Short-term effects of antimicrobial stewardship programs on antibiotics usage, clinical outcomes, and multidrug resistant organisms in the post COVID-19 era.

BACKGROUND: Antimicrobial resistance is associated with increasing mortality rates and the emergence of multidrug-resistant (MDR) organisms. There is scarcity of data on the short-term impact of Antimicrobial Stewardship Programs (ASP) on antibiotic usage, clinical outcome and MDR organisms' pattern following the COVID-19 pandemic. This study evaluated the short-term effects of ASP on antibiotic usage, clinical outcomes and MDR organisms' pattern in the post COVID-19 era. METHODS: Conducted at a tertiary academic health center, this observational study involved adult patients (≥18 years) in the general medical unit, treated with oral or intravenous antibiotics from May 1, 2021, to April 30, 2022. The applied ASP strategy was a prospective audit and feedback where a weekly meeting was held to discuss the antimicrobial therapy of admitted patient, after which recommendations were made regarding antimicrobial use. RESULTS: The study included 301 patients with 166 (55.1%) pre-ASP and 135 (44.9%) post-ASP. The median (IQR) age was 69 (55-77) years with 56.1% were female. Antibiotic usage dropped by 25.2% post-ASP. The length of hospital stay (LOS) was longer post-ASP (7 days vs. 7.9 days, p = 0.001), with MDR infections being a significant predictor (OR: 0.486, p < 0.001). There were no significant differences in 28-day readmission, recurrence of infections and all-cause mortality. Post-ASP, MDR pathogens increased (17.0% vs. 6.6%, p = 0.013), however, after separating post-ASP into two three-months periods, MDROs numbers decreased slightly (13 vs. 10). CONCLUSION: Short-term ASP implementation post COVID-19 reduced antibiotic usage while other clinical outcomes remained unchanged. Nonetheless an increase in MDR pathogens and LOS was observed. Further research is required to assess ASP's long-term impact on MDR infections rates and specific patient group outcomes.

The Stability of Analytes of Ionized Magnesium Concentration and Its Reference Range in Healthy Volunteers.

This study aimed to determine the stability of refrigerated analytes of iMg concentration at different time intervals and to establish iMg reference range in a cohort of healthy Omani volunteers (≥18 years). The concentrations of iMg were measured using the direct ion-selective electrode technique. Pearson's and Lin's concordance correlation coefficients along with the Bland-Altman plot were used to assess the levels of agreement between iMg concentrations of fresh and refrigerated blood samples at different time intervals. The study included 167 volunteers (51% females) with a median age of 21 (range: 20-25) years. The median, 2.5th, and 97.5th percentiles for fresh iMg reference ranges were 0.55, 0.47, and 0.68 mmol/L, respectively. The overall agreement between the fresh and refrigerated iMg concentrations was poor (rho-c = 0.51; p < 0.001). However, according to Altman's definition, iMg concentrations of the refrigerated samples for a period of ≤1 h had an excellent correlation with the fresh iMg concentrations (Lin's rho-c = 0.80), with a small average bias difference of 0.009 (95%CI; -0.025-0.043). A cut-off refrigeration period within ≤1 h at 2-8 °C can be considered an alternate time frame for the gold standard measurement (fresh or within 0.5 h).

