Delayed Treatment with YM90K,an AMPA Receptor Antagonist,Protects against Ischaemic Damage after Middle Cerebral Artery Occlusion in Rats

The neuroprotective effect of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride] has been examined in a rat middle cerebral artery occlusion model. Intravenous infusion of YM90K (2·5–20mgkg^?1h^?1 for 4 h) starting immediately after occlusion of the middle cerebral artery significantly reduced the cortical infarct volume 24 h after occlusion compared with the control group. The protection at the highest dose was 39% (P<0·05). Similar protective effects were observed when YM90K (20mgkg^?1h^?1 for 4 h) was delayed up to 2 h after middle cerebral artery occlusion (45% reduction, P<0·05). CNS1102 [N-(1-naphthyl)-N′-(3-ethylphenyl)-N′-methylguanidine hydrochloride], a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also reduced the cortical infarct volume when 1·3mgkg^?1 was administered by intravenous bolus injection immediately after middle cerebral artery occlusion, followed by intravenous infusion at 0·785 mgkg^?1h^?1 for 4 h (35% reduction, P<0·05). This neuroprotective effect was not observed when administration was delayed 1 h after middle cerebral artery occlusion. These results suggest that AMPA receptors might play a more important role than NMDA receptors in the late development of neuronal cell damage after focal cerebral ischaemia and that AMPA receptor blockade would be one beneficial strategy in treating acute stroke.     

Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model

The neuroprotective effects of YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist with high water solubility, were examined in rats with transient middle cerebral artery (MCA) occlusion. The right MCA of male SD rats was occluded for 3 h using the intraluminal suture occlusion method. YM872 significantly reduced the infarct volume 24 hours after occlusion, at dosages of 20 and 40 mg/kg/h (iv infusion) when given for 4 h immediately after occlusion. Furthermore, delayed administration of YM872 (20 mg/kg/h iv infusion for 4 h, starting 2 or 3 h after the occlusion) also reduced the infarct volume and the neurological deficits measured at 24 h. Additionally, the therapeutic efficacy of YM872 persisted for at least seven days after MCA occlusion in animals treated with YM872 for 4 h starting 2 h after MCA occlusion. These data demonstrate that AMPA receptors contribute to the development of neuronal damage after reperfusion as well as during ischemia in the focal ischemia models and that the acute effect of the blockade of AMPA receptors persists over a long time period. YM872 shows promise as an effective treatment for patients suffering from acute stroke.     

Antihyperglycaemic potential of the water–ethanol extract of Kalanchoe crenata (Crassulaceae)

Kalanchoe crenata is a vegetable widely used in Cameroon and largely efficient in the treatment of diabetes mellitus. The effect of the water–ethanol extract of this plant (WEKC) on blood glucose levels was investigated in fasting normal and diet-induced diabetic rats (MACAPOS 1) after a short- and medium-term treatment. Diabetes was induced by submitting Wistar rats to a hypercaloric sucrose diet over 4 months. Six hours after a single oral administration of WEKC, 135 and 200 mg kg⁻¹ body weight extracts significantly (P < 0.01) reduced the blood glucose levels both in normal and diabetic rats without real dose-dependant effect. During the medium-term treatment, 200 mg kg⁻¹ WEKC administered daily for 4 weeks significantly reduced blood glucose levels within week 1 (P < 0.05), with a maximum effect at week 4 (−52%, P < 0.01), while maintaining glycaemia within the normal range. All the WEKC-treated diabetic rats exhibited significant (P < 0.01) increase in insulin sensitivity index (K _ITT) compared with the initial time and to the untreated diabetic animals. Animals treated for 4 weeks exhibited a slight resistance in body-weight gain and decrease in food and water intake. The WEKC activities on all parameters assessed were comparable with the glibenclamide effects. Qualitative phytochemical screening revealed that K. crenata contains terpenoids, tannins, polysaccharids, saponins, flavonoids and alkaloids. The data suggest that K. crenata might contain important chemical components that could induce significant improvement in glucose clearance and/or uptake and resistance to body-weight gain and insulin sensitivity, and could be a potent alternative or complementary therapeutic substance in the control of type 2 diabetes and other insulin-resistant conditions.     

