| 1. |
- Greiff, Lennart, et al.
(författare)
-
Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
- 1997
-
Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391
-
Tidskriftsartikel (refereegranskat)abstract
- Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
|
|
| 2. |
- Deshpande, J, et al.
(författare)
-
Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death.
- 1992
-
Ingår i: Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. - 0014-4819. ; 88:1, s. 91-105
-
Tidskriftsartikel (refereegranskat)abstract
- The ultrastructural changes in the pyramidal neurons of the CA1 region of the hippocampus were studied 6 h, 24 h, 48 h, and 72 h following a transient 10 min period of cerebral ischemia induced by common carotid occlusion combined with hypotension. The pyramidal neurons showed delayed neuronal death (DND), i.e. at 24 h and 48 h postischemia few structural alterations were noted in the light microscope, while at 72 h extensive neuronal degeneration was apparent. The most prominent early ultrastructural changes were polysome disaggregation, and the appearance of electron-dense fluffy dark material associated with tubular saccules. Mitochondria and nuclear elements appeared intact until frank neuronal degeneration. The dark material accumulated with extended periods of recirculation in soma and in the main trunks of proximal dendrites, often beneath the plasma membrane, less frequently in the distal dendrites and seldom in spines. Protein synthesis inhibitors (anisomycin, cycloheximide) and an RNA synthesis inhibitor (actinomycin D), administered by intrahippocampal injections or subcutaneously, did not mitigate neuronal damage. Therefore, DND is probably not apoptosis or a form of programmed cell death. We propose that the dark material accumulating in the postischemic period represents protein complexes, possibly aggregates of proteins or internalized plasma membrane fragments, which may disrupt vital cellular structure and functions, leading to cell death.
|
|
| 3. |
- Bergqvist, Peter B F
(författare)
-
Tryptophan-related Neurotransmission in the Brain: Disturbances Associated with Experimental Hepatic Encephalopathy
- 1997
-
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.
|
|
| 4. |
- Callréus, Torbjörn
(författare)
-
Pharmacokinetic and pharmacodynamic analysis of antidiuretic peptides
- 1999
-
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.
|
|
| 5. |
- Ding, Xi-Qin
(författare)
-
Effect of Cholecystokinin-B/Gastrin Receptor Antagonists on Rat Stomach ECL Cells
- 1997
-
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.
|
|
| 6. |
- Eriksson, Tommy
(författare)
-
Pharmacokinetics of the enantiomers of thalidomide
- 1997
-
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.
|
|
| 7. |
- Nilsson, Bengt-Olof, et al.
(författare)
-
Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder
- 1998
-
Ingår i: Pharmacology and Toxicology. - 1600-0773. ; 82:6, s. 287-294
-
Tidskriftsartikel (refereegranskat)abstract
- The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.
|
|
| 8. |
- Ryman, Torsten
(författare)
-
A study of potassium channel activation as a pharmacological principle for vasodilation of cerebral blood vessels
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Increasing [K+]o is intimately coupled to progressive ischemia and reduced CBF. In isolated cerebral and mesenteric arteries, it was found that significant differences in the vascular responses to [K+]o exist. Among the species studied, human cerebral arteries were the most sensitive artery to increasing [K+]o. Rabbit basilar arteries, denuded from the endothelium, showed increased sensitivity to [K+]o which may reflect a reduced influence of EDHF as a result of the endothelial damage. This increased sensitivity could be restored with the KATP channel opener pinacidil. It was found that the effect of pinacidil in human and rabbit cerebral but not in mesenteric arteries, on K+-induced contractions, was stronger in endothelium-denuded cerebral arteries than in arteries with intact endothelium. In rabbit basilar arteries KRN2391 induced a consistent relaxation in arteries pre-contracted with endothelin-1. The nitrate-like effect of KRN2391 demonstrated in other preparations was not seen in the present study. It was concluded that in rabbit basilar arteries, KRN2391 induced a cGMP-independent relaxation, which is mediated mainly by opening of KATP channels. KRN2391 was found to be an equally effective vasodilator in both human pial and omental arteries. Similar to rabbit basilar arteries the KRN2391- induced relaxation in human pial arteries was mediated entirely by activation of the KATP channel. This relaxation appeared to be independent of both KATP channel activation and guanylate cyclase in the omental artery. KATP channel opening resulted in a more effective vasodilation of human pial than of omental arteries. The opposite was true for stimulation of guanylate cyclase with the NO-donor SIN-1. It is concluded that KATP channel activation may be a promising therapeutic principle for cerebral vasodilation and for preventing cerebral ischemia.
