Ethyl 2-([5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate as a new potent oxyisobutyrate hypolipidaemic with unusual features.

Some compounds containing the N-imidazolyl and the ethyl oxy-isobutyrate groups linked to a naphthalene ring structure and some related analogues were synthesized and tested for hypolipidaemic activity. Ethyl 2-([5,6- dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate (V) proved to be a strong hypolipidaemic agent, several times more potent than clofibrate. Structural requirements for activity and differences from clofibrate analogues are discussed.

Removal and regeneration of the endothelium of the left common carotid artery of rats with induced hypercholesterolemia compared with normocholesterolemic animals. Experimental model to quantify the endothelial layer.

Male Wistar rats were used in a study of removal of the endothelium and endothelial regeneration in the large arteries. The endothelium was stripped completely by surgery from a well-defined segment, with no branches, of the left common carotid artery of rats, drying the vessel by blowing a gentle air stream through the lumen. The animals were fed the normocholesterolic or hypercholesterolic diets. The conditions of the denuded arterial segment were checked histologically at various intervals after the operation. The exposed area became covered with new endothelial cells growing from the two margins of the damaged area; regeneration was complete by about 20 days in normocholesterollemic rats (99.06%) and in a slightly lower proportion of the rats on the atherogenic diet (90.56%). The animals with induced hypercholesterolemia, however, had a significantly larger amount of missing endothelium on day 11 after surgery than the controls. This suggests that hypercholesterolemia affects not only the severity of the lesion but also the rate of endothelial repair.

In vivo effect of indobufen and ticlopidine hydrochloride on aortic endothelial integrity of normo- or hyper-cholesterolemic rats.

Rats fed a normo- or hyper-cholesterolic diet were treated for 7 days with indobufen or ticlopidine hydrochloride (Ticl.HCl) orally, 20 mg/kg/day. At the end of treatment, the animals were perfused in vivo to fix the cell and to dye the intracellular junctions of the endothelial reticulum of the arterial wall. The integrity of the aortic endothelial layer was evaluated microscopically. Rats fed a normo- or hyper-cholesterolic diet, treated with indobufen, did not differ from the control group as regards the parameters in question. The animals treated with Ticl.HCl presented a reticulo-endothelial injury when fed a normo-lipidic diet and smooth muscle cell infiltration, an indicator of more advanced lesion, when fed a hypercholesterolic diet.

N-imidazolylchroman-4-ones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins.

A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.

Grating film for use as a cover-slide in semi-quantitative and quantitative microscopic assessment of biological specimens.

We have patented a photographic film on which a series of parallel lines or concentric circles are reproduced, in various sizes, to provide a reference measurement for counting surfaces in a histological specimen without having to alter it in any way. The area of the preparation examined can thus be determined in numerical terms. This grating film can be used as a cover-slide for example, to calculate a surface that is different from normal, to map the distribution of different areas, etc. We use the grating film in studies of the condition of the endothelium of the carotid artery and aorta from rats fed a normolipidic diet.

In vivo effect of a high-cholesterol diet on the endothelial integrity of rat aorta.

A new technique for measuring spontaneous or induced endothelial lesions in animals was used to analyse the endothelial integrity of the aortas of rats fed a normolipidic or high-cholesterol diet. Animals fed a hypercholesterolic diet for 7 days differed from animals fed a normolipidic diet in that they presented endothelial lesions in accordance with the lipid hypothesis of atherosclerosis.

Cisternal and lumbar CSF concentration of arachidonate metabolites in vasospasm following subarachnoid hemorrhage from ruptured aneurysm: biochemical and clinical considerations.

Two representative cases of subarachnoid hemorrhage in which prostaglandin D2 (PGD2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolite of prostacyclin (PGI2), were monitored with serial lumbar punctures and detected in cisternal CSF during operations for aneurysm, are reported. In the case with demonstrated arterial vasospasm, prostaglandin D2 has a concentration trend with characteristic peak related to vasospasm; the synthesis of prostacyclin appears inhibited after the hemorrhage. In the patient without radiologic evidence of vasospasm, arachidonate metabolite concentration trend appears in a steady-state. Cisternal prostaglandin D2 concentration in the patient with demonstrated vasospasm is two times the highest lumbar CSF concentration, while 6-keto-prostaglandin F1 alpha concentration is very low. This suggests the role of the clotting phenomenon and likely confirms the importance of arachidonate metabolites in the genesis of cerebral arterial spasm following subarachnoid hemorrhage.

Effect of the antilipolytic compound acipimox on peroxisome marker enzymes, lipid pattern and biotransformation related functions in rat liver.

The antilipolytic drug acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide) was given to male rats for 1 week at 500, 1000 and 2000 mg/kg/day and for 2, 6 and 7 months at 20, 100 and 500 mg/kg/day. The peroxisome proliferative effect was evaluated determining the activity of catalase and carnitine acetyltransferase, the rate of cyanide-insensitive palmitoyl CoA oxidation and the electrophoretic profile of liver polypeptides. Hepatic lipid content and distribution were evaluated after 2 and 6 months' treatment. The effect on liver detoxificating function was evaluated by assaying glutathione, cytochrome P-450, glutathione-S-transferase and glutathione-reductase activities after 7 months' treatment. Sub-acute and chronic treatment with a wide range of acipimox doses did not cause hepatomegaly, liver peroxisome proliferation or liver steatosis and did not change some important biochemical variables related to detoxification and biotransformation mechanisms. Acipimox given to rats does not have the negative side-effects of other compounds and seems a safe blood lipid lowering drug.

Inhibition of platelet aggregation by a new agent, 5-(Z,E)-13,14-didehydro-20-methyl-carbo PGI2 (FCE 22509).

FCE (+)22509, a chemically stable carboprostacyclin analogue, inhibited in vitro ADP-induced platelet aggregation in rat platelet-rich plasma (PRP) (IC50 = 7.7 ng/ml). Subcutaneous administration of the drug, inhibited both ADP-induced platelet aggregation in rat PRP (ED50 = 0.26 mg/kg) and mortality of mice induced by collagen plus adrenaline (ED50 = 0.35 mg/kg). The compound had no such preventive effects when given orally.

Inhibitory activity of indobufen (*) on platelet aggregation in vivo.

Indobufen, administered by gavage, reduced mortality induced in mice and rabbits by intravenous injection of arachidonic acid (A.A.). The doses of compound required to protect 50% of the mice and rabbits from death (ED50) were 1.3 and 0.58 mg/kg respectively. Acetylsalicylic acid (ASA) was considerably less active than indobufen (ED50 = 22.4 and 8 mg/kg). Since the lethal effect of A.A. is mostly due to the formation of platelet aggregates (Silver et al., 1974; Kohler et al., 1976), it is concluded that indobufen is a very potent inhibitor of platelet aggregation in vivo.

Hypolipidemic activity of some derivatives of 6H-dibenzo[b,d]pyran.

This paper describes the synthesis of 6-carboxy derivatives of 6H-dibenzo[b,d]pyran. These compounds are among the most rigid structures related to clofibrate ever synthesized, which means they have very few possible conformations of relative stability compared with the many for clofibrate. Compound 6H-2-chloro-6-methyl-dibenzo[b,d]pyran-6-carboxylic acid 3g showed very high hypolipidemic activity being 12 times more potent than clofibrate in reducing plasma cholesterol concentration in the hypercholesterolemic rat and 11 times more potent in reducing plasma triglyceride concentration in the normolipemic rat.