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A Küpfer

Publications and source records attributed to A Küpfer.

At least 19 recordsLinked to original sources
PubMed2000

Pharmacokinetics and organ distribution of intravenous and oral methylene blue.

OBJECTIVE: To determine the pharmacokinetics and organ distribution of i.v. and oral methylene blue, which is used to prevent ifosfamide-induced encephalopathy in oncology. METHODS: The concentration of methylene blue in whole blood was measured using high-performance liquid chromatography in seven volunteers after i.v. and oral administration of 100 mg methylene blue with and without mesna. The distribution of methylene blue in different tissues was measured in rats after intraduodenal and i.v. application. RESULTS: The time course of methylene blue in whole blood after i.v. administration showed a multiphasic time course with an estimated terminal half-life of 5.25 h. Following oral administration, the area under the concentration-time curve was much lower (9 nmol/min/ml vs 137 nmol/min/ml). Co-administration of mesna, which could influence distribution by ion-pairing, did not alter the pharmacokinetics. The urinary excretion of methylene blue and its leucoform was only moderately higher after i.v. administration (18% vs 28% dose). Intraduodenal administration to rats resulted in higher concentrations in intestinal wall and liver but lower concentrations in whole blood and brain than i.v. methylene blue. CONCLUSIONS: Differences in organ distribution of methylene blue are mainly responsible for the different pharmacokinetics after oral and i.v. administration. If methylene blue acts in the liver, where ifosfamide is primarily activated to reactive and potentially toxic metabolites, oral and i.v. methylene blue are likely to be equally effective. However, if the site of action is the central nervous system, i.v. methylene blue which results in much higher concentrations in brain seems preferable.

Administration, Oral↗
PubMed1999

Increased urinary losses of carnitine during ifosfamide chemotherapy.

Chloroacetaldehyde and thiodiglycolic acid, two metabolites of ifosfamide, interfere with mitochondrial function and may sequester carnitine. Urinary excretion of carnitine was measured in five patients before and during a continuous infusion of ifosfamide over 5 days at a dose of 2.8-3.2 g/m2 per day. The excretion of free and total carnitine increased from 85+/-53 to 2697+/-1393 micromol/day on the 1st day of chemotherapy and then gradually decreased. The average loss of carnitine during a chemotherapy cycle amounted to 8.5 mmol. The formation and excretion of esters of carnitine and metabolites of ifosfamide and/or a decreased renal tubular reabsorption could account for this marked loss, which might lead to symptomatic carnitine deficiency after several chemotherapy cycles.

Adult↗
PubMed1999

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Adult↗
PubMed1998

Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats.

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12-16 g ifosfamide/m2.day excreted thiodiglycolic acid ranging from 0.10 +/- 0.02 mmol on the first day of therapy, to a maximum of 3.27 +/- 0.15 mmol on the fourth day of ifosfamide infusion. This amounted to 5.4 +/- 0.2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days' continuous ifosfamide infusion. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-14C]palmitic acid by 55%, but affected neither the oxidation of [1-14C]octanoic acid, which is carnitine-independent, nor the oxidation of [1, 4-14C]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30 microM) inhibited oxidation of palmitic acid but not palmitoyl-L-carnitine in isolated rat liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid which may contribute to the adverse effects associated with ifosfamide chemotherapy.

Animals↗
PubMed1998

Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy.

Oral treatment with ifosfamide results in dose-limiting encephalopathy. Methylene blue is effective in reversal and prophylaxis of this side effect. In the present study, the pharmacokinetics of ifosfamide after iv and po therapy in combination with prophylactic administration of methylene blue were investigated. Nine patients with metastatic non-small cell lung cancer were treated by a combination of ifosfamide (3 days), sodium 2-mercaptoethane sulfonate (4 days), and etoposide (8 days). Cycles were repeated every 28 days. Ifosfamide was administered orally, with the exception of one of the first two cycles, when it was administered as a short infusion (randomly assigned). The patients received methylene blue in doses of 50 mg po 3 times daily; an initial dose of 50 mg was given the evening before chemotherapy. Urine samples were collected over the entire treatment period, and concentrations of ifosfamide and its major metabolite, 2-chloroethylamine, were measured by gas liquid chromatography. By the same technique, 2- and 3-dechloroethylifosfamide were determined in plasma and urine. Overall alkylating activity in urine was assayed by reaction of the alkylating metabolites with 4-(4'-nitrobenzyl)-pyridine. The chemotherapeutic regimen was well-tolerated by all of the patients studied. There was no evidence of a shift in the metabolic pattern dependent on the route of administration. From the data, we conclude that methylene blue has a neuroprotective effect and that the pharmacokinetics of ifosfamide are not influenced by its comedication.

