mesna and Hemorrhage

Cyclophosphamide is an alkylating agent associated with significant toxicities, most importantly hemorrhagic cystitis. Many approaches including mesna use were established to reduce this toxicity. However, data on mesna efficacy are conflicting.. To investigate the incidence of hemorrhagic cystitis in patients receiving cyclophosphamide therapy with or without mesna.. A retrospective chart review was done on all adult patients receiving cyclophosphamide therapy with or without mesna at the King Saud University Medical City. The incidence of hemorrhagic cystitis was recorded. Patients receiving mesna were compared with those not receiving mesna. Data were reported as numbers and percentages, and appropriate statistical tests of association were used. This step was followed by a comprehensive literature review using appropriate keywords in PubMed from the inception of the database until August 2019. All studies of interest were reported.. A total of 718 patients' medical records were reviewed. The majority of the patients received mesna (n = 433, 60%). The mesna group had a greater incidence of hemorrhagic cystitis (3.5% vs. 0.4%,

Topics: Adult; Antineoplastic Agents, Alkylating; Cohort Studies; Cyclophosphamide; Cystitis; Female; Hemorrhage; Humans; Male; Mesna; Middle Aged; Prospective Studies; Protective Agents; Retrospective Studies

Cyclophosphamide and ifosfamide are widely used drugs for malignancies and rheumatologic conditions. One of the most significant adverse reactions to these drugs is hemorrhagic cystitis. Mesna is the most widely used uroprotective agent that acts to neutralize the caustic metabolite, acrolein, responsible for induction of hemorrhagic cystitis. However, mesna is not a perfect alternative, and studies since its discovery have investigated the use of alternative drugs and adjuncts to increase mesna's efficacy. This review details some of the recent work into novel uroprotective agents for drug-induced hemorrhagic cystitis.

Topics: Antineoplastic Agents, Alkylating; Cyclophosphamide; Cystitis; Hemorrhage; Humans; Ifosfamide; Mesna; Protective Agents

Cyclophosphamide (CP) and ifosfamide (IF) are widely used antineoplastic agents, but their side-effect of hemorrhagic cystitis (HC) is still encountered as an important problem. Acrolein is the main molecule responsible of this side-effect and mesna (2-mercaptoethane sulfonate) is the commonly used preventive agent. Mesna binds acrolein and prevent its direct contact with uroepithelium. Current knowledge provides information about the pathophysiological mechanism of HC: several transcription factors and cytokines, free radicals and non-radical reactive molecules, as well as poly(adenosine diphosphate-ribose) polymerase (PARP) activation are now known to take part in its pathogenesis. There is no doubt that HC is an inflammatory process, including when caused by CP. Thus, many cytokines such as tumor necrosis factor (TNF) and the interleukin (IL) family and transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) also play a role in its pathogenesis. When these molecular factors are taken into account, pathogenesis of CP-induced bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells; (2) it then activates intracellular reactive oxygen species and nitric oxide production (directly or through NF-kappaB and AP-1) leading to peroxynitrite production; (3) finally, the increased peroxynitrite level damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to activation of PARP, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide-adenine dinucleotide and adenosine triphosphate, and consequently in necrotic cell death. For more effective prevention against HC, all pathophysiological mechanisms must be taken into consideration.

Topics: Acrolein; Antineoplastic Agents; Cell Death; Cyclophosphamide; Cystitis; Cytokines; DNA Damage; Enzyme Activation; Hemorrhage; Humans; Ifosfamide; Lipid Peroxidation; Mesna; Nitrogen; Oxygen; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Transcription Factors

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.

Topics: Administration, Oral; Ambulatory Care; Antineoplastic Agents, Alkylating; Cystitis; Drug Administration Schedule; Europe; Hematuria; Hemorrhage; Humans; Ifosfamide; Injections, Intravenous; Mesna; Tablets; United States

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.

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Graft Rejection; Hemorrhage; Humans; Immunosuppressive Agents; Mesna

Topics: Acrolein; Adolescent; Adult; Aged; Allografts; Biotransformation; Child; Cyclophosphamide; Cystitis; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hemorrhage; Histocompatibility; Humans; Incidence; Infusions, Intravenous; Mesna; Middle Aged; Proportional Hazards Models; Prospective Studies; Retrospective Studies; Transplantation Conditioning; Young Adult

Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). Mesna is the drug of choice for prevention of HC. In this study, we analyzed cystoscopic and histological changes present in bladders of patients using IFS with mesna prophylaxis.. Thirty-three patients selected for IFS plus three doses of mesna chemotherapy regime were assigned at random to two groups: Group I or reference group consisted of 18 patients yet untreated. Group II consisted of 15 patients in whom urinalysis and cystoscopy plus vesical biopsy were performed only 24 h after receiving the last dose of IFS. The cystoscopic and histological findings were used as parameters for evaluating the results. For the former the criterion adopted was macroscopic vesical changes in accordance with Gray's criteria. Histological analyses were performed by evaluation method especially adapted to this study.. Even under treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage.. The standard protocol used for prevention of IFS-induced HC with three doses of mesna does not completely prevent bladder damage. The histopathological criteria used in this study for observation of inflammatory events allowed staging the intensity of IFS-induced urothelial and mucosal injury.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Cystoscopy; Edema; Erythrocytes; Etoposide; Exocytosis; Female; Hemorrhage; Humans; Ifosfamide; Male; Mesna; Middle Aged; Urinary Bladder; Urinary Bladder Diseases; Urothelium

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Hemorrhage; Humans; Mesna; Postoperative Complications; Protective Agents

