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1 The in vivo antiatherogenic activity of the calcium antagonist lercanidipine and its (R)-enantiomer was investigated in two dierent types of atherosclerotic lesions (hyperplastic and fatty-streak lesions) in rabbits. were given by subcutaneous injection for 10 weeks to White New Zealand rabbits, with cholesterol feeding beginning at week 2. The hyperplastic lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty streak lesions were induced by cholesterol feeding. In untreated animals (n=5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries without collar showed a intima/media (I/M) ratio of 0.03+0.02, whereas in carotids with a collar the ratio was 2+0.42. In lercanidipine-treated animals a signi®cant and dose-dependent eect on intimal hyperplasia was observed. I/M ratios were 0.73+0.4, 0.42+0.1, 0.32+0.1 for 0.3, 1, and 3 mg kg 71 week 71, respectively (P50.05). The lercanidipine enantiomer (3 mg kg 71 week 71 ) was as eective as the racemate (0.41+0.11). Proliferation of smooth muscle cells, assessed by incorporation of BrdU into DNA, was reduced by about 50%, 70%, 85%, and 80% by lercanidipine (0.3, 1, and 3 mg kg 71 week 71) and its (R)-enantiomer, respectively. 3 The area of fatty-streaks in the aorta (n=11 ± 15) was signi®cantly reduced by lercanidipine (3 mg kg 71 week 71 , 16% vs 27%, P50.05), a trend was observed also with lower doses. When dierent segments of the aorta were considered (arch, thoracic, abdominal) a signi®cant and dose-dependent eect in the thoracic and abdominal aorta was observed also at lower doses. The (R)-enantiomer was as eective as lercanidipine. 4 These results suggest a direct antiatherosclerotic eect of lercanidipine, independent of modulation of risk factors such as hypercholesterolemia and/or hypertension as demonstrated by the absence of stereoselectivity.

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Plasma pharmacokinetics of VP16-213 were investigated after a 30-60 min infusion in 14 adult patients and six children. In adult the elimination half-life (T1/2 beta), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05 +/- 0.67 h, 26.8 +1- 2.4 ml/min/m2, and 15.7 +1- 1.8 l/m2; in children 3.37 +/- 0.5 h, 39.34 +1- 6.6 ml/min m2, and 9.97 +/- 3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20-30% of the dose. In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose. Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m2/24h) were around 2-5 micrograms/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.

evaluated by cystometry using saline or diluted (0.2%) acetic acid (MPEP only) infusion of bladders in conscious rats. RESULTSBinding studies confirmed the selectivity of the mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) compounds. Isovolumic bladder contractions were blocked after i.v. administration of all compounds. However, the mGlu5 antagonists were generally more potent than mGlu1 antagonists. In conscious rats with bladders infused with saline, MPEP dose-dependently and significantly increased bladder capacity starting from oral administration of 10 mg/ kg. Oral administration of NPS 2407 (up to 30 mg/kg) did not induce consistent changes in bladder capacity or micturition pressure. MPEP (10 mg/kg, orally) was also evaluated in conscious rats with bladders infused with diluted acetic acid. In this model, MPEP reduced bladder instability counteracting the decrease of bladder volume capacity induced by acetic acid. There were no consistent effects on bladder contractility. CONCLUSIONSThe results indicate that i.v. and oral administration of selective mGlu5 antagonists, but not those selective for the mGlu1 subtype, have a marked inhibitory effect on reflex micturition pathways in the rat. KEYWORDSmetabotropic glutamate receptor subtypes, micturition reflex, rat, cystometry, isovolumic bladder contractions OBJECTIVETo investigate the role of Group I metabotropic glutamate (mGlu) receptor subtypes on reflex-induced micturition in anaesthetized and conscious rats using selective mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) allosteric antagonists. MATERIALS AND METHODSThe affinity of the compounds at mGlu1 and mGlu5 receptor subtypes was evaluated by displacement of tritiated R214127 and MPEP, respectively, from rat brain tissue. Effects of intravenous (i.v.) administration of the compounds on isovolumic bladder contractions were evaluated in anaesthetized rats. Effects of MPEP and NPS 2407 on bladder filling and voiding were