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Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 183-192). Available also in a digital version from Dissertation Abstracts.

Diss. (sammanfattning) Umeå : Univ., 2005. / Härtill 4 uppsatser.

Cerebral haemodynamic status defined as cerebral vasoreactivity to carbon dioxide and pressure autoregulatory response, have been shown to be affected after traumatic brain injury (TBI) and correlate with the neurological condition and clinical outcome. Therefore, it is important to have a reliable method to determine the cerebral haemodynamic status in brain-injured patients. Blood flow velocity (BFV) measurement by transcranial Doppler ultrasonography (TCD) has been shown to give accurate indication of changes in cerebral blood flow (CBF). Transient hyperaemic response (THR) test with TCD measurement to assess the BFV response of middle cerebral artery to a brief compression of the ipsilateral carotid artery, provides a simple method for repeated assessment of the cerebrovascular autoregulatory reserve in brain injured patients. However, the test has not been validated systematically against classical assessment tests using TCD and gold standard CBF measurement. / The aims of this thesis are (1) to validate the non-invasive TCD and its haemodynamic tests with a more involved gold standard CBF measurement using stable xenon-enhanced computerized tomography. (2) To correlate the cerebral haemodynamic abnormalities with the patterns of neurochemical disturbance detected by intracerebral microdialysis. (3) To investigate the possibility to reverse or minimized the cerebral haemodynamic abnormalities and metabolic derangement by treatment. (Abstract shortened by UMI.) / The goal of intensive care management for TBI is to provide them with a favourable physiological and metabolic environment for recovery of the injured-compromised cells. The development of clinical intracerebral microdialysis has enabled documentation of the metabolic derangement that provides more understanding of the mechanism of brain damage. Continuous measurement of both neurochemical and physiological parameters including CPP defined as mean arterial blood pressure (ABP) minus intracranial pressure, BFV and CBF, enables study of the relationship between metabolic events and physiologic changes. Clinical management of patients with TBI has emphasized on maintaining an optimal cerebral perfusion pressure (CPP). This critical CPP can then be defined by TCD, CBF as well as the metabolic measurements. / Ng Chi Ping. / "June 2005." / Adviser: Wai-sang Poon. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0122. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005 / Includes bibliographical references (p. 147-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

States of abnormal pain induced by injuries to peripheral nerves share common features with opioid antinociceptive tolerance including mechanical and thermal hypersensitivity. Sustained administration of morphine in humans and in animals induces a state of abnormal pain (i.e., hyperalgesia) and may be associated with the development opioid antinociceptive tolerance. Persistent neuropathic pain states and opioid induced abnormal pain require descending facilitation arising from the rostral ventromedial medulla (RVM). Cholecystokinin (CCK), a pronociceptive peptide, may be up-regulated following opioid treatment and nerve injury in the brain and spinal cord. Therefore, it is hypothesized that CCK in the RVM may be up-regulated by sustained opioid administration and my consequently drive descending pain facilitatory mechanisms to produce hypersensitivity and antinociceptive tolerance.Acute systemic morphine administration produced a potentiation of CCK release in the RVM as measured using microdialysis techniques. Sustained systemic morphine administration sufficient to produce thermal and tactile hypersensitivity resulted in a significant increase in basal CCK release in the RVM. Spinal nerve ligation (SNL) produces similar behavioral hypersensitivity. CCK levels in the RVM also increased following SNL. These findings suggest that endogenous CCK released in the RVM drives descending facilitatory pathways to produce hypersensitivity following sustained morphine administration and neuropathic pain.Disease states such as neuropathic pain offer special challenges in drug design due to system changes that accompany these diseases. Here, novel peptides with agonist binding affinity and bioactivity at δ and μ opioid receptors and simultaneous antagonist activity at CCK receptors have been developed. Using in vivo behavioral measures, it was shown that intrathecal (i.th.) administration of these compounds suppresses the thermal and tactile hypersensitivity caused by spinal nerve ligation (SNL).These studies support the hypothesis that endogenous CCK drives descending pain facilitatory pathways and that bi-functional compounds that act as opioid agonists and CCK antagonists are effective for the treatment of neuropathic pain.

