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Evaluation of the Effects of Ascorbic Acid on Doxorubicin-Induced Hepatotoxicity in Mice Full text
2020
Hatamkhani, Ali | Shirani, Dariush | Rassouli, Ali | Bokaei, Saeed | Dezfoulian, Omid
BACKGROUND: Doxorubicin is one of the most widely used anticancer chemotherapeutic agents in small animal practice. The use of doxorubicin can cause cardiotoxicity, hepatotoxicity, neurotoxicity, and nephrotoxicity. OBJECTIVES: This study was carried out to evaluate the effects of ascorbic acid on doxorubicin hepatotoxicity in mice. METHODS: Twenty-four Balb/c mice were randomly divided into four groups. Group one received normal saline, group two received 100 mg/kg ascorbic acid, group three received 8 mg/kg doxorubicin and group four received ascorbic acid and doxorubicin intraperitoneally, with the same doses of groups 2 and 3. Twenty-one days after injection, the mice were euthanized. The activities of ALP, ALT, AST enzymes and total bilirubin levels in the serum samples were measured. Liver samples were evaluated histopathologically. RESULTS: The activities of ALP, ALT, AST, and total bilirubin levels and histopathologic scores of hepatotoxicity were significantly lower in the group that received ascorbic acid + doxorubicin in comparison to those of the doxorubicin group. CONCLUSIONS: Ascorbic acid may be useful in the prevention of doxorubicin hepatotoxicity in mice. Further studies are recommended for evaluation of the use of ascorbic acid in small animals.
Show more [+] Less [-]Histopathological findings in necrotic spaces developed with doxorubicin and 150 kHz ultrasound at low intensity and a combination of these two methods on adenocarcinoma tumor breast cancer in BALB/c mice Full text
2016
Ghaffari Khaligh, Sahar | tavasoli, abas | Marjanmehr, Seyed Hossein | Soleimani, Homa | Javaheri Vayghan, Abbas
BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women. One in eight women will be diagnosed with breast cancer in their lifetime. Chemotherapy works on active cells. Active cells are cells that are growing and dividing into more of the same type of cell. Cancer cells are active, but so are some healthy cells. Also, scientists work constantly to develop ways of providing treatment with fewer chemotherapy side effects. Objectives: The aim of this study was antitumor effect of simultaneous low-intensity, 150 kHz ultrasound, in combination with the reduced dose of anticancer drug Doxorubicin (DOX) on breast adenocarcinoma using murine model (BALB/c). Methods: Twenty-five female BALB/c mice were used in this study. The tumor was implanted under the breast skin of mice. Mice were divided into five groups, namely control, sham, drug (IV injected of 2 mg/kg of DOX), drug (IV injected of 1 mg/kg of DOX) + US (150 kHz for 15 minutes) and exposure to ultrasound (150 kHz for 15 minutes) alone. The data were analyzed employing ANOVA using SPSS software V.13 and complementary test of Tooki was done. Results: It was shown that, after injection of DOX, exposure to ultrasound at 150 kHz the necrotic spaces in adenocarcinoma tumors compared to control and sham groups have meaningful variance (p<0.001). There was also a significant difference (the bigger the necrotic spaces) between the drug+US group and drug treated group (p<0.05), It should be mentioned that the dose of DOX in drug+US group was reduced to 1mg/kg. Conclusions: The co-administration of DOX and low-intensity ultrasound provided a more effective treatment than the drug alone in murine adenocarcinoma breast cancer. The combined treatment appeared to produce synergistic effects that could prove potentially useful in reducing the side effects of DOX by lowering the required effective dose of the drug while increasing the efficiency of the therapy as a whole.
Show more [+] Less [-]In vitro drug sensitivity in canine lymphoma Full text
2016
In vitro drug sensitivity in canine lymphoma Full text
2016
Introduction: Due to the high heterogeneity of canine lymphoma, the aim of the present study was to test in vitro the chemosensitivity of canine high-grade primary lymphoma cells to various cytostatic drugs commonly used to treat dogs: 4-HO-cyclophosphamide, doxorubicin, dexamethasone, prednisolone, vincristine, etoposide, chlorambucil, lomustine, and cytosine arabinoside. Material and Methods: To determine the cell viability and drug ability to induce apoptosis two different tests were used: an MTT assay and annexin V/propidium iodide staining. Results: Both in vitro tests were found to be useful tools. Significant differences in the sensitivity, depending on the drug type, between B-, T- and mixed/null-type lymphoma cells were found for the majority of the tested drugs. B-type cells were the most sensitive in vitro, whereas T-type cells seemed to be the most resistant. Doxorubicin, chlorambucil, etoposide, and vincristine most strongly reduced the cell viability and induced apoptosis. Conclusion: In vitro assays, such as the MTT test and especially the annexin V/PI assay, may be useful tools for predicting a response to the treatment of high-grade lymphoma in dogs or improving the treatment outcomes in individual animals.
