• Biomolecules & Therapeutics
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• v.6 no.3
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• pp.317-327
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• 1998

The subchronic toxicity study of rHuEPO, a newly developed recombinant erythropoietin, was investigated for 13 weeks in Beagle dogs intravenously treated with doses of 100, 500 and 2,500 lU/kg/day. There were no significant changes in body weight, food intake, physical and opthalmic examination, urine analysis, etc. Any toxic response was not observed except for enlarged spleen and extramedullary hematopoiesis. These results indicate that the no-observed adverse effect level (NOAEL) of rHuEPO is 100 lU/kg in Beagle dogs.

• Toxicological Research
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• v.23 no.4
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• pp.391-403
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• 2007

The study was conducted to assess the repeated dose and reproduction and developmental toxicities of acetanilide, an intermediate for drug production, as a part of OECD Screening Information Data Set (SIDS) program. The test agent was administered by gavage at dose levels of 0, 22, 67, 200 and 600 mg/kg to Sprague-Dawley rats (12/group/sex) during pre-mating and mating period for males(up to 30 days) and females and pregnancy and early lactation period for females (up to 39-50 days). At 22 mg/kg, decreases in HGB, HCT (males) and MCHC (females), hyperplasia of spleen red pulp, hyperplasia of femur bone marrow (both sexes) were observed. At 67 mg/kg, salivation (males), reduced food consumption (both sexes), decreases in RBC, HGB, HCT and MCHC (males), increases in MCV (males) and spleen weight (males), hyperplasia of spleen red pulp and femur bone marrow (both sexes) were observed. At 200 mg/kg, decreases in locomotor activity and salivation (both sexes), reduced food consumption (both sexes), decreases in RBC, HGB, HCT and increases in MCV, MCH, BUN, T-BIL (males), enlargement of spleen (both sexes), increased weight of spleen (males), hyperplasia of spleen red pulp and femur bone marrow and extramedullary hematopoiesis of liver (both sexes), atrophy of thymus and corpus luteum hyperplasia of ovary (females) were observed. At 600 mg/kg, decreases in locomotor activity, cyanosis (both sexes), reddish tear, and salivation (males), mortality (4 out of 12 females), decreased body weight (females), reduced food consumption (both sexes), decreases in RBC, HGB, HCT and MCHC and increases in WBC, MCV, MCH, reticulocyte, neutrophil, lymphocyte, monocyte, AST, ALT, BUN, T-BIL, ALB, Ca and A/G ratio (males), enlargement of spleen, increased weights of spleen (both sexes), liver (males), kidney and ovary, decreased weights of thymus (females), hyperplasia of spleen red pulp, hyperplasia of femur bone marrow and extramedullary hematopoiesis of liver (both sexes), and atrophy of thymus and corpus luteum hyperplasia of ovary (females) were observed. Regarding the reproduction and development toxicities, there were no treatment-related changes in precoital time, mating index, fertility index and pregnancy index at all doses tested. At 22 and 67 mg/kg, there were no adverse effects on all the parameters observed. At 200 mg/ kg, decreased body weight of pups (day 4 p.p.) were observed. At 600 mg/kg, decreased body weight of pups (day 0 and 4 p.p.) and viability index (day 4 p.p.), increased incidence of newborns dead or with abnormal clinical signs were observed. The results suggest that the NOAELs for general toxicity are < 22 mg/kg, LOAELs are 22 mg/kg and the NOAELs for reproductive toxicity are 67 mg/kg.

• Biomolecules & Therapeutics
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• v.2 no.3
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• pp.260-269
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• 1994

This study was performed to determine the toxic effect of DA-3030(granulocyte-colony stimulating factor, G-CSF) in beagle dogs. DA-3030(G-CSF) was injected intravenously at doses of 115 $\mu\textrm{g}$/kg/day, 11.5 $\mu\textrm{g}$/kg/day and 1.15 $\mu\textrm{g}$/kg/day seven days per week for 28 days. After completion of the treatments, the dog were necropsied. The number of dead animal was zero in all groups. No specific clinical sign was found, either. In hematological results, WBC was significantly increased dose-dependently in treated groups. In histopathological findings, megakaryocyte and rubricyte were found in the liver and spleen at the dose of 115 $\mu\textrm{g}$/kg/day. Therefore, we could find the extramedullary hematopoiesis was increased. Megaka yocyte and rubricyte were increased in bone marrow, too. In conclusion, those signs were estimated the pharmacological effect of DA-3030(G-CSF). According to the results, non toxic dose of DA-3030(G-CSF) was higher than 115 $\mu\textrm{g}$/kg/day.

