Biomedical subjects

S C Fagan

Publications and source records attributed to S C Fagan.

At least 37 records · Page 2Linked to original sources

PubMed1995

Neurobehavioral and physiologic effects of trifluoromethane in humans.

Nuclear magnetic resonance (NMR) imaging shows promise in the measurement of human cerebral blood flow (CBF) in that nonradioactive indicators may be used. Our earlier investigations with trifluoromethane (FC-23) gas have shown that this compound can be used to safely and effectively measure CBF in anesthetized animal models. In this Phase I dose-escalation study we set out to determine the maximal tolerated concentration (MTC) of FC-23 in normal healthy male volunteers and to assess its feasibility as an NMR indicator. Five subjects were exposed in a blinded fashion to escalating concentrations of FC-23 between 10% and 60%, randomly interleaved with exposures to both room air and 40% nitrous oxide. On each study day, the subjects breathed the test gas for eight pulses of 3 min each with 2-min clearance periods between the pulses. The subjects underwent intensive physiologic and neurobehavioral monitoring throughout the study period. The first subject experienced an anesthetic response to 60% FC-23, and the second subject experienced "discomfort" and requested discontinuation at the initiation of 40% FC-23. The MTC was subsequently determined to be 30% FC-23 (all subjects tolerated the gas), although a small (37.6 vs. 40.5) but statistically significant retention of carbon dioxide was found (p = .003). When one subject received 30% FC-23 during an NMR imaging study, a pronounced anesthetic effect with intolerable hyperacusis was demonstrated. Human studies of FC-23 have been discontinued in our laboratory.

Administration, Inhalation↗

PubMed1995

Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy.

We evaluated the ability of monoclonal antibodies directed against leukocyte adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], CD18) to enhance the efficacy of thrombolysis in a rabbit cerebral embolism stroke model. Both tissue-type plasminogen activator (tPA) and anti-CD18 (alpha-CD18) monoclonal antibody administered 5 minutes after embolization increased the quantity of clots required to produce neurologic damage, although the combination was no more effective than either substance alone. Neither alpha-CD18 nor anti-ICAM-1 (alpha-ICAM-1) improved neurologic outcome at postischemic delays of 15 or 30 minutes. However, the combination of alpha-ICAM-1 (15 minutes after embolization) and tPA (2 hours after embolization) significantly improved neurologic outcome even though neither substance was effective alone at these postembolization delays. These findings suggest that prevention of leukocyte adhesion increases the postischemic duration at which thrombolytic therapy remains effective.

Animals↗

PubMed1994

Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons.

The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 microgram/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%.

Administration, Inhalation↗

PubMed1994

Safety of combination aspirin and anticoagulation in acute ischemic stroke.

OBJECTIVE: To assess the risk of bleeding complications in patients treated with combination aspirin and heparin for cerebral ischemia. DESIGN: A retrospective, cohort study. SETTING: A large urban teaching hospital. PATIENTS: One hundred charts of stroke patients who had received anticoagulation with or without aspirin therapy were identified from the Stroke Data Bank. Bleeding rates were compared between the two groups. RESULTS: Forty-two patients who had received heparin and/or warfarin in combination with aspirin were compared with 33 patients who had received anticoagulation alone. The mean duration of anticoagulant therapy was 8.0 and 8.4 days, respectively. Bleeding rates were not different between the two groups: 23.8 percent (10/42) (p = 0.78) and 24.2 percent (8/33), respectively. Although the bleeding rate was substantial, there was only one major bleed (severe epistaxis) occurring in a patient receiving anticoagulation only. No patient had an intracerebral hemorrhage. CONCLUSIONS: Our data suggest that combination antithrombotic therapy is safe in a controlled, inpatient setting.

Acute Disease↗

PubMed1993

Labetalol: response and safety in critically ill hemorrhagic stroke patients.

OBJECTIVE: To observe and characterize the blood pressure (BP)-lowering and adverse hemodynamic and/or central nervous system effects of intravenous bolus doses of labetalol in hemorrhagic stroke patients. DESIGN: Observational, prospective, pilot survey conducted over an eight-week period. SETTING: Surgical intensive care unit. PARTICIPANTS: Patients admitted with an intracerebral or subarachnoid hemorrhage. MAIN OUTCOME PARAMETERS: Absolute decline in systolic BP (SBP) and diastolic BP (DBP), time to peak reduction in SBP and DBP, and adverse hemodynamic and mental status changes. RESULTS: Labetalol at doses between 5 and 25 mg lowered SBP by 6-19 percent (baseline 152-184 mm Hg) and DBP by 3-26 percent (baseline 50-99 mm Hg). Adverse hemodynamic or mental status changes were not detected following labetalol administration. CONCLUSIONS: Small (< or = 25 mg) intravenous bolus doses of labetalol produce mild decreases in BP in hemorrhagic stroke patients.