Twenty patients with a variety of neoplastic diseases were treated with preparative regimens containing high-dose cyclophosphamide (CY) administered as a 2-h infusion (60 mg/kg) for 2 days or by continuous infusion (1500 mg/m2/day) for 4 days. In patients receiving CY by 2-h infusion, the uroprotectant 2-mercaptoethane sulfonate (MESNA) was administered as an intermittent, bolus intravenous infusion (20% of CY dose) every 6 h. In patients receiving continuous infusion CY, MESNA was administrated concomitantly at an equivalent dose to CY by continuous infusion. During the first 24 h of CY administration, urine was collected at 2-h intervals and analyzed for free thiols and CY-alkylating metabolites. In patients receiving CY by short infusion and MESNA by intermittent bolus infusion, urinary concentrations of alkylating metabolites peaked at 4-8 h. During each dose of MESNA, urinary free thiols peaked at 2 h following administration but fell to pre-treatment levels at subsequent intervals. In patients receiving CY by continuous infusion, CY alkylating metabolites increased gradually over the 24-h study period while free thiols remained at a constant level during this period. With bolus administration of CY and intermittent bolus administration of MESNA every 6 h, there are periods where urinary CY-alkylating metabolites are elevated and free thiol concentrations are diminished. During continuous infusion of CY and MESNA, urinary CY alkylating metabolites reached peak concentrations at 18-22 h while the exposure of the bladder to free thiols remained constant. Recommendations are provided to increase the exposure of free thiols in the bladder when MESNA is administered by bolus or continuous infusion.

Topics: Adult; Antineoplastic Agents, Alkylating; Carboplatin; Cyclophosphamide; Cystitis; Drug Administration Schedule; Female; Hemorrhage; Humans; Infusions, Intravenous; Male; Mesna; Middle Aged; Neoplasms; Sulfhydryl Compounds; Thiotepa; Urinary Bladder

Hemorrhagic cystitis (HC) after bone marrow transplantation (BMT) has been ascribed to cyclophosphamide metabolites. HC has also been associated with excretion of the BK type of polyomavirus. The relative contributions of cyclophosphamide metabolites and BK virus in the development of HC following BMT are unknown.. We conducted a randomized trial to compare mesna with forced diuresis for prophylaxis against HC in 147 BMT recipients. We studied the association of BK virus with HC in 95 consecutive BMT recipients by prospectively monitoring urinary excretion of BK virus using polymerase chain reaction amplification of viral gene sequences.. HC occurred in 37 of 147 (25.2%) transplant recipients. The incidence of HC was similar in patients given mesna (26.8%, 19 of 71) or forced diuresis (23.7%, 18 of 76), and in recipients of allogeneic (27.2%, 18 of 64) or autologous marrow (22.9%, 19 of 83). The incidence of HC was unrelated to primary disease, preparative regimen, or occurrence of graft-versus-host disease (GVHD). Excretion of BK virus was demonstrated in 50 of 95 patients (52.6%); 38 patients (40%) had persistent BK viruria (> or = two consecutive positive samples). HC occurred in 19 of 38 patients (50%) with persistent BK viruria, in one of 12 (8.3%) with only a single urine sample positive for BK virus, and in none of 45 who did not excrete BK virus (P < .0001). Shedding of BK virus also had a strong temporal correlation with onset of HC (r = .95).. Mesna and forced diuresis are equally effective in abrogating the urothelial toxicity of preparative regimens for BMT. Since HC after BMT is virtually always associated with persistent BK viruria, strategies aimed at the prevention or elimination of viruria in BK seropositive recipients are warranted.

Topics: Adult; BK Virus; Bone Marrow Transplantation; Cystitis; Diuresis; Female; Fluid Therapy; Hemorrhage; Humans; Male; Mesna; Polymerase Chain Reaction; Polyomavirus Infections; Prospective Studies; Tumor Virus Infections; Urine

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Cystitis; Hemorrhage; Humans; Ifosfamide; Mesna; Methotrexate; Middle Aged; Soft Tissue Neoplasms

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.

Topics: Adolescent; Adult; Aged; Cystitis; Female; Hemorrhage; Humans; Ifosfamide; Male; Mesna; Middle Aged

Hemorrhagic cystitis is a major complication of high-dose cyclophosphamide therapy used in preparation for allogeneic or autologous bone marrow transplantation. Although previous reports had suggested that the sulfhydryl-containing compound mesna might be superior to forced diuresis in preventing hemorrhagic cystitis, there were concerns about the effect of mesna on engraftment in these studies. To address these concerns, 100 patients were randomized to receive mesna or forced saline diuresis while undergoing bone marrow transplant conditioning with regimens that included high-dose cyclophosphamide. To try to minimize the likelihood of graft rejection, patients who were being transplanted with cyclophosphamide as a sole agent were excluded from the study. After randomization and administration of therapy, patients were monitored by microscopic and dip-stick urinalyses; they were also followed for effects of therapy on engraftment. The incidence of consistent or severe hematuria was 33% in the mesna arm and 20% in the hyperhydration arm (P = .31). Severe bleeding occurred in 12.5% of mesna patients and 7.5% of hyperhydration patients (P = .71). No unexpected toxicities were encountered, and engraftment times did not differ. Based on this randomized trial of 100 patients, we conclude that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation patients.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Female; Fluid Therapy; Hemorrhage; Humans; Male; Mesna; Middle Aged

High-dose ifosfamide (one or two courses of 6 g/m2) with or without mesna was administered to 13 patients with advanced non-small cell lung cancer. The protective effect of 2-mercapto-ethane sulfonate (mesna) against the urotoxic side effects induced by ifosfamide was examined by a randomized crossover trial. A significant reduction in the incidence of hematuria was observed in the patients receiving mesna. Macroscopic hematuria was observed in only one patient who received treatment with mesna versus seven patients treated with ifosfamide alone. Other symptoms, such as frequency and dysuria, tended to be diminished in the patients receiving mesna, although the difference was not statistically significant. Our results suggest that mesna is effective in preventing or diminishing ifosfamide-induced hemorrhagic cystitis. Concomitant use of mesna should allow the administration of a high dose of ifosfamide although more extensive studies are needed to define the optimal dose and schedule of administration of mesna to prevent or attenuate the hemorrhagic cystitis.

