Toxic epidermal necrolysis due to therapy with cyclophosphamide and mesna. A case report of a patient with seronegative rheumatoid arthritis and rheumatoid vasculitis.

Rheumatoid vasculitis usually occurs on the background of seropositive rheumatoid arthritis, although in rare cases the patients can be seronegative. We report a woman with seronegative rheumatoid arthritis with rheumatoid vasculitis who developed toxic epidermal necrolysis involving most of her body surface area, while on therapy with intravenous cyclophosphamide and mesna. After withdrawal of suspected offending agents, administration of intravenous immunoglobulin, and supportive therapy, she had a favorable outcome. Such an occurrence is rare and serves to educate about a potentially life-threatening adverse event associated with a commonly used immunosuppressive agent.

Position statement of the Brazilian society of Rheumatology on mesna use as a preventive therapy for bladder disease in patients with systemic autoimmune diseases and systemic vasculitis under cyclophosphamide treatment.

OBJECTIVE: To review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide. MATERIALS AND METHODS: The search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators. RESULTS: Eighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered. CONCLUSION: The current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.

Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol.

Gastric mucosal damage induced by ethanol is a serious medical problem. Recent evidences suggest that reactive oxygen species and inflammatory mediators play a key role in the destruction of gastric mucosa. The present study was aimed to evaluate the potential beneficial effect of MESNA (2-mercaptoethane sulfonate) against ethanol-induced gastric mucosal damage in mice. The animals were orally pretreated with vehicle or MESNA and then treated with acidified ethanol to induce gastric mucosal damage. One hour after ethanol ingestion mice were euthanized and stomach samples were collected for biochemical analysis. Macroscopic and histopathological evaluation of gastric mucosa showed that pretreatment with MESNA attenuated gastric lesions induced by ethanol. Administration of MESNA significantly increased glutathione content and superoxide dismutase and catalase activity in the gastric tissues. In addition, MESNA markedly reduced ethanol-induced lipid peroxidation, myeloperoxidase activity, tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 levels. These findings suggest that the thiol-containing compound MESNA is able to decrease alcohol-induced oxidative stress and inflammation in the gastric tissue. It seems that MESNA may have a protective effect against ethanol-induced gastric mucosal damage.

The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy.

We examined the possibility of continuing oxazaphosphorine therapy in patients with previously documented cyclophosphamide- or ifosfamide-induced hematuria by concomitant use of the uroprotective agent, mesna. Twenty-six patients with oxazaphosphorine-induced hematuria received additional cyclophosphamide or ifosfamide with mesna. Twelve, who had previously experienced hematuria with ifosfamide, received a median of 3.5 more cycles of ifosfamide/mesna. One patient developed further hematuria (grade 1). Of seven patients who experienced acute hematuria with cyclophosphamide, one experienced further hematuria after an additional course of cyclophosphamide with mesna, but none of the other six patients developed further hematuria when administered either cyclophosphamide/mesna (two) or ifosfamide/mesna (four). Seven patients who had chronic cyclophosphamide-induced hematuria had further oxazaphosphorine with mesna without worsening of their hematuria. Mesna is an effective uroprotective agent that prevents recurrent acute hemorrhagic cystitis, or worsening of chronic hemorrhagic cystitis, in patients receiving further oxazaphosphorine after previous ifosfamide- or cyclophosphamide-induced hematuria.

Oral administration of mesna with ifosfamide.

Mesna can be given orally to simplify outpatient ifosfamide therapy. Oral administration of mesna solution or tablets has been approved in Canada, Denmark, Germany, Italy, The Netherlands, and the United Kingdom, and programs for registration are ongoing in other European countries and in the United States. This review summarizes dosing schedules and the incidence of hematuria in 47 clinical studies, in which oral mesna was given to at least 1,986 patients who received more than 6,475 courses of ifosfamide. Various doses and schedules of oral mesna, usually in combination with intravenously injected mesna, provided effective uroprotection for a wide range of ifosfamide regimens.

Continuous subcutaneous administration of mesna to prevent ifosfamide-induced hemorrhagic cystitis.

Hemorrhagic cystitis is a major potential toxicity of ifosfamide that can be prevented by administering mesna along with the cytotoxic agent. Mesna is generally administered by the intravenous route, although experience with oral delivery of the drug has increased. The continuous subcutaneous administration of mesna has the advantage of not requiring intravenous access. In addition, subcutaneous delivery of the neutralizing agent will not be associated with the risk of inadequate urinary mesna concentrations, such as in a patient taking oral mesna who experiences severe ifosfamide-induced emesis and is unable to absorb the drug. Limited clinical experience with continuous subcutaneous mesna administration suggests it is a safe, practical, and economic method of drug delivery that permits ifosfamide to be administered successfully in the outpatient setting.

