Biomedical subjects

A Shuaib

Publications and source records attributed to A Shuaib.

At least 55 records · Page 3Linked to original sources

PubMed1998

Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion.

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.

Animals↗

PubMed1998

Postischemic treatment with calpain inhibitor MDL 28170 ameliorates brain damage in a gerbil model of global ischemia.

The newly-developed calpain inhibitor, MDL 28170 penetrates the blood-brain barrier and inhibits brain cysteine protease activity after systemic administration. This experiment was initiated to determine if the calpain inhibitor, MDL 28170 could, by these actions, reduce neuronal damage in an animal model of global cerebral ischemia in the gerbil. The calpain inhibitor, MDL 28170 (50 mg/kg), was initiated at 0.5 and 3 h of recirculation following 5min of global ischemia. Animals subjected to ischemia but without treatment or with vehicle treatment served as controls. Evaluation by light microscopy was carried out on paraffin-embedded brain sections of gerbils which were sacrificed 7 days post-operatively. The results show that the calpain inhibitor, MDL 28170, protects against cortical neuronal damage even if the treatment is delayed until 3 h after reperfusion. However, the neuroprotective effect of this agent is less pronounced in the hippocampal CA1 sector. The results suggest that calpain-mediated proteolysis plays an important role in neuronal death due to ischemia. However, additional mechanisms by which an increased intracellular calcium concentration leads to neuronal death may exist.

Animals↗

PubMed1998

Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model.

A number of models of focal ischemia have been created to mimic acute middle cerebral artery (MCA) occlusion. In the present series of experiments, we report our observations on the thrombin model of MCA occlusion and the neuroprotective effects of intraarterial thrombolysis with two doses of urokinase (2500 and 5000 units/kg). In all experiments male Wistar rats were used and the animals were allowed to recover for 48 h before assessment of neurobehavioral performance on a four-point scale. The extent of cerebral hemispheric damage was calculated as the percentage of brain infarction using TTC staining. Occlusion of the MCA was effected by the introduction of an autologous blood clot into the internal carotid artery (ICA) approximately 2 mm from the origin of the MCA. This clot was formed by the drawing of 10 microl of blood into a bovine thrombin (20 microg per animal) containing intraarterial catheter, which was inserted into the right ECA. After standing for 15 min to allow clot formation, the catheter was advanced gently through the ICA to the site of injection. MCA occlusion produced a consistent large infarction in all animals. Urokinase infusion (i.a. ) was started 2 h after arterial occlusion in the initial series. In animals treated with low dose urokinase infusion there was mild protection. Animals treated with high dose urokinase infusion showed a highly significant improvement in the motor recovery and a decrease in the extent of infarction compared to control animals. In the final group, the infusion of urokinase was delayed for 3 h. While producing protection in some animals, it also produced intracerebral hemorrhage in two of eight animals. Thus delay of infusion to 180 min increased the risk of hemorrhage. This model may in the future be used to test the protective effects of combination therapy with thrombolysis and neuroprotective medications.

Animals↗

PubMed1998

An increase in extracellular glutamate is a sensitive method of detecting ischaemic neuronal damage during cranial base and cerebrovascular surgery. An in vivo microdialysis study.

All patients undergoing neurological surgery are at risk for serious complications. Ischaemic damage presenting with hemiparesis or speech difficulties occurs in up to 6% of patients undergoing cerebral bypass procedures and other complicated neurosurgical procedures. Currently available methods for detection of such damage include the use of somatosensory evoked potentials (SSEPs) and electro-encephalography (EEG). Unfortunately, these techniques have false positives and may remain normal in the presence of severe focal neurological deficits. Early detection of potential deficits may prevent or minimize damage through a change in operative or anaesthetic strategy. With the availability of several potential neuroprotective compounds, it is also possible to treat patients at risk of developing ischaemic complications if the individuals are identified early. The excitatory neurotransmitter glutamate is not only a metabolic product, but is also thought to promote ischaemia induced cell injury if released into the extracellular space. It may be a significant parameter for ischaemic brain metabolism. In this report we describe 10 patients who underwent extracranial-intracranial (EC-IC) high flow bypass procedures with routine intra-operative monitoring (IOM) as well as intra-operative in-vivo microdialysis measurement of glutamate. Our aim was to compare intra-operative microdialytic findings and IOM findings with respect to patients' early postoperative clinical courses. Three patients had significant intra-operative glutamate increases indicating ischaemia. Two of these patients awoke with a new neurological deficit (hemiparesis). Routine IOM findings were either normal or showed only transient changes during the time the glutamate levels were high. Our study shows that an increase in extracellular glutamate, as monitored by in-vivo microdialysis, is an excellent early market of neuronal damage. While our glutamate measurements were done off-line, it may be possible to get in future continuous on-line measurements to serve as an early warning system for potential ischaemic damage.