Topics: Adult; Aged; Clinical Trials as Topic; Cystitis; Female; Hemorrhage; Humans; Ifosfamide; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Middle Aged; Random Allocation

A prospective randomised study was carried out to compare the effect of mesna (2-mercaptoethane sulphonate sodium) with that of forced diuresis in preventing cyclophosphamide induced haemorrhagic cystitis in marrow transplant recipients. Sixty-one consecutive BMT recipients were randomised for treatment with forced diuresis or mesna. The incidence of macroscopic haematuria was significantly lower in the mesna treated group (chi 2 = 4.03, P less than 0.05). No specific side effects of mesna were detected. The lymphopenia induced by cyclophosphamide in the aplastic recipients was similar in the mesna and forced diuresis groups suggesting that mesna has no effect on the lymphocytotoxic activity of cyclophosphamide, although 6 out of 7 episodes of graft failure documented in the study occurred in mesna treated patients. As a result of this study our present policy is to use mesna in all BMT recipients but to continue careful documentation of the incidence of graft failure.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Colony-Forming Units Assay; Cyclophosphamide; Cystitis; Diuresis; Graft Rejection; Hematuria; Hemorrhage; Humans; Leukocyte Count; Mercaptoethanol; Mesna; Postoperative Complications; Prospective Studies

Hemorrhagic cystitis is an inflammatory complication that can be caused by the administration of cyclophosphamide, which is widely used as an antineoplastic agent. In the search for new therapeutic alternatives, probiotics can suppress the inflammatory process and, therefore, can be used to prevent this disease.. Thus, this study aimed to evaluate the effects of using Lactobacillus acidophilus NCFM in the treatment of cyclophosphamide-induced hemorrhagic cystitis in Wistar rats.. GI results showed development of edema, macroscopic alterations, and signs of bleeding in the bladder; in addition, lesions in the urothelium and hemorrhage were also found. GL24H and GM presented intact urothelium, without inflammatory reaction and hematological or biochemical urine alterations.. Therefore, this study demonstrated that L. acidophilus presented uroprotective effect against the action of cyclophosphamide in both the short and long term.

Topics: Animals; Antineoplastic Agents, Alkylating; Cyclophosphamide; Cystitis; Female; Hemorrhage; Inflammation; Lactobacillus acidophilus; Mesna; Rats; Rats, Wistar

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.

Topics: Animals; Cystitis; Female; Hemorrhage; Ifosfamide; Inflammation; Interleukin-10; Mesna; Mice; Signal Transduction

Hemorrhagic cystitis (HC) is a major urotoxic complication of cyclophosphamide (CPA) therapy. This study investigated the uroprotective effect of montelukast on CPA-induced HC, compared to the efficacy of 2-mercaptoethane sulfonate sodium (MESNA).. Male albino rats were pretreated with MESNA (40 mg/kg/day, IP) or montelukast (10 mg/kg/day, orally) for three days then received a single dose of CPA (200 mg/kg, IP), 1 h after the last dose, and compared to CPA-treated rats receiving drug vehicle. Age-matched rats were used as controls. Bladders of rats were assessed biochemically, macroscopically and microscopically by light and electron microscope 24 h later.. CPA injection contributed to increased bladder weight, urothelial ulceration, vascular congestion, hemorrhage, increased collagen deposition and mast cell infiltration, compared to control rats. Montelukast preconditioning suppressed mast cell infiltration and inflammatory mediators to greater extent than MESNA. Also, montelukast enhanced autophagosomes formation in detrusor myocytes and up-regulated the autophagy-related proteins (beclin-1 & LC3-II), likely through inhibition of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Montelukast preconditioning offset the up-regulation of transient receptor potential vanilloid 4 (TRPV4) in urothelial tissue of CPA-treated rats, to greater extent than MESNA.. These results demonstrate the uroprotective effect of montelukast on CPA-induced HC, which appears to be more superior to MESNA. These findings suggest that montelukast can emerge as a novel strategy to protect against CPA-induced urotoxicity.

Topics: Acetates; Animals; Apoptosis; Autophagy; Cyclophosphamide; Cyclopropanes; Cystitis; Hemorrhage; Inflammation; Male; Mast Cells; Mesna; Oxidative Stress; Phagocytosis; Phagosomes; Quinolines; Rats; Signal Transduction; Sulfides; TRPV Cation Channels; Urinary Bladder; Urothelium

Hemorrhagic cystitis (HC) is an important complication after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-CY). Sodium 2-mercaptoethanesulfonate (MESNA) can prevent bladder injury when given with PT-CY. However, the best way to deliver MESNA is not known. This study assessed the incidence of HC after haplo-HSCT with PT-CY with 2 different methods of MESNA administration. The cumulative incidence of HC was lower in patients who received MESNA as a continuous infusion compared with those who received it as an intermittent bolus (5.6% versus 27.8%; P = .01). MESNA administration as an infusion was associated with a lower risk of developing HC (hazard ratio [HR], .19; 95% confidence interval [CI], .04 to .86; P = .02) on univariate analysis. This effect remained significant after adjustment in multivariate analysis (HR, .21; 95% CI, .04 to .88; P = .03). MESNA delivered as a continuous infusion is a simple and potentially useful way to prevent HC after PT-CY.

