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PubMed2006

Role of thiamine in managing ifosfamide-induced encephalopathy.

Encephalopathy is a well known side effect of ifosfamide, developing in approximately 10-30% of patients exposed to the drug. It is generally reversible after discontinuing the therapy; however cases of fatal neurotoxicity have been reported. Methylene blue is commonly used in the treatment and prophylaxis of ifosfamide induced encephalopathy; however its efficacy is moderate at best. We report here the utility of thiamine in both treating and preventing ifosfamide induced neurotoxicity in three patients. With the use of intravenous thiamine encephalopathy resolved in all of our patients within a mean time of 17 hours (range 10-30 hours). In three cycles where thiamine was used as prophylaxis no evidence of ifosfamide induced encephalopathy was seen. Thiamine appears to be a safe and effective treatment for reversing encephalopathy resulting form ifosfamide infusion, without any significant side effects.

Adult↗
PubMed1998

Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity.

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

Adolescent↗
PubMed1989

Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study.

Ifosfamide (isophosphamide) and mesna (2-mercaptoethane sodium sulfonate) were administered intravenously at monthly intervals to 46 patients with advanced epithelial ovarian carcinoma refractory to or recurrent after cisplatin-containing combination chemotherapy. Initially, ifosfamide was given as 1.5 g/m2/d x 5 days and mesna as 300 mg/m2 every 4 hours for three doses following ifosfamide, but the initial dose of ifosfamide was reduced to 1.2 g/m2 because of toxicity. Four of the patients initially entered were found to be ineligible: two who had had more than one prior chemotherapy regimen and two who did not have ovarian primaries. One patient received an inadequate trial and four patients had discontinuation of therapy because of toxicity, leaving 41 evaluable for response. Three patients (7.0%) had complete responses and five (13.0%) had partial responses for an overall response rate of 20.0%. Response duration ranged from 2.1 to 20.3 + months with a median of 6.9 + months. Two patients died of renal failure, one of whom had no known renal disease and received 1.5 g/m2/d x 5 days ifosfamide. The second patient received the 1.2 g/m2 dose and was found to have chronic pyelonephritis and pyonephrosis at autopsy. Gynecologic Oncology Group (GOG) grade 3 or 4 granulocytopenia was seen in eight (19.5%), grade 3 or 4 thrombocytopenia in four (9.8%), and grade 3 or 4 neurotoxicity in six (14.6%) of the 41 patients evaluable for toxicity. Ifosfamide/mesna is active in epithelial ovarian cancer. GOG trials in untreated patients are being initiated and toxicity is being evaluated.

Carcinoma↗
PubMed1990

High-dose ifosfamide with mesna uroprotection: a phase I study.

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.

Blood↗
PubMed1991

Long-term follow-up of ifosfamide renal toxicity in children treated for malignant mesenchymal tumors: an International Society of Pediatric Oncology report.

The renal function of 74 children with malignant mesenchymal tumors in complete remission and who have received the same ifosfamide chemotherapy protocol (International Society of Pediatric Oncology Malignant Mesenchymal Tumor Study 84 [SIOP MMT 84]) were studied 1 year after the completion of treatment. Total cumulative doses were 36 or 60 g/m2 of ifosfamide (six or 10 cycles of ifosfamide, vincristine, and dactinomycin [IVA]). None of them had received cisplatin chemotherapy. Ages ranged from 4 months to 17 years; 58 patients were males and 42 females. The most common primary tumor site was the head and neck. Renal function was investigated by measuring plasma and urinary electrolytes, glucosuria, proteinuria, aminoaciduria, urinary pH, osmolarity, creatinine clearance, phosphate tubular reabsorption, beta 2 microglobulinuria, and lysozymuria. Fifty-eight patients (78%) had normal renal tests, whereas 16 patients (22%) had renal abnormalities. Two subsets of patients were identified from this latter group: the first included four patients (5% of the total population) who developed major toxicity resulting in Fanconi's syndrome (TDFS); and the second group included five patients with elevated beta 2 microglobulinuria and low phosphate reabsorption. The remaining seven patients had isolated beta 2 microglobulinuria. Severe toxicity was correlated with the higher cumulative dose of 60 g/m2 of ifosfamide, a younger age (less than 2 1/2 years old), and a predominance of vesicoprostatic tumor involvement. This low percentage (5%) of TDFS must be evaluated with respect to the efficacy of ifosfamide in the treatment of mesenchymal tumors in children.

