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Biomedical subjects

D G Grosset

Publications and source records attributed to D G Grosset.

At least 19 recordsLinked to original sources
PubMed1995

Clinical pharmacology of CNS 1102 in volunteers.

The high affinity noncompetitive N-methyl-D-aspartate receptor antagonist CNS 1102 (aptiganel hydrochloride, Cambridge NeuroScience, Cambridge, MA.) is neuroprotective in preclinical models of stroke when administered as pretreatment or up to 60 minutes postischemia, and has potential for treatment of acute stroke or traumatic brain injury in man. A total of 55 healthy male subjects have participated in three separate studies to determine the clinical pharmacology of CNS 1102, 43 of whom have received CNS 1102 in doses of up to 100 micrograms/kg. Administration of CNS 1102 has been studied as a 15-minute intravenous infusion, as a 15-minute loading intravenous infusion followed by a 4-hour maintenance infusion, or as a fixed-dose intravenous bolus over 90 seconds. CNS 1102 in normal volunteers is well tolerated in total doses up to 32 micrograms/kg whether as a bolus injection, 15-minute infusion or 4-hour infusion. Central nervous system affects are evident within minutes of administration, implying rapid drug penetration. CNS 1102 has a large and variable volume of distribution (mean +/- standard deviation, 6.2 +/- 1.9 l/kg), variable clearance (115 +/- 77 l/h), and plasma half-life of approximately 4.5 hours. Adjustment of doses by subject weight does not improve variability of these parameters, and fixed doses may thus be administered. CNS 1102 causes dose-dependent elevation of blood pressure, accompanied by clinical evidence of vasoconstriction. Global cerebral blood flow is maintained, whilst middle cerebral artery flow velocity increases. Symptoms of light-headedness, disorientation and paresthesia progress through euphoria, disinhibition, and hallucinations to psychomotor retardation, paranoia and catatonia as total administered dose increases.

Adult↗
PubMed1995

Systemic and cerebral hemodynamic responses to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist CNS 1102.

The excitatory amino acid antagonists are being developed as neuroprotective drugs aimed at limiting ischemic neuronal damage. Their hemodynamic and neurologic side effects are important in assessing safety and tolerability. We studied CNS 1102, a high-affinity noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonist, in normal volunteers. The effects of 2 mg CNS 1102 were assessed in a single-blind, placebo-controlled, fixed-dose, cross-over trial comparing administration by intravenous infusion for 15 min or bolus for 2 min in 8 healthy male subjects. Cerebral hemodynamics were studied with carotid and vertebral duplex ultrasound imaging, common carotid artery walltracking, and middle cerebral artery velocity readings. CNS 1102 administration was associated with light-headedness, mild disorientation, perioral and peripheral paresthesias, and flushing. Mean arterial blood pressure (MAP) increased significantly from baseline 1 h after CNS 1102 administration, with a maximal increase of 17 mm Hg over placebo. Pulse rate was unchanged. Common carotid artery pulsatility decreased by 38.4% [8.3-64.5, 95% confidence interval (CI)] and vertebral pulsatility by 43.8% [11.5-74.1], both p < 0.02. No significant differences were detected for other velocity and flow parameters. Middle cerebral artery mean velocity increased by 4.6 cm/s (1.6-7.8 cm/s) and diastolic velocity by 4.6 cm/s (2.4-7.3 cm/s) (both p < 0.01), but systolic velocity was unchanged. The middle cerebral pulsatility index decreased by 11% (3.8-16.1), p < 0.001. CNS 1102 is well tolerated at a fixed dose of 2 mg in normal volunteers. Cerebral arteriolar constriction is inferred from the ultrasound results.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Ultrasonic evaluation of movement of the diaphragm after acute cerebral infarction.

Respiratory dysfunction is an important complication of acute stroke but its mechanisms are poorly understood. Previous indirect assessments suggest that paralysis of the diaphragm occurs contralateral to the cerebral lesion. Diaphragmatic excursion was studied with real time ultrasound during quiet and deep breathing in 50 patients within 72 hours of acute stroke and 40 controls. During quiet breathing, hemidiaphragmatic movements were not significantly different between right hemispheric stroke, left hemispheric stroke, and controls. During deep inspiration, there was a significant bilateral reduction in hemi-diaphragmatic excursion in patients with stroke, for both right hemispheric stroke and left hemispheric stroke when compared with controls (both P < 0.001). Thus isolated hemidiaphragmatic paresis does not occur but maximal excursion of the diaphragm is reduced bilaterally in patients with acute stroke. This is a likely contributor to the respiratory dysfunction after acute stroke.