Topics: Cyclophosphamide; Cystitis; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Mesna; Transplantation, Haploidentical

In this study, we investigated the effects of pomegranate on alleviating cyclophosphamide-induced hemorrhagic cystitis (HC). Initially, 16 Sprague-Dawley rats were allocated into 4 groups: group 1 (control), group 2 (CP) in which HC was induced by cyclophosphamide; group 3 (CP+M), HC-induced rats that received Mesna regimen, and group 4 (CP+P), which compromised rats that had been on a 14-day diet of pomegranate juice before HC induction. Cystometry was performed a few hours before euthanasia; after euthanasia, aortic blood samples and bladder tissue samples were obtained to perform TUNEL assay, and histopathologic and biochemical assessments. Urodynamic findings revealed that mean detrusor pressure in CP+P was significantly lower compared with that in CP and CP+M (P<0.05). Histopathologically, urothelium destruction and inflammation were lower in CP+P and CP+M compared with that in CP. Collagen destruction was less prominent in CP+P compared with that in CP and CP+M. Tissue and plasma levels of malondialdehyde were significantly lower in CP+P versus CP (P<0.05). Catalase activity and total protein thiol group levels in plasma and bladder tissue were higher in CP+P versus CP (P<0.05). The TUNEL positivity in CP+P was significantly weaker than that in CP, indicating less DNA fragmentation and apoptosis. Pomegranate's characteristics could significantly affect the inflammatory and destructive process of hemorrhagic cystitis.

Topics: Animals; Cyclophosphamide; Cystitis; Hemorrhage; Lythraceae; Male; Mesna; Plant Extracts; Rats; Rats, Sprague-Dawley; Urodynamics; Urothelium

Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 μg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 μg/kg), IFO (200 mg/kg), G-CSF (25-400 μg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1β and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC.

Topics: Animals; Antineoplastic Agents, Alkylating; Cystitis; Drug Therapy, Combination; Female; Hemorrhage; Ifosfamide; Mesna; Mice; Neutrophil Infiltration; Polysaccharides; Protective Agents

The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)-induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP-induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cyclophosphamide; Cysteine; Cystitis; Down-Regulation; Edema; Gene Expression Regulation; Hemorrhage; Mesna; Mice; Organ Size; Protective Agents; Random Allocation; RNA, Messenger; Urinary Bladder; Uroplakin II; Urothelium

Ifosfamide (IFO) is considered an essential drug for the treatment of pediatric, adolescent and young adult patients with solid tumors. Hemorrhagic cystitis (HC) is one of the dose-limiting toxicity of IFO. However, there are insufficient evidence for risk factor and supportive care of IFO-induced HC.. In this retrospective study, patients (<30-year-old) with malignant solid tumors who had been treated with IFO-based chemotherapy, were categorized according to the presence or absence of HC, and were analyzed possible risk factors for IFO-induced HC. In our institution, continuous hydration to increase urine output and intravenous 2-mercaptethane sulfonate (mesna) are used for prophylaxis of IFO-induced HC. Increased hydration and dosage of mesna are administered to patients who develop IFO-induced HC; they also receive 24-h continuous infusion of mesna in subsequent treatment cycles.. Nine treatment regimens were used in the 70 study patients. The range of daily IFO dosage was 1.2-3.0 g/m(2). HC occurred in 14/425 IFO-based chemotherapy cycles (3.3%). The daily IFO dosages (mean ± SD) in patients with or without HC were 2.23 ± 0.58 g/m(2) and 1.85 ± 0.50 g/m(2), respectively (P = 0.006). Only one of the nine patients who developed IFO-induced HC had experienced this complication in a subsequent cycle of treatment.. The incidence of IFO-induced HC may be associated with the dosage of IFO. When administering IFO higher than 2.0 g/m(2)/day, the volume of hydration, dosage of mesna and duration of mesna infusion should be increased to prevent HC.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystitis; Drug Administration Schedule; Female; Hemorrhage; Humans; Ifosfamide; Incidence; Infant; Male; Mesna; Neoplasms; Protective Agents; Retrospective Studies; Risk Factors; Young Adult

Sterile haemorrhagic cystitis (SHC) is a possible side effect of cyclophosphamide which can severely impact quality of life. Mesna and diuresis are effective in human medicine to prevent SHC. The aim of the present study was to compare the efficacy of mesna versus diuresis with furosemide in preventing SHC in dogs treated with cyclophosphamide within a multidrug chemotherapy induction protocol for malignant lymphoma. Medical records of dogs treated at the Clinic of Small Animal Medicine, Munich, between 1997 and 2009 were analysed retrospectively. Of the 131 dogs included, 33 received no prophylaxis (group 1), 43 received mesna (group 2), and 55 received furosemide (group 3). Age, gender, breed, bodyweight, body surface area, dose and application method of cyclophosphamide, and the method of SHC prophylaxis were compared between dogs with and without SHC. Six dogs (4.6 per cent) developed SHC. The incidence of SHC in groups 1, 2 and 3 was 4/33 (12.1 per cent), 1/43 (2.3 per cent), and 1/55 (1.8 per cent), respectively. Dogs receiving either mesna or furosemide were significantly less likely to develop SHC (P=0.03). Otherwise no significant differences were found. In conclusion, this study demonstrates the efficacy and the medical indication of mesna and furosemide for prevention of cyclophosphamide-induced SHC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cystitis; Diuretics; Dog Diseases; Dogs; Female; Furosemide; Hemorrhage; Lymphoma; Male; Mesna; Protective Agents; Retrospective Studies; Risk Factors; Treatment Outcome

Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CP). The aim of this study was to compare the classical efficacy of mesna (2-mercaptoethane sulfonate sodium) with three different doses of resveratrol (RES) on cyclophosphamide-induced HC in rats.. Forty-six male Sprague-Dawley rats were divided into six groups. Group 1 served as a negative control (sham). Five groups received a single dose of cyclophosphamide (150 mg/kg) intraperitoneally at the same time. Groups 2, 3, 4, 5, and 6 received only CP, CP + 20 mg/kg RES, CP + 40 mg/kg RES, CP + 80 mg/kg RES, and CP + classical protocol of three doses of mesna (30 mg/kg three times), respectively. Antioxidants, cytokines, and malondialdehyde levels were measured in all groups. In addition, histopathological alterations in tissues were examined.. CP administration induced severe HC with marked edema, hemorrhage, and inflammation in group 2. RES 20 mg/kg showed meaningful protection against bladder damage compared to the control group. It was seen that RES 40 mg/kg gave weaker protection but RES 80 mg/kg was not found to be effective.. In conclusion, marked bladder protection was found in 20 and 40 mg/kg RES applications compared to the control group, but this protection was weaker than with mesna.

