mesna and 2-2--dithiodiethanesulfonic-acid

BioNumerik Pharmacology Inc, Baxter Oncology GmbH (formerly ASTA Medica AG) and Grelan Pharmaceutical Co Ltd are developing BNP-7787 for the potential reduction of toxicity associated with cisplatin and carboplatin treatment in cancer patients.

Topics: Animals; Antiemetics; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Mesna; Structure-Activity Relationship; Vomiting

Topics: Amifostine; Antineoplastic Agents; Cell Survival; Glutathione; Humans; Mesna; Neoplasms; Platinum Compounds; Protective Agents; Thioctic Acid; Vitamin E

Any approach applied to drug discovery and development by the medical community and pharmaceutical industry has a direct impact on the future availability of improved, novel, and curative therapies for patients with cancer. By definition, drug discovery is a complex learning process whereby research efforts are directed toward uncovering and assimilating new knowledge to create and develop a drug for the purpose of providing benefit to a defined patient population. Accordingly, a highly desirable technology or approach to drug discovery should facilitate both effective learning and the application of newly discovered observations that can be exploited for therapeutic benefit. However, some believe that drug discovery is largely accomplished by serendipity and therefore appropriately addressed by screening a large number of compounds. Clearly, this approach has not generated an abundance of new drugs for cancer patients and suggests that a tangibly different approach in drug discovery is warranted. We employ an alternative approach to drug discovery, which is based on the elucidation and exploitation of biological, pharmacological, and biochemical mechanisms that have not been previously recognized or fully understood. Mechanism-based drug discovery involves the combined application of physics-based computer simulations and laboratory experimentation. There is increasing evidence that agreement between simulations based on the laws of physics and experimental observations results in a higher probability that such observations are more accurate and better understood as compared with either approach used alone. Physics-based computer simulation applied to drug discovery is now considered by experts in the field to be one of the ultimate methodologies for drug discovery. However, the ability to perform truly comprehensive physics-based molecular simulations remains limited by several factors, including the enormous computer-processing power that is required to perform the formidable mathematical operations and data processing (e.g. memory bandwidth, data storage and retrieval). Another major consideration is the development of software that can generate an appropriate and increasingly complex physical representation of the atomic arrangements of biological systems. During the past 17 years, we have made tremendous progress in addressing some of these obstacles by developing and optimizing physics-based computer programs for the purpose of obtaining increasing

Topics: Animals; Clinical Trials, Phase I as Topic; Computer Simulation; Drug Design; Humans; Lethal Dose 50; Mesna; Models, Chemical; Neurotoxicity Syndromes; Protective Agents

Platinum-type drugs have proven to be valuable in the treatment of a variety of solid tumors, beginning with the commercial approval of cisplatin 18 years ago. There are several clinically important toxicities commonly associated with the administration of these drugs. Despite the extensive use of cisplatin and carboplatin, the fundamental chemical transformations and mechanisms that underlie their antitumor and toxic effects have not been fully characterized. Several first-generation protective thiols have been clinically studied in an attempt to reduce the toxicity of platinum-type drugs; while some of these agents appear to protect against certain toxicities, nearly all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. Tumor protection by platinum-protecting drugs is an additional untoward effect that is associated with certain types of agents and must be addressed with care. Recent advances in theoretical and laboratory methods and the use of supercomputers have extended our understanding of the possible major mechanisms underlying platinum drug antitumor activity and toxicity; we present strong evidence that there are two classes of chemical species of platinum drug. One class appears to predominantly account for the antitumor activity, and the other class of chemical species produces many of the toxic effects of platinum drugs. We have discovered a new nontoxic, second-generation platinum-protecting agent, known as BNP7787, which appears to selectively inactivate and eliminate toxic platinum species. BNP7787 has recently entered phase I clinical testing in cancer patients.

Topics: Amifostine; Animals; Antineoplastic Agents; Cisplatin; Drug Interactions; Humans; Kidney Diseases; Mesna; Platinum Compounds; Protective Agents; Sulfhydryl Compounds

Topics: Cystitis; Expectorants; Humans; Mercaptoethanol; Mesna; Neoplasms

Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady-state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities.

Topics: Adult; Female; Glomerular Filtration Rate; HeLa Cells; Humans; Kidney; Male; Membrane Transport Proteins; Mesna; Middle Aged; Organic Anion Transporters; Probenecid; Protective Agents; Tissue Distribution; Young Adult

We conducted a phase I trial of BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate, Tavocept™), a novel chemoprotective and antitumor enhancing agent administered in combination with paclitaxel and cisplatin. The primary aim was to determine a safe and potentially efficacious BNP7787 dose for preventing and mitigating paclitaxel- and cisplatin-induced toxicities and to evaluate for preliminary evidence of efficacy of treatment.. Twenty-two patients with stage IIIB/IV non-small cell lung cancer (NSCLC) received BNP7787 alone 1 week before co-administration of BNP7787 with paclitaxel followed by cisplatin. Twenty-one patients were treated with BNP7787 in escalating doses of 4.1-41.0 g/m² concurrently with paclitaxel 175 mg/m² and cisplatin 75 mg/m² every 3 weeks.. The appropriate dose was determined to be 18.4 g/m² of BNP7787 although no dose-limiting toxicity was observed up to 41.0 g/m². Mild intravenous site discomfort, thirst, and nausea were the most common toxicities. One patient developed grade 2 skin rash, which was severe enough to preclude further study treatment. The AUC(0-inf) of the metabolite mesna was approximately 6.3% of the AUC(0-inf) of BNP7787. Co-administration of paclitaxel and cisplatin did not appear to influence the pharmacokinetics of BNP7787 and mesna. The overall response rate was encouraging; 43% including 11 patients with prior chemotherapy.. The recommended dose for phase II/III studies is 18.4 mg/m² of BNP7787 in combination with paclitaxel and cisplatin. Further studies are warranted to assess whether BNP7787 prevents and mitigates common and serious paclitaxel- and cisplatin-related side effects and enhances the efficacy of paclitaxel and cisplatin in advanced NSCLC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasm Staging; Paclitaxel; Treatment Outcome

We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.. Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].. This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Darbepoetin alfa; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Feasibility Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Polyethylene Glycols; Prognosis; Recombinant Proteins; Survival Rate; Taxoids

BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate; Tavocept) is a novel agent developed to protect against cisplatin (cis-diammine-dichloroplatinum(II))-associated chronic toxicities. In this study, we determined the recommended dose of BNP7787 when preceding a fixed dose of cisplatin, the pharmacokinetics (PKs) and the possible reduction of saline hydration. Patients with advanced solid tumours received BNP7787 in escalating doses of 4.1-41 g m(-2) as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m(-2) as a 60-min i.v. infusion together with pre- and postcisplatin saline hydration in a volume of 2200 ml; cycles were repeated every 3 weeks. PK was carried out using BNP7787, cisplatin and the combination. Twenty-five patients were enrolled in stage I of the study to determine the recommended dose of BNP7787. No dose-limiting toxicity was reached. The highest dose level of 41 g m(-2) resulted in a low incidence of grade 2 toxicities, being nausea and vomiting, dry mouth or bad taste and i.v. injection site discomfort. Doses of BNP7787 > or = 18.4 g m(-2) did not show a drug interaction between BNP7787 and cisplatin. In stage II of the study, patients received a fixed dose of BNP7787 of 18.4 g m(-2) preceding cisplatin and were entered in prespecified reduced saline hydration steps. A total of 21 patients in cohorts of six to nine patients received reduced saline hydration of 1600 ml (step A), 1000 ml (step B) and 500 ml (step C). In step C, two out of six evaluable patients experienced grade 1 nephrotoxicity. Cisplatin acute toxicities in all 46 patients were as expected. Only five patients complained of paresthesias grade 1 and six developed slight audiometric changes. Partial tumour response was observed in four patients and stable disease in 15 patients. In conclusion, BNP7787 was tolerated well up to doses of 41 g m(-2). The recommended dose of 18.4 g m(-2) enabled safe reduction of the saline hydration schedule for cisplatin to 1000 ml. Further studies will assess whether BNP7787 offers protection against platinum-related late side effects.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dehydration; Female; Humans; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms

BNP7787 (2',2'-dithio-bis-ethane sulfonate sodium) is a novel protector against cisplatin-induced toxicities. The pharmacokinetics of BNP7787 and its metabolite mesna were investigated in plasma and ascites of a cancer patient. We also evaluated potential pharmacokinetic interactions between BNP7787 and cisplatin.. BNP7787 and mesna were measured as mesna in deproteinized plasma and ascites using high-performance liquid chromatography with an electrochemical detector provided with a wall-jet gold electrode.. After the i.v. administration of 41 g/m(2) BNP7787, BNP7787 and mesna had a half-life of 1.5 and 3.4 h, respectively. The AUC( infinity ) of mesna was approximately 8% of the AUC( infinity ) of BNP7787. Coadministration of cisplatin did not appear to influence the plasma concentration-time curves of BNP7787 and mesna. In ascites, approximately 0.02% of the BNP7787 dose was present as mesna, whereas approximately 4% of the dose was present as BNP7787 at the time of the maximum concentration.. It can be concluded that the presence of ascites did not have a major impact on the pharmacokinetics of BNP7787 and coadministration of cisplatin did not influence the pharmacokinetics of BNP7787 and mesna.

Topics: Adult; Antineoplastic Agents; Area Under Curve; Ascites; Chromatography, High Pressure Liquid; Cisplatin; Electrochemistry; Half-Life; Humans; Male; Mesna

BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) is currently undergoing development as a chemoprotective agent to prevent common and serious cisplatin-induced side effects. In the kidneys, intestine, and liver, BNP7787 is believed to undergo intracellular conversion into 2-mercaptoethane sulfonate (mesna), which can locally inactivate toxic platinum species. Methods and objectives In a phase I trial, 25 patients with advanced solid tumors received a 1-hour intravenous infusion of 75 mg/m(2) cisplatin immediately preceded by a 15-minute intravenous infusion of BNP7787 every 3 weeks. For pharmacokinetic investigation of BNP7787 and mesna and a possible mutual pharmacokinetic interaction between BNP7787 and cisplatin, cisplatin and BNP7787 were also administered as single agents in 14 of 25 patients. The dose of BNP7787 was escalated from 4.1 to 41 g/m(2). Patients were also monitored for tumor response and possible side effects from BNP7787.. The maximum plasma concentration of mesna was reached approximately 1.7 hours after the start of the BNP7787 infusion. The maximum plasma concentration and area under the curve to infinity (AUC( infinity )) of BNP7787 and mesna increased linearly with the dose. The mean volume of distribution of BNP7787 (+/-SD) was approximately 0.26 +/- 0.08 L/kg. The mean normalized AUC( infinity ) of mesna was only approximately 8% of the normalized AUC( infinity ) of BNP7787. The pharmacokinetic profile of mesna was unaffected by cisplatin and its metabolites. None of the dose levels of BNP7787 (4.1-41 g/m(2)) administered appeared to influence the pharmacokinetic profile of total platinum, unbound platinum, or monohydrated cisplatin. The observed effects regarding a possible mutual interaction between BNP7787 and intact cisplatin were minor, and none were statistically significant at BNP7787 dose levels of 18.4 to 41 g/m(2). The confidence intervals for the pharmacokinetic parameters of BNP7787 and intact cisplatin, however, were relatively broad. Overall, BNP7787 was well tolerated at all dose levels (4.1-41.0 g/m(2)). The most frequently reported event related to BNP7787 was local intravenous site discomfort; the majority of events were mild (grade 1). Side effects of BNP7787 at the highest dose level of 41 g/m(2) were more prominent and included nausea and vomiting, as well as a warm feeling or flushing (grade 2 or lower). Partial tumor responses and stable disease were measured in 12 of 25 patients.. BNP7787 was relatively nontoxic at doses up to 41 g/m(2). The combination of BNP7787 with cisplatin did not alter the pharmacokinetic profiles of mesna or the cisplatin metabolites. At the higher dose levels of BNP7787 (18.4 to 41 g/m(2)), there appeared to be no mutual interaction between BNP7787 and intact cisplatin, which needs to be confirmed in a larger number of patients. The absence of a mutual interaction between BNP7787 and intact cisplatin is consistent with the observation that several patients had objective tumor responses with BNP7787 and cisplatin administration.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Chromatography, High Pressure Liquid; Cisplatin; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Mesna; Middle Aged; Platinum; Prospective Studies; Tissue Distribution

Although mesna has been used for more than a decade to reduce the incidence of hemorrhagic cystitis induced by ifosfamide and cyclophosphamide, the disposition of i.v. and oral mesna has not been adequately described. To obtain accurate bioavailability data for the design of mesna regimens, we developed procedures to preserve and measure mesna and dimesna in the blood and urine and studied 25 volunteer subjects who received single doses of i.v. mesna and four different formulations of oral mesna in a five-way randomized crossover study. The dose-adjusted area under the blood concentration-time curve showed no difference in bioavailability for i.v. and oral mesna; however, the maximum mesna concentration after oral doses was 16% of that estimated for i.v. doses. The short initial half-life of i.v. mesna indicated that mesna was rapidly cleared; however, the blood concentrations of mesna uniformly exceeded those of dimesna after oral as well as i.v. doses, which suggested that reduced mesna and oxidized mesna disulfide are in equilibrium. The ratio of mesna:dimesna was higher in protein-free plasma than it was in the urine, which suggested that most urinary mesna is produced by glomerular filtration of mesna rather than by renal tubular reduction of dimesna. The sum of mesna and dimesna excretion after the i.v. doses (73% of the dose) and the four oral formulations (68-73%) showed no difference in urinary bioavailability, consistent with the blood data. However, the urinary bioavailability of the therapeutically active free-thiol mesna was greater after i.v. doses (40% of the dose) than it was after oral doses (31-33%). The ratio of oral:i.v. mesna excretion ranged from 0.52-1.23 (mean, 0.82) among the 24 subjects. Urinary mesna concentrations exceeded 50 microM in all subjects for up to 12 h after oral doses as compared to 4 h after i.v. doses. About 90% of this mesna was excreted by hour 2 after i.v. doses and by hour 9 after oral doses. The mean maximum concentration of mesna in blood and excretion into urine were both 2.6 h after dosing. The oral formulations thus showed sustained urinary excretion, and their urinary bioavailability approached that of i.v. mesna.

Topics: Administration, Oral; Adult; Biological Availability; Creatinine; Cross-Over Studies; Humans; Injections, Intravenous; Male; Mesna; Protective Agents

The oxazaphosphorine antineoplastic ifosfamide (IF) is metabolized by two different initial pathways: ring oxidation ("activation"), forming 4-OH-IF ("activated IF"), and side-chain oxidation with liberation of chloroacetaldehyde (CAA), forming the inactive metabolites 3-dechloroethylifosfamide or 2-dechloroethylifosfamide (3-DCE-IF, 2-DCE-IF). 4-OH-IF and 4-OH-IF-derived acrolein are thought to be responsible for IF-induced urotoxicity (hemorrhagic cystitis), whereas CAA may be involved in IF-associated nephrotoxicity (renal tubular damage). The thiol compound 2-mercaptoethane sulfonate sodium (mesna) has proved to inactivate sufficiently the urotoxic metabolites of oxazaphosphorine cytostatics and is therefore routinely given to patients receiving IF chemotherapy. The cumulative urinary excretion of IF, 4-OH-IF, 3-DCE-IF, 2-DCE-IF, mesna, and its disulfide dimesna was studied in 11 patients with bronchogenic carcinoma receiving IF on a 5-day divided-dose schedule (1.5 g/m2 daily) with concomitant application of mesna (0.3 g/m2 at 0,4, and 8 h after IF infusion). On day 1 the mean cumulative 24-h urinary recoveries (percentage of the IF dose) recorded for IF, 4-OH-IF, 3-DCE-IF, and 2-DCE-IF were 13.9%, 0.52%, 4.8%, and 1.5%, respectively. On day 5 the corresponding values were 12.2%, 0.74%, 9.9%, and 3.6%, respectively. This time-dependent increase in urinary excretion of IF metabolites, which is caused by rapid autoinduction of hepatic oxidative metabolism, may result in a higher probability for the development of urotoxic and nephrotoxic side effects during prolonged IF application. The mean 24-h urinary recoveries (percentage of the daily mesna dose) recorded for mesna/dimesna on day 1 (day 5) were 23.8%/45.2% (21.2%/39.8%), respectively. The mean molar excess of urinary reduced ("free") mesna over 4-OH-IF ranged from 11 to 72 on day 1 and from 6 to 40 on day 5. This indicates that although urinary excretion of 4-OH-IF rises with repeated IF application, mesna in standard doses should sufficiently inactivate the urotoxic IF metabolites.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Carcinoma, Bronchogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged

