Cyclophosphamide-induced Hemorrhagic Cystitis Research Articles

Slightly photo-crosslinked chitosan/silk fibroin hydrogel adhesives with hemostasis and anti-inflammation for pro-healing cyclophosphamide-induced hemorrhagic cystitis

Cyclophosphamide is commonly used in the treatment of various cancers and autoimmune diseases, while concurrently imposing substantial toxicity on the bladder, frequently manifesting hemorrhagic cystitis. Intravesical interventions, such as hyaluronic acid supplementation, present a therapeutic strategy to reinstate bladder barrier function and alleviate the effects of metabolic toxicants. However, it remains a great challenge to achieve efficient cyclophosphamide-induced hemorrhagic cystitis (CHC) management with accelerated tissue repair owing to the low wet-adhesion, poor hemostasis, and acute inflammatory responses. To address these issues, a hemostatic and anti-inflammatory hydrogel adhesive of chitosan methylacryloyl/silk fibroin methylacryloyl (CHMA/SFMA) is developed for promoting the healing of CHC. The obtained hydrogels show a high adhesive strength of 26.21 N/m with porcine bladder, facilitating the rapid hemostasis within 15 s, and reinstate bladder barrier function. Moreover, this hydrogel adhesive promotes the proliferation and aggregation of SV-HUC-1 and regulates macrophage polarization. Implanting the hydrogels into CHC bladders of a SD rat model, they not only can be completely biodegraded in 14 days, but also effectively control hematuria and inflammation, and accelerate angiogenesis, thereby significantly promote the healing of bladder injury. Overall, CHMA/SFMA hydrogels exhibit rapid hemostasis for treating CHC and accelerate muscle tissue repair via angiogenesis and inflammation amelioration, which may provide a new path for managing severe hemorrhagic cystitis in the clinics.

Ferroptosis contributes to cyclophosphamide-induced hemorrhagic cystitis

Cyclophosphamide (CYP) is extensively used in tumor therapy, but its clinical application is limited by its toxic effects on the bladder. Since CYP-induced cystitis is believed to be mediated by acrolein (ACR), a product of lipid peroxidation that triggers ferroptosis, we hypothesized that ferroptosis might be an essential molecular mechanism underlying CYP-induced cystitis. The purpose of this study was to test this hypothesis. Intraperitoneal injection of CYP led to bladder hemorrhage and edema, along with increased oxidation, inflammation, and cell injury. Further analysis revealed these changes were associated with altered ferroptosis markers in the bladder, such as FPN1, ACSL4, SLC7A11, and GPX4, indicating the existence of ferroptosis. Administration of ferroptosis inhibitor dexrazoxane (DXZ) improved ferroptosis and prevented CYP-induced pathological changes in the bladder. Collectively, our study revealed that ferroptosis is an important mechanism underlying CYP-induced cystitis, and therapeutic approaches targeting ferroptosis could be developed to treat CYP-induced cystitis.

Uro-protective role of chrysin against cyclophosphamide-induced hemorrhagic cystitis in rats involving the turning-off NF-κB/P38-MAPK, NO/PARP-1 and STAT-3 signaling cascades

BackgroundChemotherapeutic agents are used to treat a wide range of cancer types, but they cause serious side effects which must be managed after treatment. Cyclophosphamide (CYP) is one of chemotherapeutic drugs that causes hemorrhagic cystitis (HC) induced by acrolein. ObjectiveThe current investigation intended to uncover the role of chrysin (CHR) in CYP-induced HC in rats and explore the signaling pathway beyond this effect. Analysisprocess: A single dose of CYP (200 mg/kg/IP) was injected, meanwhile CHR (25, 50 and 100 mg/kg, P.O) was administered respectively for 7 days prior to CYP administration and resume for 7 days afterwards. Urinary bladder tissue was then isolated from all rats to assess oxidative stress and inflammatory biomarkers. Moreover, histopathological examinations were performed. ResultsTreatment with CHR showed a marked alleviation in oxidative stress biomarkers induced by CYP. Furthermore, CHR treatment presented a dose-dependent boost in the anti-inflammatory; IL-10 levels and a drop in the pro-inflammatory biomarkers; IL-1β, IL-6, and TNF–α. Additionally, stabilization of the PARP-1 protein expression was also detected thus preventing DNA damage. Similarly, CHR restored the urinary bladder cGMP levels. Notably, CHR treatment was accompanied with inhibition in NF-κB/p38-MAPK, NO/PARP-1 and STAT-3 signaling pathways inflammatory cascades. All these findings conformed with the histopathological examinations as well as iNOS immunostaining in the urinary bladder tissue. ConclusionCo-administration of CHR and CYP attained uro-protective therapeutic potential to guard against HC as well as spot the tangled mechanism of CHR in attenuating the HC induced by CYP.

