Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs

The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0-h occlusion followed by a 3.0-h reperfusion, KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P < 0.05), and reduced the reperfusion-induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin-I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR-33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle-treated group. In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.     

斑蝥素在比格犬体内的药代动力学和口服生物利用度研究

目的:测定斑蝥素单剂量静脉和口服给药后的比格犬体内的药-时曲线,并与斑蝥素静脉单剂量给药相比,计算其体内的药代动力学参数和生物利用度.方法:6只比格犬给药,血样盐酸酸化后,乙酸乙酯萃取,使用GC-MS方法测定血浆中的微量斑蝥素,用WinNonLin程序计算药代动力学参数和生物利用度.结果:比格犬静脉注射斑蝥素(34 μg·kg~(-1))的主要药代学参数:AUC(203.5±23.8)h·μg·L~(-1),CL(168.8±18.6)mL·h~(-1)·kg(-1).t_(1/2)(0.69±0.03)h;比格犬单剂量口服斑蝥素(102μg·kg~(-1))主要药代学参数是:AUC(160.4±26.9)h·μg·L~(-1),CL(649.1±97.7)mL·h~(-1)·kg~(-1),t_(1/2)(0.38±0.1)h.与静脉注射相比,生物利用度为26.7%.结论:比格犬口服斑蝥素后,斑蝥素在犬体内的吸收较少,提示要提高斑蝥素的口服生物利用度,提高临床用药有效性.     

THE ABSORPTION,PHARMACODYNAMICS, METABOLISM AND EXCRETION OF 14C-SUMATRIPTAN FOLLOWING INTRANASAL ADMINISTRATION TO THE BEAGLE DOG

The pharmacodynamics, pharmacokinetics, metabolism, and excretion of ¹⁴C-sumatriptan have been studied in the beagle dog following administration by the intranasal and other routes. The pharmacological response which was monitored, an increase in carotid arterial vascular resistance, correlated with the plasma levels of unchanged sumatriptan following intranasal, intravenous, or intraduodenal administration to the anaesthetised dog. The pharmacokinetics and metabolism of sumatriptan were then confirmed in conscious male and female dogs. Intranasal administration of ¹⁴C-sumatriptan resulted in rapid absorption of part of the dose. The overall bioavailability of sumatriptan was 40–50%. Sumatriptan was eliminated from plasma with a half-life of 1·5 or 1·9 h after intravenous or intranasal dosage respectively. Radioactivity was largely excreted in urine (up to 75% of the dose) with small amounts in the bile and faeces after intravenous and intranasal dosing, as sumatriptan and a major metabolite. The results from these studies suggest that intranasal administration provides a viable method for delivering sumatriptan to the systemic circulation. © 1997 John Wiley & Sons, Ltd.     

Inhibitory effects of YM175, a bisphosphonate, on the progression of experimental periodontitis in beagle dogs

This study examined the efficacy of YM175 [disodium dihydrogen (cycloheptylamino) methylene-1,1 -bisphosphonate] in reducing alveolar bone loss caused by experimental periodontitis in beagle dogs. Thirty-six dogs were used and divided into 6 groups. Periodontitis was induced in 30 dogs (groups 2–6) by ligating the bilateral mandibular third and fourth premolar teeth with silk ligatures and by feeding a soft diet. Six dogs were sham-operated (group 1). Saline (placebo), flurbiprofen (0.02mg/kg) and YM175 (0.01, 0.1 and 1.0 mg/kg) were administered to the dogs (groups 2–6) 5 d/wk for 25 wk. Radiographic and morphometric analyses were performed. In placebo-treated animals (group 2), the ligation caused a significant decrease in the alveolar bone height by 0.57 and 1.91 mm at 2 and 25 wk, respectively. YM175 (1.0 mg/kg) prevented the decrease in bone height by 47 and 31% at 2 and 25 wk. YM175 (0.1 mg/kg) and flurbiprofen tended to prevent bone loss after 15 wk. Although the ligation elicited no significant change in bone mineral density, it significantly decreased bone volume. YM175 (1.0 mg/kg) and flurbiprofen tended to increase the bone volume. The number of formative or resorptive Haversian canals and the bone turnover through the periosteal bone surface were increased by the ligation, indicating the increased turnover of the cortical bone. YM175 (1.0 mg/kg) reduced the increased bone turnover. The gingival index was maximally increased at 2 wk and was suppressed by YM175. These results suggest that YM175 prevents alveolar bone loss by reducing the increased alveolar bone turnover in dogs with periodontitis.     

Paucity of morphological changes in the brains of ageing beagle dogs: further evidence that alzheimer lesions are unique for primate central nervous system

Twelve regions of grey matter from the brains of 25 Beagle dogs, varying from one to over 16 years in age, were serially sectioned and sequentially scanned with a semi-automated sampling stage microscope, in a morphometric search for neuritic plaques, neurofibrillary tangles, and evidence of nerve cell loss. Examination of 227,776 light microscopic fields failed to reveal any senile plaques or neurofibrillary tangles. The neuronal densities, which ranged from 473 to 37,014 nucleolated neurons/mm³, showed no significant relationship with ageing. Neuronal lesions of Alzheimer type may be more typical of the human CNS; and physiological evidence for regionally reduced glucose metabolic rate in this animal model may require other structural alterations for its explanation.     