Overview of the use of antiarrhythmic drugs at a tertiary hospital in Oman

Background: Antiarrhythmic drugs are commonly used to treat arrhythmia. However, data on the usage pattern of antiarrhythmic drugs, associated side effects, and the role of clinical pharmacist interventions in the Middle East are scarce. Objective: The purpose of this study was to describe the usage pattern, side effects, and clinical pharmacist interventions of antiarrhythmic drugs at the Sultan Qaboos University Hospital (SQUH), a tertiary care hospital in Oman. Methods: This retrospective observational study included adult patients (≥18 years) who received at least one dose of antiarrhythmic drugs at SQUH between January 2020 and December 2021. Ethical approval was obtained prior to conducting the study. Results: In total, 400 patients were enrolled in this study. Their mean age was 62.5 ± 16.6 years (range:19-96), and 55.3% (221/400) were male. Atrial arrhythmias were the most commonly observed (344/400, 86.0%). Beta-blockers (337/500, 67.4%) were the most prescribed class of drugs. The most commonly prescribed drugs were bisoprolol (263/400, 65.8%), carvedilol (65/400, 16.3%), and amiodarone (59/400, 14.8%). The majority of patients (300/400, 75.0%) received monotherapy, whereas 25% (100/400) received combination therapy. A total of 109 side effects were reported in 45 patients, resulting in an incidence rate of 11.3 %, with cardiovascular side effects accounting for the majority (41/109, 37.6%) of these. Amiodarone had the highest prevalence of adverse effects (33/109, 30.3%). A total of 122 clinical pharmacist interventions were observed in 13.0 % (52/400) of patients. Beta-blockers were associated with more than half of the interventions (61/122, 50.0%). (AU)

The Prevalence and Impact of Evidence-Based Medications on Cardiovascular and Cerebrovascular Outcomes in Patients with Acute Coronary Syndrome Post-Revascularization in Oman.

OBJECTIVES: International cardiovascular guidelines recommend prescribing a combination of five evidence-based medications (EBM) for acute coronary syndrome (ACS) patients post-revascularization. This study aims to assess the prevalence and impact of prescribing the full (five medications) versus partial (four medications or fewer) EBM combination on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with ACS post-revascularization. METHODS: Data from patients with ACS who had revascularization between January 2016 and September 2021 were collected retrospectively. Patients were then followed up until March 2022 for MACCE. RESULTS: The full EBM combination was prescribed to 70% of the patients. However, after taking into account the presence of contraindications and clinical factors, the actual adherence to the guidelines was 95%. Patients who received the full EBM combination were younger (58 versus 62 years; p = 0.0 and 3) and had lower rates of chronic kidney disease (11% versus 41%; p < 0.001) and heart failure (9% versus 20%; p = 0.012) when compared to patients who received the partial EBM. Compared to the partial EBM group, the full EBM group was associated with lower MACCE rates (54% versus 37%, p = 0.012). After employing the propensity score technique utilizing the 1:1 nearest neighbor matching method without replacement, the univariate findings were further re-affirmed with those on full EBMs (compared to those on partial EBMs) associated with a significant reduction in the MACCE rate (average treatment effect of -25%; 95% confidence interval: -10--40%; p = 0.001). CONCLUSIONS: The full EBM utilization was significantly high in our setting and in line with international guidelines. The full EBM combination was predominantly prescribed in younger and less comorbid patients and was associated with lower MACCE rates. The findings were further reaffirmed by the propensity score matching method.

The Effect of an Extract and Fractions of Date Pits on Some Plasma Constituents, Reproductive Hormones, and Testicular Histology in Male Mice.

Pits of dates (Phoenix dactylifera L.) have numerous nutritional benefits that could have wide-ranging applications. This study aimed to examine the effects of administering three extracts from powdered date pits on some basic physiological parameters, plasma constituents, reproductive hormones, and testicular histology in CD1 male mice. Three groups received doses of 100 mg/kg/day of lyophilized extract, a nonpolar fraction, and a polar fraction of date pits by oral gavage for 28 consecutive days. For the control, one group was administered a 1 mL/kg concentration of distilled water. The three different extracts significantly increased the plasma testosterone level but showed no significant effect on estradiol or luteinizing hormone levels, except for estradiol reduction in the polar extract group. The measured physiological or biochemical parameters or testicular histology also demonstrated no significant differences between the control mice and those mice treated with the three extracts, except for reductions in plasma urea in all extracts and in total protein in the nonpolar extract. Therefore, date pit extracts may potentially be used as a safe and effective dietary supplement. However, further investigation is needed.

A Snapshot of Potentially Inappropriate Prescriptions upon Pediatric Discharge in Oman.

