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Hemoglobin-vesicles (HbV, d = 251 nm) are an artificial oxygen carrier encapsulating a concentrated Hb solution in polyethylene glycol-modified phospholipid vesicles (liposomes). Their safety and efficacy as artificial red blood cells and a fluid for oxygen therapeutics have been extensively studied in various rodent models. We have previously reported the efficacy of HbV as a resuscitation fluid in canine hemorrhagic shock model. However, long term safety was not yet studied. In this chapter, we report the results of efficacy and safety study in Beagle dog using hemorrhagic shock model. We observed the animals for one year. Twenty-six male beagle dogs were used. For acute study, a dog was anesthetized by 2.0–2.5 % sevoflurane and spontaneous respiration was maintained. A thermodilution catheter was introduced into pulmonary artery for measurement of cardiovascular parameters. Fifty percent of estimated blood volume was withdrawn from right femoral artery, and the shock state was stabilized for 1 h. The dogs were resuscitated either with isovolemic 5 % recombinant human serum albumin alone (rHSA) HbV suspended in rHSA (HbV/rHSA), or shed autologous blood (SAB). HbV/rHSA group showed immediate recovery of hemodynamic and blood gas parameters as did SAB, and no abnormal hypertension was observed. HbV contributed to about 34-38 % of the total delivery of oxygen and 26–29 % of total consumption of oxygen for 4 h. For chronic phase study, the beagle dogs resuscitated with HbV/rHSA or SAB were caged for up to 1 year. All dogs survived and gained weight. Results of hematological and plasma biochemical analyses and pathological examination showed no notable abnormalities except the transient accumulation of HbV in reticuloendothelial system and a release of cholesterol derived from HbV. The present results using beagle dogs reassure that HbV suspended in rHSA shows a similar resuscitative ability and safety to that of SAB.

The purpose of this study was to evaluate spatio-temporal and pressure parameters in two different sized dogs: large-breed (Retriever) and small-breed dogs (Beagle), by using a pressure sensors walkway. 55 healthy adult dogs from 1 to 4.5 years old: 28 Retriever (mean weight: 29.7 kg) and 27 Beagle (mean weight: 10.8 kg) were tested by GAITRite® system. It is a portable pressure walkway of 4.3 meters long and 16128 sensors, which measures spatio-temporal and pressure parameters. Data collected included: stance time; relative stance time (stance time/stride time), stride time; stride length; peak vertical pressure, number of activated sensors by each paw; cadence and walking velocity. Symmetry left/right and ratio fore/hind limbs were also calculated. No significant difference for mean of velocity for Retriever (1.09 m/s) and Beagle dogs (1.14 m/s), but a significant different for the cadence between large (1.6) and small dogs (2.09) stride/s. No significant difference between the left and right forelimbs or left and right hind limbs for any parameters in either group. But the differences were significantly for all parameters between two groups.

A colony of Beagle dogs was used within the last 6 years to develop an allergie dog model. The dogs were sensitized to various allergens, such as recombinant Betvi (birch) and Phi p5 (timothy), ovalbumin, peanut and many others. The first observation was that dogs clearly segregated into high and low IgE responder dogs when immunized for the first time by intradermal or subcutaneous injections of allergen within l month of birth. Characteristic for the high IgE response was the possibility to boost it at any time later in life and to extend it later to other allergens, like is usually the case in atopic man. Low IgE responder dogs showed a low response which was not boostable and could not be extended to other allergens later on. Numerous breeding experiments over 5 years demonstrated clearly that the high IgE response is inherited as a dominant trait.

The aim of this study was to investigate whether intrathymic injection (ITI) of donor splenocytes in dogs might lead to specific immunomodulation as assessed by mixed lymphocyte culture (MLC) tests.

The effect of synthetic corticosteroids given intratracheally or orally on the adrenal glands of beagle dogs was investigated. The adrenal function was evaluated using a standardized ACTH stimulation test. In addition, histological and morphometrical examinations of the adrenal cortex were performed at the end of the study.

Yeast (Candida maltosa) obtained by fermentation of F.U. grade n-paraffins (C12–C19) was incorporated into the diet at concentrations of 7.2 and 18.4% by weight, supplying 20 and 50% of the diet protein respectively. These two diets along with a standard one were fed to groups of 20 beagle dogs (10 males and 10 females) each. Biochemical and haematological analyses were performed before and 3, 6, 12, 18, and 24 months. Thereafter the animals were killed, autopsied and various tissues prepared for histological examination. There were no differences in diet consumption but a decrease in body weight gain proportional to the amount of yeast present in the diet was observed. The only difference between animal fed the regular and yeast supplemented diet was confined to blood glucose, amylase and alkaline phosphatase content. No differences in pathological patterns between controls and treated animals. These findings are discussed.