Modulation of platinum-induced toxicities and therapeutic index: mechanistic insights and first- and second-generation protecting 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.

Mesnum as a protector against kidney and bladder toxicity with high-dose ifosfamide treatment.

Thirty-two patients with advanced cancer were treated in a phase I-II trial with ifosfamide plus mesnum. At doses up to 300 mg ifosfamide/kg the administration of mesnum prevented most of the expected kidney and bladder toxicity. With this high dose range hemopoietic dose-limiting. Only one of twelve evaluable patients with breast cancer showed definite therapeutic benefit. Complete remission or partial remission was seen in three patients with non-Hodgkin lymphoma and one patient with Hodgkin's disease.

Prevention and treatment of hemorrhagic cystitis.

Hemorrhagic cystitis is a syndrome associated with certain disease states as well as exposure to drugs, viruses, and toxins. It manifests as diffuse bleeding of the endothelial lining of the bladder. Treatment includes intravesical, systemic, and nonpharmacologic therapies, all of which have advantages and disadvantages.

Evaluation of ifosfamide plus mesna as first-line chemotherapy in women with metastatic breast cancer.

Ifosfamide is an oxazaphosphorine analogue of cyclophosphamide with proven activity in breast cancer but substantial urotoxicity. The introduction of mesna as a uroprotective agent provided a stimulus for reexamination of ifosfamide for therapy of women with metastatic breast cancer. Twenty women with measurable (18 patients) or evaluable (2 patients) disease were entered into a phase II clinical trial of ifosfamide plus mesna as first-line chemotherapy. Ifosfamide was administered i.v. at a dose of 1,800 mg/m2 in 1 L D5W over 2 h on five consecutive days. Mesna was administered i.v. at a dose of 400 mg/m2 over 15 min immediately before and 1 h after ifosfamide, and then every 4 h for three more doses. The last three doses could be given either i.v. or orally. The planned cycle length was 28 days. Three patients (15%), all with measurable disease, achieved a partial response (95% confidence interval: 3 to 38%). Median time to progression was 137 days and median survival was 407 days. Toxicities included cumulative myelosuppression and substantial nausea and emesis. Four patients were removed from treatment because of toxicity alone and a fifth refused further therapy. We conclude that ifosfamide, plus mesna, as given in this protocol has definite but limited antitumor activity and poor tolerability.

Mistabron in the intensive care unit.

Mistabron is the trade-name of a new mucolytic agent, that has certain advantages over older mucolytic agents. This drug has been used to a great extent in patients with tracheobronchial secretions in the department of intensive care medicine. Its application makes expectoration easier while its preventive administration diminishes greatly the incidence of lung complications.

[Anticancer chemotherapy. Prevention of complications]. / Chimiothérapie anticancéreuse. Prévention des complications.

OPTIMAL CHEMOTHERAPY DOSE: The goal of cancer chemotherapy is to eradicate the malignant disease while minimizing severe toxic effects. There is an optimal chemotherapy dose intensity above which palliation is adversely affected by toxicity; below this level the effect is also adverse because of a low rate of tumor response. METHODS FOR REDUCING TOXICITY: There are several methods by which one can reduce the toxicity of cancer chemotherapy, such as the application of rationally designed dosage schedules, alternative routes of administration, biochemical modulation, and the development of drug camers and analogs. Growth factors, interleukins can accelerate the recovery of the hematopoietic cell population after chemotherapy. CHEMOPROTECTORS: Chemoprotectors achieve selective protection of normal tissues. These include mercaptoethanesulfonate (Mesna) for oxazophosphorouros, the cardioprotectant iron chelator, cardioxane, the nucleophilic tripeptide glutathione, and perhaps aminothiolaminofostine. QUALITY OF LIFE: Considerable effort has been made to reduce the negative effect of chemotherapy-induced nausea and vomiting on the quality of life of cancer patients. 5 HT3 receptor antagonist plus dexamethasone led to a significantly higher rate of control of emetic episodes after chemotherapy.

Practical use of MESNA in atelectatic ears and adhesive otitis media.