Background: Identifying and quantifying potentially inappropriate prescribing (PIP) practices remains a time-consuming and challenging task, particularly among the pediatric population. In recent years, several valuable tools have been developed and validated for assessing PIP. This study aimed to determine the prevalence of PIP and related risk factors in pediatric patients at a tertiary care hospital in Oman. Materials and Methods: A retrospective study was conducted by reviewing the medical records of pediatric patients (<18 years) from 1 October to 31 December 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) were assessed using an internationally validated pediatric omission of prescriptions and inappropriate prescriptions (POPI) tool. Results: A total of 685 patients were included; 57.5% were male, and 30.5% had at least one comorbidity. Polypharmacy was identified in 70.2% of these patients, with a median of 2 (1−3) medications. PIM was observed in 20.4% of the cohort, with the highest in ENT-pulmonary disease (30.5%), followed by dermatological disorders (28.6%). PPO was identified in 6.9% of the patients with digestive and neuropsychiatric disorders, with the highest rate of 54% and 24%, respectively. Age (p = 0.006), number of medications (p = 0.034), and prescriber rank (p = 0.006) were identified as significant predictors of PIM, whereas age (p = 0.044) was the only significant predictor for PPO. Conclusions: The rates of PIM and PPO were high in this study population. In light of these findings, educational and interventional activities and programs are needed.

A snapshot on the usage pattern of gabapentinoids in Oman

Background: Since their introduction as adjunct anticonvulsants, the use of gabapentinoids (gabapentin and pregabalin) has increased substantially worldwide to include a wide range of clinical conditions. Various reports have demonstrated that they possess addiction liability and can produce effects similar to traditional recreational drugs, such as significant euphoric effects, enhanced sociability, and relaxation. However, there is limited information on the use of these agents in the Middle East. Objectives: Here, we describe the usage pattern of gabapentinoids at Sultan Qaboos University Hospital, a tertiary care medical institution in Oman. Methods: Adult patients (≥18 years) who were prescribed gabapentinoids for six months (March–August 2019) were included in this retrospective cross-sectional study. Indications and dosing regimens were reviewed according to the Food and Drug Administration labeling. (AU)

Appropriateness of antifungal prescribing in Oman.

Background: The inappropriate use of antimicrobials has substantially contributed to the development of antimicrobial drug resistance. Appropriate antibacterial prescribing has been emphasised, with minimal focus on appropriate prescribing of antifungals. Evaluation of antifungal use in the clinical setting is essential to prevent unnecessary drug exposure, development of resistance, adverse effects, and high hospitalisation costs. Objective: The purpose of this study was to assess the appropriateness of antifungal prescribing among adult patients at the Sultan Qaboos University Hospital (SQUH) in Oman. Methods: In this retrospective, observational study, the study population comprised adult patients treated with oral or intravenous antifungals between July 2018 and December 2019. The appropriateness of treatment was assessed using guidelines from the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN), as well as a set of literature-based criteria that were modified by SQUH infectious diseases team to suit local practices. These criteria included indication, dosage, and potential drug interactions. The primary outcome was the frequency of adherence to the treatment guidelines for fungal infections. Descriptive statistics were used for data analysis. Results: A total of 400 prescriptions were collected, of which 158 (39.5%) were for empirical therapy, 135 (33.8%) for targeted therapy, 69 (17.3%) for prophylactic therapy, and 38 (9.5%) for pre-emptive therapy. The overall appropriateness was 74.8%. The indication, dosage, and potential for antifungal-drug interactions were considered appropriate in 391 (97.8%), 314 (78.5%), and 381 (95.3%) prescriptions, respectively. Anidulafungin was the most prescribed antifungal agent, with 210 prescriptions (52.5%), followed by fluconazole with 102 prescriptions (25.5%), and voriconazole with 48 prescriptions (12%). Conclusion: In comparison with publised literature, our study revealed appropriate antifungal drug prescribing practices. However, studies with larger sample size in various hospital settings are necessary to confirm our findings on a national scale, and to obtain better statistical inferences and generalisability.