Adult↗

PubMed1998

Canadian guidelines for intravenous thrombolytic treatment in acute stroke. A consensus statement of the Canadian Stroke Consortium.

BACKGROUND: The thromobolytic drug, tissue plasminogen activator (tPA) has been approved in the United States for the treatment of acute ischemic stroke amid controversy and concern about the balance of risk and benefit. The Canadian Stroke Consortium (CSC), a national network of neurologists who collaborate on joint projects in stroke medicine, including clinical trials and consensus statements, has developed guidelines for the use of tPA in Canada. METHODS AND RESULTS: The CSC Board of Directors wrote a preliminary report based on existing publications, including randomized drug trials and the report of a special committee struck by the Stroke Council of the American Heart Association. This draft was circulated to the CSC membership-at-large for suggestions or amendments, to produce this final draft. CONCLUSIONS: The present guidelines have been devised to represent a Canadian viewpoint of management. The Health Protection Branch of the Ministry of Health of Canada has not yet produced an evaluation. Further modification of these guidelines may be necessary when more data from clinical trials and experience with the drug become available.

Acute Disease↗

PubMed1998

Hypothyroidism-evoked shifts in hippocampal adrenergic receptors: implications to ischemia-induced hippocampal damage.

Hypothyroidism was induced in a group of male Fischer 344 rats by administration of 0.05% propylthiouracil (PTU) in the drinking water for 12 weeks. Control rats were not treated. Plasma levels of thyroid hormones indicated that PTU treatment had produced severe thyroid hormone deficiency. In PTU-treated rats compared to control rats, levels of total T3 and total T4 were reduced 54.5% and 53.7%; while levels of free T3 and free T4 were reduced 87.1% and 96.5%. Functional hypothyroidism was demonstrated by: (i) a 49.1% decrease in hepatic plasma membrane alpha1-adrenergic receptor binding, and (ii) a 11.2-fold increase in hepatic gamma-glutamyltranspeptidase activity; relative to the expression of these parameters in control rats. Membranes were isolated from hippocampi of control, PTU-induced hypothyroid and thyroxine-replaced rats and specific adrenergic receptor binding determined by radioligand binding techniques. Hypothyroidism resulted in a shift in the balance of alpha1 and beta2 adrenergic receptor binding by evoking: an increase in alpha1-adrenergic receptor binding to 1.57-fold of control levels; and, a decrease in beta2-adrenergic receptor binding to 64% of control levels. Thyroid hormone replacement carried out in PTU-treated hypothyroid rats at 30 microg/kg s.c. per day for the last 3 days of the 12 week PTU-treatment protocol, which reversed physical and functional hypothyroidism, reversed the observed changes in hippocampal adrenergic receptor binding, indicating them to be thyroid hormone, and not PTU, -dependent. This receptor shift evoked by hypothyroidism may, in part, explain the protective effect of hypothyroidism on ischemia-induced hippocampal damage by favoring inhibitory input and limiting excitotoxic input by catecholamines.

Animals↗

PubMed1998

Aging and ischemia in gerbils impair spatial memory performance.

Gerbils aged 3 months and 24+ months were subjected to 5 min of global forebrain ischemia and tested in a radial arm maze (1 trial/day, 50 days). Compared with age-matched, sham-operated controls, ischemic animals were impaired on measures of both working and reference memory. Aged animals were impaired on working memory, but not on reference memory, compared with their younger counterparts. Hippocampal CA1 and CA2 regions were significantly and comparably damaged in the 2 ischemic groups but were unaffected by aging. The results suggest that aging and ischemia have functionally similar effects on working memory, but the 2 processes differentially impact reference memory.

Age Factors↗

PubMed1998

Intraoperative on-line monitoring of cerebral pH by microdialysis in neurosurgical procedures.