The pharmacokinetics of mesna (sodium 2-mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna. The mean maximum mesna concentration after i.v. administration was 111 (s.d. +/- 28.3) nmol ml-1 and the mean maximum dimesna concentration was 183 (s.d. +/- 41.6) nmol ml-1. Following oral mesna dosing the mean peak mesna concentration was 19.6 (s.d. +/- 10.2) nmol ml-1 but mesna was only found in the plasma of five of the six subjects. The mean peak dimesna concentration was 22.5 (s.d. +/- 12.4) nmol ml-1. Following i.v. mesna administration, the mean half-life of mesna was 21.8 (s.d. +/- 3.1) min and total body clearance 1.23 (s.d. +/- 0.31) l kg-1 h-1. The mean half-life of dimesna was 1.17 (s.d. +/- 0.32) h. It was not possible to determine their half-lives after oral mesna administration. The mean mesna concentration in the 0-4 h urine collection was 9.6 (s.d. +/- 10.7; range 1.4-28.7) nmol ml-1 following i.v. mesna injection. After oral mesna the highest mesna concentration occurred in either the 0-4 or 4-8 h urine collections. The mean peak mesna concentration was 2.5 (s.d. +/- 1.7) mumol ml-1 (c.f. estimated uroprotective concentration of 1.7 mumol ml-1). The mean 4 h urinary clearance of the uroprotective species mesna was 0.413 (s.d. +/- 0.136) l kg-1 h-1. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Female; Humans; Injections, Intravenous; Kinetics; Male; Mercaptoethanol; Mesna; Middle Aged

Transitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of nephrotoxicity. Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased the required infusion/diuresis volume in clinical trials in humans.. We hypothesized that Tavocept would decrease diuresis volume and time and facilitate safe administration of a cisplatin/piroxicam protocol to dogs with bladder cancer. Secondary objectives were to compare response rate and survival times to an historical comparator group treated without Tavocept.. Fourteen client-owned dogs were prospectively enrolled.. Tumor volume was measured by computed tomography at days 0, 42, and 84. Dogs received combination Tavocept/cisplatin with a shortened diuresis protocol. A total of 4 doses was planned, with concurrent administration of piroxicam. Serial biochemical analyses were evaluated for azotemia.. A 90-minute infusion/diuresis time was used for all dogs. Three dogs (21%) had concurrent increases in serum creatinine (>2.0 mg/dL) and BUN (>42 mg/dL) concentrations; 2 of these dogs were isosthenuric. This frequency of nephrotoxicity is significantly less (P = 0.0406) than that of an historical control group treated without Tavocept. Overall response rate was 27%. Median survival time was comparable to historical controls (253 vs. 246 days).. Tavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia. Survival time was comparable, but the response rate was inferior to an historical comparator group. Further evaluation in other tumors susceptible to platinum agents is warranted.

Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Carcinoma, Transitional Cell; Cisplatin; Creatinine; Diuresis; Dog Diseases; Dogs; Drug Therapy, Combination; Mesna; Piroxicam; Prospective Studies; Renal Insufficiency; Treatment Outcome; Urinary Bladder Neoplasms

It is important for sarcoma patients to receive the correct dose of Mesna as an adjuvant with ifosfamide to reduce the risk of hemorrhagic cystitis. This paper describes a study conducted to evaluate the physicochemical stability of Mesna for injection formulation over 14 days.. Mesna samples (n = 4, 20 mg/ml) were incubated in glass vials at 37 + 0.5ºC. Mesna concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS), and nuclear magnetic resonance spectroscopy (NMR) was used to detect degradation products. Evaporative losses and pH were also monitored.. Our results differed from those published in existing literature. Both LC-MS/MS and NMR indicated that Mesna was unstable. The mean percentage decrease in Mesna concentration was 40% by day 14 of the analysis. The presence of Mesna's dimer Dimesna was detected on day 0 and its concentration increased over time. Dimesna was the only by-product identified.. Both LC-MS/MS and NMR analyses confirmed the instability of Mesna and its conversion into Dimesna.

Topics: Chromatography, Liquid; Drug Stability; Drug Storage; Hydrogen-Ion Concentration; Injections; Magnetic Resonance Spectroscopy; Mesna; Tandem Mass Spectrometry

The chemical reduction of the disulfide homodimer dimesna to its constituent mesna moieties is essential for its mitigation of nephrotoxicity associated with cisplatin and ifosfamide anticancer therapies and enhancement of dialytic clearance of the cardiovascular risk factor homocysteine. The objective of this study was to investigate potential enzymatic and non-enzymatic mechanisms of intracellular dimesna reduction. Similar to endogenous intracellular disulfides, dimesna undergoes thiol-disulfide exchange with thiolate anion-forming sulfhydryl groups via the two-step SN2 reaction. Determination of equilibrium constants of dimesna reduction when mixed with cysteine or glutathione provided a mechanistic explanation for dramatic cysteine and homocysteine depletion, but sparing of the endogenous antioxidant glutathione, previously observed during mesna therapy. Dimesna was reduced by recombinant enzymes of the thioredoxin system; however, oxidation of NADPH by the glutaredoxin system was only observed in the presence of combined dimesna and reduced glutathione, suggesting formation of oxidized glutathione following an initial non-enzymatic reduction of dimesna. Production of mesna by enzymatic and non-enzymatic mechanisms in HeLa cell lysate following dimesna incubation was demonstrated by a loss in mesna production following protein denaturation and prediction of residual non-enzymatic mesna production by mathematical modeling of thiol-disulfide exchange reactions. Reaction modeling also revealed that mixed disulfides make up a significant proportion of intracellular thiols, supporting their role in providing additional nephroprotection, independent of direct platinum conjugation.

Topics: Animals; Cell Line; Cysteine; Female; Glutathione; Homocysteine; Humans; Kidney; Liver; Mesna; Mice; Oxidation-Reduction

Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC) studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi-targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation by functionally distinct intracellular pathways could have many potentially useful therapeutic applications.

Topics: Antineoplastic Agents; Binding Sites; Crystallography, X-Ray; Cysteine; Glutaredoxins; Homeodomain Proteins; Humans; Mass Spectrometry; Mesna; Models, Molecular; Peroxiredoxins; Protein Structure, Tertiary

Previous studies from our laboratory have identified a role for gamma-glutamyl transpeptidase (GGT) in BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate, dimesna, Tavocept™)-mediated cisplatin nephroprotection. Dekant has proposed that gamma-glutamyl transpeptidase (GGT), aminopeptidase N (APN) and cysteine-conjugate-β-lyase (CCBL) comprise a multi-enzyme pathway that acts on xenobiotic-glutathione conjugates converting them to nephrotoxic metabolites. We report modulation of APN activity within this pathway by BNP7787-derived mesna-disulfide heteroconjugates.. A fluorimetric assay was used to determine the effect of BNP7787, BNP7787-derived mesna-disulfide heteroconjugates, and the BNP7787 metabolite, mesna (sodium 2-mercaptoethane sulfonate), on the initial velocity and overall progress curve of the human APN reaction in vitro.. Neither BNP7787 nor mesna-cysteinyl-glutamate inhibited human APN. Select BNP7787-derived mesna-disulfide heteroconjugates (mesna-cysteine, mesna-glutathione, mesna-cysteinyl-glycine) and high concentrations of mesna inhibited APN activity. Allosteric effects on the enzyme progress curve outside of the linear initial velocity region were observed for mesna-cysteinyl-glycine, mesna-glutathione and mesna-cysteinyl-glutamate and appeared to be a function of having both mesna and di- or tri-peptide functionalities in one molecule. In situ-generated mesna-cisplatin conjugates were not a substrate for human APN.. BNP7787-mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve APN inhibition by certain BNP7787-derived mesna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for BNP7787-mediated nephroprotection of cisplatin-induced nephrotoxicity involving the GGT, APN and CCBL nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity.