Effects of α-tocopherol on nerve conduction velocity and regeneration following a freeze lesion in immature diabetic rats

We investigated whether anti-oxidant treatment with α-tocopherol (1 g kg^–1 day^–1) could prevent the blunting of the normal maturational increase in motor and sensory nerve conduction velocity when diabetes is induced by streptozotocin in young rats. A further study in the same rats examined effects on myelinated fibre regeneration distance 14 days after a punctate sciatic nerve lesion by a liquid nitrogen cooled probe. In non-diabetic rats between 8 and 14 weeks of age, sciatic motor and saphenous sensory conduction velocity increased by approximately 28% (P < 0.001) and 21% (P < 0.001) respectively. Diabetes induced at 8 weeks blunted this maturational change by 65% for sciatic motor and almost completely for saphenous sensory fibres (P < 0.001). Treatment with α-tocopherol from diabetes induction totally prevented motor conduction velocity deficits (P < 0.001). For sensory saphenous nerve, conduction abnormalities were markedly attenuated (72%, P < 0.001) although a significant deficit remained compared to age-matched non-diabetic rats (P < 0.01). Sciatic nerve myelinated fibre regeneration distance, 14 days post lesion, was 15% reduced (P < 0.001) by untreated diabetes. However, in diabetic rats treated with α-tocopherol, regeneration distance was significantly improved (P < 0.001), being within the non-diabetic range. Thus, the data highlight the importance of reactive oxygen species in the aetiology of impaired nerve maturation and regeneration in experimental diabetes and indirectly support the view that anti-oxidant treatment could have a therapeutic role in patients. Received: 23 July 1996 / Accepted: 26 September 1996     

Anti-ulcer Activity of Cromakalim (BRL 34915), a Potassium-channel Opener,Against Experimentally Induced Gastric and Duodenal Ulcers in Rats and Guinea-pigs

The effect of cromakalim, a potassium-channel opener, was studied on pylorus ligation-induced, aspirin-induced and water-immersion plus restraint stress-induced gastric ulcers in rats and on histamine-induced duodenal ulcer in guinea-pigs. Pretreatment with cromakalim (50–500 μg kg^?1, p.o.) resulted in a significant reduction in the incidence of gastric and duodenal ulceration in each model. The anti-ulcer activity of cromakalim was comparable with that of cimetidine. Cromakalim at 100, 250 and 500 μg kg^?1 caused a reduction in the volume of the gastric content in pylorus-ligated rats, and a dose of 250 μg kg^?1 resulted in a significant reduction in total acidity (28.81 ± 11.73 mEq L^?1, P < 0.02) in the pylorus ligation model. A significant reduction in total acid output was observed at doses of 250 μg kg^?1 (84.27 ± 22.33 mEqH+, P < 0.02) and 500 μg kg^?1 (120.17 ± 24.49 mEq H+, P < 001) in pylorus-ligated rats. A significant reduction in the ulcer index in pylorus-ligated rats was observed at all cromakalim doses: 50 μg kg^?1 (0.23 ± 009, P < 0.05), 100 μg kg^?1 (0.15 ± 0009, P < 0.02), 250 μg kg^?1 (0.12 ± 0.05, P < 0.01) and 500 μg kg^?1 (0.14 ± 0.03, P < 0.02). A significant reduction in the ulcer index of aspirin-treated rats was also observed at all cromakalim dose levels: 50 μg kg^?1 (0.39 ± 0.03. P < 0.01), 100 μg kg^?1 (0.28 ± 0.06, P < 0.01), 250 μg kg^?1 (0.22 ± 0.04, P < 0.001) and 500 μg kg^?1 (0.28 ± 0.03, P < 0.01). In the water-immersion plus restraint stress-induced gastric ulcer model, cromakalim significantly reduced gastric ulceration at all the dose levels: 50 μg kg^?1 (28.2 ± 2.12, P < 0.001), 100 μg kg^?1 (20.24 ± 1.71, P < 0.01), 250 μg kg^?1 (19.95 ± 1.46, P < 0.001) and 500 μg kg^?1 (21.61 ± 3.00, P < 0.001) but there was no consistent reduction of gastric bleeding. In addition to gastric ulcers, duodenal lesions were also reduced by pretreatment with cromakalim at all dose levels: 50 μg kg^?1 (97.87 ± 20.03 mm², P < 0.02). 100 μg kg^?1 (70.72 ± 12.82 mm², P < 0.02), 250 μg kg^?1 (48.32 ± 8.42 mm², P < 0.01) and 500 μg kg^?1 (55.50 ± 12.50 mm², P < 0.01). Cromakalim at a dose of 100 μg kg^?1 also reduced total acidity (99.36 ± 9.12 mEq L^?1, P < 0.02) and total acid output (172.22 ± 45.33 mEq of H+, P < 0.05) in this model. These findings demonstrate the anti-ulcer activity of cromakalim in different experimental models and suggest its potential use in ulcer therapy.     