Administration, Oral↗
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

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↗
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

Analysis of mephenytoin, 4-hydroxymephenytoin and 4-hydroxyphenytoin enantiomers in human urine by cyclodextrin micellar electrokinetic capillary chromatography: simple determination of a hydroxylation polymorphism in man.

Using cyclodextrin micellar electrokinetic capillary chromatography (CD-MECC), baseline separation of mephenytoin, 4-hydroxymephenytoin and 4-hydroxyphenytoin enantiomers in urine was effected with beta-cyclodextrin. After single-dose administration of 100 mg of racemic mephenytoin, the 0-8 h urine was collected, and enzymatically hydrolyzed urine specimens were applied. For extensive metabolizers, a single peak for 4-hydroxymephenytoin was detected corresponding to the S-enantiomer. This peak was either very small or undetectable in samples of poor metabolizers. Typically, mephenytoin could not be detected in these samples. However, application of undeglucuronidated extracts revealed the presence of free S-4-hydroxymephenytoin and R,S-mephenytoin and thus permitted phenotyping via both the urinary S:R enantiomeric ratio of mephenytoin and the hydroxylated metabolite. Application of enzymatically hydrolyzed and extracted urines after phenytoin administration (100 mg; 0-8 h urine collection) revealed the presence of S-4-hydroxyphenytoin. Thus, CD- MECC is shown to be a simple and attractive approach for (i) the confirmation of the stereoselectivity of the aromatic hydroxylation of mephenytoin and phenytoin, (ii) the simple and rapid differentiation between extensive and poor metabolizers for mephenytoin, and (iii) assessment of compliance.

Buffers↗
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↗
PubMed1993

Depletion of circulating cyst(e)ine by oral and intravenous mesna.

The sulfhydryl status of normal and tumour cells is critically important in determining their susceptibility to various cytostatic agents. As a sulfhydryl compound, mesna (sodium 2-mercaptoethane-sulfonate) which is used in large doses to prevent haemorrhagic cystitis associated with certain chemotherapeutic regimens might derange cellular thiol homeostasis. In order to investigate the effects of mesna on the concentrations of thiols in plasma, cysteine, glutathione and their disulfides were measured by HPLC following the oral and intravenous administration of mesna to healthy volunteers. After 7.3 mmol mesna i.v. free cysteine rose from 8.2 (95% CI 7.0-9.4) nmol ml-1 to 53.6 (47.4-59.8) nmol ml-1 at 5 min, most likely due to reduction of circulating cystine by the sulfhydryl drug. This initial rise was followed by a marked decrease of total cyst(e)ine in plasma from 276 (215-337) nmol ml-1 to a nadir of 102 (89-115) nmol ml-1 between 30-120 min after infusion, most likely due to an increased uptake of cysteine into cells and an increased urinary excretion of cyst(e)ine. Qualitatively similar changes were seen after oral mesna. The present data indicate that mesna depletes circulating cyst(e)ine and may thereby markedly alter the sulfhydryl status of cells in vivo although the drug itself is not taken up by most cells.

Administration, Oral↗
PubMed1991

Subcutaneous continuous infusion of ifosfamide and cyclophosphamide in ambulatory cancer patients: bioavailability and feasibility.