Topics: Allosteric Regulation; Biocatalysis; CD13 Antigens; Cisplatin; Cysteine; Dipeptides; Glutathione; Glycine; Humans; Kidney Diseases; Kinetics; Mesna; Models, Biological; Protective Agents; Recombinant Proteins

BNP7787, an investigational drug undergoing global Phase III development, appears to have potential advantages over other cytoprotective compounds that have been evaluated for preventing and mitigating cisplatin-induced nephrotoxicity. Herein, we characterized the in vitro accumulation of BNP7787 in human renal proximal tubule cells (HK-2) in which cisplatin is known to be taken up and accumulate. HK-2 cells were incubated with pharmacological concentrations of BNP7787 for varying times. Temperature-dependent accumulation of BNP7787 in cells was observed and the BNP7787-derived metabolite, mesna, formed intracellularly was directly monitored. The peak level of BNP7787-derived mesna measured in HK-2 cells was approximately 0.6 nmol/10(6) cells; this is pharmacologically similar to reported platinum concentrations in kidney cells and may be sufficient to afford nephroprotection. Therefore, in addition to previously suggested glomerular filtration, the cellular accumulation of BNP7787 by HK-2 cells is a plausible newly identified mechanism by which BNP7787 may accumulate in renal tubular cells, where it can exert its pharmacological effects to protect against cisplatin-induced nephrotoxicity by direct covalent conjugation of mesna with cisplatin, or by the formation of BNP7787-derived mesna-disulfide heteroconjugates that exert nephroprotective effects by inhibition of the key toxification enzyme targets γ-glutamyltranspeptidase and aminopeptidase N.

Topics: Cell Line; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Kidney Tubules, Proximal; Mesna

The mechanisms for cisplatin-induced renal cell injury have been the focus of intense investigation for many years with a view to provide a more effective and convenient form of nephroprotection. BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; dimesna, Tavocept), is a water-soluble disulfide investigational new drug that is undergoing clinical development for the prevention and mitigation of clinically important chemotherapy-induced toxicities associated with platinum-type chemotherapeutic agents. We hypothesized that part of BNP7787's mechanism of action (MOA) pertaining to the potential prevention of cisplatin-induced nephrotoxicity involves the inhibition of gamma-glutamyl transpeptidase (GGT) activity, mediated by BNP7787-derived mesna-disulfide heteroconjugates that contain a terminal gamma-glutamate moiety [e.g., mesna-glutathione (MSSGlutathione) and mesna-cysteinyl-glutamate (MSSCE)].. Inhibition studies were conducted on human and porcine GGT to determine the effect of mesna-disulfide heteroconjugates on the enzyme's activity in vitro. These studies utilized a fluorimetric assay that monitored the hydrolysis of L-gamma-glutamyl-7-amino-4-trifluoromethylcoumarin (GG-AFC) to AFC.. Mesna-disulfide heteroconjugates that contained gamma-glutamyl moieties were potent inhibitors of human and porcine GGT. An in situ-generated mesna-cisplatin conjugate was not a substrate for GGT.. The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatin nephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.

Topics: Animals; Antineoplastic Agents; Cisplatin; gamma-Glutamyltransferase; Humans; Kidney; Mesna; Protective Agents; Swine

Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept; disodium 2,2'-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane- and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN.

Topics: Animals; Antineoplastic Agents; Cattle; Cisplatin; Drug Interactions; Mesna; Microtubule Proteins; Microtubules; Paclitaxel; Polymerization

BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; Tavocept) is a novel water-soluble investigational agent that is undergoing clinical development for prevention and mitigation of cisplatin-induced nephrotoxicity. BNP7787 is a disulfide that undergoes thiol-disulfide exchange reactions in vivo with physiological thiols. Mesna-disulfide heteroconjugates that form as a result of these exchange reactions may play a key role in the protection against cisplatin-induced nephrotoxicity. Although several analytical methods have been used to detect thiols and disulfides, they have notable limitations including (i) low sensitivity, (ii) interference by chemical modification by derivatization reagents, and (iii) cumbersome sample preparation. In this paper, a sensitive micro-HPLC-EC method is described that identifies BNP7787 and mesna in plasma and phosphate buffer across a broad concentration range from 500nM to 100microM. This method utilizes a dual electrochemical detector equipped with a wall-jet gold electrode. The approach described here facilitates the identification of BNP7787 and mesna down to nanomolar levels. Although we did not focus on optimizing the approach for other thiol and disulfide compounds, we believe this approach could be optimized and used in the identification of other thiols and disulfides in plasma. The assay requires significantly less sample preparation and does not involve the use of derivatizing agents (i.e., the thiol and disulfide species can be detected directly) and represents an important advance over previous methods. This method was used to detect and quantitate BNP7787 and to monitor and kinetically characterize the interactions of BNP7787 with glutathione, cysteine, cysteinyl-glycine, cysteinyl-glutamate and homocysteine.

Topics: Buffers; Chromatography, High Pressure Liquid; Disulfides; Humans; Mesna; Phosphates; Sensitivity and Specificity; Sulfhydryl Compounds

Expression systems based on self-cleavable intein domains allow the generation of recombinant proteins with a C-terminal thioester. This uniquely reactive C-terminus can be used in native chemical ligation reactions to introduce synthetic groups or to immobilize proteins on surfaces and nanoparticles. Unfortunately, common refolding procedures for recombinant proteins that contain disulfide bonds do not preserve the thioester functionality and therefore novel refolding procedures need to be developed.. A novel redox buffer consisting of MESNA and diMESNA showed a refolding efficiency comparable to that of GSH/GSSG and prevented loss of the protein's thioester functionality. Moreover, introduction of the MESNA/diMESNA redox couple in the cleavage buffer allowed simultaneous on-column refolding of Ribonuclease A and intein-mediated cleavage to yield Ribonuclease A with a C-terminal MESNA-thioester. The C-terminal thioester was shown to be active in native chemical ligation.. An efficient method was developed for the production of disulfide bond containing proteins with C-terminal thioesters. Introduction of a MESNA/diMESNA redox couple resulted in simultaneous on-column refolding, purification and thioester generation of the model protein Ribonuclease A.

Topics: Mesna; Oxidation-Reduction; Protective Agents; Protein Folding; Recombinant Proteins; Ribonuclease, Pancreatic

In preclinical studies, BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg x kg(-1), were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1). high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2). in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3). the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4). the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (P<0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.

