Search PubMed⌕ Search

Biomedical subjects

C Gopinath

Publications and source records attributed to C Gopinath.

At least 19 recordsLinked to original sources
PubMed1996

Oncogenicity studies of the new serotonin (5-HT)3-receptor antagonist ramosetron in mice and rats.

Oncogenicity studies of ramosetron ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity, were carried out in male and female mice and rats. Six groups (two control and four treated) of B6C3F1 mice and F344 rats were given YM060, dissolved in distilled water, once daily by oral intubation at doses of 0, 1, 10, 30 and 100 mg/kg/d. Toxicokinetics indicated that sufficient exposure of the animals to the test material was achieved during the oncogenicity studies. Cmax and AUC of YM060 at 100 mg/kg/d were in the range of 3-5 micrograms/ml and 8 micrograms.h/ml in mice, 1-5 micrograms/ml and 7-16 micrograms.h/ml in rats, respectively. The administration of YM060 resulted in a slightly increased mortality rate among female rats treated with 30 or 100 mg/kg/d, particularly during the Weeks 38-87. Body weights of the high-dosed male and female rats during the Weeks 36 to 96 were significantly decreased when compared to controls. An approximately 30% suppression of body weight gain was recorded during Weeks 36-96 for both male and female rats, and 15% suppression of body weight gain was recorded during Weeks 0-104 for male mice. There was no evidence of a treatment-related effect on the incidence of any tumor or tumor type, and there were no non-neoplastic findings considered to be related to the administration of YM060. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged B6C3F1 mice and F344 rats. In conclusion, there was no evidence of an oncogenic effect of YM060 in mice and rats.

Animals↗
PubMed1996

Pathology of toxic effects on the immune system.

The lymphoid organs/tissues are widely distributed throughout the body. However, a study of the primary and secondary lymphoid organs provides an adequate assessment of immune status. A histopathological approach to investigate immunotoxicity of various agents is described. The advantages and limitations of this approach are discussed. The usefulness of immunocytochemistry as an aid to study the various sub-populations of lymphocytes are stressed. Histopathological assessments are useful in evaluating immunosuppressive responses. Their value is somewhat less obvious in studying the potentials of test compounds for allergic and hypersensitive reactions. Variable factors affecting the structure and function of lymphoid organs such as stress, nutrition and age are discussed. Pathological lesions produced by various agents in lymphoid organs such as thymus, bone marrow, spleen, and lymph nodes are described.

Adjuvants, Immunologic↗
PubMed1995

beta-Cyclodextrin: 52-week toxicity studies in the rat and dog.

A 52-wk toxicity study by dietary administration was performed in Sprague-Dawley rats and in pure-bred beagle dogs with beta-cyclodextrin, a starch derivative that acts as a molecular inclusion agent. Doses of 0 (control), 12,500, 25,000 and 50,000 ppm were selected for the rat study, and 0 (control), 6200, 12,500 and 50,000 ppm were selected for the dog study. The liver and kidney were identified at the histopathological examination as target organs for toxicity in the rat at doses of 50,000 and 25,000 ppm, with the hepatic changes associated with increased plasma liver enzyme and reduced plasma triglyceride concentrations. In the dog study, there was no pathological evidence of systemic toxicity, although there were minor changes in urinalysis and biochemical parameters and a slightly higher incidence of liquid faeces. These changes were considered to be of no toxicological importance. The results in these studies, therefore, indicate that the non-toxic effect level was 12,500 ppm in the rat (equivalent to 654 or 864 mg/kg/day for males or females, respectively) and 50,000 ppm in the dog (equivalent to 1831 or 1967 mg/kg/day for males or females, respectively).

Analysis of Variance↗
PubMed1995

[Four-week intravenous toxicity study of montirelin hydrate (NS-3) in dogs followed by 4-week recovery test].

