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The paper describes the case of a 69-year-old man with non-small-cell lung cancer who, owing to a mistake, received intravenously 500 mg of vinorelbine. Within 3 days of intoxication, the bone marrow of the patient was damaged with subsequent pancytopenia that did not respond to treatment. On the fifth day after the poisoning, features of intestinal obstruction appeared. The patient died on the sixth day after the drug overdose. The case presented by us constitutes the first description of a fatal iatrogenic poisoning with this drug.

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A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.

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A new diterpene, identified as (+)-6-(4-hydroxy-4-methyl-2-pentenoyl)-4,6-dimethyl-5-(3-methyl-2-butenyl)-1,3-cyclohexadienecarbaldehyde (1, cubelin), was isolated from a methanol extract of Litsea cubeba fruits by normal phase column chromatography and purified by preparative HPLC. The structure elucidation was conducted by spectroscopic methods (UV, IR, ESI-TOF-MS, 1-D and 2-D NMR). Cubelin exhibited activity against HeLa cell viability and proliferation. The cells also exhibited changes in nuclear morphology which are hallmarks of apoptotic cell death. The presence of cleaved caspase-3/-7, caspase-8 and caspase-9 in the cubelin treated population indicated the potential of the compound to induce apoptosis in HeLa cells via both intrinsic and extrinsic pathways.

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Vincristine (VCR) is a fundamental component of various chemotherapy protocols. Several reports of accidental intramuscular (i.m.) administration or overdose of VCR have been published in the medical literature. We report on an uneventful clinical course of both i.m. and overdose of VCR in a 6-year-old girl with Wilms' tumor. To prevent the administration of overdosed drug by the i.m. route accidentally, chemotherapy should be administrated only by experienced medical doctors.

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Accidental intrathecal vincristine administration results in progressive ascending radiculomyeloencephalopathy usually leading to fatal outcome. No specific therapy for intrathecal vincristine toxicity has been reported. We report a 63-year-old man with diffuse large B-cell lymphoma at the right testis who inadvertently received intrathecal vincristine. Direct CSF aspiration and irrigation was done 30 minutes after the incident. Ventriculostomy and lumbar drain was placed. Intrathecal irrigation was started at 6.5 hours using FFP-containing lactate solution and continued for 11 days. In addition, antineurotoxic and neuroprotective agents were given. His neurological symptom deteriorated slowly and he died on day 12. Among 16 reported cases undergoing lumbar drainage and/or irrigation, 56.3% can survive 30 days or more and 37.5% had survive more than 6 months. Immediate CSF drainage and early irrigation is related to good outcome (prolonged survival with no encephalopathy). In our case, his poor outcome might be due to the delayed starting of irrigation. In conclusion, the appropriate and effective management of this complication is unknown. However, emergency cerebrospinal fluid drainage and irrigation remains the principal of management.

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OBJECTIVE: This paper reports a rare case of an occupational hypersensitivity reaction to an antineoplastic agent. METHODS: This is a clinical case report of a 45-year-old nurse who developed throat irritation and chronic nasal congestion followed by sinusitis shortly after beginning work at an oncological out-patient clinic. The symptoms disappeared upon leaving the clinic two years later, but they returned when she resumed work at the oncology unit at Hillerød Hospital, Denmark, handling chemotherapy on a daily basis. We performed in vitro histamine release tests against nine suspected antineoplastic agents. RESULTS: The patient's histamine release test against the antineoplastic agent etoposide was positive; the other test results were negative. The histamine release test against etoposide using passive sensitization was also negative. Upon leaving the oncology department, the symptoms of the nurse disappeared once again. She was given a diagnosis of rhinosinusitis. CONCLUSION: This case of a hypersensitivity reaction to etoposide was judged to be of occupational origin. It was not clear whether it was immunoglobulin E (IgE) or non-IgE mediated.

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A 6-year-old female neutered Burmese cat received a 10 times overdose (5mg/m(2)) of vincristine, administered in error. Supportive therapy, including administration of calcium folinate, was instigated within 8h. Despite treatment, the patient exhibited deterioration in renal and respiratory function and died 72 h after overdose. Necropsy was performed within 24h of death. Gross examination revealed pulmonary oedema and a pale brown liver with a prominent lobular pattern. Histological examination revealed marked apoptosis and necrosis of the bone marrow myeloid series, and mild to moderate apoptosis and necrosis of the erythroid and megakaryocyte series. Multifocal necrosis of the renal tubules, hepatocytes, and small intestinal crypt epithelium was also observed. Use of calcium folinate as a rescue therapy following vincristine overdose in humans has been previously documented. If treatment is to be successful in cases of vincristine overdose in cats, then a more complete understanding of the pathogenesis of vincristine toxicity in companion animal species is required.

