Cyclophosphamide Group Research Articles

Comparison of the Effectiveness and Safety of Mycophenolate Mofetil and Cyclophosphamide in Lupus Nephritis: Evidence from a Real-World Study.

Both mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC) have been recommended in the induction therapy of lupus nephritis (LN) for years; nevertheless, their effectiveness and safety in a real-world setting are extremely lacking. Therefore, we decided to conduct this real-world study. A total of 195 Chinese patients with LN who were initially treated with MMF (n = 98), or intravenous CYC (n = 97) as induction therapy were enrolled. All of the patients were followed up to 12months. Complete renal remission (CRR) was defined as 24-h urinary protein (24h-UTP) < 0.5g, and partial renal remission (PRR) was defined as ≥ 50% reduction in 24h-UTP to the subnephrotic level, however > 0.5g, both with a change of serum creatinine (SCr) within 10% from baseline. The proportions of CRR, PRR, and total renal remission (TRR), as well as adverse events, were compared by Chi-square test and Kaplan-Meier analysis (log-rank test). Inverse probability of treatment weighting (IPTW) was used for propensity score matching and multivariable logistic regression analyses were employed. The cumulative proportion of TRR in 6months (79.4 vs. 63.8%, p = 0.026) and CRR in 12months (72.8 vs. 57.6%, p = 0.049) in MMF group were significantly higher than CYC group, and the above conclusions were further confirmed by IPTW. The proportions of PRR, CRR, and TRR at other time points were equivalent between two groups. Further subgroup analysis in 111 patients with biopsy-proven III-V LN also showed a significantly higher proportion of TRR at 6months in the MMF group than in the CYC group (78.3 vs. 56.9%, p = 0.026). In the Kaplan-Meier analysis and after IPTW, the MMF group showed better TRR and CRR responses than CYC group in 12months. Multivariable logistic regression analyses revealed that MMF use was the only predictor of CRR (HR 2.12, 95% CI 1.90-4.09, p = 0.026), while low complement level was also a predictor, albeit risk was reduced (HR 0.38, 95% CI 0.17-0.86, p = 0.019). Moreover, compared to the CYC group, MMF group patients were more likely to have significantly lower SCr (μmol/l) [72.5 (62.5, 86.5) vs. 79.0 (71.1, 97.5), p = 0.001] and daily dose of prednisone (mg/day) (15.7 ± 5.2 vs. 18.6 ± 11.3, p = 0.022) at 6months; lower 24h-UTP (g) [0.1 (0.1, 0.3) vs. 0.2 (0.1, 0.9), p = 0.005] and daily dose of prednisone (mg/day) (9.6 ± 3.3 vs. 11.2 ± 5.5, p = 0.023) at 12months. Infection was the most common adverse event. Pneumonia and gastrointestinal discomfort were more frequently observed in the CYC group. Real-world data are a key component of the evidence supporting the effectiveness of drugs and are of interest to all stakeholders. Our comparative study demonstrated the effectiveness of MMF in LN induction therapy was at least equivalent to intravenous CYC, with superior tolerance.

P-395 Protective effect of metformin on the ovarian reserve of prepubertal mice under cyclophosphamide chemotherapy