玛咖提取物对大鼠耐力和血抗氧化酶活性的影响

目的 探讨玛咖提取物对大鼠耐力和血抗氧化酶活性的影响。方法 采用循环水流自由游泳和/或给予大鼠8.0、16.0、32.0 g.kg_-1体重玛咖提取物,连续给药15 d,第16天测定耐力和血丙二醛(malondialdehyde,MDA)、 超氧化物歧化酶(superoxide dismutase ,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-px)水平。结果 给予玛咖提取物8.0、16.0、32.0 g.kg_-1体重15 d,沉下前游泳时间和游泳总时间分别延长了34.38%、84.25%、126.07%和37.42%、47.03、107.24%( P<0.01),大鼠沉下次数比单纯游泳组分别减少了17.65%、33.28%、55.50%( P<0.01), MDA水平分别降低了34.63%、54.13%、63.73％(P<0.01),SOD和GSH-px水平分别升高了67.78%,108.25%、154.49％和48.57%、110.28%、154.86%(P<0.01)。结论 玛咖提取物具有抵抗疲劳,增强运动能力的作用。其机制与降低血MDA水平,提高血SOD和GSH-px活性作用有关。     

Pharmacological and Pharmacokinetic Characteristics of YM435, a Novel Dopamine DA1-Receptor Agonist,in Anaesthetized Dogs

Time-course of plasma concentration of unchanged drug of the dopamine DA₁-receptor agonist (–)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs. Continuous intravenous infusion of YM435 (0.1–3 μg kg^? min^?) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P < 0.0001) and between the former and the reduction in blood pressure (r = 0.93, p < 0.0001). The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.     

YM872: a selective,potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist

This review focuses on the in vitro and in vivo neuropharmacology of YM872, a potential neuroprotective agent currently undergoing clinical trials in the United States (trial name: AMPA Receptor Antagonist Treatment in Ischemic Stroke - ARTIST). Its neuroprotective properties in rats and cats with induced focal cerebral ischemia are described. YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetic acid monohydrate, is a selective, potent and highly water-soluble competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. YM872 has a potent inhibitory effect on [(3)H]AMPA binding with a K(i) value of 0.096 microM. In contrast, YM872 has very low affinity for other ionotropic glutamate receptors. The solubility of YM872 is approximately 500 to 1000 times higher than that of the other competitive AMPA antagonists: YM90K, NBQX, or CNQX. The neuroprotective efficacy of YM872 was investigated in rats and cats subjected to permanent occlusion of the left middle cerebral artery. The animals were assessed either histologically or neurologically following ischemia. In rats with occluded middle cerebral artery (MCAO) YM872, by i.v. infusion, significantly reduced infarct volume measured at 24 h and 1 week after ischemia. Significant neuroprotection was maintained even when drug administration was delayed for up to 2 h after ischemia. In addition, YM872 significantly improved neurological deficit measured at 1 week after ischemia. In cats with MCAO YM872, by i.v. infusion, dose-dependently reduced infarct volume at 6 h after ischemia. YM872 produced no behavioral abnormalities and was not nephrotoxic. The evidence for the neuroprotective efficacy of YM872 suggests its therapeutic potential in the treatment of acute stroke in humans.     