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Vincristine has a high neurotoxicity level. If given intrathecally by accident, it can cause ascending radiculomyeloencephalopathy, which is almost always fatal. The authors report a rare case in which vincristine was accidentally injected intrathecally into a 32-year-old man. The patient, who had Burkitt lymphoma, was neurologically intact, and it is likely that his survival was made possible due to aggressive neurosurgical therapy. After immediate cerebrospinal fluid (CSF) aspiration, external ventricular and lumbar drains were placed for CSF irrigation, which was continued for 6 days. This CSF irrigation was combined with 1) the intrathecal administration of fresh-frozen plasma to bind the vincristine and 2) an intravenous antineurotoxic therapy involving pyridoxine, folic acid, and glutamic acid. The patient's first sensorimotor deficits occurred after 2 days, led to an incomplete sensorimotor dysfunction below T-9 within the next 17 days, but progressed no further. Supported by the scarce data culled from the reviewed literature, the authors hypothesize that prolonged CSF irrigation combined with antineurotoxic therapy contributed to the patient's satisfactory outcome. In conclusion, accidental intrathecal vincristine injection requires emergency and adequate neurosurgical therapy.

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The purpose of the study is a presentation of a fatal case involving an 83-year-old woman, who died due to an overdose of vinblastine-a cytostatic agent of a vinca alkaloid employed in cancer chemotherapy. The postmortem investigation included an autopsy and histological examination, as well as a toxicological analysis of post-mortem specimens collected in the course of autopsy. The authors performed a toxicological assessment of vinblastine employing liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC-MS-MS-APCI). The determined vinblastine concentration levels amounting to 29 ng/g in blood and 52.5 ng/g in liver were in a considerable excess of values encountered in patients on chemotherapy using the drug. The fatality was investigated in the context of medical error. In the described case, the erroneous and medically unjustified administration of vinblastine was identified by a series of unfortunate events involving as many as three acting consecutively individuals: a physician, a pharmacist and a nurse. The report may thus document the clinical course of vinblastine poisoning along with postmortem changes resulting from the drug action.

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Although vincristine sulfate is indicated for IV use only, it has been inadvertently administered intrathecally. Accidental vincristine administration via the spinal route (intrathecally via a lumbar puncture or intraventricularly via an Ommaya reservoir) causes rapid sensory and motor dysfunction, usually followed by encephalopathy, coma, and death (Schulmeister, 2004). Autopsy findings include grossly edematous and congested brain and spinal cord tissue, with axonal degeneration and myelin loss of the spinal nerves (Kwack et al., 1999; Williams et al., 1983).

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The use of alternative medicines is increasing and poorly regulated. We describe a case of severe cyanide poisoning arising from amygdalin, a putative vitamin supplement. A 32-year-old woman arrived in the emergency department by ambulance unresponsive, shocked and with fixed dilated pupils. She was hypothermic and tachycardic but was breathing spontaneously. Despite her age, she had documented breast cancer with hepatic metastases. Conventional treatment having failed, she only took 'vitamin supplements' bought on the Internet, her father said. Over the next 6 h she required mechanical ventilation and increasing doses of inotropes. Diabetes insipidus developed. As the appropriateness of further treatment was considered, a relative arrived with her medications including 'vitamin B 17' or amygdalin. An Internet search identified this as a debunked cancer remedy and cyanogen. Serum thiocyanate level was markedly elevated. She recovered fully over 8 h. While various antidotes to cyanide exist, in this case supportive therapy alone proved effective.

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Severe, life-threatening toxicity may be caused by errors in chemotherapy administration. To contribute with some useful information on drug-induced toxic effects and salvage therapy, we report a case of vinblastine (VBL) overdose (25 mg/m(2)) in a 12-year-old child affected by an end-stage metastatic primitive neuroectodermal tumor. Early signs of toxicity were acute, severe musculoskeletal pain and fever. This was followed by intestinal hypotonia, severe esophagitis, and peripheral neuropathy. Two consecutive plasma exchange procedures were performed at 4 and 18 hr after the administration of the overdose of VBL. The overall toxicity this child experienced was much less severe than expected; this finding, in combination with the known pharmacokinectis data of VBL in children, made us hypothesize that plasma exchange might have had a role in lowering the side effects of drug over dosage.

