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Biomedical subjects

Ashfaq Shuaib

Publications and source records attributed to Ashfaq Shuaib.

At least 37 records · Page 2Linked to original sources
PubMed2005

NMDA/NR2B selective antagonists in the treatment of ischemic brain injury.

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtype-selective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.

Animals↗
PubMed2005

Role of MC-1 alone and in combination with tissue plasminogen activator in focal ischemic brain injury in rats.

OBJECT: Pyridoxal-5-phosphate (PLP), the biologically active form of pyridoxine, can rescue neurons from death in vitro and in vivo. In the present project, the authors have studied whether MC-1, an analog of PLP, alone or in combination with the thrombolytic agent tissue plasminogen activator (tPA), can protect the brains of rats injured by ischemia. METHODS: Ischemic brain injury was induced in rats by injecting a preformed blood clot in the middle cerebral artery (MCA). Neurological deficits and infarct volumes caused by the embolus were measured to evaluate the effects of MC-1 on the ischemic injury. Systemic blood pressure and local brain blood flow were also monitored. Administration of different doses of MC-1 1 hour after embolization significantly reduced the infarct volume and improved functional recovery. Injection of MC-1 (40 mg/kg) at 3 or 6 hours after embolization also reduced the volume of the infarct significantly and improved functional recovery. Combined treatment with MC-1 and tPA was also neuroprotective, although it was not superior to treatment involving either MC-1 or tPA alone. Treatment with MC-1 did not result in significant changes in either systemic blood pressure or local blood flow in the ischemic brain. CONCLUSIONS: These data support the hypothesis that in the focal embolic stroke model in rats MC-1 is a neuroprotective agent. The neuroprotection this compound provides still exists when MC-1 administration is delayed up to 6 hours after ischemic injury.

Animals↗
PubMed2004

Endothelial progenitor cells during cerebrovascular disease.

BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPCs) are associated with endothelial repair after ischemia in cardiac or peripheral circulation. There are no reports of EPCs with cerebrovascular disease. We present our experience with EPCs in patients with cerebrovascular disease. SUMMARY OF REPORT: EPC counts differed significantly (P<0.001) between stroke patients (acute stroke: median 4.75 and range 0 to 33; stable stroke: median 7.25 and range 0 to 43) and control subjects (median 15.5 and range 4.3 to 50), independent of age. The level of EPCs was significantly correlated with the Framingham coronary risk score (FCRS) (rho=-0.349; P=0.002). CONCLUSIONS: Similar to cardiac experience, the low EPC levels may play a role in the pathophysiology of cerebrovascular disease.

Acute Disease↗
PubMed2004

Pyridoxine as a template for the design of antiplatelet agents.

The B(6) vitamers have been shown to display beneficial therapeutic effects in cardiovascular related disorders. The design of novel antiplatelet agents using pyridoxine as a template has led to the discovery of a class of novel cardio- and cerebro-protective agents. The present study describes the synthesis of several of these derivatives along with the antiplatelet and antiischemic activity of derivative 16.

Animals↗
PubMed2004

Current and future concepts in stroke prevention.

Stroke is a major cause of morbidity and mortality in an aging population. The current understanding of the pathophysiology of atherosclerotic diseases, the most common cause of stroke, and the evidence for existing therapeutic interventions for the prevention of stroke are presented. Specifically, we review the evidence for antiplatelet agents, anticoagulants, antihypertensive medications, lipid-lowering agents and carotid endarterectomy for stroke prevention.

Anticoagulants↗
PubMed2004

Effect of zinc in ischemic brain injury in an embolic model of stroke in rats.

Zinc is prevalent in the mammalian central nervous system and its role in ischemic brain injury is still controversial. In the present study, the effect of zinc in ischemic brain injury was examined in an embolic model of stroke in rats. Furthermore, the effect of zinc in combination with bicuculline, a GABAa antagonist, was also examined in the ischemic injury. Treatment with zinc or zinc plus bicuculline increased infarct volume significantly and also worsened neurological deficits. Moreover, treatment with zinc plus bicuculline also enhanced ischemic brain edema. These results thus support the hypothesis that administration of zinc i.p. worsens the outcome of ischemic brain injury in the embolic model of stroke in rats.

Animals↗
PubMed2004

Agreement between patient and proxy assessments of health-related quality of life after stroke using the EQ-5D and Health Utilities Index.