Acute Kidney Injury↗
PubMed1992

No benefit of ifosfamide in Ewing's sarcoma: a nonrandomized study of the French Society of Pediatric Oncology.

PURPOSE: To undertake a new protocol with the goals of improving the chemotherapeutic treatment of pediatric Ewing's sarcoma by introducing ifosfamide, and to widen the indications for surgical resection of Ewing's tumor to obtain better local control and to reduce radiation doses. PATIENTS AND METHODS: The French Society of Pediatric Oncology initiated its first cooperative Ewing's sarcoma study in 1978, using a four-drug regimen (cyclophosphamide, dactinomycin, Adriamycin [doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France], and vincristine). Ninety-five patients were included, and, at 5 years, the disease-free survival reached a plateau of 51%. After encouraging responses of recurrent soft tissue or bone sarcomas to ifosfamide, a second study began in 1984 using a new chemotherapy regimen in which cyclophosphamide was replaced by ifosfamide. Sixty-five patients were treated. RESULTS: By February 1992, the median follow-up was 5.8 years. The estimated 5-year disease-free survival was 52%. We observed unexpected cardiac toxicity. Three patients experienced acute cardiac failure that was lethal in two cases. The acute toxicity of ifosfamide prompted us to stop the protocol. Retrospectively, the lack of efficacy reinforced our decision. CONCLUSION: We conclude that ifosfamide did not improve the outcome of the patients despite the fact that these two treatment regimens were not randomized.

Bone Neoplasms↗
PubMed1993

Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas.

PURPOSE: This three-armed phase III study in adults with advanced soft tissue sarcomas was planned as a comparison of objective regression rates, toxicity, and survival of patients receiving doxorubicin alone, ifosfamide plus doxorubicin, and mitomycin plus doxorubicin plus cisplatin. PATIENTS AND METHODS: Between December 1987 and July 1990, 279 patients with histologically confirmed sarcomas were enrolled to receive treatment A (doxorubicin 80 mg/m2), treatment B (ifosfamide 7.5 g/m2 plus doxorubicin 60 mg/m2), or treatment C (mitomycin 8 mg/m2 plus doxorubicin 40 mg/m2 plus cisplatin 60 mg/m2). RESULTS: Of 262 assessable patients, 74 (29%) achieved objective tumor regression. Objective regression occurred in 20% of the 90 patients who received doxorubicin alone (complete remission [CR] rate, 2%), in 34% of the 88 who received ifosfamide plus doxorubicin (CR rate, 3%), and in 32% of the 84 who received mitomycin plus doxorubicin plus cisplatin (CR rate, 7%). With grade 3 or greater myelosuppression in 53% of group A, 80% of group B, and 55% of group C, regimen B was significantly more myelosuppressive than either regimen A or C (P = .01) with two, three, and one treatment-related deaths, respectively. Synovial sarcomas were responsive to ifosfamide plus doxorubicin, especially among patients younger than 40 years of age. CONCLUSION: Ifosfamide plus doxorubicin produced a significantly higher regression rate (P = .03) than did doxorubicin alone; however, this was achieved at a level of myelosuppression significantly more intense than that produced by the single agent or by the three-drug combination. Mitomycin, doxorubicin, and cisplatin also appeared to be more active than the single agent; however, at a myelosuppression level similar to that of doxorubicin alone, this trend (P = .07) did not attain the usual level for significance. No significant survival differences were observed.

Adult↗
PubMed1994

High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group.