Topics: Animals; Biomarkers; Cyclophosphamide; Cystitis; Hemorrhage; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Mesna; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Topics: Adolescent; Adult; Aged; Cystitis; Female; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Injections, Intravenous; Male; Mesna; Middle Aged; Transplantation Conditioning; Young Adult

We investigated whether interleukin-4 (IL-4) is present and capable of reducing inflammatory changes seen in ifosfamide-induced hemorrhagic cystitis. Male Swiss mice were treated with saline or ifosfamide alone or ifosfamide with the classical protocol with mesna and analyzed by changes in bladder wet weight (BWW), macroscopic and microscopic parameters, exudate, and hemoglobin quantification. In other groups, IL-4 was administered intraperitoneally 1 h before ifosfamide. In other experimental groups, C57BL/6 WT (wild type) and C57BL/6 WT IL-4 (-/-) knockout animals were treated with ifosfamide and analyzed for changes in BWW. Quantification of bladder IL-4 protein by ELISA in control, ifosfamide-, and mesna-treated groups was performed. Immunohistochemistry to tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) as well as protein identification by Western blot assay for inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was carried out on ifosfamide- and IL-4-treated animals. In other experimental groups, antiserum against IL-4 was given 30 min before ifosfamide. In IL-4-treated animals, the severity of hemorrhagic cystitis was significantly milder than in animals treated with ifosfamide only, an effect that was reverted with serum anti-IL-4. Moreover, knockout animals for IL-4 (-/-) exhibit a worse degree of inflammation when compared to C57BL/6 wild type. Exogenous IL-4 also attenuated TNF-α, IL-1β, iNOS, and COX-2 expressions in ifosfamide-treated bladders. IL-4, an anti-inflammatory cytokine, attenuates the inflammation seen in ifosfamide-induced hemorrhagic cystitis.

Topics: Animals; Cyclooxygenase 2; Cystitis; Hemorrhage; Ifosfamide; Interleukin-1beta; Interleukin-4; Male; Mesna; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Tumor Necrosis Factor-alpha; Urinary Bladder

ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide.. Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry.. Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1β and TNF-α. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC.. P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition.

Topics: Animals; Cell Movement; Cyclophosphamide; Cystitis; Cytokines; Dose-Response Relationship, Drug; Gene Expression Regulation; Genes, fos; Hemorrhage; Inflammation; Macrophages; Male; Mesna; Mice; Mice, Knockout; Nociception; Purinergic P2X Receptor Antagonists; Pyridines; Receptors, Purinergic P2X7; Tetrazoles; Urinary Bladder

Ifosfamide (IFS) is often involved in the occurrence of hemorrhagic cystitis due to direct contact of its metabolite acrolein with uroepithelium. It has been shown that COX-2 is involved in this pathogenesis. Thus, we aimed to study the functional changes on the urinary bladder in the putative modifications induced by IFS, as well as the COX-2 role in this process.. IFS-treated rats were evaluated by cystometrography in absence or presence of COX inhibitors indomethacin or etoricoxib or in the presence of mesna. Experiments with isolated strips of urinary bladder obtained from animals with IFS-induced cystitis, either treated or not treated with COX inhibitors or mesna, were performed. Histological analyses, immunohistochemistry for COX-2, and measurement of plasma PGE(2) were also performed.. IFS treatment caused severe inflammation of the bladder tissue. Cystometrography recordings of IFS-treated rats revealed bladder with increased micturition frequency and enhanced filling intravesical pressure. Contractility of the isolated smooth muscle from the rat's bladder with IFS-induced cystitis showed decreased force development in response to KCl and CCh. Almost all effects induced by IFS were ameliorated by the use of COX inhibitors or mesna. Enzyme expression in the urinary bladder tissue was positive, and plasma concentration of PGE(2) was increased in IFS-treated animals and decreased significantly in etoricoxib-treated animals.. IFS causes important changes in the micturition physiology in rats, and the inhibition of the isoenzyme COX-2 could be an important event that could prevent the detrimental effects elicited by IFS-induced hemorrhagic cystitis.

Topics: Animals; Antineoplastic Agents, Alkylating; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cystitis; Dinoprostone; Disease Models, Animal; Hemorrhage; Ifosfamide; Inflammation; Male; Mesna; Muscle Contraction; Muscle, Smooth; Rats; Rats, Wistar; Severity of Illness Index; Urination

Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (six to eight per group, 220-250 g). HC was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters--breathing rate, closing of the eyes, and specific posture--were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Apocynaceae; Cyclophosphamide; Cystitis; Disease Models, Animal; Glycosides; Hemorrhage; Male; Mesna; Organ Size; Pain Measurement; Peroxidase; Protective Agents; Rats; Rats, Wistar; Steroids; Urinary Bladder

Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC.. Male Wistar rats (150-200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-alpha inhibitor), pentoxifyllin (non-selective TNF-alpha inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin.. COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically.. COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-alpha inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.

