Biomedical subjects

T Cerny

Publications and source records attributed to T Cerny.

At least 73 records · Page 4Linked to original sources

PubMed1997

Cladribine (2-CDA) given as subcutaneous bolus injections is active in pretreated Waldenström's macroglobulinaemia. Swiss Group for Clinical Cancer Research (SAKK).

Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenström's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration-time profile is very different from intravenous administration. We designed this phase II multi-institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenström's macroglobulinaemia. Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44-85). All except one patient had been pretreated with more than one regimen (median 2, range 0-10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0.5 mg/kg per cycle as s.c. bolus injections divided over 5 d at > or = 4 week intervals, for a maximum of six cycles. All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1-6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21-61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range 0.5-33) and 8 months (5-29), respectively. Four patients (16%) suffered from infections W.H.O. grade > or = 2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed. Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenström's macroglobulinaemia and resulted in durable remissions.

Adult↗

PubMed1997

Five putative drug resistance parameters (MDR1/P-glycoprotein, MDR-associated protein, glutathione-S-transferase, bcl-2 and topoisomerase IIalpha) in 57 newly diagnosed acute myeloid leukaemias. Swiss Group for Clinical Cancer Research (SAKK).

UNLABELLED: Using a modified quantitative reverse transcriptase (RT) PCR assay in 57 patients with acute myeloid leukaemia (AML) from a Swiss Phase III multicentre study (SAKK 30/85), we measured the m-RNA expression of the genes from the multidrug resistance gene 1 (MDR1), the multidrug resistance associated protein (MRP), glutathione-S-transferase (GST) pi, bcl-2 and topoisomerase (topo) IIalpha. P-glycoprotein (p-gp) was measured by Western blot, and GST activity by functional assays. To analyse progression-free (PFS) and overall survival (OS), parameters were prospectively divided into "low" and "high" groups, according to their median values (exceptions: MDR1 and p-gp). Median follow-up was 60 months. RESULTS: MDR1- and MRP mRNA levels correlated with each other (r=0.54, Spearman), FABM4/M5 and extramedullary disease. "Low" bcl-2-mRNA predicted longer PFS: 22 months vs. 7 months (median,p=0.02, log rank), and longer OS: 64 months vs. 14 months (p=0.06). "Low" topo IIalpha predicted poorer outcome: median PFS 9 vs. 19 months (p=0.03); median survival 12 months vs. "not reached" (p=0.03). An improved outcome tendency, albeit nonsignificant, was seen in p-gp-negative patients. In a Cox model adjusted for age, performance status, presence of Auer rods, FAB type and clinical response, bcl-2 and topo IIalpha mRNA levels retained their predictive values.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Dose-finding study of paclitaxel and cyclophosphamide in women with advanced breast cancer.

The primary aim of this study was to define the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion and cyclophosphamide given by intravenous bolus every 3 weeks in patients with breast cancer. Patients had received a maximum of one prior chemotherapy for advanced disease. The maximum tolerated dose of the combination was also determined with granulocyte colony-stimulating factor (G-CSF) support. The 80 women who took part in this study received 347 fully evaluable courses of therapy. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2; G-CSF support (5 microg/kg subcutaneously) was added at the subsequent cycle if specific dose-limiting toxicities had occurred during the previous cycle. Febrile neutropenia and severe thrombocytopenia defined the maximum tolerated doses as paclitaxel 200 mg/m2 and cyclophosphamide 2,000 mg/m2, with or without G-CSF support, in patients with or without a prior chemotherapy. Recommended doses were paclitaxel 200 mg/m2 and cyclophosphamide 1,750 mg/m2 in these two groups of patients. The overall response rate was 25% among patients who had received prior therapy for metastatic disease and 50% in patients who had not been previously treated. Complete remissions were reported in 9% of patients, but only among those who were previously untreated.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy.

