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PubMed1991

Cyclosporine nephrotoxicity--experimental models.

Cyclosporine A (CsA) represents one of the more important therapeutic advances in the field of kidney transplantation. However, its effectiveness is limited by serious side effects, most notably nephrotoxicity. Investigation of the mechanisms of CsA-induced renal dysfunction has been hampered by the lack of a suitable experimental model. The majority of studies using the rodent have failed to exhibit all of the structural changes seen in chronic CsA-induced nephrotoxicity reported in man, using pharmacologic doses administered orally, subcutaneously, or intravenously. More recently, studies using the rabbit as an experimental model have demonstrated leucocyte infiltration, tubular atrophy, interstitial fibrosis, and arteriolopathy after therapeutic doses of CsA over 30 days. These changes are similar to those seen in chronic CsA-induced nephrotoxicity in man.

Animals↗

PubMed1980

Experimental models for study of common respiratory viruses.

Numerous epidemiological studies have shown that there is excess respiratory disease morbidity in areas of high atmospheric pollution, implying an interactive effect on the clinical illness associated with these common infections. The principal etiologic agents of human respiratory infections are respiratory syncytial virus (RSV), influenza viruses (IV), parainfluenza virus types 1 and 3 (P1, P3), adenoviruses (AD), rhinoviruses (RV) and Mycoplasma pneumoniae (Mpn). Understanding the pathogenesis of the excess morbidity related to pollutants would facilitate detection of undesirable human health effects and provide a basis for intervention strategies. Through use of experimental model systems the mechanism of toxic effects could be defined (whether microbiological, immunological, pathological or physiological) to provide direction for appropriate studies in the human host. Small animal models of IV and Mpn infections have been available for many years; recently, experimental models of several more common viral diseases have been developed. A parallel to human RSV infections is provided by the ferret: virus replicates in the lungs of infant animals, but only in the noses of adults. The common cotton rat infected with RSV develops small airways lesions which may mimic the pathophysiologic changes of bronchiolitis. Both guinea pigs and Syrian hamsters are susceptible to human P3 virus, developing peribronchiolar and interstitial lesions. Practical small animal models for human AD and RV infections are not available because of the high host-specificity of these agents. Both the RSV and P3 model infections are nonlethal which enables study for long-term sequelae. Recent reports of pulmonary function abnormalities among children suffering bronchiolitis in infancy underscores the importance of defining toxic influences which could play a role by making the initial infections more severe.

Adenoviridae Infections↗

PubMed1996

Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats.

BACKGROUND & AIMS: Keratinocyte growth factor (KGF) is known to enhance tissue repair in the skin; however, its role in the gastrointestinal tract is largely unknown. The aim of this study was to evaluate the effects of exogenous KGF in an experimental model of colitis in rats. METHODS: KGF was administered before or after induction of colitis with 2,4,6-trinitrobenzenesulfonic acid/ethanol. In the first two study groups, KGF (5 mg/kg) was administered intraperitoneally 24 hours and 1 hour before induction of colitis; animals were killed 8 hours (n=10) and 1 week (n=10) after injury. In subsequent study groups, KGF or vehicle treatment was begun 24 hours after the induction of colitis at doses of 5 (n=20), 1 (n=10), and 0.1 (n=10) mg/kg intraperitoneally and continued once daily for 1 week. Colonic tissue samples were evaluated macroscopically and microscopically for mucosal injury and assayed for myeloperoxidase activity. RESULTS: Administration of KGF after but not before induction of colitis significantly ameliorated tissue damage. Macroscopic necrosis and microscopic ulcerations were reduced by 40%-50% at KGF doses of 1 and 5 mg/kg. CONCLUSIONS: Exogenous KGF has a key role in mucosal healing in an experimental model of colitis in rats.

Animals↗

PubMed1987

Rem sleep deprivation in an experimental model of Parkinson's disease.

Previous investigations have shown that REM sleep deprived (REM SD) rats display an enhanced response to dopamine agonists. This action seems to be mediated through a supersensitivity of dopamine post-synaptic receptors. Accordingly, REM SD was performed on rats with an experimental model of Parkinson's disease. The animals were bilaterally lesioned in the nigrostriatal pathway through a stereotaxically directed electrical current. Seven days after the surgery the animals were REM SD for 72 hours and immediately after the end of this period were observed in an open field for ambulation, rearing, grooming, and latency. In comparison with non-deprived rats there was a significant increase in ambulation and rearing, a response that appeared again after a second REM SD period on day 21th after the surgery. These data of improvement of two parameters of an experimental model of Parkinson's disease suggest that SD may be useful in this condition.

