Cyclophosphamide Intoxication Research Articles

Complete recovery of a cyclophosphamide overdose after vincristine administration in a dog

AbstractA 4‐year‐old, entire, male boxer diagnosed with a T‐cell multicentric lymphoma was referred for managing cyclophosphamide overdose complications after a prescription mistake during a 19‐week WM‐CHOP rescue protocol (vincristine, cyclophosphamide, doxorubicine, prednisolone). Adverse events included myelosuppression with grade IV neutropenia and thrombocytopenia, fever, haematuria, rectorrhagia and petechiae. With supportive care and the use of granulocyte‐macrophage colony‐stimulating factor, the patient recovered completely 23 days after the overdose. Once recovered, the protocol continued with doxorubicin as a single agent. The dog was euthanased due to lymphoma relapse without overdose sequelae. This case report describes for the first time, a recovery after cyclophosphamide intoxication produced immediately after the administration of vincristine in a cancer patient. Therefore, vincristine at therapeutic dose did not seem to add toxicity synergistically in this patient. Security strategies have to be put in place in all the centres to minimise the risk from these life‐threatening accidents.

Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide-induced renal toxicity and peripheral neuropathy via PPAR-γ mediated inhibition of inflammation and apoptosis

BackgroundPicrorhiza kurroa Royle (Scrophulariaceae) is an important medicinal herb being widely used in variety of ailments. PurposeThe present study was envisaged to evaluate the effects of iridoid glycosides enriched fraction (IGs) from Picrorhiza kurroa rhizome against cyclophosphamide (CP) -induced renal toxicity and peripheral neuropathy. MethodsMice in different groups were pretreated with 25, 50 and 100 mg/kg; p.o. doses of IGs for 21 days, followed by cyclophosphamide intoxication for consecutive two days. Further, to identify the putative role of PPAR-γ receptors for the protective effect of IGs, an additional group of mice were pretreated with PPAR-γ antagonist BADGE (5 mg/kg; i.p.) followed by IGs (100 mg/kg; p.o.) for 21 days before CP intoxication. ResultsIGs pretreatment decreased the hyperalgesic responses toward acetone and heat in acetone drop and tail immersion tests. The abolition of intramyelin odema, cytoplasmic vacuolization and axonal degeneration of sciatic nerve were observed in IGs pretreated mice in a dose-dependent manner. IGs treatment also attenuated the altered serum biochemical markers for renal injury. Furthermore, the treatment prevented renal tubular swelling, granular degeneration and glomerular damage. The levels of IL-1β and TNFα in different group revealed the anti-inflammatory effect of IGs, which was further confirmed by improvement in altered expressions of NF-kB in kidney and sciatic serve. Bax/Bcl-2 expressions and caspase 3/9 activity in renal tissues showed the anti-apoptotic effect of IGs. IGs pretreatment also improved the PPAR-γ expression in the kidney tissues. All the observed protective effects of IGs were suppressed after pretreatment with BADGE. ConclusionPresent study concludes that IGs from Picrorhiza kurroa attenuates CP-induced renal toxicity and peripheral neuropathy via PPAR-γ –mediated pathways.

Clinical, Pathological and Immunohistochemical Evaluation of a Primary Hemangiosarcoma in a Pinscher Dog

Background: Hemangiosarcoma (HSA) is a malignant tumor that arises from the vascular endothelium affecting more often dogs than other species as cats, cows and horses. It comprises approximately 2% of all tumors in dogs. The most common primary site for the HSA in dogs is the spleen, and other locations include the right atrium, pericardium, liver andprostate. Other authors have reported this tumor in lungs, kidney, oral cavity, muscle, bone, urinary bladder, left ventricle, tongue and retroperitoneum. Due to the importance of the HSA in canine species, the aim of this study was to describe the clinical and pathological fndings, besides therapeutic protocol in an unusual case of HSA.Case:A six-year-old male pinscher was referred to the veterinary hospital with a history of cyanosis and choking. The animal was submitted to radiographic examination in lateral cervical view, which identifed the presence of a mass of 1.2 cm in diameter near the pharynx. In order to evaluate the oral cavity, general anesthesia was performed, and it was possible to see a soft, rosy, circumscribed and vascularized lump in pharyngeal region. Due to suspicion of neoplasm, excisional biopsywithout surgical margin was performed. The histopathological exam diagnosed hemangiosarcoma. Immunohistochemistry against vimentin, factor VIII, VEGF and Ki67 was performed and confrmed diagnosis of low grade hemangiosarcoma. Antineoplastic chemotherapy protocol was initiated with doxorubicin and cyclophosphamide every 21 days totaling sixsessions. However, the animal died after the cyclophosphamide intoxication with a three-fold recommended dose (660 mg/m² total in the last session), showing a median survival rate of 220 days.Discussion: The most common primary site for HSA in dogs is the spleen. The pharyngeal location is rare, with only a few reports in literature. In the present case, solitary tumor was observed in pharynx with no involvement of other organs, evidenced by radiographic examination, abdominal ultrasound and echocardiogram, suggesting that pharynx was theprimary location of the tumor. Main features of HSA comprise a solitary nodule or multifocal lesions within the organ or widely disseminated. Histologically, they consist of pleomorphic immature endothelial cells with formation of vascular spaces with variable amount of blood and/or thrombi. In some cases, HSA shows a polymorphic subtype and immunohistochemistry is necessary to provide a defnitive diagnosis. The sample was submitted to histopathological examination which revealed proliferation of endothelial cells with pronounced pleomorphism ranging from polygonals to ovoid, sparse cytoplasm, round to oval nucleus with visible nucleolus, few mitotic fgures, some of them, aberrant, which confrmed diagnosis of HAS. Due to the unusual location, we performed immunohistochemical staining for vimentin, factor VIII,VEGF and Ki67 antibodies to confrm mesenchymal origin of the tumor. In IHC, it was possible to identify positive reac tion for vimentin protein, factor VIII, VEGF and few Ki67 positive cells, confrming histopathological diagnosis. Despite literature describes an aggressive biological behavior of canine HSA, with common occurrence of metastasis, recurrencewas not observed at the site of the removal of the tumor. In histopathological evaluation, it was observed low number ofmitoses, besides the low Ki67 expression on IHC, featuring a low grade tumor with minor ability to metastasize. To the author’s knowledge, this case describes an unusual presentation of HSA, with low metastatic potential, in which chemo therapy protocol achieved survival time of 220 days.Keywords: angiosarcoma, dogs, immunohistochemistry, pharynx.