In cancer chemotherapy with ifosfamide the occurrence of a drug-related encephalopathy represents a severe adverse-effect of unknown origin. We found that the underlying mechanism resides in the mitochondrial toxicity of ifosfamide metabolites. The electron accepting drug methylene blue can substitute for the demonstrated flavoprotein deficiency and its administration leads to resolution of the encephalopathy in patients. The prophylactic administration of methylene blue is equally effective via another principal mechanism, namely oxidation of the excessive quantity of NADH formed during ifosfamide metabolism. The inhibition by methylene blue of multiple amine oxidase activities also prevents formation of the neurotoxic chloroacetaldehyde from ifosfamide-derived chloroethyl amine. Thus, methylene blue exhibits several synergistic modes of actions which enable the dose-limiting neurotoxicity of alkylating chemotherapy with ifosfamide in cancer patients to be overcome.

Administration, Oral↗

PubMed1996

Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer.

Amplification of the CCDN1 gene encoding cyclin D1 was examined by Southern blotting and multiplex polymerase chain reaction (PCR) and occurred in 8 of 53 patients (15%) with primary resected non-small-cell lung cancer (NSCLC). These tumours and 17 additional tumours with a normal gene copy number showed overexpression of cyclin D1 (25/53, 47%), as assessed by immunostaining using a monoclonal antibody. In 22/25 cases, cyclin D1 was localised in the cytoplasm, but some (7/25) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3'untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29/53 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin D1 overexpression was associated with a poorly differentiated histology (P = 0.04), less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin D1 overexpression (P = 0.01, Cox regression analysis). We conclude that genetic alteration of cyclin D1 is a key abnormality in lung carcinogenesis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC.

Aged↗

PubMed1996

2-chlorodeoxyadenosine (2-CDA) therapy in previously untreated patients with follicular stage III-IV non-Hodgkin's lymphoma.

PURPOSE: This phase II multi-institutional trial was designed to assess response and toxicity of 2-chlorodeoxyadenosine (2-CDA) in patients with previously untreated follicular lymphoma. The clinical significance of detecting cells carrying the t(14;18) translocation (bcl-2/JH rearrangement) in peripheral blood and bone marrow by polymerase chain reaction (PCR) before, during and after treatment was also examined. PATIENTS AND METHODS: Between May 1993 and October 1995, 37 patients were accrued: male/female: 15/22, median age 51 years (range: 20-78), stage III/IV: 9/28. Patients received a total 2-CDA dose of 0.7 mg/kg as continuous s.c. or i.v. infusions over 7 days, every 28 days for a maximum of 5 cycles. A total of 165 cycles were administered. In 25 patients, blood and bone marrow before, during and after treatment were available for PCR analysis of the bcl-2/JH rearrangements. RESULTS: All 37 patients were evaluable for response and toxicity. The overall response rate was 84% (95% confidence interval, 68%-94%) with 14% CR (n = 5) and 70% PR (n = 26) and a median time to treatment failure of 15.7 months. bcl-2/JH rearrangement in peripheral blood and/or bone marrow was found in 10/25 of patients (40%) before treatment and 5 of these became repeatedly negative after 2-CDA therapy. There was no apparent association between bcl-2/ JH result and response. In 11 patients, 2-CDA was stopped because of progressive disease (n = 4), myelotoxicity (grade 2-3, n = 4), and other causes (n = 3, pulmonary embolism, metabolic disorder, and patient's decision). Four patients (11%) suffered from infections (grade 2-3). In 6 patients, persistent thrombocytopenia of 7.5 months (range: 3-21) occurred after completion of the 5 cycles. CONCLUSION: 2-CDA is active in untreated follicular lymphomas, but time to treatment failure suggests no advantage compared with standard treatment and toxicity on haematopoietic stem cells appears to be more pronounced. Molecular remission is induced in a considerable proportion of patients with disappearance of the bcl-2/JH rearrangement, and its possible significance as a predictive factor for quality of response and relapse warrants further study.

2-Chloroadenosine↗

PubMed1996

Inhibition of (mono)amine oxidase activity and prevention of ifosfamide encephalopathy by methylene blue.