BACKGROUND AND PURPOSE: Proxy informants can provide information on patients who are limited in ability to self-assess health-related quality of life (HRQL) after stroke. One alternative is to exclude assessments of such patients and attenuate generalizability. The purpose of this study was to examine patient-proxy agreement on the domains and summary scores of the EQ-5D and Health Utilities Index Mark 3 (HUI3) after stroke. METHODS: An observational longitudinal cohort of 124 patients hospitalized after ischemic stroke and their family caregivers completed the HRQL measures at baseline and were followed up for 6 months. Patient and proxy agreement was assessed by use of weighted kappa or the intraclass correlation coefficient (ICC). RESULTS: At baseline, the more observable domains of HRQL demonstrated greater agreement than the more subjective components. Cross-sectional point estimates of agreement were generally acceptable (ICC >0.70) for the EQ-5D Index and HUI3 summary scores when assessed >or=1 month after baseline. Agreement between change scores was generally poor to fair (ICC <0.60), but systematic bias was not observed for the indirect preference-based summary scores between baseline and 6 months. CONCLUSIONS: Results suggest that proxy assessments obtained 6 months after stroke are more reliable than those obtained within 2 to 3 weeks after stroke. Although proxy-assessed change scores for indirect preference-based summary scores of the EQ-5D and HUI3 provided suboptimal agreement with patient assessment, limited systematic bias may support their consideration as alternatives to missing data or statistical imputation. Further research into the validity and reliability of proxy assessments is suggested.

Aged↗
PubMed2004

Can rt-PA be administered to the wrong patient? Two patients with somatoform disorder.

BACKGROUND: Intravenous rt-PA (i.v. rt-PA) for acute stroke has raised many concerns, including its inadvertent use in patients presenting with acute stroke-like symptoms as the expression of their somatoform disorder. Diagnosis of the somatoform disorder is often delayed, and thrombolytics in these patients for their stroke-like presentation subjects them to risk for hemorrhage. METHODS: The presentation, neurological findings, and the therapeutic decision making was audited in 85 patients who received i.v. rt-PA for a diagnosis of acute stroke. All the surviving patients were re-examined neurologically at least three months after i.v. rt-PA. Baseline and follow-up brain CT scans were re-reviewed by a neuroradiologist who was blinded to clinical presentation and outcome. Patients whose clinical presentation, brain CT and neurological outcome did not fit into known or expected anatomical and clinical patterns of stroke underwent psychological assessment using the Minnesota Multiphasic Personality Inventory-2. RESULTS: In two patients three stroke-like presentations of somatoform disorder inadvertently were treated with i.v. rt-PA. This was primarily caused by abbreviated neurological examination and narrow differential diagnosis. INTERPRETATION: Patients with somatoform disorder may present with symptoms mimicking acute stroke. Under the time constraints of i.v. rt-PA use, a diagnosis of somatoform disorder can be missed, subjecting such patients to the potential complications of thrombolytics.

Acute Disease↗
PubMed2003

Improved detection of microbubble signals using power M-mode Doppler.

UNLABELLED: Background- Power motion-mode transcranial Doppler (TCD) (PMD) is a new, multigated technique that may simplify and enhance detection of embolus. We developed criteria for emboli detection using PMD. Then, we performed a blinded comparison of transcranial PMD with single-gate spectral TCD in TCD bubble study patients. METHODS: Patients with right-to-left shunt as detected with standard TCD were selected for this study. The international emboli criteria for spectral TCD were used. We defined novel PMD criteria for detecting emboli signature on PMD as follows: (1) signature at least 3 dB higher than the highest spontaneous PMD display of background blood flow; (2) embolic signature reflects motion in one direction at a minimum spatial extent of 7.5 mm and temporal extent of 30 ms; (3) embolus must traverse a prespecified depth. Each study was blindly assessed for microbubble signals (MBS) count on either modality. RESULTS: Thirty-six patients were included in the study. Mean age was 44.4 (SD 14.4), 50% were male, and median time from stroke onset to TCD bubble test was 12 days. Median MBS count in middle cerebral arteries (MCA) was 4 on both modalities. Spectral TCD MBS counts were highly correlated (rho=0.97) with PMD MBS counts in MCA and similarly in anterior cerebral arteries (ACA) (rho=0.79). When PMD microbubble counts in the ACA and MCA were summed, a clear 2-fold difference emerged between 2 modalities (P<0.001). CONCLUSIONS: When compared with spectral TCD, PMD detects more MBS with higher counts by identifying ACA as well as MCA emboli. Pitfalls of overcounting emboli with PMD can be avoided by following such criteria.