Protective and Antigenotoxic Effects of Silymarin and Curcumin in Experimental Cyclophosphamide Intoxication in Rats

The aim of this study was to investigate the protective effects of silymarin (SLY) and curcumin (CUR), which have strong antioxidant properties, against the toxic effects of high dose of cyclophosphamide (CP) on the liver and kidneys of rats. For this purpose, a total of 36 adult Wistar albino female rats at the weight of, 250±10 g were used. Biochemical parameters were found to be significantly higher in the CP-only group than in the other groups. In the groups in which SLY and CUR were administered concurrently with CP, biochemical parameters were found to be significantly lower than in the CP-only group. In the SLY+CP and CUR+CP groups, biochemical parameters were correlated with the severity of histopathological findings. In genotoxic examination, the comet parameter levels in the SLY+CP and CUR+CP-treated groups were lower than those in the CP-treated group. The present study established that both SLY and CUR are effective against the toxic effects of high doses of CP.

Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice.

Chemotherapy is an integral part of modern day treatment regimen but anticancer drugs fail to demarcate between cancerous and normal cells thereby causing severe form of systemic toxicity. Among which pulmonary toxicity is a dreadful complication developed in cancer patients upon cyclophosphamide (CP) therapy. Oxidative stress, fibrosis, and apoptosis are the major patho-mechanisms involved in CP-induced pulmonary toxicity. In the present study, we have synthesized Nano-Se, nanotechnology-based new form of elemental selenium which has significantly lower toxicity and acceptable bioavailability. In order to meet the need of effective drugs against CP-induced adverse effects, nano selenium (Nano-Se) was tested for its possible protective efficacy on CP-induced pulmonary toxicity and bone marrow toxicity. CP intoxication resulted in structural and functional lung impairment which was revealed by massive histopathological changes. Lung injury was associated with oxidative stress/lipid peroxidation as evident by increased in reactive oxygen species, nitric oxide level, and malondialdehyde (MDA) formation with decreased in level of antioxidants such as reduced glutathione, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. Furthermore, CP at a dose of 25 mg/kg b.w. increased pulmonary DNA damage ('comet tail') and triggered DNA fragmentation and apoptosis in mouse bone marrow cells. On the other hand, Nano-Se at a dose of 2 mg Se/kg b.w., significantly inhibited CP-induced DNA damage in bronchoalveolar lavage cells, and decreased the apoptosis and percentage of DNA fragmentation in bone marrow cells and also antagonized the reduction of the activities of antioxidant enzymes and the increase level of MDA. Thus, our results suggest that Nano-Se in pre- and co-administration may serve as a promising preventive strategy against CP-induced pulmonary toxicity.

Effects of Cyclophosphamide and Lactulose on the Release of Ammonia and Medium-Molecular-Weight Substances from the Intestine into Blood in Rats

The effects of lactulose on the release of ammonia and medium-molecular-weight substances from the intestine into the blood and on the severity of cyclophosphamide intoxication were studied in rats. The pH and urease-dependent component of ammonia-producing activity of the cecal chyme decreased over 6 h after lactulose administration, while ammonia content in the chyme increased. Cyclophosphamide caused an increase in ammonia and, less so, glutamine level in the portal blood and in the blood collected after decapitation; this drug stimulated release of methylene blue and endogenous substances of medium-molecular-weight to the portal blood. Lactulose was virtually inessential for these changes and for the neurological status, mortality, and medium life span of rats. Hence, lactulose did not prevent cyclophosphamide-induced leakage of ammonia and medium-molecular-weight substances from the gastrointestinal tract into blood and did not reduce the severity of intoxication.

