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Biomedical subjects

C Shea

Publications and source records attributed to C Shea.

At least 19 recordsLinked to original sources
PubMed2002

Study of brain uptake and biodistribution of [11C]toluene in non-human primates and mice.

Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain phamacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radio-tracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.

Administration, Inhalation↗
PubMed2001

Evidence that L-deprenyl treatment for one week does not inhibit MAO A or the dopamine transporter in the human brain.

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.

Adult↗
PubMed2001

Species differences in [11C]clorgyline binding in brain.

[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.

Animals↗
PubMed2001

Attention and motor performance: preferences for and advantages of an external focus.

This study examined individuad differences in the preference for and effectiveness of the type of attentional focus for motor learning. In two experiments, participants practicing a balance task (stabilometer) were asked to find out whether focusing on their feet (internal focus) or on two markets in front of their feet (external focus) was more effective. In Experiment 1, participants switched their attentional focus from trial to trial on Day 1 and used their preferred attentional focus on Day 2. In Experiment 2, participants were free to switch their attentional focus any time during 2 days of practice. Retention tests were performed on Day 3. Most participants chose an external focus. Also, they were more effective in retention than participants who preferred an internal focus.

Attention↗
PubMed2000

Evidence that gingko biloba extract does not inhibit MAO A and B in living human brain.

Extracts of Ginkgo biloba have been reported to reversibly inhibit both monoamine oxidase (MAO) A and B in rat brain in vitro leading to speculation that MAO inhibition may contribute to some of its central nervous system effects. Here we have used positron emission tomography (PET) to measure the effects of Ginkgo biloba on human brain MAO A and B in 10 subjects treated for 1 month with 120 mg/day of the Ginkgo biloba extract EGb 761, using [11C]clorgyline and [11C]L-deprenyl-D2 to measure MAO A and B respectively. A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambdak3, a model term which is a function of the concentration of catalytically active MAO molecules. Ginkgo biloba administration did not produce significant changes in brain MAO A or MAO B suggesting that mechanisms other than MAO inhibition need to be considered as mediating some of its CNS effects.

Adult↗
PubMed2000

Reproducibility of repeated measures of deuterium substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) binding in the human brain.

The purpose of this study was to assess the reproducibility of repeated positron emission tomography (PET) measures of brain monoamine oxidase B (MAO B) using deuterium-substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) in normal subjects and to validate the method used for estimating the kinetic constants from the irreversible 3-compartment model applied to the tracer binding. Five normal healthy subjects (age range 23-73 years) each received two PET scans with [11C]L-deprenyl-D2. The time interval between scans was 7-27 days. Time-activity data from eight regions of interest and an arterial plasma input function was used to calculate lambda k3, a model term proportional to MAO B, and K1, the plasma to brain transfer constant that is related to blood flow. Linear (LIN) and nonlinear least-squares (NLLSQ) estimation methods were used to calculate the optimum model constants. A comparison of time-activity curves for scan 1 and scan 2 showed that the percent of change for peak uptake varied from -18.5 to 15.0% and that increases and decreases in uptake on scan 2 were associated with increases and decreases in the value of the arterial input of the tracer. Calculation of lambda k3 showed a difference between scan 1 and scan 2 in the global value ranging between -6.97 and 4.5% (average -2.1 +/- 4.7%). The average percent change for eight brain regions for the five subjects was -2.84 +/- 7.07%. Values of lambda k3 for scan 1 and scan 2 were highly correlated (r2 = 0.98; p < 0.0001; slope 0.955). Similarly, values of K1 showed a significant correlation between scan 1 and scan 2 (r2 = 0.61; p < 0.0001; slope 0.638) though the values for scan 2 were generally lower than those of scan 1. There was essentially no difference between the values of model constants calculated using the NLLSQ or LIN methods. Regional brain uptake of [11C]L-deprenyl-D2 varied between scan 1 and scan 2, driven by the differences in arterial tracer input. Application of a 3-compartment model to regional time-activity data and arterial input function yielded lambda k3 values for scan 1 and scan 2 with an average difference of -2.84 +/- 7.07%. Linear regression applied to values of lambda k3 from the LIN and NLLSQ methods validated the use of the linear method for calculating lambda k3.