Adult↗

PubMed1992

Transcranial Doppler to evaluate the effects of antihypertensive medication on cerebral blood flow velocity.

The effect of oral nifedipine on cerebral blood flow velocity was studied in six elderly hypertensive patients using transcranial Doppler. Serial measurements of blood pressure (BP), middle cerebral artery (MCA) flow velocity and nifedipine serum concentrations were obtained over an 8-hour period. The authors found a significant inverse relationship between MCA velocities and nifedipine concentrations, independent of BP changes. These results are consistent with a direct vasodilatory effect of nifedipine on cerebral vessels and support the use of TCD in pharmacodynamic investigations of the cerebral vasculature.

Aged↗

PubMed1992

"Brain attack": an indication for thrombolysis?

OBJECTIVE: The primary objective of this article is to introduce the reader to the use of thrombolytics in the acute treatment of ischemic stroke. Theory and experimental evidence to support this approach are emphasized in addition to potential adverse effects of thrombolysis. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, including reviews. STUDY SELECTION: Studies were selected for detailed review if they involved stroke patients and addressed possible toxicities of therapy. Any abstracts concerning ongoing clinical trials also were reviewed. DATA EXTRACTION: Data from animal investigations using tissue plasminogen activator for the acute treatment of several models of cerebral ischemia were used to support the importance of early treatment (within six hours of symptom onset). Also, studies performed in animal models of stroke revealed that thrombolysis could be accomplished safely in acute ischemic stroke. All human studies published to data are anecdotal case reports, but point to the safety of thrombolysis if administered early. Reviews of ongoing multicenter trials are taken from published abstracts and proceedings. DATA SYNTHESIS: Thrombolysis holds promise as a hyperacute therapy for acute stroke; however, the risk of intracerebral hemorrhage remains. Crucial to the success of this and any other therapy for acute stroke is the ability to treat patients within hours of symptom onset. Also, the importance of concomitant medications such as heparin and aspirin has not yet been addressed. CONCLUSIONS: Pharmacists need to be knowledgeable of new treatments of stroke and the risks associated with them. As patient educators, pharmacists can contribute to public awareness by promoting the early recognition of stroke symptoms. As pharmacotherapists, pharmacists need to understand the risks and the important monitoring parameters related to thrombolysis. The results of ongoing multicenter clinical trials are awaited before making a final judgment on the usefulness of thrombolysis in acute ischemic stroke.

Anistreplase↗

PubMed1992

Cerebral blood flow changes with enalapril.

Patients with carotid artery occlusive disease (CAOD) may be at increased risk of iatrogenic cerebral hypoperfusion. Using the 133xenon-inhalation technique, we evaluated the effects of enalapril on regional cerebral blood flow (CBF) in 14 patients with chronic hypertension, 7 with CAOD and 7 without CAOD (no CAOD). Regional CBF and blood pressure were measured before and 60 minutes after a single dose of enalapril. Changes in mean arterial pressure after enalapril were not significantly different between the two groups: CAOD -4.67 +/- 8.7 mm Hg, no CAOD -6.18 +/- 8.2 mm Hg. Changes in mean CBF after enalapril were also not statistically different: CAOD -1.0 +/- 3.9, no CAOD 1.0 +/- 2.8. In the CAOD group only, however, changes in CBF were significantly related to increasing age (r = -0.9253, p less than 0.01), such that in patients 65 years or older CBF tended to decrease, whereas in younger patients it increased. Elderly patients with CAOD may be at increased risk of iatrogenic cerebral hypoperfusion, and it may be appropriate to evaluate prospectively the effects of antihypertensive medications on CBF.

Age Factors↗

PubMed1991

Nimodipine and bradycardia in acute stroke--drug or disease?

A patient who had suffered an acute ischemic stroke experienced bradycardia while being treated with nimodipine 80 mg tid. This became evident after the initiation of nimodipine and progressed, leading to the drug being discontinued after three days of therapy. The bradycardia resolved shortly after the treatment was terminated and normal heart rate was maintained throughout 23 days of hospitalization and in subsequent outpatient follow-up. Although nimodipine-induced bradycardia is possible, hemispheric cerebral infarction may also cause transient bradyarrhythmias in the acute stroke period. There is a need to monitor the heart rate and rhythm of all acute stroke patients, especially those receiving nimodipine.