• Journal of Veterinary Clinics
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• v.33 no.4
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• pp.231-233
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• 2016

A 10-year-old intact female, mixed breed dog presented with abdominal distention of 2 months duration and three days of decreased appetite. The patient was conscious and no other gross abnormalities were noted. A tentative diagnosis of idiopathic massive hematoma or hemangiosarcoma was made on evaluating all clinical findings. Splenectomy was performed for treatment of abdominal distention and histopathological investigation was initiated to confirm the diagnosis. The hematoma was extremely massive on gross morphology, with the size of $20.2{\times}12.4cm$ and the splenic mass was diagnosed as hematoma formation, with moderate to marked lymphoid hyperplasia and adjacent moderate extramedullary hematopoiesis, based on microscopic description of spleen histology. This is the first case report in veterinary literature of a dog with extremely rare splenomegaly, an unusually large hematoma, with no malignancy or remarkable clinical signs.

• Korean Journal of Veterinary Research
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• v.40 no.3
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• pp.611-625
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• 2000

For the improvement of quality control of laboratory mouse, we investigated the environmental condition, histopathological findings and serological test using ELISA to mouse hepatitis virus(MHV), Mycoplasma pulmonis(MP), Clostridium piliforme(TZ) and Sendai virus (HVJ) of ICR, C57BL/6, CBA and C3H/He mice that were supplied from conventional laboratory animal facility. 1. The ammonia concentration of facility was below the recommended concentration, 15ppm, by the KNIH, and the room temperature($21{\sim}23^{\circ}C$) and relative humidity(40~60%) was optimum range recommend by the Ministry of Health and Welfare, respectively. 2. The incidence rate of inapparent disease was 86.6% and the major findings in the liver were vacuolar degeneration with nucleic pleomorphism. The lung was shown the thickening of alveolar wall and interstitial pneumonia with congestion. The kidney and spleen were observed the mild congestion and extramedullary hematopoiesis, respectively. 3. The positive reaction rates against MHV and MP in serological test was 97.9% and 37.5%, respectively but HVJ and TZ were negative. These results suggest that laboratory mice could be infected with MHV and MP under conventional environments. Therefore we recommend to select thoroughly inapparent infected mice and to convert conventional system into SPF facility as soon as possible.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8629-8631
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• 2016

Background: Primary idiopathic myelofibrosis (PMF) is a clonal Philadelphia chromosome-negative myeloproliferative neoplasm characterized by extramedullary hematopoiesis and marrow fibrosis. It is an uncommon hematopoietic malignancy which primarily affects elderly individuals. The rational of this study was to determine its clinico-epidemiological profile along with risk stratification in Pakistani patients. Materials and Methods: In this retrospective cross sectional study, 20 patients with idiopathic myelofibrosis were enrolled from January 2011 to December 2014. Data were analyzed with SPSS version 22. Results: The mean age was $57.9{\pm}16.5years$ with 70% of patients aged above 50. The male to female ratio was 3:1. Overall only 10% of patients were asymptomatic and the remainder presented with constitutional symptoms. In symptomatic patients, major complaints were weakness (80%), weight loss (75%), abdominal discomfort (60%), night sweats (13%), pruritus (5%) and cardiovascular accidents (5%). Physical examination revealed splenomegaly as a predominant finding detected in 17 patients (85%) with the mean splenic span of $22.2{\pm}2.04cm$. The mean hemoglobin was $9.16{\pm}2.52g/dl$ with the mean MCV of $88.2{\pm}19.7fl$. The total leukocyte count of $17.6{\pm}19.2{\times}10^9/l$ and platelets count were $346.5{\pm}321.9{\times}10^9/l$. Serum lactate dehydrogenase, serum creatinine and uric acid were $731.0{\pm}154.1$, $0.82{\pm}0.22$ and $4.76{\pm}1.33$ respectively. According to risk stratification, 35% were in high risk, 40% in intermediate risk and 25% in low risk groups. Conclusions: The majority of PMF patients were male and presented with constitutional symptoms in our setting. Risk stratification revealed predominance of advanced disease in our series.

• Biomolecules & Therapeutics
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• v.10 no.1
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• pp.59-69
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• 2002

Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. YHB216 is a new rHu-EPO developed by Yuhan Research Institute. In this study, we investigated the single dose and 4-week repeated dose toxicity of YHB216 in Beagle dogs. In the single dose toxicity study, YHB216 was administered intravenously at single dose levels of 0 and 25,000 IU/kg to dogs (2 dogs/sex/group). There were no treament-related changes in survivals, clinical signs, body weight gain, hematological values, blood chemical values, and necropsy finding during experimental period. In the repeated dose toxicity study, YHB216 was administered intravenously to dogs for 4 weeks at the dose levels of 0, 100, 500, and 2,500IU／kg (3 dogs/sex／group). There were no toxicologically significant changes in clinical signs, body weights, food and water consumptions, ophthalmoscopy, urinalysis and blood chemistry. There were increased values of red blood cell, hemoglobin, and hematocrit at all treated groups. Spleen revealed increased weight and extramedullary hematopoiesis at 500 IU/kg or more. These changes are all considered to be Pharmacology-related effects and were recovered after 4-week recovery period. From these results, it is concluded that LD50 value was above 25,000 IU/kg in the single dose toxicity study of YHB216 in dogs and the no observed adverse effect level (NOAEL) was 100 IU/kg day in the repeated dose toxicity study of YHB216 in dogs.

