Pharmacokinetics of intravenous and oral sodium 2‐mercaptoethane sulphonate (mesna) in normal subjects.

James, Christopher; Mant, Tim; Rogers, H. J.

doi:10.1111/j.1365-2125.1987.tb03092.x

Cited by 43 publications

(34 citation statements)

References 14 publications

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“…It was shown that concomitant 2-mercaptosulfonic acid (mesna) administration protects the urothel from IFOtherapy-induced damage, such as hemorrhagic cystitis. Mesna is oxidized by ethylenediaminetetraacetic acid (EDTA) inhibitable constituents in the blood to the physiologically inert disulphide metabolite dimesna, which is excreted by the kidneys [11][12][13]. Part of the filtered dimesna is taken up into renal tubule cells and reduced to mesna [14].…”

Section: Introductionmentioning

confidence: 99%

Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells

et al. 2007

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Chloroacetaldehyde (CAA) is formed in the body from the chemotherapeutically used drug ifosfamide (IFO). CAA leads to cell death in proximal tubule cells mainly through the mechanism of necrosis rather than apoptosis. During chemotherapy, 2-mercaptosulfonic acid (mesna) is used with IFO to protect the urothel from cell damage. Little is known of the effect of mesna on renal proximal tubule cells, the primary site of damage after IFO treatment. Mesna contains a sulfhydryl (SH) group. To clarify whether SH-group-containing molecules can prevent CAA-induced cell death, we studied the effect of mesna and cysteine on necrosis, apoptosis, and protein content in a human proximal tubule-derived cell line (IHKE cells) treated with CAA. Both substances prevented CAA-induced necrotic cell death and protein loss and restored CAA-inhibited caspase-3 activity. CAA also prevented cisplatin-induced apoptosis. This inhibition was reversible in the presence of glutathione (GSH). We conclude that SH-containing molecules can protect proximal tubule cells from cell death because they interact with CAA before CAA can disturb other important cellular SH groups. A sufficient supply of intra- and extracellular SH groups during IFO chemotherapy may therefore have the ability to protect renal tubule cells from cell death.

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Section: Introductionmentioning

confidence: 99%

Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells

et al. 2007

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“…Since much lower plasma concentrations of free mesna are seen after oral administration (James et al, 1987) the effect of oral mesna on the thiol status was also investigated.…”

Section: Methodsmentioning

confidence: 99%

“…Since much lower plasma concentrations of free mesna are seen after oral administration (James et al, 1987) (Aebi et al, 1991). Total mesna and cyst(e)ine in urine were measured following the same protocol as for disulfides in plasma.…”

Section: Methodsmentioning

confidence: 99%

“…Urine was collected before and during the 4 h after administration of mesna. In two patients peripheral blood mononuclear cells were isolated using Ficoll-Paque at baseline and 30 and 120 min following the infusion of mesna and were processed as previously described for the determination of intracellular cysteine (DeQuay et al, 1992).Since much lower plasma concentrations of free mesna are seen after oral administration (James et al, 1987) the effect of oral mesna on the thiol status was also investigated.Mesna was administered at a dose of 1.2 g (ASTA MEDICA, four tablets of 300 mg) together with 200 ml of water and blood was collected after 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h. Urine was collected before ingestion of mesna and at intervals thereafter for 8 h. Food and liquids were allowed 2 h after the administration of mesna.Analytical methods Five ml of blood were collected into heparinised tubes containing L-serine-Na-borate (final concentration 2 mmol I') in order to prevent the degradation of glutathione by gammaglutamyltransferase and were immediately centrifuged. (Aebi et al, 1991).…”

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confidence: 99%

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

Stofer-Vogel

Cerny²,

Küpfer³

et al. 1993

Br J Cancer

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Summary 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-mercaptoethanesulfonate) 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' to 53.6 (47.4-59.8) nmol ml-' 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-' to a nadir of 102 (McGown & Fox, 1986). Similarly, the sulfhydryl status of normal cells is an important determinant of their defense against the toxic effects of the same cytostatic drugs (Chasseaud, 1979). Mesna (sodium 2-mercaptoethanesulfonate) is increasingly used to prevent haemorrhagic cystitis associated with chemotherapeutic regimens containing high doses of ifosfamide and cyclophosphamide (Dechant et al., 1991). Although mesna is very polar and does not passively enter cells to a significant extent (Ormstad et al., 1983), the sulfhydryl drug could still markedly affect cellular thiol homeostasis. High concentrations of the sulfhydryl could reduce circulating cystine, thereby making more cysteine available to cells since cysteine is more readily taken up by many cell types than cystine (Issels et al., 1988). In addition, cysteine-mesna mixed disulfides have been identified in urine (Jones et al., 1985;Duran et al., 1981). Mesna might thus result in a substantial loss of cyst(e)ine. Since the effects of intravenous and oral mesna on circulating physiological thiols are not known and the mesna-induced loss of cyst(e)ine has not been quantitated, the concentrations of cysteine, glutathione and their disulfides in plasma and urine were measured following the oral and intravenous administration of mesna to healthy volunteers. Subjects and methodsThe effects of mesna (sodium-2-mercaptoethane-sulfonate) on plasma cyst(e)ine and glutathione after intravenous and oral administration were studied in eight healthy volunteers, two females and six men, 24 to 39 years of age, all within 10% of ideal body weight. Informed consent was obtained from each of the participants. The study was approved by the ethics committee of the local medical school. After an overnight fast an indwelling catheter was placed into an antecubital vein of both arms in order to obtain blood repeatedly without tourniquet. Two blood samples were obtained 10 min apart before the administration of mesna in order to determine the basal concentrations of glutathione and cyst(e)ine.Intravenous mesna was infused over 2 min at a dose of 1.2 g (7.3 mmol; AS...

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“…Samples were deproteinised and the total amount of mesna and BNP7787 was measured by HPLC (with electrochemical detection) according to the method described (James et al, 1987;El-Yazigi et al, 1997;Verschraagen et al, 2001). For the analysis of total platinum, intact cisplatin, monohydrated cisplatin and unbound platinum, plasma samples were collected just before treatment and at 0.5, 1, 1.5, 2, 3, 4 and 6 h after the start of the cisplatin infusion.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule

et al. 2005

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BNP7787 (disodium 2,20 -dithio-bis-ethane sulphonate; Tavoceptt) is a novel agent developed to protect against cisplatin (cisdiammine-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 À2 as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m À2 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 À2 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 X18.4 g m À2 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 À2 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 À2 . The recommended dose of 18.4 g m À2 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.

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Pharmacokinetics of intravenous and oral sodium 2‐mercaptoethane sulphonate (mesna) in normal subjects.

Cited by 43 publications

References 14 publications

Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells

Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells

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

Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule

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