The clinical application of ifosfamide is hampered by a central nervous side effect, the so-called ifosfamide encephalopathy. Methylene blue is effective in prophylaxis and reversal of this side effect. In the present study, the in vitro inhibition of (mono)amine oxidases by methylene blue is demonstrated in two different experimental systems. The results provide an explanation for the preventive action of methylene blue in ifosfamide neurotoxicity, because the generation of chloroacetaldehyde (a potential neurotoxin of ifosfamide metabolism) is prevented in liver mitochondria and extrahepatic tissues. Generation of alkylating metabolites was also studied in rat liver perfusions, and methylene blue did not show any inhibition of ifosfamide activation. From these data, we conclude that the clinical effectiveness of methylene blue in treatment and prevention of ifosfamide encephalopathy might be based on inhibition of (mono)amine oxidases. Hepatic bioactivation of ifosfamide is not influenced by methylene blue.

Alkylation↗

PubMed1995

[Diagnosis and therapy of multiple myeloma: current aspects].

The crucial first step in management of multiple myeloma is to be certain regarding the diagnosis. Multiple myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. Therapy should be administered to patients with advanced and active myeloma involving anemia, osteolysis or renal failure. Chemotherapy with a single agent (melphalan) is the preferred initial treatment for overt, symptomatic multiple myeloma. Cytostatic drug combinations produce a higher response rate, but survival and remission during are the same compared with melphalan/prednisone therapy. However, in patients with renal failure and/or poor prognostic factors (advanced stage, elevated beta 2-microglobulin, high bone marrow plasma cell labeling index, high levels of C-reactive protein and lactate dehydrogenase and/or nodular pattern of bone marrow infiltration), combined treatment with adriamycin, vincristine and prednisone should be administered to prevent nephrotoxicity and attain a rapid paraprotein decrease. Alpha interferon treatment as maintenance seems to prolong the duration of the plateau state after response to chemotherapy, but apparently does not prolong survival. Allogeneic bone marrow transplantation involves significant early mortality (50%); the risk of graft versus host disease, infections and renal failure is a problem, and relapse is common. High dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem cell reinfusion may prolong survival and free time to progression, but, to date, there are no indications of cure. This therapeutic procedure, therefore, should be considered for randomized trials for young patients with poor prognostic factors.

Aged↗

PubMed1995

[Participation in multicenter studies as quality control in the therapy of Hodgkin disease: an interim report].

UNLABELLED: From 1988 to 1992 the Swiss Group for Clinical Cancer Research (SAKK) entered 113 patients with Hodgkin's disease into three stage adapted trials (HD-4-6) from the German Hodgkin Study Group (DHSG). In an interim analysis freedom from treatment failure (FFTF) and overall survival (OS) of the SAKK patients (SAKK-pt) were compared to the remaining study population (GHSH-pt) (median follow-up: 30 months for HD-4 and HD-5, 24 months for HD-6). RESULTS: HD-4: SAKK (n = 16), DHSG (n = 241), FFTF-SAKK: 100%, FFTF-DHSG: 85%, p: ns, OS-SAKK: 100%, OS-DHSG: 99%, p: ns, HD-5: SAKK (n = 66), DHSG (n = 639), FFTF-SAKK: 90%, FFTF-DHSG: 85%, p: ns, OS-SAKK: 93%, OS-DHSG: 95%, p: ns, HD-6; SAKK (n = 31), DHSG (n = 411): FFTF-SAKK: 62%, FFTF-DHSG: 68%, p: ns, OS-SAKK: 70%, OS-DHSG: 88%, p < 0.008. The results in the SAKK patients with advanced disease are unsatisfactory. Despite the fact that the treatment was given on time with full doses, 10/30 patients achieved no complete remission (CR). Only one patient relapsed after an initial CR. 6 patients had primary progressive disease. 6 patients died despite conventional salvage chemotherapy. High dose chemotherapy/autologous bone marrow transplantation (HDC/ABMT) was only given to 3 out of 8 potential candidates. Only 2/11 patients are still alive and disease-free after relapse or initial progression. Both had received HDC/ABMT as part of their salvage regimen. This interim analysis identifies a group of patients in which treatment strategies need to be optimized.