Abstract Study question Can metformin reduce the side effects of cyclophosphamide on the ovaries of prepubertal mice treated with cyclophosphamide? Summary answer Yes, metformin, as an inhibitor of mTOR and, by affecting the HIPPO pathway, can exert its protective effect in the chemotherapy mice model. What is known already PI3K/AKT and HIPPO pathways are influential pathways in the process of activation of primordial follicles and proliferation of cell growth, which are affected by various agents and drugs such as cyclophosphamide. One of the side effects of cyclophosphamide is the reduction of the ovarian reserve through abnormal changes in the PI3K/AKT and HIPPO pathways. Metformin is a drug that is used to treat type 2 diabetes and at the same time regulates PI3K/AKT and HIPPO pathways and prohibits the proliferation of cancer cells. Study design, size, duration Controlled experimental study. After metformin and cyclophosphamide dose adjustment, 12 female NMRI 14-day-old mice were randomly divided into four groups: the control group (CONT), metformin group (MET), cyclophosphamide group (CYC) and metformin with cyclophosphamide group (MET-CYC). Participants/materials, setting, methods Mice were treated by intraperitoneal injection of a dose of 150mg/kg of metformin for 11 consecutive days, and/or a dose of 65mg/kg of cyclophosphamide every three days (The third, sixth and ninth days). The mice were sacrificed 24 hours after the last metformin injection or 3 days after the last cyclophosphamide injection. The ovaries were collected for stereological evaluation, and expression of Pten, Mtor, Yap-1, p53, Bcl-2, and Bax genes by qRT-PCR method. Main results and the role of chance The stereological evaluation showed that the ovarian volume and primordial follicle number in the CYC group were decreased compared to the other groups (P &amp;lt; 0.05), and also in the MET-CYC group reduced compared to the CONT and MET groups, but increased significantly compared to the CYC group (P &amp;lt; 0.05). A significantly increased number of growing follicles was observed in the CYC group compared to the other groups (P &amp;lt; 0.05). The molecular analysis showed that the Pten expression in the CYC group was lower than CONT and MET groups (P &amp;lt; 0.05). Mtor expression in the CYC group was significantly increased compared to other groups (P &amp;lt; 0.05). The expression of Yap-1 was significantly decreased in the MET group compared to other groups (P &amp;lt; 0.05), and was lower in the MET-CYC than in the CYC group (P &amp;lt; 0.05). The of P53 expression in the MET-CYC group was higher than CONT and MET groups (P &amp;lt; 0.05), and was increased in the CYC compared to the CONT group (P &amp;lt; 0.05). Bcl-2 expression was higher in CONT and MET groups than in MET-CYC and CYC groups (P &amp;lt; 0.05). The expression of Bax in the CYC group was significantly increased compared to CONT and MET groups (P &amp;lt; 0.05). Limitations, reasons for caution Due to ethical issues in less use of mice, dose of metformin was obtained according to the articles used in adult mice and also by using the human to animal dose conversion formula. Wider implications of the findings It can be concluded that metformin during cyclophosphamide treatment can maintains ovarian volume, reserve, and activity in prepubertal mice by regulating PI3K/AKT and HIPPO pathways. Considering the relatively acceptable cost and long-term safety of metformin, it is a promising factor to be used to preserve fertility during chemotherapy. Trial registration number not applicable

Efficacy and Safety of Mizoribine in comparison with Cyclophosphamide for Treatment of Refractory Nephrotic Syndrome: Protocol for a Multi-center, Controlled, Open-label, Randomized Controlled Trial.

Nephrotic syndrome that is resistant to steroidal therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease (ESRD). Immunosuppressants are utilized to treat RNS, however prolonged may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy that has few adverse effects, but data on its long-term use in patients with RNS are unavailable. We propose a trial to examine the efficacy and safety of MZR compared to cyclophosphamide (CYC) in Chinese adult patients with RNS. This is a multi-center, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study was reviewed and approved by the Medical Ethics Committees of all 34 medical centers. Patients with RNS consented to participation, and were enrolled and randomized into an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants were assessed for adverse effects and collection of laboratory results at 8 visits during the treatment phase on week-4, week-8, week-12, week-16, week-20, week-32, week-44, and week-52 (exit visit). Participants were able to withdraw voluntarily and investigators were required to remove patients when there were safety concerns or deviations from protocol. The study started in November 2014, and was completed in March 2019. A total of 239 participants from 34 hospitals in China were enrolled. Data analysis is completed. The results are waiting to be finalized by Center for Drug Evaluation. The purpose of the current study is to evaluate the efficacy and safety of MZR in comparison with CYC for treatment of RNS in Chinese adult patients with glomerular diseases. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. ClinicalTrials.gov Register, NCT02257697. Registered 2014-10-01, https://clinicaltrials.gov/ct2/show/NCT02257697?term=MZR&rank=2.

#3507 IV CYCLOPHOSPHAMIDE VERSUS MYCOPHENOLATE MOFETIL AS INDUCTION REGIMEN IN PROLIFERATIVE LUPUS NEPHRITIS: A STUDY FROM NORTH-EAST INDIA