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The aim of this thesis was to develop and evaluate a new way of monitoring blood flow with microdialysis. A thin catheter consisting of a semipermeable membrane is implanted in the tissue being studied. The catheter is perfused by a solution that closely resembles interstitial fluid, and small water-soluble substances are allowed to diffuse passively through the pores of the membrane with the aim at reaching equilibrium with the surrounding tissue.  The minimally invasive character of microdialysis, and its ability to sample from the organ being studied, make microdialysis attractive in most research settings as well as for clinical surveillance. It has, however, become increasingly evident that microdialysis under conditions of non-equilibrium - for example, fluctuating regional blood flow, will alter the results gained. We have therefore aimed to explore the possibilities of developing a new marker of blood flow that will yield information about changes in blood flow that occur in the area of the microdialysis catheter itself. We hypothesised that the changes in the diffusion of exogenous urea could be used as markers of changes in tissue blood flow. The theoretical basis for this approach is that the mass transfer of urea will increase across the dialysis membrane secondary to increased blood flow. As removal of urea from the vicinity of the dialysis membrane increases with increased blood flow, the concentration gradient of urea between the perfusate and tissue will also increase. This in turn will result in a greater loss of urea from the perfusate. The changes noted in retrieval of urea from dialysate by the system are therefore thought to be inversely related to changes in blood flow. We tested our hypothesis in two species of animal (rat and pig) and in man, and in three organ systems (muscle, liver, and skin), and present four papers that indicate that the urea clearance technique provides reliable and reproducible results. The technique was evaluated against conventional metabolic markers (lactate and glucose), the ethanol clearance technique (microdialysis), laser Doppler perfusion imaging (LDPI), and polarisation light spectroscopy (TiVi). We present evidence that the urea clearance technique can be used to assess blood flow in the organs studied reliably and reproducibly with microdialysis. The microdialysis technique is minimally invasive and safe for the recipient, and catheters can easily be implanted during operation to monitor organs at risk. Urea is easily analysed as a standard assay among other “basic” metabolic markers (in a standard microdialysis kit) and has favourable characteristics with a standardised measurement system that is routinely used for monitoring metabolites in the clinic. The technique is also effective when used at lower perfusate flow rates (<1 μl/minute), which is advantageous as the recovery of metabolic markers increases at low perfusate flow rates.

Stimulant medications such as D-amphetamine, mixed-salts (75% D- and25% L-) amphetamine; Adderall®, and methylphenidate are first-line treatmentsfor Attention-Deficit/Hyperactivity Disorder (ADHD). In vivo studies havepredominantly focused on these stimulants in the context of drug abuse, andtheir therapeutic mechanistic properties are only theoretical. Previously, in vivotechniques have been limited by poor temporal and spatial resolution, andcharacterizations of these medications in rodent models have not been possibleat low, clinically relevant levels. In order to address these issues, our laboratoryused in vivo high speed chronoamperometric microelectrodes to characterize theeffects of local applications of D-amphetamine, L-amphetamine, D,Lamphetamine,and Adderall® at low levels in the striatum and nucleusaccumbens of 3-6 month old, male Fischer 344 (F344) rats. Our results showedsignificant differences between the faster kinetics of dopamine (DA) releasesignals caused by D,L-amphetamine and the slower kinetics resulting from Damphetamine.These data support that resulting DA concentrations evoked by DandD,L-amphetamine are correlated with the amount of D-amphetamine in thedrug and only the time courses of the signals are affected by L-amphetamine.Additionally, locally applied D- and L-amphetamine caused DA release signalswith similar amplitudes or concentrations of evoked DA; however, the signalswere significantly faster for L-amphetamine. Adderall® caused significantlygreater DA release that lasted over a longer time course compared to DA releasecaused by D- or D,L-amphetamine. These data support the hypothesis thatamphetamine isomers, alone or in combination, interact differently with the DAtransporter (DAT) to subsequently cause reversal of transport of DA out ofpresynaptic membranes of DA neuronal projections. Finally, reversemicrodialysis studies were carried out to assess low levels of D-amphetamine,Adderall® (75% D-, 25% L-amphetamine), methylphenidate, and a new mixedsaltsamphetamine that we referred to as Reverse Adderall (75% L-, 25% Damphetamine)in the striatum of F344 rats. These data reveal a stimulantconcentration-response curve for DA with double plateaus that may be explainedby dual mechanisms of reverse transport of DA through the DAT. In addition,reverse microdialysis of methylphenidate caused DA overflow similar to theeffects of the other stimulants.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Göteborg : Univ. , 2006. / Härtill 4 uppsatser.