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.002, 0.02, 0.2, 2 and 20 mg/kg in males and 0, 0.2, 2 and 20 mg/kg in females. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0 and 20 mg/kg groups. No deaths related to the treatment were observed. There were no changes in body weight gain, and food and water consumptions. Nasal discharge was seen in all dose groups. Salivation, emesis and hypoactivity were observed in the 0.2 mg/kg group and over. Licking chops were seen in the 2 and 20 mg/kg groups. Trembling and agitated/restless behavior were seen in the 20 mg/kg group. Electrocardiographic examination revealed elevated heart rate in the 0.2 mg/kg group and over. Ophthalmoscopic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed increases in T3 level in the 2 and 20 mg/kg groups of males and in T4 level in the 0.2 mg/kg group and over of males. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group and below was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 4-week repeated dose toxicity in dogs.

Akathisia, Drug-Induced↗
PubMed1994

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats.

A 52-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30, 100 and 300 mg/kg/d were selected for this study. Treatment-related findings were confined to the 300 mg/kg/d level and, to a lesser extent, the 100 and 30 mg/kg/d levels, with the investigations indicating the kidney as the main target organ for toxicity. The microscopic pathology examination of this organ showed papillary epithelial hyperplasia and/or collecting duct epithelial hyperplasia, with cortical scarring and occasional mineralisation in the papilla. Histopathological changes in the liver, centrilobullar hepatocyte enlargement (accompanied by fine vacuolation) and foci/areas of eosinophilic hepatocytes were considered to reflect the induction of drug-metabolising enzymes in the liver. Other tissues showing treatment-related findings included the salivary glands, urinary bladder, spleen, pancreas and adrenals. Additionally, other notable findings included (in the high dosage males only) a decline in body weight (from week 34), lower erythrocytic characteristics and slightly higher plasma urea nitrogen and alkaline phosphatase values. The results in this study, therefore, indicated that the non-toxic effect level was 10 mg/kg/d of nefiracetam.

Animals↗
PubMed1994

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogs.

A 52-week toxicity study by oral administration (capsule) was performed in beagle dogs with nefiracetam (N-(2,6-dimethylphenyl)-2-(2- oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30 and 90 mg/kg/d were selected for this study. Treatment-related findings were confined to the 90 mg/kg/d level and indicated the kidney and the testis as the main target organs for toxicity. Signs of systemic toxicity, as indicated by the laboratory investigations, were not apparent until the second half of the study and included the principal findings of higher urea nitrogen, and creatinine, with higher urinary volumes and corresponding lower specific gravity, osmolarity and protein values. The microscopic pathology examination showed various changes at the renal papilla, collecting ducts, and medullary and cortical scarring. This examination also revealed decreased spermatogenesis in the testes, with associated decreased numbers/absence of spermatozoa in the epididymides. At the 30 mg/kg/d level, the minor microscopic pathology changes seen in the kidneys of one male animal were considered to be of equivocal toxicological importance. There were no treatment-related findings at the low dosage level (10 mg/kg/d) and, therefore, this level was considered as the non-toxic effect level of nefiracetam.

Animals↗
PubMed1993

Toxicity of the novel anti-peptic ulcer agent catena-(S)-[mu-[Na- (3-aminopropionyl)histidinato(2-)-N1,N2,Q:N tau]-zinc in male cynomolgus monkeys.

A preliminary dose-range finding study and a 13-week toxicity study were performed in male cynomolgus monkeys with catena-(S)-[mu-[N a-(3-aminopropionyl) histidinato (2-)-N1,N2,O:N tau]-zinc] (Z-103, CAS 107667-60-7), a novel anti-peptic ulcer agent, as part of a safety evaluation program. In the preliminary ascending dose study emesis was observed in animals treated at 625 mg/kg and transient reductions in food intake with associated body weight loss in a male treated at 625 or 312.5 mg/kg. Plasma zinc levels were also increased in all animals treated at 625 or 312.5 mg/kg. As a result dosages of 0, 20, 63 and 200 mg/kg/day were selected for the 13-week toxicity study. In this study, treatment-related changes were confined to the 200 mg/kg/day dosage and consisted of emesis, piloerection and transient body weight loss in one animal, increased plasma zinc concentrations, and zinc and copper deposition in the liver and kidneys without any associated morphological change. The no observed effect level was estimated to be 63 mg/kg/day in this study.