Abstract Background and Aims SLE is a chronic autoimmune disorder that can affect all organ systems. Clinically evident renal disease known as Lupus Nephritis (LN) occurs in upto 50% patients of SLE and upto 10% of LN patients develop ESRD. LN carries a significant morbidity and mortality and requires an early aggressive management. Our Aim is to study the effect of IV Cyclophosphamide (CYC) vs Mycophenolate Mofetil (MMF) as Induction regimen in proliferative Lupus Nephritis patients of North- East India. Method This is a prospective observational study conducted in the department of Nephrology, Gauhati Medical College, over a period of 1 year. Haematological and biochemical assay including serum creatinine, blood urea, serum albumin, ANA, Anti ds DNA, C3 and C4,24h urinary protein, estimated glomerular filtration rate (eGFR) of all patients were taken into account. Renal biopsy was performed under ultrasonographic guidance. SLEDAI Score and Activity and Chronicity Indexes were calculated for all patients. Statistical analysis was done by SPSS Version 22 for windows. Two tailed p&amp;lt;0.05 was considered to be statistically significant. A total of 64 biopsy proven LN patients of Class III, Class IV and Class V (Plus Class III/ Class IV) were enrolled in the study. We randomly assigned 34 patients with Class III through V lupus nephritis to IV CYC (NIH protocol/monthly) and 30 patients to MMF (2 gm/day) for 24 weeks as Induction Regimen. Both the groups received prednisone, tapered from a maximum starting dosage of 60 mg/day. All the patients were followed up for 6 months. Complete Response (CR) was considered when proteinuria&amp;lt;0.5g/g and Partial Response (PR) when proteinuria&amp;lt; 3g/g or there is reduction in proteinuria by at least 50%. Baseline characteristics and CR and PR were compared between the two groups. Results Of the total 64 patients, 57 patients (89%) were female, and 7 patients were male (11%) with the mean age of 31± 9.45 years. 24% patients had Class III LN and 76% had class IV LN. Complete Response was achieved in 13 patients (43%) in the MMF group and in 15 patients (44%) in CYC group. Partial Response was achieved in 11 patients (36.67%) in the MMF group and in 12 patients (35%) in the CYC group. There was a non-significant statistical difference between the two groups (p value ≥0.05 for both CR and PR). Conclusion The Northeastern population of India consists of various ethnic groups and there are records of variation in response to the Regimens in different geographical areas. In our study from North-east India, IV Cyclophosphamide and Mycophenolate Mofetil showed similar efficacy as Induction Regimen in proliferative Lupus Nephritis. However, there were higher rates of infection in the Cyclophosphamide group.

Saponin protects against cyclophosphamide-induced kidney and liver damage via antioxidant and anti-inflammatory actions.

The liver and kidney are organs affected by chemotherapy drugs such as cyclophosphamide (CP). This study examined the protective effects of treatment with saponin (SP) against CP-induced nephrotoxicity and hepatotoxicity. 24 adult male mice were divided into four groups (N = 6): Control group, CP (15 mg kg-1), SP (2.5 mg kg-1) and CP + SP. After treatment, blood samples were collected for the determination of biochemical parameters. Liver and kidney samples were taken for histological analysis and assessment of oxidative stress and inflammatory markers. Cyclophosphamide decreased renal and liver functions and antioxidant enzymes, which significantly increased blood urea nitrogen and creatinine (BUN, Cr), liver enzyme levels, malondialdehyde, nuclear factor kappa β (NF-kB) and Interleukin 1 beta (IL-1B) concentrations. Moreover, histopathological findings of the CP group showed that there were acute tubular necrosis and glomerular atrophy in the renal tissues and lymphocyte infiltration in the liver samples. Treatment with saponin improved hepatic and renal functions, pathological changes and antioxidant capacity, and also decreased lipid peroxidation and inflammation. It seems that saponin could exert a hepato-nephroprotective effect against cyclophosphamide toxicity.

The (–)-Borneol Effect on Addiction/Abstinence by Morphine in Mice

Opioids such as morphine are the first choice in acute and chronic pain treatment. However, they lead to addiction. Several studies have searched (i) to find a molecule that can replace morphine use or (ii) to reduce its adverse effects. This work aimed to evaluate whether (–)-Borneol [(–)-BOR], a bicyclic monoterpene, in doses of 25, 50, and 100 mg/kg (i.p.), has an antiaddictive effect on morphine (5 mg/kg, i.p.) and reduces its withdrawal symptoms precipitated by naloxone (8 mg/kg, i.p.) in Swiss mice. Furthermore, the (–)-BOR genotoxic potential was also investigated by the comet assay. The antiaddictive effect of (–)-BOR was evaluated by the conditioned preference place (CPP). The CPP was induced by morphine administration during the conditioning phase. The effects of (–)-BOR on the rewarding characteristics of morphine were tested in mice with the administration of (–)-BOR, naloxone, or vehicle (NaCl 0.9%), 30 min before morphine. This work also investigated the (–)-BOR effect on morphine withdrawal symptoms precipitated by naloxone. Morphine withdrawal symptoms were induced by administering morphine twice daily for 5 days, precipitated by naloxone administration on the sixth day. The effect of (–)-BOR on reducing morphine withdrawal symptoms was evaluated in mice that received (–)-BOR before daily morphine administration. Finally, the comet assay was performed to assess the DNA damage degree caused by the (–)-BOR (100 mg/kg, i.p.) administration. The comet assay was performed on peripheral blood taken from the tail of each animal. Cyclophosphamide (50 mg/kg, i.p.) was used to induce DNA damage. After starting the protocol, analyses were performed for 4 h (acute effect) and 24 h (repair effect). The (–)-BOR (100 mg/kg, i.p.) significantly attenuated (*** p &lt; 0.001) the acquisition of morphine-induced CPP and reduced only the jumping behavior in the morphine withdrawal model. The best-studied dose was 100 mg/kg, being evaluated, then, in the comet assay. (–)-BOR at 100 mg/kg did not show the genotoxic effect when compared with the cyclophosphamide group (CYCLO, 50 mg/kg, i.p.) after 4 h or 24 h, a period that corresponded to the repair time of DNA fragmentation. The study showed that (–)-BOR attenuated the acquisition of CPP by morphine and made opioid withdrawal milder. In the comet assay, although (–)-BOR caused DNA damage, this damage was significantly less than the damage by CYCLO, at either 4 h or 24 h after the treatments.

