Relative dose intensity of taxane-based chemotherapy in breast cancer patients in a tertiary hospital.

INTRODUCTION: Breast cancer (BC) is the most diagnosed tumor among women worldwide. The aim of this study was to investigate the incidence and causes of low relative dose intensity (RDI) < 85% for taxane-based chemotherapy regimens used in the treatment of BC in Sultan Qaboos University Hospital (SQUH). METHODS: This was a retrospective study that included 303 BC patients, treated with taxane-based chemotherapy protocols at SQUH. RDI was calculated for each chemotherapy regimen and causes and predictors of low RDI < 85% were identified. Prophylactic and therapeutic supportive measures for certain toxicities were studied. RESULTS: 50.8% of the patients had neoadjuvant chemotherapy, 38% had adjuvant chemotherapy, and 11.2% of patients were given palliative treatment. AC-T and AC-THP were the most used regimens (40.3% and 17.2%). Mean RDI of used taxane-based chemotherapy regimens was 93.4%. Dose delays, dose reductions, and treatment discontinuation occurred in 36.6%, 14.8%, and 11.5%, respectively. Thirty-eight patients (12.5%) had low RDI < 85% which was reduced to 9.9% after the use of an alternative taxane. Age and chemotherapy intent were significant risk factors. 83.8% received primary granulocyte colony stimulating factor. CONCLUSION: An optimal RDI greater than 85% was achieved in most cases. Furthermore, prophylactic and therapeutic supportive measures were widely used.

Prescription Patterns of Analgesic Drugs in the Management of Pain Among Palliative Care Patients at a Tertiary Hospital in Oman: A Retrospective Observational Study.

Objectives Analgesic drugs are commonly used to alleviate the pain experienced by palliative care (PC) patients. Thus, we sought to determine the prescription patterns of analgesic drugs in the management of pain among haematology and oncology palliative care patients at Sultan Qaboos University Hospital (SQUH) and then see if they were following the World Health Organization (WHO) guidelines. Methods A retrospective observational cross-sectional study was conducted, and adult PC patients prescribed analgesics for pain relief between January 2018 and January 2021 at SQUH constituted the sample. Data were collected from patients' electronic medical records using the SQUH TrakCare system. The data was then presented descriptively using graphs and tables. Results Data from 200 PC patients were analyzed. Breast cancer was the most common malignancy, with 73 (36.5%) patients diagnosed with it. Severe pain was the most reported degree of pain, with exactly 100 (50.0%) patients experiencing it. More patients experienced mild pain than moderate pain. Opioids were the most prescribed analgesics, followed by analgesics and antipyretics, anticonvulsants, and finally non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol was the most prescribed analgesic for pain overall, with 127 (63.5%) patients utilizing it. For severe pain, morphine was the most prescribed analgesic, with 65.0% of patients using it. Fentanyl and pregabalin, the strongest two analgesics, increased in prescription for severe pain compared to mild and moderate pain, with both being prescribed to 23.0% of patients suffering from severe pain. The oral route of administration was the most prescribed, with 128 (64.0%) utilizing it. Conclusion This study showed the prescription patterns of analgesic drugs for palliative care patients at SQUH. The findings were similar to those of other studies, though there were some differences. The prescription patterns of analgesic drugs prescribed for the various pain levels among PC patients were found to be in accordance with the WHO guidelines.

Potentially Harmful Drug-Drug Interactions and Their Associated Factors Among Hospitalized Cardiac Patients: A Cross-Sectional Study.