Animals↗
PubMed1992

Age-related changes in thyroid structure and function in Sprague-Dawley rats.

Investigation of thyroid glands from 500 male and 500 female Sprague-Dawley rats, at time points of 8, 17, 30, 56, and 108 weeks of toxicity studies conducted at the Huntingdon Research Centre between 1981 and 1984, revealed age-related structural and functional changes that have previously not been well documented. The number of ultimobranchial cysts decreased with age, while area(s) of C-cell hyperplasia appeared with age. Beginning at 56 weeks, some of the thyroid follicles were hyperdistended with colloid, had irregular lumens, and were lined by flattened epithelium. These follicles had clumped, granular, and stratified colloid. Follicular tumors were found in 8% of the males and 6% of the females at 108 weeks. There was an increase in absolute thyroid weights (males from 21.8 +/- 4.0 g to 46.5 +/- 19.05 g, females from 17.2 +/- 4.53 g to 41.7 +/- 26.92 g) and body weights (males from 382.0 +/- 70.6 g to 806.0 +/- 120.7 g, females from 220.0 +/- 21.0 g to 495.0 +/- 127.3 g) with age in both sexes, but the relative thyroid weights were not significantly affected. Negative allometry was observed. With an increase in the age of the rats, there was a decrease in the height of the follicular epithelium and an increase in the internal follicular diameter and the total number of follicles. No prediction for sex could be detected. Serum T3 and T4 concentrations were constant until 56 weeks of age, but at 108 weeks, the values were markedly reduced (in males, serum T3 concentration decreased from 91.60 +/- 13.970 ng/100 ml to 32.90 +/- 10.878 ng/100 ml, and in females, from 90.80 +/- 11.338 ng/100 ml to 48.10 +/- 8.875 ng/100 ml; in males, serum T4 concentration decreased from 5.94 +/- 0.679 microgram/100 ml to 3.04 +/- 0.604 microgram/100 ml, and in females, from 4.59 +/- 0.717 microgram/100 ml to 2.77 +/- 0.786 microgram/100 ml). The data suggest that the thyroid function of Sprague-Dawley rats reduces as the rats age.

Aging↗
PubMed1990

Morphological assessment of visual dysfunction.

The eye is an isolated unit but with a potentially high degree of sensitivity to toxic substances. The multiplicity of types of reaction to injury reflects the unique anatomical, physiological and biochemical features of the eye. The following are examples of such: The albino rat is not a good model for retinal toxicity because of problems of phototoxic retinopathy, the absence of pigment within the pigment epithelial layer and the high incidence of spontaneous retinal pathologies; The ocular toxicity of a compound cannot be anticipated from its chemical structure; Pharmacological side effects are similar between species, and are predictive for man; Mechanisms of ocular toxicity are poorly understood.

Animals↗
PubMed1990

Harderian gland tumours in mice.

A survey of the occurrence of harderian gland tumours in Charles River CD-1 mice (Caesarian derived) showed a relatively higher incidence of harderian gland adenomas in males (5%) in comparison with females (2%) among 3302 untreated control mice from two-year carcinogenicity studies. This sex difference did not apply to the incidence of harderian gland carcinomas. Porphyrin pigment was observed in some of the tumours. Metastasis of the harderian gland carcinoma was seen in lymph node and lung, and in one case the thymus and liver was also affected. Vacuolation, due to fat was seen as helpful diagnostic feature.

Adenoma↗
PubMed1988

Giant-cell tumour of soft tissue in two Sprague-Dawley rats.

Two cases of soft tissue giant-cell tumours are reported in Sprague-Dawley rats. The lesions had the characteristic appearance of multinucleate tumour giant cells and were unassociated with bone. A search of the literature failed to reveal any previous report of this lesion in the rat.

Animals↗
PubMed1987

Central-peripheral delayed neuropathy caused by diisopropyl phosphorofluoridate (DFP): segregation of peripheral nerve and spinal cord effects using biochemical, clinical, and morphological criteria.

