Effects of the lipolysis inhibiting agent beta-pyridylcarbinol (Ronicol) in acute myocardial ischaemia.

The antilipolytic, nicotinic acid analogue beta-pyridylcarbinol (Ronicol) has previously been reported to decrease the free fatty acid (FFA) concentration of the arteria-blood, and to moderate the FFA-uptake and O2-consumption of the myocardium; on this basis, the drug may be expected to exert a cardioprotective action. The cardiac effects of Ronicol were therefore studied on a self-control, 'single-vessel' coronary artery ligature dog model. The left anterior descending coronary artery (LAD) was prepared in the in situ heart of anaesthetized, thoracotomized animals. Following the control ligation, a stabilization period and Ronicol infusion (1 mg/kg iv. during 10 minutes), the LAD was repeatedly ligated. The duration of the individual occlusions was 10 minutes. Ronicol significantly decreased the arterial FFA concentration and the epicardial ST segment elevation; its antilipolytic and anti-ischaemic effects were protracted and were still observed 120 minutes after pretreatment. The drug did not decrease the inhomogeneity of ventricular depolarization in the ischaemic myocardium and in the dose applied it had no influence on the heart rate, arterial blood pressure, left ventricular end-diastolic pressure and left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of Ronicol (1 mg/kg iv.) is about 120 minutes. It has the advantage that it does not possess the unwanted cardiovascular side-effects displayed by nicotinic acid observed by us too in this model earlier (Cardiol. Hung. 13, 33-41, 1984).

Unusual but reversible hepatic lesions following long-term treatment with pyridylcarbinol for familial hypercholesterolemia.

We report two cases of unusual hepatic lesions following years of monotherapy with pyridylcarbinol (timespan) in a daily dose of 1.35 to 1.5 g for familial hypercholesterolemia. Mild elevations of liver enzymes correlated to a large tumor-like mass in the gallbladder region in one case and nodular changes in the whole liver (diagnosed by ultrasound) similar to metastatic lesions. After discontinuation of pyridylcarbinol the changes in the liver regressed markedly in both cases.

[Indications for and the therapeutic action of hypolipidemic agents in patients with hyperlipoproteinemias]. / Pokazaniia i lechebno vuzdeistvie na niakoi khipolipidemichni sredstva pri bolni s khiperlipoproteinemii.

Seventy three patients with hyperlipoproteinemia (HLP) type II and IV were divided into three groups and treated with different pharmaceuticals. The first group was treated with 300 mg Radecol daily, the second--with 750 mg Probucol and the third--with 600 mg Bezalip. Best results in the patients with HLP, type II A, as regards the effect on total cholesterol were obtained in those treated with Probucol, in type II B the results from the treatment with Radecol and Probucol are similar. In type IV HLP the reduction of triglycerides is best manifested in those treated with Bezalip. The tolerance and indications for the treatment of the patients with the three preparations are evaluated with a view to individualization of the medicamentous treatment.

[Experimental hyperlipoproteinemia and arteriosclerosis in minipigs--effect of various drugs]. / Experimentelle Hyperlipoproteinämie und Arteriosklerose bei Minischweinen--Zum Einfluss verschiedener Medikamente.

Experimental hyperlipoproteinemia and atherosclerosis were produced in mini-pigs of the Göttingen strain by adding egg yolk and cholesterol to the diet for one and a half year. Phenotyping of the hyperlipoproteinemia showed a great similarity with the human type IIa according to the Fredrickson classification system. Cholesterol ester-rich atherosclerotic lesions were developed, predominantly located in the abdominal aorta and the coronary arteries. Prophylactic treatment of the hyperlipoproteinemia with the drugs niceritrol (Perycit) and beta-pyridylcarbinol (Ronicol) significantly reduced the elevated plasma cholesterol level and reduced the degree of atherosclerosis in the abdominal aorta and the coronary arteries. Studies of the regression of the cholesterol ester accumulation showed an important difference between the two vascular regions. A very slow regression was observed in the abdominal aorta, while a more marked regression was present in the coronary arteries. Treatment with the drug clofibrate (Atromidin) normalized the plasma cholesterol level within a month and enhanced the regression of cholesterol esters in the coronary arteries.

