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.

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.

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.

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.

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats.

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300-350 g, n=6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1-0.8 microg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1-4 microg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.

The effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on gentamicin nephrotoxicity in mice.

This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg-1 per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg-1 per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates. GEN treatment induced nephrotoxicity as evidenced by significantly (P<0.0001) increasing the plasma concentrations of urea, creatinine, circulatory cytokines, cystatin C, sclerostin, and TNFα. Treatment with GEN also significantly elevated urinary N-acetyl-ß-d glucosaminidase (NAG) concentration (P<0.0001). Moreover, GEN caused significant increase in oxidative stress in the kidneys (P<0.0001). Histopathological examination revealed massive tubular injury, necrosis, infiltration of inflammatory cells and intraluminal hyaline casts in mice treated with GEN. Sitagliptin alone did not significantly affect any of the indices measured. However, concomitant treatment with sitagliptin and GEN significantly mitigated most of the nephrotoxic actions of GEN. Pending further studies, sitagliptin may potentially be useful as a nephroprotectant agent.

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.

The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant.

N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodynamic effects and mechanisms of vasorelaxation. Hemodynamic effects of NAGLY in rats were assessed using a Biopac system and its vascular responses were assessed using a wire myograph. NAGLY (1mg/kg) decreased blood pressure by 69.4±5.5% and reduced renal blood flow by 88±12% and the effects were not sensitive to inhibition by O-1918 (3mg/kg). In resistant vessels, NAGLY (1-30µM) induced concentration- and endothelium-dependent vasorelaxation and the effect was inhibited by the nitric oxide synthase inhibitor, L-NAME (300µM), a cGMP synthase inhibitor, ODQ (10µM), the antagonists of "endothelial anandamide" receptor, rimonabant (3µM) and O-1918 (10µM) and the inhibitor of Na+/Ca2+ exchanger (NCX), KB-R7943 (10µM). On the other hand, NAGLY-induced vasorelaxation was not affected by CID 16020046 (GPR55 antagonist), AM 251 (cannabinoid CB1 receptor antagonist), AM 630 (cannabinoid CB2 receptor antagonist), capsazepine (TRPV1 antagonist), indomethacin (cyclooxygenase inhibitor), TRAM34 (IKCa channel blocker), iberiotoxin (BKCa channel blocker) and GW9662 (PPARɤ antagonist). At low concentrations of carbachol, NAGLY potentiated carbachol-induced vasorelaxation. NAGLY is an endothelium-dependent vasodilator and hypotensive lipid. The vasorelaxation is predominantly via activation of nitric oxide-cGMP pathway and NCX and probably mediated by the "endothelial anandamide" receptor, while the hypotensive effect of NAGLY appears not to involve the anandamide receptor. NAGLY also potentiates carbachol-induced vasorelaxation, the mechanism of which might involve stimulation of NO release.

Effect of aqueous extract and anthocyanins of calyces of Hibiscus sabdariffa (Malvaceae) in rats with adenine-induced chronic kidney disease.

OBJECTIVES: The aim of this work was to assess the possible beneficial effects of aqueous extracts of Hibiscus sabdariffa L. calyces and anthocyanins isolated therefrom in an adenine-induced chronic kidney disease (CKD) model. METHODS: Rats were orally given, for 28 consecutive days, either adenine alone or together with either aqueous extract of H. sabdariffa calyces (5 and 10%) or anthocyanins (50, 100 and 200 mg/kg of anthocyanin concentrate). For comparative purposes, two groups of rats were given lisinopril (10 mg/kg). KEY FINDINGS: When either H. sabdariffa aqueous extract or the anthocyanins isolated from it was administered along with adenine, the adverse effects of adenine-induced CKD were significantly lessened, mostly in a dose-dependent manner. The positive effects were similar to those obtained by administration of lisinopril. CONCLUSIONS: The results obtained show that both H. sabdariffa and its anthocyanins could be considered as possible promising safe dietary agents that could be used to attenuate the progression of human CKD. This could have added significance as H. sabdariffa tea is widely consumed in many parts of Africa and Asia and is thus readily available.

Preparation and Validated Analysis of Anthocyanin Concentrate from the Calyces of Hibiscus sabdariffa.

Extracts of Hibiscus sabdarnffa calyces have been shown to have various medicinal properties, some of which have been reported to be due to anthocyanins present in the calyces. To study whether these claims are valid, it is necessary to produce an extract with a high anthocyanin content and to have available a method to identify and quantify the individual compounds in the product. A method of extraction and purification has been developed based on a polyamide column chromatographic purification step. Using this method, anthocyanin concentrates were produced containing from 57 to 64% of delphinidin-3- sambubioside plus cyanidin-3-sambubioside. A rapid, efficient and validated HPLC analytical method was developed and used for the analysis of the anthocyanin concentrate.