Evaluation of the Efficacy of Lactobacillus acidophilus in the Treatment of Cyclophosphamide-induced Hemorrhagic Cystitis in Wistar Rats.

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. Lactobacillus acidophilus NCFM (2x108 CFU) was used in the treatment of cyclophosphamide- induced hemorrhagic cystitis (200 mg/kg, intraperitoneal) in 77 female Wistar rats. Rats were distributed into experimental groups (n = 9): control group (GC), zero control group (GCZ), inflammation group (GI), 24-hour acute treatment groups: 24-hour lactobacilli treatment group (GL24H) and mesna group (GM), and 30-day chronic treatment groups: lactobacilli treatment group (GTL) and mesna+lactobacilli group (GM+L). After treatment, animals were euthanized and biological materials were collected for blood count, biochemical analyses, examination of abnormal sediment elements (EAS), and histopathological analysis. 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.

Why Are Some People with Lower Urinary Tract Symptoms (LUTS) Depressed? New Evidence That Peripheral Inflammation in the Bladder Causes Central Inflammation and Mood Disorders.

Anecdotal evidence has long suggested that patients with lower urinary tract symptoms (LUTS) develop mood disorders, such as depression and anxiety, at a higher rate than the general population and recent prospective studies have confirmed this link. Breakthroughs in our understanding of the diseases underlying LUTS have shown that many have a substantial inflammatory component and great strides have been made recently in our understanding of how this inflammation is triggered. Meanwhile, studies on mood disorders have found that many are associated with central neuroinflammation, most notably in the hippocampus. Excitingly, work on other diseases characterized by peripheral inflammation has shown that they can trigger central neuroinflammation and mood disorders. In this review, we discuss the current evidence tying LUTS to mood disorders, its possible bidirectionally, and inflammation as a common mechanism. We also review modern theories of inflammation and depression. Finally, we discuss exciting new animal studies that directly tie two bladder conditions characterized by extensive bladder inflammation (cyclophosphamide-induced hemorrhagic cystitis and bladder outlet obstruction) to neuroinflammation and depression. We conclude with a discussion of possible mechanisms by which peripheral inflammation is translated into central neuroinflammation with the resulting psychiatric concerns.

Tropisetron Ameliorated Cyclophosphamide-Induced Hemorrhagic Cystitis via Restraining TLR-4/NF-κB and JAK1/STAT3 Signaling Pathways.

The main pathological changes of hemorrhagic cystitis (HC) are bladder inflammation, bladder epithelial damage and mast cell infiltration. Tropisetron has been corroborate to conduct a protective role in HC, but its specific etiology remains unclear. The objective of this research was to estimate the mechanism of action of Tropisetron in haemorrhagic cystitis tissue. Cyclophosphamide (CTX) was utilized to induce the construction of HC rat model, and rats were handled with different doses of Tropisetron. The impact of Tropisetron on the expression of inflammatory factors and oxidative stress factors in the rats with cystitis were measured by western blot, as well as the related proteins of toll-like receptor 4/nuclear transcription factor-κB (TLR-4/NF-κB) and januskinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) pathways. CTX-induced cystitis in rats was accompanied by notable pathological tissue damage and increased bladder wet weight ratio, elevated mast cell numbers and collagen fibrosis compared to controls. Tropisetron ameliorated CTX-induced injury in a concentration-dependent manner. Futhermore, CTX induced oxidative stress and inflammatory damage, while Tropisetron can alleviate these injuries. Besides, Tropisetron ameliorated CTX-induced cystitis by restraining TLR-4/NF-κB and JAK1/STAT3 signalling pathways. Taken together, Tropisetron ameliorates cyclophosphamide-induced haemorrhagic cystitis via modulating TLR-4/NF-κB and JAK1/STAT3 signalling pathways. These findings carry important implication for the study of the molecular mechanisms of pharmacological treatment of hemorrhagic cystitis.

