A uniform method for the simultaneous blood group phenotyping of Fya , Fyb , Jka , Jkb , S, sÌ , P1, k applying lateral-flow technique.

BACKGROUND AND OBJECTIVES: A lateral flow assay for simultaneous blood group typing of ABO, RhD, C, E, c, e, Cw and K with stable end-point and without centrifugation is in routine use since several years (MDmulticard® ). The typing of extended phenotype parameters belonging to the Duffy, Kidd, MNSs blood group systems and others, however, has not yet been demonstrated for this technique. Reliable detection of Fyx , a weak Fyb phenotype with a pronounced quantitative reduction of the number of Fyb antigens on the erythrocyte surface, remains a weakness of current serological blood grouping techniques. MATERIAL AND METHODS: The performance characteristics of the following reagents were evaluated in donor and patient samples in lateral flow technology (MDmulticard® ): Anti-Fya , -Fyb , -Jka , -Jkb , -S, -s̅, -P1 and -k. The sensitivity to detect Fyx was in addition evaluated with Fyx positive samples, which had been preselected by MALDI-TOF MS-based genotyping. RESULTS: All results obtained with the MDmulticard® were in full accordance with those of the CE-certified reference products for all the eight reagent formulations used: Anti-Fya , -Fyb , -Jka , -Jkb , -S, -s̅, -P1 and -k. Also, all Fyx phenotypes of the selected population of 93 positive samples, originally identified by MALDI-TOF MS-based genotyping, were reliably detected by the lateral flow assay. CONCLUSION: Extended phenotype blood group parameters, including the serologically challenging Fyx phenotype, can be determined simultaneously, rapidly and accurately using the lateral flow (MDmulticard® ) technology, even in cases when IgG class antibodies are the only source of diagnostic antibodies.

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

[Chronic venous insufficiency of the forefoot as a complication of intravenous drug abuse]. / Chronisch-venöse Insuffizienz am Vorfuss als Komplikation nach intravenösem Drogenabusus.

We report a 23 years old woman exhibiting localized chronic venous insufficiency of the forefeet after cocaine and heroin application into the foot veins. The diagnosis was confirmed by capillaroscopy (characteristic microangiopathy).

RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.

Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides.

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.