Mesna Therapy Research Articles

Urotoxicity and safety data of low-dose intravenous cyclophosphamide therapy for rheumatic diseases: A Single-Center retrospective cohort study

Despite its effectiveness in rheumatic diseases, cyclophosphamide (CYC) treatment should be used with caution due to its side effects. CYC is thought to pose a risk in the development of hemorrhagic cystitis and bladder cancer. This study aims to determine the incidence of hemorrhagic cystitis and bladder cancer with intravenous low-dose CYC therapy used in the treatment of rheumatic diseases. A total of 211 adult patients with rheumatic disease treated with intravenous CYC were evaluated in this retrospective study conducted between January 2006 and May 2021. Patient data including cumulative CYC dose, treatment frequency, duration of treatment, side effects, such as hemorrhagic cystitis and bladder cancer were acquired from medical archives. The mean follow-up period was 48.5 (3–180) months, and the mean cumulative CYC dose was 5g (2–19g). None of the patients received mesna therapy concurrent with CYC therapy. 11 patients developed hemorrhagic cystitis (5.2%). Hemorrhagic cystitis was found to be statistically significantly associated with the number of CYC cycles (p=0.04). All patients were asymptomatic. No statistically significant difference was observed between hemorrhagic cystitis, treatment duration, and cumulative dose for CYC therapy in rheumatic diseases. Malignancy developed in 12 patients (5.7%) after CYC treatment. Bladder cancer was observed in 1 patient. According to our findings, the only risk factor for hemorrhagic cystitis in patients receiving CYC was the number of CYC cycles. Intravenous CYC regimen did not cause symptomatic hemorrhagic cystitis. Low-dose IV CYC may be safe in terms of serious urotoxic side effects when used at the appropriate dose, duration and frequency.

Reducing Time to Discharge after Chemotherapy by Standardizing Workflow and Providing Outpatient Intravenous Hydration.

Patients receiving cyclophosphamide or ifosfamide chemotherapy require intravenous fluid hydration to prevent hemorrhagic cystitis. In selected patients without medical contraindications (ie, excess nausea/vomiting), this hydration may be completed after discharge. We aimed to reduce the time to discharge after completing mesna in patients receiving cyclophosphamide or ifosfamide therapy on an inpatient chemotherapy service. The quality improvement team performed a medical record review to capture the time to discharge after mesna therapy and the readmission rate and used quality improvement methods to redesign discharge workflow and increase patient involvement with the discharge process. From August 2017 through July 2018, there were 160 admission encounters (73 patients) for cyclophosphamide or ifosfamide on a dedicated chemotherapy service. Of those encounters, 89 (55.6%) were appropriate for outpatient hydration; 48 (53.9%) of these encounters involved a patient who elected to receive outpatient hydration. Although the median time to discharge for the whole cohort did not change, in encounters where patients chose intravenous outpatient hydration, the median time to discharge was reduced from 2.82 to 0.66 hours (76.6% reduction) after implementing the new discharge workflow. No patients experienced readmission within 48 hours. Discharge workflow redesign and standardization reduced the time to discharge after chemotherapy in patients who chose outpatient hydration. Outpatient intravenous hydration after cyclophosphamide or ifosfamide appears safe and feasible in selected patient populations.

ANTIFIBROTIC ACTIVITY OF MESNA AGAINST AMIODARONE-ASSOCIATED LUNG INJURY IN WISTAR RATS

Objective: Lung fibrosis is a progressive respiratory disease with a high percentage of mortality. Till now, it had bad prognosis to conventional medications. This study was designed to evaluate the role of mesna, the well-known antioxidant agent, against pulmonary fibrosis.Methods: Pulmonary fibrosis was induced by administration of amiodarone to Wistar rats. Lung indices, leukocytes count, oxidative stress markers, cytokines levels, and hydroxyproline contents, in addition to the histopathological tests, were done for control, amiodarone, and mesna plus amiodarone group.Results: The elevated ratio of lung/body weight and total leukocytes count within bronchoalveolar lavage fluid for amiodarone rats was decline significantly when cotreated with mesna therapy. Furthermore, mesna significantly brought down the lipid peroxidation of amiodarone in lung tissue, represented by decreasing malondialdehyde level and increasing superoxide dismutase (SOD) and catalase activity. In addition, mesna diminished the profibrotic transforming growth factor-β1 level while elevated the antifibrotic interferon-γ level, and the high activity of the enzyme matrix metalloproteinase-7 was restored within mesna group. Meanwhile, mesna counteracts the increment of hydroxyproline contents and Ashcroft grading scale within amiodarone group. Histologically, critical improvement in the inflammatory cell penetration and alveolar septa was seen in the lung tissue of rats within mesna group, contrasted with those received just amiodarone. Trichome staining clarified that collagen deposition was notably diminished in the peri-alveolar and peri-bronchial area within mesna group. Moreover, mesna therapy downregulated SMAD3 protein level, which was overexpressed by amiodarone challenge.Conclusion: This study gives evidence that mesna therapy may act as a protective agent against amiodarone-mediated pulmonary fibrosis.