Adult↗
PubMed2003

Atrial myxoma as a cause of stroke: case report and discussion.

Cardiac myxoma is a source of emboli to the central nervous system and elsewhere in the vascular tree. However, nonspecific systemic symptoms and minor embolic phenomena may be overlooked in the absence of any history of cardiac problems. In this situation, cardiac investigations may not be performed, and diagnosis of this rare condition may be delayed until the onset of more significant embolic disease, such as stroke with functional impairment, as in the case reported here. The clinical presentation of cardiac myxoma is discussed, along with appropriate investigations and treatment, which may prevent such sequelae.

Echocardiography, Transesophageal↗
PubMed2003

Cervical arterial dissection: time for a therapeutic trial?

BACKGROUND AND PURPOSE: Cervical arterial dissection is a major cause of stroke in young adults, yet despite standard treatment with anticoagulants or antiplatelet drugs, its management remains uncertain. The goal of this study was to assess the natural history of the disorder and to decide on the feasibility of a therapeutic trial. METHODS: Collaborating members of the Canadian Stroke Consortium prospectively enrolled consecutively referred patients with angiographically proven acute vertebral or carotid arterial dissection. Data recorded included clinical and radiological details, recurrence of ischemic cerebral events, and medical or surgical treatment. RESULTS: Of 116 patients, 67 had vertebral and 49 had carotid dissections, with no difference in age or sex. In 68 (59%), trauma occurred at the time of dissection. During the course of a 1-year follow-up, at least 17 patients (15%) had recurrent transient ischemic attacks, stroke, or death, mainly in the weeks immediately after the dissection. In 105 patients with complete follow-up, the event rate in those treated with anticoagulants was 8.3% and in those treated with aspirin was 12.4%, a nonsignificant difference of 4.1%. Using these data, we calculate that for a 2-arm trial (aspirin versus anticoagulants) with 80% power and 5% significance, 913 patients are needed in each group. CONCLUSIONS: From our data indicating an initial relatively high recurrence rate, a multicenter trial of anticoagulants versus aspirin involving a total of 2000 patients is feasible.

Adult↗
PubMed2003

Effects of hyperthermia on infarct volume in focal embolic model of cerebral ischemia in rats.

Hyperthermia worsens outcome of stroke in patients and also in animal models. In the present study, we tested the effects of hyperthermia in a focal embolic model of cerebral ischemia in rats. Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery. Hyperthermia significantly increased the brain infarct volume as compared to the normothermic controls measured at 48 h following the ischemic insult. Neurological deficits were also significantly elevated in the animals undergoing hyperthermic treatment. In addition, hyperthermia also significantly increased mortality. Our data thus show that hyperthermia exacerbates neuronal injury in the focal embolic model of cerebral ischemia in rats.

Animals↗
PubMed2003

Acetylsalicylic acid reduces perfusion deficit in ischemic injured brain in rats.

Acetylsalicylic acid (ASA) is an antiplatelet agent which has been used in treatment and prevention of stroke in humans. In the present study, the effects of ASA on perfusion deficits in the brain have been studied in an embolic model of stroke. Data showed that perfusion deficits were observed in all rats sacrificed immediately after middle cerebral artery (MCA) occlusion. Treatment with ASA significantly reduced perfusion deficits 1 h but not 3 h after the MCA occlusion. These findings thus support that ASA is useful agent in treatment and prevention of stroke, and show that its mechanism of action is likely through the reopening of cerebral microvessels.

Animals↗
PubMed2003

Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.

BACKGROUND: This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. METHODS AND RESULTS: Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. CONCLUSIONS: Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Administration, Oral↗
PubMed2003

The relative importance of barriers to the prescription of warfarin for nonvalvular atrial fibrillation.