Adult↗
PubMed2000

Endometrial cryoablation with ultrasound visualization in women undergoing hysterectomy.

STUDY OBJECTIVES: To evaluate tissue effects of cryosurgical endometrial ablation in women just before hysterectomy, characterize ultrasound monitoring of freezing, determine the feasibility of a new probe-angling procedure, and assess the safety profile by monitoring serosal surface temperatures. DESIGN: Single arm safety study enrolling ten women at two centers (Canadian Task Force classification II-2). SETTING: Two clinical sites. Patients. Ten women scheduled for hysterectomy. INTERVENTION: Hysterectomy with a new cryosurgical device (First Option, CryoGen, Inc., San Diego, CA) that achieves surface temperatures below -90 inverted exclamation mark C to freeze endometrium. MEASUREMENTS AND MAIN RESULTS: The freeze protocol involved angling the probe toward each cornu. Maximum ice front diameter at the end of the first angled freeze ranged from 24 to 34 mm, and maximum ice ball diameter at the end of the second freeze ranged from 28 to 37 mm. The margin between the advancing ice front and serosal surface was monitored by ultrasound. In all cases the margin was safe and no reduction in serosal surface temperatures occurred. Depth of necrosis ranged from 9 to 12 mm as determined by tetrazolium staining and electron microscopy, and there was no full-thickness myometrial destruction. Total endometrial destruction was achieved. CONCLUSION: Cryosurgical ablation of the endometrium with the First Option system with angled freezes and ultrasound monitoring appears to be feasible and safe given our preliminary data.

Adult↗
PubMed2000

Maintenance of brain monoamine oxidase B inhibition in smokers after overnight cigarette abstinence.

OBJECTIVE: The authors' goal was to replicate a previous finding that smokers have lower brain monoamine oxidase B (MAO-B) levels than comparison nonsmoking subjects and to determine if levels recover after overnight cigarette abstinence. METHOD: Brain MAO-B levels were measured by means of positron emission tomography in six smokers who were scanned twice: 11.3 hours (baseline) and 10 minutes after smoking one cigarette. RESULTS: Average MAO-B levels in smokers in the present study were similar to those found in the previous study and averaged 39% (SD=17) lower than those found in a comparison group of nonsmokers. Brain MAO-B levels did not differ between baseline levels and 10 minutes after smoking. CONCLUSIONS: This study reinforces the need to investigate whether MAO-B inhibition may account for some of the behavioral and epidemiological features of smoking.

Adult↗
PubMed2000

Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria.

OBJECTIVE: To establish specific criteria by which selective serotonin reuptake inhibitor (SSRI) discontinuation syndrome may be identified. DATA SOURCES: MEDLINE and PSYCHLIT databases were searched for case reports published from 1986 to 1997 inclusive, and references of relevant articles were also searched. STUDY SELECTION: Forty-six case reports of symptoms following the discontinuation of fluoxetine, fluvoxamine, paroxetine or sertraline were selected. Three studies of SSRI discontinuation were also reviewed. DATA EXTRACTION: Demographic and treatment information, as well as the timing, duration, number, nature and frequency of dicontinuation symptoms. DATA SYNTHESIS: Paroxetine was most frequently implicated. The drug had been tapered in half of the cases. In some cases, symptom onset began during taper, whereas, in most cases, symptoms began within 1 to 3 days of drug discontinuation. Fifty-three different symptoms were reported, with dizziness being the most common. Other common symptoms were nausea or emesis, fatigue, headache, gait instability and insomnia. Shock-like sensations, paresthesia and visual disturbances were the most rare. Without intervention, symptoms persisted for more than a week in half of the cases. In cases in which the SSRI was restarted, symptoms resolved within 72 hours. In some cases, withdrawal symptoms recurred when the same SSRI was again discontinued. CONCLUSIONS: Findings were used to construct diagnostic criteria for the SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.

Adult↗
PubMed1999

Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers.

