PubMed Health⌕ Search

Biomedical subjects

E C Witte

Publications and source records attributed to E C Witte.

7 recordsLinked to original sources
PubMed1990

Reduction of BM 15.766-induced 7-dehydrocholesterol accumulation by bezafibrate and mevinolin in rats. A non-isotopic in vivo test system for compounds reducing cholesterol synthesis.

The effects of mevinolin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor and bezafibrate, a modulator of lipoprotein metabolism, were measured on BM 15.766-induced 7-dehydrocholesterol (7-DHC) accumulation in liver and serum of rats. BM 15.766, an inhibitor of delta 7 sterol reductase, leads to an accumulation of 7-DHC, which can be used as a measure of cholesterol (CH) synthesis de novo. The investigations were carried out to evaluate the usefulness of this new non-isotopic in vivo method for testing compounds that affect directly and indirectly the CH-biosynthetic pathway. Mevinolin showed a dose-dependent reduction of BM 15.766-induced 7-DHC accumulation after a single oral dose. The dose range for reduction of 7-DHC in the liver of rats was comparable with that for serum CH-lowering in humans. Bezafibrate reduced the BM 15.766-induced 7-DHC accumulation in liver in a dose- and time-dependent manner. These findings agree with the reported reduced activity of HMG-CoA reductase and support the view, that bezafibrate reduces CH biosynthesis by modulation of lipoprotein metabolism. The 7-DHC levels in serum do not reflect those in the liver and cannot be used as a measure of CH biosynthesis. The investigations show that BM 15.766-induced 7-DHC accumulation in liver of rats is an appropriate measure for CH de novo synthesis and can be used for testing compounds that interfere directly and indirectly with the CH-biosynthetic pathway. In contrast to previously described methods, no radiolabelled precursors are necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Synthesis and hypolipidemic and antidiabetogenic activities of beta,beta,beta',beta'-tetrasubstituted, long-chain dioic acids.

beta,beta,beta',beta'-Tetrasubstituted, long-chain dioic acids of the general formula HOOC-C(XY)-C(R2)-Q-C-(R2)-C(XY)-COOH have been synthesized and evaluated as hypotriglyceridemic-hypocholesterolemic agents in rats and as antidiabetogenic agents in ob/ob diabetic mice. The free carboxyl function of analogues of the series was mandatory for their hypolipidemic-antidiabetogenic effect while nonhydrolyzable diesters were inactive. Other structure-activity relationships were determined as a function of the overall chain length (C12-C22), alpha,alpha'-substitutions (X, Y = H, F, Cl, Br, OH, CN), beta, beta'-substitutions (R = CH3, C6H5), and core substitutions [Q = (CH2)10, (CH2)4CH = CH(CH2)4, 1,4-C6H10[(CH2)3]2, 1,4-C6H4[(CH2)3]2, 1,4-C6H4(CH = CHCH2)2, CH2(OCH2CH2)3OCH2)]. The most effective hypolipidemic-antidiabetogenic members of the series were alpha,alpha'-nonsubstituted, beta,beta'-methyl-substituted analogues of 14-18-carbon chains having either a saturated aliphatic core or a 1,4-bis(propenyl)benzene core in the cis/trans configuration. The hypotriglyceridemic rather than the hypocholesterolemic capacity of members of the series was found to correlate with their respective capacities as liver peroxisomal proliferators in rats.

Animals↗
PubMed1989

Chemical synthesis of picumast dihydrochloride.

The chemical synthesis of the antiallergic substance picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) is described.

Chemical Phenomena↗
PubMed1988

Irreversible inhibition of the TXA2/PGH2 receptor of human platelets by a photoaffinity ligand.

In order to tag the TXA2/PGH2 receptor of human platelets, we synthesized azido-BSP (= 4-[2-(4-azido-benzenesulfonylamino)-ethyl]phenoxyacetic acid), a photolabile derivative of the specific TXA2/PGH2 receptor antagonist sulotroban (= BM 13.177). If protected from UV light, azido-BSP competitively inhibited the shape change of human washed platelets stimulated by the TXA2 mimetic U 46619. Schild analysis revealed a pA2 = 6.7 (apparent KD = 0.2 mumol/l). Irreversible inhibition of the U 46619-induced platelet activation was achieved by irradiating for 5 min with UV light of 254 nm a platelet suspension containing azido-BSP. After subsequent washing, the platelets were stimulated with U 46619, ADP or PAF. Under these conditions azido-BSP inhibited the shape change, aggregation and [3H]serotonin release induced by U 46619 but not the shape change induced by ADP or PAF. The concentrations of azido-BSP which blocked the U 46619-induced [3H]serotonin release and the aggregation were 0.5 mumol/l and 1.0 mumol/l, respectively, whereas even 50.0 mumol/l of azido-BSP only partially inhibited the U 46619-stimulated shape change. Obviously, increasing numbers of thromboxane receptors have to be blocked in order to inhibit the [3H]serotonin release, the aggregation and the shape change. Even at an azido-BSP concentration equal to 250 times the apparent dissociation constant, enough receptor sites remained active to allow U 46619 to induce the shape change. In sulotroban was added prior to irradiation, the blocking effect of azido-BSP decreased with increasing concentrations of sulotroban. These results show that azido-BSP is a specific and high affinity ligand of the TXA2/PGH2 receptor and that it covalently links to the receptor under irradiation. Azido-BSP is a new tool to identify and characterize the TXA2/PGH2 receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

The pharmacological profile of the thromboxane A2 antagonist BM 13.177. A new anti-platelet and anti-thrombotic drug.

BM 13.177 (4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid) is a representative of a new class of sulfonamidophenylcarboxylic acids which possess platelet-inhibitory and anti-thrombotic activity and inhibits the contraction of rabbit aorta stimulated by PG endoperoxides and TXA2. BM 13.177 5 mg/kg body weight p.o. protected rabbits from arachidonate-induced sudden death and greater than or equal to 10 mg/kg dose-dependently reduced the experimental thrombus formation induced in the rabbit aorta by perivascular administration of silver nitrate. In guinea-pigs, the collagen-induced bronchoconstriction was inhibited in a dose- and time-dependent fashion. The formation of TXA2 and the TXA2-induced platelet aggregation and smooth muscle contraction are probably crucial events in these experimental models. The protective effect of BM 13.177 may, therefore, be due to the TXA2-antagonizing effect of BM 13.177, which has been conclusively demonstrated in human platelets (PATSCHEKE and STEGMEIER, Thrombosis Res., 33, 277-288 (1984). The antagonism of TXA2 is supported by the observation that BM 13.177 also specifically inhibits the contraction of isolated arterial strips from rabbits which were stimulated with the thromboxane A2 mimetic U 46619. Schild-plot with a slope close to unity suggests a competitive type of antagonism. BM 13.177 exhibited neither anti-inflammatory nor ulcer-inducing activity of cyclooxygenase inhibitors. Furthermore it did not block the TXB2 formation in spontaneously clotting blood from rabbits and did not inhibit the release of prostacyclin-like activity from rabbit aortas. The lack of toxicological effects in long-term toxicity studies in rat and dog, together with the absence of objective and subjective side effects in the first human studies have encouraged us to initiate clinical trials in order to evaluate the therapeutic benefit of this new approach in humans.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