|
|
| 9. |
- Thorsson, Lars
(författare)
-
Studies on the deposition, bioavailability and systemic activity of glucocorticoids in man
- 1998
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The local deposition, pharmacokinetics, and systemic activity of inhaled and intranasal glucocorticosteroids in different formulations and devices(ICSs) has been investigated. After nasal administration of the ICS budesonide (Bud), the systemic availability (F) was found to be significantly higher from an aqueous pump spray and from the powder inhaler Turbuhaler, than from a pressurized metered dose inhaler (pMDI), and the uptake process was slower and less complete with the pMDI formulation. Lung deposition of Bud from a pMDI plus Nebuhaler, and from Turbuhaler, was found to be twice as high as with a pMDI alone, whereas Ftotal was only about 50% higher. Thus, a larger proportion of Ftotal was derived from lung deposited Bud when using a pMDI plus Nebuhaler, spacer and Turbuhaler, than when using a pMDI. It was also found that the pMDI resulted in a significantly larger variability in lung deposition than Turbuhaler. In addition, a marked reduction in F was found when the pMDI canisters were not shaken properly before administration which confirms that the pMDI is very dependent on proper handling. Fluticasone propionate (FP), was found to accumulate in plasma during repeated dosing due to a slow systemic elimination. The accumulation is a probable explanation for the marked plasma cortisol suppression observed with repeated dosing within the clinical dose range. In conclusion, the present study has shown differences in local deposition, pharmacokinetics and systemic activity of inhaled glucocorticoid formulations, features which may contribute to differences in therapeutic properties.
|
|
| 10. |
- Korsgren, Magnus, et al.
(författare)
-
Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice
- 1997
-
Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 185:5, s. 885-892
-
Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulins (Ig), particularly IgE, are believed to be crucially involved in the pathogenesis of asthma and, equally, in allergic models of the disease. To validate this paradigm we examined homozygous mutant C57BL/6 mice, which are B cell deficient, lacking all Ig. Mice were immunized intraperitoneally with 10 micrograms ovalbumin (OVA) plus alum, followed by daily (day 14-20) 30 min exposures to OVA aerosol (OVA/OVA group). Three control groups were run: OVA intraperitoneally plus saline (SAL) aerosol (OVA/SAL group); saline intraperitoneally plus saline aerosol; saline intraperitoneally plus OVA aerosol (n = 6-7). Lung and large airway tissues obtained 24 h after the last OVA or SAL exposure were examined by light microscopy and transmission electron microscopy (TEM). The Ig-deficient mice receiving OVA/ OVA treatment had swollen and discolored lungs and exhibited marked eosinophilia both in large airway subepithelial tissue (49.2 +/- 12.0 cells/mm basement membrane [BM] versus OVA/ SAL control 1.2 +/- 0.3 cells/mm BM; P < 0.001), and perivascularly and peribronchially in the lung (49.3 +/- 9.0 cells/unit area versus OVA/SAL control 2.6 +/- 0.6 cells/unit area; P < 0.001). The eosinophilia extended to the regional lymph nodes. TEM confirmed the subepithelial and perivascular localization of eosinophils. Mucus cells in large airway epithelium increased from 1.5 +/- 0.8 (OVA/SAL mice) to 39.5 +/- 5.7 cells/mm BM in OVA/OVA treated mice (P < 0.001). OVA/SAL mice never differed from the other control groups. Corresponding experiments in wild-type mice (n = 6-7 in each group) showed qualitatively similar but less pronounced eosinophil and mucus cell changes. Macrophages and CD4+ T cells increased in lungs of all OVA/OVA-treated mice. Mast cell number did not differ but degranulation was detected only in OVA/OVA-treated wild-type mice. Immunization to OVA followed by OVA challenges thus cause eosinophil-rich inflammation in airways and lungs of mice without involvement of B cells and Ig.
|
|
