Acetylation pharmacogenetics: experimental models for human toxicity

Hereditary acetylation polymorphisms well-suited to experimental pharmacogenetic investigation are now known in three laboratory animal species (rabbit, mouse, and hamster). These animal models provide new evidence for the profound influence of this trait on the metabolic fate of arylamines and hydrazines, and on their pharmacological and toxicological profiles. The rabbit polymorphism most closely resembles that in humans. For the rabbit model, studies have shown that 1) monoacetylhydrazine is a polymorphic substrate for liver N-acetyltransferase in rapid and slow acetylators. This observation, in conjunction with human epidemiological data of others, opposes the commonly held view that rapid acetylators are predisposed to isoniazid (INH)-induced hepatotoxicity. 2) Slow acetylators are much more sensitive than rapid acetylators to the lethal central nervous system toxicity of INH. 3) In hepatocytes in short-term culture and exposed to arylamines and hydrazines, DNA damage is produced by hydralazine in slow acetylator hepatocytes but not in rapid acetylator hepatocytes, whereas hepatocytes from rapid acetylators are more sensitive to toxicity and DNA damage from 2-aminofluorene and benzidine. These investigations in animal models of the acetylation polymorphism provide new insights into human toxicity resulting from environmental arylamines and hydrazines.     

Comparative evaluation of Bacopa monniera and Panax quniquefolium in experimental anxiety and depressive models in mice

The present study was undertaken to compare medicinal plants against mixed anxiety-depressive disorder (MAD) to evaluate their potency in combating MAD disorders. Previous studies from our lab have shown that Bacopa monniera (BM), and Panax quniquefolium (PQ) have significant adaptogenic properties. Hence, we have further confirmed their activity in stress related disorders like anxiety and depression in animal model, rodents and assessed their efficacy. In our experimental protocol, gross behaviour was observed through Digiscan animal activity monitor. Anxiety was studied through light dark test, elevated plus maze test and holeboard test. Depression experiments were conducted following tail suspension test and forced swim test. Further, rotarod test was also used to study any defects in motor in-coordination in mice. It was observed that BM at the dose of 80 mg/kg (po) and PQ at 100 mg/kg (po) were effective as an anti-anxiety as well anti-depressant activity and had no motor in-coordination in mice. Hence, these extracts can be used as a potent therapeutic agent in treating mixed anxiety-depressive disorder (MAD).     

Neuropeptides in spinal cord injury: Comparative experimental models

The possible role of endogenous opioids in the pathophysiology of spinal cord injury was evaluated utilizing a variety of experimental models and species. In the cat, we have shown that β-endorphin-like immunoreactivity was increased in plasma following traumatic spinal injury; such injury was associated with a decrease in spinal cord blood flow (SCBF) which was reversed by the opiate receptor antagonist naloxone. Naloxone treatment also significantly improved functional neurological recovery after severe injury. Thyrotropin-releasing hormone (TRH), possibly through its “anti-endorphin” actions, was even more effective than naloxone in improving functional recovery in the cat. In a rat model, utilizing a similar trauma method, TRH proved superior to naloxone in improving SCBF after injury. In addition, naloxone at high doses attenuated the hindlimb paralysis produced by temporary aortic occlusion in the rabbit. The high doses of naloxone required to improve neurological function after spinal injury suggest that naloxone's actions, if opiate receptor mediated, may be mediated by non-μ receptors. Dynorphin, an endogenous opioid with a high affinity for the κ receptor, produced hindlimb paralysis following intrathecal administration in rats. Taken together, these findings suggest that endogenous opioids, possibly acting at κ receptors in the spinal cord, may serve as pathophysiological factors in spinal cord injury.     

Estimation of possible use of interferon inductors for prevention of postvaccional reactions to TEOVac in animal models

The experiments on guinea pigs showed that arbidol administered orally in a single dose 24 hours prior vaccination with TEOVAC and ridostin administered in a single dose intranasally on the 4th day after the vaccination lowered the vaccine virus accumulation in the animal organs and tissue without any effect on the vaccine immunogeneity. The results are someway indicative of the possible use of the interferon inductors for prevention of postvaccinal reactions to TEOVAC.     