Interaction of nimesulide, a cyclooxygenase-2 inhibitor, with cisplatin in normotensive and spontaneously hypertensive rats.

We investigated the effect of administration of nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, on cisplatin (CP)-induced nephrotoxicity in rats. WKY rats and SHRs were divided into four groups, each. The first and second groups received saline and oral nimesulide (20mg/kg/day for 6 days), respectively, whereas the third and fourth groups received a single intraperitoneal (i.p.) injection of CP (5mg/kg) and CP (5mg/kg) and nimesulide (20mg/kg/day for 5 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow (RBF) were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE). Nephrotoxicity was evaluated histopathologically and biochemically. CP caused a reduction in baseline RBF in both WKY and SHRs. It increased the concentrations of urea and creatinine and kidney relative weight, and decreased body weight in both WKY and SHRs. Histopathologically, CP caused remarkable renal damage in both WKY rats and SHRs. Treatment with nimesulide alone did not produce any significant change in any of the above measurements. However, nimesulide aggravated CP-induced renal tissue damage in SHRs, but not in WKY rats. The results show that administration nimesulide augmented the histopathological indices of nephrotoxicity in SHRs, but not in WKY rats.

Differential responses to various classes of drugs in a model of allergic rhinitis in guinea pigs.

Different drugs from various pharmacological classes were compared for their ability to protect against the nasal effects of acute allergen challenge in a guinea pig model. In the model, sneezing and nose rubbing were recorded after an initial allergen challenge in guinea pigs previously sensitized to egg albumin. Four days later the same guinea pigs were re-challenged a second time when anesthetised. In these anaesthetized animals, nasal airway pressure, pulmonary inflation pressure and cellular infiltration into nasal lavage fluid were measured. The drug tested were autacoid antagonists (mepyramine--3mg/kg, cetirizine--3mg/kg and montelukast--10mg/kg), L-NAME (10 or 20mg/kg), heparin (20mg/kg) and dexamethasone (20mg/kg) given either intraperitoneally or intravenously; all were given shortly before challenge. Sneezing induced by allergen challenge was statistically significantly reduced by mepyramine, cetirizine and dexamethasone whereas only cetirizine reduced nose rubbing. Changes in nasal airway pressure due to allergen exposure were reduced by cetirizine, montelukast, L-NAME, and heparin, but not by mepyramine, nor dexamethasone. In the presence of L-NAME, nasal airway pressure actually changed in the opposite direction. Cellular infiltration, as assessed by cytometry in nasal lavage fluid 60min after acute allergen challenge, was reduced by montelukast and heparin but not by antihistamines, L-NAME nor dexamethasone. This pattern of effects of the drugs, given by doses and routes previously described in the literature as being effective was not completely consistent with expected responses. The lack of effect of dexamethasone probably reflects the fact that it was given acutely whereas in the clinic chronic administration is used. The two antihistamines were not identical in their actions, presumably reflecting the fact that cetirizine has therapeutic actions not entirely confined to blockade of H1 receptors. Montelukast has not been reported to have major effects on sneezing and itching in the clinic but reduces nasal obstruction (lower nasal airway pressure or nasal patency). Montelukast's effects on cellular infiltration indicate the possible involvement of leukotrienes. Heparin has actions on inflammatory cell infiltration. This could explain its profile of reducing both cellular infiltration, and increased nasal airway pressure.

Allergic rhinitis and its pharmacology.

The pathophysiology of allergic rhinitis and its drug treatment is reviewed. Special emphasis is placed upon potential new treatments. Allergic rhinitis is characterized by allergen(s), symptoms (sneezing, itching, rhinorrhea, nasal congestion and nasal hypersensitivity), and signs such as invasion of nasal mucosa by inflammatory cells. Such pathological changes are due to inflammatory responses mediated by way of allergen-immunoglobulin E (IgE)-cell complex formation. The complexity of the disease and the multiple pathways involved offer many targets for drug treatment, but to date no single drug is totally effective. This review summarizes the current knowledge of allergic rhinitis, its prevalence, pathophysiology and experimental and clinical treatments. In the search for new drugs, different experimental animal models of allergic rhinitis are required. As a result the models have also been reviewed. Furthermore, particular aspects of the pathophysiology of allergic rhinitis are discussed in greater detail including the immune cells involved in the mediation of the disease, chemical mediators, their actions, and the receptors on which they act. Therapy, particularly that with current drugs, targets many of the known mediators and some of the cellular processes with varying success. Other drugs, for example, vasoconstrictors given to reduce rhinorrhea, provide symptomatic relief by counteracting symptoms. Since the incidence of allergic rhinitis is prevalent and growing in many parts of the world and current treatments are not ideal, it is important to continue to study the pharmacology of this disease as part of a search for better drugs.