PURPOSE: This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer. PATIENTS AND METHODS: Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response. RESULTS: The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%). CONCLUSION: High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.

Adult↗
PubMed1999

Treatment of invasive thymoma with single-agent ifosfamide.

PURPOSE: To evaluate single-agent ifosfamide in the treatment of invasive thymoma. PATIENTS AND METHODS: Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m(2) was given on days 1 to 5, with mesna as a uroprotector. RESULTS: Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated. CONCLUSION: Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.

Adult↗
PubMed2005

Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Adolescent↗
PubMed1989

Inhibition of ifosfamide-induced urotoxicity by disulfiram in mice.

The effect of disulfiram on the urotoxicity induced by ifosfamide was studied in mice. Ifosfamide administered intraperitoneally to mice caused a dose-related increase in bladder weight within 48 hr of treatment. Disulfiram prevented ifosfamide-induced bladder damage when administered orally within 1 hr of ifosfamide treatment. The results indicate that disulfiram is an effective protective agent against bladder damage caused by ifosfamide treatment.

Administration, Oral↗
PubMed1990

Genetically engineered V79 Chinese hamster cells metabolically activate the cytostatic drugs cyclophosphamide and ifosfamide.

V79 cells, genetically engineered to express active cytochromes P450IIB1 and P450IA1, were used to study the cytotoxicity and mutagenicity of cyclophosphamide and ifosfamide. Cyclophosphamide, tested up to a concentration of 2 mM, was not cytotoxic in V79 nor in the P450IA1-expressing V79-derived cell line XEM2. Pronounced cytotoxicity was, however, observed in the P450IIB1-expressing V79-derived cell line SD1. Induction of gene mutations (acquisition of 6-thioguanine resistance) was observed in SD1 cells as well, but the effects were weak. Ifosfamide was inactive in V79 cells, but was cytotoxic in SD1 cells. Ifosfamide mustard, an active metabolite of ifosfamide, was equally cytotoxic and showed similar mutagenic effects in SD1 and parental V79 cells. The results indicate that cyclophosphamide and ifosfamide are metabolically activated by cytochrome P450IIB1. In contrast, cytochrome P450IA1 was not capable of activating cyclophosphamide. Thus, V79-derived cell lines defined for their expression of a specific form of cytochrome P-450 can be used as diagnostic tools to identify the cytochrome P-450 that is responsible for the metabolic activation of drugs.

Animals↗
PubMed2003

Vascular neurotoxicity following chemotherapy with cisplatin, ifosfamide, and etoposide.

OBJECTIVE: To report a case of acute central nervous system (CNS) toxicity with multiple hemorrhages restricted to the corpus callosum associated with combination therapy of cisplatin, ifosfamide, and etoposide. CASE SUMMARY: A 38-year-old white man with a testicular germ cell tumor received a cisplatin-based chemotherapy consisting of cisplatin 45 mg (20 mg/m2), etoposide 570 mg (250 mg/m2), and ifosfamide 4600 mg (2000 mg/m2) given on 5 consecutive days during each course. After the first course of chemotherapy, the patient appeared to be neuropsychologically impaired with episodes of decreased alertness and features of a depressive syndrome. He became severely diminished in mental function, orientation, and psychomotor activity after a second course of treatment. In addition, he showed transient urinary incontinence. Motor and sensory deficits could not be detected. Magnetic resonance imaging demonstrated multiple hemorrhages restricted to the corpus callosum. An objective causality assessment revealed that an adverse drug reaction was probable. DISCUSSION: Neurotoxicity has been associated with the administration of various antineoplastic agents. In particular, cisplatin and ifosfamide can cause both acute and delayed CNS toxicity. While ifosfamide neurotoxicity has been predominantly associated with neuropsychological impairment without evidence of structural abnormalities in neuroimaging studies, cisplatin has been shown to cause cerebrovascular complications. Various pathophysiologic conditions may contribute to these complications including thrombosis secondary to vascular endothelial injury or thromboembolic events. To our knowledge, as of December 2, 2003, vascular lesions restricted to the corpus callosum have not been reported as a complication of cisplatin- or ifosfamide-based chemotherapy. CONCLUSIONS: Clinicians should be aware of the potential neurovascular adverse effects of cisplatin-based protocols. This is especially true in patients with subtle neurologic or neuropsychological symptoms. Chemotherapy-induced neurotoxicity should be considered in the differential diagnosis.