Animals↗

PubMed1992

Effects of L-156,602, a C5a receptor antagonist, on mouse experimental models of inflammation.

L-156,602, a C5a receptor antagonist, was found as an immunosuppressant with preferential effects on delayed-type hypersensitivity (DTH) in our screening program and it was shown that L-156,602 suppressed the efferent phase of DTH. Here, we tested its effects on experimental models of inflammation induced in mice. L-156,602 did not suppress serotonin- and carrageenan- induced inflammation while it completely suppressed concanavalin A-induced inflammation 4 h after elicitation. The inflammation appeared 24 h after the elicitation with concanavalin A and it was significantly suppressed by L-156,602. Muramyl dipeptide (MDP)-induced acute joint inflammation was also significantly suppressed by L-156,602. These results demonstrated the unique immunomodulating properties of L-156,602 in mouse experimental models of inflammation.

Animals↗

PubMed1989

Experimental models of brain injury.

General categories of experimental brain injury models are reviewed regarding their clinical significance, and two new models are presented that use different methodology to produce injury. This report describes and characterizes the pathophysiologic changes produced by a novel fluid percussion (FP) method and a controlled cortical impact (CI) technique, both developed at the General Motors Research Laboratories (GMRL). The new models are compared to prior experimental brain injury techniques in relation to ongoing physical and analytical modeling used in automotive safety research by GMRL. Experimental results from our laboratory indicate that although the FP technique, currently the most widely used method for producing brain injury, is useful for producing graded injury responses systemically and centrally, it is not well-suited for detailed biomechanical analyses. This conclusion is based on high-speed cineradiographic studies where the physiologic saline in the FP cannula was substituted with a radiopaque contrast medium (Conray 1:1 dilution/saline). High speed x-ray movies (1000 fps) were taken of the fluid percussion pulse (1.5-3.4 atm/20 msec) in sagittal, dorsal, and frontal planes of orientation. When viewed together, the cineradiography revealed a complex, dynamic interaction between the injected fluid and the skull/cranial contents. Rapid lateral and anterior/posterior epidural fluid flow suggest that the pathology and dysfunction following FP brain injury reflects diffuse mechanical loading of the brain. Because fluid is used to transfer mechanical energy to brain tissue, and because fluid flow characteristics (i.e., direction, velocity, and displacement) are dependent on the brain geometry and species used, accurate analytical and biomechanical analyses of the resultant injury would be difficult at best. In contrast, the cortical impact model of experimental brain injury uses a known impact interface and a measurable, controllable impact velocity and cortical compression. These controlled variables enable the amount of deformation and the change in deformation over time to be accurately determined. In addition, the CI model produces graded, reproducible cortical contusion, prolonged functional coma, and extensive axonal injury, unlike the FP technique. The quantifiable nature of the single mechanical input used to produce the injury allows correlations to be made between the amount of deformation and the resultant pathology and functional changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Experimental model for comparative evaluation of pharmacologically induced vasodilation of arterial wall mechanical properties.

Arterial wall compliance (C) and distensibility coefficient (DC) are key factors of pathologic physiology, especially in arteries less than 2 mm in diameter. The aim of this study was to design an experimental model allowing comparative measurement of C and DC during pharmacologically induced vasodilation on small-diameter arteries. Both femoral arteries were exposed in eight New Zealand White rabbits. Diameter (d) and systolic/diastolic diameter changes (deltad) were measured simultaneously, and C and DC were calculated before and after topical application of 1 mL of 4% papaverine on the right side and topical application of 1 mL of 1% lidocaine on the left side. Diameter measurements were performed by echo tracking with 20-MHz implanted microprobes. After papaverine and lidocaine application, respectively, d increased from 1.36 mm to 2.23 mm (P < 0.0001) and from 1.45 mm to 2.4 mm (P < 0.0001), deltad increased from 0.0568 mm to 0.0571 mm (P = 0.34) and from 0.064 mm to 0.077 mm (P < 0.01), C increased from 5.7 x 10(-3) mm/mm Hg to 6 x 10(-3) mm/mm Hg (P < 0.02) and from 6.23 x 10(-3) mm/mm Hg to 8.49 x 10(-3) mm/mm Hg (P < 0.01), and DC decreased from 4.22 x 10(-3) mm Hg(-1) to 2.61 x 10(-3) mm Hg(-1) (P < 0.0004) and from 4.36 x 10(-3) mm/mm Hg to 3.46 x 10(-3) mm/mm Hg (P < 0.005). Papaverine- and lidocaine-induced changes were significantly different for deltad, C, and DC (P < 0.01). These results suggest that, unlike that with papaverine, lidocaine-induced vasodilation leads the artery up to the nonlinear part of its pressure/diameter relationship, with decreased distensibility contrasting with increased diameter and compliance. Our experimental model may be useful to compare the effects of different vasoactive drugs at different concentrations on the mechanical properties of the arterial wall.