Adult↗

PubMed1995

[Successful treatment of a case of cutaneous Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide].

We describe the case of a 65-year-old female patient with cutaneous Langerhans' cell granulomatosis without any signs of disease in other organs. She also had systemic lupus erythematosus that had been diagnosed several years before. The coexistence of these two diseases has not been described before as far as we know. The purine analogue 2-chlorodeoxyadenosine (Cladribin), which has been used successfully in the treatment of hairy cell leukaemia, induced complete remission in our patient after 1 week of treatment. After 2 months, however, the patient had a relapse; this was successfully treated with thalidomide. A new understanding of Langerhans' cells granulomatosis as a reactive but not cancerous disease has emerged as a result of recent investigations showing that tumour necrosis factor-alpha (TNF-alpha) plays an important part in the induction of Langerhans' cells from their immature precursors. Because thalidomide has been shown to inhibit TNF-alpha production, down-modulation of this cytokine seems to be a useful treatment strategy in Langerhans' cell granulomatosis. Some asspects of the diagnosis and therapy of this disease are briefly reviewed.

Aged↗

PubMed1995

Quality versus quantity of life in the treatment of patients with advanced small-cell lung cancer? A randomized phase III comparison of weekly carboplatin and teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Based on a promising pilot study with weekly carboplatin and teniposide (CBDCA/VM) the Swiss Group for Clinical Cancer Research (SAKK) performed a randomised phase III trial in patients with extensive-disease small-cell lung cancer aimed at the development of an effective palliative treatment with low subjective toxicity. PATIENTS AND METHODS: From September 1989 to September 1991 patients were randomised to a weekly regimen of CBDCA/VM or to our 'standard chemotherapy' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine (PAV-CyMOC). RESULTS: The trial was closed before the planned accrual of 140 evaluable patients due to a significant survival difference shown by an interim analysis. Of the 61 patients 59 were eligible and included in the final analysis. The results achieved with the PAV-CyMOC regimen were significantly better than those observed in patients treated with weekly CBDCA/VM (remission rate of 65% vs. 29%; p = 0.006). The median survival of patients treated with the PAV-CyMOC combination was significantly longer than that of patients receiving weekly CBDCA/VM (260 days vs. 147 days; p = 0.0035). The 1-year survival rate was 30% in the PAV-CyMOC arm compared to 4% in the CBDCA/VM-treated patients. As expected, side effects including myelosuppression, alopecia and mucositis were significantly more pronounced in patients treated with the PAV-CyMOC regimen. No significant difference was found in patient-rated tumor symptoms and general quality-of-life categories. CONCLUSION: Contrary to our initial expectation that we would achieve similar therapeutic results with less subjective toxicity, in this randomised prospective trial the results achieved by weekly carboplatin and teniposide were significantly inferior in terms of remission rate and survival to those of our 'standard regimen' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. The weekly regimen was less toxic than the standard chemotherapy. Whether patients are willing to accept a significant trade-off between quantity and quality of life remains to be evaluated.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Early versus late alternating chemotherapy in small-cell lung cancer. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: From 1984 to 1989, the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial comparing early versus late alternating chemotherapy in patients with small-cell lung cancer. PATIENTS AND METHODS: 406 eligible patients were entered into the trial. Regimen A consisted of PAV (cisPlatin, Adriamycin, VP 16-213, and Regimen B of CyMOC (Cyclophosphamide, Methotrexate, Oncovin, CCNU). Cycles were repeated as rapidly as possible. patients were randomized to receive either ABABAB (early alternating chemotherapy) or AAABBB (late alternating chemotherapy). After six cycles patients with limited disease in complete or partial remission and those with extensive disease in complete remission received irradiation to the primary (45 Gy) and the CNS (36 Gy). RESULTS: The overall remission rate was 87% with 31% complete remissions. The median survival of all 406 eligible patients was 346 days with 15% of the patients alive at two years. The overall remission rate, the rate of complete remission, the median survival and the rate of long-term survival were not significantly different in the two treatment arms. In limited disease the estimated percentages of survival at 2 years were 33% in the early and 24% in the late alternating chemotherapy arms. Patients with extensive disease survived significantly longer with late alternating chemotherapy than on the early alternation regimen (median survival 336 days versus 301 days, p = 0.01). In the latter patients the received dose intensities (RDI) of cisplatin, adriamycin and etoposide were significantly higher in the late-alternation arm. Patients treated with early alternating chemotherapy rated their tumor symptoms, functional states, fatigue/malaise and restriction of social activity significantly better, reflecting an improved subjective adjustment. CONCLUSIONS: Alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is a feasible and effective treatment for small-cell lung cancer, with acceptable toxicity. Whereas patients with early alternating chemotherapy achieve a better subjective adjustment, late alternating chemotherapy allows for a higher RDI of cisplatin, adriamycin and etoposide, which results in a significantly longer median survival of patients with extensive disease.