Protective effects of ursolic acid on cyclophosphamide induced hemorrhagic cystitis in rats

Cyclophosphamide (CP) is a commonly used antineoplastic agent despite its adverse effects. Hemorrhagic cystitis (HC)is one of the most common side effects of CP. Although Mesna is commonly used to prevent HC, it suffers from few sideeffects. Therefore, search for better alternate substance still continues. In this study, we studied the effects of ursolic acid(UA), one of the active ingredients of Plantago major, commonly called plantain or white man’s foot, in CP-inducedhemorrhagic cystitis in rats. Forty-nine Sprague−Dawley rats in seven equal groups viz. control (C); cyclophosphamide(CP); cyclophosphamide+Mesna (CPMesna); cyclophosphamide+ursolic acid [100 (CPUA100) and 200 mg (CPUA200)],and cyclophosphamide+ mesna+ ursolic acid (100, (CPMesnaUA100) and (200 mg (CPMesnaUA200) were investigated forinducible nitric oxide synthetase (iNOs), total antioxidant status (TAS), total antioxidant status (TOS), TNF–α, interleukin10 (IL–10) and interleukin 6 (IL–6) levels from blood samples. The data obtained were statistically analyzed using SPSSand both Kruskall Wallis and Dunn tests were performed. Value of P &lt;0.05 was considered as statistically significant. Ourresults have revealed that the UA applied groups better preserve compared to CP group. However, it was observed that thisprotection is comparatively weaker than the Mesna and UA-Mesna combinations. Hence, it is suggested that the urosilicacid could prevent cyclophosphamide induced hemorrhagic cystitis, and also extends support to Mesna applications.Overall, it has been observed that ursolic acid has limited protective effects against CP-induced hemorrhagic cystitis, andcan serve as a supportive agent in inhibiting hemorrhagic cystitis.

Eulophia gracilis pseudobulb extract mitigates cyclophosphamide-induced genotoxicity and oxidative stress on murine hepatic tissue

The reports over the years on chemotherapeutic regimen involving cyclophosphamide (CYP), a bifunctional alkylating agent, demonstrated hepatotoxic side effect. Eulophia gracilis (EG) is a medicinal plant with folkloric utility in the treatment of liver damage and blood related diseases. However, there is a knowledge gap on the impact of E. gracilis effectiveness on CYP-associated hepatic toxicity in the literature. We investigated on potency of aqueous methanolic extract of E. gracilis (AMEG) and CYP-mediated hepatic toxicity in rats. Experimental rats were administered with CYP (2 mg/kg) or co-treated with AMEG (200 or 400 mg/kg) for 7 days consecutively. The result showed that co-treatment with AMEG significantly reduces alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and lactate dehydrogenase activities compared to the CYP group. Moreover, AMEG abated CYP-induced decreases in superoxide dismutase, catalase and glutathione peroxidase enzymes in the liver homogenate. AMEG alleviated CYP-facilitated surges of hepatic concentration of advanced oxidized protein product (AOPPs) and lipid peroxidation in rats. Additionally, AMEG reduced pathological lesions in the liver of co-treated rats and elicited anti-genotoxic effect by mitigating CYP-mediated increases of frequency of formation of polychromatic erythrocyte in the bone marrow and hepatic percentage DNA fragmentation in CYP-exposed rats. Overall, AMEG protective effect improved liver dysfunction occasioned by CYP-mediated toxicities in rats by abating oxidative stress and alleviating genotoxic responses.