Pramipexole and Lactoferrin ameliorate Cyclophosphamide-Induced haemorrhagic cystitis via targeting Sphk1/S1P/MAPK, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1β signalling pathways and modulating the Nrf2/HO-1 pathway

BackgroundThe use of cyclophosphamide (CP) as a chemotherapeutic agent is limited by its major complication haemorrhagic cystitis (HC). Finding preventive, safe, and efficient treatments for such problems is extensively ongoing. ObjectiveThis research aims to assess the uroprotective effect of pramipexole (PPX) and/or lactoferrin (LF) against CP-induced HC, in addition to shedding light on their possible molecular targets. MethodsAdult male Sprague-Dawley rats were orally administered PPX (3 mg/kg) and/or LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). ResultsPretreatment of CP-intoxicated rats with either PPX or LF mitigated oxidative urinary bladder damage via upregulation of the Nrf2/HO-1 signalling pathway, resulting in a significant reduction in bladder MDA and 8-OHdG levels with concomitant elevations in SOD activity and GSH content. Simultaneously, both drugs markedly halted inflammation in bladder tissue through inhibition of the TLR4/NF-κB signalling pathway, followed by a significant decrease in inflammatory cytokine levels (TNF-α and IL-6). Interestingly, the PPX/LF protocol downregulated p-p38, p-ERK1/2, Sphk1, and S1P protein expression and inhibited the NLRP3/caspase1/IL-1β axis. PPX/LF also significantly reduced BAX and caspase-3, in addition to increasing Bcl-2 levels in bladder tissue of CP-treated animals. These biochemical findings were supported by the improvement in the histological alterations induced by CP in the urinary bladder. ConclusionsThe current study verified the protective effect of PPX and LF against CP-induced HC by halting oxidative stress, inflammation, and apoptosis. The molecular mechanism underlying this protective effect may involve targeting the crosstalk among Sphk1/S1P/MAPK/NF-κB, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1β signalling pathways and modulating the Nrf2/HO-1 signalling pathway.

Potentilla chinensis aqueous extract attenuates cyclophosphamide-induced hemorrhagic cystitis in rat model

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 CYP-induced 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, OTC3, 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.

Olmesartan ameliorates cyclophosphamide-induced hemorrhagic cystitis in rats via Nrf2/HO-1 signaling pathway

Hemorrhagic cystitis (HC) is considered a fatal complication of cyclophosphamide (CP). Down-regulation of Nrf2 and induction of pro-inflammatory mediators are the main pathological factors. Recently, ameliorative potential of the angiotensin II (AII) type-1 (AT1) receptor blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines was reported. The current study aims to investigate the possible protective effect of OLM on CP-induced HC in Wistar rats. The animals were divided into the control group (0.5% W/V carboxymethylcellulose, p.o.); OLM group (20 mg/kg, p.o., for 21 days); CP group (a single dose of 100 mg/kg, i.p.); and the remaining groups that received CP i.p. with oral OLM 5, 10 and 20 mg/kg for 21 days, respectively. The bladder tissue was collected for histopathology, immunohistochemistry, ELISA, Western blot, and oxidative stress assay. The OLM at doses of 10 and 20 mg/kg attenuated increase in TNF-α, IL-6, NF-kB, iNOS, and COX-2 induced by CP. Additionally, it up-regulated the Nrf2/HO-1 pathway, bladder GSH content, and CAT and SOD activities. The data indicated that OLM inhibited ROS-induced NF-kB, which caused inhibition of pro-inflammatory cytokines and activation of the Nrf2/HO-1 pathway. Hence, OLM holds great promise for preventing CP-induced HC.

