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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
71

Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling

Tunblad, Karin January 2004 (has links)
<p>The transport of drugs across the blood-brain barrier (BBB) has been investigated in different species using morphine and morphine-6-glucuronide (M6G) as model compounds. The influence of probenecid on the BBB transport of morphine and M6G was investigated, and the consequences of meningitis and severe brain injury on the concentrations of morphine in the brain were examined. All data were obtained by microdialysis, and data analysis using mathematical models was emphasised.</p><p>Morphine is exposed to active efflux at the BBB in rats, pigs and humans. In addition, the half-life of morphine is longer in the brain than in blood in these species. These interspecies similarities show the predictive potential of the two animal models for the BBB transport of morphine in humans. In the pig the exposure of the brain to morphine was higher in the presence of meningitis than when healthy. This was interpreted as a decrease in the active efflux and an increase in the passive diffusion over the injured BBB. In contrast, there was no significant difference in the concentrations of morphine in the “better” (uninjured) or the “worse” (injured) brain tissue in brain trauma patients. The extent of the transport across the BBB is similar for morphine and M6G. However, co-administration of probenecid only increased the brain concentrations of morphine, demonstrating that morphine and M6G are substrates for different efflux transporters at the BBB. An integrated model for the analysis of data obtained by microdialysis was developed. This model makes fewer assumptions about the recovery, the protein binding and the time of the dialysate observation than a previous model and traditional non-compartmental analysis and should, therefore, yield more reliable parameter estimates.</p><p>Knowledge of the consequences of efflux transporters and disease on the brain concentrations of a drug can be useful for individualising the dosing regimen in patients. </p>
72

Role of the Blood-Brain Barrier in Stereoselective Distribution and Delay in H<sub>1</sub> Receptor Occupancy of Cetirizine in the Guinea Pig Brain

Gupta, Anubha January 2006 (has links)
<p>Cetirizine, an H<sub>1</sub>-antihistamine, is prescribed for allergic disorders. It exists as a racemic mixture, with levocetirizine being the active enantiomer. The central nervous system side-effects of H<sub>1</sub>-antihistamines are caused by their penetration into the brain. In this thesis the plasma pharmacokinetics, transport across the blood-brain barrier (BBB) and H<sub>1</sub> receptor occupancy of cetirizine enantiomers was investigated <i>in vivo</i> in guinea pigs. The transport across the BBB was quantified using the microdialysis technique. Stereoselective brain distribution was investigated by measuring both unbound and total concentrations in plasma and brain. The time aspects of the H<sub>1</sub> receptor occupancy of levocetirizine was studied in the brain and the periphery.</p><p>The plasma pharmacokinetics of cetirizine was stereoselective with clearance and volume of distribution of levocetirizine being approximately half that of dextrocetirizine. This was mainly due to the differences in plasma protein binding of the enantiomers. The stereoselectivity in brain distribution indicated by the partition coefficient K<sub>p</sub> (total AUC ratio brain to plasma) was caused by stereoselective plasma protein binding. The transport across the BBB measured in this thesis by the unbound partition coefficient K<sub>p,uu</sub> (unbound AUC ratio brain to plasma) was the same for the two enantiomers. Binding within the brain was also not significantly different. The H<sub>1</sub> receptor occupancy of levocetirizine in brain lagged behind the plasma concentrations whereas it was not delayed with respect to the brain concentrations. This indicates that the delayed brain H<sub>1</sub> receptor occupancy of levocetirizine is caused by a slow transport across the BBB.</p><p>In summary, the results of this thesis emphasize the importance of measuring both the unbound and total concentrations in blood and brain to characterize stereoselective brain distribution. The thesis also emphasize the importance of taking local brain pharmacokinetics into consideration in understanding pharmacokinetic-pharmacodynamic relationships of drugs with central activity.</p>
73

Intracranial Compliance and Secondary Brain Damage. Experimental and Clinical Studies in Traumatic Head Injury