Actuarial Analysis↗

PubMed1995

Phase I clinical and pharmacokinetic study of oral etoposide phosphate.

PURPOSE: To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS: In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS: Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION: The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.

Administration, Oral↗

PubMed1995

Patterns of drug resistance parameters in adult leukemia.

P-glycoprotein (Pgp), Glutathione (GSH), Glutathione S-Transferase (GST), and O6-Alkylguanine-DNA Alkyltransferase (ATase) were measured in parallel as putative indicators of drug resistance in adult leukemia. The patterns of resistance parameter expression of chronic and acute leukemia were different. In acute leukemia on average all parameters were increased as compared to normal bone marrow. In chronic leukemia GSH and GST were increased, whereas Atase, GPx and frequency of Pgp-expression were low. Treatment with cytostatic drugs did not influence median levels of expression/activity of the resistance parameters. Resistance parameter expression/activity of leukemic cells was also compared with various other tissue and tumor types. Generally the pattern of resistance parameter expression reflected the resistance status of the tissue, constitutively resistant tumor types and their corresponding normal tissue on average having higher levels than leukemic cells and other tissue and tumor types with acquired resistance. For individual patients with acute leukemia, however, none of the parameters was directly correlated with response to treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer.

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

[Current aspects in the treatment of malignant melanoma].

The incidence of melanoma continues to increase throughout the world. Caucasians with particular phenotypic features seem to be affected most. Epidemiologic studies suggest that intermittent sun exposure, especially in early age, increases the risk of melanoma. If melanoma is diagnosed early and treated with adequate surgery, prognosis is excellent. Once melanoma has metastasized to the regional lymph nodes, the majority of patients have a recurrence within 5 years. Adjuvant modalities, currently being tested in many phase III studies, are designed to improve survival of these patients. Isolated limb perfusion with tumor necrosis factor induces complete responses in the majority of patients with in-transit disease. Median survival of patients with distant metastasis is only 6-8 months, and thus far systemic therapy has not significantly prolonged survival, despite remission rates of 30-50%.

Chemotherapy, Adjuvant↗

PubMed1994

Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue.

The antineoplastic ifosfamide produces dose-dependent signs of neurotoxicity. After ifosfamide overdose in a patient, we found excessive urinary excretion of glutaric acid and sarcosine, which is compatible with glutaric aciduria type II, a defect in mitochondrial fatty acid oxidation that results from defective electron transfer to flavoproteins. We therefore used the electron-accepting drug methylene-blue as an antidote for ifosfamide encephalopathy. In one patient, ifosfamide neurotoxicity was rapidly reversed by methylene-blue 50 mg intravenously. In another patient with previous episodes of ifosfamide encephalopathy, methylene-blue was administered orally prophylactically. No symptoms of neurotoxicity were noted.

Administration, Oral↗

PubMed1994

Depletion of total cysteine, glutathione, and homocysteine in plasma by ifosfamide/mesna therapy.

The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from 6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/- 1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.

Adult↗