Development and biological evaluation of protective effect of kidney targeted N-acetylated chitosan nanoparticles containing thymoquinone for the treatment of DNA damage in cyclophosphamide-induced haemorrhagic cystitis

Thymoquinone (TQ), the most prominent constituent of Nigella sativa seeds, essential oil, is reported to possess an organ protective effect via Nrf2 expression and activation of Phase-II antioxidant enzymes. Haemorrhagic cystitis is the sudden onset of haematuria combined with bladder pain and irritable bladder symptoms are the known toxic effects of cyclophosphamide (CYP) chemotherapy. The objective of the present study was to investigate and compare the protective effect of thymoquinone (TQ) and thymoquinone nanoparticles (TQ-NP) in the kidney against CYP-induced haemorrhagic cystitis. Primarily, TQ-NP was fabricated by synthesis of N-acetylated chitosan and nanoparticle preparation by the ionic gelation technique. They were characterized by particle size, polydispersive index (PDI), zeta potential, entrapment efficiency (EE), SEM, and dynamic scattering calorimetry (DSC). Moreover, fluorescein isothiocyanate (FITC) labeled NPs were prepared for biodistribution studies. The protective mechanisms of TQ-NP included its anti-inflammatory activity, inhibitory effects on cytokine levels, and protection against the DNA damage in the bladder epithelium. The cystitis was induced in rats by orally administering 200 mg/kg of CYP. The dose-dependent protective effect of the TQ-NP was determined by intravenously administering 1, 2, and 5 mg/kg of the TQ-NP to CYP-treated rats. The present study revealed that the TQ-NP prepared by ionic gelation method provides kidney targeted delivery of TQ as compared to TQ solution. The mean particle size, PDI, and %EE of TQ-NP were 272.6 nm, 0.216, 70.81 ± 0.12% respectively. The zeta potential of thymoquinone-loaded nanoparticles was found to be −20.7 mV and − 22.6 mV respectively before and after lyophilization. SEM study also confirmed the small size and spherical shape. Pharmacokinetic studies revealed the improvement in half-life and prolonged action of the TQ-NP as compared to the TQ solution. Also, TQ-NP administration showed more protection against the characteristic histological alterations in the bladder in comparison to TQ solution. The present study indicates that TQ-NP exerts potent anti-oxidant, DNA protective and cytokine inhibitory activity at considerably lower concentrations as compared to plain TQ solution. The nano formulation of TQ using N-acetylated chitosan provides effective kidney targeted delivery of TQ, which in turn improves its retention and protective efficacy against CYP-induced haemorrhagic cystitis.

Red propolis reduces inflammation in cyclophosphamide-induced hemorrhagic cystitis in rats.

Introduction. Cyclophosphamide (CP) is used to treat malignant neoplasias and control autoimmune diseases. Still, one of its metabolites, acrolein, is toxic to the urothelium and can lead to hemorrhagic cystitis and severe discomfort.Objective. To evaluate the ability of red propolis to prevent and treat CP-induced hemorrhagic cystitis in rats.Materials and methods. Red propolis was extracted in 1% gum arabic and administered subcutaneously (sc). In the first experiment, groups IA, IIA, and IIIA and groups IB, IIB, and IIIB received water, gum arabic (GA), or propolis, respectively, for 30 days. Then water (controls) or CP (treatment) was administered i.p. In the second experiment, groups IVA, VA, and VIA received water i.p. while groups IVB, VB, and VIB received CP i.p. This was followed by 5 injections at 2-hour intervals with either water, GA, or propolis. Bladder tissue was examined according to Gray’s criteria.Results. The total inflammatory histology score was significantly smaller in group VIB (11.33 ± 2.07). Mild inflammation predominated in group VIB while most of the animals in group IVB had severe inflammation (p=0.0375). Ulcers were predominantly multiple in Groups IVA and VB but rare or absent in Group VIB (p=0.0118). Urothelial cells were mostly absent in groups IVB and VB and present/normal in group VIB (p=0.0052). Fibrin was abundant in groups IVB and VA but mostly absent in group VIB (p=0.0273).Conclusions. Red propolis can reduce inflammation in CP-induced hemorrhagic cystitis in rats.