Acute Disease↗

PubMed1991

Assessing the effects of antihypertensive medication on cerebral blood flow: demonstration in internal carotid artery occlusion.

Dynamic cerebral blood flow (CBF) studies using acetazolamide or hypercapnia as a vasodilatory challenge have attempted to evaluate intracranial hemodynamics. We report two patients with asymptomatic internal carotid artery occlusion in whom the vasodilatory stimulus was a single oral dose of antihypertensive medication (prazosin hydrochloride or enalapril maleate). In both patients, changes in regional CBF occurred that were larger than those seen in nine normal controls. One patient experienced an improvement in regional CBF with a reduction in probe pair asymmetry. In the other patient, who had bilateral carotid artery disease, a decrease in regional CBF in all 16 probes (mean decrease 12 percent) and an accentuation of the predose asymmetry were observed. Both patients remained asymptomatic throughout the study. Assessing these effects on cerebral circulation may help identify patients at risk for iatrogenic focal cerebral ischemia and provide information regarding the functional status of the cerebral vasculature.

Aged↗

PubMed1991

Accelerated intracranial occlusive disease, oral contraceptives, and cigarette use.

We report clinical and angiographic features of accelerated intracranial occlusive disease resembling moyamoya vasculopathy in five young women who used oral contraceptives (OCs) and smoked cigarettes, but generally had no other obvious risk factors for cerebrovascular disease. Three women had been on OCs for at least 4 years, one woman each had been on OCs for 3 months and for 2 weeks. All five women had smoked cigarettes for at least eight pack-years. Intermittent and progressive multifocal cognitive, visual, motor, or sensory hemispheric symptoms and signs developed in all. All patients developed strokes, four preceded by transient ischemic attacks. Cerebral angiography demonstrated bilateral supraclinoid internal carotid artery stenosis in four patients and proximal posterior cerebral artery stenosis in one. Additional features included rete mirabile, telangiectasias, prominent lenticulostriate collaterals, and multifocal distal cerebral branch occlusions. Three had mild abnormalities of serum fibrinogen, antinuclear antibody, erythrocyte sedimentation rate, or CSF IgG. After discontinuing OCs and reducing cigarette use, four women have not had further strokes over a mean follow-up of approximately 5 years. In certain young women, clinical and angiographic features resembling moyamoya may develop with the use of OCs and cigarettes. We speculate that an immunologically mediated vasculopathy may explain, in part, this unusual cerebrovascular syndrome in otherwise healthy young women.

Adult↗

PubMed1991

Ticlopidine: a new antiplatelet agent for cerebrovascular disease.

Ticlopidine is a new prototype antiplatelet drug chemically unrelated to currently available agents. It causes an alteration in platelet membrane reactivity to a variety of aggregating stimuli and a marked prolongation of bleeding time, the mechanism of which remains unclear. Two major phase III multicenter trials, the ticlopidine-aspirin stroke study (TASS) and the Canadian-American ticlopidine study (CATS) reported that the agent may reduce the occurrence of stroke, myocardial infarction, or vascular death in patients of both sexes who have had recent cerebral ischemia. Ticlopidine has been well tolerated in preliminary studies, with the most commonly described adverse effects being rash and gastrointestinal complaints. The most important adverse effect is neutropenia, which was reported in both TASS and CATS, approximating a frequency of 0.9% and 0.8%, respectively. Ticlopidine holds considerable promise as adjunctive therapy in selected patients.

Cerebrovascular Disorders↗

PubMed1990

Fluorocarbon-23 measure of cat cerebral blood flow by nuclear magnetic resonance.

We employed fluorocarbon-23 (trifluoromethane) as a nuclear magnetic resonance gaseous indicator of cerebral blood flow in seven cats. Pulsed inhalation of this indicator and switching between two coils allowed the acquisition of both an arterial input and a cerebral response function, making possible multicompartmental curve fits to cerebral uptake and clearance data. The brain:blood partition coefficient for trifluoromethane was 0.9 for both gray and white matter. Fast-compartment blood flows were normal and showed appropriate CO2 reactivity. Slow-compartment blood flows did not demonstrate CO2 reactivity, probably because cranial as well as white-matter blood flows were lumped together in the slow compartment. Although cerebral blood flow was stable during administration of 60% trifluoromethane, the compound did prove to be a mild cardiac sensitizer to epinephrine in five cats.

Animals↗

PubMed1990

Acute toxicity of a nuclear magnetic resonance cerebral blood flow indicator in cats.