Comparative systemic analysis of experimental models of chemical hepatic carcinogenesis in the rat

The aim of this work is to compare several experimental protocols inducing hepatocarcinogenesis in the rat. The results show that the experimental protocols using an initiator and a promotor are not equivalent (in term of latency period and premalignant lesions) to experimental protocols using a chronic administration of one carcinogenic compound.     

Comparative evaluation of 99mTc-labeled aminothiols as possible brain perfusion imaging agents

Several new ^99mTc aminodithiols were prepared and evaluated comparatively in experimental animals. The ligands were diamine, triamine or tetramine dithiols. Substituents were either attached on one of the nitrogens or introduced in between the two nitrogens of diamino dithiol (DADT) backbone. ^99mTc-derivatives prepared by coupling DADT to secondary amines via ethylene group showed in mice high initial brain uptake and significant retention in brain tissue. These preparations were mixtures of more than one ^99mTc-complex differing in brain uptake and clearance from the brain. The highest brain retention (brain to blood ratio 2.53, 15 min p.i.) was achieved with the ^99mTc-complex prepared by coupling DADT with ethylene pyrrolidine. Lengthening the chain between the nitrogens of DADT moiety by introducing methyl or amino alkyl groups resulted in ^99mTc-complexes with poor brain accumulation.     

Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models

There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60 years ago. Despite years of effort, there has been relatively little progress towards identifying orally available chemotypes active against the parasite in vivo. Here, we report the lead optimization of a purine-nitrile scaffold that inhibits the essential TbcatB protease and its evaluation in murine models. A lead inhibitor that had potent activity against the trypanosomal protease TbcatB in vitro and cultured parasites ex vivo was optimized by rationally driven medicinal chemistry to an inhibitor that is orally available, penetrates the CNS, has a promising pharmacokinetic profile, and is non-toxic at 200mg/kg in a repeat dosage study. Efficacy models using oral administration of this lead inhibitor showed a significantly increased survival time in Trypanosoma brucei brucei infected mice but little effect on Trypanosoma brucei rhodesiense infected mice.     

Molecular alterations of canalicular transport systems in experimental models of cholestasis: possible functional correlations.

The discovery of unidirectional, ATP-dependent canalicular transport systems (also termed "export pumps") for bile salts, amphiphilic anionic conjugates, lipophilic cations, and phospholipids has opened new opportunities for understanding biliary physiology and the pathophysiology of cholestasis. In addition, ATP-independent canalicular transport systems for glutathione and bicarbonate contribute to (bile acid-independent) bile formation. Canalicular excretion of bile salts and several non-bile acid organic anions is impaired in various experimental models of cholestasis. Recent cloning of several canalicular transport systems now facilitates studies on their molecular regulation in cholestasis. Although the picture is far from complete, experimental evidence now exists that decreased or even absent expression of canalicular transport proteins may explain impaired transport function resulting in hyperbilirubinemia and cholestasis. With the increasing availability of molecular probes for these transport systems in humans, new information on the molecular regulation of canalicular transport proteins in human cholestatic liver diseases is beginning to emerge and should bring new insights into their pathophysiology and treatment. This article gives an overview on molecular alterations of canalicular transport systems in experimental models of cholestasis and discusses the potential implications of these changes for the pathophysiology of cholestasis.     

Study of possible influence of mixed lymphocyte reaction on experimental models used in biological dosimetry]

The study aimed to investigate whether "mixed lymphocyte reactions" could interfere with the results of experiments in which irradiated blood from one person is mixed with non-irradiated blood from another. This experimental model had been designed to simulate, in vitro, non-homogeneous in vivo exposure such as could occur after accidents with ionizing radiation. The results show that the experimental models gives valid results for donors with related blood characteristics.     

Development and validation of experimental protocols for use of cardinal models for prediction of microorganism growth in food products

An experimental protocol to validate secondary-model application to foods was suggested. Escherichia coli, Listeria monocytogenes, Bacillus cereus, Clostridium perfringens, and Salmonella were observed in various food categories, such as meat, dairy, egg, or seafood products. The secondary model validated in this study was based on the gamma concept, in which the environmental factors temperature, pH, and water activity (aw) were introduced as individual terms with microbe-dependent parameters, and the effect of foodstuffs on the growth rates of these species was described with a food- and microbe-dependent parameter. This food-oriented approach was carried out by challenge testing, generally at 15 and 10 degrees C for L. monocytogenes, E. coli, B. cereus, and Salmonella and at 25 and 20 degrees C for C. perfringens. About 222 kinetics in foods were generated. The results were compared to simulations generated by existing software, such as PMP. The bias factor was also calculated. The methodology to obtain a food-dependent parameter (fitting step) and therefore to compare results given by models with new independent data (validation step) is discussed in regard to its food safety application. The proposed methods were used within the French national program of predictive microbiology, Sym'Previus, to include challenge test results in the database and to obtain predictive models designed for microbial growth in food products.     