BACKGROUND: Cardiovascular diseases are responsible for a significant proportion of mortalities worldwide. Elderly patients are the most affected by cardiovascular diseases, and because of factors such as polypharmacy, multimorbidity, and age-related changes in drug availability and metabolism, they are highly susceptible to the occurrence of drug-drug interactions. Drug-drug interactions are among the many drug-related problems leading to negative outcomes among inpatients and outpatients. Thus, it is important to investigate the prevalence, involved drugs, and factors related to potential drug-drug interactions (pDDIs) to properly optimize pharmacotherapy regimens for these patients. OBJECTIVE: We aimed to determine the prevalence of pDDIs, drugs most frequently implicated, and significant predictors associated with these interactions among hospitalized patients in the Cardiology Unit at Sultan Qaboos University Hospital in Muscat, Oman. METHODS: This retrospective cross-sectional study included 215 patients. Micromedex Drug-Reax® was used to identify pDDIs. Data extracted from patients' medical records were collected and analyzed. Univariable and multivariable linear regression was applied to determine the predictors associated with the observed pDDIs. RESULTS: A total of 2057 pDDIs were identified, with a median of nine (5-12) pDDIs per patient. Patients with at least one pDDI accounted for 97.2% of all the included patients. The majority of pDDIs were of major severity (52.6%), fair level of documentation (45.5%), and pharmacodynamic basis (55.9%). Potential drug-drug interactions between atorvastatin and clopidogrel were the most frequently observed (9%). Of all the detected pDDIs, around 79.6% of them included at least one antiplatelet drug. Having diabetes mellitus as a comorbidity (B = 2.564, p < 0.001) and the number of drugs taken during the hospitalization period (B = 0.562, p < 0.001) were factors positively associated with the frequency of pDDIs. CONCLUSIONS: Potential drug-drug interactions were highly prevalent among hospitalized cardiac patients at Sultan Qaboos University Hospital, Muscat, Oman. Patients having diabetes as a comorbidity and with a high number of administered drugs were at a higher risk of an increased number of pDDIs.

The effect of diminazene, an angiotensin-converting enzyme 2 activator, on adenine-induced chronic kidney disease in rats.

The present study investigated the effect of diminazene, lisinopril, or valsartan on adenine-induced chronic kidney disease (CKD) in rats. The animals were divided into five groups (n = 6). The first and second groups received normal diet and adenine in the feed at a dose of 0.25% w/w for 35 days, respectively. The third, fourth, and fifth groups were treated as the second group but also received diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), and valsartan (30 mg/kg/day), respectively, for 35 days. Adenine significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), calcium, phosphorus, and uric acid. In addition, adenine increased urinary albumin/creatinine ratio and N-Acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio and reduced creatinine clearance. Adenine also significantly increased the plasma concentrations of inflammatory cytokines (plasma tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1ß]) and significantly reduced antioxidant indices (catalase, glutathione reductase [GR], and superoxide dismutase [SOD]). Histopathologically, renal tissue from adenine-treated rats showed necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. All drugs ameliorated adenine-induced biochemical and histopathological changes. The protective effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Our results show that administration of diminazene, lisinopril, or valsartan had a comparable effect on the reversal of the biochemical and histopathological indices of adenine-induced CKD in rats.

Antibiotics utilization patterns and dosage appropriateness among patients receiving hemodialysis.

Chronic kidney disease (CKD) is a global health challenge, with a reported prevalence of around 10%. Prescribing for patients receiving hemodialysis (HD) is challenging and complicated by polypharmacy, comorbidities, and changes in clearance of medications. The aim of this study was to evaluate antibiotics utilization patterns and dosage appropriateness in patients receiving HD at a tertiary hospital. A retrospective study was carried on 287 adult inpatients, who received HD and at least one antibiotic in a tertiary hospital in Oman. Data were extracted using the hospital's electronic patient information system. Dosage appropriateness was assessed by identifying the dosage and frequency of prescribed antibiotics and comparing them with international guidelines. The main outcome measures were antibiotics utilization patterns and dosing inappropriateness. The most commonly prescribed parenteral antibiotic was piperacillin + tazobactam (20%), while the most common prescribed oral antibiotic was azithromycin (41.7%). For prophylaxis, cefazolin (54.6%) was the main antibiotic prescribed. The most commonly used antibiotic for external use was mupirocin ointment (38.5%). The overall dosing inappropriateness was 29.5%. Vancomycin was the most common parenteral antibiotic subjected to dosing inappropriateness (19.8%). However, trimethoprim + sulfamethoxazole was more inappropriately prescribed among the oral route (28.6%). In conclusion, the most utilized antibiotic was piperacillin + tazobactam followed by vancomycin. The study reported some inappropriate dosing of antibiotics. Such a study opens the door for the establishment of local guidelines for the improved practice of antibiotics use in HD patients.

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study.