This paper reports an unusual behavioural change in the beagle bitch after 2 years treatment with dieldrin. A leg cocking position was taken up by the animal during running Changes in the electroencephalogram showed high voltage activity on the contralateral side of the brain. No histopathological changes were found.

Temofel (2,5-dimethyl-α-ethyl-benzhydrol) is a choleretic compound. Safety studies required for Phase I and II clinical trials were performed. No oestrogenic, antioestrogenic, androgenic or antiandrogenic effect was induced in infantile rats treated with 100 and 200 mg/kg. No CNS effects were induced by 50 mg/kg in mice. No haemodynamic or respiratory changes were induced in dogs by 300 mg/kg. In a 28-day oral toxicity study with 40, 80,160, 320, 640 and 1280 mg/kg doses on Lati: CFY (SD) rats died at the 2 highest doses (640 and 1280 mg/kg). Large necrotic foci in the liver were found at the highest dose 1280 mg/kg. In rats treated with 320 mg/kg and higher doses, hepatic hyperplasia, renal tubular hyperplasia and protein retention in the renal cortex were observed. Testicular atrophy, damaged spermiogenesis, spermiohistogenesis and regulative Leydig-cell hyperplasia were induced by 640 and 1280 mg/kg. In a 28-day study on Velz:BEAGLE dogs with daily doses of 40, 120 and 360 mg/kg sporadically increased SAP activity occurred at the high dose. In a 6-month study rats were fed 400, 2000 and 10000 ppm Temofel. Growth was retarded in the medium and high dose group, no sperm could be seen in the urinary sediment of the high dose group. Testicular atrophy, complete lack of spermiogenesis, spermiohistogenesis occurred in this group. In contrast to the administration of 1280 mg/kg for 28 days by gavage, no hepatic or renal changes were induced by 10000 ppm consumed for 6 months. A 6-month canine study with 40, 120 and 360 mg/kg doses revealed sporadic SAP increase at the high dose. It was concluded that 6 mg/kg Temofel given orally was not contraindicated for human application.

Indomethacin is a popular anti-inflammatory agent. One of its side-effects is gastrointestinal irritation. For the development of less irritating drug formulations it is useful to have a suitable animal model. The aim of the present study was to test the domestic swine (Yorkshire) and beagle dog for this purpose. According to previous studies the alimentary canal of the omnivorous swine may resemble human more than that of the beagle dog (Mount and Ingram 1971).

Increased serum alkaline phosphatase (SAP) activity in dogs is a frequent biochemical abnormality, for which the cause cannot always be identified. High values are mostly related to cholestasis, hepatocellular, kidney and bone disorders, as well as to enzyme induction.

The development of lymphocytic thyroiditis is well-known in dogs, particularly in purebred beagles (Tucker 1962; Mawdesley-Thomas and Jolly 1967; Beier-waltes and Nishiyama 1968; Mawdesley-Thomas 1968; Musser and Graham 1968; Fritz et al. 1970; Niki et al. 1972; Bigazzi and Rose 1975). The highest incidence of thyroiditis is found in dogs between 30 months and 7 years of age (Fritz et al. 1970; Bigazzi and Rose 1975).

Light water nuclear power reactor fuel cycles at various stages contain substantial quantities of β-emitting radionuclides. Thus, in the event of an accident, there is potential for inhalation exposure of man to various types and forms of β-emitting radionuclides. In order to study the biological effects of such potential exposures, a series of life span studies have been initiated in which beagle dogs have been exposed to inhalation to achieve graded lung burdens of a relatively insoluble fused clay form of β-emitting radionuclides. The specific radionuclides, 90Y, 91Y, 144Ce, or 90Sr, were selected on the basis of physical half-life to produce a variety of radiationdose patterns to the lung. Early effects have been the development of radiation pneumonitis and progressive pulmonary fibrosis. In general, dogs which receive high- and rapidly-declining dose-rate exposure from 90Y or 91Y die earlier and at lower cumulative doses than dogs exposed to 144Ce or 90Sr. By contrast, the incidence of later-occurring malignant lung tumors and the degree of inflammatory response is greater in dogs which received protracted low dose-rate exposure associated with 144Ce and 90Sr. Of particular note is the nature of the lung tumors thus far observed. These have been of endothelial origin — hemangiosarcomas rather than the epithelial carcinomas that are seen in uranium miners or dogs exposed to 239PuO2. This association between β-radiation exposure and vascular neoplasms will be discussed further.

