| 31. |
- 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.
|
|
| 32. |
- Schröder, Annette
(författare)
-
Factors Contributing to Detrusor Overactivity - Obstruction, Hypertrophy and Afferent Nerve Stimulation
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The consequences of bladder outlet obstruction (BOO) with respect to detrusor hypertrophy, structural and functional changes, and obstruction-induced detrusor overactivity were investigated in vivo and in vitro utilizing various animal models. Possible pathophysiological pathways and therapeutic approaches were tested by drug treatment and the use of knockout models. Furthermore the role of estrogen receptor (ER) subtypes in normal micturition and afferent signaling was tested in estrogen receptor knockout-mice, as well as the response of bladder strips to in-vitro stimulation. In rabbits it was found that 2 weeks of BOO caused significant changes in bladders shape, and regional differences occurred in response to different in-vitro stimuli. It was concluded that the bladder is an inhomogeneous organ with significant differences in both its mechanical and pharmacological properties. The effect of an orally administered Endothelin-converting-enzyme (ECE) inhibitor was investigated in rats undergoing 2 weeks of BOO. ECE-inhibition did not prevent the increase of bladder weight after BOO, but seemed to preserve contractile function in vivo. Detrusor overactivity did not occur, in contrast to the untreated obstructed animals. In mice it was found that early BOO-induced overactivity may develop without bladder hypertrophy, and marked differences in voiding pattern can correlate to bladder weight. It was concluded that changes in the afferent function may play a greater role than changes in smooth muscle or efferent neurotransmission, as changes in vitro were subtle. In EP1 receptor knockout mice it was found that the EP1 receptor does not seem to be important in normal micturition, but seems to play a role in the development of detrusor overactivity following BOO, presumably by an effect on the afferent arm of the signaling pathway. PGE2 induced detrusor overactivity appears to be mediated solely by the EP1 receptor. Lack of ERalpha, ERbeta, or both had little or no effect on in-vitro contractility or on continuous cystometry in conscious animals under normal conditions. However, afferent signaling involving capsaicin-sensitive fibers appears to be partly linked to ER subtype-distribution.
|
|
| 33. |
- Sturesson, Helena
(författare)
-
Distribution and function of TRP ion channels in primary sensory neurons
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is frequently argued that cannabinoids exert part of their analgesic and anti-inflammatory effects via activation of the cannabinoid CB1 receptor located on TRPV1-expressing primary sensory nerve fibres in peripheral tissues. However, we find no evidence of CB1 receptor immunoreactivity on nerve fibres in rat or mouse hindpaw skin and mesenteric artery. The CB1 receptor agonists anandamide and HU210 also fail to inhibit TRPV1-mediated calcitonin gene-related peptide (CGRP) release from primary sensory neurons in rat hindpaw skin and mesenteric artery. Therefore, this study do not support the general view that the analgesic and anti-inflammatory effects of CB1 receptor agonists are due to direct inhibition of TRPV1-expressing primary sensory nerve terminals in the periphery. Garlic contains a number of organosulphur compounds, including allicin and diallyl disulfide (DADS), some of which may contribute to its pungent and vasodilator properties. Our results show that raw garlic extract, allicin and DADS activate TRPA1 ion channels on primary sensory neurons in culture and nerve fibres in the vascular system. These findings highlight TRPA1 as a novel ion channel in the vascular system and provide novel pharmacological tools for investigating the role of this ion channel. Whether activation of TRPA1 in the vascular system explains the beneficial antihypertensive effect observed by garlic treatment remains to be shown. This study also expands our understanding of how TRPA1 is regulated on a molecular basis, which is of importance for development of novel drug therapies for pain, inflammation and vascular disease. The skin is a major sensory organ that contains a large number of nerves. The TRP ion channels TRPV2 and TRPM8 are expressed in the somatosensory nervous system in animals and are therefore likely to be expressed in humans as well. Fluorescence immunohistochemistry was used to identify these channels and compare their expression and distribution patterns with known neuronal markers of the sensory nervous system in skin from healthy volunteers and from individuals with a mutation in the gene encoding nerve growth factor beta (NGF?) that causes Norrbottnian congenital insensitivity to pain. This study shows for the first time the presence of TRPV2 and TRPM8 in sensory nerves in the human skin. TRPV2 and TRPM8 as well as TRPV1 immunoreactive nerve fibres are present in unmyelinated nerve fibres in epidermis and papillary dermis, in nerve bundles, and around blood vessels and hair follicles. In contrast to TRPV1, TRPV2 and TRPM8 are found mainly in the papillary dermis and seem to be restricted to peptidergic nerve fibres, of which the majority contains the sensory neuropeptides CGRP or SP. There is a substantial loss of nerve fibres containing TRPV1, TRPV2 and TRPM8 in skin from individuals with Norrbottnian congenital insensitivity to pain. Insight into the role of TRPV2 and TRPM8 in human skin may open new avenues for treatment of neuropathic pain and inflammatory skin diseases.
|
|
| 34. |
- 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.