We evaluated the impact of olanzapine on metabolic changes in patients with psychotic disorders. This was a retrospective cohort study involving patients prescribed olanzapine and attending Sultan Qaboos University Hospital (Muscat, Oman). Patients were followed up retrospectively from March 2006 until April 2021. Cardiovascular treatment targets were evaluated as per the 2019 European Society of Cardiology guidelines. We enrolled 253 patients (mean age: 40±17 years). Olanzapine monotherapy was associated with increased body weight (+8 kg; 95% confidence interval (CI): 6-9; P < .001), body mass index (+3 kg/m2; 95% CI: 2-4; P < .001), total cholesterol (+.4 mmol/L; 95% CI: .3-.5; P < .001), low-density lipoprotein cholesterol (LDL-C) (+.3 mmol/L; 95% CI: .1-.4; P < .001), fasting triglycerides (+.2 mmol/L; 95% CI: .1-.3; P<.001), fasting glucose (+.6 mmol/L; 95% CI: .4-.7; P< .001), HbA1c (+.3%; 95% CI: .2-.4; P < .001), systolic blood pressure (BP) (+9 mmHg; 95% CI: 6-12; P < .001) and diastolic BP (+4 mmHg; 95% CI: 2-6; P < .001) levels. Cardiovascular therapeutic goals were attained in 38% (n = 97), 61% (n = 154), 71% (n = 180), and 59% (n = 150) for LDL-C, non-high-density lipoprotein cholesterol, triglycerides, and BP, respectively. Olanzapine was associated with adverse metabolic changes. Therefore, many patients were not at their target cardiovascular treatment goals.

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.

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.

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.

Evaluation of the appropriateness of meropenem prescribing at a tertiary care hospital: A retrospective study in Oman.

OBJECTIVES: The aim of this study was to evaluate the use of meropenem in terms of indication and continuation of treatment at Sultan Qaboos University Hospital (SQUH), Muscat, Oman. METHODS: A retrospective observational study, conducted by reviewing the medical records of 400 adults, admitted patients who received at least one dose of meropenem during the study period (January 2017 to September 2017). The analysis was performed using univariate statistics. RESULTS: Meropenem was prescribed empirically in 382/400 (96%) of the cases. The majority (315/361 (87%)) of the patients received the proper meropenem dose. The indication for meropenem was considered appropriate in only 196/400 (49%) of the cases. The continuation of treatment was evaluated according to culture and sensitivity results in 202 cases, out of which 112 (55%) were justified. Most of the inappropriate uses were seen in oncology and hematology cases (31/42 (74%) and 61/101 (60%), respectively) and among respiratory and urinary tract infections (126/155 (81%) and 40/46 (87%), respectively). CONCLUSIONS: Approximately half of the meropenem orders at SQUH in Oman were inappropriate and unjustified by culture-test results. New strategies are needed to optimize the rational use of meropenem and to ensure appropriate de-escalation and discontinuation of meropenem whenever indicated.

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.

Effect of levosimendan, an inodilator, on streptozotocin-induced diabetic nephropathy in rats.

This study examined the effect of levosimendan on streptozotocin-induced early diabetic nephropathy. Rats were distributed into four groups and treated for six weeks. The first and third group received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. The second and fourth groups were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg) and were treated as the first and third groups, respectively. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and hyperglycemia as well as, increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR) with no change in creatinine clearance. In addition, diabetes was associated with increased oxidative stress as evidenced by reduced plasma total antioxidant capacity (TAC) and catalase activity and increased plasma malondialdhyde (MDA) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α). Kidneys from streptozotocin-treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and mild interstitial fibrosis at the cortico-medullary junction. Levosimendan significantly attenuated the streptozotocin-induced physiological and biochemical changes and there was less clear renal tubular cells. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This could be partly due to its antioxidative and anti-inflammatory effects.

Effect of infliximab, a tumor necrosis factor-alpha inhibitor, on doxorubicin-induced nephrotoxicity in rats.

Treatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by nephrotoxicity. We investigated the possible protective effect of infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor on DOX-induced nephrotoxicity. Rats were treated with a single intraperitoneal (ip) injection of DOX (17.5 mg/kg) in the absence or presence of infliximab (5 mg/kg, i.p.). Plasma and urinary markers of kidney function, oxidative stress, and inflammation were measured. Kidney and heart tissue was evaluated histopathologically. DOX-induced nephrotoxicity was confirmed by increased plasma urea, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and clusterin concentrations. In addition, DOX increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, kidney injury molecule (KIM-1) concentrations, and reduced creatinine clearance. DOX significantly reduced renal antioxidants and increased plasma inflammatory markers and adiponectin concentrations. Concomitant treatment with infliximab did not significantly affect DOX-induced changes in plasma creatinine, cystatin C, or creatinine clearance. However, infliximab significantly reduced DOX-induced action on plasma urea, NGAL, clusterin, and adiponectin. Infliximab also significantly reduced urinary albumin/creatinine ratio, NAG activity, and KIM-1 concentrations, as well as the occurrence of fibrotic lesions in kidney tissue. Fibrosis detected in the heart was unchanged. In addition, infliximab reduced DOX-induced effects on plasma inflammatory markers, renal superoxide dismutase (SOD) and total antioxidant capacity. Our results show that infliximab is partially effective in mitigating DOX-induced nephrotoxicity in rats.

Effect of tocilizumab, an interleukin-6 inhibitor, on early stage streptozotocin-induced diabetic nephropathy in rats.

The aim of this study was to examine the effect of tocilizumab, an interleukin-6 (IL-6) inhibitor on streptozotocin-induced diabetic nephropathy. Male Sprague-Dawley rats (n = 36) were distributed into six groups and treated for 4 weeks. Groups 1, 3, 5 received either saline, tocilizumab (2 mg/kg), or tocilizumab (8 mg/kg) injection intraperitoneally (i.p.), every 2 weeks, respectively. Groups 2, 4, 6 were rendered diabetic by a single i.p. injection of streptozotocin (65 mg/kg) and were treated as in groups 1, 3, 5, respectively. Biochemical parameters were measured in plasma, urine, and kidneys. In the untreated diabetic group, there was a significant decrease in body weight, polyuria, and increased kidney weight. There was increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin also induced a significant increase in creatinine clearance. In addition, diabetes was associated with increased oxidative stress [reduced renal glutathione reductase (GR), superoxide dismutase (SOD), catalase activities, and increased malondialdhyde (MDA)] and increased plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) concentrations. Kidneys from streptozotocin-treated rats showed marked vacuolation of the proximal tubular epithelium with focal tubular necrosis and the glomeruli showing increase in mesangial cells. Tocilizumab significantly mitigated the increase in UACR and UNCR, renal MDA, plasma TNF-α, IL-6 and NO levels, and the decrease in renal SOD and catalase activities in diabetic rats. Tocilizumab did not significantly improve creatinine clearance; however, it attenuated the histopathological changes induced by streptozotocin. This study shows that tocilizumab was able to ameliorate some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This is mainly due to its anti-inflammatory and antioxidative effects.

Effect of levosimendan, a calcium sensitizer, on cisplatin-induced nephrotoxicity in rats.

We investigated the effect of levosimendan on cisplatin (Cis)-induced nephrotoxicity. Rats were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (6 mg/kg) on day 7, respectively. The third and fourth groups received a single intraperitoneal (i.p.) injection of Cis on day 7 and levosimendan (1 mg/kg/day, orally) or vehicle for 10 days, respectively. At day 11, animals were anaesthetized and blood collected and kidneys removed. Another four groups were treated the same as the previous four groups to measure renal blood flow. Cis induced nephrotoxicity as evidenced by biochemical, histopathological and hemodynamic changes. Levosimendan partially reduced Cis-induced increase in plasma urea, creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels and decrease in creatinine clearance. Levosimendan partially reduced Cis-induced increase in urinary albumin/creatinine ratio, N-Acetyl-ß-D-Glucosaminidase (NAG) and kidney Injury Molecule-1 (KIM-1). Levosimendan significantly attenuated the effect of Cis on plasma concentration of plasma tumor necrosis factor-alpha (TNF-α), antioxidant indices [catalase and superoxide dismutase (SOD)] and lipid peroxidation. Cis induced acute tubular necrosis with tubular dilatation, interstitial edema and congestion. Levosimendan attenuated the remarkable renal damage and reduced renal blood flow induced by Cis. In conclusion this study shows that levosimendan has a partial protective effect on Cis-induced nephrotoxicity. The protective effect of levosimendan is shown to be related to its anti-inflammatory, antioxidant and vasodilator effects.

