Involvement of nitric oxide pathway in the anti-inflammatory effect of modafinil on indomethacin-, stress-, and ethanol -induced gastric mucosal injury in rat.

Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs (NSAIDs), stress conditions, and alcohol, resulting in an inflammatory condition in the gastric mucosa. The aim of this study was to explore the protective effects of modafinil on gastric erosions induced by indomethacin, water-immersion stress, and alcohol in rats and to evaluate the role of nitric oxide (NO) pathway. Animals were allocated to the three experimental models of gastric ulcer - indomethacin (30 mg/kg PO), water-immersion stress, and ethanol (5 ml/kg PO). Induction of gastric ulcer in all models caused an increase in J-score (macroscopic assessment), biochemical markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and myeloperoxidase (MPO), and microscopic destructions. Administration of modafinil (50 and 100 mg/kg i. p) significantly improved J-score in the indomethacin (P < 0.05) and stress models (P < 0.001). Moreover, the level of TNF-α IL-1ß, and MPO was deceased after modafinil administration (P < 0.001). However, modafinil did not have any effects on gastric injury induced by ethanol. In addition, co-administration of L-NAME (a non-specific NO synthase inhibitor) and aminoguanidine (an inducible NO synthase inhibitor) with modafinil significantly neutralized the gastroprotective effect of modafinil in the indomethacin and water-immersion stress groups (P < 0.05, and P < 0.01; respectively), while 7-nitroindazole (a neuronal NO synthase inhibitor) did not show such reversing effects. In conclusion, modafinil possesses gastroprotective effects on the gastric lesions induced by indomethacin and stress, which are probably mediated via the inflammation inhibition and NO pathway modulation.

Beneficial effects of dapsone on ischemia/reperfusion injury following torsion/detorsion in ipsilateral and contralateral testes in rat.

Testicular torsion is a serious urologic emergency and one of the causes of infertility in males. Hence, prompt diagnosis and treatment are important to prevent testicular damages. It has been proved that dapsone (4, 40 diamino-diphenyl sulfone) has anti-oxidative and anti-inflammatory effects. Therefore, the aim of this study was to investigate the influence of dapsone on ischemia/reperfusion (I/R) injury in bilateral testes after unilateral testicular torsion/detorsion (T/D) in rats. In this experiment, eighteen male Wistar rats were allocated into three groups, including sham-operated, T/D + vehicle, and T/D + dapsone (12.5 mg/kg). Testicular torsion was induced for 1 h by rotating right (ipsilateral) testis 7200 in the clockwise direction. After 7 days of reperfusion, bilateral orchiectomy was conducted and evaluations of biochemical markers - tumor necrosis factor alpha (TNF-α) and superoxide dismutase (SOD) - and histological changes were performed. While induction of testicular T/D remarkably increased the level of TNF-α in the ipsilateral (torted) and contralateral (non-torted) testes, intraperitoneal (i.p) administration of dapsone (12.5 mg/kg) significantly lowered the TNF-α level (p < 0.001). Additionally, after induction of T/D, SOD activity was notably decreased, whereas administration of dapsone (12.5 mg/kg, i.p.) significantly raised SOD activity in the bilateral testes (p < 0.001). I/R injury also caused lesions in the microscopic pattern of the bilateral testicular tissues, while administration of dapsone (12.5 mg/kg, i.p.) led to a significant improvement in testicular damages. It was concluded that dapsone had a protective impact on I/R injury in the rat model of testicular T/D, and this effect was most likely induced by anti-inflammatory and anti-oxidative properties of dapsone.

Protective effects of sumatriptan on ischaemia/reperfusion injury following torsion/detorsion in ipsilateral and contralateral testes of rat.

This study was planned to evaluate the effects of sumatriptan, 5-HT1B/1D receptors agonist, on ischaemia/reperfusion injury in bilateral testes after unilateral testicular torsion/detorsion in rats. Male Wistar rats (n = 42) were allocated into a sham-operated group, a control group and treatment groups which were injected sumatriptan (0.1, 0.3 and 1 mg/kg), GR-127935 (0.01 mg/kg)-5-HT1B/1D receptors antagonist-and sumatriptan (0.1 mg/kg) + GR-127935 (0.01 mg/kg). Torsion was induced for 1 hr by rotating right testis 7200 in the clockwise direction, and after 7 days of detorsion, bilateral orchiectomy was conducted. While the level of TNF-α rose in testicular tissue after inducing torsion/detorsion, sumatriptan injection notably lowered TNF-α level in ipsilateral (torted) and contralateral (nontorted) testes (p < 0.001). Moreover, after inducing testicular torsion/detorsion, SOD activity was decreased, whereas administration of sumatriptan significantly increased SOD activity in bilateral testes (p < 0.001). After induction of torsion/detorsion, macroscopic and histological analyses also showed severe damages which were improved by sumatriptan injection. Interestingly, co-administration of sumatriptan with GR-127935 reversed the beneficial impacts of sumatriptan on macroscopic appearance, microscopic pattern and biochemical markers. It is concluded that sumatriptan presumably via stimulation of 5-HT1B/1D receptors decreased inflammation, oxidative stress and deteriorations induced by ischaemia/reperfusion injury following testicular torsion/detorsion.

Betrixaban for first-line venous thromboembolism prevention in acute medically ill patients with risk factors for venous thromboembolism.

INTRODUCTION: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients. Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population. Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.