In dog model

Cardiac MRI may have a role in risk stratification for SCD due to its ability to detect myocardial scar. The use of gadolinium, which accumulates in infarcted tissue, has allowed delayed enhancement MRI to detect scar burden. Early experiments in dog models performed by coronary artery occlusion compared acute and chronic infarcts to pathologic specimens of the dog heart postmortem (89,90). Delayed enhancement MRI was remarkably accurate in imaging the infarcted tissue in comparison to the pathologic specimen. The spatial extent of hyperenhancement was the same as the spatial extent of myocyte necrosis at every stage post-MI. Reversible ischemia did not show delayed gadolinium uptake. Thus, delayed enhancement MRI can distinguish between reversible and irreversible injury, and... 

OA were aborted in 2003 due to the development of mild to moderate liver fibrosis in dogs treated for 9 months with high doses of pralnacasan. This was in spite of recent evidence demonstrating the effectiveness of pralnacasan treatment in the acute dextran sulfate sodium (DSS)-induced colitis model, which resembles Crohn s disease (CD) characteristics, and in transient ischemia induced brain damage. 

Watanabe M, Shin oka T, Tohyama S, et al. Tissue-engineered vascular autograft Inferior vena cava replacement in a dog model. Tissue Eng, 2001, 7, 429 39. 

This model was developed after pioneering experiments carried out in the USA by Overmier and Seligman (1967) who reported profound behavioural changes in dogs after their exposure to inescapable, uncontrollable stress (footshock). Subsequent work has concentrated on rats and mice, which show a similar behavioural response. This is expressed as appetite and sleep disturbance, general passivity and, on re-exposure of subjects to the stress, a failure to attempt to escape ( escape deficits ), even when this is feasible. 

Idebenone, an inhibitor of lipid peroxidation, was shown to prolong survival time and delay the onset of ischaemic seizures in a bilateral carotid occlusion model in rats. It is marketed in Japan as a therapy to improve cerebral metabolism and performance after a stroke (Suno and Nagaoka, 1984). Cerebral protective effects after an ischaemic insult in dogs and rabbits have been seen with the hydroxyl radical scavenger, mannitol (Meyer et al., 1987). 

Chelators of transition metals like iron can remove free iron from the injury cascade. The iron chelator, desferri-oxamine, prevented the accumulation of lipid peroxides in 15 min cardiac arrest model in dogs followed by 2 h of resuscitation (Komara et al., 1986). 

Predictions based on the model have been compared to observed time courses for lung, liver, and skeletal americium burden in dogs that inhaled americium oxide (Mewhinney and Griffith 1983). Data on lung retention for four humans who accidentally inhaled americium were also compared to model predictions. The empirical observations fell within predicted retention patterns for particle sizes (AMAD) 0.5 and 1.8 im (Mewhinney and Griffith 1983). 

Fig. 7 Thiopental concentrations in various tissues following 25-mg/kg IV bolus doses. Solid symbols indicate data in dogs the open circles are from data in humans. Lines correspond to predicted values in various tissues using a perfusion model containing compartments corresponding to the blood, viscera, lean, and adipose tissues. (From Ref. 26.)...

Predictions of human in vivo permeability can be made with a particularly high degree of accuracy in all predinical models for drugs with passive diffusion as their main mechanism. It is only the dog model that seems to absorb low-permeability... 

A number of animal diseases caused by viruses involve primary demyelination and often are associated with inflammation. These diseases are studied as animal models, which may provide clues about how a viral infection could lead to immune-mediated demyelination in humans [1, 5, 6]. Canine distemper virus causes a demyelinating disease, and the lesions in dog brain show a strong inflammatory response with some similarities to acute disseminated encephalomyelitis in man [ 1 ]. Visna is a slowly progressive demyelinating disease of sheep caused by a retrovirus [ 1 ]. 

The most extensively used animal model to evaluate the action of SERMs on bone has been the ovariectomized (OVX) rat. In rats, tamoxifen antagonizes bone resorption and uterine growth (Turner et al. 1987,1988) and reduces the number and size of osteoclasts. The inhibitory effect on bone resorption of tamoxifen has also been reported in dogs and immobilized male rats (Wakley et al. 1988 Waters et al. 1991). As an antiresorptive agent, however, tamoxifen is less effective than 17/3-estradiol (17/9E2) (Williams et al. 1991) and has no effect when the endogenous production of estrogens is normal (Evans et al. 1994). 

It is ironic that possibly the first animal model of relevance to immunotoxicology was reported by Portier and Richet in 1902 [45] in an attempt to induce tolerance to a sea anemone toxin, they accidentally produced a shock reaction in dogs. Since this was not the protective effect they had hoped to produce (phylaxis for protection in Greek), they named the reaction anaphylaxis [46], The irony, of course, is that this serious reaction, mediated by IgE in humans, has proven to be notoriously difficult to predict based on animal studies. This is no trivial issue, since anaphylaxis is a serious, life-threatening reaction associated with exposure to drugs, foods, cosmetic ingredients, and other exogenous substances [47],... 

The tetralins 18a and 18b were potent serotonin agonists in dog vascular smooth muscle (33) but did not elicit hallucinogen-like action in a conditioned avoidance response model in rats (156). However, 18b is a potent pyretic agent in rabbits and produces a rage response in cats (166). Addition of a double bond into the 3,4-position of the tetralins led to decreased serotonin-like action... 

The hypothesis that HNO is not involved during NO-release from sydnonimines was confirmed by the study of NO-release from C78-0652 109, the dimethyl derivative of SIN-1A (Scheme 6.19). This product closely resembles SIN-1A in its biological and pharmacological behavior, showing a clear NO-dependent vasodilating effect on guinea pig pulmonary arteries and hypotensive action in anesthetized and conscious dog models [105]. 

Pirsidomine showed a prolonged vasodilating activity in vitro and a long duration of action in vivo in a dog model. Compared with isosorbite-5-mononitrate (IS-5-MN) this sydnonimine developed no tolerance in a conscious dog model at doses of both drugs that produced similar pharmacological effects (Fig. 6.7) [121-123]. 

The lack of tolerance has been explained by the fact that the N O-release from these compounds is spontaneous and independent of the presence of thiols [124], that, by contrast, may be an essential cofactor in the action of the nitrate. Martorana et al. [125] showed a marked antiischemic effect of Pirsidomine in a dog model of myocardial infarction. 

In other work, C87-3754has been compared with SIN-1, the equivalent metabolite from molsidomine, and from the organic nitrate class, isosorbide-5-mononitrate (IS-5-MN) [146]. In this latter study, which involved long term oral administration in a dog model, IS-5-MN showed tolerance whilst the sydnonimines showed no self- or cross-tolerance. Elsewhere, tolerance studies in dogs by oral or continuous infusion of C87-3754 have shown benefits in the treatment of a failing heart, without tolerance [147] and with better results than those observed by nitroglycerin [148]. 

ACT-078573 (20) is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, 0X1 and 0X2 [61]. In animal models, the administration of 20 resulted in a dose-dependent decrease in alertness and increased non-REM and REM sleep. The compound, administered at oral doses ranging from 10 to 300 mg/kg, dose-dependently decreased alertness in rats and exhibited increased duration of REM and non-REM sleep, indicating no intrusive REM sleep that is characteristic of narcolepsy. In dogs, treatment with 20 (10-100 mg/kg p.o.) resulted in dose-dependent reductions in mobility and also induced signs of clinical somnolence. 

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