The effect of leaf hydroalcoholic extract of Ephedra pachyclada infertility in male rats treated with cyclophosphamide: An experimental study.

Cyclophosphamide (CP) has clinical applications in treating diverse malignancies and autoimmune disorders; at the same time, it also has harmful effects on the body tissues, particularly the genitals. The most significant side effects of CP are changing the reproductive system's function and infertility. This study determines the Ephedra hydroalcoholic extract (EP) role on testicular tissue and the pituitary-gonadal axis in CP-treated male rats. In this experimental study, 48 adult Wistar rats were separated into 6 groups (n = 8/each): control, sham, CP recipients, and CP recipients with gavage-fed EP (250, 500, and 1000 mg/kg). On the 29 day, the blood of the weighed animals' was drawn from their heart, and serum concentrations of follicle-stimulating hormone, luteinizing hormone, and testosterone were measured. After preparing testicular tissue segments, cells were counted. While CP decreased follicle-stimulating hormone, luteinizing hormone, and testosterone levels (p 0.05), the use of EP changed them and even reached the control. Serum gonadotropin-releasing hormone increased significantly in all EP groups compared to the control and CP groups. Compared to the control, a significant decrease in total antioxidant capacity and plasma glutathione peroxidase was observed in the CP groups. EP (all doses) significantly increased their concentration compared to the CP group (p 0.05); significant reduction in serum total oxidant status and malondialdehyde in CP groups changed by EP (p 0.05). Although CP's role on spermatogonia counts (57.5 5.2 in CP, 67.1 6.0 in control), higher doses of EP had no significant effect on this but did affect spermatocyte and spermatid cells count. Due to its antioxidant characteristics, EP mitigated the effects of CP on the investigated parameters in rats.

Preventive Effects of Traditional Plant Concoction “Combo” on the Cyclophosphamide-Induced Ovarian Toxicity in Wistar Rats

Exposure to chemotherapeutic agents like cyclophosphamide (a drug for cancer treatment), leads to infertility due to its toxic effect on the ovaries. Combo, “a commonly used plant concoction in traditional medicine for the treatment of infertility” is composed of Clove (dried flower), garlic (bulb), ginger (rhizome), and turmeric (rhizome). The aim of this study was to evaluate the possible prophylactic effects of Combo therapy in cyclophosphamide-induced ovarian toxicity in female Wistar rats. Female Wistar rats were divided into 6 groups (A-F) of 6 animals each. Group A (normal control) received distilled water only. Group B (negative control) received 200mg/kg of cyclophosphamide only, while group C (positive control) received only 29mg/kg of Combo. On the other hand, groups D, E and F were pretreated with Combo doses of (15, 29, and 290 mg/kg) and were later treated with 200mg/kg of cyclophosphamide after 7 days. All administrations were done orally. The reproductive hormones assayed were oestrogen and progesterone, while the oxidative stress biomarkers evaluated include glutathione, malondialdehyde, and nitric oxide. Their levels were used as diagnostic markers for assessing the reproductive functions of the ovaries. Combo pre-treatment significantly (p&lt;0.05) decreased the levels of malondialdehyde and nitric oxide, and significantly (p&lt;0.05) increased glutathione, oestrogen and progesterone levels when compared with cyclophosphamide group. Histopathological investigation showed that Combo mitigated degenerative cells in follicles, stromal oedema, and atresia of the follicles when compared with cyclophosphamide group. In conclusion, Combo has fertility potentials and can protect against ovarian degeneration in cyclophosphamide-induced toxicity.

The Gonadotoxic Effects of Conditioning Chemotherapy Regimens Prior to Hematopoietic Stem Cell Transplantation [ID: 1376168