Adult↗
PubMed2006

Methylene blue for management of Ifosfamide-induced encephalopathy.

OBJECTIVE: To evaluate the use of methylene blue for the treatment of ifosfamide-induced encephalopathy. DATA SOURCES: MEDLINE (1966-August 2005) and International Pharmaceutical Abstracts (1971-August 2005) were searched using the terms methylene blue, ifosfamide, encephalopathy, and neurotoxicity. DATA SYNTHESIS: Several case reports and one retrospective chart review described the use of methylene blue for ifosfamide-induced encephalopathy, but no controlled clinical trials were found. Methylene blue appeared to aid in the resolution of encephalopathic symptoms as rapidly as within 10 minutes of administration in some patients, but it had modest efficacy in most patients. Symptoms in patients who did not receive methylene blue resolved in the same time frame; this indicates that ifosfamide-induced encephalopathy may resolve without treatment. CONCLUSIONS: Available data from case reports indicate that methylene blue is an option in the treatment of ifosfamide-induced encephalopathy, especially in patients with severe symptoms of toxicity. However, the lack of controlled clinical trials and the possibility of spontaneous resolution of encephalopathy make the usefulness of methylene blue unclear.

Humans↗
PubMed1993

High-dose ifosfamide is associated with severe, reversible cardiac dysfunction.

OBJECTIVE: To determine the incidence and characterize the occurrence of cardiac toxicity with high-dose ifosfamide. DESIGN: Retrospective chart review. SETTING: Biomedical research referral center. PATIENTS: Fifty-two consecutive patients with advanced lymphoma or carcinoma enrolled in phase I trials of high-dose ifosfamide as part of combination chemotherapy with autologous bone marrow transplantation. INTERVENTIONS: Patients were given escalating doses (10 to 18 g/m2) of ifosfamide in combination with carboplatin and etoposide or with lomustine and vinblastine. MEASUREMENTS: The chart review focused on clinical, radiographic, or electrocardiographic evidence of cardiovascular dysfunction. Data from invasive hemodynamic monitoring, radionuclide cineangiography, and echocardiography were also reviewed. RESULTS: Nine of the patients treated with ifosfamide developed congestive heart failure (17%; 95% Cl, 8% to 30%). Eight of these patients, experiencing dyspnea, tachycardia, weight gain, and signs of pulmonary edema, required admission to an intensive care unit. Left ventricular contractility was found to be depressed when evaluated by radionuclide cineangiography, echocardiography, or both. Most patients responded to diuretic, vasodilator, and inotropic therapies. Two patients developed malignant ventricular arrhythmias. One patient died of intractable cardiogenic shock. Five patients died of multiorgan failure, despite showing improvement in left ventricular ejection fraction. Three patients survived and regained baseline left ventricular ejection fraction. CONCLUSIONS: High-dose ifosfamide is associated with severe but usually reversible myocardial depression and malignant arrhythmias.

Adolescent↗
PubMed2001

Insights into the mechanisms of ifosfamide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cellular acidification in mouse cortical neurons.