Controlled trial of the action of a toothpaste containing nicomethanol hydrofluoride in the treatment of dentine hypersensitivity.

A double-blind clinical trial was performed on 76 patients with dentine hypersensitivity. For four weeks the patients used either a toothpaste containing nicomethanol hydrofluoride or one containing potassium nitrate and sodium monofluorophosphate. After one, two and four weeks the pain responses of the teeth to three types of stimuli were assessed. In normal conditions of oral hygiene, the nicomethanol hydrofluoride toothpaste was found at least as effective as the potassium nitrate/sodium monofluorophosphate preparation.

Effect of plasma exchange with and without concomitant drug treatment on lipids and lipoproteins in patients with familial hypercholesterolemia confirmed by tissue culture.

Repeated plasma exchange is an effective treatment for young patients with familial hypercholesterolemia. We treated 2 homozygous and 1 heterozygous patient with very high cholesterol levels with continuous plasma exchange using human albumin solution as exchange medium. The treatment was repeated every 2 weeks in 2 patients and weekly in the third. Treatment periods of plasma exchange alone and of plasma exchange with concomitant drug therapy were compared. For drug treatment beta-pyridylcarbinol, the alcohol corresponding to nicotinic acid (0.9 g/day equivalent to 3 g of nicotinic acid) and cholestyramine (16 g/day) were used. Plasma exchange alone resulted in a decrease of all lipids by 55% and of apolipoproteins by 50-60% as compared to the plasma levels before exchange. Subsequently all lipoproteins rose again to reach pre-exchange levels within about 2 weeks. There was no difference between the homozygous and the heterozygous patients. Beta-pyridylcarbinol or cholestyramine given concomitantly did not alter the post-exchange increase of total, LDL, HDL cholesterol nor of the corresponding apolipoproteins except of apolipoprotein B.

[Blood pharmacokinetics of fluorine in man after the oral administration of nicomethanol hydrofluoride]. / Pharmacocinétique sanguine du fluor après administration orale chez l'homme du fluorhydrate de nicométhanol.

The pharmacokinetic parameters of fluoride have been studied, after a single oral administration to human volunteers of two fluoridated compounds: sodium fluoride, and a new organic fluoride salt, nicomethanol hydrofluoride. The results obtained with these two compounds were very similar, suggesting that no abnormal accumulation of fluoride in the body occurs after using nicomethanol hydrofluoride.

Sudden death related to advanced coronary atherosclerosis in mini-pigs: influence of some drugs.

Advanced coronary atherosclerosis was produced in 30 mini-pigs by a combination of a hypercholesterolaemic diet and X-irradiation to the precordial region. Within 11-25 weeks after the irradiation, 13 of the 30 animals died a sudden death probably caused by coronary atherosclerosis. The contents of free and ester-bound cholesterol in the right coronary artery were significantly higher in the animals which died spontaneously than in surviving animals. In an untreated group of 12 animals 7 died whereas in a group treated with beta-pyridylcarbinol only 1 out of 5 died. In the coronary arteries, the contents of both free and ester-bound cholesterol were significantly lower in the beta-pyridylcarbinol-treated animals. In a sulfinpyrazone-treated group 3 out of 8, and in a metoprolol-treated group 2 out of 5 animals died. None of these drugs reduced the accumulation of cholesterol in the coronary arteries. The rate of sudden death was 26 +/- 6% (P less than 0.05) lower in the combined group of treated animals than in the untreated ones. By regular ECG recordings, signs which could predict the fatal outcome of the experiment were looked for. Although depressed ST segments were present before death in a few animals, this was not a regular phenomenon. It is concluded that advanced coronary atherosclerosis in mini-pigs often leads to sudden death and that this animal model seems suitable for testing the potential therapeutic effects of drugs.