ANTIFIBROTIC ACTIVITY OF MESNA AGAINST AMIODARONE-ASSOCIATED LUNG INJURY IN WISTAR RATS

Objective: Lung fibrosis is a progressive respiratory disease with a high percentage of mortality. Till now, it had bad prognosis to conventional medications. This study was designed to evaluate the role of mesna, the well-known antioxidant agent, against pulmonary fibrosis.Methods: Pulmonary fibrosis was induced by administration of amiodarone to Wistar rats. Lung indices, leukocytes count, oxidative stress markers, cytokines levels, and hydroxyproline contents, in addition to the histopathological tests, were done for control, amiodarone, and mesna plus amiodarone group.Results: The elevated ratio of lung/body weight and total leukocytes count within bronchoalveolar lavage fluid for amiodarone rats was decline significantly when cotreated with mesna therapy. Furthermore, mesna significantly brought down the lipid peroxidation of amiodarone in lung tissue, represented by decreasing malondialdehyde level and increasing superoxide dismutase (SOD) and catalase activity. In addition, mesna diminished the profibrotic transforming growth factor-β1 level while elevated the antifibrotic interferon-γ level, and the high activity of the enzyme matrix metalloproteinase-7 was restored within mesna group. Meanwhile, mesna counteracts the increment of hydroxyproline contents and Ashcroft grading scale within amiodarone group. Histologically, critical improvement in the inflammatory cell penetration and alveolar septa was seen in the lung tissue of rats within mesna group, contrasted with those received just amiodarone. Trichome staining clarified that collagen deposition was notably diminished in the peri-alveolar and peri-bronchial area within mesna group. Moreover, mesna therapy downregulated SMAD3 protein level, which was overexpressed by amiodarone challenge.Conclusion: This study gives evidence that mesna therapy may act as a protective agent against amiodarone-mediated pulmonary fibrosis.

Enzymatic and non-enzymatic mechanisms of dimesna metabolism.

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.

Urinary excretion of ifosfamide, 4-hydroxyifosfamide, 3- and 2-dechloroethylifosfamide, mesna, and dimesna in patients on fractionated intravenous ifosfamide and concomitant mesna therapy

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.

Efficacy of mesna for prevention of hemorrhagic cystitis after high-dose cyclophosphamide therapy.

For these reasons, a definitive statement about the relative efficacy of mesna for prophylaxis of cyclophosphamide-associated HC in BMT patients cannot be made. Because HC is a frequent and potentially serious complication of high-dose cyclophosphamide therapy, the implementation of some preventive measure is mandatory in all patients. Unless medically contraindicated, provision of sufficient hydration and diuresis to maintain adequate high urine flow should be a component of all prophylactic regimens. It is unclear whether the addition of mesna therapy or bladder irrigation to intravenous hydration provides greater protection. Studies indicate that mesna probably has no adverse effect on engraftment. This is consistent with its chemistry and pharmacology, as the drug is hydrophilic and activated only in the kidneys. Thus, it is inactive in the bloodstream and unable to penetrate cell membranes and interfere with the action of cyclophosphamide. Although safety issues surrounding the use of mesna for prevention of cyclophosphamide-associated HC appear to have been resolved, efficacy issues must await the completion of further well-controlled comparative trials.