|
|
| 35. |
- Wikell, Cecilia
(författare)
-
Antidepressant drug effects in vivo: Focus on pharmacokinetic and pharmacodynamic responses in different experimental paradigms
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pharmacokinetic and pharmacodynamic activities of the antidepressants venlafaxine (VEN) and citalopram (CIT) were investigated in the portacaval shunted (PCS) rat, a model of chronic hepatic encephalopathy (HE), and normal/control rats. The levels of VEN in serum and brain were higher in PCS rats than in controls after a single injection and chronic treatment with VEN (10 mg/kg). After reducing the dose by 50% to PCS rats (i.e. 5 mg/kg, single injection), the levels of VEN were still higher in experimental HE than in controls. Furthermore, since the T1/2 for VEN was prolonged by 80% in experimental HE, the results suggest that liver-insufficient patients may have to be treated with both reduced doses and with longer dosing intervals than patients with intact liver function. The S/R ratio of the enantiomers of VEN differed between serum and brain in both experimental HE and controls, but the ratio was not altered in experimental HE versus controls. This could be reassuring regarding drug safety for VEN in patients suffering from HE. There were no major differences in S/R ratio of CIT between serum and brain of normal rats. The levels of 5-HT in brain dialysis samples were higher in the PCS rats compared to controls following administration of 10 mg/kg to both groups. However, the 5-HT levels were not higher in experimental HE compared to normal rats when the dose of VEN was reduced in PCS rats. In conclusion, both pharmacokinetic and pharmacodynamic alterations were observed in experimental HE after administration of the antidepressant drugs VEN and CIT.
|
|
| 36. |
- Merwood, Andrew, et al.
(författare)
-
Genetic associations between the ADHD symptom dimensions and Cloninger's temperament dimensions in adult twins
- 2013
-
Ingår i: European Neuropsychopharmacology. - Amsterdam, Netherlands : Elsevier. - 0924-977X .- 1873-7862. ; 23:6, s. 416-425
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have identified phenotypic associations between Cloninger's temperament dimensions and the symptoms of attention deficit hyperactivity disorder (ADHD) in adults. However the underlying aetiology of these associations remains unclear. We investigate the extent to which genetic and environmental influences contribute to the relationship between temperament and ADHD, examining the ADHD symptoms of inattention (IA) and hyperactivity/impulsivity (HI) separately. Participants were 886 adult twin pairs aged 19-20 years. ADHD symptoms of IA and HI were measured using a DSM-IV based rating scale. Temperament was measured using Cloninger's Temperament and Character Inventory (TCI), across four dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS). The twin method was used to decompose phenotypic variance/covariance among these variables into genetic and environmental components. We found that NS was genetically associated with both ADHD symptom dimensions (IA and HI), but that HA was genetically associated with IA only. There was also some evidence of genetic association between PS, IA and HI. These findings suggest that unique profiles of temperament are genetically related to the two ADHD symptom dimensions in adults. Further work is now needed to elucidate the mechanisms that underlie both the combined and separate symptom factor domains of ADHD.
|
|
| 37. |
- Nilsson, Mats F., et al.
(författare)
-
Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
- 2010
-
Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 29:2, s. 156-163
-
Tidskriftsartikel (refereegranskat)abstract
- Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20nM, and arrhythmias at 200-400nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.
|
|
| 38. |
- Hedna, Khedidja, 1978, et al.
(författare)
-
Clinical relevance of alerts from a decision support system, PHARAO, for drug safety assessment in the older adults
- 2019
-
Ingår i: BMC Geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 19:1, s. 164-
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundPHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patient's medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients.MethodsSide-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons 65years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients' medications. Symptoms possibly related to side-effects were extracted from medical records data.ResultsThe PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20-0.25.ConclusionsThe PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients' medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.
|
|
| 39. |
- Walladbegi, Java, et al.
(författare)
-
Innovative intraoral cooling device better tolerated and equally effective as ice cooling.
- 2017
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 80:5, s. 965-972
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Most of the patients who receive myeloablative therapy prior to stem cell transplantation develop oral mucositis (OM). This adverse reaction manifests as oral mucosal erythema and ulcerations and may require high doses of morphine for pain alleviation. OM may also interfere with food intake and result in weight loss, a need for parenteral nutrition, and impaired quality of life. To date, there have been very few studies of evidence-based interventions for the prevention of OM. Cryotherapy, using ice chips, has been shown to reduce in an efficient manner the severity and extent of OM, although clinical applications are still limited due to several shortcomings, such as adverse tooth sensations, problems with infectious organisms in the water, nausea, and uneven cooling of the oral mucosa. The present proof-of-concept study was conducted to compare the tolerability, temperature reduction, and cooling distribution profiles of an intra-oral cooling device and ice chips in healthy volunteers who did not receive myeloablative treatment, and therefore, did not experience the symptoms of OM.METHODS: Twenty healthy volunteers used the cooling device and ice chips for a maximum of 60 min each, using a cross-over design. The baseline and final temperatures were measured at eight intra-oral locations using an infra-red thermographic camera. The thermographic images were analysed using two digital software packages. A questionnaire was used to assess the tolerability levels of the two interventions.RESULTS: The intra-oral cooling device was significantly better tolerated than the ice-chips (p = 0.0118). The two interventions were equally effective regarding temperature reduction and cooling distribution.CONCLUSIONS: The intra-oral cooling device shows superior tolerability in healthy volunteers. Furthermore, this study shows that temperature reduction and cooling distribution are achieved equally well using either method.
|
|
| 40. |
- Persson, Carl, et al.
(författare)
-
Unbalanced research
- 2001
-
Ingår i: Trends in Pharmacological Sciences. - 0165-6147. ; 22:10, s. 538-541
-
Tidskriftsartikel (refereegranskat)
|
|