Aggravation of Cyclophosphamide-Induced Acute Neurological Disorders under Conditions of Artificial Acidification of Chyme in Rats

The effect of artificial acidification of the intestinal content on neurological manifestations of acute severe cyclophosphamide intoxication was studied in rats. The animals were gavaged with 20 ml/kg sulfuric (0.05 M), hydrochloric, boric, or lactic acids (0.1 M) 3 h before intraperitoneal injections of the cytostatic in doses of 0, 200, 600, or 1000 mg/kg. The decrease in pH (by.0) and ammonia-producing activity of the cecal chyme developed within 3 h after administration of acids. Cyclophosphamide caused hyperammonemia; glutamine/ammonia and urea/ammonia ratios in the blood decreased. These changes augmented after administration of acids (boric acid produced maximum and lactic acid minimum effects). Acid treatment resulted in greatest elevation of ammonia level in the portal venous blood and a lesser elevation in the vena cava posterior blood. Acid treatment promoted manifestation of cyclophosphamide neurotoxic effect and animal death. Hence, acidification of the chyme inhibited the formation of ammonia in it, while ammonia release from the gastrointestinal tract into the blood increased; the treatment augmented hyperammonemia and aggravated the neurological manifestations of cyclophosphamide intoxication.

Correction of cyclophosphan hepatotoxicity by water-soluble polysaccharides from Tussilago farfara and Acorus calamus

In experiments on rats with Walker-256 carcinosarcoma the ability of water-soluble polysaccharides from Tussilago farfara and Acorus calamus influence on efficiency antineoplastic therapy and hepatotoxicity investigated. Polysaccharides reduce a level of liver enzymes in blood serum of rats at cyclophosphamide damaged liver, as well as increase the antimetastatic effect of cytostatics. Water-soluble polysaccharides from Acorus calamus restore most efficiently biochemical disturbances at cyclophosphamide intoxication.

Increase of Ammonia Pool in the Gastrointestinal Tract of Rats Potentiates Acute Toxicity of Cyclophosphamide

For evaluation of the impact of changes of ammonia pool in the gastrointestinal tract on acute toxicity of cyclophosphamide, the dynamics of blood levels of ammonia and urea of rats was studied after intraperitoneal injection of cyclophosphamide (600 mg/kg) and clinical manifestations of intoxication and lifespan of rate were studied after cyclophosphamide injections in doses of 200, 600, 1000, and 1400 mg/kg alone or in combination with ammonium acetate. Ammonium acetate stimulated the hyperammoniemic and uremic effects of cyclophosphamide. Combined effects of the toxicants were associated with symptoms characteristic of acute poisoning with ammonium salts; these symptoms were not observed under the effect of ammonium acetate alone. Ammonium acetate stimulated the lethal effect of cyclophosphamide injected in doses of 200, 600, 1000, or 1400 mg/kg: the mean lifespan of rats decreased by 1.5, 2.1, 2.8, or 6.1 times, respectively. These data indicate that ammonia redistribution from the gastrointestinal tract into circulating blood is one of the mechanisms of thanatogenesis in acute cyclophosphamide intoxication.

Cyclophosphamide-induced leakage of gastrointestinal ammonia into the common bloodstream in rats

The kinetics of ammonia of gastrointestinal origin has been studied in rats in hematopoietic or neurovascular forms of acute lethal cyclophosphamide intoxication. Portal and caval blood ammonia, glutamine and urea, and blood markers of cytolysis were determined, and transperitoneal ammonia and glutamine fluxes were estimated after the single high-dose cyclophosphamide intraperitoneal (i.p.) administration. Within 3 hours after the administration of cyclophosphamide (200, 600, or 1,000 mg/kg), the portal ammonia level increased 1.4, 1.8, and 2.5 times, respectively; the ammonia level in v. cava caud. caudally of vv. renales inflow increased 1.5, 2.1, and 3.3 times, and cranially of vv. hepaticae, 1.8, 2.7, and 4.2 times, respectively; glutamine:ammonia and urea:ammonia ratios decreased. The rate of ammonia and glutamine accumulation in saline solution injected i.p. exceeded that in control rats dose dependently. At 18 hours after the administration of cyclophosphamide, the increased blood ammonia, glutamine and urea, and glutamine:ammonia ratio persisted. Therefore, in the rat, the high-dose i.p. administration of cyclophosphamide induces the early hyperammonemia, resulting from the enhanced transperitoneal diffusion of gastrointestinal ammonia into the blood, combined with the restriction of glutamine and urea synthesis. These alterations may contribute to neurological complications of myelosuppressive therapeutic regimens of cyclophosphamide administration.

Modulation of cyclophosphamide-induced early lung injury by curcumin, an anti-inflammatory antioxidant.

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid. Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angiotensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection by catatoxic steroids against cyclophosphamide-induced organ lesions.

In rats, fatal cyclophosphamide intoxication can be prevented by certain catatoxic steroids, particularly PN (pregnenolone-16α-nitrile), SC-11927 and spironolactone. Numerous other steroids, known to possess catatoxic activity against different poisons fail to prevent cyclophosphamide intoxication.