Hazem Elewa

Minocycline for Short-Term Neuroprotection

Minocycline is a widely used tetracycline antibiotic. For decades, it has been used to treat various gram‐positive and gram‐negative infections. Minocycline was recently shown to have neuroprotective properties in animal models of acute neurologic injury. As a neuroprotective agent, the drug appears more effective than other treatment options. In addition to its high penetration of the blood‐brain barrier, minocycline is a safe compound commonly used to treat chronic infections. Its several mechanisms of action in neuroprotection—antiinflammatory and antiapoptotic effects, and protease inhibition—make it a desirable candidate as therapy for acute neurologic injury, such as ischemic stroke. Minocycline is ready for clinical trials of acute neurologic injury.

Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes

BackgroundInterruption of flow through of cerebral blood vessels results in acute ischemic stroke. Subsequent breakdown of the blood brain barrier increases cerebral injury by the development of vasogenic edema and secondary hemorrhage known as hemorrhagic transformation (HT). Diabetes is a risk factor for stroke as well as poor outcome of stroke. The current study tested the hypothesis that diabetes-induced changes in the cerebral vasculature increase the risk of HT and augment ischemic injury.MethodsDiabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.ResultsInfarct size was significantly smaller in GK rats (10 ± 2 vs 30 ± 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 ± 0.01 vs 1.34 ± 0.06, P < 0.001) indicative of changes in vessel architecture.ConclusionThese findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.

Vascular Protection with Candesartan after Experimental Acute Stroke in Hypertensive Rats: A Dose-Response Study

We have shown that candesartan decreases the acute stroke-induced elevation of mean arterial blood pressure (MAP) in Wistar rats and improves functional outcome. The aim of the present study was to determine whether the same benefit could be achieved in spontaneously hypertensive rats (SHR). Animals were subjected to middle cerebral artery occlusion (MCAO) or sham for 3 h followed by reperfusion. Either candesartan (0.1, 0.3, or 1.0 mg/kg) or saline was administered. MAP of the rats was monitored by means of telemetry, and neurological function was assessed. Infarct size, edema formation, and hemoglobin content in the ischemic hemisphere were evaluated 24 h after the stroke. MAP of SHR increased immediately upon MCAO from 135 (baseline) to 189 mm Hg, and it remained elevated until reperfusion. Candesartan decreased MAP in a dose-dependent manner, with a drop below baseline after a dose of 1.0 mg/kg. SHRs experienced greater blood pressure (BP)-lowering effects of candesartan after stroke compared with a sham condition (p < 0.0001). Neurological deficit after stroke was reduced in candesartan-treated animals, revealing a dose-dependent effect (p < 0.01). Infarct size, edema formation, and hemoglobin content were all reduced by candesartan at doses of 0.1 and 0.3 mg/kg (p < 0.05 for all). Candesartan (1 mg/kg) was not different from saline. Low doses of candesartan provide neurovascular protection after stroke in SHRs. Caution is warranted because acute stroke increases the sensitivity to BP lowering, which, in turn, increases the likelihood of overshooting.

Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke

BACKGROUND AND PURPOSE We have shown that acute treatment with candesartan in an experimental model of stroke resulted in vascular protection and improved outcomes at 24 hours poststroke, but the mechanisms are unknown. We now examine effects of candesartan on proangiogenic factors and 7-day outcomes using the same treatment paradigm. METHODS Male Wistar rats underwent 3 hours of middle cerebral artery occlusion followed by reperfusion. A single dose of 1 mg/kg candesartan intravenously was given at reperfusion. Animals received neurobehavioral testing before middle cerebral artery occlusion, at 24 hours after middle cerebral artery occlusion, and at 7 days. Blood pressure was measured by telemetry. Animals euthanized at 24 hours had brain tissue and cerebrospinal fluid collected for matrix metalloproteinase activity, vascular endothelial growth factor expression, and tube formation assay. Neurobehavioral testing included elevated body swing test, Bederson, beam walk, and paw grasp. Cerebrovascular density was quantified using immunohistochemistry at 24 hours and 7 days. RESULTS Matrix metalloproteinase-2 activity and vascular endothelial growth factor expression were higher (P=0.035, P=0.042, respectively) and cerebrospinal fluid was significantly more proangiogenic (5x tube formation; P=0.002) in the candesartan group at 24 hours. Although no difference was seen in infarct size at 7 days, treatment improved Bederson scores (2.1 versus 2.9, P=0.0083), elevated body swing test (22.9 versus 39.4, P=0.021), and paw grasp (1.29 versus 2.88, P=0.0001) at 7 days. Candesartan treatment resulted in increased vascular density in the striatum at 7 days (P=0.037). CONCLUSIONS Candesartan after reperfusion augments ischemia-induced angiogenic state and provides long-term benefits. The beneficial effects may involve vascular protection and enhancement of early angiogenic remodeling.