Show more [+] Less [-]In vitro drug sensitivity in canine lymphoma Full text
2016
Pawlak Aleksandra | Obmińska-Mrukowicz Bożena | Zbyryt Iwona | Rapak Andrzej
Introduction: Due to the high heterogeneity of canine lymphoma, the aim of the present study was to test in vitro the chemosensitivity of canine high-grade primary lymphoma cells to various cytostatic drugs commonly used to treat dogs: 4-HO-cyclophosphamide, doxorubicin, dexamethasone, prednisolone, vincristine, etoposide, chlorambucil, lomustine, and cytosine arabinoside. Material and Methods: To determine the cell viability and drug ability to induce apoptosis two different tests were used: an MTT assay and annexin V/propidium iodide staining. Results: Both in vitro tests were found to be useful tools. Significant differences in the sensitivity, depending on the drug type, between B-, T- and mixed/null-type lymphoma cells were found for the majority of the tested drugs. B-type cells were the most sensitive in vitro, whereas T-type cells seemed to be the most resistant. Doxorubicin, chlorambucil, etoposide, and vincristine most strongly reduced the cell viability and induced apoptosis. Conclusion: In vitro assays, such as the MTT test and especially the annexin V/PI assay, may be useful tools for predicting a response to the treatment of high-grade lymphoma in dogs or improving the treatment outcomes in individual animals.
Show more [+] Less [-]Taraxacum Officinale (Dandelion) Roots Extract Mitigates Doxorubicin-Induced HematoCardiotoxicity in Male Albino Rats Full text
2019
Dina R. S. Gad El-Karim
The present study was designed to evaluate the probable ameliorative effect of dandelion extract against doxorubicin hemato-cardiotoxicity. To accomplish this study, four groups of male albino rats (n=7) were used as follow, Group I: served as a control group, Group II: received dandelion extract (200 mg/ kg), Group III: received doxorubicin (2.5 mg/kg) and Group IV: received dandelion extract and doxorubicin identically to groups II and III. Doxorubicin was administrated 3times/week for two consecutive weeks, while dandelion extract was administrated daily for two consecutive weeks before doxorubicin administration and continued during doxorubicin treatment. The results illuminated that, administration of doxorubicin has a deleterious effect on both of blood cellular components and cardiac tissues, which was indicated by significant pancytopenia (decrease in all blood cell types), elevated serum cardiac enzymes activity (CK-MB and LDH), increased serum level of cardiacrelated proteins (troponin I, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) with a depletion of cardiac tissues antioxidant (GSH, and SOD enzyme) and elevated lipid peroxide (MDA) level in this tissues. Coadministration of dandelion extract with doxorubicin significantly alleviated its hemato-cardiotoxic effect which was reflected positively on hematobiochemical changes and cardiac histopathological alterations.
Show more [+] Less [-]Comparison of body surface area-based and weight-based dosage protocols for doxorubicin administration in dogs
1994
Arrington, K.A. | Legendre, A.M. | Tabeling, G.S. | Frazier, D.L.
Pharmacokinetics and toxicity of a single dose of doxorubicin, at dosages of 30 mg/m2 of body surface area and 1 mg/kg of body weight, were compared in 17 dogs. Effects of doxorubicin on complete blood cell count, platelet count, and the dogs' clinical condition were evaluated for 14 days. Cluster analysis, on the basis of clinical signs of doxorubicin toxicosis at the 30-mg/m2 dosage, revealed that 6 of 7 small dogs (less than or equal to 10 kg) became ill, whereas 7 of 10 large dogs (> 10 kg) remained clinically normal. Small dogs that received doxorubicin at a dosage of 30 mg/m2 had higher peak plasma concentrations, greater area under the curve for plasma drug concentration vs time, longer drug elimination half-lives, greater volumes of distribution, and more clinical signs of toxicosis than had large dogs (P less than or equal to 0.05). Five of 9 small dogs that received doxorubicin at a dosage of 30 mg/m2 developed severe myelosuppression (< 1 X 103 granulocytes/microliter). In contrast to the toxicoses with body surface area-based dosing, myelosuppression was not induced in small dogs that received doxorubicin at a dosage of 1 mg/kg. In small and large dogs given doxorubicin at a dosage of 1 mg/kg, pharmacokinetic characteristics and clinical signs of toxicosis were similar. Mean WBC counts and granulocyte counts for all dogs were lower on day 7 with 30 mg of doxorubicin/ m2 (n = 17), compared with that for 1 mg of doxorubicin/kg (n = 14; P S 0.01). This study indicated that a body weight-based (milligram per kilogram) dosing regimen may result in more uniform therapeutic and toxic responses in dogs. Limited toxicosis was observed in dogs weighing > 10 kg treated with doxorubicin with either dosing scheme; however, differences in pharmacokinetic profiles suggested that 1 mg/kg may be an inappropriately low dosage.