The use of techniques of sensory evaluation as a framework for teaching experimental methods

Several simple techniques of sensory assessment are described and the conditions for their satisfactory performance stated. The manner in which these experiments can be used to provide open-ended practical exercises for classes is discussed and its advantages as a relatively cheap and simple method of teaching experimentation is described. Experiments are described in which the diffusion of salt into potatoes after cooking them in boiling salted water is investigated using several techniques of sensory assessment, and other suitable areas ofinvestigation are suggested     

The possible role of enantiodiscrimination in bilirubin toxicity

The possibility that enantiodiscrimination of bilirubin might be involved in neuronal membrane destabilization, and therefore in bilirubin toxicity, was investigated, by circular dichroism, on model membranes composed of phospholipids. The equilibrium between bilirubin enantiomers is displaced at some extent by the interaction with certain phospholipids. The extent of equilibrium displacement depends on the molecular structure of phospholipids and on the state of charge of bilirubin. The results obtained validate the hypothesis of a possible involvement of chirality in bilirubin toxicity and support a previously suggested model for the molecular mechanism of the interaction of bilirubin with the synaptic membrane.     

Histopathological investigation of experimental ocular toxocariasis in gerbils

Male gerbils were inoculated intragastrically with embryonated Toxocara canis eggs. They were euthanised, and their eyes were excised at different days p.i. to identify the number of larvae as well as lesions resulting in these organs. In most animals, larvae were detected from day 5 to day 60 p.i. (end of the study). From days 10 to 20 p.i., larvae and haemorrhage were observed in the choroid and in the ciliary process. At days 30 and 40 p.i., some eyes had larvae surrounded by an infiltrate of neutrophils, oedema, haemorrhages and tissue damage in the retina or the ciliary process. On day 60 p.i., there were granulomatous lesions in the retina. This study provides a model for the study of ocular toxocariasis.     

光系统II实际光化学量子效率对光的响应模型的比较

为了比较光系统II实际光化学量子效率(Φ_PSII)对光的响应机理模型(简称机理模型)、负指数模型和指数模型的优缺点, 用LI-6400-40B光合作用测定仪控制CO₂浓度和温度, 测量了剑叶金鸡菊(Coreopsis lanceolata)、黄荆(Vitex negundo)和大狼杷草(Bidens frondosa)的电子传递速率(ETR)对光的响应曲线(ETR-I)和Φ_PSII对光的响应曲线(Φ_PSII-I), 然后用这3个模型分别拟合了这些数据。拟合结果表明: 3个模型都可以较好地拟合这3种植物的ETR-I的响应数据和Φ_PSII-I的响应数据, 但由指数模型拟合ETR-I和Φ_PSII-I的响应数据得到相应的饱和光强(PAR_sat)和光系统II最大光能利用效率(F_v/F_m)之间存在显著差异, 且估算的饱和光强远低于实测值。由机理模型可知, Φ_PSII不仅与光强的函数有关, 还与植物的内禀特性有关, 即与天线色素分子的本征光能吸收截面、激子的传递效率、能级的简并度、光化学反应常数、热耗散常数和处于最低激发态的平均寿命等参数有关。此外, 由机理模型还可知, Φ_PSII随光强的增加而下降的原因是捕光色素分子的有效光能吸收截面随光强增加而降低。     

Comparative evaluation of the toxicity of aqueous extracts of the ashes of brown coals

The toxicity of industrial waste--the ashes of brown coals in connection with the possibility of their utilization in agriculture has been studied. It has been proved that ash water extracts which give low pH values are practically nontoxic for test objects. Ash extracts rich in calcium and magnesium oxides provide high pH values and has a negative effect on hydrobionts. The neutralization removes the acute toxic effect.