Guideline-directed medical therapy in heart failure patients with reduced ejection fraction in Oman: utilization, reasons behind non-prescribing, and dose optimization

Background: Objective: To determine the reasons behind guideline-directed medical therapy (GDMT) non-prescribing, drug utilization before and after excluding those intolerable to GDMT, as well as dose optimization in heart failure (HF) patients with reduced ejection fraction (<40%) (HFrEF) in Oman. Methods: The study included HF patients seen at the medical outpatient clinics at Sultan Qaboos University Hospital, Muscat, Oman, between January 2016 and December 2019 and followed up until the end of June 2021. The use of renin-angiotensin-system (RAS) blockers (angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNIs)), beta blockers and mineralocorticoid receptor antagonists (MRAs) were evaluated as per the European, American, and Canadian HF guidelines. Analyses were performed using univariate statistics. Results: A total of 171 HFrEF patients were enrolled for this study, the overall mean age of the cohort was 63 ± 15 years old and 59% were male. Over 65% of the patients had chronic kidney disease. Almost 55% of the patients were intolerable to GDMT. The proportion of patients on beta blockers, RAS blockers/ hydralazine-isosorbide dinitrate combination, and MRAs, before and after excluding those intolerable to GDMT, were 89%, 97%, and 77%, and, 94%, 47% and 85%, respectively, while the proportion of patients on the GDMT combination concomitantly was 41% and 83%, respectively. A total of 61%, 44% and 100% of the patients were prescribed ≥50% of the target dose for beta blockers, RAS blockers/ HYD-ISDN combination and MRAs respectively, while 19%, 8.2% and 94% of the patients attained 100% of the target dose for beta blockers, RAS blockers/ HYD-ISDN combination and MRAs respectively. (AU)

Appropriateness of antifungal prescribing in Oman

Background: The inappropriate use of antimicrobials has substantially contributed to the development of antimicrobial drug resistance. Appropriate antibacterial prescribing has been emphasised, with minimal focus on appropriate prescribing of antifungals. Evaluation of antifungal use in the clinical setting is essential to prevent unnecessary drug exposure, development of resistance, adverse effects, and high hospitalisation costs. Objective: The purpose of this study was to assess the appropriateness of antifungal prescribing among adult patients at the Sultan Qaboos University Hospital (SQUH) in Oman. Methods: In this retrospective, observational study, the study population comprised adult patients treated with oral or intravenous antifungals between July 2018 and December 2019. The appropriateness of treatment was assessed using guidelines from the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN), as well as a set of literature-based criteria that were modified by SQUH infectious diseases team to suit local practices. These criteria included indication, dosage, and potential drug interactions. The primary outcome was the frequency of adherence to the treatment guidelines for fungal infections. Descriptive statistics were used for data analysis. Results: A total of 400 prescriptions were collected, of which 158 (39.5%) were for empirical therapy, 135 (33.8%) for targeted therapy, 69 (17.3%) for prophylactic therapy, and 38 (9.5%) for pre-emptive therapy. The overall appropriateness was 74.8%. The indication, dosage, and potential for antifungal-drug interactions were considered appropriate in 391 (97.8%), 314 (78.5%), and 381 (95.3%) prescriptions, respectively. Anidulafungin was the most prescribed antifungal agent, with 210 prescriptions (52.5%), followed by fluconazole with 102 prescriptions (25.5%), and voriconazole with 48 prescriptions (12%). (AU)

Effect of flaxseed on systemic inflammation and oxidative stress in diabetic rats with or without chronic kidney disease.