Show more [+] Less [-]Use of biological extract of Serratia marcescens to decrease doxorubicin-induced myelosuppression in dogs
1992
Ogilvie, G.K. | Elmslie, R.E. | Cecchini, M. | Walters, L.M. | Pearson, F.C.
Fifteen dogs were given doxorubicin, IV, at a dosage of 30 mg/m(2) of body surface. A commercially available biological extract of Serratia marcescens (BESM) was administered sc to 9 of these dogs (0.04 mg/kg of body weight every third day, n = 2; 0.08 mg/kg every other day, n = 2; and 0.08 mg/kg daily, n = 5), beginning the day after administration of doxorubicin, in an attempt to find an optimal dosage and schedule of administration of BESM to reduce the duration and severity of chemotherapy-induced myelosuppression. Nine additional dogs were randomized into 3 groups of 3 dogs to receive 1 of the following dosages of BESM SC: 0.08, 0.16, and 0.32 mg/kg. Serum was harvested immediately prior to treatment and at 2, 4, 6, 8, 12, 24, 48, and 72 hours from this latter group of dogs for subsequent analysis of canine granulocyte colony-stimulating factor (G-CSF) by enzyme immunoassay. Increasing the dosage and schedule of administration of BESM reduced the duration and severity of doxorubicininduced myelosuppression. Neutrophil counts of the group of dogs given BESM daily at a dosage of 0.08 mg/kg and the controls were evaluated statistically. The neutrophil count increased significantly (P < 0.05) above pretreatment values in BESM-treated dogs after day 7. Median neutrophil counts of the BESM-treated dogs were never significantly lower than pretreatment values, whereas the median counts of the dogs treated with doxorubicin alone were significantly below normal for 6 days (days 7-12). The median counts decreased below normal (< 3,000 cells/microl) for 1 day in the dogs given BESM and doxorubicin, and for 3 days in the dogs that were given only doxorubicin. Four of the 6 dogs not treated with BESM and none of those given BESM developed serious neutropenia (< 1,500/microl). There was an increase in canine G-CSF 4 to 6 hours after BESM was administered to dogs at dosages of 0.16 and 0.32 mg/kg. These findings demonstrate that BESM is capable of reducing the duration and severity of doxorubincin-induced myelosuppression, and that this may be at least partially mediated by G-CSF.
Show more [+] Less [-]Transmissible venereal tumour (TVT) in bitches and therapy: a review Full text
2018
Ülküm Cizmeci, Sakine | Guler, Mehmet
TVT, also known as infectious sarcoma, venereal granuloma, transmissible lymphosarcoma or sticker tumour is a benign reticuloendothelial tumour that affects particularly mucosa of external genital organs and rarely internal genital organs in dogs of both genders. TVT is usually transmitted by coitus but also can be transmitted by licking, sniffing, biting,and scrabbling of the tumour affected area or through damaged skin of mucosa. Transmissible venereal tumour (TVT) is usually observed in stray animals live in tropical and subtropical lands. The affected animals are usually within 9-13 months of age and with high sexual activity. Tumour is frequently located in posterior vagina and vestibulovaginal junction. The averagechromosome count of TVT cells is 59 (57- 64). TVT specific antibodies were found in blood samples of affected animalswhich suggest that they may have a role in natural regression mechanism. The primary objective of tumour treatment is total elimination by surgery, radiotherapy, immunotherapy and/or chemotherapy. Controlling of the disease is very difficult because stray dogs are carriers.
