mesna and Edema

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

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

MINE chemotherapy is used to treat refractory Hodgkin's disease. Cutaneous adverse effects of MINE regimen are uncommon and chiefly consist of erythema and oedema of the extremities. More recently, a number of cases of panniculitis and subcutaneous inflammatory oedema have been described.. We report the case of a 17-year-old girl developing acute and painful oedema of the limbs with panniculitis of the trunk. This incident was associated with inflammatory lesions of mucous membrane, in particularly in the genital area and on the tongue. These signs occurred 7 days after initiation of MINE chemotherapy, with no other drugs being introduced. A drug-induced reaction was suspected due to the absence of any other aetiology, particularly infectious disease. The condition gradually improved with symptomatic pain therapy. The patient's chemotherapy was subsequently modified.. The chronology of the symptoms, spontaneous improvement after the end of treatment, and the absence of other potential causative factors resulted in a hypothesis of a cutaneous adverse reaction to the MINE regimen. The signs could be due to capillary leak syndrome resulting from the toxicity of vinorelbine on endothelial cells. Dermatologists should be aware of these cutaneous adverse effects and of the inflammatory lesions of mucous membrane newly described herein.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Edema; Etoposide; Female; Glossitis; Hodgkin Disease; Humans; Hyperalgesia; Ifosfamide; Mesna; Mitoxantrone; Mucositis; Panniculitis

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

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

The ability of 2-mercaptoethane sodium sulfonate to prevent histologic damage to the bladder from cyclophosphamide was studied. Male rats receiving 2-mercaptoethane sodium sulfonate in conjunction with cyclophosphamide had a statistically significant decrease in ulceration, inflammation and edema of the bladder compared to those treated with cyclophosphamide alone. Most bladders of animals given prophylactic 2-mercaptoethane sodium sulfonate with a dose of cyclophosphamide were histologically indistinguishable from controls receiving neither drug. The relevance of these findings to the short and long-term effects of cyclophosphamide on the urothelium is discussed.

Topics: Animals; Cyclophosphamide; Cystitis; Drug Evaluation, Preclinical; Edema; Male; Mercaptoethanol; Mesna; Rats; Rats, Inbred Strains; Ulcer; Urinary Bladder; Urinary Bladder Diseases