Salci, Konstantin January 2006 (has links)
<p>Traumatic brain injury (TBI) renders the brain more vulnerable to secondary insults. The increased vulnerability can probably be explained by a combination of disturbances in hemodynamics, metabolism and craniospinal dynamics. Reduced ability to compensate for added intracranial volume, i.e. reduced intracranial compliance (IC), is one possible mechanism. The <i>aim</i> of this thesis was to study the role of IC on the effect of secondary insults after TBI. </p><p>A rat TBI model was developed where IC could be altered without causing pathological increases in intracranial pressure (ICP). Reduction of IC was made by placing rubber film between the dura mater and bilateral bone flaps. A reduction of IC in terms of reduced Pressure Volume Index was confirmed. Microdialysis (MD) of extracellular fluid was used to monitor neurochemical changes. Reduced IC after TBI proved to increase the vulnerability of the brain to secondary intracranial volume insults according to neurochemical microdialysis markers. Reduced IC or intracranial volume insults alone did not cause any metabolic changes as compared to controls. Moderate posttraumatic hypotension (50mmHg for 30 min) induced 2 hrs after TBI, did not aggravate posttraumatic extracellular neurochemical changes significantly, irrespective of the level of IC. Although controversial, a mild to moderate hypotensive insult after initial posttraumatic stabilization may not be as detrimental as earlier believed.</p><p>The Spiegelberg Compliance Monitor and MD were simultaneously used in 10 TBI patients to get an impression of the clinical value of IC monitoring and the relationship between IC, temperature and MD Lactate/Pyruvate ratio. IC and MD could be monitored simultaneously in TBI patients. Higher L/P ratios were seen when IC was low. Patients with induced coma treatment had significantly higher average L/P ratios, possibly due to their poorer neurological condition. An indication was also found that in TBI patients with high temperatures, L/P ratio rose as IC decreased, but in patients with low temperature there was no effect of IC on L/P ratio. These data suggest the importance of avoiding hyperthermia in TBI patients, especially in patients with low or decreased IC (monitored or anticipated).</p>
74

Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport

Boström, Emma January 2007 (has links)
<p>The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs.</p><p>Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a K<sub>p,uu</sub> of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the K<sub>p,uu</sub> of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM.</p><p>In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.</p>
75

Methodological aspects on microdialysis sampling and measurements

Abrahamsson, Pernilla January 2010 (has links)
Background:     The microdialysis (MD) technique is widely spread and used both experi­mentally and in clinical practice. The MD technique allows continuous collection of small molecules such as glucose, lactate, pyruvate and glycerol. Samples are often analysed using the CMA 600 analyser, an enzymatic and colorimetric analyser.  Data evaluating the performance of the CMA 600 analysis system and associated sample han­dling are sparse. The aim of this work was to identify sources of variability related to han­dling of microdialysis samples and sources of error associated with use of the CMA 600 analyser. Further, to develop and compare different application techniques of the micro­dialysis probes both within an organ and on the surface of an organ.  Material and Methods:  Papers I and II are mainly in vitro studies with the exception of the No Net Flux calibration method in paper I where a pig model (n=7) was used to exam­ine the true concen­tration of glucose and urea in subcutaneous tissue. Flow rate, sampling time, vial and caps material and performance of the analyser device (CMA 600) were examined. In papers III and IV normoventilated anaesthetised pigs (n=33) were used. In paper III, heart ischemia was used as intervention to compare microdialysis measurements in the myocardium with corresponding measurements on the heart surface. In paper IV, microdialysis measurements in the liver parenchyma were compared with measurements on the liver surface in associa­tion with induced liver ischemia. All animal studies were approved by the Animal Experi­mental Ethics Committee at Umeå University Sweden. Results:  In paper I we succeeded to measure true concentrations of glucose (4.4 mmol/L) and Urea (4.1 mmol/L) in subcutaneous tissue. Paper II showed that for a batch analyse of 24 samples it is preferred to store microdialysis samples in glass vials with crimp caps. For reliable results, samples should be centrifuged before analysis. Paper III showed a new application area for microdialysis sampling from the heart, i.e. surface sampling. The sur­face probe and myocardial probe (in the myocardium) showed a similar pattern for glucose, lactate and glycerol during baseline, short ischemic and long ischemic interventions. In paper IV, a similar pattern was observed as in paper III, i.e. data obtained from the probe on the liver surface showed no differences compared with data from the probe in liver paren­chyma for glucose, lactate and glycerol concentrations during baseline, ischemic and reperfusion interven­tions. Conclusion:  The MD technique is adequate for local metabolic monitoring, but requires methodological considerations before starting a new experimental serie. It is important to consider factors such as flow rate, sampling time and handling of samples in association with the analysis device chosen. The main finding in this thesis is that analyses of glucose, lactate and glycerol in samples from the heart surface and liver surface reflect concentra­tions sampled from the myocardium and liver parenchyma, respectively.
76

Cerebral ischemia studied with positron emission tomography and microdialysis

Frykholm, Peter January 2002 (has links)
Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes. Early changes in cerebral blood flow (CBF) and metabolism (CMRO2) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO2 was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.
77

Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling

Tunblad, Karin January 2004 (has links)
The transport of drugs across the blood-brain barrier (BBB) has been investigated in different species using morphine and morphine-6-glucuronide (M6G) as model compounds. The influence of probenecid on the BBB transport of morphine and M6G was investigated, and the consequences of meningitis and severe brain injury on the concentrations of morphine in the brain were examined. All data were obtained by microdialysis, and data analysis using mathematical models was emphasised. Morphine is exposed to active efflux at the BBB in rats, pigs and humans. In addition, the half-life of morphine is longer in the brain than in blood in these species. These interspecies similarities show the predictive potential of the two animal models for the BBB transport of morphine in humans. In the pig the exposure of the brain to morphine was higher in the presence of meningitis than when healthy. This was interpreted as a decrease in the active efflux and an increase in the passive diffusion over the injured BBB. In contrast, there was no significant difference in the concentrations of morphine in the “better” (uninjured) or the “worse” (injured) brain tissue in brain trauma patients. The extent of the transport across the BBB is similar for morphine and M6G. However, co-administration of probenecid only increased the brain concentrations of morphine, demonstrating that morphine and M6G are substrates for different efflux transporters at the BBB. An integrated model for the analysis of data obtained by microdialysis was developed. This model makes fewer assumptions about the recovery, the protein binding and the time of the dialysate observation than a previous model and traditional non-compartmental analysis and should, therefore, yield more reliable parameter estimates. Knowledge of the consequences of efflux transporters and disease on the brain concentrations of a drug can be useful for individualising the dosing regimen in patients.
78

