Bioavailability of metronidazole from sugar-coated tablets in humans. II. Evaluation of beagle dogs as an animal model

The bioavailability of metronidazole from five sugar-coated tablets exhibiting different dissolution behaviors relative to pH was determined in beagle dogs, and compared with that in humans administered the same preparations. The gastric pH of beagle dogs, which was determined after collecting the gastric fluid through a catheter inserted into the stomach, ranged in pH from 1.8 to 7.8. From statistical analysis of C_max and AUC_0–24, it was concluded that gastric acidity definitely affects the bioavailability of metronidazole from sugar-coated tablets. The relative values of C_max and AUC_0–24, compared with those of the tablet exhibiting the highest values, ranked similarly between corresponding gastric acidity groups of beagle dogs and humans. A significant correlation was shown between AUC_0–24 for beagle dogs and humans having low gastric acidity (P < 0.05). These results suggest the possibility that beagle dogs may be used as an animal model for testing the bioavailability of a drug preparation showing gastric acidity-dependent bioavailability in humans.     

New born chicks can serve as an experimental animal model for human campylobacteriosis

Campylobacter enteritis is an emerging food borne zoonotic disease. Improperly cooked chicken serve as a potential source for this infection. Diarrheogenic potential of Campylobacter jejuni is tested either by in-vivo rat ileal loop (RIL) test or by molecular methods. This study reveals that 3-day-old chicks can serve as an animal model for toxigenic C. jejuni.     

Mice with liver composed of human hepatocytes as an animal model for drug testing

Conventionally, rodents, mostly mice and rats, have been utilized as animal models for studying drug metabolism and toxicity of new medicines. However, there have been two major problems inherent to these models. One is that there are species differences in major enzymes responsible for drug metabolisms and detoxification such as cytochrome P450 between rodents and humans, and the other is that human hepatitis viruses do not infect rodent livers, which hampers studies for anti-hepatitis virus drugs using these models. As an approach to overcome these intrinsic shortages, we devised a method to generate mice whose livers are mostly ( > 80%) repopulated with healthy human hepatocytes 7 years ago. Since then, these mice called simply chimeric mice or liver-humanized mice have been widely utilized among researchers in the areas for new drug developments, which, as a result, have proved that the chimeric mouse is a practical solution to solve the above two issues. The hitherto accumulated studies demonstrating the similarities of the chimeric mouse liver to the human crude liver are summarized and reviewed in the present article. In addition, there have been also studies that show us the presence of dissimilarities between them, such as human hepatocytes' manifestation of hyperplasia in mouse liver and their steatotic alterations when the mice are maintained for > 50 days post-transplantation. These dissimilarities between them are also reviewed in details, considering that the information of the similarities and the dissimilarities is quite useful to researchers who utilize chimeric mice as a drug discovery tool for correctly evaluating the obtained results.     

Evaluation of reward processes in an animal model of depression

Rationale Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.     

The guinea pig as an animal model for asthma

Experimental guinea pig asthma is a reliable and clinically relevant facsimile of human disease. The guinea pig is the preferred choice for use as a model of allergic bronchial asthma in the evaluation of anti-asthmatic drugs, since the airway anatomy and the response to inflammatory mediators is similar to humans. Further, the great strength of this model is the direct anaphylactic bronchoconstriction upon antigen challenge. Under certain conditions a late asthmatic response can be measured and airway hyperresponsiveness is observed in vitro and in vivo. Moreover, the inflammatory response is comparable with the human situation. More recent studies describe a chronic model for asthma in which airway remodeling is induced as can be observed in the asthmatic patients. The focus here is to demonstrate that guinea pig asthma models are useful for testing novel therapeutics.     

动态脑电图对癔病与哭笑型癫痫发作的评估作用

目的探讨脑电图在辨别癔病与哭笑型癫痫发作的应用价值。方法对32例诊断为癔病的患者行24～72h的动态脑电图检查，并分析癔病发作时和发作前、后的脑电图表现。结果32例诊断为癔病患者的动态脑电图正常27例，非特异性异常3例，出现癫痫样放电2例。结论部分癔病和哭笑型癫痫发作有关，如有条件，应对癔病患者行动态脑电图检查。     

Evaluation of hypoglycemic effect of Morus alba in an animal model

Objective:

The objective of the present investigation was to evaluate the therapeutic efficacy of mulberry leaves in an animal model of diabetes.

Materials and Methods:

Animals were treated with mulberry leaf extract 400 mg and 600 mg/kg body weight for 35 days. Blood glucose, glycosylated hemoglobin, triglyceride, LDL, VLDL, HDL, blood urea, cholesterol, number of β cells, and diameter of the islets of Langerhans were measured at the beginning and at the end of the experiment.