OBJECTIVE: MESNA is a synthetic sulfur compound that produces mucolysis by disrupting disulfide bonds. This study aimed to address indications and technique of MESNA application in otologic surgery, especially in retraction pockets and adhesive otitis media. METHODS: MESNA application was performed in 42 ears of 39 patients. The diagnoses were retraction pockets fixed to incudostapedial joint, stapes or promontorium, and adhesive otitis media in 24 and 17 ears, respectively. Calculations were performed according to 24 ears of 23 patients with follow-up data. RESULTS: One or more of the following surgical interventions were performed: MESNA application alone and ventilation tube insertion, reinforcement or mastoidectomy in addition to MESNA application. Sensorineural hearing loss was not encountered after MESNA application. The operation was successful in 79.2%. Overall revision surgery was needed in 20.8% of the ears. In 71.4% of the ears treated with MESNA alone, revision surgery was needed. CONCLUSION: In the light of our experience, we advocate the use of MESNA in atelectatic ears, because it makes the operation easy and safe by allowing elevation of the tympanic membrane by its mechanical and chemical actions.

[Uroprotection with mesna in the chemotherapy of malignant tumors with oxazaphosphorines. Biometric evaluation of a sequential clinical study]. / Uroprotektion mit Mesna bei der Chemotherapie maligner Tumoren mit Oxazaphosphorinen. Biometrische Auswertung einer sequentiellen klinischen Prüfung.

A multicentre, randomised, clinical study was performed by sequential analysis to quantify the uroprotective efficacy of sodium 2-mercaptoethane sulfonate (mesna, Asta D 7093, Uromitexan) during high-dosed chemotherapy with oxazaphosphorines. Patients were entered as matched pairs serially according to time of admission, trial centre, cytostatic therapy (cyclophosphamide, Endoxan; ifosfamide, Holoxan) and tumor diagnosis, and were given uroprotection at random either with mesna or standard prophylactic measures. The maximum number of erythrocytes in the urine (n/microliter) was chosen as effect variable in a qualitative manner: effective protection delta less than or equal to 15 erythrocytes/microliter urine ineffective protection delta greater than 15 erythrocytes/microliter urine. The scheme of sequential analysis was based on 1. a uroprotective efficacy of 70% of the standard prophylaxis, 2. an assumed efficacy of 95% of mesna treatment and 3. an alpha-error and beta-error of 0.05 and 0.10 respectively. The admission of the twentieth patient completed the eighth matched pair of patients. This pair proved to be the sixth discordant pair with regard to uroprotective efficacy. The significant uroprotective superiority (p less than 0.05) of mesna was proven in view of clear decisions in favour of the test compound.

Ifosfamide and mesna in the treatment of malignant disease mesna as urothelial protector.

One hundred and forty-six patients with advanced malignant disease were treated with 6 different dosage schedules of ifosfamide (IFX). Mesna was used as urothelial protector. With mesna, urothelial toxicity was moderate, and single doses of up to 7 g/m2 could be administered without intolerable urotoxicity. Leukopenia was the dose-limiting factor in this study. Unexpected pulmonary edema occurred in 3 patients. Therapeutic results were disappointing. A malignancy identified in this study that warrants further investigation with IFX and mesna, is malignant mesothelioma.

Feasibility and efficacy of arginine 2-mercaptoethanesulfonate (ARGIMESNA) in the prevention of hemorragic cystitis from ifosfamide (IFO).

Tolerability and efficacy of the new uroprotective agent ARGIMESNA was assessed within a randomized cross-over study comparing it to sodiummercaptoethanesulfonate (MESNA), in patients treated with IFO. MESNA i.v., 20% of IFO dose, was given to all patients before chemotherapy; 4 h later, at random, they received ARGIMESNA p.o., 20% of IFO dose every 2 h x 4, or MESNA p.o., 40% of IFO dose every 4 h x 2. Overall, 78 cycles of oral uroprotection were administered: 37 for ARGIMESNA capsules; 41 for MESNA vials p.o. ARGIMESNA was subjectively better tolerated, determining gastro-intestinal discomfort in only 12 out of 37 cycles versus 34/41 of MESNA p.o. (p less than 0.001). Both preparations were equivalent for subjective and objective efficacy since no cycles were complicated by urinary symptoms (dysuria, stranguria, or hematuria). Nevertheless, 2 patients (7.7%) refused further oral assumption of both uroprotectors, whereas MESNA i.v. was added in other 7 patients because of nausea and vomiting caused by chemotherapy. In conclusion, this new oral preparation of mercaptoethanesulfonate turned out to be well tolerated, safe and active in the prevention of haemorrhagic cystitis from IFO.