Acute Disease↗
PubMed1995

A pilot study of streptokinase for acute cerebral infarction.

We evaluated intravenous streptokinase in the treatment of cerebral infarction. Following neurological assessment and cerebral computed tomography (CT), patients aged 40-80 years with symptoms of anterior circulation acute ischaemic stroke were given 1.5 M units streptokinase or saline placebo in a double-blind randomized study. Twenty patients (10 streptokinase, 10 placebo), 11 males, 9 females, aged 57-79 years, were treated out of 512 consecutive admissions to the acute stroke unit over a 2-year period. Initial CT was normal in 11 (6 placebo, 5 streptokinase) and showed early signs of cerebral infarction in nine (4 placebo, 5 streptokinase). Median times from symptom onset to treatment were 5.2 h (placebo) and 5.8 h (streptokinase). Streptokinase treatment was associated with symptomatic hypotension in one patient. Repeat CT at 72 h demonstrated intracerebral haematoma in two patients and haemorrhagic infarction in one patient in the streptokinase group; the two cases of haematoma formation were associated with neurological deterioration and death. One patient in the placebo group had evidence of haemorrhagic infarction at 72 h. There were three deaths in each treatment group, all within the first 14 days. Patients with acute stroke can be evaluated with CT and treated with streptokinase within 6 h, but the opportunity for treatment is currently limited to few patients. Streptokinase treatment is not without risk, but potential clinical benefit justifies ongoing multicentre randomized trials.

Acute Disease↗
PubMed1995

Transcranial Doppler ultrasound signals associated with prosthetic heart valves: an in vitro study.

The application of transcranial Doppler (TCD) ultrasonography to asymptomatic prosthetic heart valve patients can result in detection of localized bursts of high intensity signals, similar to those caused by the passage of emboli. The origin of these signals is not known. In order to investigate this phenomenon in a simplified, more controllable environment, a TCD machine was used to record flow downstream from mechanical prosthetic heart valves in a mock circulatory loop. The model, which uses a saline solution seeded with silk particles (< 15 micrometers) as the circulatory fluid, recreates the principal hydrodynamic characteristics of the left heart and systemic circulation. Reproducibility of the system was established through repeated testing of a Monostrut valve. Three different mechanical valve types, (Monostrut, Medtronic Hall, St. Jude Medical) were tested over a range of simulated cardiac outputs, and the effect of valve size was investigated with four Omniscience tilting disc valves (21, 23, 25 and 29 mm). Average energy of the reflected Doppler signal was used to quantify the amount of high intensity Doppler signal, QTCD. TCD signals recorded in vitro were visually and aurally similar to those found in prosthetic heart valve patients. All valve types generated exponentially more QTCD with increasing simulated cardiac output. Differences amongst valve types were only significant at higher flow outputs, with the Monostrut valve producing the greatest QTCD. Larger valves consistently generated greater QTCD than smaller valves. In conclusion, TCD signals found in prosthetic heart valve patients can be reproduced, at least qualitatively, using a mock circulatory loop which does not incorporate the formed elements of blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic Valve↗
PubMed1995

Transcranial Doppler ultrasound in commercial air divers: a field study including cases with right-to-left shunting.

Many cases of decompression illness occur in divers using recommended decompression tables. Doppler ultrasound has been used for over 20 yr and has shown the presence of venous bubbles in asymptomatic divers working well within decompression limits. Previous studies have demonstrated an increased prevalence of patent foramen ovale in divers who have suffered neurologic decompression illness. It has been postulated that right-to-left shunting through a patent foramen ovale could allow arterialization of these bubbles, causing symptoms and signs of acute decompression illness and possibly chronic subclinical neurologic impairment. We set out to determine the incidence of bubbles in the cerebral circulation of commercial divers decompressing from air dives. Using transcranial Doppler ultrasound (TCD), the middle cerebral arteries of 17 divers were monitored after surfacing from depths ranging between 3 and 50 m. Peripheral contrast injection with simultaneous transthoracic echocardiography and TCD was used to screen for right-to-left shunting. Right-to-left shunting was detected in four divers by TCD (one at rest, two after a Valsalva maneuver, and one only after coughing); however, echocardiography was positive in only one of these subjects after a Valsalva maneuver (TCD was positive at rest in this subject). Seventy-three TCD recordings were performed in four settings: 41 after underwater decompression, 18 after surface decompression, 10 in the interval between surfacing and entering the decompression chamber, and 4 after a chamber dive. Twenty-three of these recordings were in four subjects with right-to-left shunting; no bubbles were detected in any of these recordings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

On the origin of cerebrovascular microemboli associated with prosthetic heart valves.