5-Aminolevulinic acid has the potential to prevent bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis.

To investigate the effects of pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis in rats. Male Wistar rats (340-460 g) were pretreated with vehicle or with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (100/157 or 300/471 mg/kg/day, po) once daily for 7 days before cystometry. Saline or cyclophosphamide (150 mg/kg, ip) was administered 2 days before cystometry. Cystometry was performed under urethane anesthesia (0.8 g/kg, ip) via a catheter inserted into the bladder. After cystometry, bladder tissues were collected to perform hematoxylin and eosin staining for pathological evaluation (neutrophil infiltration, edema, and bleeding scores), and for enzyme-linked immunosorbent assay and real-time polymerase chain reaction for investigating tissue levels of myeloperoxidase, and mRNA levels of haem oxygenase-1 as a cytoprotective molecule. Compared to controls, cyclophosphamide induced a shorter intercontraction interval, lower bladder compliance, increased number of non-voiding contractions, and increased pathological scores and myeloperoxidase expression in the bladder. Pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (300/471 mg/kg/day) significantly improved cyclophosphamide-induced intercontraction interval shortening and increases in number of non-voiding contractions and neutrophil infiltration/bleeding scores and enhanced haem oxygenase-1 expression in the bladder. In addition, cyclophosphamide-induced decreases in bladder compliance and increases in myeloperoxidase were not detected with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate pretreatment. Pretreatment with 5-aminolevulinic acid expects protective effects on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis by improving inflammatory changes in bladder tissues perhaps via up-regulation of haem oxygenase-1.

The Isopropyl Gallate Counteracts Cyclophosphamide-Induced Hemorrhagic Cystitis in Mice.

Simple SummaryIfosfamide (IFOS) is an antineoplastic drug used to treat various cancers. Hemorrhagic cystitis (HC) is the main adverse effect related to the use of IFOS. Acrolein, a metabolite of IFOS, is the main molecule responsible for this side-effect, resulting in increased oxidative stress and production of inflammatory mediators, which culminate in the degradation of bladder tissue. In clinical practice, mesna is used to reduce the incidence of HC. However, this drug presents some dose-dependent side effects. Isopropyl gallate (IPG), a gallic acid-derived compound, is promising for the development of new anti-inflammatory agents. In the present study, the effects of oral administration of IPG against IFOS-induced hemorrhagic cystitis in mice were investigated. Interestingly pretreatment of IPG was able to reduce IFOS-induced bladder damage evidenced by a decrease of inflammatory parameters and improvement in histology and antioxidants of the urinary bladder. Furthermore, IPG significantly decreased the expression levels of inflammatory biomarkers in the bladder tissue. These preliminary findings suggest that IPG represents a promising adjuvant therapy for protecting against IFOS-induced urotoxicity.Hemorrhagic cystitis is the main adverse effect associated with the clinical use of oxazaphosphorine, resulting in increased oxidative stress and proinflammatory cytokines, which culminate in injury of the bladder tissue. The aim of this study was to evaluate the protective effect of isopropyl gallate (IPG) against ifosfamide (IFOS)-induced hemorrhagic cystitis in mice. The induction of the hemorrhagic cystitis model was carried out using a single dose of IFOS (400 mg/kg, i.p.) four hours after oral pretreatment with IPG (6.25, 12.5, 25, and 50 mg/kg) or saline (vehicle). Mesna (positive control; 80 mg/kg, i.p.) was administered four hours before and eight hours after induction of cystitis. In the present study, IPG 25 mg/kg significantly decreased edema and hemorrhage, with a reduction of the bladder wet weight (36.86%), hemoglobin content (54.55%), and peritoneal vascular permeability (42.94%) in urinary bladders of mice. Interestingly, IPG increased SOD activity (89.27%) and reduced MDA levels (35.53%), as well as displayed anti-inflammatory activity by decreasing TNF-α (88.77%), IL-1β (62.87%), and C-reactive protein (56.41%) levels. Our findings demonstrate that IPG has a substantial protective role against IFOS-induced hemorrhagic cystitis in mice by enhancing antioxidant activity and proinflammatory mechanisms. Thus, IPG represents a promising co-adjuvant agent in oxazaphosphorine-based chemotherapy treatments.