INTRODUCTION: Primary ovarian insufficiency secondary to high-dose chemotherapy in females undergoing the conditioning regimen before hematopoietic stem cell transplantation is a challenging late complication. Limited studies have investigated the ovarian toxicity of various conditioning regimens. This study aimed to explore the gonadotoxic effects of cyclophosphamide (CY) and busulfan (BU) in CD-1 mice strain. METHODS: Sixteen 1-month-old female CD-1 mice (n=4/group) were subcutaneously injected with solvent, BU, CY, or BU+CY, respectively. The doses (144 mg/kg BU and 300 mg/kg CY) and injection plan were adjusted to human doses. The ovaries and female reproductive tracts were harvested 1 week after the last administration. Follicle counting was performed. The levels of serum antimüllerian hormone (AMH) and 17-beta-estradiol were measured. Animal use approval was obtained from the Institutional Animal Care and Use Committee at the University of Nebraska Medical Center. RESULTS: All mice survived the injections and grossly appeared normal. The average ovary weight was significantly lower in BU (P=.0007) and BU+CY (P&lt;.0001) groups than in the control and CY groups. The primordial (P&lt;.0001) and primary follicles (P=.01) in treatment groups were decreased compared to the control group. The serum AMH level in the BU group was also significantly lower than the control and CY group (P=.003). CONCLUSION: We show that conditioning chemotherapy with CY and BU can reduce the ovarian reserve in CD-1 mice strain and may have a synergic effect. Future studies to investigate the mechanism of chemotherapy-related ovarian follicle death are needed to improve fertility outcomes in patients receiving conditioning chemotherapy.

Efficacy of Gonadotropin-Releasing Hormone Agonist (GnRH-a) in Ovarian Preservation in Females With Systemic Lupus Erythematosus (SLE) Receiving Cyclophosphamide (CYC) [ID: 1375370

INTRODUCTION: Systemic lupus erythematosus (SLE) female patients with severe disease manifestations are treated with cyclophosphamide (CYC), which causes ovarian cytotoxicity. Gonadotropin-releasing hormone agonist (GnRH-a) is often co-administered with CYC to preserve ovarian function and reproductive potential. However, there is a lack of evidence to support this use of GnRH-a. We conducted a retrospective study and questionnaire of SLE patients who received CYC with or without GnRH-a to evaluate its efficacy in preserving ovarian function. METHODS: This study was approved by the IRB of the National Institutes of Health (IRB#:001011). Review of medical records resulted in 50 female SLE patients treated with CYC who were less than 40 year old at the time of treatment: CYC only (n=20, group 1), CYC and GnRH-a (n=30, group 2). These patients were age/gender-matched with 50 SLE patients not treated with CYC (group 3). Data about demographics, SLE disease activity, damage accrual, cumulative CYC exposure, and pregnancy outcomes were collected by chart review. Self-reported questionnaires were used to collect data assessing menses cycles, pregnancies and their outcome, or infertility. RESULTS: There was no significant difference in SLE disease activity, baseline demographics, total damage accrual, or other clinical parameters between groups 1 and 2. The mean cumulative CYC dose was 1.2 g (group 1) and 1.5 g (group 2) (P=.16). Number of pregnancies were similar: mean (SD) group 1=2 (1.6); group 2=1.2 (1.4); group 3=1.3 (1.4) (P=.18). There were more miscarriages in group 1 compared to groups 2 and 3 (P=.015). CONCLUSION: Our data suggest use of GnRH-a improves pregnancy outcomes in SLE patients on CYC, but prospective studies are needed to establish its safety and efficacy.

Comparative analysis of the efficacy of different treatments for idiopathic membranous nephropathy: a retrospectively real-world study

Background This study aimed to explore the clinical efficacy of different treatment regimens for idiopathic membranous nephropathy (IMN). Methods Patients with IMN were retrospectively analyzed by dividing into two groups: glucocorticoids combined with cyclophosphamide group (GC + CYC) and glucocorticoids combined with calcineurin inhibitor group (GC + CNIs). After 1 year of treatment, those who found that the initial treatment was not effective were switched to another regimen. Patients continued to be followed up for at least 1 year to observe the treatment effects of different treatment regimens. Results This study found that the rate of complete and partial remission (CR + PR) in the GC + CYC and GC + CNIs groups was 76.19 vs. 82.63% after 1 year of follow-up (p > .05). In the GC + CYC and GC + CNIs groups, 27.78 and 11.95% of the patients switched treatment regimens, respectively. After 2 years of follow-up, the CR + PR rate was significantly higher in the change to GC + CNIs group after the switch compared to before the switch (80.00 vs. 31.43%, p < .001). It was also significantly higher in the change to GC + CYC group compared to before the switch (68.42 vs. 31.58%, p = .023). The recurrence rate was significantly higher in the maintain GC + CNIs and change to GC + CNIs groups than in the maintain GC + CYC and change to GC + CYC groups (25.14 vs 6.36%, p < .001). The disengagement rate from immunotherapy was significantly higher in the maintain GC + CYC group and the change to GC + CYC group than in the maintain GC + CNIs group and the change to GC + CNIs group (76.36% vs 29.71%, p < .001). High titer of anti-phospholipase A2 receptor (anti-PLA2R) antibody (95%CI: 0.199–0.947, p = .036) and serum C3 (95%CI: 0.030–0.570, p = .007) were independent risk factors, while serum IgG (95%CI: 1.000–1.331, p = .050) was a favorable factor for achieving CR. Anti-PLA2R antibody was the independent risk factor that affected the worse renal condition (p = .023). Conclusions Timely change of treatment regimen can significantly enhance therapeutic effect. Compared with patients administered with CYC, those administered with CNIs were less likely to leave treatment and had a higher recurrence rate.