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats.

BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1ß, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on cisplatin-induced nephrotoxicity in mice.

Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that is currently available for the management of type 2 diabetes mellitus. The present study investigated the effect of canagliflozin on cisplatin (CP)-induced nephrotoxicity in mice. The animals were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (20 mg/kg) on day 7, respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (20 mg/kg) on day 7 and canagliflozin (10 mg/kg/day) and (30 mg/kg/day), for 10 days, respectively. At day 11, animals were anesthetized and blood collected and kidneys were removed. CP significantly increased the plasma urea, creatinine, cystatin C, and clusterin concentrations and neutrophil gelatinase-associated lipocalin (NGAL) activity. In addition, CP increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, and liver-type fatty acid-binding protein (L-FABP) concentrations and reduced creatinine clearance. CP also significantly increased the plasma concentration of inflammatory cytokines [plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß)] and significantly reduced antioxidant indices [catalase, glutathione reductase (GR), and superoxide dismutase (SOD)]. Histopathologically, CP caused a remarkable renal damage compared with control. Canagliflozin significantly ameliorated CP-induced biochemical and histopathological changes. The protective effect of canagliflozin is most likely due to anti-inflammatory and antioxidant effects. Our results show that administration of canagliflozin reversed the biochemical and histopathological indices of CP-induced nephrotoxicity in mice.

The effect of sildenafil on rats with adenine-Induced chronic kidney disease.

The erectile dysfunction drug sildenafil has cardiopulmonary protective actions, and a nephroprotective action in cisplatin and ischemia-reperfusion-induced acute kidney injury. Here, we assessed its possible ameliorative action in a model of chronic kidney disease (CKD) using adenine feeding. Eight groups of rats were treated with saline (controls), adenine (0.25% w/w in feed daily for 5 weeks), and oral sildenafil (0.1, 0.5 or 2.5 mg/kg), either alone, or concomitantly with adenine. Urine was collected 24 h after the end of the treatments from all rats and blood pressure measured, followed by collection of blood and kidneys for the measurement of several functional, biochemical and histopathological parameters. Adenine treatment reduced body weight, creatinine renal clearance, and increased water intake and urine output, as well as the plasma concentrations of urea and creatinine, neutrophil gelatinase-associated lipocalin, and N-acetyl-ß-D-glucosaminidase activity, and albumin in urine. Adenine also increased the concentrations of the uremic toxins indoxyl sulfate, uric acid and phosphate, and a number of proteins and inflammatory cytokines, and decreased that of several anti - oxidant indices. Renal histopathological markers of damage (inflammation and fibrosis) were significantly increased by adenine. Sildenafil, given simultaneously with adenine, induced a dose - dependent improvements in most of the above parameters, suggesting its possible use as adjunct treatment for CKD in humans.

Effect of infliximab and tocilizumab on fructose-induced hyperinsulinemia and hypertension in rats.

Fructose administration can induce hypertension, insulin resistance and hypertriglyceridemia. Here, we investigated the possible protective effect of infliximab (IFX), a tumor necrosis factor alpha (TNF-α) inhibitor, or tocilizumab (TOC), an interleukin-6 (IL6) inhibitor, on fructose-induced increase in blood pressure, insulin resistance and hyperlipidemia in rats. The animals were fed a 60% fructose diet in the absence or presence of IFX (5 mg/kg, i.p., once weekly) or TOC (8 mg/kg, i.p., once every two weeks). Fructose significantly increased blood pressure, heart rate and homeostatic model assessment of insulin resistance (HOMA-IR). Fructose also significantly raised the concentrations of fasting plasma insulin, triglycerides, total cholesterol, uric acid, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdhyde (MDA) and nitric oxide. Fructose also significantly decreased plasma superoxide dismutase (SOD) and catalase activities. In addition, fructose significantly increased aortic endothelin and nitric oxide concentrations. Both IFX and TOC attenuated the fructose-induced increase in blood pressure, insulin resistance, and the concentrations of uric acid, MDA and IL-6. TOC significantly reduced fructose-induced increase in triglycerides and cholesterol. In addition, IFX increased plasma SOD and catalase activities. Our results showed that both IFX and TOC were partially successful in reversing fructose - induced changes.