[Effect of a 3-month-interval running exercise in combination with vasodilative therapy on microcirculation of the lower leg in peripheral arterial circulation disorders (stage I and II)]. / Die Wirkung einer dreimonatigen Intervallaufübung in Kombination mit einer Vasodilatantien-Therapie auf die Mikrozirkulation im Unterschenkel bei peripheren arteriellen Durchblutungsstörungen (Stadium I und II).

The authors report results of a three-month-interval running exercise under continuous vasodilatory therapy (Radecol and Jupal) in cases of peripheral arterial blood disturbances (stage I and II). Apart from control examination with the whipping test, the ultra-sound-Doppler method, phlebemphraxis-plethysmography, the paper reports above all the effects of interval running on the peripheral microcirculation of the working muscles which were determined by means of Xenon-133-clearance-half-life. Independent of the type of drug therapy used, significant (1 per cent) improvements of peripheral haemodynamics were found regarding the therapeutic regime presented.

[Modification of pathologic fatty acid patterns in old age by combined clofibrinic and nicotinic acid treatment]. / Beeinflussung pathologischer Fettsäurenmuster im höheren Lebensalter durch kombinierte Clofibrin- und Nikotinsäurebehandlung.

71 patients (42 men and 29 women, aged between 45 and 76) with primary hyperlipoproteinaemia (HLP) types IIa, IIb and IV, were treated with clofibric acid (Regadrin) and nicotinic acid derivatives (Radecol, Jupol) over a three-year period. Every four months, they underwent gas chromatographic analyses of the fatty acid spectrum (fa) in the fractions of cholesterol ester (Chol.E) and triglyceride (TGL) of the serum. The therapy resulted in an increase in the linoleic, linolenic, arachidonic, and eicosapentaenoic acids, and a fall in the palmitic, palmitoleic, stearic, oleic and eicosatrienic acid levels in the Chol.E fraction in the case of HLP types IIa and IIb, and in the TGL fraction in the case of HLP types IIb and IV. Selective competitive inhibition by unesterified fatty acids, blocked lipolysis, an impaired hepatogenic fatty-acid metabolism, an affected LCAT and an increased esterification of polyunsaturated fatty acids are discussed as possible mechanisms. The increase in polyunsaturated fatty acids and the decrease of saturated and monounsaturated fatty acids must be considered, as they are interrelated with the prostaglandin metabolism, to be a positive and vasoprotective effect which assumes special importance in middle and older age.

[Clinico-experimental long-term study on the combined effect of clofibrin and nicotinic acid on abnormal fatty acid patterns in lipid metabolism disorders in the aged]. / Klinisch-experimentelle Lanzeitstudie zum Kombinationseffekt von Clofibrin- und Nikotinsäure auf abnorme Fettsäurenmuster bei Fettstoffwechselstörungen im Alter.

Seventy-one patients (forty-two males and twenty-nine females aged forty-five to seventy-six) with disturbances of fat metabolism were treated for three years with clofibric acid and nicotinic acid derivatives. Regular gas chromatographic analyses of the composition of cholesterol ester and triglyceride fatty acids in the serum showed an increase of linoleic, linolenic, arachidonic, and eicosane-pentaenoic acids and a decrease of palmitic, palmitoleic, stearic, oleic, and eicosanetrienic acids during treatment. These changes were far more strongly marked than under monotherapy. Possible causes of the observed changes include selective competitive inhibition of unesterified serum fatty acids, inhibition of lipolysis, effects upon hepatogenic fatty acid metabolism and LCAT, as well as better utilization of alimentary polyunsaturated fatty acids as a result of combination treatment. The increase of polyunsaturated fatty acids and the decrease of saturated and monounsaturated fatty acids with their reciprocal relations to the prostaglandin metabolism may be considered a positive vasoprotective effect which is of particular importance in middle and old age.