Two cases of Bacillus Calmette-Guérin cystitis treated with hyperbaric oxygen

Hyperbaric oxygen (HBO2) therapy is a UHMS-approved treatment for radiation cystitis and has been used for other causes of cystitis such as cyclophosphamide-induced hemorrhagic cystitis and interstitial cystitis, among others. Immunotherapy with Bacillus Calmette-Gu.rin (BCG) is the most effective treatment of non-muscle invasive bladder cancer. BCG acts as a non-specific stimulant of the reticuloendothelial system, causing a local inflammatory response. BCG attaches to bladder tumor cells as well as urothelial cells which then stimulates an immune response involving a multitude of cytokines and local migration of polymorphonuclear cells that leads to death of the cancer cells. The typical protocol of a single six-week course has been shown to provide long-term protection from tumor recurrence and to reduce disease progression. Irritative bladder side effects are common, but serious side effects are uncommon. Two cases of severe BCG-cystitis treated with HBO2 are presented. Two male patients with bladder cancer were treated with intravesicular BCG. Each developed complications of pain, spasms, urinary frequency and nocturia; one developed gross hematuria. Cystoscopy showed friable mucosa. They failed standard medical therapy and were referred for HBO2. They were treated in a multiplace chamber at 2.2-2.4 ATA. One patient received 60 and the other 40 treatments. Both experienced substantial reduction in their symptoms. BCG cystitis may be considered for HBO2 if other standard therapy has failed.

171 - An Evaluation of Hyperhydration for the Prevention of Cyclophosphamide-Induced Hemorrhagic Cystitis in Allogeneic Bone Marrow Transplantation

171 - An Evaluation of Hyperhydration for the Prevention of Cyclophosphamide-Induced Hemorrhagic Cystitis in Allogeneic Bone Marrow Transplantation

Experimental study: a comparison of the uro-protective efficacy of mesna with hyperhydration in cyclophosphamide-induced haemorrhagic cystitis in sprague dawley rats

Background: Haemorrhagic Cystitis (H.C) is well known as a dose-limiting side effect of cyclophosphamide (CyP). The aim of this study was to investigate the effect of Mesna in protecting against CyP-induced H.C and compare its efficacy to that of hyperhydration. Research design: This animal study was conducted at the Hospital Clinic de Barcelona's Experimental Animals Breeding and Medical Research Centre. Materials and Methodology: Male Sprague Dawley rats (360-510 g, 5 rats per group) were divided into four groups at random: No medications were given to Group 1 (Control group). Group 11 (received CyP 150mg/kg intraperitoneally alone), Group 111 (received CyP150mg/kg, and mesna 150 percent of the CyP dose immediately and at 4 and 8 hours after administration of CyP, both drugs IV injection by intra jugular vein), and Group 1V (received CyP150mg/kg, and hyperhydration by catheterization of the animal jugular vein with a constant infusion of glucose water 5%, 3ml/hour/48 hours). 48 hours later, the bladders of the animals were examined macroscopically and histologically. The existence of edema and haemorrhagic edema, as well as histological and gross evaluations of bladder injury, were assessed, and statistical analysis was employed. Results: HC was found in all of the animals in group 11. When compared to group 1 (p0.001), this group had significantly more histological damage and macroscopic alterations. When compared to group 11, the median ratings of bladder injury in groups 111 and 1V were considerably lower. There was significant difference between groups 11 apart, and both groups111, 1V when the median scores for bladder injury were compared. Conclusion: This study shows the efficacy of mesna or hyperhydration in the prevention of cyclophosphamide-induced haemorrhagic cystitis.