Animals↗

PubMedDate not supplied

[Toxicology of reproduction: predictive value of experimental models. Round Table No 1 at Giens XIII].

The carrying out of clinical trials with a view to the marketing of drugs for human use is directly related to results of some animal studies. This workshop was devoted to evaluation of the quality and interest of these experimental models in reproductive toxicology. The predictive ability of preclinical trials to make extrapolations from animals to man decreases from foetotoxic to tetratogenic risks respectively and from the effects on fertility in both sexes to postnatal risks. As a result of this workshop, we propose the following improvements: (1) standardization and generalization of fertility test evaluations, especially the spermogram, in order to improve animal and human correlations; (2) development of knowledge and standardization of the follow up of the oestral cycle; (3) improvement of standardization, harmonization and diffusion of postnatal tests that prove relevant in animals; (4) increase in initiatives aimed at better mutual understanding of all drug partners; (5) creation of registers for new drugs, as soon as possible during clinical trials, to study their effects on the whole reproductive process; (6) recommendations for the creation of guidelines for International Conference on Harmonisation (ICH) to enable classification of observed effects in experimental models. This could lead to specific (potentially for each phase of the reproductive cycle) guidelines, precautions for use and/or contraindications which are listed in the summary of product characteristics.

Animals↗

PubMed1999

Experimental models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by the progressive loss of motor neurons, leading to profound weakness and eventual death of affected individuals. For the vast majority of patients with ALS, the etiology of the disorder is unknown, and although multiple clinical trials of various therapeutic agents have been undertaken, truly effective therapy is not currently available for the disease. The selection of treatments used in ALS clinical trials frequently has its basis in promising data obtained from experimental model systems in which the proposed agent has shown some effect in protecting motor neurons from a particular insult. The likelihood of a successful clinical outcome for a given treatment in ALS would therefore depend on two principal factors, including the similarity of the model to the disease and the biologic action of the potential therapeutic agent. Partly because early experimental models of ALS failed to replicate the disease process, treatment success in these models did not carry over into human trials. Recently, however, a variety of newer model systems have been developed and utilized to investigate motor neuron degeneration as related to ALS. For example, in this issue, Corse et al. use a rat spinal cord organotypic slice subjected to glutamate excitotoxicity as a model system to test the effectiveness of neurotrophic factors in preventing motor neuron degeneration. This review will assess the strengths and weaknesses of differing ALS model systems that have been used to preclinically test potential drug efficacy in ALS.

Animals↗

PubMed2003

An experimental model for the transplantation of fetal central nervous system cells to the injured spinal cord in rats.

INTRODUCTION: Traumatic spinal cord injury is one of the most disabling conditions occurring in man and thus stimulates a strong interest in its histopathological, biochemical, and functional changes, primarily as we search for preventive and therapeutic methods. PURPOSE: To develop an experimental model for transplantation of cells from the fetal rat central nervous system to the site of an injured spinal cord of an adult rat in which the transplanted cells survive and become integrated. This experimental model will facilitate investigations of factors that promote regeneration and functional recovery after spinal cord trauma. MATERIAL AND METHODS: Fifteen adult Wistar rats underwent laminectomy, and an spinal cord lesion was made with microdissection. Fetal spinal cord tissue was then transplanted to the site of the injury. The rats were monitored over a 48-hour period, and then their vertebral column was completely removed for histological analysis. RESULTS: In 60% of transplanted rats, the fetal tissue at the injured site remained viable in the site of the lesion.