Korean Ginseng Berry Polysaccharide Enhances Immunomodulation Activities of Peritoneal Macrophages in Mice with Cyclophosphamide-Induced Immunosuppression.

Korean ginseng (Panax ginseng C. A. Meyer), a member of the Araliaceae family, is known as a traditional medicinal plant to have a wide range of health properties. Polysaccharides constitute a major component of Korean ginseng, and its berries exhibit immune-modulating properties. The purpose of this study was to investigate the immune effects of crude polysaccharide (GBPC) extracted from Korean ginseng berry on peritoneal macrophages in mice with cyclophosphamide (CY)- induced immunosuppression. BALB/c mice were divided into eight groups: normal control, normal control + CY, levamisole + CY, ginseng + CY, and four concentrations of 50, 100, 250, and 500mg/kg BW/day of GBPC + CY. Mice were orally administered with samples for 10 days. Immunosuppression was established by treating mice with CY (80 mg/kg BW/day) through intraperitoneal injection on days 4 to 6. The immune function of peritoneal macrophages was then evaluated. Oral administration of 500mg/kg BW/day GBPC resulted in proliferation, NO production, and phagocytosis at 100%, 88%, and 91%, respectively, close to the levels of the normal group (100%) of peritoneal macrophages. In CY-treated mice, GBPC of 50-500 mg/kg BW/day also dose-dependently stimulated the proliferation, NO production, and phagocytosis at 56-100%, 47-88%, and 53-91%, respectively, with expression levels of immune-associated genes, such as iNOS, COX-2, IL-1β, IL-6, and TNF-α, of about 0.32 to 2.87-fold, compared to those in the CY group. GBPC could be a potential immunomodulatory material to control peritoneal macrophages under an immunosuppressive condition.

Histological study of the role of CD34+ stem cells and mast cells in cyclophosphamide-induced thymic injury in rats and the possible attenuating role of melatonin

Cyclophosphamide (CP) is an anticancer drug that adversely affects immunity and thymus structure. Melatonin is a hormone secreted by the pineal gland. It boosts immunity and has antioxidant properties. Therefore, the present study was conducted to investigate the possible protective effect of melatonin on CP-induced changes in the rat thymus. Forty male albino rats were used and divided equally into four main groups. Group I was the control group. Group II (melatonin group) received melatonin at a dose of 10 mg/kg body weight/day by intraperitoneal injection throughout the experimental period. Group III (CP group) received 200 mg/kg body weight CP by a single intraperitoneal injection. Group IV (CP + melatonin group) received melatonin intraperitoneally at a dose of 10 mg/kg body weight/day starting 5 days prior to CP injection until the end of the experiment. All rats were euthanized 7 days after CP injection. Administration of CP in group III resulted in depletion of the cortical thymoblasts. In addition, CD34-immunopositive stained stem cells decreased and mast cell infiltration increased. Electron microscopy showed degeneration of thymoblasts and vacuolization of epithelial reticular cells. Administration of melatonin with CP in group IV showed considerable protection of thymic histology. In conclusion, melatonin may protect against CP-induced thymic injury.

Impact of protocatechuic acid on alleviation of pulmonary damage induced by cyclophosphamide targeting peroxisome proliferator activator receptor, silent information regulator type-1, and fork head box protein in rats