• Korean Journal of Veterinary Research
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• v.36 no.1
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• pp.221-233
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• 1996

This experiment was carried out to study the toxic effect of solublized methylcellulose (MC). Sprague-Dawley rats were dosed with 1%(w/v) MC in 0.9% saline by gavage at a dose of 10ml/kg b.w/day or by intravenous injection at a dose of 5ml/kg b.w/day for 28 days. Clinical signs were observed once a day. Body weights, water and food consumptions were measured and urinalysis was performed several times during the experiment. Rats were sacrificed on days 3, 7, 15 and 28 for hematology, blood chemistry, organ weights and histopathology. The relative weight of the spleen and foamy cells of the spleen were increased in the gavage group. Body weight gain, food consumptions, the values of RBC, Hb, MCH, Hct, serum proteins, glucose, bilirubin, AST, and ALP were decreased in I.V. treatment group. On the other hand, water consumptions, the values of serum cholesterol, creatinine, and BUN were increased. Microscopic findings were granulomas, distended sinusoids, and hypertrophy of Kupffer cells with vacuoles in the liver. Spleen exhibited granuloma, increased extramedullary hematopoiesis, and congestion. Kidney exhibited foamy cells in the glomeruli, distension of the tubules. The findings appeared more severe when the treatment was extended. In conclusion, MC solution is not a safe vehicle for intravenous administration because of the toxic effects on the liver, kidney and spleen. In addition, a long-term and large dosage of oral administration of MC appears to be unsafe also and needs to be investigated further.

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.182-190
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• 1998

DA-3585 is a recombinant human erythropoietin produced by Dong-A pharmaceutical Co. Ltd. using recombinant DNA technique. Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. In this study, we examined acute and subacute toxicity of DA-3585 in rats. DA-3585 was intravenously administered to rats at dose levels of 0, 6,250, 12,500 and 25,000 lU/kg for single dose toxicity study and at dose levels of 0,100,500 and 2,500IU/kg daily for 4 week-repeated dose toxicity study. In the single dose toxicity study, there were no death, clinical signs and changes in body weight gain related to the treatment. Necropsy revealed no evidence of toxicity related to DA-3585, In the repeated dose toxicity study, all the rats survived throughout the study. There were no treatment-related changes in clinical signs, food and water intake, and body weight. Hematological examination showed increases in the number of erythrocytes, hemoglobin concentration, hematocrit value and mean corpuscular volume, and decrease in the number of platelet in 500 and 2,500 lU/kg dosed groups. Extramedullary hematopoiesis in the spleen and erythroid hyperplasia in the bone marrow were noted as treatment-related histological changes. Toxicologically significant changes were not observed in blood biochemistry, urinalysis, organ weights and in any other examinations. The treatment-related changes observed in this study were hematological or histological changes associated with pharmacological effects of DA-3585. On the basis of the results of this study, LD5n value of DA-3585 was above 25,000 lU/kg and the no-observed-adverse-effect-level was estimated to be 100 lU/kg.

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.171-181
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• 1998

DA-3585, a biosynthetic recombinant human erythropoietin has been developed as a treatment for anemia associated with chronic renal failure in Dong-A pharmaceutical Co. Ltd. This study was carried out to assess its acute and subacute toxicities in rabbits. DA-3585 was intravenously administered to rabbits at dose levels of 6250, 12500 or 25000 lU/kg for single dose toxicity study and at dose levels of 100, 500 or 2500 lU/kg/day for 4-week repeated dose toxicity study. In the acute toxicity study, dose up to 25000 lU/kg had no adverse effect on the behavior or body weight gain. Pathological examinations revealed no abnormal gross lesions related to DA-3585. In the subacute toxicity study, all animals survived until termination of treatment. DA-3585 had no influence on clinical signs, food and water intake or on body weight changes. Hematological examination showed increases in the number of RBC, hemoglobin contents and hematocrit values with a dose dependent manner in the animals treated with DA-3585. Histopathological examination revealed erythroid hyperplasia in the bone marrow and extramedullary hematopoiesis in the liver. The changes detected in the hematological and histopathological examination presumably represent exaggerated pharmacological effects of erythropoietin. The NOAEL (no-observed-adverse-effect-level) of DA-3585 was estimated to be 100 lU/kg/ day under this study condition.