Positron emission tomography (PET) studies with [11C]L-deprenyl-D2 have shown that brain monoamine oxidase (MAO) B is 40% lower in smokers than in non-smokers. Here we investigated whether MAO B inhibition can be detected after smoking a single cigarette. Eight normal healthy non-smokers (35 +/- 11 years) received two PET studies 2 h apart with [11C]L-deprenyl-D2, one at baseline and the second 5-10 min after the subject had smoked a single cigarette. Plasma nicotine and expired carbon monoxide (CO) were measured prior to smoking and 10 min after smoking completion as an index of tobacco smoke exposure. A three-compartment model was used to calculate lambda k3, a model term which is proportional to MAO B activity and which is derived from the time course of carbon-11 in the brain and the time course of the radiotracer in the plasma and K1, the plasma-to-brain transfer constant (for [11C]L-deprenyl-D2) which is related to brain blood flow. Subjects experienced difficulty inhaling and became dizzy and/or nauseous after smoking. Plasma nicotine averaged 11.6 +/- 5.5 ng/ml and expired CO averaged 8 +/- 10 ppm after smoking. The average lambda k3 and K1 for 11 different brain regions did not differ significantly between baseline and smoking. These results indicate that the reduction in MAO B in smokers probably occurs gradually and requires chronic tobacco smoke exposure.

Adult↗
PubMed1998

An acute dose of nicotine does not inhibit MAO B in baboon brain in vivo.

Tobacco smoke exposure has been shown to inhibit brain and platelet MAO B in animals and in humans. Though the mechanism(s) responsible for MAO B inhibition are not known, studies in rodents have shown that nicotine administration does not inhibit brain MAO B. In this study we investigated whether brain MAO B is also unaffected by nicotine in the living primate. Brain MAO B was measured with positron emission tomography (PET) and deuterium substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) in three baboons at baseline and 5 minutes after the injection of (-)-nicotine (0.3 mg administered intravenously). A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambda k3, which is a function of the concentration of catalytically active MAO B molecules. Nicotine administration did not produce significant changes in either of these parameters. This study in living baboons confirms previous studies in rodents and solidifies the notion that other mechanisms for MAO B inhibition observed in smokers need to be considered.

Animals↗
PubMed1998

Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients.

Dementia with Lewy bodies (DLB) is common. Symptomatic treatment can be difficult. We reviewed nine consecutive patients with DLB (mean age 77.5 [range 67 to 84] years; seven men and two women; mean duration of disease 3.7 [range 1.5 to 8.0] years) who had been treated with donepezil. Each initially received 2.5 to 5 mg per day of donepezil, and was stabilized on 5 mg per day. Donepezil was increased to 10 mg per day in five patients. The mean observation period was 12 (range 8 to 24) weeks. Target symptoms included cognition, hallucinations, parkinsonism, and functional abilities. By both cognitive testing and family reports, cognition improved in seven of nine patients, remained the same in one of nine, and fluctuated in one of nine (mean Mini-Mental State Examination change 4.4 +/- 6.3 points). Function was improved or maintained in six of nine patients and fluctuated in two of nine. Hallucinations initially worsened, then fluctuated in one patient, but improvement in frequency, duration, and content was reported in eight of nine cases. In three of nine patients, treatment with donepezil resulted in worsening of parkinsonism, which in each case responded to levodopa/carbidopa. Treatment of DLB patients with donepezil for 12 weeks most commonly improved hallucinations, and sometimes improved cognition and overall function. Treatment with donepezil was sometimes associated with worse parkinsonism.

Activities of Daily Living↗
PubMed1997

Intravesical dimethyl sulfoxide (DMSO) for interstitial cystitis--a practical approach.

OBJECTIVES: To provide a brief overview of intravesical dimethly sulfoxide (DMSO) therapy for interstitial cystitis and offer a practical approach to patient treatment. METHODS: A review of the literature and a summation of the experience with treatment of > 300 patients with DMSO at the Interstitial Cystitis Clinic, New England Medical Center. RESULTS: DMSO is helpful in a significant number of patients and it has acceptable morbidity and an excellent safety profile. CONCLUSIONS: Intravesical DMSO (singly or in combination) is one of the mainstays in the pharmacologic treatment of interstitial cystitis.

Administration, Intravesical↗
PubMed1996

Brain monoamine oxidase A inhibition in cigarette smokers.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term lambda k3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean lambda k3 values for the whole brain were 0.18 +/- 0.04 and 0.13 +/- 0.03 ccbrain (mlplasma)-1 min-1 for nonsmokers and smokers, respectively; P < 0.0003). Tranyl-cypromine treatment reduced lambda k3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.

Adolescent↗