Comparison of uroprotective efficacy of mesna and amifostine in Cyclophosphamide- induced hemorrhagic cystitis in rats (original) (raw)
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Bone Marrow Transplantation, 1999
The role of amifostine in the prevention of cyclophosphamide-induced hemorrhagic cystitis (HC) was evaluated in the rat model. Urinary bladders from control rats that received no drugs (group I) were compared with those from rats receiving cyclophosphamide alone at a dose of 150 mg/kg (group II), and two other groups receiving amifostine at 100 mg/kg (group III) and 200 mg/kg (group IV), 15 min prior to cyclophosphamide. Bladders were assessed macroscopically and histologically at 24 h and after 7 days. All the animals that received cyclophosphamide alone developed severe HC. On the basis of the scores of macroscopic and histologic changes, animals that received amifostine showed excellent uroprotection. Only 2/6 rats in group III and 1/6 rats in group IV developed mild HC at 24 h. None of the rats in either of these groups showed any evidence of HC at 7 days. It is concluded that amifostine protects the urothelium against cyclophosphamide-induced HC.
Journal of Urology, 1997
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.
Prevention and treatment of cyclophosphamide and ifosfamide-induced hemorrhagic cystitis
Journal of Molecular Pathophysiology, 2012
Free radicals and non-radical reactive molecules as well as several cytokines (e.g. tumor necrosis factor-α and interleukin family) and transcription factors (e.g. nuclear factor-κB and activator protein-1) are now known to take part in the pathogenesis of cyclophosphamide (CP) and ifosfamide (IF) induced hemorrhagic cystitis (HC). When these molecular factors are taken into account pathogenesis of bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells, (2) activates intracellular ROS and NO production (directly or through transcription factors) leading to peroxynitrite production, and (3) finally the elevated peroxynitrite level basically damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to PARP activation, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), and consequently in necrotic cell death. There is no doubt that for an effective prevention against CP-and IF-cystitis all pathophysiological mechanisms must be taken into consideration. Experimental works reporting beneficial effects of antioxidants, iNOS inhibitors, cytokine blockers or hyperbaric oxygen (HBO) treatment, against CP-and/or IF-induced HC exist in literature. In this article, we discussed the possible mechanisms and effectiveness of agents used in addition to mesna to prevent CP-and IF-cystitis. In conclusion, antioxidants, iNOS inhibitors, peroxynitrite scavengers, anti-inflammatory agents, as well as HBO therapy may be added to mesna administration in clinical trials in order to obtain the best protocol to improve quality of patients comfort
International Journal of Molecular Sciences
The purpose of this study was to determine if asiatic acid may act efficiently in the model of cyclophosphamide (CYP)-induced cystitis in rats. We performed experiments after administration of CYP (single dose 200 mg/kg, intraperitoneally), asiatic acid (30 mg/kg/day for 14 consecutive days, by oral gavage), or CYP plus asiatic acid, during which conscious cystometry, measurements of urothelium thickness and bladder edema, as well as selected biomarkers analyses were conducted. In rats that received asiatic acid together with CYP, a drop in bladder basal pressure, detrusor overactivity index, non-voiding contraction amplitude, non-voiding contraction frequency, and the area under the pressure curve were observed, when compared to the CYP group. Furthermore, a significant increase in threshold pressure, voided volume, intercontraction interval, bladder compliance, and volume threshold to elicit NVC were found in that group accordingly. Administration of the asiatic acid successfully ...
2021
Cyclophosphamide is one of the most prescribed antineoplastic agents. Hemorrhagic cystitis is one of the most common side effects of cyclophosphamide. Captopril is usually used as an anti-blood pressure agent. On the other hand, as a thiol group-containing agent, captopril has potent antioxidant activity. This study aims to evaluate the effect of captopril on cyclophosphamide-induced hemorrhagic cystitis in rats. Twenty-five male Sprague-Dawley rats were equally divided into five groups. Group I received saline (10 ml/kg, i.p.), Group II received a single dose of Cyclophosphamide (200 mg/kg, i.p), Groups III-V received cyclophosphamide and mesna (40 mg/kg, i.p.) or captopril (20 and 40 mg/kg, i.p.). Histopathological changes of bladder, liver, and kidney and lipid peroxidation and glutathione contents in the kidney and liver were monitored. Moreover, serum markers of organ injury were measured. It was found that captopril (20 and 40 mg/kg, i.p) and mesna (40 mg/kg, i.p), as the stan...
Journal of Oncology Pharmacy Practice, 2020
Background 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. Objective To investigate the incidence of hemorrhagic cystitis in patients receiving cyclophosphamide therapy with or without mesna. Methods 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. Results A total of 7...