Application of transcranial Doppler ultrasonography to asymptomatic prosthetic heart valve patients can result in the detection of transient high intensity signals, similar to those induced by the passage of emboli. However, the origin of these signals is unknown. An in vitro study has been undertaken to investigate the capacity of prosthetic heart valves to generate high intensity Doppler signals in the absence of blood. A pulse duplicator, filled with a seeded saline solution, was used to function prosthetic heart valves under mock-physiological conditions. A Björk-Shiley Monostrut valve was mounted in the aortic port while a tri-leaflet control valve was fixed in the mitral port. At stations upstream and downstream from the Björk-Shiley valve, flow was monitored using pulsed wave Doppler ultrasound (Nicolet TC-2000, 2 MHz probe). The effect of damping the harsh closure of the mechanical valve was investigated by applying a thin layer of soft adhesive tape between the valve occluder and outer ring. For all valve configurations, transient high intensity Doppler signals, characteristic of microemboli and similar to those observed in clinical studies of prosthetic heart valve patients, were detected downstream from the aortic port. The number of microemboli signals did not change significantly between sites at 20 cm and 40 cm downstream from the aortic valve. Damping the Björk-Shiley valve closure greatly reduced (by 80%) the number of microemboli signals detected. It is concluded that Doppler microemboli signals can be generated by prosthetic heart valves while functioning in the absence of the formed elements of blood, and that the number of microemboli signals produced depends upon the rate of energy dissipation at valve closure.

Aortic Valve↗
PubMed1994

Poor accuracy of stroke scoring systems for differential clinical diagnosis of intracranial haemorrhage and infarction.

The differentiation of cerebral infarction and cerebral haemorrhage is the most important first step in the management of acute stroke, because clinical management of the two disorders differs substantially. The Guy's Hospital and Siriraj stroke diagnostic scores were developed to aid clinicians in this decision. We have tested the performance of the two scores on a group of 1059 patients admitted to the acute stroke unit (ASU) at the Western Infirmary, Glasgow, with suspected stroke between May, 1990, and December, 1993. The diagnosis was confirmed as stroke by computed tomography (CT) scanning or necropsy (n = 10) in 991 patients. For each clinical score we subjectively identified the cut-off point that maximised sensitivity to cerebral haemorrhage with the smallest loss of specificity. At its optimum cut-off point the Guy's Hospital score had a sensitivity for the diagnosis of haemorrhage of 70% and specificity of 64%. The corresponding figures for the Siriraj score at its optimum cut-off point were 68% sensitivity and 64% specificity. The overall predictive accuracy of both scores was 64%. The greater complexity of the Guy's Hospital score (thirteen variables included) did not result in substantially superior performance to the Siriraj score (five variables). This validation study suggests that neither score is useful for exclusion of haemorrhage before anticoagulant treatment is initiated or as a diagnostic screening procedure for trials of low-risk treatments such as aspirin. Our findings emphasise the need for routine CT scanning in this setting, since this method remains the most accurate for differentiating between haemorrhage and infarction.

Acute Disease↗
PubMed1994

Prediction of delayed neurological deficit after subarachnoid haemorrhage: a CT blood load and Doppler velocity approach.

The predictive value of cranial computed tomography (CT) blood load and serial transcranial Doppler sonography for the development of delayed ischaemic neurological deficit was assessed in 121 patients following subarachnoid haemorrhage. Of the 121 patients, 81 (67%) had thick layers of blood or haematoma, including intraventricular bleeding. The proportion of patients who developed delayed deficit was higher with increasing amounts of subarachnoid blood on the admission CT (51% of 53 cases in Fisher grade 3; 35% of 33 cases in grade 2; 28% of 7 cases in grade 1, P < 0.01). Doppler velocities obtained from readings at least every 2 days following admission were higher in patients with delayed neurological deficit (peak velocity for grade 3 patients 176 +/- 6 cm/s (mean +/- SE), versus grade 2: 164 +/- 7 cm/s; grade 4 149 +/- 9, both P = 0.04, Mann-Whitney). Peak velocity and maximal 24-h rise tended to be higher within different CT grades in patients with a deficit than in those without; this difference was significant for grade 3 patients (P < 0.01). We conclude that a combined approach with CT and Doppler sonography provides greater predictive value for the development of delayed ischaemic neurological deficit than either test considered independently. The value of Doppler sonography may be greatest for patients with Fisher grade 3 blood, in whom the risk of delayed ischaemia is greatest.