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects

Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg^–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (V_ss) 673 l; volume corrected by real body weight (V_ss · kg^–1) 11.2 l ·  kg^–1; total clearance (CL) 51.6 h^–1; and terminal half-life (t_1/2) 10.3 h. The V_ss (898 l) and CL (71.6 l · h^–1) were significantly higher in obese patients. But V_ss · kg^–1 (9.4 l · kg^–1) and t_1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h^–1) and the t_1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant. Received: 22 December 1995 / Accepted in revised form: 5 June 1996     

Bronchodilator and anti-inflammatory activities of SCA40: Studies in human isolated bronchus, human eosinophils, and in the guinea-pig in vivo

There is currently interest in the use of inhibitors of cyclic nucleotide phosphodiesterases (PDE) as potential anti-asthma agents. In this study we examined the effects of SCA40 (6-bromo-8-methylaminoimidazol[1,2-a] pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 also endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of asthma. SCA40 (1 nM–0.1 mM) produced concentration-dependent inhibition of spontaneous and stimulated tone of human isolated bronchus and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (–log EC₅₀ values) of SCA40 against spontaneous tone (6.52 ± 0.10) was greater than against tone raised by equieffective concentrations (∼ 70%) of histamine (5.76 ± 0.06), leukotriene C₄ (5.44 ± 0.11), and acetylcholine (4.98 ± 0.09). In the presence of cytochalasin B, the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.5 μM) induced leukotriene C₄ production in human eosinophils isolated in discontinuous metrizamide gradients. The production of leukotriene C₄ was inhibited by SCA40 in a concentration-related fashion (–log IC₅₀ = 6.04 ± 0.20; n = 6). Rolipram, a selective PDE 4 inhibitor, was also effective (–log IC₅₀ = 7.29 ± 0.32) but the selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 10 μM). In ovalbumin sensitized guinea-pigs, SCA40 (1 mg kg^–1, i.p.) given 30 min before antigen challenge significantly inhibited the acute bronchoconstriction produced by aerosol antigen (5 mg ml^–1, 30 s) (antigen response was 185 ± 13 and 91 ± 21 cmH₂O l^–1 s^–1 in control and SCA40-treated animals, respectively, P < 0.05). Pretreatment with SCA40 (1 mg kg^–1, i.p., 30 min pre- and 3 h post-antigen exposure) prevented airway hyperreactivity to histamine which developed 24 h after exposure of conscious guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by SCA40 (from 6.15 ± 0.86 in control to 1.27 ± 0.27 in treated animals; expressed as eosinophils × 10⁶; P < 0.05). SCA40 (1 mg kg^–1, i.p.) also inhibited the microvascular leakage produced after inhaled antigen (5 mg ml^–1, 30 s) at all airway levels. The haemodynamic effects of SCA40 (1 mg kg^–1, i.p.) consisted of a rapid decrease (peak at 5 min) in mean arterial blood pressure (–39.4 ± 2.4%) and tracheal mucosal blood flow (–13.5 ± 2.0%) that slowly recovered with time. These data support previous work showing that PDE inhibition results in anti-spasmogenic and anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these effects are probably related to its activity as a mixed PDE inhibitor. Received: 13 March 1997 / Accepted: 28 July 1997     

促甲状腺素释放激素(TRH)类似物YM14673对大鼠脑损伤并发脑水肿的作用

用雄性Wistar大鼠,采用Feeney等的落体撞击法造成左顶颅脑挫伤。动物随机分组,给于TRH类似物YM14673(0.1 mg·kg^-1或1.0 mg.kg^-1,ip)或等体积生理盐水。治疗组可明显地减轻脑水肿。     

清脑胶囊对大鼠局灶性脑缺血神经功能的保护作用

目的研究清脑胶囊对大鼠局灶性脑缺血神经功能的保护作用。方法以线栓法阻塞大脑中动脉(Middle cerebral artery occlusion,MCAO)制作大鼠模型,分别于4h和24h进行神经功能评分,观察清脑胶囊对脑缺血造成的行为障碍的影响。结果清脑胶囊可减轻大鼠局灶性脑缺血和24h的行为障碍,与模型组比较有统计学意义(P<0.05)。结论清脑胶囊对大鼠局灶性脑缺血的神经功能有保护作用。     

Modification of the P-Glycoprotein Dependent Pharmacokinetics of Digoxin in Rats by Human Recombinant Interferon-α