Protective and therapeutic effect of hydrogen sulfide on hemorrhagic cystitis and testis dysfunction induced with cyclophosphamide

Backround/aimCyclophosphamide (CP) is a drug used for treatment of many malignant diseases. However, it can cause serious side effects such as hemorrhagic cystitis and male infertility. Hydrogen sulfide (H2S) is a gaseous mediator and is suggested to have antioxidant, antiinflammatory, and antiapoptotic effects. In this study, dose-dependent effects of H2S donor sodium hydrosulfide (NaHS) on cyclophosphamide-induced hemorrhagic cystitis and testicular dysfunction were investigated in rats.Material and methodsRats were divided into 5 groups (n = 8): control, CP, NaHS25 μmol/kg, NaHS50 μmol/kg, and NaHS100 μmol/ kg. After treatment for 7 days intraperitoneally (ip), a single ip dose of CP 200 mg/kg was given on the 8th day. Then, treatment was continued for 7 days. In bladder and testicular tissues, IL 6, IL 10, cGMP, NO, H2S, FSH, LH, and testosterone levels were measured by ELISA. Histopathological examination with H&E staining, as well as immunohistochemical staining for acrolein in bladder and caspase-3 and APAF-1 in testis were performed.ResultsNaHS prevented the increased IL 6 and IL 10 values induced by CP as well as prevented the decrease in cGMP values associated with CP. There was no significant change in FSH values, but the LH value, which increased with CP, decreased with 25, 50, and 100 μmol/kg NaHS. In contrast, testosterone decreased in the CP group and increased in the treatment groups. NaHS was effective in many biochemical and histopathological parameters at 25 and 50 μmol/kg doses, and this effect decreased at 100 μmol/kg dose.ConclusionH2S has a protective and therapeutic effect on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide. It can be suggested that H2S is a promising molecule in facilitating cancer treatment.

The Potential of Asiatic Acid in the Reversion of Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats.

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 restored concentrations of biomarkers both in bladder urothelium (BDNF, CGRP, OCT-3, IL-1β, IL-6, NGF, nitrotyrosine, malondialdehyde, TNF-α, SV2A, SNAP23, SNAP25, PAC-1, ORM1, occludin, IGFBP-3, HB-EGF, T–H protein, Z01, and HPX) and detrusor muscle (Rho kinase and VAChT) in CYP-treated rats. Finally, asiatic acid significantly decreased urothelium thickness and bladder oedema. Asiatic acid proved to be a potent and effective drug in the rat model of CYP-induced cystitis.

Endovascular Interventional Radiology of the Urogenital Tract.

Interventional radiology of the male urogenital system includes percutaneous and endovascular procedures, and these last consist mostly of transcatheter arterial embolizations. At the kidney level, arterial embolizations are performed mainly for palliative treatment of parenchymal tumors, for renal traumas and, less frequently, for arteriovenous fistulas and renal aneurysms and pseudoaneurysms. These latter may often require emergency intervention as they can cause renal or peri-renal hematomas or significant hematuria. Transcatheter arterial embolization is also an effective therapy for intractable severe bladder hematuria secondary to a number of neoplastic and inflammatory conditions in the pelvis, including unresectable bladder cancer and radiation-induced or cyclophosphamide-induced hemorrhagic cystitis. Endovascular interventional procedures for the penis are indicated for the treatment of post-traumatic priapism. In this article, we review the main endovascular radiological interventions of the male urogenital system, describing the technical aspects, results, and complications of each procedure at the various anatomical districts.

A histopathological evaluation on the effect of captopril in cyclophosphamide-induced hemorrhagic cystitis

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 standard treatment of cyclophosphamide-induced hemorrhagic cystitis, conspicuously attenuated the macroscopic and microscopic damage in the bladder induced by cyclophosphamide. In contrast, mesna did not significantly improve histopathological changes. No significant difference in the serum level of liver and kidney injury biomarkers, tissue biomarkers of oxidative stress, and histopathological alteration were detected between control and cyclophosphamide-treated animals. On the other hand, both captopril and mesna alleviated histopathological bladder changes. Although the mechanism of action of captopril seems not to be mediated by alleviating oxidative stress, the present study results indicate that this drug could have a protective effect on cyclophosphamide-induced hemorrhagic cystitis.