Results:

Blood glucose level and other parameters (except HDL) were elevated in the diabetic group, but were brought to control group level in the diabetic group treated with 600 mg/kg body weight of mulberry leaf extract. The diameter of the islets and the number of β cells were reduced in the diabetic group; both parameters were brought to control group level after treatment with mulberry leaf extract.

Conclusion:

Mulberry leaf extract, at a dose of 600 mg/kg body weight, has therapeutic effects in diabetes-induced Wistar rats and can restore the diminished β cell numbers.     

Evaluation of antipsychotic and relative drugs using disruption of prepulse inhibition as an animal model for schizophrenia

The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. The PPI, a model of sensorimotor gating, is deficient in patients with schizophrenia and some other psychiatric disorders. In rodents, PPI can be disrupted by methamphetamine or phencyclidine, which causes psychotomimetic symptoms, and the dopaminergic agonist-induced PPI is reversed by dopamine D2 receptor antagonists and a dopaminergic partial agonist aripiprazole. However, in general, the glutamate receptor antagonist-induced PPI is reversed by atypical antipsychotics such as clozapine, but not by typical antipsychotics such as haloperidol. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics. Recently, various inbred mouse strains and genetically modified mouse lines have been examined and the studies using PPI indicated the involvement of various neurotransmitters such as dopamine, glutamate, serotonin, GABA and neuropeptide in the biological basis of sensorimotor gating. In addtition, mood stabilizers such as valproate and lamotrigine or alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption.     

Evaluation of Supermix as an in vitro model of human liver microsomal drug metabolism

SUPERMIX is a commercially available formulation of insect cell-expressed human drug-metabolizing cytochrome P450 (CYP) isoforms, mixed in proportions that are optimized to parallel their relative activities in human liver microsomes. We have evaluated the apparent functional affinity and capacity of individual CYP isoforms in SUPERMIX in comparison with microsomes from a panel of 12 human livers, using enzyme kinetic studies of isoform-selective index reactions. In addition, we have measured the concentration of NADPH cytochrome P450 oxidoreductase (OR) in SUPERMIX and compared it with the concentrations of this accessory electron transfer protein in human liver microsomes. No important differences were evident in the catalytic activities of CYPs 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 between SUPERMIX and human liver microsomes. However, SUPERMIX lacks CYP2B6 activity and did not hydroxylate the antidepressant bupropion, a clinically relevant substrate of this enzyme. In addition, the concentration of OR in SUPERMIX (1198 pmol mg protein(-1)) is 17-fold higher than the mean value in human liver microsomes (70 pmol mg protein(-1)). In conclusion, SUPERMIX lacks CYP2B6 activity and contains supraphysiological concentrations of the accessory electron transfer protein OR. These factors should be considered when this formulation is used as an in vitro model in human liver microsomal drug metabolism studies.     

Development and applications of an animal model for human tumor xenografts

Wistar rats treated with cyclophosphamide (4x 10 mg/kg), total lymphoid irradiation (9.0 Gy; dose rate 0.60 Gy/min) and cyclosporin A (15 mg/kg, daily, orally) developed a state of immune suppression permitting the growth of human tumor xenografts. Immunosuppression was monitored by lymphocyte counts, serum IgG determination. PHA and Con A lymphocyte-responses, proportion of B cells and histopathological studies of the lymphoid organs. The lymphocyte counts, IgG levels, PHA and Con A stimulation values remained severely depressed, during the period of cyclosporin A administration. Repopulation of the paracortical areas of the lymph nodes and the peri-arteriolar sheaths of the spleen did not occur, neither the reconstruction of the germinal centers in these organs. The thymus underwent severe atrophy. Seven of eight different types of human tumors were successfully xenografted in the immunomodified rat. The xenografted tumors maintained their original morphologic features and the mitotic rate did not change during subsequent transplantations.     

The beagle dog as an animal model for marihuana smoking studies

Dogs were trained to smoke marihuana cigarettes in a manner similar to that in man. By measuring the radioactivity in plasma and excreta it was estimated that the daily [³H]tetrahydrocannabinol dose retained by dogs that smoked 13 marihuana cigarettes was about 2 mg/kg of body weight. Respiration and heart rate were both decreased by marihuana, but tolerance developed to the effect on heart rate. After about six marihuana cigarettes were smoked the dogs developed muscular weakness and losses of reflexes that were dose dependent throughout the study. There were no changes in blood cell counts or blood chemistry after a year of smoking. At necropsy there were no significant changes in peripheral blood or bone marrow chromosomes, nor were there changes in any organs studied indicating damage from smoking a high dose of marihuana for a year. The sleeping time of dogs that smoked marihuana and were then injected with sodium pentobarbital increased in proportion to the number of cigarettes smoked. The study indicates that the sensitivity of this species to injected canabinoids does not preclude their usefulness for studying the effects of marihuana administered by smoking.     