Topics: Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cystitis; Drug Therapy, Combination; Etoricoxib; Hemorrhage; Ifosfamide; Immunoenzyme Techniques; Indomethacin; Male; Mesna; Pentoxifylline; Protective Agents; Pyridines; Rats; Rats, Wistar; Sulfones; Thalidomide

Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or acrolein (25, 75, 225 microg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 microg/bladder), as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid), which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

Topics: Acrolein; Animals; Cystitis; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hemorrhage; Male; Mesna; Mice; Protective Agents; Urinary Bladder

The aim of this study was to evaluate whether combination of antioxidants and mesna may prevent cystitis induced by cyclophosphamide better than mesna alone.. A total of 46 male Sprague-Dawley rats were divided into six groups. Five groups received single dose of cyclophosphamide (CP, 100 mg/kg) intraperitoneally with the same time intervals: group 2 received CP only, group 3 received mesna (21.5 mg/kg for three times), group 4 beta-carotene (20 mg/kg for two times) and mesna, group 5 received alpha-tocopherol (20 mg/kg for two times) and mesna, and group 6 received melatonin (5 mg/kg for two times) and mesna on the day of CP injection. Group 1 served as control.. CP injection resulted in severe cystitis. Mesna has showed meaningful but not full protection against CP toxicity. Although beta-carotene did not show any additional beneficial effect when combined with mesna, alpha-tocopherol and especially melatonin with mesna resulted full protection that the pathologist, blinded to the slides, could not differ from sham control.. Oxidants may be important in the pathogenesis of CP-induced cystitis. Melatonin and alpha-tocopherol may help to ameliorate bladder damage along with other drugs such as mesna and diuretics.

Topics: Animals; Antioxidants; Cyclophosphamide; Cystitis; Disease Models, Animal; Hemorrhage; Male; Mesna; Protective Agents; Rats; Rats, Sprague-Dawley; Urinary Bladder

To establish the most appropriate prophylactic therapy and risk factors for predicting hemorrhagic cystitis (HC) after stem cell transplantation (SCT), we retrospectively analyzed the clinical records of 450 transplant patients treated from 1982 to 2002. In all, 81 patients developed early- and/or late-onset HC (early=29, late=48, both=4). For the incidence of early-onset HC, administration of cyclophosphamide (CY) (p=0.0079, odds ratio (OD)=5.109, 95% confidence interval (CI)=1.533-17.030), busulfan (BU) (p=0.0015, OD=3.336, 95% CI=1.584-7.027), BU+CY (p=0.0001, OD=4.369, 95% CI=2.055-9.292), antithymocyte globulin (p=0.0009, OD=3.368, 95% CI=1.642-6.911), nonradiation (p=0.0163, OD=2.564, 95% CI=0.181-0.841), 2-mercaptoethane sodium sulfonate (Mesna) (p=0.0001, OD=7.519, 95% CI=2.847-19.858), and bladder irrigation (p=0.0001, OD=4.950, 95% CI=2.328-10.523) were risk factors. By Fisher's exact test, the combination of BU and Mesna was a more significant risk factor (P<0.001) than Mesna alone (p=0.008) compared to the administration of neither agent. By multivariate analysis, prophylactic administration of Mesna (p=0.0105, OD=5.301, 95% CI=1.477-19.026) and bladder irrigation (p=0.0001, OD=9.469, 95% CI=3.872-23.156) were significant risk factors of early-onset HC. We conclude that (i). high-dose BU as well as CY is a cause of HC, (ii). protective bladder irrigation has an opposite effect, and (iii). Mesna possibly has a toxic effect on bladder mucosa.

Topics: Adolescent; Antilymphocyte Serum; Busulfan; Cyclophosphamide; Cystitis; Drug Synergism; Female; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Incidence; Male; Mesna; Multivariate Analysis; Retrospective Studies; Risk Factors; Therapeutic Irrigation; Transplantation, Homologous

Hemorrhagic cystitis (HC) is a limiting side-effect of chemotherapy with ifosfamide (IFS). In the study presented here, we investigated the use of dexamethasone in combination with mesna for the prevention of IFS-induced HC.. Male Wistar rats (150-200 g; 6 rats per group) were treated with saline or mesna 5 min (i.p.) before and 2 and 6 h after (v.o.) administration of IFS. One, two or three doses of mesna were replaced with dexamethasone alone or with dexamethasone plus mesna. Cystitis was evaluated 24 h after its induction by the changes in bladder wet weight and by macroscopic and microscopic analysis.. The replacement of the last dose or the last two doses of mesna with dexamethasone reduced the increase in bladder wet weight induced by IFS by 84.79% and 89.13%, respectively. In addition, it almost abolished the macroscopic and microscopic alterations induced by IFS. Moreover, the addition of dexamethasone to the last two doses of mesna was more efficient than three doses of mesna alone when evaluated microscopically.. Dexamethasone in combination with mesna was efficient in blocking IFS-induced HC. However, the replacement of last two doses of mesna with saline or all of the mesna doses with dexamethasone did not prevent HC.

Topics: Animals; Anti-Inflammatory Agents; Cystitis; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemorrhage; Ifosfamide; Male; Mesna; Organ Size; Protective Agents; Rats; Rats, Wistar; Sodium Chloride; Treatment Outcome; Urinary Bladder

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Benzamides; Bone Neoplasms; Cystitis; Diphosphonates; Drug Approval; Gastrointestinal Neoplasms; Hematuria; Hemorrhage; Humans; Ifosfamide; Imatinib Mesylate; Imidazoles; Mesna; Multiple Myeloma; Orphan Drug Production; Piperazines; Protective Agents; Pyrimidines; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; Zoledronic Acid

Topics: Bone Marrow Transplantation; Chronic Disease; Cystitis; Hemorrhage; Humans; Mesna; Protective Agents

Hyperbaric oxygen therapy and mesna have been successfully used for hemorrhagic cystitis. We defined the protective effects of hyperbaric oxygen and mesna in further cyclophosphamide induced hemorrhagic cystitis in guinea pigs.. A total of 48 male guinea pigs were divided into 6 groups. All groups received 2 doses of 68.1 mg./kg. cyclophosphamide intraperitoneally at the same time intervals but group 1 served as controls. Group 2 received cyclophosphamide only, group 3 received hyperbaric oxygen treatment (2.8 ATA for 90 minutes twice daily) before and the day after further cyclophosphamide, group 4 received 21.5 mg./kg. mesna intraperitoneally only with further cyclophosphamide, group 5 received hyperbaric oxygen and mesna with further cyclophosphamide, and group 6 received hyperbaric oxygen before initial cyclophosphamide, between the 2 doses and after the further dose of cyclophosphamide, and mesna on the days of cyclophosphamide.. Although mesna alone provided protection against cyclophosphamide induced cystitis in animal bladders, there was also significant damage compared with controls. When the uroprotective efficacy of mesna was supported with hyperbaric oxygen, bladder protection was promoted since mean histological scores and hematuria levels in this group did not differ from those in controls.. According to this animal study using hyperbaric oxygen as adjuvant therapy in humans may be a better tool than mesna alone for the prophylaxis and treatment of cyclophosphamide induced hemorrhagic cystitis.