Topics: Animals; Antineoplastic Agents; Area Under Curve; Cisplatin; Colonic Neoplasms; Female; Humans; Injections, Intravenous; Kidney; Mesna; Neoplasms, Experimental; Protective Agents; Rats; Rats, Inbred F344

Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellular conversion into mesna (2-mercapto ethane sulfonate), which in turn can prevent cisplatin induced toxicities. In the present study, we have investigated whether the reduction of BNP7787 into the reactive compound mesna is restricted to the kidney or whether it can also occur in other organs, cells and physiological compartments, including the cytosolic fraction of the renal cortex, plasma, red blood cells (RBCs), liver and small intestine from rats and several tumors (OVCAR-3, MRI-H-207 and WARD). We also determined whether the endogenous thiols glutathione (GSH) and cysteine and the enzyme systems glutaredoxin and thioredoxin, which are all present in the kidney, can be involved in the BNP7787 reduction. UV detection and micro-HPLC with dual electrochemical detection were used to analyze the various incubation mixtures. Our observations are that, in contrast to plasma, a very large reductive conversion of BNP7787 to mesna was measured in RBC lysate. Intact RBCs, however, did not take up BNP7787. Although BNP7787 could be reduced in cytosol of liver and several tumors, this reduction will not be relevant in vivo, since these tissues do not take up large amounts of BNP7787. Kidney cortex cytosol was, similar to the small intestine cytosol, able to substantially reduce BNP7787 to mesna. The ability to reduce BNP7787 in the presence of the endogenous thiols GSH and cysteine, the glutaredoxin system as well as the thioredoxin system, could at least in part explain the high BNP7787 reductive activity of the kidney cortex cytosol. In conclusion, the high reduction of BNP7787 into mesna in the kidney as well as our earlier observation that the distribution of BNP7787 and mesna was mainly restricted to rat kidney are strong arguments in favor of selective protection of the kidney by BNP7787.

Topics: Animals; Antineoplastic Agents; Cisplatin; Cysteine; Cytosol; Electrochemistry; Enzymes; Erythrocytes; Glutathione; Humans; Mesna; Protective Agents; Rats; Tissue Distribution

BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) was evaluated in a phase I clinical trial with paclitaxel and cisplatin to assess the safety and potential efficacy for preventing or reducing cisplatin- and paclitaxel-induced toxicities. During this trial the effects of BNP7787 administration on the total concentrations (oxidized plus free) of cysteine, homocysteine and GSH in plasma, free and total GSH in WBC and rate of urinary excretion of cysteine were studied. The pharmacokinetics of ultrafilterable (free, non-protein bound) platinum were also determined after cisplatin (75 mg/m(2)) treatment which followed paclitaxel (175 mg/m(2)) and BNP7787 (8.2 to 27.6 g/m(2)).. Plasma thiols were measured by HPLC with fluorescence detection and platinum was measured by atomic absorption spectrophotometry.. BNP7787 administration produced a significant depletion of all plasma thiols in all the patients studied. Differences were noted in the kinetics of BNP7787-induced depletion of cysteine and other thiols. A significant depletion of cysteine occurred with a time lag of about 2 h after the end of BNP7787 infusion, while a reversible depletion of GSH and homocysteine occurred immediately following the start of BNP7787 infusion, with the plasma thiol/disulfide nadir corresponding to the end of infusion. The mean half-life of cysteine depletion following BNP7787 administration was 2.2 h, significantly longer than for homocysteine (0.23 h), or GSH (0.18 h; P<0.05 for both). A several-fold increase in the urinary excretion of cysteine occurred following BNP7787 administration in all patients. The BNP7787-induced thiol/disulfide depletion in plasma was not affected by cisplatin administration ( P>0.05). BNP7787 administration had no effect on the ultrafilterable platinum pharmacokinetics. The 2-h lag in the depletion of cysteine, the most abundant thiol in plasma, suggests that the process may be related to the formation of free mesna from BNP7787 and that increased levels of mesna are not in circulation until after 2 h after BNP7787 administration. No effect of BNP7787 was seen on the GSH concentration in WBC, possibly reflecting the inability of these cells to take up BNP7787.. The results suggest that BNP7787 has the potential to enhance cisplatin antitumor activity by depleting the reactive thiols in plasma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chromatography, High Pressure Liquid; Cisplatin; Cysteine; Disulfides; Glutathione; Half-Life; Humans; Infusions, Intravenous; Kinetics; Mesna; Neoplasms; Paclitaxel; Sulfhydryl Compounds

Sensitive, accurate, and precise assays are described to determine BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) and its metabolite mesna (sodium 2-mercaptoethane sulfonate) simultaneously in plasma and tissue by micro-high-performance liquid chromatography (HPLC) with dual electrochemical detection. After separation of BNP7787 and mesna by micro-HPLC, the disulfide BNP7787 was reduced to mesna by a reactor cell with a glassy carbon working electrode (-1.6 V versus Hy-REF). At the second electrode, which consisted of a gold wall-jet electrode, the mesna generated from BNP7787 and the mesna already present in the samples were detected (+0.85 V versus Ag/AgCl). The lower limit of quantification (LLQ) of both compounds was 3 microM in plasma and 20 nmol/g in tissue. The dynamic range of the assay in plasma was 3-120 microM for mesna and 15-1200 microM for BNP7787. In tissue, the dynamic range was 20-2000 nmol/g for both compounds. The recovery of mesna from plasma and tissue ranged from 61.4 to 90.5% and 82.7 to 90.2%, respectively, and seemed to be concentration dependent. The recovery of BNP7787 from plasma and tissue was complete (i.e., 101.5 and 96.4%, respectively). The within- and between-day accuracy and precision for the plasma and tissue assay were within 14 and 7%, respectively. The utility of the assay was shown by determination of the stability of mesna and BNP7787 in a kidney sample of a rat and by analysis of plasma samples obtained from a patient receiving 18.4 g/m(2) BNP7787 as a 15-min intravenous infusion.

Topics: Animals; Chromatography, High Pressure Liquid; Humans; Infusions, Intravenous; Kidney; Mesna; Protective Agents; Rats; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution

BNP7787 is a new chemoprotective agent presently under clinical investigation to protect against cisplatin-induced toxicities, especially nephrotoxicity and neurotoxicity. In the kidneys BNP7787 is postulated to undergo selective conversion into mesna, which can locally detoxify cisplatin. The reactivity of cisplatin with this new chemoprotective agent and with its metabolite mesna was investigated at clinically observed plasma concentrations and compared with the nucleophiles thiosulfate (TS) and DDTC, and with the endogenous compounds glutathione (GSH) and oxidized glutathione (GSSG).. Reaction kinetics experiments were performed at 37 degrees C and pH 7.4 in the presence of a high chloride concentration (0.15 M). The degradation of cisplatin was measured over time using HPLC with off-line flameless atomic absorption spectrophotometry.. The degradation half-lives of cisplatin (13.5 microM) with 17.2 m M BNP7787, 340 microM mesna and 17.2 m M mesna were 124 min, about 790 min and 73 min, respectively. Cisplatin reacted at least 9.5 times more slowly with 17.2 mM BNP7787 and 5.5 times more slowly with 17.2 mM mesna than with 17.2 mM of the modulating agents DDTC or TS (i.e. half-lives 11 and 13 min, respectively). The half-lives of cisplatin with 17.2 m M GSH and GSSG (i.e. 122 and 115 min, respectively) were comparable with the half-life obtained with BNP7787. The thiol mesna was shown to be a stronger nucleophile than its corresponding disulfide BNP7787.. The much slower relative reactivity of BNP7787, the short residence of BNP7787 (approximately 2 h) and the much lower concentration of mesna in the circulation following BNP7787 administration precludes chemical inactivation of cisplatin in the circulation, and thus the antitumor activity of cisplatin is maintained.

Topics: Algorithms; Antineoplastic Agents; Chromatography, High Pressure Liquid; Cisplatin; Disulfides; Ditiocarb; Expectorants; Glutathione; Half-Life; Kinetics; Mesna; Spectrophotometry, Atomic; Thiosulfates

Raman, and infrared spectra of mesna and dimesna have been collected in the present spectroscopic studies. Based on the group frequencies, relative intensities and Raman depolarization measurements, some vibrational assignments have been suggested. For both mesna and dimesna, at least two rotational conformers have been identified. Adsorption behavior was investigated from the recorded surface-enhanced Raman scattering (SERS) spectra. It was found that both mesna and dimesna adsorbed as thiolate on silver sol particles with the cleavage of the S-H bond in mesna and the S-S bond in dimesna. For the adsorbed thiolate, two conformers existed in the adsorption state.

