraction (FF) and renal PAH extraction (EPAH) or renal tubular PAH extraction fraction (EPAH-FFPAH). Thus, even at low PAH concentration in a. plasma, renal PAH extraction may only be assumed to be constant if the filtration fraction is constant.

Notes: Abstract In brown-eyed and blue-eyed rabbits, irises treated with argon laser photomydriasis (ALP) were studied by using fluorescein angiography and by evaluating the aqueous humor protein concentration. The following results were obtained. Immediately after ALP, a breakdown of the blood-aqueous barrier is demonstrated by a marked influx of fluorescein into the ciliary processes and into the anterior and posterior chambers. The dye flow into the aqueous humor decreases to normal values within 3 days. There is no fluorescein leakage from laser impacts themselves. Peripupillary capillary loops are permanently occluded, but in a few cases, recanalization occurs. Neovascularization did not occur during 56 days of observation. ALP initially leads to a six- to eightfold increase in normal aqueous humor protein concentration, which decays to normal values within 3 days.

Notes: Abstract The serum concentrations of 3-ketodesogestrel (KDG) and gestodene have been measured in 30 and 31 women respectively who took low dose oral contraceptives containing 30 μg ethinylestradiol together with either 150 μg desogestrel or 75 μg gestodene for 6 months. On days 1, 10 and 21 of the first third and sixth treatment cycles blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4 and 24 h. KDG and gestodene levels were measured by radioimmunoassays and were evaluated for Cmax (peak serum concentration), tmax (time to Cmax), and AUC (area under the curve) to 4 and 24 h. The overall total gestodene concentrations were higher and the accumulation of the steroid throughout a cycle greater than that of KDG. For example, the AUC0-4 of gestodene increased in cycle 1 by a factor of 2.8 (day 10 vs. day 1) and 3.6 (day 21 vs. day 1) compared to 2.3 and 2.6 for KDG. The higher concentration of gestodene reflects a lower volume of distribution than KDG, and is consistent with gestodene binding to sex hormone binding globulin (SHBG) with a higher affinity than KDG. Concentrations of KDG and gestodene were higher on day 1 of cycles 3 and 6 than on day 1 of cycle 1. The serum concentrations of KDG and gestodene during multiple dosing cannot be predicted on the basis of single dose pharmacokinetics.