Mecinarone (18.25 mg/kg twice a day orally for 6 months) induces an increase of melanin content of pigmented skin and mucosae in the Beagle dog. This effect is reversible.

The effects of reproductive steroids on animal mammary glands should not be compared with those on the human breast because animals differ from humans in their endogenous steroids, estrus patterns, gestations, and lactational histories. There are also marked differences in life span, genetic influences, mammary histology, and the types of spontaneous neoplasms. Beagle dogs seem especially prone to mammary nodules and are therefore a poor test animal for comparison with the human (Nelson et al. 1973). Since there is so little basis for comparison, only the effect of combined oral contraceptive steroids on the mammary tissues on primates is considered below. The effects of oral contraceptive steroids on the mammary glands of various animal species are summarized elsewhere (Casey et al. 1979; Hamilton 1974).

Ftorafur, 1-(2-tetrahydrofuryl)-5-fluorouracil, is a cancer drug very widely used in treatment of cancer in Japan; in particular, it is administered orally for treatment of tumors of the gastrointestinal tract. Recently a new preparation with an enteric coating became available for oral administration. Ftorafur itself is absorbed mainly from the jejunum and ileum, and slightly from the duodenum, but not from the stomach. This new preparation was designed to release ftorafur only in the intestine, and in experiments with beagle dogs it was shown to be absorbed more easily than the earlier preparation. With the same dose, approximately 20% greater total absorption into the blood was estimated with the new preparation. In clinical trials, side effects of the new preparation, especially to the upper digestive organs, were less evident than those of the previous one, which released nearly 100% ftorafur into the stomach within 10 min after the oral administration. The new preparation was tolerated by patients at daily doses of approximately 1 000 mg/m2 for continuous treatment.

Differentiation of T-lymphocytes is regulated by thymopoietin, a 49 amino acid polypeptide chain. The site of immunological activity is in the 32–36 (Arg-Lys-Asp-Val-Tyr) fragment. This pentapeptide can be reduced to a tetrapeptide (RGH-0206: Arg-Lys-Asp-Val) and further to a tripeptide (RGH0205: Arg-Lys-Asp) which still retains immunological activity. To prepare Phase I and II clinical trials preclinical toxicity studies were duly performed. Mice, rats and dogs tolerated a single 1000 mg/kg dose i. v. without any symptom. In a 14-day i. v. test on Lati:Han:WISTAR rats daily doses of 10, 25, 62.5, 150, 400 and 1000 mg/kg of either test compound were tolerated without symptom or damage. In a 28-day i.v. toxicity test on Wobe:BEAGLE dogs given daily doses of 6, 20 and 60 mg/kg of either test compound, no adverse reaction occurred. The low toxicity of both RGH-0205 and RGH-0206 are probably attributable to their short half-life, as half-life of the pentapeptide fraction is less than 30 sec in humans. It was concluded that the planned clinical dose of 1 mg/kg i. v. was safe for both peptides for short-term administration.

Four groups of 38 male and 38 female Charles River CD albino rats and of CD-1 mice were fed diets containing 0 (control), 0.01, 0.1, or 1.0% trinitroglycerin (TNG) for 2 years. Rats fed the high dose had decreased food consumption and weight gain. Periodic hematological examination found compensated anemia with reticulocytosis, elevated serum transaminases and occasional methemoglobinemia in high dosage rats. At the 1 year necropsy, 8 high-dose rats examined had cholangiofibrosis and some had hyperplastic foci in the liver. At 2 years, all 13 surviving high-dose rats and 6 of the 16 middle-dose rats had enlarged and grossly abnormal livers which on microscopic examination revealed severe cholangiofibrosis and hepatocellular carcinomas. One-half of the high-dose males had interstitial cell tumors in the testes. No apparent toxic effects were observed in the low-dose animals. Mice fed the high-dose of TNG had decreased food consumption and weight gain. At 1 year, the high-dose mice had heme-derived pigment deposits in various organs, and liver dysplasia. At 2 years, the pigmentation occurred in most high-dose and some middle-dose mice while minimal liver dysplasia was found in all the treated groups. Four groups of 6 male and 6 female beagle dogs were given capsules containing 0 (control), 1, 5 or 25 mg/kg/day of TNG for 1 year. Transient methemoglobinemia only was observed in most of the dogs at all the dose levels.