The objective of this study was to improve the ability to detect cerebrovascular complications in patients undergoing complicated neurosurgical procedures using on-line monitoring of cerebral pH with in vivo microdialysis. We employed on-line pH monitoring in patients with a variety of neurosurgical procedures including high-flow bypass surgery, aneurysm clipping, and temporal resection in epilepsy treatment. The pH was monitored with a microdialysis probe, usually inserted into the frontal cortex and pH of the dialysate was measured on-line with a pH electrode. We monitored 17 cases: 12 high-flow extracranial-intracranial (EC-IC) bypass procedures, 3 surgeries to clip large basilar tip aneurysms under protection of hypothermic circulatory arrest, and 2 surgeries for intractable seizure disorders. In the patients undergoing high-flow bypass, the pH remained stable in 5 patients and all had an uneventful outcome. In 3 patients, the pH decreased during surgery. One patient had a severe hemiparesis on awaking from anesthesia. The fall in pH in another patient was corrected when the blood pressure was raised during surgery. The pH was also responsive to changes in intraoperative ventilation and probably also to brain edema with elevation of pH values. In the three patients undergoing basilar tip aneurysm clipping under hypothermic circulatory arrest, the pH fell to 6.41 in one patient. This patient awoke with a mild hemiparesis. In the other two patients, the pH was stable during the hypothermia and neither patient had complications. In the patients undergoing temporal lobectomy and hippocampectomy, the pH fell rapidly with the onset of ischemia. We conclude that it is possible to monitor the cerebral extracellular pH with on-line microdialysis. The information obtained may alert the surgeon to the possibility of impending cerebral ischemia or other complications. However, further experience is needed before the technique can be recommended for general use.

Adult↗

PubMed1998

Cortical brain microdialysis and temperature monitoring during hypothermic circulatory arrest in humans.

OBJECTIVES: Critical vascular surgery of the brain or the heart occasionally requires total cessation of the circulatory system. Profound hypothermia is used to protect the brain from ischaemic injury. This study explores the use of microdialysis to measure metabolic indices of ischaemia: glutamate, lactate, and pH, and cerebral temperature during profound hypothermia and circulatory arrest. METHODS: Effluent from a microdialysis catheter placed in the cerebral cortex of three patients undergoing complete circulatory arrest was continuously sampled. Samples were pooled over 10 minute periods and glutamate and lactate concentrations were measured postoperatively. Brain temperature and pH were measured on line intraoperatively. Electroencephalography and monitoring of somatosensory evoked potentials and brainstem auditory evoked potentials were simultaneously carried out. RESULTS: Patient 1 had normal glutamate and lactate. PH was 6.75 to 6.85 and increased to 6.9 after warming ensued. Patient 2 had raised glutamate and lactate during most measurements. The glutamate concentrations peaked at 305 microM/l at the start of the measurements and fell below 20 microM/l after warming. The lactate concentrations peaked at 680 microM/l before cooling, rose to 1040 microM/l during the cooling process, decreased to 212 microM/l during circulatory arrest, and rose again to 620 microM/l after warming. The pH started at 7.06 and continued a downward course until stabilising at a pH of 6.5 after circulatory arrest. Patient 3 had a transient, mild increase in glutamate and lactate during the cooling and warming period. pH was stable throughout. CONCLUSION: Microdialysis combined with temperature and pH measurements of the cerebral cortex promises to be an important tool in detecting cerebral ischaemia. Further studies are needed to validate our findings and test the feasibility of modifying ischaemic changes.

Acid-Base Equilibrium↗

PubMed1997

Attenuated glutamate release during ischemia in ethanol-administered gerbils.

Previous studies have found an association between prior ethanol consumption and aggravated stroke outcome. Gerbils were intermittently given ethanol injections (s.c.) for 21 days at doses of 1 and 4 g/kg. After cessation of injections and appropriate weight gain, subjects underwent bilateral carotid occlusion while amino acid neurotransmitter levels in the hippocampus were monitored. Both the low and high dose ethanol groups demonstrated significantly decreased glutamate release compared with saline-treated controls during ischemia (p < 0.05). These results are consistent with a long-lasting ethanol-induced decrease in synaptic density in the hippocampus. That no intergroup differences on histological or neurobehavioral measures was found may suggest a functional dissociation of glutaminergic involvement in the pathogenesis of aggravated stroke outcome with alcoholism.

Animals↗

PubMed1997

Zonisamide as a neuroprotective agent in an adult gerbil model of global forebrain ischemia: a histological, in vivo microdialysis and behavioral study.

