Biomedical subjects

Andrea L Malizia

Publications and source records attributed to Andrea L Malizia.

6 recordsLinked to original sources

PubMed2006

The role of emission tomography in pharmacokinetic and pharmacodynamic studies in clinical psychopharmacology.

Position Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) can be used for both pharmacokinetic and pharmacodynamic measures in vivo in man. As such they have a wide range of applications including description of neurochemical changes in disease, occupancy, brain effects of medicines and discovery and validation of biomarkers. The power of these tools is in their chemical specificity and sensitivity, and in the ability to describe processes in vivo, thus documenting the effects of genetic and environmental interactions. The future of these technologies is dependent on an investment in bringing out and validating new radiotracers.

Brain↗

PubMed2004

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

Adult↗

PubMed2004

Structural and functional brain changes in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a highly disabling condition that is associated with intrusive recollections of a traumatic event, hyperarousal, avoidance of clues associated with the trauma, and psychological numbing. The field of neuroimaging has made tremendous advances in the past decade and has contributed greatly to our understanding of the physiology of fear and the pathophysiology of PTSD. Neuroimaging studies have demonstrated significant neurobiologic changes in PTSD. There appear to be 3 areas of the brain that are different in patients with PTSD compared with those in control subjects: the hippocampus, the amygdala, and the medial frontal cortex. The amygdala appears to be hyperreactive to trauma-related stimuli. The hallmark symptoms of PTSD, including exaggerated startle response and flashbacks, may be related to a failure of higher brain regions (i.e., the hippocampus and the medial frontal cortex) to dampen the exaggerated symptoms of arousal and distress that are mediated through the amygdala in response to reminders of the traumatic event. The findings of structural and functional neuroimaging studies of PTSD are reviewed as they relate to our current understanding of the pathophysiology of this disorder.

Amygdala↗

PubMed2003

Naloxone displacement at opioid receptor sites measured in vivo in the human brain.

We report the use of a sensitive non-tomographic positron detecting system to measure the dose-response curve of naloxone in human brain. [11C]Diprenorphine was administered to normal volunteers in tracer amounts and, 30 min later, various bolus doses of naloxone were given (1.5-160 microg/kg) intravenously and change in [11C]diprenorphine binding monitored over the next 30 min. We found that this method produced results consistent with existing data. It was observed that approximately 13 microg/kg of naloxone ( approximately 1 mg in an 80 kg man) was required to produce an estimated 50% receptor occupation. This is consistent with the clinical dose of naloxone used to reverse opiate overdose (0.4 mg-1.2 mg).

Binding Sites↗

PubMed2003

Functional connectivity analysis of the neural circuits of opiate craving: "more" rather than "different"?

We investigated the functional connectivity of brain regions activated during opiate craving. Previously we used recorded autobiographical scripts to induce opiate craving in 12 abstinent opiate-dependent subjects while they were undergoing positron emission tomography (PET) scanning using the regional cerebral blood flow (rCBF) tracer H2 15O. SPM99 was used to examine the connectivity patterns associated with the primary brain regions activated in response to drug-craving memories (anterior cingulate, AC) and correlated with opiate craving (orbitofrontal cortex, OFC). Two separate connectivity patterns were identified associated with the OFC and AC regions. The AC region was associated with activity in the left temporal region. The left OFC region activity correlated with activity in the right OFC, and left parietal and posterior insular regions. There was also a positive association with the hippocampus and brainstem. Both the AC and OFC regions showed a negative association with posterior visual areas. We suggest that the patterns of functional connectivity reflect the ability of drug-related stimuli to activate attentional and memory circuits to a greater degree than non-drug-related stimuli. This argues that neural circuits of dependence and craving are not specific "craving" or "addiction" brain regions but are "normal" circuits activated to a greater degree.

Brain Stem↗

PubMed2002

Receptor binding and drug modulation in anxiety.

Anxiety is an emotion that allows an individual to prepare for, or respond to, changes in the environment. For many people, however, this emotion is expressed inappropriately and impairs their lives causing considerable distress and disability. These disorders cause a great deal of personal distress, result in reduced life expectancy and, in the UK alone, have an estimated cost of approximately pound 5 billion per year. Despite a great deal of research, an adequate account of the mechanisms that underlie these human disorders is still lacking. An understanding of the brain substrates underlying these disorders is likely to provide such adequate explanations, but one of the principal challenges facing the investigators has been the reciprocal mapping of pre-clinical and clinical knowledge. Altogether, the last 10 years have seen a consolidation of imaging techniques. These are now mature in many areas and are likely to provide fundamental contributions in our understanding of human psychopharmacology.

Animals↗