Plutonium-238, an alpha-emitting radionuclide, is used as a heat source in thermoeleltric power generators such as have been employed on lunar expeditions or communications satellites and in cardiac pacemakers. It has an 86.4 year half-life and emits 5.5 MeV alpha particles. Beagle dogs were given single 10 – 30 minute exposures to 238PuO2 aerosols to study the long-term translocation of plutonium and biological effects. Dogs with a terminal body burden ranging from 7 – 260 μCi were euthanized due to respiratory insufficiency related to plutonium-induced pneumonitis during the first 3 years after exposure. Nine of the 11 dogs euthanized during the 4 – 6 year postexposure period had osteosarcomas. The terminal plutonium body burden in the tumor-bearing dogs ranged from 0.5 – 2.6 μCi with 30 – 55% of the plutonium in the skeleton. Experiments are in progress to further define the dose-effect relationship of inhaled 238PuO2 and investigate the mechanisms of plutonium-induced neoplasia.

Changes in serum alkaline phosphatase (SAP) and alanine aminotransferase activities are of clinical diagnostic significance in determining hepatic injuries. Drugs, however, can alter the activities of these enzymes by various mechanisms. Phenobarbital increases SAP activity in dogs as a result of hepatic microsomal induction (Litchfield and Corning, 1971). We examined the effect of related enzyme inducers. Beagle dogs (2/sex/group) were dosed orally with phenobarbital or diphenylhydantoin at 40 mg/kg or primidone at 40 to 80 mg/kg for 7 weeks. Only phenobarbital increased SAP; bromsulfophthalein retention was not affected. Plasma antipyrine half-life decreased and liver cytochrome P-450 content increased in each group compared with values from a control group. No histological changes of the liver were seen. Data indicate the specificity of phenobarbital. Some drugs decrease serum enzyme activities, e.g., alanine aminotransferase activity. Cefazolin was given s.c. to rats at 2 g/kg/day on days 1–18 and at 0.5 g/kg/day on days 19–32. Isoniazid was given orally at 20 mg/kg/day for 33 days to a similar group. Half of each group received pyridoxal HCl s.c. at 0.2 mg/ kg/day on days 1–18 and at 2 mg/kg/day on days 19–46. Serum alanine aminotransferase decreased in each group, but returned to normal on day 32 in rats dosed with isoniazid-pyridoxal combination. Isoniazid is known to interfere with alanine aminotransferase activity by decreasing the availability of this coenzyme. The mechanism of the cefazolin effect has not been elucidated.

In studies for the chronic toxicity of estrogens and gestagens, lysozyme and hemolytic complement (CH50U) in sera of beagle dogs and minipigs were measured. Various doses of the sexsteroids were given: 0.01 mg, 0.1 mg and 1.0 mg/kg respectively. The influence of the steroids on the tested parameters after an application for 6 months was not significant, only in a single series with unphysiologically, high dosages of the preparations were some values changed significantly.

Female and male beagle dogs were administered orally STS 557 (17α-cyanomethyl-17β-hydroxy-13β-methyl-gon-4,9(10)-dien-3-one) for 6 months at dose levels of 0.01, 0.1, or 1.0 mg/kg/day, and levonorgestrel at a dose of 1.0 mg/kg/day, respectively. The results mainly confirmed the gestagenic efficacy on the reproductive organs of both compounds acting directly or via the anterior pituitary gland. In contrast to levonorgestrel, STS 557 did not show any androgenic activity, but had slightly estrogenic effects. Neither clinical, functional nor morphological investigations revealed toxic side effects of the drugs on the liver, the kidneys, the bone marrow, or on blood clotting function.

Judkin et al. have shown that the mortality from atherosclerotic heart disease was more closely related to sugar consumption than fat consumption. Some people claim that Judkin’s data are not supported by experimental evidence. It has been reported by our group and Dalderup et al. that high sucrose feeding can induce vascular lesions in aorta, heart, and kidney in rabbits, rats, and beagle dogs. We reported precise pathologic findings of sucrose-induced vascular lesions in those animals. The purpose of the present study was to investigate the vascular lesions and metabolic changes in male crab-eating monkeys fed a high-sucrose diet for 42 months. Since the crab-eating monkey is more closely related to human phylogenetically, it is reasonable to postulate some aspects of human atherosclerosis by investigating the correlation between metabolic changes and pathologic findings observed in monkeys fed a high-sucrose diet.

The oral toxicity of Tifemoxone, phenoxymethyl-6 tetrahydroxa-zine-1, 3 thione-2, a new potential antidepressant was studied during 6 months in rats at 30, 85 and 230 mg/kg/d and in beagle dogs at 10, 55 and 300 mg/kg/d.