Show more [+] Less [-]Clinical efficacy and toxicity of doxorubicin encapsulated in glutaraldehyde-treated erythrocytes administered to dogs with lymphosarcoma
1994
Matherne, C.M. | Satterfield, W.C. | Gasparini, A. | Tonetti, M. | Astroff, A.B. | Schmidt, R.D. | Rowe, L.D. | DeLoach, J.R.
Doxorubicin was encapsulated in canine erythrocytes, treated with 0.32% glutaraldehyde, and administered at a dosage equivalent to 30 mg of free doxorubicin/m(2) of body surface area to dogs with diagnosis of lymphosarcoma. Compared with administration of free doxorubicin, this method of drug delivery substantially reduced peak plasma concentration and prolonged higher plasma concentration of doxorubicin. As such, this method was comparable to continuous IV infusion. Previous studies have indicated this method's potential for reduction in toxic side effects, particularly cardiotoxicosis, while allowing higher total doses of doxorubicin to be administered. In this study, doxorubicin encapsulated in glutaraldehyde-treated erythrocytes induced a triphasic exponential decay of doxorubicin from plasma, the highest relative contribution to the total area of the curve being the terminal phase. The treatment was effective in inducing complete and partial remissions of lymphosarcoma, with minimal acute toxicosis and no evidence of cardiotoxicosis. However, substantial, unanticipated, chronic, nonregenerative myelosuppression developed, and was most strikingly expressed as profound thrombocytopenia. Efforts to ameliorate or circumvent this toxic effect will be required prior to further consideration of this doxorubicin delivery system for treatment of systemic neoplasia.
Show more [+] Less [-]In vitro assay of nuclear uptake of doxorubicin hydrochloride in osteosarcoma cells of dogs
1991
Weinstein, M.J. | Berg, J. | Kusuzaki, K. | Springfield, D.S. | Gebhardt, M.C. | Mankin, H.J.
A rapid, simple chemosensitivity assay, assessing tumor cell nuclear uptake of doxorubicin hydrochloride, was evaluated in 16 dogs with appendicular osteosarcoma. Doxorubicin was administered to dogs in 5 biweekly treatments, and surgical resection was performed after the second or third treatment, The chemosensitivity assay was performed on biopsy specimens from all dogs before chemotherapy. It was repeated on tissue from resected tumors, and tumors were evaluated histologically to determine the degree of necrosis resulting from chemotherapy. Disease-free and total survival time correlated significantly (P < 0.05 in both cases) with the degree of postchemotherapy necrosis of the primary tumors. Significant correlation was not apparent between the percentage of tumor cells with nuclear uptake of doxorubicin (in either biopsy or resection samples) and disease-free or total survival time. The percentage of cells with nuclear uptake of doxorubicin in surgically resected tumors correlated significantly (P < 0.05) with percentage of necrosis,
Show more [+] Less [-]Pharmacokinetic properties of doxorubicin encapsulated in glutaraldehyde-treated canine erythrocytes
1991
Tonetti, M. | Astroff, A.B. | Satterfield, W. | De Flora, A. | Benatti, U. | DeLoach, J.R.
Canine erythrocytes were loaded with the antineoplastic drug doxorubicin and then treated with 0.16% glutaraldehyde. This procedure has been previously shown to slow down the efflux of doxorubicin from erythrocytes and to result in the selective targeting of the carrier erythrocytes to liver. Three dogs were treated each with 2 different schedules of IV bolus administration of doxorubicin (0.4 mg/kg of body weight): free drug and doxorubicin encapsulated in glutaraldehyde-treated erythrocytes. The 2 treatments yielded consistent differences in the plasma pharmacokinetic properties of doxorubicin and of its only metabolite, doxorubicinol. A triphasic exponential decay of doxorubicin plasma concentrations was observed on injection of the free drug. Conversely, in the case of erythrocyte-encapsulated doxorubicin, 4 phases of plasma concentrations of doxorubicin were found. The plasma concentrations of doxorubicinol, after a steady increase during the first hour, followed patterns of decay comparable to those of the parent drug. On the basis of the kinetic variables calculated with the 2 administration schedules, area under curve concentrations of plasma doxorubicin were 136 microgram.h/L (free infusion) and 734 microgram.h/L erythrocyte-encapsulated drug). Significant alterations of hematologic and hematochemical factors were not observed in the 3 dogs during and after the 2 treatments. On the basis of our findings, doxorubicin-loaded and glutaraldehyde-treated erythrocytes may potentially be used in the treatment of systemic and hepatic tumors in dogs.
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