Therapeutic value of the alkylating agent ifosfamide has been limited by major side effects including encephalopathy. Although the underlying biochemical processes of the neurotoxic side effects are still unclear, they could be attributed to metabolites rather than to ifosfamide itself. In the present study, the effects of selected ifosfamide metabolites on indices of neuronal activity have been investigated, in particular for S-carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA). Because of structural similarities of SCMC with glutamate, the Ca(2+)(i) response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca(2+)(i) concentration that could be abolished by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but only partly diminished by the N-methyl-D-aspartate receptor antagonist 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK=801). Cyclothiazide (CYZ), used to prevent AMPA/kainate receptor desensitization, potentiated the response to SCMC. Because activation of AMPA/kainate receptors is known to induce proton influx, the intracellular pH (pH(i)) response to SCMC was investigated. SCMC caused a concentration-dependent acidification that was amplified by CYZ. Since H(+)/monocarboxylate transporter (MCT) activity leads to similar cellular acidification, we tested its potential involvement in the pH(i) response. Application of the lactate transport inhibitor quercetin diminished the pH(i) response to SCMC and TDGA by 43 and 51%, respectively, indicating that these compounds may be substrates of MCTs. Taken together, this study indicates that hitherto apparently inert ifosfamide metabolites, in particular SCMC, activate AMPA/kainate receptors and induce cellular acidification. Both processes could provide the biochemical basis of the observed ifosfamide-associated encephalopathy.

Animals↗
PubMed2002

[Continuous-infusion high dose ifosfamide as salvage treatment for pre-treated soft tissue sarcoma].

BACKGROUND & OBJECTIVE: Adriamycin, dacarbazine and ifosfamide are three effective chemotherapy drugs in treating progressive soft tissue sarcoma. However, few regimen is effective for the patients who failed in treatment with prior Adriamycin and ifosfamide at standard dose. This study was designed to observe and evaluate the efficacy and toxicity of high dose ifosfamide(HDI) regimen on pre-treated soft tissue sarcoma. METHODS: Ten patients with advanced soft tissue sarcoma and 5 patients after surgical resection were treated with HDI administered by continuous infusion at a dose of 14 g/m2 per cycle over 6 days. All patients were pretreated with anthracycline +/- standard dose ifosfamide. RESULTS: An overall response rate of 40% was observed with 2 complete and 2 partial remission. In the follow up at 4-48 month, the overall median survival time was 21 +/- 3.29 months and the median response duration was 6 +/- 1.45 months. The major toxicity was myelosuppression. 45.9% patients experienced grade 3-4 neutropenia. CONCLUSION: HDI is an active salvage regimen in anthracycline +/- standard dose ifosfamide pretreated soft tissue sarcoma.

Adolescent↗
PubMed2003

[Polymorphism at the glutathione S-transferase pi locus as a risk factor for ifosfamide nephrotoxicity in children].

The aim of the study was an assessment of various risk factors for nephrotoxicity of ifosfamide (IF) in children taking into account the importance of the concentrations of toxic metabolites of the drug excreted with urine and the polymorphism of genes encoding S-glutathione transferases of mi, pi, and theta classes (GSTM1, GSTP1 and GSTT1). The study was carried out in 37 children aged 2-17 years (mean age 8.9 +/- 4.5 years) treated with IF in 3 g/m2 dose for various malignant diseases. For the assessment of the incidence of deletion of GSTM1 and GSTT1 genes PCR method was applied while in the case of GSTP1 gene the polymorphism of A-G codon 105 was detected by the PCR-RFLP method. Before and after each treatment cycle the cumulative ifosfamide dose was calculated and the biochemical indices of renal canalicular and glomerular function were assessed which were graduated according to extended WHO criteria. Additionally, nuclear magnetic resonance 31P NMR method was applied for calculation of the concentrations of ifosfamide nephrotoxic metabolites and of the unchanged drug excreted with urine. The analysis performed demonstrated that in children with GSTP1 gene A-G codon 105 transition, a statistically significantly (p = 0.01) higher urinary excretion of toxic ifosfamide metabolites occurred, that increased with the cumulative drug dose. The age, sex and deletions of GSTM1 and GSTT1 genes exerted no effect on the concentrations of the toxic metabolites excreted with urine. The results of the studies demonstrate that GSTP1 gene mutations are the genetic risk factor for nephrotoxic complications of ifosfamide use.

Adolescent↗