Role of the Blood-Brain Barrier in Stereoselective Distribution and Delay in H1 Receptor Occupancy of Cetirizine in the Guinea Pig Brain

Gupta, Anubha January 2006 (has links)
Cetirizine, an H1-antihistamine, is prescribed for allergic disorders. It exists as a racemic mixture, with levocetirizine being the active enantiomer. The central nervous system side-effects of H1-antihistamines are caused by their penetration into the brain. In this thesis the plasma pharmacokinetics, transport across the blood-brain barrier (BBB) and H1 receptor occupancy of cetirizine enantiomers was investigated in vivo in guinea pigs. The transport across the BBB was quantified using the microdialysis technique. Stereoselective brain distribution was investigated by measuring both unbound and total concentrations in plasma and brain. The time aspects of the H1 receptor occupancy of levocetirizine was studied in the brain and the periphery. The plasma pharmacokinetics of cetirizine was stereoselective with clearance and volume of distribution of levocetirizine being approximately half that of dextrocetirizine. This was mainly due to the differences in plasma protein binding of the enantiomers. The stereoselectivity in brain distribution indicated by the partition coefficient Kp (total AUC ratio brain to plasma) was caused by stereoselective plasma protein binding. The transport across the BBB measured in this thesis by the unbound partition coefficient Kp,uu (unbound AUC ratio brain to plasma) was the same for the two enantiomers. Binding within the brain was also not significantly different. The H1 receptor occupancy of levocetirizine in brain lagged behind the plasma concentrations whereas it was not delayed with respect to the brain concentrations. This indicates that the delayed brain H1 receptor occupancy of levocetirizine is caused by a slow transport across the BBB. In summary, the results of this thesis emphasize the importance of measuring both the unbound and total concentrations in blood and brain to characterize stereoselective brain distribution. The thesis also emphasize the importance of taking local brain pharmacokinetics into consideration in understanding pharmacokinetic-pharmacodynamic relationships of drugs with central activity.
79

Intracranial Compliance and Secondary Brain Damage. Experimental and Clinical Studies in Traumatic Head Injury

Salci, Konstantin January 2006 (has links)
Traumatic brain injury (TBI) renders the brain more vulnerable to secondary insults. The increased vulnerability can probably be explained by a combination of disturbances in hemodynamics, metabolism and craniospinal dynamics. Reduced ability to compensate for added intracranial volume, i.e. reduced intracranial compliance (IC), is one possible mechanism. The aim of this thesis was to study the role of IC on the effect of secondary insults after TBI. A rat TBI model was developed where IC could be altered without causing pathological increases in intracranial pressure (ICP). Reduction of IC was made by placing rubber film between the dura mater and bilateral bone flaps. A reduction of IC in terms of reduced Pressure Volume Index was confirmed. Microdialysis (MD) of extracellular fluid was used to monitor neurochemical changes. Reduced IC after TBI proved to increase the vulnerability of the brain to secondary intracranial volume insults according to neurochemical microdialysis markers. Reduced IC or intracranial volume insults alone did not cause any metabolic changes as compared to controls. Moderate posttraumatic hypotension (50mmHg for 30 min) induced 2 hrs after TBI, did not aggravate posttraumatic extracellular neurochemical changes significantly, irrespective of the level of IC. Although controversial, a mild to moderate hypotensive insult after initial posttraumatic stabilization may not be as detrimental as earlier believed. The Spiegelberg Compliance Monitor and MD were simultaneously used in 10 TBI patients to get an impression of the clinical value of IC monitoring and the relationship between IC, temperature and MD Lactate/Pyruvate ratio. IC and MD could be monitored simultaneously in TBI patients. Higher L/P ratios were seen when IC was low. Patients with induced coma treatment had significantly higher average L/P ratios, possibly due to their poorer neurological condition. An indication was also found that in TBI patients with high temperatures, L/P ratio rose as IC decreased, but in patients with low temperature there was no effect of IC on L/P ratio. These data suggest the importance of avoiding hyperthermia in TBI patients, especially in patients with low or decreased IC (monitored or anticipated).
80

Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport

Boström, Emma January 2007 (has links)
The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs. Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a Kp,uu of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the Kp,uu of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM. In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.

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