Animals↗

PubMed2003

Renal kallikrein-kinin system damage and salt sensitivity: insights from experimental models.

The importance of tubulointerstitial injury in the pathophysiology of human essential hypertension, and particularly salt sensitivity, is increasingly recognized. Since the renal kallikrein-kinin system (KKS) is located in the tubulointerstitial region of the kidney it is reasonable to expect that injury to this area, whatever the cause, may impair KKS production and compromise its role in blood pressure regulation. In this review we discuss evidence of injury in the renal kallikrein-producing structures in three different experimental models characterized by prominent tubulointerstitial lesions: subtotal nephrectomy; inhibition of nitric oxide synthase; and overload proteinuria. These three experimental models have in common the development of important tubulointerstitial damage and salt-sensitive hypertension expressed after the initial injury has ceased. In these three models, reduced KKS activity may contribute to the establishment of a pathophysiologic state characterized by unopposed hyperactivity of the renin-angiotensin system, resulting in salt retention.

Animals↗

PubMed1992

Fatal systemic candidiasis of gastrointestinal origin: an experimental model in mice compromised by anti-cancer treatment.

An experimental model of fatal systemic candidiasis originating from the gastrointestinal (GI) tract of compromised mice is presented. ICR female mice were compromised by a single anti-cancer treatment: irradiation (4 or 6 Greys i.e. 400-600 rads), methotrexate (MTX) (3 mg per mouse, intraperitoneally) or 5-fluorouracil (5FU) (200 mg kg-1, intravenously). Three days later, compromised and non-treated control mice were exposed to Candida albicans administered orally. Morbidity and mortality due to candidiasis were monitored for 30 days post-candidal inoculation. Increased and longer GI colonization was noted among the MTX and 5FU treated mice, or 6 Greys irradiated mice (up to 92.3% for over 30 days in anti-cancer treated mice). The stomach was found to be the major part of the GI tract involved in fungal colonization. A significant number (53.8-83.3%) of the anti-cancer treated mice developed systemic candidiasis originating from the GI tract, which was fatal in 30-80% of the infected animals. In systemically infected animals, candidal antigen was demonstrated in the serum, and fungal abscesses containing C. albicans were observed in the liver, kidneys and spleen. C. albicans was isolated from the infected organs. The severity of the infection, as reflected by the number of fungi in visceral organs, and by mortality during the 30 days post-candidal inoculation, indicated differences in the course and nature of the infection among the three treatment groups (i.e. MTX, 5FU, 6 Greys).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1976

Intranasal challenge of mice with herpes simplex virus: an experimental model for evaluation of the efficacy of antiviral drugs.

An experimental model of herpetic infection based on intranasal challenge of 12-day-old mice with herpes simplex virus (type 1) has been developed for assessment of the efficacy of a variety of antiviral compounds with clinical potential: cytosine arabinoside, adenine arabinoside, iododeoxyuridine, ribavirin, chloriteoxidized oxyamylose, polyriboinosinic-polyribocytidylic acid, and interferon. The model employed is reminiscent of herpetic encephalitis in humans in both the portal of entry (nasopharyngeal cavity) and the mode of transmission (nerve route) of the virus to the target organ (brain). The mortality rate from viral infection was significantly reduced (greater than or equal to 30%) by the following treatment regimens: cytosine arabinoside, adenine arabinoside, iododeoxyuridine, and ribavirin, administered daily for seven consecutive days starting immediately after inoculation of virus, at dosage levels of 4-20 mg/kg, 20-100mg/kg, 100mg/kg, and 20-100 mg/kg, respectively; and chlorite-oxidized oxyamylose, polyriboinosinic-polyribocytidylic acid, and mouse interferon, administered 24 hr before viral challenge, as single doses of 100-500 mg/kg, 20mg/kg, and 10(7)-10(8) international reference units/kg respectively. Similar doses of polyriboinosinic-polyribocytidylic acid and mouse interferon administered after inoculation of virus did not alter the final mortality rate.

Animals↗

PubMed1984

Experimental models in primates for reconstructive surgery utilizing tissue transplants.