A re-evaluation of social defeat as an animal model of depression.

Social defeat by aggressive Tryon Maze Dull (TMD) rats, resulting in loss of rank of a previously dominant rat, has recently been advanced as a model of loss of self-esteem in humans. Since low self-esteem is a major symptom of depression, a further claim has been made that loss of rank can be used as a model of depression. In support of this claim, it has been suggested that loss of rank can be reversed by the antidepressant imipramine. However, antidepressant treatment has not yet been shown to reverse the effects of defeat for more than a single test session. Consequently, the present study was designed to more fully assess the effects of antidepressant treatment on the behaviour of defeated animals. Six pairs of male Lister Hooded (LH) rats were observed biweekly for 30 min at the onset of the dark phase of the light-dark cycle. In five of the six pairs, a stable social hierarchy (assessed by the observation of aggressive behaviours such as attacks and pushes, and submissive behaviours such as submissive posture) was established over a period of 10 weeks. The dominant animals of these five pairs were defeated once a week, in the home cage, by a singly housed male TMD for a period of 15 min. After 5 weeks of defeat by TMD, all five of the dominant animals showed an effect of defeat on behaviours relevant to status, although a reversal in status within the LH pairs was apparent in only one case. All defeated animals, regardless of whether or not defeat affected status, received daily injections of imipramine (5 mg/kg) for 5 weeks. Imipramine markedly worsened behaviours relevant to status in the treated animals. Indeed, animals treated with imipramine were more likely to lose encounters with their cage-mates. Consequently, the results cast doubt on the validity of social defeat as a model of depression, at least when the effects of defeat are assessed in terms of social status.     

Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer's type

Alzheimer's disease (AD) is the most common type of dementia disorder of elderly affecting millions of people. The pathophysiology of the disease is complex and involves multiple pathways of neuronal damage. Sporadic dementia of Alzheimer's type (SDAT) has been shown to be associated with microtubular dysfunction and is characterized by the appearance of specific cytoskeletal cellular abnormalities, including neurofibrillary tangles and senile plaques. Intracerebroventricular (i.c.v) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction as evidenced by poor retention of memory in both Morris water maze and elevated plus-maze task paradigms that is associated with excessive free radical generation. Biochemical analysis revealed that icv colchicine injection significantly induced lipid peroxidation, increased nitrite and depleted reduced glutathione (GSH) and acetylcholinesterase (AChE) level in rat brains. Chronic treatment with rivastigmine (0.625 and 2.5 mg/kg, po) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment and reduced AChE level. The results of the present study clearly indicated that colchicines-induced cognitive impairment and oxidative stress in animals and can be used as an animal model for drug screening for Alzheimer's disease.     

Non-specificity of "behavioral despair" as an animal model of depression

When mice are forced to swim in a restricted space, they will cease attempts to escape and adopt a characteristic immobile posture which can be readily identified and timed. Imipramine decreased the duration of immobility in a 4 min swimming test in a dose-related manner. Likewise, caffeine, triiodothyronine and pentobarbital reduced immobility. These latter findings shed doubt upon the specificity of the behavioral despair swimming test to identify substances with antidepressant activity.     

Elevated T-maze as an animal model of memory: effects of scopolamine

The elevated T-maze (ETM) is a putative model for the assessment of anxiety and memory in rodents. This study was designed to further evaluate the utility of the ETM in the study of memory processes. We compared the performance of rats in the ETM, the water maze (WM) and the two-way avoidance task (TWA), after pretreatment with scopolamine (SCO; 0.3 or 1.2 mg/kg i.p.). In the ETM, rats were first trained to meet the criterion of remaining inside the enclosed arm for 300 seconds. Seventy-two hours after training, a retrieval test session was performed. At the lower dose, SCO impaired performance in the retrieval session on all three tasks, whereas in the training session an effect was noted only on the WM task. At the higher dose, SCO impaired the performance of rats in the training sessions for ETM and WM, but not TWA. In a fourth experiment using the elevated plus-maze, SCO showed anxiolytic-like effects at the higher dose only. In conclusion, the effects of SCO in rats submitted to the ETM were dose dependent, with the lower dose exerting a selective effect detected only on retrieval, whereas the higher dose induced motor effects that disrupted inhibitory avoidance acquisition, resulting in impaired retrieval. The results are discussed in terms of the utility of the ETM in the study of drug effects and the neurobiological mechanisms underlying anxiety, learning and memory.