Diverse effects of statins on angiogenesis: new therapeutic avenues.

Angiogenesis is an important process for a variety of physiologic and pathologic conditions. Different angiogenic modulating targets are under extensive investigation both experimentally and clinically. The 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are the first‐line agents used in hypercholesterolemia. They are also characterized by having other benefits apart from their lipid‐lowering effects. Among these pleiotropic effects are the pro‐and antiangiogenic properties of statins. The pleiotropic effects of statins and how they modulate new blood vessel formation are discussed in this review. The currently available data from both animal and human studies regarding the effects of statins on angiogenesis in ischemic heart disease, stroke, ocular diseases, and cancer are also reviewed. Statins are safe, orally available agents that may acquire novel therapeutic indications through their angiogenic modulating effects.

Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection.

Background There is evidence that acutely elevated blood pressure (BP) after stroke is associated with increased cerebral hemorrhage and edema. Previous experiments in our laboratory have shown that candesartan 1 mg/kg administered after reperfusion in a model of hypertension after experimental ischemic stroke reduces neurovascular damage and improves outcome. These results could be either mediated by BP lowering or a BP-independent cerebrovascular protective effect. Objectives To determine the contribution of BP lowering to the neurovascular protection previously reported with candesartan after stroke. Methods Male Wistar rats (280–305 g) underwent 3 h of middle cerebral artery occlusion (MCAO). At reperfusion, either hydralazine 1 mg/kg (n = 8), enalapril 5 mg/kg (n = 7) or enalapril 10 mg/kg (n = 8) were administered intravenously. BP was measured by telemetry for 2 days before and 24 h after MCAO. After neurological function was assessed, brain tissue was processed for infarct size and hemoglobin content analyses. Results Mean arterial pressure (MAP) increased from 92 to 124 mmHg immediately upon MCAO and decreased to 112 mmHg after reperfusion, remaining elevated for 24 h (P < 0.0001) in the saline group. Hydralazine reduced MAP (P = 0.048) and infarct size (53 versus 30%, P = 0.0083), and there was a trend towards decreased hemoglobin content. Enalapril 5 mg/kg did not significantly change MAP or other outcomes. Enalapril 10 mg/kg reduced MAP (P < 0.0001) and infarct size (53 versus 29%, P = 0.003). There was an intermediate effect on both hemoglobin content and neurological function, neither one was significant. The time course of BP lowering varied with each treatment. Conclusion Acute BP lowering after reperfusion in acute ischemic stroke is an effective strategy to achieve neurovascular protection. The rate, extent and mechanism of BP lowering may determine the magnitude of protection.

Early Atorvastatin Reduces Hemorrhage after Acute Cerebral Ischemia in Diabetic Rats

Ischemic stroke is a leading cause of death in the United States, and diabetes mellitus is a major risk factor for stroke. Our previous work showed that type II diabetic rats [Goto-Kakizaki (GK)] have more bleeding after stroke than their normoglycemic controls (Wistar). Our aim was to evaluate the vascular protective properties of acute atorvastatin therapy after experimental ischemic stroke in diabetes and to explore the effect of stroke in GK rats compared with their normoglycemic controls. Fifty male Wistar and 40 GK rats (270–305 g) underwent 3 h of middle cerebral artery occlusion followed by reperfusion for 21 h. Animals received atorvastatin (5 mg/kg), atorvastatin (15 mg/kg), or vehicle, administered by oral gavage, one dose 5 min after reperfusion and a second dose after 12 h. At 24 h, functional outcome was measured, and brain tissue was analyzed for infarct volume, hemoglobin content, and molecular biomarkers. Plasma was collected for analysis of atorvastatin concentrations. Atorvastatin-treated groups had significantly lower bleeding rates (p = 0.0011) and infarct volume (p = 0.0007) compared with controls. There was a significant reduction in hemoglobin content and infarct volume only in the higher dose group (15 mg/kg) (p < 0.05), and these benefits were more than 4 times greater in the diabetic animals. Atorvastatin (15 mg/kg) improved neurological outcome in both Wistar and GK rats (p = 0.029) at a peak concentration of 27 to 77 ng/ml and was associated with an increase in Akt phosphorylation (p = 0.0007). We concluded that atorvastatin is a vascular protective agent after experimental ischemic stroke, especially in diabetes.

Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review

The broad-spectrum triazole antifungal agent voriconazole is highly efficacious against invasive fungal infections (IFIs) caused by Aspergillus spp. and Candida spp. IFIs are associated with high rates of mortality and morbidity, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. Efficacy of voriconazole in these patients is critical to ensure positive outcomes and reduce mortality. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity. As such, therapeutic drug monitoring (TDM) has been suggested as a mechanism to optimize both efficacy and safety. The aim of this review was to summarize and evaluate evidence from the primary literature that assessed TDM outcomes for voriconazole as well as evaluate the association between CYP2C19 polymorphism and the clinical outcomes of voriconazole. Findings showed associations for both efficacy and safety outcomes with measurement of drug concentrations, yet exact targets or thresholds remain unclear. As such, TDM should be reserved for those patients not responding to therapy with voriconazole or those experiencing adverse drug reactions. Future studies should attempt to further define these populations within controlled settings. Studies that evaluated the effect of CYP2C19 genetic polymorphism on clinical outcomes found no significant relationship between CYP2C19 genotype and hepatotoxicity. These negative findings may be due to lack of power, use of phenotypes not well-defined, and the presence of other interacting factors that may impact voriconazole pharmacokinetics. Future well-designed studies are warranted to confirm these findings.

Trends in oral anticoagulant use in Qatar: a 5-year experience

In Qatar, dabigatran was introduced in 2011 followed by rivaroxaban in 2014. In this study, we aim to explore the trends in oral anticoagulant use in Qatar over the past 5 years and to what extent did DOACs replace warfarin. We also explored the extent of switching between different anticoagulants (from warfarin to DOACs and vice versa). We collected all anticoagulant prescriptions dispensed as in- or out-patient from 2011 to 2015 in all Hamad Medical Corporation (HMC) hospitals. Overall number of patients using warfarin, dabigatran and rivaroxaban over the last 5 years collectively was calculated. Per each calendar year, we calculated the number of all 3 OAC used (warfarin, dabigatran and rivaroxaban), frequency of use of each one of the OAC prescribed and compared the change in proportion of DOACs to warfarin prescriptions over the years. Overall, 6961 patients were using OAC over the past 5 years among which 5849 (84%) used warfarin, 496 (7.1%) used dabigatran and 616 (8.8%) used rivaroxaban. Oral anticoagulants use increased gradually from 2091 in 2011 to 3688 in 2015. Number of patients receiving DOACs increased significantly compared to warfarin [11 (0.5%) in 2011 vs. 849 (23%) in 2015 (p < 0.0001)]. Since its introduction in 2014, number of rivaroxaban users increased significantly compared to dabigatran [212 (40.9%) in 2014 vs. 544 (64.1%) in 2015]. DOACs have been gradually replacing warfarin in Qatar and the trend of their use is similar to that reported in other countries. Warfarin remains the most commonly used oral anticoagulant.

Cancer-Associated Venous Thromboembolism

Opinion statementCancer patients are at high risk for venous thromboembolism (VTE) which is considered the second leading cause of death among this population. Both cancer and cancer treatment increase this risk. Since the risk of VTE is not the same in all cancer patients, it is important to understand what factors increase the risk of incident and the risk of recurrent VTE in this patient population. In an effort to combine multiple factors into a single risk stratification system, a scoring system for recurrent VTE risk in cancer patients has been developed and externally validated. While vitamin K antagonists (VKA) or the direct oral anticoagulants (DOACs) are first-line therapies for non-cancer-associated VTE treatment, low-molecular-weight heparin (LMWH) agents are the first-line anticoagulant for treatment of cancer-associated VTE. In this review, we discuss the epidemiology, pathophysiology, and risk stratification used in cancer-associated VTE. We also discuss the current therapies for cancer-associated VTE and the evidence supporting their use from the literature.