Purpose This study was conducted to investigate in vivo the impact of interferon-alpha (IFN)-α on P-glycoprotein (P-gp) activity in rats by studying how its administration modifies the bioavailability of digoxin, a fairly pure P-gp substrate. Methods Human recombinant IFN-α was given to rats (n = 5–7 per group) daily for 8 days at different doses (IntronA^? 10⁶, 2.10⁶, or 4.10⁶ IU kg⁻¹, s.c.), whereas pegylated-IFN-α (ViraferonPeg^?, 29 μg kg⁻¹) was given s.c. three times a week. Rats were then given digoxin (32 μg kg⁻¹) i.v. or orally. The pharmacokinetics of digoxin was studied. Intestinal P-gp expression was also examined. Results The pharmacokinetics of i.v. administered digoxin was not modified by IFN-α, but a dose-dependent increase in areas under the curve (AUCs) was observed in the orally administered digoxin parameters in rats (AUCs: 392 ± 83 min μg L⁻¹, p < 0.01 and 550 ± 97 min μg L⁻¹, p < 0.001, respectively, vs. 286 ± 111 min μg L⁻¹ for control). A decrease in P-gp expression in the ileum (relative intensities: 0.70 ± 0.19 for 4 Million International Unit (MIU) kg⁻¹ IFN-α-treated animals vs. 1.00 ± 0.13 for controls, p < 0.05) and mainly in the jejunum (relative intensities: 0.46 ± 0.13 for 4 MIU kg⁻¹ IFN-α-treated animals vs. 1.00 ± 0.08 for controls, p < 0.001) was observed. Conclusion IFN-α induces in vivo a significant dose-dependent inhibitory effect on intestinal P-gp activity related to a local decrease in its expression, thereby predicting important clinical consequences when IFN-α and other P-gp substrates are associated.     

Stimulation of forward locomotion by SCH-23390 and raclopride in d-amphetamine-treated rats

In d-amphetamine-treated (4.0 mg kg^–1 s.c.) rats the selective dopamine D₁ and D_2/3 receptor antagonists SCH-23390 (2.5–20.0 μg kg^–1 s.c.) and raclopride (12.5–100.0 μg kg^–1 s.c.), respectively, produced a biphasic pattern of effects on forward locomotion, as observed in an open-field arena (≈0.5 m²). Thus, at the low doses of SCH-23390 (2.5–10.0 μg kg^–1) or raclopride (12.5–50.0 μg kg^–1), there was a statistically significant increase in forward locomotion, followed by suppression of the behavior at the higher doses. The SCH-23390-induced (5.0 μg kg^–1) stimulation of forward locomotion was partially antagonized by concomitant raclopride treatment (12.5–25.0 μg kg^–1) and the corresponding raclopride-induced (12.5 μg kg^–1) stimulation was fully antagonized by treatment with SCH-23390 (2.5–5.0 μg kg^–1). Furthermore, the SCH-23390- or raclopride-induced stimulation of forward locomotion was also antagonized by treatment with the α₁-adrenoceptor antagonist prazosin (1.0 mg kg^–1 s.c.). These observations suggest that under conditions of an increased general tone at brain dopamine receptors, there is a mutual inhibitory synergy between dopamine D₁ and D_2/3 receptors. Received: 21 July 1997 / Accepted: 6 March 1998     

5-HT<Subscript>6</Subscript> receptor antagonists improve performance in an attentional set shifting task in rats

Rationale and objective Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to ‘shift attention’ between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT₆ receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT₆ receptor antagonists upon attentional set shifting in rats. Methods Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg⁻¹ bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. Results Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05–0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05–0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01). Conclusion 5-HT₆ receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.     

Efficacy of activated charcoal versus gastric lavage half an hour after ingestion of moclobemide, temazepam, and verapamil

Objective: To compare the efficacy of activated charcoal and gastric lavage in preventing the absorption of moclobemide, temazepam, and verapamil 30 min after drug ingestion. Methods: In this randomized cross-over study with three phases, nine healthy volunteers received a single oral dose of 150 mg moclobemide, 10 mg temazepam, and 80 mg verapamil after an overnight fast. Thirty minutes later, they were assigned to one of the following treatments: 25 g activated charcoal as a suspension in 200 ml water, gastric lavage (10 × 200 ml), or 200 ml water (control). Plasma concentrations of moclobemide, temazepam, and verapamil were determined up to 24 h. Results: Activated charcoal reduced the area under the plasma concentration–time curve from 0 h to 24 h (AUC_0–24 h) of moclobemide and temazepam by 55% (P < 0.05) and by 45% (P < 0.05), respectively. The AUC_0–24 h of verapamil was not significantly reduced by charcoal. Gastric lavage decreased the AUC_0–24 h of moclobemide by 44% (P < 0.05), but had no significant effect on that of temazepam or verapamil. The peak plasma concentration (C_max) of moclobemide, temazepam, and verapamil was reduced by 40%, 29% (P < 0.05), and 16%, respectively, by activated charcoal. Gastric lavage did not significantly decrease the C_max of any of these drugs. Conclusion: The absorption of moclobemide, temazepam, and verapamil can be moderately reduced by activated charcoal given 30 min after drug ingestion, while gastric lavage seems to be less effective. Received: 15 December 1999 / Accepted in revised form: 16 March 2000     