Mesna Therapy and Hypertension

Mesna Therapy and Hypertension

Ifosfamide/etoposide and mesna uroprotection in advanced breast cancer

The object of the study was to evaluate the effectiveness of ifosfamide/etoposide and mesna therapy in advanced breast cancer. A total of 44 patients with breast cancer were included in the trial. Eligibility criteria included measurable, refractory disease; prior anthracycline therapy (or its contraindication); a life expectancy of at least 3 months; and adequate hepatic, renal, CNS and bone marrow function. All patients were less than or equal to 70 years of age and had a Karnofsky performance status of greater than or equal to 50%. There were 36 evaluable cases. Sites of metastatic disease included bone (19), skin (18), liver (9), lung (14), lymph node (19), and miscellaneous (7). Treatment consisted of 1,500 mg/m2 ifosfamide given i.v. on days 1-5, 120 mg/m2 etoposide given i.v. on days 1-3, and 400 mg i.v. mesna given with and at 4 and 8 h after ifosfamide. Cycles were repeated every 28 days. Initial doses were reduced by 25% or 50% in patients who had previously undergone both chemotherapy and radiotherapy. A median of 4 cycles (range, 2-8) were given. The myelotoxicity was marked: WHO grades 3/4 leukopenia (n = 37), grades 3/4 thrombocytopenia (n = 12), and grades 2/3 anemia (n = 13). Due to myelotoxicity, dose reduction or prolongation of treatment-free intervals was necessary in 28 cases. Alopecia was seen in 35 patients and CNS toxicity, in 8. Partial remission (PR) was obtained in five cases and complete remission (CR), in three. Sites of response included the lung (5), skin (4), lymph node (5), and peritoneum (1). The duration of response was 4 (n = 2) and 8 (n = 1) months for CR and 2 (n = 2), 6 (n = 2), and 10 (n = 1) months for PR. We conclude that the ifosfamide/etoposide and mesna regimen is effective, but its myelotoxicity is treatment-limiting.

False-positive ketone tests: a bedside measure of urinary mesna

The sulfhydryl mesna is increasingly used to protect the bladder and kidney from effects of chemotherapy with ifosfamide and cyclophosphamide. Mesna reacts with reagents on urinary test strips designed to detect ketones. Test-strip results were correlated to sulfhydryl concentrations in 931 urine specimens obtained after infusions of mesna. These data may be used to estimate urinary mesna concentrations at the bedside or to test compliance in outpatients given oral mesna therapy.

Tubular nephrotoxicity during long-term ifosfamide and mesna therapy.

The nephrotoxic effects of ifosfamide were assessed in 18 children and adolescents given cumulative doses of 32-112 g/m2 (1.6 g/m2 per day in sequential 5-day courses) with the uroprotectant mesna (1.2 g/m2 per day). Tubular nephrotoxicity was evaluated by measuring the urinary concentrations of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and total protein before and during sequential courses of therapy. Of 15 patients who had normal levels of tubular markers before ifosfamide therapy, only 1 developed a persistent increase in baseline values of the three tubular markers with the sixth course of ifosfamide. Although transient increases in the excretion of these markers were observed during each 5-day course of ifosfamide, the magnitude did not increase over sequential courses in these 15 patients. Of the remaining three patients who had increased NAG levels before ifosfamide therapy, two showed a progressive increase in enzymuria and proteinuria, and serum creatinine concentrations increased in a single patient who had obstructive uropathy. Our data suggest that children with normal renal function can be given large cumulative amounts of ifosfamide in fractionated doses with little risk of progressive clinical nephrotoxicity.

Ifosfamide by bolus as treatment for advanced non-small cell lung cancer.

Ifosfamide at 5 g/m2 was given as a bolus to 48 patients with advanced progressing non-small cell lung cancer. Mesna (5 g/m2) was also given with the ifosfamide, both over 30 min. Further mesna was then given p.o. (3 g/m2) at 4, 8, and 12 h. If oral mesna was not acceptable then one or, if necessary, two 4-h to 6-h infusions (3 g/m2) were administered. A maximum of six courses at 3-weekly intervals was prescribed. A total of 174 courses was administered, and oral mesna was given during 64 courses: discharge was considered possible within 8-10 h after 55% of courses. Haematological toxicity was mild and no renal dysfunction was noted. Two patients became drowsy shortly after ifosfamide, but recovered 24-36 h later. The objective response rate was 29%, with one complete responder. A further 31% of patients (symptomatic responders) with stable disease symptomatically improved after the chemotherapy, by 20 or more points on the Karnofsky scale. The median survival was 5 months for the whole group, and 8 months each for the objective and symptomatic responder groups. Most patients' Karnofsky and respiratory scores improved with the chemotherapy. Ifosfamide with mesna can be given by short infusions, and the mesna given p.o. prevents any urothelial toxicity. Further exploration of short-infusion ifosfamide and mesna therapy would reduce hospitalization and allow for day-case regimens.

High-Dose Ifosfamide and Mesna Therapy in the Outpatient Setting

Ifosfamide and mesna as a chemotherapeutic and protective combination has increased oncologists' choice of agents in the treatment of various forms of cancer today. Additional responsibility is placed on both patient and caregiver when high doses of these drugs are administered in an outpatient setting. Of utmost importance is the education of the patient and the caregiver in their immediate responsibilities, as well as required procedures after the course of the drug has been completed. In this article, areas of concern to the patient and caregiver are described in detail. Initial therapy and any subsequent side effects are managed on an outpatient basis except in rare circumstances.