Cyclophosphamide (CP) is a chemotherapeutic agent that causes pulmonary damage by generating free radicals and pro-inflammatory cytokines. Pulmonary damage has a high mortality rate due to the severe inflammation and edema occurred in lung. PPARγ/Sirt 1 signaling has been shown to be cytoprotective effect against cellular inflammatory stress and oxidative injury. Protocatechuic acid (PCA) is a potent Sirt1 activator and exhibits antioxidant as well as anti-inflammatory properties. The current study aims to investigate the therapeutic impacts of PCA against CP-induced pulmonary damage in rats. Rats were assigned randomly into 4 experimental groups. The control group was injected with a single i.p injection of saline. CP group was injected with a single i.p injection of CP (200 mg/kg). PCA groups were administered orally with PCA (50 and 100 mg/kg; p.o.) once daily for 10 consecutive days after CP injection. PCA treatment resulted in a significant decrease in the protein levels of MDA, a marker of lipid peroxidation, NO and MPO along with a significant increase in GSH and catalase protein levels. Moreover, PCA downregulated anti-inflammatory markers as IL-17, NF-κB, IKBKB, COX-2, TNF-α, and PKC and upregulated cytoprotective defenses as PPARγ, and SIRT1. In addition, PCA administration ameliorated FoxO-1 elevation, increased Nrf2 gene expression, and reduced air alveoli emphysema, bronchiolar epithelium hyperplasia and inflammatory cell infiltration induced by CP. PCA might represent a promising adjuvant to prevent pulmonary damage in patients receiving CP due to its antioxidant and anti-inflammatory effects with cytoprotective defenses.

An evaluation of the effects on the ovaries of hyperbaric oxygen therapy in a rat model of premature ovarian failure created with cyclophosphamide.

To evaluate hyperbaric oxygen therapy (HBO) based on ovarian histology, total antioxidant status (TAS), total oxidant status (TOS), and anti-müllerian hormone (AMH), in the ovarian insufiency (POI) model created with cyclophosphamide (CYP). The rats were separated into 3 groups of the control group (n=6), the CYP group (n=6), and the CYP+HBO group (n=6). The rats in the CYP group and the CYP+HBO group were injected intraperitoneally with 200 mg/kg CYP on day 1, followed by 8 mg/kg/day for 14 days to create POI. From the 15th day onwards, the rats in the CYP+HBO group were placed in a hyperbaric cabin and exposed to 100% oxygen at 2.4 atm pressure for one h, and were then returned to their cages at the end of the hour. A statistically significant decrease was determined in the primordial and primary follicle counts in the CYP group compared with the control group (p<0.05). In the CYP+HBO group, a statistically significant increase was determined in the primordial and primary follicle counts (p<0.05). The serum AMH levels were seen to be significantly decreased in the CYP group compared with both the control group and the CYP+HBO groups. The HBO was seen to decrease TOS and increase TAS. HBO could be an alternative treatment to minimize the effect of ovarian follicle loss caused by CYP, which is used for treating tumors that commonly occur in young females of reproductive age.

Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity.

Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway. Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS. Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection. DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.

Identification of royal jelly as a potential new drug to protect the ovarian reserve and uterus against cyclophosphamide in rats.

The aim of this study was to investigate the effect of royal jelly (RJ), a powerful natural antioxidant, on cyclophosphamide-induced ovarian damage. Thirty-two Wistar albino rats were divided into four groups. Oral treatment was administered to all rats for 16 days after a single intraperitoneal injection. The control group received intraperitoneal and oral saline; the RJ group received intraperitoneal saline and 100 mg/kg/day oral RJ; the cyclophosphamide group received intraperitoneal 100 mg/kg cyclophosphamide and oral saline; and the treatment group received intraperitoneal 100 mg/kg cyclophosphamide and 100 mg/kg/day oral RJ. The groups were compared in terms of ovarian reserve tests and histopathological changes in the ovary and uterus. All follicle counts were higher in the treatment group than in the cyclophosphamide group. The increase in the number of preantral follicles (p=0.001) and the decrease in the number of atretic follicles (p=0.004) were statistically significant. RJ treatment significantly improved follicular degeneration and cortical fibrosis in the ovary and epithelial and gland degeneration in the uterus due to cyclophosphamide toxicity. According to these results, RJ reduces cyclophosphamide-related ovarian and endometrial damage in rats. For this reason, it should be further investigated to determine its effects on reproductive function.

Medicago sativa ameliorated cyclophosphamide-induced thrombocytopenia and oxidative stress in rats

Effect of Medicago sativa (MS) hydro-ethanolic extract against the cyclophosphamide (CP)-induced toxicity was evaluated in rats grouped as: Control; CP (100 mg/kg subcutaneous, day 1–3); and CP+ MS100, 200, and 400 mg/kg/day, orally for 14 days. Hematologic, lipid, hepatic and oxidative stress markers were analyzed. Platelet, WBC, RBC, Hb and Hct in the CP group were lower than the control. The MS200 and MS400 groups had lower lipids, liver enzymes, nitrite and malondialdehyde levels but higher platelet, WBC, thiol, superoxide dismutase and catalase levels than the CP group. MS ameliorated CP-induced thrombocytopenia, oxidative stress, and increases in serum lipids and hepatic enzymes.