The oxazaphosphorines ifosfamide (IFO) and cyclophosphamide (CTX) are standard alkylating agents. Both drugs show an increased therapeutic index when given as a fractionated dosage over several days. Maximal fractionation is achieved by continuous infusion. We have studied the feasibility and bioavailability of a subcutaneously (s.c.) administered isotonic and neutral (pH 7) solution of IFO (10 h up to 5 days infusion) and CTX (12-24 h infusion) in patients with advanced cancer. A portable disposable gas-driven infusor syringe was used for ambulatory patients. Our results show 90%-100% bioavailability of s.c. IFO and CTX. The isotonic solution of IFO and CTX (pH 7) showed no significant local toxicity (one local infection in 51 cycles) during or after s.c. administration of 33 cycles with IFO and 18 with CTX. Haematotoxicity of both drugs was equal after s.c. and i.v. application. For IFO-treated patients no uro- or neurotoxicity was observed. We conclude that this novel continuous s.c. oxazaphosphorine infusion over a prolonged period is a rational, well-tolerated and economic way of delivering this drug on an outpatient basis.

Adult↗
PubMed1991

Continuous 5-day infusion of ifosfamide with mesna in inoperable pancreatic cancer patients: a phase II study.

Phase II studies on ifosfamide and mesna in pancreatic cancer have mostly been inconclusive. In all of these studies ifosfamide was administered as an i.v. bolus or by short infusions. Since dose fractionation of ifosfamide over several days increases its therapeutic index, we chose to maximize the dose fractioning by selecting a continuous-infusion schedule (1.75 g/m2 on days 1-5 every 21-28 days, with mesna 60%-100% of the ifosfamide dose up to 12 h after ifosfamide). Since 1987 29 patients (performance status less than or equal to 2) with advanced inoperable adenocarcinoma of the pancreas were studied (8 women and 21 men; median age 58 years: 36-73 years). A total of 25 patients are evaluable for response (1 ineligible; 3 inevaluable: 2 early deaths due to disseminated intravascular coagulation, 1 refusal). One female patient with a complete response on computed tomography scan (after five cycles) but residual liver metastases on surgical exploration survived for 473 days. Three male patients with partial response survived for 205, 335 and 355 days. Six more patients with minor response (3) or no change (3) but significant decrease of tumour marker CA 19-9 had a median survival of 213 days (106-243). Responders seemed to benefit in terms of pain relief and general well-being. The median overall survival of all patients was 148 days (21-473). Haematotoxicity was rarely dose-limiting [median nadirs: white blood cells = 2.1 x 10(9)/l (0.45-6.4), Hb = 10.7 g/dl (7.5-13), platelets = 137 x 10(9)/l (21-411)]. Nausea and vomiting were mild with prophylactic oral metoclopramide. No central nervous system toxicity or urotoxicity was observed. Alopecia was seen in all patients who had received at least two cycles. Continuous infusion of ifosfamide was generally well tolerated and useful for palliation in 10 of 25 patients. A higher dose intensity is recommended.

Adenocarcinoma↗
PubMed1991

Metabolism and pharmacokinetics of oral and intravenous ifosfamide.

The initial metabolism of ifosfamide (IF) consists of two different pathways: enzymatic hydroxylation at carbon-4 forms the cytostatically active metabolite 4-OH-IF ("activated ifosfamide") whereas side-chain oxidation results in the liberation of chloroacetaldehyde, a compound with possible neurotoxic properties. The pharmacokinetics of ifosfamide and its activated form were investigated in 12 cancer patients, who received both oral and i.v. treatment in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n = 7) or 1.5 g/m2 (n = 5). In 3 patients the pharmacokinetics of chloroacetaldehyde were also investigated. After oral application, ifosfamide absorption proceeded rapidly, the oral bioavailability was 0.92. Independent of the route of ifosfamide application on day 1, the terminal half-life on day 3 (when the drug was given by the alternative route) was decreased in 6 out of the 12 patients, thus indicating self-induction of hepatic metabolism. 4-OH-IF was already present 20 min after ifosfamide administration. In the individual patient the concentrations of 4-OH-IF were always higher after oral than after i.v. IF application: the mean p.o.:i.v. ratios for cmax and the area under the concentration/time curve were 2.3 and 1.7 respectively (P less than 0.05). In a first series of 3 patients the chloroacetaldehyde concentrations measured after oral ifosfamide application were about twice as high as those when the drug was given intravenously. These results indicate that (in comparison to the i.v. route) orally administered ifosfamide may be more cancerotoxic but also leads to higher levels of chloroacetaldehyde. This would explain the neurotoxic side-effects previously seen after oral administration of comparatively low ifosfamide doses.

Acetaldehyde↗