Topics: Adsorption; Hydrogen; Hydrogen-Ion Concentration; Mesna; Molecular Conformation; Protective Agents; Spectrophotometry; Spectrophotometry, Infrared; Spectrum Analysis, Raman; Sulfur

BNP7787 (2',2'-dithio-bis-ethane sulphonate sodium), a water-soluble disulphide, is chemically and mechanistically different from other sulphur-containing chemoprotective agents. Presently, BNP7787 is under investigation for its protective properties with regard to the side-effects of platinum compounds. In this study, we evaluated BNP7787, mesna and amifostine for their effects on the antitumour activity of platinum compounds. Continuous exposure to BNP7787 did not affect the antiproliferative effects of cisplatin or carboplatin, but the efficacy of both compounds was reduced in the presence of mesna in vitro in two human ovarian cancer cell lines. BNP7787 or amifostine combined with cisplatin or carboplatin given in standard schedules for the treatment of nude mice bearing well-established OVCAR-3 xenografts did not interfere with platinum-induced inhibition of tumour growth. Of interest, BNP7787 or amifostine co-administered with carboplatin was significantly more effective than carboplatin alone (P<0.01). In the presence of amifostine, doses of cisplatin and carboplatin could be safely increased by factors of 1.6 and 1.5, respectively. Unlike in a previous study of BNP7787 in tumour-bearing rats, BNP7787 did not protect against additional weight loss following treatment with higher doses of cisplatin in OVCAR-3-bearing mice. Pharmacokinetics of (mixed) disulphides including BNP7787 and extractable mesna in deproteinised plasma revealed a rapid disappearance of BNP7787 and an AUC(5-60) value of mesna 9-fold lower than that calculated after an equivalent dose of mesna by weight. We can conclude that BNP7787 does not interfere with the antitumour activity of platinum compounds in vitro and in vivo. Clinical trials are underway to evaluate the protection of normal tissues by BNP7787 when combined with cisplatin.

Topics: Amifostine; Animals; Antineoplastic Agents; Carboplatin; Cell Division; Cisplatin; Drug Interactions; Female; Humans; Lethal Dose 50; Mesna; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Protective Agents; Radiation-Protective Agents; Transplantation, Heterologous; Weight Loss

A sensitive and accurate assay was developed and validated to determine BNP7787 (dimesna), a new protector against cisplatin-induced toxicities, and its metabolite mesna in plasma and urine of patients. Both analytes were measured as mesna in deproteinized plasma or in urine diluted with mobile phase using high-performance liquid chromatography with an electrochemical detector provided with a wall-jet gold electrode. The assays for BNP7787 and mesna in deproteinized plasma were linear over the range of 1.6-500 microM and 0.63-320 microM, respectively. In plasma, the mean recovery of BNP7787 over the whole concentration range was 100.6% and of mesna 94.6%. The lower limits of quantitation (LLQs) of BNP7787 and mesna in deproteinized plasma were 1.6 microM and 0.63 microM, respectively. For both compounds the within- and between-day accuracy and precision of the assay was better than 12%. The assays for BNP7787 and mesna in urine were linear over the range of 0.8-1200 microM and 0.63-250 microM, respectively. In urine, the mean recovery of BNP7787 over the whole concentration range was 94.1% and of mesna 93.1%. The LLQ of BNP7787 in urine was 0.8 microM and of mesna 1.6 microM. The within- and between-day accuracy and precision of the assay for BNP7787 and mesna was lower than 15%. The stability of mesna in urine increased with an increasing concentration of mesna, lower temperature and addition of EDTA (1 g/l) and hydrochloric acid (0.2 M). BNP7787 in urine was stable for at least 24 h at temperatures in the range of -20 degrees C up to 37 degrees C and independent of the concentration. The developed assays are currently applied for samples of patients with solid tumors participating in a phase I trial of BNP7787 in combination with cisplatin.

Topics: Chromatography, High Pressure Liquid; Electrochemistry; Half-Life; Humans; Mesna; Reproducibility of Results; Sensitivity and Specificity

Topics: Breast Neoplasms; Central Nervous System Diseases; Computer-Aided Design; Controlled Clinical Trials as Topic; Drug Design; Drug Interactions; Female; Humans; Mesna; Paclitaxel

Mesna is administered with ifosfamide and cyclophosphamide to reduce the incidence of hemorrhagic cystitis. In the present model of mesna metabolism and disposition, mesna is rapidly and irreversibly oxidized to dimesna in the plasma, passes unchanged through the liver, and is then reduced by the kidney and excreted. Our detection of a high ratio of mesna to dimesna in the plasma of clinical samples led us to reinvestigate the hepatic metabolism of mesna and dimesna. We perfused isolated rat livers from female Sprague Dawley rats with protein-free buffered solution containing dimesna at concentrations observed during therapy. In single-pass perfusions, each liver was perfused with up to three dimesna concentrations during consecutive 20-min periods. Recirculating perfusions were used to study single supratherapeutic concentrations of dimesna or mesna. Mesna and dimesna concentrations were measured by specific chromatographic procedures. Dimesna reduction, adjusted by the effluent flow rate and liver weight (0.4-58.5 nmol/min/g liver), correlated closely by linear regression (r = 0.98; n = 36) to the perfused dimesna concentration (4.2-249 microM), indicating a clearance of 0.20 ml/min/g liver. The concentration of dimesna that entered the liver closely matched the summed concentration of mesna and dimesna emerging in the effluent perfusate (single-pass experiments: slope, 0.98; intercept, -0.30; r = 1.00; n = 31). Only trace amounts of unidentified thiols were detected in the bile during recirculation of perfusates with 1 mM mesna or 250 microM dimesna. The effluent mesna concentration correlated inversely with the flow rate, which was consistent with a low extraction ratio in the perfusion model. These data suggested that the dimesna reduction rate was limited by hepatic uptake. Dimesna reduction was decreased by agents that deplete glutathione. Pretreatment of rats with up to 100 mg/kg ifosfamide did not impair hepatic dimesna reduction. In control experiments, dimesna was not reduced during recirculation through the apparatus without a liver. Mesna was oxidized to dimesna during oxygenation of the perfusate in the reservoir, but mesna injected directly into the perfusate just before entry into the liver passed unchanged into the effluent. Extrapolation of the dimesna clearance data from the perfusion model to humans suggests that hepatic dimesna reduction may counterbalance the rapid oxidation of mesna in plasma. The proposed equilibrium is consistent

Topics: Animals; Biotransformation; Buthionine Sulfoximine; Female; Glutathione; In Vitro Techniques; Kinetics; Liver; Mesna; Oxidation-Reduction; Perfusion; Rats; Rats, Sprague-Dawley

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoing bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30-mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship between and urinary excretion of mesna and dimesna also was examined by comparing the data obtained in patients who developed hemorrhagic cystitis versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urine was analyzed by liquid chromatography with electrochemical detection. Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration-time data of mesna exhibited the characteristics of the two-compartment model well, and the mean +/-SD values of the distributive phase half-life (t1/2 alpha), postdistributive phase half-life (t1/2 beta), volume of distribution of the central compartment (Vdc), volume of distribution at steady state (Vdss), volume of distribution during the postdistributive phase (Vd beta), total clearance (Cl), and mean residence time (MRT) observed were 0.12 +/- 0.15 hours, 2.12 +/- 1.61 hours, 0.324 +/- 0.336 L/kg, 1.09 +/- 1.18 L/kg, 2.09 +/- 3.0 L/kg, 0.755 +/- 0.507 L/hr.kg, and 6.77 +/- 0.72 hours, respectively. The mean +/-SD values of t1/2 and MRT of dimesna were 1.29 +/- 0.6 hours and 6.68 +/- 1.05 hours, respectively, and the ratio of the area under the concentration-time curve (AUC) of mesna to that of dimesna was 1.21 +/- 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (fu) were 0.361 +/- 0.15 and 0.482 +/- 0.25, and the renal clearance (ClR) values were 0.244 +/- 0.201 L/hr.kg and 0.157 +/- 0.156 L/hr.kg, respectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusion, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those who did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Cystitis; Female; Hemorrhage; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Mesna