Scientific Reports, 2022
Cyclophosphamide (CYP) damages all mucosal defence lines and induces hemorrhagic cystitis (HC) leading to detrusor overactivity. Patients who undergo combined chemio-radiotherapy are at higher risk of HC. Potentilla chinensis extract (PCE) prevent oxidative stress-dependent diseases. Thus, the aim of the study was to investigate the effect of PCE on urinary bladder function in CYPinduced HC in preclinical study. 60 rats were divided into 4 groups, as follows: I-control, II-rats with CYP-induced HC, III-rats received PCE in dose of 500 mg/kg, and IV-rats with CYP-induced HC which received PCE in dose of 500 mg/kg. PCE or vehicle were administered orally for 14 days. The cystometry was performed 3 days after the last dose of the PCE. Next, urothelium thickness and oedema measurement and biochemical analyses were performed. Cyclophosphamide induced hemorrhagic cystitis. PCE had no influence on the urinary bladder function and micturition cycles in normal rats. PCE diminished the severity of CYP-induced hemorrhagic cystitis. In the urothelium the cyclophosphamide induced the elevation of CGRP, TNF-α, IL-6, IL-1β, OTC 3, NIT, and MAL. Also, the level of T-H protein, HB-EGF, and ZO1 was decreased. Moreover, the level of ROCK1 and VAChT in detrusor muscle increased. cyclophosphamide caused an increased concentration of BDNF and NGF in the urine. In turn, PCE in cyclophosphamide-induced hemorrhagic cystitis caused a reversal of the described biochemical changes within urothelium, detrusor muscle and urine. PCE attenuates detrusor overactivity. In conclusion, our results revealed that PCE attenuates detrusor overactivity in case of cyclophosphamide-induced hemorrhagic cystitis. The potential properties of PCE appear to be important in terms of preventing of oxidative stress-dependent dysfunction of urinary bladder. PCE may become a potential supportive treatment in patient to whom cyclophosphamide-based chemotherapy is used. Chemotherapy based on oxazophorine alkylating agents (cyclophosphamide-CYP or ifosfamide) and radiotherapy in the area of urinary bladder play role in hemorrhagic cystitis (HC) pathogenesis. Patients who undergo combined chemio-radiotherapy are at higher risk of HC development 1. CYP treatment damages all mucosal
Urology, 2016
Objective: To evaluate the hemostatic efficacy and histopathological effects of Ankaferd Blood Stopper ® (ABS) in an experimental rat model of cyclophosphamide-induced (CYP) hemorrhagic cystitis (HC). Methods: Forty male Sprague-Dawley rats were included in the study. Firstly, 10 rats were divided equally into 2 groups where the first group was administered only an intraperitoneal (i.p.) injection of normal saline to constitute the negative control group (CON). The remaining 5 rats were administered only a single i.p. injection of CYP (without any further treatment) for induction of HC to constitute the positive control group (HC). Subsequently, remaining 30 rats, which also received i.p. CYP for induction of HC, were divided into 3 groups to which intravesical saline (SAL group), epinephrine (EPN group), and ABS (ANK group) were administered for 3 consecutive days. Ten days after the third instillation, Page 2 of 25 3 cystectomy was performed for histopathological examination. Specimens were evaluated for presence of congestion, edema, necrosis, ulceration and regenerated epithelium, and scores were given for each parameter according to the severity. Results: No statistically significant difference was observed for congestion, edema, necrosis and ulceration between HC-SAL, and also between CON-ANK groups (all p values >0.05). There was a significant difference for total scores between EPN and ANK groups (p=0.009). There was statistically significant difference for regenerating epithelium between CON-EPN, CON-ANK, HC-ANK and SAL-ANK groups. Conclusions: Intravesical administration of ABS is at least as efficacious as EPN in terms of congestion, edema, necrosis and ulceration. Moreover, ABS can be considered as a better option in inducing regenerating epithelium than EPN.
Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis
International Journal of Urology, 2003
Aim : 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. Methods : 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. Results : 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. Conclusion : 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.
Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis
Introduction: Ifosfamide (IFS) is an antineoplastic alkylating agent whose major side effect is hemorrhagic cystitis (HC). This toxicity is attributed to the renal excretion of acrolein (ACR), a highly urotoxic IFS metabolite. Despite the clinical use of mesna to prevent HC, a significant percent (~33%) of patients present with at last one feature of HC, mainly hematuria. Aim: To investigate the use of two antioxidants-amifostine and glutathione-for the prevention of experimental IFS-and ACR-induced HC. Materials and methods: Male Swiss mice were treated intraperitoneal (i.p.) with saline (control), glutathione (125, 250 or 500 mg/kg) or amifostine (25, 50 or 100 mg/kg), and 30 min later they received a single i.p. injection of IFS at a dose of 400 mg/kg. To investigate the systemic effects of the antioxidants on ACR-induced HC, the animals were treated with saline, amifostine (50 mg/kg, i.p.) or glutathione (500 mg/kg, i.p.), and 30 min afterward with 75 lg ACR intravesically (i.ve.). In another set of experiments, the antioxidants were injected directly into the bladder, where the mice received a single i.ve injection of ACR (75 lg) plus amifostine (1.5 mg/kg) or glutathione (2 mg/kg). HC was measured 3 h after IFS or ACR injection according to bladder wet weight, macroscopic (edema and hemorrhage) and microscopic changes, i.e., edema, hemorrhage, cellular infiltration, fibrin deposition and urothelial desquamation. Results: Pretreatments with amifostine or glutathione prevented IFS-induced HC in a dose-dependent manner. Furthermore, ACR-induced HC was also prevented by systemic (i.p.) or local (i.ve.) pretreatment with glutathione or amifostine. The greatest protective effect was seen with local amifostine treatment (2 mg/kg i.ve.) (P < 0.05). Conclusions: Glutathione and amifostine show a beneficial effect in experimental IFS-and ACRinduced HC. Thus, they should be investigated as an alternative treatment to prevent HC observed in patients undergoing IFS treatment.