| 1. |
- Andersson, Ingemar, 1950-
(författare)
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Rehabilitering vid långvarig smärta
- 2010. - 2
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Ingår i: Smärta och smärtbehandling. - Stockholm : Liber. - 9789147084135 ; , s. 401-409
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Mercke Odeberg, Johanna
(författare)
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Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics. 3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants. Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.
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| 3. |
- Malm-Erjefält, Monika
(författare)
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Assessment of eosinophil degranulation in allergic diseases and experimental models
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In allergic disorders, the eosinophilic granulocytes migrate to affected tissues and release granule proteins with cytotoxic, immunoregulatory, and remodeling-promoting properties. Given that degranulation is reflected by a loss in eosinophil granule density of living cells, or by cell membrane rupture and release of intact granules, these morphological changes may represent a biomarker of the allergic disease. In this thesis, eosinophil structural changes were quantified by transmission electron microscopy. The main objective was to reveal the degranulation status of blood eosinophils during allergic disease, and to determine the eosinophil morphology in common experimental cell- and animal models used for studying eosinophil activation and its pathogenic consequences. First, the eosinophil ultrastructure in common mouse models of allergic airway inflammation was determined and the relevance of these models to human disease was assessed. Both in vivo and in vitro studies revealed that eosinophil degranulation occurred in human but not in mouse eosinophils. Thus, eosinophil-driven pathologic events, reflecting human allergic disease, should not unconditionally be expected in current mouse models. Furthermore, the granule structure of isolated human blood eosinophils was studied and compared with the baseline morphology in blood to examine whether the transformation from an intact eosinophil to a degranulating phenotype can be accurately studied in vitro. The standard procedures of erythrocyte lysis were shown to induce artefactual eosinophil degranulation that also increased the susceptibility of cells to further treatment. Hence, caution should be taken when assessing data and concepts generated in the many previous studies on isolated human blood eosinophils. However, by a novel protocol described herein, eosinophils with minimal granule abnormalities can now be recovered and used for studies on the events regulating the early degranulation. Finally, using a novel approach to assess the ultrastructure of blood eosinophils the degranulation status of circulating eosinophils in a variety of allergic diseases was determined. The results showed that in symptomatic allergic disease, eosinophils retain their granule contents until they have reached their target organ. Hence, eosinophil degranulation in the circulation cannot be used as a biomarker of allergic disease. This finding also suggests that eosinophils in different body compartments have different effector functions and may have distinct susceptibility to therapeutic interventions. Altogether, this thesis underlines the general importance of validating samples and applied methodology when exploring eosinophil degranulation in vitro or in allergic disease.
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| 4. |
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| 5. |
- Andersson, David
(författare)
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Vasodilator actions of EDHF and anandamide
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vasodilator responses to endothelium-derived hyperpolarizing factor (EDHF) and anandamide in isolated arteries were investigated. A combination of the potassium channel blockers charybdotoxin and apamin inhibits EDHF-mediated relaxations. Experiments in which charybdotoxin or apamin was substituted with other potassium channel inhibitors indicated that small- and intermediate-conductance calcium-activated potassium channels contribute to EDHF-mediated relaxations. The possibility that EDHF is potassium ions was also examined. Potassium ions failed to mimic the action of EDHF and no evidence was found for involvement of Na+/K+ ATPase and inwardly rectifying potassium channels in EDHF-mediated responses. In the presence of the Na+/K+ ATPase inhibitor ouabain, acetylcholine and KCl stimulated release of CGRP from sensory nerves. Relaxant responses to the endogenous cannabinoid anandamide were examined in isolated rat and guinea pig arteries. Cannabinoid receptors did not mediate anandamide-induced relaxations. Capsaicin pretreatment, the CGRP receptor antagonist CGRP 8-37 and the vanilloid receptor antagonist capsazepine inhibited anandamide-induced relaxations, indicating that vanilloid receptors on perivascular sensory nerves mediate the effects of anandamide. Anandamide also activated the cloned rat vanilloid receptor (VR1). Effects of anandamide and related vanilloid receptor ligands in guinea-pig mesenteric arteries and main bronchi were compared. Capsaicin was equally potent in the two tissues, while anandamide, resiniferatoxin and olvanil were more potent vasodilators than bronchoconstrictors. Schild plots for capsazepine yielded similar pA2 values in both tissues. Data simulations suggested that the differences in effects of the vanilloid receptor agonists might be explained by differences in agonist efficacies and receptor densities rather than by receptor heterogeneity.