We describe in this report an expedient and accurate liquid chromatographic method for measurement of mesna and dimesna in plasma and urine. The separation of mesna and the internal standard (p-aminobenzoic acid, IS) was achieved on a 10-microns, 8 mm (i.d.) x 10-cm C18-Resolve cartridge in conjunction with radial compression system. An aqueous solution of sodium citrate (0.1 M), tetrabutyl ammonium phosphate (0.001 M), and triethylamine (1:10,000, vol/vol), adjusted to pH 5 with 85% phosphoric acid was used at a flow rate of 2 ml/min as a mobile phase. The compounds were detected in the effluent electrochemically at +450 mV. After an appropriate amount of IS was added, the plasma sample (100 microliters or fraction thereof) was deproteinized with an equal volume of 0.0825 M sulfuric acid containing sodium hexametaphosphate (1.25% wt/vol), whereas urine was diluted 1:50 with water and mixed 1:1 with an aqueous solution of sodium hexametaphosphate (1.25% wt/vol). Dimesna was reduced back to mesna with sodium borohydride before analysis of the total mesna. The peak height ratio (drug/IS) varied linearly with the concentration, and the correlation coefficient was > 0.992 for both mesna and dimesna. The intrarun precision at different concentrations of mesna was equally good and the coefficient of variation was consistently < 4.5%. No interference from endogenous substances or any concomitantly used drug was observed. This assay is currently being used for measurement of mesna and dimesna in plasma of bone marrow recipients who receive high doses of cyclophosphamide.

Topics: Bone Marrow Transplantation; Chromatography, Liquid; Humans; Injections, Intravenous; Mesna; Time Factors

Ifosfamide (IF) is an alkylating cytostatic with urotoxic (haemorrhagic cystitis) and nephrotoxic (Fanconi syndrome) side effects. Cyclophosphamide (CP), a structural isomer of IF, shows urotoxic but no nephrotoxic side effects. The development of haemorrhagic cystitis during therapy with IF or CP can be prevented by the uroprotective drug sodium-2-mercaptoethanesulphonate (MESNA). However, even in the presence of MESNA, Fanconi syndrome may still develop after therapy with IF. Using the renal tubular cell line LLC-PK1, we investigated whether there is a protective effect of either MESNA or of its major metabolite DIMESNA, in combination with metabolites of IF or CP, on thymidine incorporation, uridine incorporation or total protein. DIMESNA, the dimer of MESNA, is the dominant form of the molecule in the circulation; the proximal tubular cell must convert this back to MESNA at the expense of glutathione, before it can exert its uroprotective action. We did not find a protective effect of DIMESNA under any of the experimental conditions tested. LLC-PK1 cells exposed to 3 mmol/l DIMESNA did not convert DIMESNA to MESNA. The toxic effect of the CP metabolite 4-OOH-CP was more pronounced in the presence of DIMESNA than in its absence. MESNA completely prevented the toxic effects of acrolein and of 4-OOH-CP. The toxic effects of 4-OOH-IF and of chloracetaldehyde, two major metabolites of IF, were significantly reduced in the presence of MESNA. However, even at 30-fold molar excess of MESNA over a 4-OOH_IF, thymidine incorporation remained reduced by 40% compared with controls, indicating incomplete protection of tubular cells against metabolites of IF. Similarly, the effect of chloracetaldehyde was not completely reversed by MESNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Line; Cells, Cultured; Cyclophosphamide; DNA; DNA Replication; Drug Combinations; Ifosfamide; Kidney Tubules; Mesna; RNA; Thymidine; Uridine

The reactive and rapidly excreted thiol mesna (2-mercaptoethane-sulphonate sodium) has the potential to reduce the dose-limiting nephrotoxicity of cisplatin by chemical neutralisation of the latter in the kidney. The reaction kinetics of cisplatin with mesna and its disulphide, dimesna, was studied at 37 degrees C in unbuffered 0.15 mol/l NaCl (pH 5.3) and in 0.15 mol/l NaCl buffered with 0.02 mol/l Hepes (pH 7.4). The reaction mixtures were analysed for intact cisplatin. In the presence of mesna or dimesna 0.5 mol/l as anticipated in urine for conditions of renal protection, the half-life (t1/2) of 0.2 mmol/l cisplatin was less than 6 min. t1/2 of 151 and 629 min were found in the presence of mesna and dimesna concentrations of 5 mmol/l and 3 mmol/l, respectively, anticipated in plasma under conditions of renal protection. Cis-diamminemonoaquamonochloroplatinum(II) 0.2 mmol/l reacted rapidly with 50 mmol thiosulphate and 0.5 mol/l (di)mesna (t1/2 less than or equal to 1 min). This platinum species also reacted rapidly with 2.6 mmol/l thiosulphate (t1/2 less than 1 min), a concentration reached in plasma for conditions under renal protection. Reaction of the monoaquated form of cisplatin proceeded slowly in the presence of dimesna or mesna concentrations (less than 5 mmol/l), as anticipated in plasma under renal protecting conditions. It is hypothesised that renal protection by the strong nucleophiles, thiosulphate, mesna and dimesna occurs rather by neutralisation of the aquated species in the lumen of the renal tubulus than by neutralisation of intact cisplatin, and that neutralisation of these species in plasma contributes significantly to the protecting effect.

Topics: Chromatography, Ion Exchange; Cisplatin; Drug Interactions; Half-Life; Kinetics; Mesna; Thiosulfates

We evaluated the stability of the aqueous formulation of mesna during storage in syringes and after dilution in beverages and syrups. Measurements of the concentrations of mesna showed that the undiluted formulation was stable for at least 9 days in standard polypropylene syringes at 5 degrees, 24 degrees, and 35 degrees C. There was no detectable oxidation of mesna to dimesna over the course of at least 1 week when mesna was diluted 1:2 and 1:5 in syrups and incubated at 24 degrees C in capped tubes. Concentration changes were clinically negligible for 1:2, 1:10, and 1:100 dilutions of mesna in six carbonated drinks, two juices, and milk after incubation for 24 h at 5 degrees C. Thus, the aqueous mesna formulation is stable when diluted and stored in a variety of beverages and syrups under conditions suitable for oral administration.

Topics: Administration, Oral; Beverages; Colorimetry; Drug Stability; Drug Storage; Mesna; Solutions; Syringes; Time Factors

Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) of cis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection the elimination of CDDP is a first-order process determined by kCDDP,P = kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration of N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obtained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m-2h), the estimates of Rinact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of Rinact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m-2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m-2 h systemic diethyldithiocarbamate (DDTC). Rinact was greater than 0.65 or 0.87 in plasma and greater than 0.75 in the peritoneal cavity for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.

Topics: Animals; Cisplatin; Ditiocarb; Half-Life; Injections, Intraperitoneal; Injections, Intravenous; Mesna; Models, Biological; Peritoneal Cavity; Thiosulfates

Dimesna was given to volunteers (n = 6) and levels of free thiols, mesna, cysteine and disulphides measured in urine. Mesna is excreted in the urine following oral dimesna administration. Peak urinary free thiol levels occur between 10 and 20 hr. Cysteine and mixed disulphides are also excreted. Mesna might be useful in prolonged bladder protection during oxazaphosphorine cancer chemotherapy.

Topics: Administration, Oral; Adult; Chromatography, High Pressure Liquid; Disulfides; Female; Humans; Male; Mercaptoethanol; Mesna; Sulfhydryl Compounds

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Fluorouracil; Male; Mesna; Methotrexate; Neoplasms, Multiple Primary; Rats; Vincristine

The effect of 2-mercaptoethane sulphonate (mesna) on the inhibition of the human MLR by 4-hydroxycyclophosphamide or azathioprine was studied. 4-Hydroxycyclophosphamide (34 microM) completely inhibited the MLR and this inhibition was unaffected by 122 microM of 2-mercaptoethane sulphonate or its disulphide. At high concentrations (mM) 2-mercaptoethane sulphonate inhibited the MLR reaching 85% at 24 mM. 2-Mercaptoethane sulphonate (15-122 microM) had no effect on azathioprine (36 microM) inhibition. The results of these in vitro studies suggest that 2-mercaptoethane sulphonate does not interfere with cyclophosphamide or azathioprine induced suppression of cellular immunity.