Systemic injection of diisopropyl phosphorofluoridate (DFP; 1 mg/kg, sc) causes delayed neuropathy in hens. This effect is associated with a high level of organophosphorylation of neuropathy target esterase (NTE) followed by an intramolecular rearrangement called "aging." Phenylmethanesulfonyl fluoride (PMSF) also attacks the active center of NTE but "aging" cannot occur. This compound does not cause neuropathy and protects against a subsequent challenge systemic dose of DFP. Intraarterial injection of DFP (0.185 mg/kg) into only one leg of hens caused a high NTE inhibition (greater than 80%) in the sciatic nerve of the injected leg, but not in other parts of the nervous system (37% average). A unilateral neuropathy with typical histopathological lesions developed in the injected leg. PMSF (0.55 mg/kg) injected into each sciatic artery caused 47% inhibition of sciatic nerve NTE but only 17-22% inhibition of NTE elsewhere; it did not produce clinical or histopathological lesions. When these hens were challenged with DFP (1 mg/kg, sc), high inhibition of residual-free NTE (greater than 85%) occurred throughout the nervous system and clinical signs of a syndrome different from the classical delayed neuropathy developed: this spinal cord type of ataxia was associated with histopathological lesions in the spinal cord but not in peripheral nerve. PMSF (1 mg/kg) injected into only one sciatic artery caused selective protective inhibition of sciatic nerve NTE of that leg. After systemic challenge by DFP, clinical effects expressed were a combination of spinal cord ataxia plus unilateral peripheral neuropathy. The challenge dose of DFP (1 mg/kg, sc) was insufficient to produce clear histopathological lesions in unprotected peripheral nerves although spinal lesions were found in these hens. Thus clinical evaluation of the peripheral nervous system by means of walking tests and a simple test of "leg retraction" reflexes was more sensitive and specific in diagnosis of peripheral neuropathy than was the histopathology.

Animals↗
PubMed1987

A report on drug-induced kerato-conjunctivitis sicca in dogs.

Kerato-conjunctivitis sicca is reported in beagle dogs treated with an antispasmodic compound for 26 weeks during a routine toxicity study. There was a deficiency of lachrymal secretion associated with keratitis and corneal vascularization. Histopathologically, the changes were characterized by vascularization, fibroblast proliferation and infiltration of inflammatory cells in the substantia propria. In some cases, the inflammation also occurred in corneal epithelium, ocular conjunctiva and corneal limbi.

Animals↗
PubMed1987

Mesovarian leiomyomas in the rat.

Prolonged treatment with two chemically distinct beta-stimulants, Salbutamol and Terbutaline, resulted in mesovarian leiomyomas in Sprague-Dawley rats. Development of these tumors induced by Salbutamol was prevented by concurrent administration of the beta-blocker Propranolol. Mesovarian leiomyomas induced by Salbutomol did not show any regression or progression during a 44-week postdosing recovery period. This report also gives the first recorded incidence of spontaneous mesovarian leiomyomas in the rat.

Albuterol↗
PubMed1986

Spontaneous brain tumours in Sprague-Dawley rats.

Data were collected over a 5-yr period on brain tumours occurring spontaneously among Sprague-Dawley-derived rats in the HRC laboratories. Gliomas, like meningiomas, tended to occur more among males than in females, and in general appeared to be lesions of older rats. Astrocytic tumours of rats were less differentiated than those in man. The characteristic patterns of human glioblastoma multiforme were not observed in this series. Most of the astrocytomas were located in the cerebral areas. Secondary deposits observed in brain included those from tumours of Zymbal's gland, squamous-cell carcinoma, mammary adenocarcinoma, osteosarcoma and lymphoreticular neoplasms.

Age Factors↗
PubMed1986

The toxicity of gossypol to the male rat.

When (+/-) gossypol acetic acid was administered to male Sprague-Dawley rats for 26 weeks, the most significant toxicological finding was marked suppression of body weight gain in rats receiving 25 mg/kg per day. Minor biochemical changes were noted at this dosage level. Terminal studies showed 6 out of 20 rats receiving 25 mg/kg per day to have varying degrees of testicular pathology. Five mg/kg per day was shown to be a "no effect" level.

Animals↗