一种空间维持装置应用于上颌窦骨增量术的实验研究

目的 观察一种空间维持装置进行上颌窦骨增量术后新骨形成情况,并探究上颌窦黏膜穿孔对该技术的影响。方法 采用纯钛制作上颌窦黏膜提升空间维持装置,3只比格犬拔除上颌后牙构建上颌后牙缺失上颌窦区骨量不足的动物模型,自然愈合3个月后行双侧的上颌窦黏膜提升,随机选取一侧在黏膜完整情况下放入空间维持装置,对侧在黏膜穿孔情况下放入空间维持装置。3个月后处死实验动物,制取标本进行组织学分析。结果 空间维持装置内部可见新骨呈帽状凸起,与提升空间的形态相适应,但尚未充满整个提升的空间,窦底骨与新骨之间界限明显,新骨为未成熟的编织骨,疏松排列的骨小梁交错成网,骨小梁内可见软骨陷窝分布;无骨粉充填的上颌窦骨增量术在黏膜完整、穿孔后新骨面积分别为（8.17±5.63） mm2,（9.92±4.65） mm2,差异没有统计学意义。结论 单纯利用空间维持装置进行的上颌窦骨增量术可以诱导新骨形成,且较小的黏膜穿孔对其没有影响,具体新骨形成机制仍有待探索。     

LC－MS/MS法测定升麻葛根汤颗粒在犬体内的药代动力学研究

[目的]建立液相色谱-质谱联用(LC-MS/MS)的方法测定犬灌胃给药升麻葛根汤颗粒后葛根素、芍药苷、异阿魏酸的药代动力学。[方法]采用Waters ACQUITY UPLCBEH C18柱(2.1 mm×50 mm,1.7μm),流动相:0.05%甲酸水(A)-乙腈(B)梯度洗脱;流速:0.2 mL/min;柱温:25℃;进样量:5μL。以甲苯磺丁脲为内标,采用电喷雾离子源(ESI离子源),在负离子检测方式下进行多反应离子检测(MRM),检测离子对分别为m/z 415.2→294.9(葛根素)、m/z 525.0→449.0(芍药苷)、m/z 193.05→133.9(异阿魏酸)、m/z 269.09→169.9(甲苯磺丁脲,内标)。[结果]葛根素、芍药苷、异阿魏酸在10～4 000 ng/mL范围内线性关系良好。血浆中内源性物质不干扰测定,方法回收率、基质效应、精密度、准确度和稳定性均符合生物样品的测定要求。[结论]该方法准确度强,专属性好,灵敏度高,可用于检测葛根素、芍药苷、异阿魏酸的药代动力学。     

贯叶金丝桃中金丝桃苷在比格犬体内的药代动力学研究

目的:建立beagle犬血浆样品中金丝桃苷的HPLC含量测定方法,研究贯叶金丝桃提取物在beagle犬体内的药代动力学。方法:采用Dikma C18(2)色谱柱(4.6 mm×250 mm,5μm),乙腈-0.1%磷酸(42∶58)为流动相,检测波长360 nm,流速1.0 mL.min-1,以普拉洛芬为内标,建立含量测定方法。选用6只健康beagle犬作为试验动物,口服贯叶金丝桃提取物胶囊后,分别于给药前和给药后0.5,1,2,3,4,5,6,8,12,24 h取血,通过HPLC测定金丝桃苷的含量,并采用Kinetica 4.4软件进行非房室模型拟合,计算药代动力学参数。结果:金丝桃苷线性范围为0.5～100 mg.L-1,日间、日内精密度<5.9%,在冷冻放置、冻融以及室温放置的条件下准确度均在91.23%～100.32%,回收率为89.95%～95.32%。金丝桃苷的主要药代动力学参数为Tmax=(2.17±0.41)h,Cmax=(13.88±1.26)mg.L-1,AUC0-24=(68.52±12.96)μg.h-1.mL-1,AUC0-∞=(96.69±30.94)μg.h-1.mL-1,MRT=(8.28±3.79)h。结论:建立了金丝桃苷beagle犬血药浓度的HPLC测定方法,操作方便,结果准确,可用于金丝桃苷的药代动力学研究。     

Bone reactions adjacent to titanium implants subjected to static load of different duration. A study in the dog (III)

The aim of the present experiment was to study the effect of a long-standing lateral static load on the peri-implant bone. Three beagle dogs were used. The mandibular premolars were extracted and 12 weeks later 3 titanium implants (ITI(R) Dental Implant System) were installed in each quadrant. Crowns were fitted to all implants 12 weeks after the installation procedure. The anterior and central crowns were fused and connected to the posterior crown by an expansion screw. In the right side of the mandible, the expansion screws were activated every 2 weeks during a 46-week period. During the last 10 weeks of this period, an expansion force similar to that of the right side was applied in the left. The animals were sacrificed and block biopsies of each implant site harvested and prepared for histological analysis. Sites subjected to 10 weeks or 46 weeks of lateral load had a similar (i) distribution of bone markers (ii) proportion of bone density and (iii) degree of bone-to-implant contact. The proportion of fluorochromes was higher at sites subjected to 10 weeks of loading than at sites subjected to 46 weeks of loading.