Effect of pituitary adenylate cyclase activating polypeptide 1–27 on ocular, cerebral and skin blood flow in humans

The aim of the study was to assess the effects of a neuropeptide, pituitary adenylate cyclase activating polypeptide 1–27 (PACAP), on ocular, cerebral and skin blood flow in man. PACAP (0.01–10 pmol kg^–1 min^–1) was administered intravenously to eight healthy male subjects in a placebo-controlled, double-blind dose escalation trial. Fundus pulsation amplitude was measured by laser interferometry, mean blood flow velocity in the ophthalmic artery and the middle cerebral artery measured by Doppler sonography, and regional blood flow of the skin was estimated by laser Doppler flowmetry. Infusion of PACAP at the highest dose of 10 pmol kg^–1 min^–1 induced a significant increase in fundus pulsation amplitude (+83.4%), mean flow velocity in the ophthalmic artery (+91.9%) and regional skin blood flow (+260.3%, P<0.01, ANOVA; each parameter). In contrast, PACAP did not cause any change in middle cerebral artery blood flow velocity or systemic hemodynamics. Our findings indicate that the vasculatures of the eye and the skin are particularly sensitive to PACAP and may implicate a potential role for this peptide in the regulation of blood flow in these vascular beds. Received: 19 June 1998 / Accepted: 23 September 1998     

Cardiotoxicity of adrenochrome in isolated rabbit hearts assessed by epicardial NADH fluorescence

Noradrenaline in a micromolar concentration has recently been shown to contribute to ischemic tissue injury by direct cardiotoxic effects independent of functional alterations. Oxygen free radicals, generated during the auto-oxidation of catecholamines, are important mediators of catecholamine cardiotoxicity. However, the role of the oxidative products (aminochromes) is still unclear. We examined the effects of adrenochrome on functional parameters and on regional myocardial ischemia (MI) in isolated electrically-driven rabbit hearts with depleted catecholamine stores (reserpine 7.0 mg/kg i.p. 16 – 24 h before preparation, Langendorff, constant pressure: 70 cm H₂O, Tyrode solution, Ca⁺⁺ 1.8 mmol/l, 37°C). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH fluorescence photography. Adrenochrome-treatment (10^– 6 M or 10^– 4 M) was started after a reperfusion period of 20 min. The left ventricular pressure (LVP) was significantly enhanced by adrenochrome (p <0.05), but it fell thereafter to below its initial value in hearts treated with adrenochrome 10^– 4 M. The global coronary flow (CF) was not affected by adrenochrome 10^– 6 M (P >0.05), but it was significantly decreased by adrenochrome 10^– 4 M (P <0.05). The relative CF (= CF/LVP × heart-rate) was numerically decreased by adrenochrome 10^– 6 M (p >0.05) and more markedly by adrenochrome 10^– 4 M (p <0.05). Whereas epicardial NADH fluorescence was similar after repetitive coronary artery occlusions in controls and in hearts treated with adrenochrome 10^– 6 M (p >0.05), it was significantly enhanced by adrenochrome 10^– 4 M (p <0.05). In isolated rabbit hearts, adrenochrome possesses deleterious effects on MI only at a very high concentration but not in a micromolar concentration. Therefore, it seems that aminochromes may be less cardiotoxic than catecholamines. Received: 28 February 1994 / Accepted: 2 May 1994     

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg⁻¹ (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic–pharmacodynamic (PK–PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg⁻¹ compared with WKY rats. PK–PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E _max, −27.6 ± 3.9%; p < 0.05) compared with WKY group (E _max, −13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E _max, −45.5 ± 5.0%; p < 0.05) with regard to WKY group (E _max, −17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.