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| 6. |
- Bergqvist, Peter B F
(författare)
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Tryptophan-related Neurotransmission in the Brain: Disturbances Associated with Experimental Hepatic Encephalopathy
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the present study, L-tryptophan (TRP)-related disturbances in the brain in experimental hepatic encephalopathy (HE) were investigated. The endogenous NMDA-receptor agonist and L-TRP metabolite quinolinic acid (QUIN) has been suggested to be involved in the pathogenesis of HE. We were, however, unable to detect any increases in QUIN levels in rats subjected to a chronic portacaval shunt (PCS) either in plasma, brain tissue, or brain extracellular fluid. Furthermore, administration of ammonium acetate (NH4Ac) or L-TRP did not result in any difference in QUIN levels between PCS and sham-operated rats. The other main part of the actual study concerned investigations on the release of serotonin (5-HT) in the brain in HE. Despite a previously evidenced profound increase in brain metabolism of 5-HT in experimental HE, the neocortical release of 5-HT was found not to be changed in this situation. Challenges with L-TRP did not mainly affect the brain 5-HT release in either sham or PCS. NH4Ac administration caused a transient increase in brain 5-HT release of PCS rats during a time-period at which these rats were in a state of reversible coma. KCl provocation also resulted in clear elevations of the 5-HT output of PCS rats compared with matched controls. No difference in the 5-HT response to a d-fenfluramine (dFEN) administration was seen between sham and PCS rats. A clear difference in brain 5-HT release was, however, observed following p-chloroamphetamine (pCA) perfusion possibly indicating a larger extravesicular pool of 5-HT in PCS rats than in the brains of the sham-operated controls. In a final study, differences in pharmacodynamics as well as pharmacokinetics for the serotonin reuptake inhibitor citalopram were observed between PCS and sham. It is concluded that QUIN is not involved to any major extent in the pathogeneis of HE. The basal brain 5-HT release in not altered in experimental chronic PSE but an augmented neocortical 5-HT release compared with the normal in vivo situation is available under certain conditions. Based on these data a more restrictive use for e.g. potent novel 5-HT-acting drugs should be advocated in patients suffering from liver dysfunction and pending HE.
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| 7. |
- Callréus, Torbjörn
(författare)
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Pharmacokinetic and pharmacodynamic analysis of antidiuretic peptides
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The clinical pharmacology of desmopressin and a new vasopressin analogue (F992) was investigated in healthy human subjects. The common procedure of overhydration of healthy volunteers when studying the antidiuretic effect of a drug, may affect the pharmacokinetics, in particular the volumes of distribution. Hence, the estimated parameters may not be relevant to euhydrated patients. F992 was found safe to administer as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin. The influence of changes in gastrointestinal motility, induced by erythromycin and loperamide, on the pharmacokinetics of orally administered desmopressin was investigated. Presumably due to a slowing of gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax, pretreatment with erythromycin did not significantly influence the absorption of the drug. In one study, the pharmacokinetics and pharmacodynamics of desmopressin were investigated in healthy male subjects at different levels of hydration. In this particular study, we did not find any significant effects of different levels of hydration on the estimates of the pharmacokinetic and pharmacodynamic model parameters. The indirect-response model used in the study to estimate the pharmacodynamic parameters, offers a mechanistic approach of modelling the effect of desmopressin in overhydrated subjects. The influence of lithium, on the antidiuretic effect of desmopressin in overhydrated subjects, was investigated with the previously used indirect-response model. The results demonstrate how the IC50 value increases as a result of higher lithium concentrations and urine flow at baseline, whereas higher urine osmolarity at baseline decreases the IC50 value. We found that an indirect-response model can be a useful tool in investigating and describing the interaction between drugs, in this particular case, between lithium and desmopressin.
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| 8. |
- Ding, Xi-Qin
(författare)
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Effect of Cholecystokinin-B/Gastrin Receptor Antagonists on Rat Stomach ECL Cells
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The histamine- and pancreastatin- containing ECL cells in the acid-producing mucosa of the rat stomach operate under the control of circulating gastrin. The present work examines how cholecystokinin (CCK)-B/gastrin receptors regulate the activity of the ECL cells. The oxyntic mucosal histidine decarboxylase (HDC) activity and the circulating pancreastatin concentration are two markers for the activity of the ECL cells. A series of candidate CCK-B/gastrin receptor antagonists was screened for their potency and selectivity in vivo with particular emphasis on their effect on the gastrin-evoked ECL-cell HDC activation. YF476, YM022, RP73870, JB93182 and AG041R were found to be potent and selective antagonists of the ECL-cell CCK-B/gastrin receptors, while the dipeptoid compounds PD136450, PD135158 and PD134308 were found to be partial agonists rather than antagonists. YM022 and RP73870 were selected for further studies. Sustained CCK-B/gastrin receptor blockade (7 days) impaired the functional activity of the ECL cells and prevented the adaptation of the ECL cells to hypergastrinemia as manifested in the reduced oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and chromogranin A (CGA) mRNA concentrations and in the reduced serum pancreastatin concentration and the hypergastrinemia. CCK-B/gastrin receptor blockade deactivated the ECL cells according to a complex time pattern in which histamine and pancreastatin secretion and protein synthesis were promptly inhibited (hours to days) while longer times (days to weeks) were required to lower their histamine and pancreastatin contents. In addition, YM022 and RP73870 abolished the gastrin-induced gastric acid secretion without affecting the basal and vagally stimulated acid secretion. The results support the view that CCK-B/gastrin receptors are essential for the maintenance and adaptation of the ECL cells and for gastrin-stimulated gastric acid secretion.
