General steps in the discovery and development of novel drugs in the United States are presented. The first step is the discovery of novel drugs. Brief histories and mechanisms of a few novel drugs in the American market are outlined. In this presentation preclinical animal toxicologic studies (drug safety evaluateion) are emphasized in regard to drug development. When preclinical animal studies have defined the toxicity and the doses at which it occurs an Investigational new Drug Application (IND) is submitted to the Food and Drug Administration (FDA) An IND notifies the FDA the intention to begin testing a novel drug in human subjects.

This study was carried out to investigate the testicular toxicity of environmental toxicant, 2-bromopropane(2-BP) recently caused occupational intoxication in Korea by light microscopy and electron microscopy. To evaluate the effect on spermatogenesis and find target germ cell 10 weeks old male Sprague-Dawley rats were treated with 5g/10m ℓ/kg/day of 2-bromopropane for 3 consecutive days orally and observed on day 1 or day 7 after treatment. 2-BP induced depletion of spermatogonia and early spermatocytes on stages I-IX or extensive degeneration of germ cells on the other stages on day 1. But extensive degeneration of germ cells without stage specificity was observed and round spermatid formed multinucleated giant cells in the lumen of seminiferous tubules on day 7. Electron microscopically Sertoli cells showed irregular shape of nucleus and cytoplasmic vauolation. And spermatocyte showed a extensive heterochromatin and cytoplasmic vacuolation. But there was no histopathological changes in the interstial cells. On the base of the results the target germ cell was spermatogonia in the early of the study but Srtoli cells also effected by high-dosed 2-BP in the late of the study.

The anticarcinogenic effects of allyl methyl trisulfide(AMT) and methyl propyl disulfide(MPD) were studied in a 28 weeks rat multi-organ carcinogenesis model. Tumor incidence rate was decreased by AMT or MPD treatment comparing with the positive control. AMT treatment significantly decreased the incidence of neoplastic and preneoplastic lesions in the kidney thyroid gland urinary bladder alimentary tract lung and Zymbal's gland. MPD also inhibited incidence of noplastic and preneoplastic lesions in the liver kidney urinary bladder alimentary tract lung and Zymbal's gland but increased that in the thyroid gland. GST-p positive foci in the liver were slightly decreased by AMT or MPD. There was no significant histopathological lesions in AMT or MPD treated group without pretreatment of carcinogens.

The objective of this study was to develop digoxigenin (DIG)-labeled in situ hybridization (ISH) test for diagnosis of Aujeszky's Disease(AD) in infected organs. Specific DNA with well conserved gene sequences encoding gp50 antigen in AD virus (ADV) was obtained by Polymerase Chain Reaction (PCR) method. A pair of oligonucleotide primers used in PCR allowed amplification of a 217 bp sequence from the gp50 ADV gene. The DNA was then labeled with DIG by primer labeling method for use as probe in ISH test to detect ADV nucleic acids in various tissue. Positive hybridization was demonstrated by dark pigmentation in nuclei and cytoplasm of ADV infected cells particularly in brain tonsillar crypt epithelium and pulmonary alveolar cells. This result suggests that ISH is a valuable sensitive and rapid diagnostic test for AD.

Porcine Reproductive and Respiratory Syndrome Virus infection (PRRSV) was confirmed by serology histopathology immunohistochemistry and bacteriologic examination in young pigs. Four suckling and six weaned piglets submitted from three different farms showed coughing sneezing labored rapid abdominal respiration lethargy and anorexia. Grossly apical and cardiac lung lobes appeared mottled with pale to dark tan discoloration. Submandibular and bronchial lymph nodes were tan and enlarged. All piglets were seropositive for PRRSV antibodies by the indirect immunofluorescent antibody(IFA) test. Microscopically lung lesions were characterized by hyperplasia and hypertrophy of type 2 pneumocytes infiltration of mononuclear cells in alveolar intersitium accumulation of necrotic debris in alveolar spaces accompanied by proliferation of alveolar multinucleated syncytial cells. Using immunohistochemical technique PRRSV antigens were demonstrated in alveolar macrophages and type 2 pneumocytes in histologic lung tissue sections. Also PRRSV antigens were detected in brain lymph nodes spleen and heart. Additionally piglets showed nonsuppurative meningoencephalitis mandibular necrotic lymphadenopathy splenic atrophy and myocardial necrosis.

A pulmonary keratinizing cyst was found incidentally in a 30-week-old female Sprague-Dawley rat. The cyst was lobe of the lung, lined by stratified squamous epithelium and filled with concentric layers of desquamated keratin. The wall consisted of 2-4 layers of well differenciated squamous cells. The adjacent lung tissues were slightly compressed but not otherwise damaged by the cyst. There was no inflammatory reaction or mitotic figures observed in the cyst.

Two dead and two terminally sick badgers with signs of lacrimation and nasal discharge were submitted to the Pathology Division of the National Veterinary Research Institute for necropsy. The major gross findings included chronic dermatitis and pneumonia. histologically intracytoplasmic and intranuclear acidophilic inclusion bodies consistent with Canine Distemper (CD) virus particles in lung kidney urinary bladder skin foot pad stomach and small intestine. Additionally there were diffuse bronchointerstitial pneumonia hyperkeratosis of foot pads and focal non-suppurative encephalitis. Canine distemper infection in these badgers was further confirmed by immuofluorescent technique which demonstrated CD virus-specific antigens in lung and kidney sections.

A 13-years and 8-months old Jindo dog showed vomiting and pale red vulvular discharge. At necropsy, the uterus was swollen and endometrium was diffusely thickened by numerous protruding cysts which measured approximately from 0.5 to 1 cm in diameter. On sectioning the cysts exuded pale red watery fluid. histologically the endometrium was thickened and characterized by mild to moderate edema congestion and hemorrhagic foci. The cystic endometrial glands were lined by a single layer of flattened cuboidal or vacuolated columnar epithelium. Occasional dilated glands had traversed through the submucosa into the myometrial region. Afew mixed inflammatory cells infiltrated in the lamina propria. Bacteriologically Escherichia coli was isolated from the uterine contents. Gross and microscopic finding were consistent with cystic endometrial hyperplasia.

This is the first recorded case of Sarcoptes scabiei in a Korean female raccoon confirmed by light and scanning electron microscopies. Grossly the skin on the abdomen head and legs was markedly thickened with alopecia and encrustation. histopathologically skin showed epidermal hyperplasia with spongiotic degeneration and parakeratosis. Ectoparasites were present in superficial and deep epidermal layers. Small numbers of leukocytes predominantly neutrophils were associated with the parasitic infestation. Scanning electron microscopy examination of affected skin scraping demonstrated round to oval parasitic mites measuring approximately 180 -250 x 220 - 350 um in size. The mites possessed four pairs of legs of which the two anterior pairs appeared relatively long with unjointed stalks while the two posterior leg pairs were rudimentary. these morphological features were consistent with Sarcoptes scabiei.

Two 2 and 7 months-old holstin and one 3 months-old native Korean calf suffering from respiratory illness were submitted to the National Veterinary Research Institute for euthanasia and pathologic examination. At necropsy diffuse lobar pneumonia was present in apical cardiac and diaphragmatic lobes in all calves. Microscopically acute multifocal bronchiolitis and interstitial syncytial cell formation were frequently observed. in addition occlusion of bronchiolar lumen due to cellular proliferation and fibrosis accompanied by interlobular septal emphysema were also present. Immunohistochemically bovine respiratory syncytial virus antigen were positively identified in lung lesions including bronchial and bronchiolar epithelium alveolar macrophages and lymphocytes.