Topics: Animals; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Cyclophosphamide; Cystitis; Guinea Pigs; Hemorrhage; Hyperbaric Oxygenation; Male; Mesna; Protective Agents

Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP), is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC) becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna) treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group) were treated with saline or Mesna (40 mg/kg, ip) immediately and 4 and 8 h after ip administration of CYP (200 mg/kg). One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip). The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05), which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%). The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYP-induced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cyclophosphamide; Cystitis; Dexamethasone; Hematuria; Hemorrhage; Male; Mesna; Protective Agents; Rats; Rats, Wistar

Topics: Antineoplastic Agents; Cyclophosphamide; Cystitis; Hemorrhage; Humans; Hyperbaric Oxygenation; Mesna

Bromofosfamides, the group of novel compounds closely related to ifosfamide, are currently in the stage of advanced preclinical evaluation. Ifosfamide, although itself the effective antineoplastic drug useful in situations which have proved refractory to cyclophosphamide therapy, has the side-effect toxicities caused by its metabolities that pose clinically a very real problem. One of their manifestations is the severe urinary tract toxicity which now could be adequately managed by conjunctive administration of mesna (sodium 2-mercaptoethane sulphonate). In this study we have compared the magnitude of urotoxic effects elicited by ifosfamide and two bromofosfamide compounds--racemate and S(-) isomer of chlorobromofosfamide (ClBrs)--selected previously on the base of their superior antitumor activity in advanced animal tumor models. The urotoxic effects, expressed by the increase of urinary bladder weight and histopathologically defined organ wall edema, were estimated in healthy mice 24 h following single intraperitoneal or oral administrations of tested compounds which were applied in amounts equal to curative, sublethal or lethal doses. It was found that the expression of toxic effects revealed by both ClBrs was statistically significantly lower as compared to ifosfamide. Mesna coadministration prevented urotoxic effects almost completely in mice treated with ifosfamide or racemic ClBr. Somewhat lower efficacy of uroprotection with mesna was observed in the case of S(-) isomer of ClBr.

Topics: Administration, Oral; Animals; Cystitis; Edema; Female; Hemorrhage; Ifosfamide; Injections, Intraperitoneal; Lethal Dose 50; Maximum Allowable Concentration; Mesna; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Necrosis; Stereoisomerism; Urinary Bladder

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

To prevent hemorrhagic cystitis, mesna is typically injected intravenously (i.v.) at the time of an ifosfamide dose and 4 and 8 h later. To simplify outpatient ifosfamide therapy, we gave the second and third mesna doses orally.. The mesna doses (400 or 600 mg/m2) were 40% (w/w) of each ifosfamide dose (1.0 or 1.5 g/m2), which was given daily for 5 days. We evaluated urinary mesna excretion and plasma concentrations in ten patients from the beginning of mesna infusion until the time of the second oral dose. The first oral dose was administered at hour 2 in the last six patients to allow time for absorption of mesna.. The rate and amount of mesna excretion was less variable over time and among patients after oral than after i.v. administration. No macrohematuria was observed in these ten patients nor in an additional 50 patients given oral mesna at hours 2 and 8 during at least two cycles of ifosfamide therapy.. These pharmacokinetic and clinical efficacy data support the use of a combined regimen of i.v. and oral mesna to simplify outpatient ifosfamide administration.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Antineoplastic Agents, Alkylating; Cystitis; Female; Hemorrhage; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Treatment Outcome; Urinary Bladder

The aim of this research was to compare the protective effects of mesna, hyperbaric oxygenation (HBO), and their combination in cyclophosphamide-induced hemorrhagic cystitis in guinea pigs. Following one dose of i.p. 21.5 mg./kg. mesna administration 20 minutes before i.p. 68.1 mg./kg. cyclophosphamide, 3 additional doses of mesna were given every three hours. A total of 8 HBO exposures, 5 of which were applied prophylactically before cyclophosphamide, were performed at 2.8 ATA for 90 minutes 2 times a day. Although mesna or HBO provided significant protection for cyclophosphamide-cystitis in animal bladders, there was also significant damage compared with controls. The combination of mesna and HBO, which act through independent mechanisms, resulted in complete protection, since mean histological scores and hematuria levels in this group were not different from controls (p >0.05). Therefore, this combination may be a useful tool in the prophylaxis and treatment of cyclophosphamide-induced hemorrhagic cystitis.

Topics: Animals; Cyclophosphamide; Cystitis; Guinea Pigs; Hemorrhage; Hyperbaric Oxygenation; Male; Mesna

Topics: Antineoplastic Combined Chemotherapy Protocols; BK Virus; Cyclophosphamide; Cystitis; Cytarabine; Hemorrhage; Humans; Immunocompromised Host; Mesna; Papillomavirus Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Tumor Virus Infections; Vincristine

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.