Adult↗
PubMed1994

Subclinical embolism in patients undergoing cardiac valve implantation and coronary artery bypass surgery.

Patients undergoing prosthetic valve insertion and coronary artery bypass surgery were examined with transcranial Doppler ultrasound, recently shown to be capable of detecting continuing subclinical emboli in patients with embolic sources. In 30 patients examined at least 1 year after valve surgery, and in whom warfarinisation was stable within defined limits, 20 of 24 patients (83%) with mechanical valves and 3 of 6 patients (50%) with porcine valves had embolic signals. In a serial preoperative and postoperative study in a further 30 patients, of whom 29 had native or bioprosthetic valves, only the one patient with a previous mechanical mitral valve prosthesis had embolic signals preoperatively. The incidence of embolic signals increased to 9 (30%) on the first postoperative day, and 20 (67%) on day 5. In a similar serial study in 25 patients undergoing coronary bypass surgery, 8 (32%) had preoperative embolic signals, which were explicable by cardiac and/or carotid disease in 6 cases. The embolus signal incidence and count did not increase postoperatively in this group. No embolic signals were found in 15 volunteer controls. The results indicate that prosthetic valves cause continuing microembolisation, detectable by transcranial Doppler; coronary artery bypass cases may have incidental embolic signals which are unaffected by cardiac surgery. This new application of Doppler ultrasound may improve the clinical assessment of embolic risk of new prosthetic valve types and deserves further examination.

Adult↗
PubMed1994

Detection of intracranial emboli in patients with carotid disease.

Transcranial Doppler emboli signal detection has been reported in several patient groups, including patients with symptomatic internal carotid artery stenosis. The potential of this technique in assessing embolic risk and selecting patients for surgery was examined in this study. Selected patients with symptomatic internal carotid artery stenosis underwent combined extracranial and transcranial Doppler study in the Vascular Surgery and Neurovascular Unit. Patients and normal controls were monitored with transcranial Doppler over both middle cerebral arteries. Severity of carotid disease was diagnosed with colour Duplex ultrasound examination or angiography. Selected patients underwent cranial computed tomography and transthoracic echocardiography. Patients undergoing carotid endarterectomy were re-examined one month after surgery. Fifty symptomatic patients, six asymptomatic patients and 30 normal controls were examined. Carotid disease was unilateral in 34 and bilateral in 22 cases. Emboli signals were detected in 94% of patients. The emboli signal count in patients with unilateral carotid stenosis was significantly higher in the middle cerebral artery distal to the stenosed internal carotid compared to the contralateral middle cerebral artery [14 (10-22) versus 2 (0-7) signals per hour, median and 95% confidence intervals, p < 0.001] and in symptomatic compared to asymptomatic cerebral hemispheres [15 (11-21) versus 4 (2-9) signals per hour, p < 0.001]. Emboli were detected in the contralateral middle cerebral artery in 40% of patients with unilateral carotid disease, in 85% of whom an additional embolic source was identified. No emboli signals were detected after carotid endarterectomy distal to the operated internal carotid, or in any of the normal controls. In conclusion, intracranial emboli signals are common in patients with carotid stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers.

1. Non-competitive antagonists at the glutamatergic N-methyl D-aspartate receptor significantly reduce the volume of ischaemic cerebral infarction in animals and are potential agents for the treatment of acute stroke in humans. 2. CNS 1102, a novel non-competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volunteers in a double-blind, placebo-controlled, dose-ranging study. This was the first administration to man. 3. Clinically significant sedation, increased mean arterial pressure and pulse rate were seen at doses of 30 micrograms kg-1 and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 45 micrograms kg-1 and above. 4. Rapid onset of central nervous system effects after administration is in keeping with rapid distribution of CNS 1102 to brain. Steady state volume of distribution was large (444 l) and terminal elimination half-life from plasma was approximately 4 h. 5. Pharmacokinetic properties are favourable for a potential neuroprotective therapy. The maximum tolerated dose for conscious individuals was 30 micrograms kg-1 given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise administered dose with minimal side effects.

Adult↗