BACKGROUND AND PURPOSE: Despite the publication of a number of randomized, controlled trials demonstrating a substantial reduction in stroke with anticoagulation in patients with nonvalvular atrial fibrillation, the 'real world' use of warfarin is sub-optimal. Previous surveys have attempted to explain this problem but have significant limitations. The purpose of this study was to assess the relative importance of various barriers that may influence the prescription of warfarin in patients with nonvalvular atrial fibrillation. METHODS: This cross-sectional survey was mailed to all practising cardiologists, neurologists and internists, as well as a random sample of family physicians within Alberta. Physicians caring for patients with NVAF rated the relative importance of potential barriers using a Likert scale. RESULTS: Sixty-seven per cent of all physicians returned the survey. Overall, barriers pertaining to the patient's clinical characteristics were rated to be more important than those pertaining to the physician or to the organization required when prescribing these therapies. Specifically, an ongoing history of falls, a history of bleeding within the previous year and an inability to comply with therapy were rated as important barriers by 64%, 55% and 53% of physicians, respectively. Most physicians strongly believed that patients should receive information on the benefits and risks of warfarin (96%) and that patients should have a say in whether warfarin is prescribed (86%). IMPLICATIONS: This study suggests that most of the barriers to warfarin use pertain to patient clinical characteristics and the need for patients to be involved in the decision to initiate therapy. The use of decision support technologies would facilitate involvement of the patient and serve to educate both the patient and physician on the risks and benefits of warfarin therapy.

Adult↗
PubMed2003

Effects of minocycline alone and in combination with mild hypothermia in embolic stroke.

Inflammatory reactions occurring in the brain after ischemia may contribute to secondary damage. In the present study effects of minocycline, an anti-inflammatory agent, alone or in combination with mild hypothermia, on focal embolic brain ischemia have been examined. Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA). Infarct volume was measured at 48 h after the injury. Administration of minocycline alone or minocycline plus mild hypothermia reduced infarct volume significantly. However, mild hypothermia in combination with minocycline did not show any additive effect. These results suggest that minocycline is beneficial in focal ischemic brain injury, and the lack of the enhanced neuroprotection may be due to the brief exposure to hypothermia.

Animals↗
PubMed2003

The role of taurine in cerebral ischemia: studies in transient forebrain ischemia and embolic focal ischemia in rodents.

Sudden cessation of blood flow to the brain results in a series of events that either result in rapid loss of brain cells or delayed neuronal injury in certain vulnerable regions of the brain. Research over the last three decades has allowed for a better understanding of how neurons and other brain cells die from the effects of ischemia and hypoxia in the central nervous system. Excitatory and inhibitory neurotransmitters exist in a very precise balance for normal function of the brain. Ischemia very rapidly disrupts this balance resulting in a rapid build-up of excitatory neurotransmitters, especially glutamate in the extracellular space. The increased glutamate together with energy loss opens a number of different types of calcium and sodium channels resulting in the build-up of these ions in neurons, leading to cellular dysfunction and death. While most ischemia research has focused on antagonism of excitatory amino acids, there are some reports on enhancement and amplification of inhibitory responses in focal and global ischemia. The majority of work relates to potentiation of GABA, either endogenous or through GABA potentiating medications. Taurine has neuroinhibitory properties and may also have potential for neuroprotection in cerebral ischemia. This present review focuses on the role of taurine as a neuroprotective agent, possibly acting through several different inhibitory mechanisms. Taurine may inhibit neurotransmitter release and may result in normal intracellular osmolality. In transient global ischemia in gerbils, we studied in vivo microdialysis of amino acids before, during and after ischemia. We were able to show that taurine resulted in attenuation of glutamate during ischemia (however did not reach significance). In similar experiments, neuronal damage was assessed in the hippocampus. Our results show 48% damage in taurine treated animals, 60% in alanine treated animals and 69% in control groups (trend towards protection but again did not reach significance) Focal ischemia was induced by embolizing a thrombus into the distal internal carotid artery and origin of the middle cerebral artery. Again, in studies where we compared taurine to a placebo treated animal, there was no significant decrease in the amount of damage with taurine. There are reports in the literature that taurine may attenuate neuronal injury during ischemia. Our studies in two models of cerebral ischemia in rodents did not reveal neuronal protection. It is possible that higher doses or possibly prolonged use of taurine may show better results. Taurine may also potentially offer additive protective effects when used in combination with thrombolysis or other neuroprotective agents. Further studies are necessary to better understand the potential for taurine as a neuroprotective agent in cerebral ischemia.

Animals↗