Topics: Azathioprine; Chromatography, Thin Layer; Cyclophosphamide; Humans; In Vitro Techniques; Lymphocyte Culture Test, Mixed; Mercaptoethanol; Mesna

[14C]-Mesna (sodium 2-mercaptoethanesulphonate) has a short serum t1/2 (about 16.5 min) and is excreted in the urine. Within 24 h approx. 77% of the administered dose appeared in the urine. It is bound to serum albumin and immunoglobulins. Total serum protein binding is about 9.7% of the total amount present in serum. [14C]-mesna + [14C]-dimesna (bis[2-mercaptoethane sulphonate]) are present in the blood stream, and so are found in the body organs at low concentration, however, localisation of radioactivity occurs in the kidneys. The binding of [14C]-mesna to proteins and the localisation of [14C]-mesna or [14C]-dimesna in the kidneys are discussed in the context of the cell killing efficacy of the oxazaphosphorines.

Topics: Animals; Carbon Radioisotopes; Immunoglobulins; Kidney; Male; Mercaptoethanol; Mesna; Rats; Rats, Inbred Strains; Serum Albumin; Tissue Distribution

The influence of disodium 2-mercaptoethane sulfonate disulfide (mesna, Uromitexan) and sodium 2-mercaptoethane sulfonate (dimesna) on the carrier mediated exchange of 35S-sulfate in human red blood cells was investigated in vitro in order to contribute to the understanding of pharmakokinetics and organospecific action of mesna. Countertransport indicated uptake of mesna in washed red blood cells by the carrier. In contrast, dimesna inhibited the transport of sulfate in a competitive manner. However, when 35S-sulfate uptake into red cells was studied with whole blood, addition of mesna was found to be inhibitory, which was caused by its rapid conversion to dimesna by plasma components. It is concluded that conversion of the anion carrier substrate mesna into the inhibitor dimesna is the reason that mesna or dimesna cannot be detected in red blood cells in vivo.

Topics: Erythrocytes; Humans; In Vitro Techniques; Ion Exchange; Kinetics; Mercaptoethanol; Mesna; Sulfates; Sulfur Radioisotopes

Topics: Chromatography, High Pressure Liquid; Electrochemistry; Half-Life; Humans; Mercaptoethanol; Mesna

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Male; Mesna; Neoplasms, Experimental; Nitrogen Mustard Compounds; Nitrosourea Compounds; Rats; Structure-Activity Relationship

Urotoxic side effects, particularly haemorrhagic cystitis, have been a limiting factor for the therapeutic use of the oxazaphosphorine cytostatics cyclophosphamide, ifosfamide and trofosfamide. The development of mesna (Uromitexan) has made it possible to carry out regional detoxification in the kidneys and the efferent urinary tract and thus to achieve clinically prophylaxis against the urotoxic side effects of oxazaphosphorines. In the body, mesna is rapidly converted to the biologically inactive disulfide form (dimesna). After glomerular filtration, dimesna is reduced by interaction with the glutathione system of the renal tubular cells and is excreted in the urine as mesna, the free thiol compound. This compound is then capable of definitively detoxifying the oxazaphosphorine metabolites in the urine. In extensive experiments on rats, it has been demonstrated that the cyclophosphamide-induced occurrence of urinary bladder tumours could be reduced or even eliminated by simultaneous administration of mesna. Detoxification by mesna enables the clinical use of higher doses and, consequently, a possible increase in therapeutic efficiency.

Topics: Animals; Biotransformation; Cyclophosphamide; DNA; Glutathione; Ifosfamide; Kidney; Leukemia, Experimental; Mercaptoethanol; Mesna; Rats; Structure-Activity Relationship; Urinary Bladder; Urinary Bladder Neoplasms

Topics: Electrophoresis; Humans; Mercaptoethanol; Mesna

An experimental model was developed, in which urinary bladder cancer was induced by cyclophosphamide in rats, thus reproducing cyclophosphamide-induced urinary bladder carcinogenesis observed in humans. It was possible in this model to achieve a highly significant reduction of cyclophosphamide-induced urinary bladder cancer by concomitant administration of sodium 2-mercaptoethane sulfonate (mesna). A significant delay of urinary bladder carcinogenesis by administration of the uroprotective substance mesna was also observed when using butylbutanolnitrosamine for inducing urinary bladder cancer. It was thus for the first time possible to assure chemoprevention of this tumor type by administration of a specific antidote.

Topics: Animals; Carcinoma, Transitional Cell; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Male; Mercaptoethanol; Mesna; Papilloma; Rats; Rats, Inbred Strains; Urinary Bladder Neoplasms

Cyclophosphamide (CP) was administered orally at a dose of 2.5 mg/kg body weight five times a week to 300 male Sprague-Dawley rats in a carcinogenicity experiment. Four groups of 50 rats were treated with two different doses of sodium 2-mercaptoethane sulfonate (mesna, Uromitexan) (single doses of 5 or 15 mg/kg body weight), or disodium 2,2'-dithio-bis-ethane sulfonate (dimesna) (single doses of 12 or 35 mg/kg body weight), and the effect on carcinogenicity by cyclophosphamide was investigated. Two groups received mesna or dimesna only, and one additional group of 100 rats served as an untreated control. Evaluation of the study after 20 months proved CP to be carcinogenic, the induced neoplasms being in a variety of organs including tumors of the urinary bladder in 30% of the rats. The additional administration of mesna and dimesna significantly reduced the bladder tumor risk, this reduction being dose-related. In the 100 rats treated with mesna or dimesna only, no evidence of a carcinogenic response or signs of other toxic effects were observed.

Topics: Animals; Cyclophosphamide; Dose-Response Relationship, Drug; Male; Mercaptoethanol; Mesna; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Risk; Urinary Bladder Neoplasms

Topics: Animals; Cyclophosphamide; Male; Mercaptoethanol; Mesna; Rats; Rats, Inbred Strains; Urinary Bladder Neoplasms

Sodium 2-mercaptoethane sulfonate (mesna, Uromitexan) is oxidized in the organism of rats to 2,2'-dithiodi-(ethane sodium sulfonate) (dimesna). Dimesna is partially reduced to the mercapto compound mesna (kidneys); both compounds are eliminated via the urine. Even after administration of dimesna mesna can be detected in the urine. Accordingly dimesna also proved to be an effective antidote against the urotoxic actions of cyclophosphamide and ifosfamide.

Topics: Animals; Cyclophosphamide; Ifosfamide; Kidney Diseases; Mercaptoethanol; Mesna; Oxidation-Reduction; Rats; Rats, Inbred Strains

The transport and reduction of dimesna (Na-2-mercaptoethane sulfonate disulfide) was studied in vitro using isolated, perfused rat kidney, and isolated renal epithelial cells. Cellular uptake of dimesna was found to be dependent on an active transport mechanism working across the luminal brush border, with an app. Km of approximately 22 microM and Vmax approximately 1.4 nmol . 10(6) cells-1 . min-1. Among other low molecular thiols or disulfides reduced glutathione was the only one to exert competitive inhibition. gamma-GT-activity or cellular GSH status had no influence on renal uptake of dimesna, but the intracellular reduction rate was dependent on access to reduced glutathione as a cofactor.

Topics: Animals; Biological Transport; Glutathione; Kidney; Kinetics; Male; Mercaptoethanol; Mesna; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

Topics: Electrophoresis; Mercaptoethanol; Mesna

Topics: Equipment and Supplies; Indoles; Mesna; Otolaryngology