[Effect of beta-pyridylcarbinol on lipids and lipoprotein in primary type IIa hyperlipoproteinemia]. / Zur Wirkung von beta-Pyridylcarbinol auf Lipide und Lipoproteine bei primärer Typ IIa-Hyperlipoproteinämie.

The effect of long-term treatment over 16 weeks with beta-pyridylcarbinol (test substance Ronicol 300) on lipids and lipoproteins was investigated in 10 patients with primary hyperlipoproteinemia type IIa. A placebo period preceded and followed the treatment period. The lipoprotein fractions VLDL, DL and HDL (very low density lipoproteins, low density lipoproteins and high density lipoproteins, respectively) were isolated by preparative ultracentrifugation. beta-Pyridylcarbinol reduced total cholesterol from 410 +/- 39 mg/dl to 319 +/- 19 mg/dl (p less than 0.05). The decrease was mainly caused by a reduction in LDL-cholesterol by 25%. The HDL-cholesterol rose only slightly during treatment. The reduction in total triglycerides (132 +/- 12 mg/dl to 110 +/- 12 mg/dl) was less marked. The decrease was attributable to a reduction in VLDL- and LDL-triglycerides. Phospholipids and proteins behaved in an analogous fashion. The composition (in %) of the lipoprotein fractions VLDL, LDL and HDL didn't change under treatment. The typical nicotinic acid flush could be observed in all 10 patients.

Vitamins E and A in vascular diseases.

The major pathogenetic factors of the atherosclerotic diseases are: a) vasal endothelium distress; b) rheological disturbs; c) alterations in plasma lipid pattern; d) dietary intake of saturated and polyunsaturated fatty acids; e) alteration of mitochondrial and microsomal membranes; f) vascular injury induced by immune complexes; g) increased lipid peroxidations. Many well documented reports state a positive effect of vitamins A and E on some of the factors previously considered. Vitamins A and E have an endothelium-protective activity and an antiperoxidative effect; they act as antiaggregant factors, affect O2 transport and utilization processes, increase HDL-cholesterol, potentiate the hypolipidemic action of the nicotinic acid.

[Vitamins in the prevention of hyperlipoproteinemia and atherosclerosis (author's transl)]. / Vitamine e prevenzione delle iper-lipoproteinemia e dell'aterosclerosi.

Primary and secondary vitamin deficiencies cause many metabolic diseases which possible are life-threatening. Nevertheless none of the hypovitaminosis is known to give rise to hyperlipoproteinemias and/or atherosclerosis. On the other hand, the hypolipemic effect of several vitamins, like retinol, ascorbate, tocopherol and nicotinate, has clearly been demonstrated. This effect takes place either on clinically non-demonstrable hypovitaminosis, or by a true pharmacological activity of those factors. In the last case several different mechanisms are probably involved, which are described in the present paper. The use of vitamins in metabolic disorders is justified both for the primary prevention, in order to correct the causes of hyperlipoproteinemias, and in the secondary one, to diminish the blood fat levels, which increase the risk of atherogenesis.

Lipids and lipoproteins in hyperlipidemia type IIa during treatment with different lipid lowering drugs.

In the present study we examined the effect of different lipid lowering drugs on lipids and lipoproteins in hyperlipoproteinemia type IIa. We have treated over 24 weeks 10 patients with 900 mg beta-pyridylcarbinol daily, 11 patients with 3 g of xantinolnicotinate, 4 patients with 600 mg bezafibrate daily and 10 patients with a combination of 2.4 g inositolnicotinate and 1.5 g clofibrate daily. One patient with familial hypercholesterolemia (untreated total cholesterol 800 mg%) received a combined drug treatment during 5 years. Total cholesterol decreased to 200 mg%, mainly due to decreases in LDL-cholesterol. However in HDL significant decreases of about 50% could be observed. Treatment with the four different drugs showed significant decrements in low density lipoproteins (LDL) whereas an increase of protective high density lipoproteins could not be observed.