Topics: Administration, Oral; Ambulatory Care; Antineoplastic Agents, Alkylating; Cystitis; Hemorrhage; Humans; Ifosfamide; Injections, Intravenous; Injections, Subcutaneous; Mesna; Safety; Urinary Tract; Vomiting

Investigators from Belarus Center for bone marrow transplantation examined the efficacy of preventing hemorrhagic cystitis induced by high-dose cyclophosphamide in preparation for hemopoiesis precursor transplantation in 22 patients with hematological diseases. The proposed preventive method implied administration of mesna (2-merkaptoetan-sulphonate) and alkaline forced diuresis. Its effectiveness was found high.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclophosphamide; Cystitis; Diuresis; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Male; Mesna

Hemorrhagic cystitis is a potentially serious complication of high-dose cyclophosphamide therapy administered before bone marrow transplantation. As standard practice at our institution, patients who are scheduled to receive a bone marrow transplant are treated prophylactically with forced hydration and bladder irrigation. In an attempt to obviate the inconvenience of bladder irrigation, we conducted a feasibility trial of uroprophylaxis with mesna, which neutralizes the hepatic metabolite of cyclophosphamide that causes hemorrhagic cystitis. Of 97 patients who received standard prophylaxis, 4 had symptomatic hemorrhagic cystitis. In contrast, two of four consecutive patients who received mesna uroprophylaxis before allogeneic bone marrow transplantation had severe hemorrhagic cystitis for at least 2 weeks. Because of this suboptimal result, we resumed the use of bladder irrigation and forced hydration to minimize the risk of hemorrhagic cystitis.

Topics: Academic Medical Centers; Bone Marrow Transplantation; Causality; Cyclophosphamide; Cystitis; Feasibility Studies; Fluid Therapy; Hemorrhage; Humans; Incidence; Infusions, Intravenous; Mesna; Minnesota

Based on clinical data, indicating that chloroacetaldehyde (CAA) is an important metabolite of oxazaphosphorine cytostatics, an experimental study was carried out in order to elucidate the role of CAA in the development of hemorrhagic cystitis. The data demonstrate that CAA after i.v. administration does not contribute to bladder damage. When instilled directly into the bladder, CAA exerts urotoxic effects, it is, however, susceptible to detoxification with mesna.

Topics: Acetaldehyde; Animals; Cyclophosphamide; Cystitis; Female; Hemorrhage; Ifosfamide; Male; Mesna; Rats; Rats, Inbred Strains

Topics: Antineoplastic Combined Chemotherapy Protocols; Cystitis; Hemorrhage; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms

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.

Topics: Adolescent; Adult; Child; Child, Preschool; Cyclophosphamide; Cystitis; Female; Hematuria; Hemorrhage; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasms

Following bone marrow transplantation employing conditioning including 'high-dose' cyclophosphamide, 65 patients were studied for the subsequent development of symptomatic haemorrhagic cystitis. There was no protection from the urothelial toxicity of cyclophosphamide metabolites afforded by the concurrent administration of 2-mercaptoethane sodium sulphonate (mesna) if timing errors in administration were made. Other factors which might increase the risk of haemorrhagic cystitis due to cyclophosphamide administration include the prior administration of busulphan to patients with chronic granulocytic leukaemia, in whom the incidence of haemorrhagic cystitis was 36% compared with 4% in all other patients. We have also investigated the use of intravesical prostaglandin E2 as a treatment for haemorrhagic cystitis in eight patients, two of whom appeared to obtain major benefit.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Cystitis; Female; Hematuria; Hemorrhage; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mesna; Middle Aged; Risk Factors

In 125 allogeneic bone marrow transplant recipients conditioned with cyclophosphamide (CY) with or without total body irradiation (TBI), three different protocols for prevention of CY urotoxicity have been used. The three protocols consisted of forced alkaline diuresis alone and then in combination with mesna (sodium 2-mercaptoethane sulfonate) at a low or high dose (60-90% and 150% of the CY dose, respectively). Hemorrhagic cystitis (HC) occurred in 21 patients: there were four immediate episodes without subjective symptoms which healed within a week after starting CY and 20 late episodes, starting between 17 and 51 (median 27) days. There was no correlation between the occurrence of HC and the different protocols used for prevention of urothelial toxicity. Late HC, however, except in one patient, always appeared together with acute graft-versus-host disease (GVHD) and the severity of the HC correlated with the severity of the GVHD (p less than 0.001). When acute GVHD commenced the HC started within 24 hours in three patients and in 11 patients when the dose of prednisolone given for an ongoing GVHD was reduced. In four other patients CY was not used for conditioning, but mustargen or melphalan in combination with TBI. In this group no urothelial protection was used. One of these patients developed a severe HC together with a grade II GVHD. Adenovirus and cytomegalovirus infections were not associated with HC.

Topics: Acute Disease; Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Diuresis; Epithelium; Graft vs Host Disease; Hemorrhage; Humans; Mesna

Topics: Anemia, Aplastic; Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Fluid Therapy; Furosemide; Hemorrhage; Humans; Leukemia; Mercaptoethanol; Mesna; Postoperative Complications

The situation regarding hemorrhagic cystitis after conditioning for bone marrow transplantation (BMT) in Japan was surveyed and analyzed. Thirty-seven of 110 patients (33.6%) developed hemorrhagic cystitis after conditioning for BMT with cyclophosphamide (CY) and total body irradiation. In two of these 37 patients the cystitis was virus (adenovirus)-induced. In the others it was diagnosed as CY-induced. The severity and duration of CY-induced hemorrhagic cystitis were related to its onset. The delayed type of hemorrhagic cystitis induced by CY seemed to have a poor prognosis and often continued until the patient died. Therefore, late-onset hemorrhagic cystitis should be followed carefully and its prophylaxis may be important. 2-Mercaptoethane sulphonate (mesna) injections for prophylaxis of CY-induced hemorrhagic cystitis were found to be effective in reducing the incidence of the delayed type in 21 (53.8%) of 39 patients treated, but did not reduce the total incidence of CY-induced hemorrhagic cystitis.

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Female; Hemorrhage; Humans; Male; Mesna; Sex Factors

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Cyclophosphamide; Cystitis; Female; Hemorrhage; Humans; Leukemia; Male; Mercaptoethanol; Mesna

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Diuresis; Hemorrhage; Humans; Mercaptoethanol; Mesna