We studied trifluoromethane as a potential gaseous indicator in nuclear magnetic resonance measurements of cerebral blood flow. We considered the effects of trifluoromethane on cerebral blood flow in 17 cats and on the electroencephalogram and electrocardiogram in nine cats and compared these with the effects of the more toxic compound chlorodifluoromethane in five cats. Inhaled at 60%, trifluoromethane had no effect on cerebral blood flow, the cerebral metabolic rate for oxygen, or oxyhemoglobin content. At 70%, trifluoromethane sensitized the cats' hearts to epinephrine, but to a much lesser degree than 40% chlorodifluoromethane, and produced only moderate changes in cerebral electrical activity as measured by the electroencephalogram. We found trifluoromethane to be suitable for use in animals, but its toxicity needs to be studied further before it can be used in humans for the measurement of cerebral blood flow.

Animals↗

PubMed1989

Nonlinear distribution of atenolol between plasma and cerebrospinal fluid.

Long Evans rats were given atenolol doses ranging from 0.27 to 5.4 mg/kg by intraperitoneal injection Animals were dosed once every 2 hr for a total of five doses. Atenolol concentrations 1 hr after the last dose were measured from simultaneously obtained plasma and cerebrospinal fluid (CSF) samples CSF concentrations of atenolol were not proportional to plasma concentrations. The ratio of CSF/plasma concentrations was higher (0.33) at lower plasma atenolol levels (less than 100 ng/ml) than at the higher atenolol plasma levels (0.05) (P less than 0.001). The relationship between plasma and cerebrospinal fluid atenolol concentrations was best described by the sum of a Michaelis-Menten and linear function. Animals were also given atenolol doses and then subjected to global cerebral ischemia. The relationship of atenolol concentrations from plasma and CSF in these animals was linear, with a constant partition ratio of 0.02. Together these data show that atenolol partitioning between plasma and CSF is nonlinear and possibly an energy-dependent process.

Animals↗

PubMed1989

Hemodynamic vertebrobasilar insufficiency as an adverse effect of antihypertensive therapy.

A 63-year-old white male with a 25-year history of hypertension experienced the onset of intermittent diplopia and gait disturbance 24 hours after a change in antihypertensive medication from atenolol 50 mg/d to enalapril 5 mg bid. Three weeks later, the patient was admitted with a worsening of symptoms. Cerebral arteriography revealed significant bilateral vertebral artery stenosis. Symptoms continued to progress in the hospital, and at the time of posterior circulation revascularization the patient had a persistent bilateral internuclear ophthalmoplegia and right ptosis. The need for a neurovascular workup and adjustment of therapy in patients with antihypertensive-associated cerebral ischemia is discussed.

Antihypertensive Agents↗

PubMed1989

Risk of cerebral hypoperfusion with antihypertensive therapy.

The effective treatment of hypertension is a major factor in the declining incidence of stroke in North America. There are subsets of patients, however, in which antihypertensive therapy may actually cause cerebral ischemia and infarction. Elderly patients and those with malignant hypertension, acute stroke, and occlusive cerebrovascular disease appear to be the populations at greatest risk of iatrogenic stroke. This article reviews the effect of beta-blockers, angiotensin-converting enzyme inhibitors, direct vasodilators, and calcium-channel blockers on cerebral blood flow in various populations. Although many investigations have been performed, it remains difficult to predict the risk of cerebral hypoperfusion due to antihypertensive medication in an individual patient. It is best for practitioners to be aware of the patient populations at risk and treat high blood pressure cautiously in these patients.

Antihypertensive Agents↗

PubMed1988

Effect of nimodipine on blood pressure in acute ischemic stroke in humans.

Nimodipine is currently under investigation for the treatment of acute stroke. Although relatively specific for the cerebrovasculature, acute reductions in blood pressure after a dose may adversely affect neurologic outcome. We studied 29 consecutive acute ischemic stroke patients treated with placebo (n = 9) or either 120 (n = 10) or 240 (n = 10) mg/day of nimodipine. Blood pressure was recorded before and 30 and 60 minutes after a dose for the first 8 days. Ten neurologic physicians were asked to predict the treatment group (placebo or drug) of randomly selected patients based on blood pressure results. Only those patients on 240 mg/day of nimodipine had significant decreases in blood pressure after a dose (p less than 0.001); however, these were minimal (average 10 mm Hg systolic). Only 26 of 48 treatment predictions (54%) were correct. At the studied doses, nimodipine has a minimal effect on blood pressure in the acute stroke period.

Acute Disease↗