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BACKGROUND/AIMS: Mature hepatocytes divide to restore liver mass after injury. However, when hepatocyte division is impaired by retrorsine poisoning, regeneration proceeds from another cell type: the small hepatocyte-like progenitor cells (SHPCs). Our aim was to test whether SHPCs could originate from mature hepatocytes. METHODS: Mature hepatocytes were genetically labeled using retroviral vectors harboring the beta-galactosidase gene. After labeling, retrorsine was administered to rats followed by a partial hepatectomy to trigger regeneration. A liver biopsy was performed one month after surgery and rats were sacrificed one month later. RESULTS: We observed the proliferation of small hepatocytes arranged in clusters in liver biopsies. These cells expressed Ki67 antigen and displayed a high mitotic index. At sacrifice, regeneration was completed and clusters had merged. A significant proportion of clusters also expressed beta-galactosidase demonstrating their origin from labeled mature hepatocytes. Finally, the overall proportion of beta-galactosidase positive cells was identical at the time of hepatectomy as well as in liver biopsy and at sacrifice. CONCLUSIONS: The constant proportion of beta-galactosidase positive cells during the regeneration process demonstrates that mature hepatocytes are randomly recruited to proliferate and compensate parenchyma loss in this model. Furthermore, mature hepatocytes are the source of SHPC after retrorsine injury.

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We report a 67-yr-old woman with hepatitis C-related liver cirrhosis and hepatoma who had developed severe bone marrow suppression after taking Cantharanthus roseus as an alternative anticancer treatment. The patient developed severe pancytopenia with initial presentations of vomiting, diarrhea, oral ulcer, and fever about 1 week after taking 5-days' course of Cantharanthus roseus. Bone marrow biopsy showed autolysis, which indicated massive necrosis of the hematopoietic cells. There was no malignant cell infiltration. The patient also had severe gastrointestinal disturbances, bacteremia, urinary tract infection, and impaired renal and liver function. Supportive care with broad-spectrum antibiotics, granulocyte colony-stimulating factor, repeated blood transfusions, and albumin supplement was given. She recovered and was discharged after 48 days hospitalization. Coadministration of Cantharanthus roseus and cisapride was noted, and these two drugs are both substrates of cytochrome P450 3A4 enzymes (CYP 3A4). Because the vinca alkaloids are extensively metabolized by the liver cytochrome P450 enzymes, poor hepatic function and drug-herb interaction might predispose the patient to develop the bone marrow toxicity. This case report demonstrated possible effect of oral dose of vinca alkaloids and also hinted that all the substrates and inhibitors of CYP 3A4 have propensity to interfere with metabolism of vinca alkaloids.

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BACKGROUND: Vincristine, an antineoplastic agent, must never be injected intrathecally because of its devastating neurotoxic effects, which are usually fatal. We report a case of fatal myeloencephalopathy secondary to inadvertent intrathecal administration of vincristine. CASE REPORT: Intrathecal vincristine was inadvertently injected into a twelve-year-old girl with acute lymphocytic leukemia. The error was immediately recognized and treated with cerebrospinalfluid drainage and cerebrospinal fluid exchange. Clinical evolution during the 83 days until death is described Multiple samples of cerebrospinal fluid were assayed for vincristine sulfate. Neuropathological post-mortem changes in the brain and spinal cord are reported CONCLUSION: We compare our case with other previously reported cases in which patient survival was achieved with the same treatment. We summarize preventive measures to avoid such unfortunate occurrences.

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BACKGROUND: Inadvertent intrathecal administration of vincristine has been reported and is uniformly fatal except in two of three cases treated with spinal fluid exchange. We report a case of inadvertent direct intraventricular vincristine administration. CASE REPORT: A 59-year-old woman developed acute lymphocytic leukemia with meningeal involvement and was being treated with intraventricular cytarabine (beta-cytosine arabinoside, Ara-C) injected via an Ommaya reservoir, intravenous (i.v.) vincristine, prednisone, and i.v. daunorubicin. The vincristine (2 mg in 10 mL diluent) was inadvertently injected into her Ommaya reservoir. Within 10 minutes, the error was realized. Despite optimal care, nausea and vomiting developed the first night, followed sequentially by coarse tremor, disorientation, horizontal nystagmus, and stupor. Her mental status waxed and waned until day 9, at which time she became responsive only to noxious stimuli. By day 11, she was deeply comatose and on day 40 she died without regaining any neurological function. CONCLUSION: Despite aggressive and immediate therapy, intraventricular vincristine infusion produced neurologic toxicity, with progressive loss of mental function, followed by coma and death. Systems need to be developed to prevent inadvertent central nervous system administrations.

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