Brief periods of global cerebral ischemia are known to produce characteristic patterns of neuronal injury both in human studies and in experimental animal models. Ischemic damage to vulnerable areas such as the CA1 sector of the hippocampus is thought to result from excitotoxic amino acid neurotransmission. The objective of this study was to determine the ability of a novel sodium channel blocking compound, zonisamide, to reduce neuronal damage by preventing the ischemia-associated accumulation of extracellular glutamate. Using a gerbil model, animals were subjected to 5 min ischemic insults. Both pre- and post-ischemic drug administration (zonisamide 150 mg/kg) were studied. Histological brain sections were prepared using a silver stain at 7 and 28 days post ischemia. The animals sacrificed at 28 days also underwent behavioral testing using a modified Morris water maze. In vivo microdialysis was performed on a separate group of animals in order to determine the patterns of ischemia-induced glutamate accumulation in the CA1 sector of the hippocampus. Pyramidal cell damage scores in the CA1 region of the hippocampus were significantly reduced in animals pre-treated with zonisamide compared to saline-treated controls, both at 7 days (drug pre-treated: 0.812 +/- 0.28, n = 8; controls: 1.625 +/- 0.24, n = 8; *P < 0.05) and 28 (drug pre-treated: 0.833 +/- 0.22, n = 12; controls: 1.955 +/- 0.26, n = 11; **P < 0.01) days post ischemia. However, animals receiving zonisamide post-treatment did not display significant differences from controls. Behavioral studies also showed significant preservation of function in drug-treated animals. Microdialysis studies confirmed a reduction in glutamate release in drug-treated animals compared to saline-treated controls. Our data suggest that zonisamide is effective in reducing neuronal damage by a mechanism involving decreased ischemia-induced extracellular glutamate accumulation and interruption of excitotoxic pathways.

Animals↗

PubMed1997

Effects of clomethiazole on radial-arm maze performance following global forebrain ischemia in gerbils.

The functional and neuroanatomical protective effects of clomethiazole (CMZ) were examined in an animal model of global forebrain ischemia. Gerbils underwent sham-surgery or were rendered ischemic by the application of aneurysm clips to both carotid arteries for 6 min. Three treatment groups received CMZ (50 mg/kg, 100 mg/kg, or 150 mg/kg) 30 min before ischemia, and one group was given 150 mg/kg of CMZ 30 min after ischemia. Following recovery, the gerbils were tested in a radial-arm maze to assess memory functions. Histological evaluation was assessed blindly using a percentile scoring system. The results indicate that pre-ischemic treatment with 100 mg/kg and 150 mg/kg of CMZ reduced brain damage and working memory errors significantly. Treatment dosage of 150 mg/kg of CMZ was the most effective in preventing neuronal damage in the hippocampus and eliminating the working memory deficit typically induced by ischemia.

Animals↗

PubMed1997

GABA and glutamate levels in the substantia nigra reticulata following repetitive cerebral ischemia in gerbils.

Repetitive cerebral ischemia produces more severe damage than a similar single duration insult. We have previously shown that, in gerbils, damage in the substantia nigra reticulata (SNr) is seen with repetitive insults rather than a single insult. We have also shown that there is a progressive decrease in the extracellular GABA in the striatum in the days preceding such damage, speculating that a loss of GABA may be in part responsible for this damage. This study evaluates the GABA levels in the SNr in animals exposed to repetitive ischemic insults. Each animal received a total of three ischemic insults of 3-min duration at hourly intervals. In vivo microdialysis was carried out to analyze the GABA and glutamate dialysate levels on Days 1, 3, 5, 7, and 14 following the ischemic insult. In the control and treated (ischemic) animals, there was a significant increase in the GABA levels with the introduction of nipecotic acid on Days 1, 3, 5, and 14. However, on Day 7 there was a significant attenuation in the GABA response to nipecotic acid in the treated animals in comparison to the controls. The glutamate levels in the treated animals were similar to the control animals on Days 1, 3, 5, and 7. However, on Day 14 the glutamate levels were significantly lower than on previous days. Our experiments for the first time measure extracellular glutamate and GABA responses in the SNr in animals exposed to repetitive ischemic insults. Our experiments show that there is a significant decrease in the GABA concentrations at a time when ischemic damage is developing in this region. This confirms our hypothesis that a decrease in GABA may be one factor contributing to neuronal damage during the period following repetitive ischemic insults. Further, the rebound increase in GABA levels on Day 14 with a concomitant fall in glutamate levels would indicate that reparative processes are still active in the 2 weeks following the insult.

Animals↗

PubMed1997

Inhibitory mechanisms in cerebral ischemia: a brief review.

Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular Ca2+ buildup, relative lack of inhibitory responses, generation of oxygen free radicals, especially during the reperfusion period and several other destructive cascades. Therapies aimed at decreasing the ill effects of glutamate are either not effective or have serious side-effects. Ca2+ entry blockers are generally not effective in cerebral ischemia, and data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 h after the ischemic insult. Many such medications have few side-effects and are in clinical use for other indications. This review will summarize inhibitory mechanisms that may be important in cerebral ischemia, and provide experimental evidence for their potential efficacy.

Animals↗

PubMed1997

EC-IC bypass improves chronic ischemia in a patient with moyamoya disease secondary to sickle cell disease: an in vivo microdialysis study.

Patients with sickle cell disease may develop intracranial vascular disease, with the occlusion or obstruction of the large or small arteries, which may lead to the secondary development of moyamoya disease. In this report, we describe the neurochemical changes in the brain before, during, and after an extracranial-intracranial bypass procedure on a patient with sickle cell disease and a moyamoya disease like pattern on angiography. We used the in vivo microdialysis technique to measure the on-line pH, lactate and amino acid concentrations in the extracellular fluid. There were relatively high resting glutamate levels and a lower-than-normal pH in the extracellular fluid prior to the bypass, associated with chronic ischemia. During the bypass there was a short-lived increase in the glutamate levels. After revascularization, there was a rapid decrease in the glutamate levels and an increase in the pH value. The patient's preoperative neurological deficit improved post-operatively, corresponding to the biochemical changes towards normal values. These changes after revascularization suggest that chronic biochemical abnormalities due to brain ischemia may improve after cerebral revascularization.

Adult↗

PubMed1997

Economic evaluation of oral sumatriptan compared with oral caffeine/ergotamine for migraine.

We conducted an economic comparison of oral sumatriptan with oral caffeine/ergotamine in the treatment of patients with migraine. Cost-effectiveness, cost-utility and cost-benefit analyses were conducted from societal and health-departmental perspectives. A decision tree was used. Utilities were assigned to health states using the Quality of Well-Being Scale. Simple and probabilistic sensitivity analyses were also carried out. From a societal perspective, using sumatriptan instead of caffeine/ergotamine resulted in an incremental cost-effectiveness ratio of -25 Canadian dollars ($Can) per attack aborted, an incremental cost-utility ratio of -$Can7507 per quality-adjusted life-year (QALY), and a net economic benefit of $Can42 per patient per year (1995 values). From the perspective of the health department, the incremental cost-effectiveness ratio was $Can98 per attack aborted, the incremental cost-utility ratio was $Can29,366 per QALY; the grade of recommendation based on past decisions regarding health technology for adoption into health insurance plans was 'moderate'. Sensitivity analysis showed that the results were robust to relatively large changes in the input variables. The incremental health benefits obtained from using oral sumatriptan rather than oral caffeine/ergotamine were achieved at moderately acceptable incremental costs, if past decisions on the adoption of other health technologies are used as a guide.

Administration, Oral↗

PubMed1997

Amplification of inhibitory mechanisms in cerebral ischemia: an alternative approach to neuronal protection.

The central nervous system consumes 20% of the cardiac output for normal function. The neurons are very sensitive to the effects of ischemia. Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular calcium (Ca2+) buildup, relative lack of inhibitory responses, generation of oxygen free radicals (especially during the reperfusion period) and several other destructive cascades. Medications that antagonize the effects of glutamate at post-synaptic receptors are either ineffective or have serious side-effects. Ca2+ entry blockers have shown disappointing results in clinical trials in patients with acute cerebral infarction. Data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 hours after the ischemic insult. Many such medications have few side-effects and are in clinical use for other indications. This review will summarize inhibitory mechanisms that may be important in cerebral ischemia, and provide experimental evidence for their potential efficacy.

Adenosine↗

PubMed1997

Comparative study of 18 gauge and 20 gauge intravenous catheters during transcranial Doppler ultrasonography with saline solution contrast.

A formal technical protocol has not been established for transcranial Doppler ultrasonography in the detection of venous to arterial shunts; techniques have been adapted from contrast echocardiography. We evaluated the effect of different diameter indwelling intravenous catheters on the detection of right-to-left shunts by transcranial Doppler ultrasonography. Fifteen patients underwent transcranial Doppler sonographic evaluation with saline solution contrast using both 18 gauge and 20 gauge indwelling intravenous catheters. The larger bore intravenous catheter delivered a greater number of signals in a shorter time to the insonated middle cerebral artery. We recommend that a standardized method for transcranial Doppler sonographic contrast studies include an 18 gauge intravenous catheter.

Adult↗