BACKGROUND: Diabetes mellitus (DM) and chronic kidney disease (CKD) are common causes of morbidity and mortality. Flaxseed contains several bioactive compounds that have been shown to possess anti-inflammatory and antioxidative properties. The aim of the present study was to investigate the possible effect of flaxseed in diabetic rats with adenine-induced CKD. METHODS: Male Wister rats (n = 48) were randomly divided into seven equal groups and treated for 33 consecutive days as follows: G1: control. G2 adenine, G3: streptozotocin (STZ), G4: flaxseed, G5: adenine+flaxseed, G6: STZ+flaxseed, G7: adenine+STZ+flaxseed). DM or CKD were experimentally induced by a single intraperitoneal injection of streptozotocin (STZ) or by adenine via oral gavage, respectively. RESULTS: Rats fed adenine alone exhibited several changes including decreased body weight, increased food and water intake and urine output, increased urinary albumin/creatinine ratio. They also showed an increase in plasma urea and, creatinine, indoxyl sulfate, neutrophil gelatinase-associated lipocalin and cystatin C, and a decrease in renalase activity. These were associated with significant changes in inflammatory and oxidative biomarkers, e.g., increase in 8-isoprostane, 8 -hydroxy -2-deoxy guanosine and decrease in antioxidant enzymes, as well as increase in interleukins 1ß and 6, and NF-κB, and a decrease in interlukin-10. Histopathologically, there was increased tubular necrosis and fibrosis. Concomitant administration of adenine and STZ further worsened the renal damage induced by adenine alone. Flaxseed significantly ameliorated the changes caused by adenine and STZ, given either singly or in combination. CONCLUSION: These findings suggest that flaxseed is a potential therapeutic agent in attenuating the progression of CKD in diabetes.

The Effects of Furosemide on Behavioral and Hormonal Parameters in Male and Female Mice Subjected to Immobilization and Cold-Water Stress.

INTRODUCTION: The diuretic agent furosemide (FUR, 25 and 50 mg/kg) has been shown in a single report to act as an anti-stressor agent in two models of acute stress in mice, viz. electric foot-shock stress and immobilization (IMS). The present work aimed to investigate the possible anti-stressor action of FUR on two models of acute stress in mice, cold-water stress (CWS) and IMS, and tried to determine whether gender has any impact on the effect of FUR. METHODS: FUR (40 mg/kg) was injected intraperitoneally, and after 30 minutes, mice were subjected to CWS (4°C for three minutes) or IMS (fixing movement for two and a half hrs using adhesive tape). Motor and exploratory activities, neuromuscular coordination, and thermal nociception were then tested. Blood was collected from the mice and used to measure the concentrations of three stress hormones (corticosterone, epinephrine and prolactin). RESULTS: Mice subjected to CWS and IMS had significantly reduced motor and exploratory activities, neuromuscular coordination, and increased nociception. CWS and IMS also significantly increased the plasma concentrations of the three hormones. FUR pretreatment significantly mitigated these stress-induced hormonal changes. There was no significant sex difference when CWS or IMS was applied. DISCUSSION: IMS and CWS stimuli in male and female mice caused significant elevations in the plasma concentrations of corticosterone, epinephrine, and prolactin, accompanied by a significant reduction of motor and exploratory activities, neuromuscular coordination, and thermal nociception. There were no sex differences when IMS was applied. In stressed mice, prior administration of FUR (40 mg/kg) significantly decreased the concentrations of stress hormones, and this effect significantly mitigated the stress-induced behavioural and motor changes.

The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease.

This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.

The salutary action of melatonin and betaine, given singly or concomitantly, on cisplatin-induced nephrotoxicity in mice.

Cisplatin (CP) is commonly used in the treatment of various solid tumors. Its use, however, is hampered by nephrotoxicity. In this study, we compared the effect of betaine and melatonin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in mice. CP (20 mg/kg, given intraperitoneally on the 8th day of 12 days of the experiment) showed the typical physiological, biochemical, and histologic features of nephrotoxicity. CP-treated mice showed a significant reduction in food intake, body weight, and urine and fecal output. It also induced significant increases in the plasma concentrations of urea, creatinine, uric acid, phosphorous, adiponectin, interleukin-1ß, interleukin-6, transforming growth factor -ß1, tumor necrosis factor-α, and cystatin C. All these effects were significantly reduced by daily administration of betaine or melatonin at oral doses of 200 mg/kg and 10 mg/kg, respectively. Furthermore, using the two agents in combination caused further significant reductions in the above parameters. These findings suggest that betaine and melatonin concomitant use is likely to provide greater protection against CP-induced nephrotoxicity than when they are given singly, rendering them potentially suitable and safe agents to use in clinical trials to assess their possible beneficial actions in cancer patients receiving CP.

Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats.

Cisplatin (CP) is nephrotoxic, and this side effect is used as an animal model for acute kidney injury (AKI). Earlier research has been focused on CP-induced AKI, with relatively little attention being paid to its ability to progress to chronic kidney disease (CKD) on repeated administration. We aimed here to test the dose dependency of its nephrotoxic actions by comparing various physiological, biochemical, molecular, and histopathological indices using repeated increasing doses of CP in rats. Furthermore, we investigated whether these doses of CP would result in the development of CKD. Biochemical, molecular, and histopathological measurements were conducted in plasma, urine, and/or kidneys of rats treated with increasing doses of CP at 1.6, 3.2, and 4.8 mg kg-1 weekly for four consecutive weeks. These doses induced significant and dose-dependent elevations in most of the measured renal indices. These included increased renal fibrosis, as suggested histopathologically and biochemically by the significant increase in transforming growth factor-ß1, significant decrease in actin alpha 2, and variable actions of collagen I and IV. CP also dose-dependently increased nuclear factor (erythroid-derived 2)-like 2 and caspase-3. Multiple repeated doses of CP (1.6 to 4.8 mg kg-1) induced multiple episodes of AKI, leading to CKD after the 4th weekly dose and confirmed that this dosage regimen could be used as an experimental animal model of AKI progressing to CKD. These actions were driven by inflammation, oxidative, and nitrosative stress.

The influence of the prebiotic gum acacia on the intestinal microbiome composition in rats with experimental chronic kidney disease.

Chronic kidney disease (CKD) is a globally common and important disease and there are evidence for a bidirectional relationship between microbiota and CKD. The aim of the study was to examine the influence of prebiotic - gum acacia (GA) on the intestinal microbiota in rats with adenine-induced CKD. Animals were randomly distributed into four equal groups (n = 6): control, adenine, GA and adenine + GA groups. CKD was induced by adenine (0.75% w/w) given in the diet daily for four weeks, and GA was administered in drinking water at a concentration of 15% w/v. The 16s rRNA analysis was performed on Illumina Miseq targeting V3-V4 region to characterize microbial composition. The abundance of Actinobacteria, Proteobacteria, Tenericutes and Verrucomicrobia bacteria was increased in adenine-induced CKD, and GA treatment successfully reversed those levels. Interestingly, alpha and beta diversity index were both reduced with GA treatment in rats with CKD. Short chain fatty acids (SCFAs) measurement and PICRUSt analysis have shown that GA treatment completely restored the depleted butyrate level and various perturbated functional pathways, respectively, in CKD rats. Taking together, our results suggest that GA supplementation has a beneficial role in treating CKD, through an increased production of butyrate, as well as its anti-inflammatory, antioxidant capacity and anti-nitrosative properties.

Effect of concomitant treatment of curcumin and melatonin on cisplatin-induced nephrotoxicity in rats.

Cisplatin (CP) is a potent anticancer drug used to treat solid tumors. Its use, however, is dose-limited by its nephrotoxicity. We aimed to compare the effect of melatonin and curcumin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in rats. CP (6 mg/kg, given once intraperitoneally) induced nephrotoxicity as evidenced by several significant adverse physiological, biochemical and histopathological actions that included a reduction in body weight, increased urine production, and significant alterations in some conventional and novel renal damage indices in plasma, urine and kidneys. CP also elevated several pro-inflammatory cytokines and caused renal oxidative/nitrosative stress. Supplementation with either curcumin (200 mg/kg) or melatonin (10 mg /kg) given singly by oral gavage for eight consecutive days prior to CP injection and four days thereafter, significantly mitigated the adverse renal effects of CP, by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in renal tissues of CP- treated rats. When curcumin and melatonin were given together, the ameliorative effect was augmented in some of the measured indices e.g. tumor necrosis factor alpha, cystatin C, uric acid, phosphorus in plasma and, urine creatinine and creatinine clearance. Renal platinum concertation was reduced more with curcumin than that with melatonin, while the reduction was maximized when both melatonin and curcumin were given. Pending further pharmacological and toxicological studies, a combination of these two agents is likely to be mor effective in mitigating the adverse renal effects of CP administered to cancer patients.

Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patients who received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800-900 ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15 years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration-time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.

Gum arabic reduces inflammation, oxidative, and nitrosative stress in the gastrointestinal tract of mice with chronic kidney disease.

The aim of this study was to investigate some biochemical indices of inflammation and oxidative and nitrosative stresses in the gastrointestinal tract of mice with experimental chronic kidney disease (CKD) and treated with gum arabic (GA). Male CD1 mice (n = 28) were randomly distributed into four groups and treated for four consecutive weeks: group 1: Control: received the same diet without treatment until the end of the study; group 2: Adenine: switched to a powder diet containing adenine (0.2% w/w in feed); group 3: Gum acacia (GA): given normal feed and GA in drinking water at a concentration of 15% w/v; and group 4: Adenine + GA: given adenine in the feed as in the second group plus GA in the drinking water at concentration of 15% w/v. CKD was induced to mice by adenine feeding and concomitantly treated with the prebiotic dietary fiber gum acacia, GA (15% in drinking water). Duodenal mucosa from CKD mice had significantly higher concentrations of TNF-alfa, IL- 6, and TGF-beta-1 and lipid peroxidation. Moreover, low concentrations of IL-10, some antioxidants (catalase, glutathione reductase, total antioxidant capacity, and superoxide dismutase), and nuclear factor erythroid 2-related factor 2 were found in the duodenum. The levels of nitrosative stress (nitrite, nitrate, and total nitrate) were significantly increased by CKD, as well as the concentrations of ammonia and urea creatinine in the cecal content. Concomitant GA treatment significantly mitigated these harmful effects. Taken together, GA reduces inflammation and duodenal oxidative and nitrosative stress in the gastrointestinal tract of mice with CKD.

Testicular Toxicity of Water Pipe Smoke Exposure in Mice and the Effect of Treatment with Nootkatone Thereon.

There is a worldwide increase in the popularity of water pipe (shisha) tobacco smoking including in Europe and North America. However, little is known about the effects of water pipe smoke (WPS) exposure on male reproductivity. We have recently demonstrated that WPS exposure in mice induces testicular toxicity including inflammation and oxidative stress. Nootkatone, a sesquiterpenoid found in grapefruit, has antioxidant and anti-inflammatory effects. However, the possible protective effect of nootkatone on WPS-induced testicular toxicity has not been reported before. Here, we tested the effects of treatment of mice with nootkatone on WPS-induced testicular toxicity. Mice were exposed to normal air or WPS (30 minutes/day, for 30 days). Nootkatone (90 mg/kg) was given orally to mice by gavage, 1 h before WPS or air exposure. Nootkatone treatment significantly ameliorated the WPS-induced increase in plasma levels of inhibin, uric acid, and lactate dehydrogenase activity. Nootkatone also significantly mitigated the decrease in testosterone, androgen-binding protein, and estradiol concentrations in the plasma induced by WPS. In testicular homogenates, WPS exposure caused a decrease in the total nitric oxide level and an increase in the proinflammatory cytokine interleukin-1ß level and oxidative stress markers including malondialdehyde, cytochrome C, and 8-Oxo-2'-deoxyguanosine. All the latter effects were significantly alleviated by nootkatone treatment. Moreover, in testicular homogenate, nootkatone inhibited the expression of nuclear factor-kappaB induced by WPS. Likewise, histological examination of mouse testes showed that nootkatone treatment ameliorated the deterioration of spermatogenesis induced by WPS exposure. We conclude that nootkatone ameliorated the WPS-induced testicular inflammation and oxidative stress and hormonal and spermatogenesis alterations.