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| 9. |
- Eriksson, Tommy
(författare)
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Pharmacokinetics of the enantiomers of thalidomide
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thalidomide has a chiral center and the racemate of (+)-(R) and (-)-(S)-thalidomide was introduced as a hypnotic/sedative drug in 1957. In 1961 it was withdrawn due to teratogenicity and neuropathy. There is a growing interest in thalidomide treatment of immunomodulatory diseases. Given this renewed interest the aim of this thesis was to achieve a more rational use of thalidomide. Therefore some chemical and pharmacological aspects of the racemate and of the enantiomers were studied, with special emphasis on the pharmacokinetics of the enantiomers. HPLC assays for determination of thalidomide, its enantiomers and some hydroxylated metabolites were developed. So were different compartment models to describe the pharmacokinetics of the enantiomers of oral and i.v. administration. Solutions for i.v. administration of the enantiomers and methodology for concentration-effect relationship studies (sedation) of the enantiomers were developed. In addition, methods were created to avoid hydrolysis and chiral inversion in blood samples and during assay. The plasma protein binding was 56 for (+)-(R)- and 66% for (-)-(S)-thalidomide. Serum albumin catalysed the inversion, but not the degradation, at pH 7.4. This catalysis was inhibited to various extents in human plasma, and by capric acid, ASA or physostigmine. This supports that chiral inversion and hydrolysis occur by different mechanisms. The pharmacokinetics in a total of 22 healthy male volunteers was studied. The t½ was lower (4.7 h) than previously reported. CLtot was 14 and 24 L/h, and Vdss was 48 and 66 L for (+)-(R)- and (-)-(S)-thalidomide, respectively. It was shown that (+)-(R)-thalidomide is responsible for the sedative effects in humans. Other researchers have shown that the teratogenic and immunomodulatory effects possibly reside in the (-)-(S)-enantiomer. However, the tragedy in the 60s could not have been avoided with the use of the (+)-(R)-enantiomer since this study shows that there is rapid chiral inversion between the enantiomers in humans. The (+)-(R)-enantiomer is predominating at pseudoequilibrium, 8-10 hours after an oral dose of the separate enantiomers. 5'-hydroxy thalidomide but not three other hydroxylated metabolites were found in low concentrations in plasma from all 8 subjects, with a detection limit of 1-2 ng/ml. Three of the hydroxylated metabolites were identified after incubation with human S9 liver homogenate. Further development and studies of oral and i.v. administration forms based on (-)-(S)-thalidomide is suggested.
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| 10. |
- Johansson, Rebecka
(författare)
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Regulation of inducible nitric oxide synthase - Consequences in experimental models of bladder disease
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inducible nitric oxide synthase (iNOS) expression is associated with various pathophysiological conditions in the lower urinary tract. The aims of this thesis have been to investigate the regulation of iNOS in bladder smooth muscle cells and the consequences on neuromuscular regulation, cell growth and differentiation. Primary cultures of rat bladder smooth muscle cells (BSMC) expressed iNOS mRNA and protein upon stimulation with the cytokines IL-1β and TNF-alpha in combination. No constitutive isoforms of NOS were detected at the mRNA level. BSMC were put into different stages of differentiation. The capacity of BSMC to express iNOS was negatively correlated to differentiation status measured as smooth muscle myosin-heavy chain expression. iNOS was shown to be preferentially expressed in immature dedifferentiated BSMC. Actin cytoskeletal dynamics and Rho signalling were involved in regulation of cytokine-induced iNOS expression in BSMC. Phenotypic changes and impairment in actin cytoskeletal formation may potentiate cytokine activation and in turn increase NO production during bladder disease. The consequences of iNOS induction on bladder neuromuscular function were investigated by incubating isolated rat bladder strips with cytokines and recording the mechanical activity in organ baths. iNOS protein was observed in the smooth muscle layer in cytokine stimulated bladder strips. Nerve-mediated, but not acetylcholine-mediated, contraction of the bladder was impaired in bladder strips exposed to cytokines. This impairment was restored by the iNOS inhibitor aminoguanidine and partially by the neurotrophic factor BDNF. iNOS induction affected bladder function and bladder nerves were more sensitive to NO exposure than smooth muscle. The activity and expression of different NOS isoforms were investigated in an in vivo model of bladder hypertrophy induced by urethral obstruction in rats. During obstruction the nNOS activity decreased whereas iNOS activity increased initially. The total NOS activity was decreased. iNOS was expressed in smooth muscle, urothelium and inflammatory cells. Exogenous NO exposure decreased DNA- and protein-synthesis and stimulated differentiation in cultured BSMC. The results indicate that the decreased NO production during obstruction may stimulate a growth response and phenotypic changes in the bladders smooth muscle. The results in this thesis show that the smooth muscle in the bladder should be considered as a source of iNOS expression and NO production during inflammation. Neuronally derived NO is suggested to be involved in bladder smooth muscle physiology by maintaining and stabilizing the smooth muscle phenotype.
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