Two experimental models for tissue transplantation between unrelated individuals of a primate species have been designed to study survival and reinnervation. The first is a neurovascular free flap consisting of the entire soft tissue coverage of the index finger. The second is an entire hand transplant through the distal forearm. Ongoing studies show that cyclosporin A at high doses, in combination with a tapering regimen of steroids to a low maintenance level, permits prolonged survival of both transplant models. Careful biochemical, hematological, and cyclosporin A serum trough level monitoring permits use of this drug a very high dosages in primates. Continuing experiments should yield detailed neurophysiological data on the reinnervation of these transplants over the next 6 to 18 months.

Animals↗

PubMedDate not supplied

Acute gastric mucosal lesions--a new experimental model and effect of parenteral nutrition.

Experiments were performed on 94 male Sprague-Dawley rats to explore the influence of starvation and parenteral nutrition on the development of acute gastric mucosal changes under stress. Comparative assessments were made of lesions in the gastric mucosa of rats on 1- or 6-day repeated exposure to the stress consisting of restraint with immersion in water. Marked hemorrhagic lesions over the extensive area of the glandular stomach and pronounced ulcerative changes in the nonglandular stomach were observed in 6-day stress group as compared to 1-day stress group where only a few hemorrhagic lesions were observed. Thus, this model has proven to provide an excellent experimental model suitable to the purpose of the present investigation. Parenteral nutrition significantly suppressed the development of mucosal damage either in the nonglandular or glandular stomach of rats under 6-day stress. Furthermore, it has been demonstrated that lesions caused in the glandular stomach increase in severity via exposure to stress and starvation while those evoked in the nonglandular stomach rise in incidence even in the presence of starvation alone.

Animals↗

PubMed2005

Experimental model of gastroesophageal reflux in rats.

PURPOSE: To develop an experimental model of gastroesophageal reflux in rats. METHODS: Sixty Wistar rats underwent surgery and were assigned to one of the three groups of twenty animals each. The animals in group A underwent total esophageal myectomy and, in group (B), underwent partial myectomy. The third group was the control group (C). A contrast radiographic study of the esophagus was performed to evaluate gastroesophageal reflux. The anatomopathological study of the esophagus was used to evaluate esophagitis. RESULTS: During the 30-day postoperative follow-up, 14 animals in group A presented with reflux of barium in the esophagus. The presence of barium in the esophagus was observed in 7 animals in group B and in 2 animals in the control group. The result of the histopathology examination was controversial. A marked weight loss in the rats undergoing total myectomy was observed, however there was no significant statistical difference. CONCLUSION: Total myectomy in the lower third of the esophagus caused gastroesophageal reflux in the majority of the animals.

Animals↗

PubMed2006

[Evaluation of an experimental model of necrotizing enterocolitis in rats].

OBJECTIVE: To evaluate an experimental model of necrotizing enterocolitis in rats proposed by OKUR e col. in 1995. METHODS: On their first day of life, 28 EPM-Wistar rats weighing between 4 and 6 grams were submitted to hypoxia (H) by placing them in a CO2 gas chamber for rodents' sacrifice, where they received a 100% CO2 air flow for 5 minutes. After the hypoxia the animals were reanimated (R) with a 100% O2 air flow, also for 5 minutes. The animals were allocated in two groups: G1: control (n=12): rats not submitted to H-R; G2: (n=16): rats submitted to H-R. Segments of the small intestine and colon were prepared for histological analysis. The remaining intestine was used to measure tissular malondialdehyde. RESULTS: Mean malondialdehyde dosages were 1.05 (0.44-2.03) and 2.60 (0.59- 6.4) nmol MDA/mg protein for G1 and G2, respectively. G2's mean value was significantly higher than in the control group (p<0.002). Significant statistical difference between the studied groups was found in relation the level of injury, with G1 presenting significantly lower levels than G2. CONCLUSIONS: The model showed that neonatal hypoxia may cause intestinal wall injury in rats. Despite the discreet histological injuries found, the method is suitable for evaluation of tissular free radicals.

Animals↗

PubMed1995

Experimental model of allergic conjunctivitis to ragweed in guinea pig.

An experimental model of ocular allergy was developed in the guinea pig by exposing these animals to ragweed through topical contact on nasal and conjunctival mucosae, followed by subsequent challenge with ragweed contact on the conjunctiva. Animals developed clinical and histological signs of allergy with and without the use of interleukin 4 as adjuvant. This model mimics human hay fever conjunctivitis more naturally than do animal models previously reported, and it may be subsequently more valuable in the study of the response of allergic conjunctivitis to different therapeutic approaches.

Adjuvants, Immunologic↗