| 1. |
- Berg, Tove, et al.
(författare)
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Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects.
- 2014
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Ingår i: Pharmacology research & perspectives. - : Wiley. - 2052-1707. ; 2:4, s. e00054-
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Tidskriftsartikel (refereegranskat)abstract
- This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.
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| 2. |
- Ekman, Elisabet, 1953-, et al.
(författare)
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Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers
- 2010
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Ingår i: Drug, Healthcare and Patient Safety. - United States : Dove Medical Press Ltd. - 1179-1365. ; 2, s. 21-25
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe spontaneously reported cases of erectile dysfunction (ED) in association with angiotensin II type I blockers (ARB) and other antihypertensive drugs.SUBJECTS AND METHODS: All spontaneously reported cases of ED submitted to the Swedish Medical Products Agency (MPA) between 1990 and 2006, where at least one antihypertensive drug was the suspected agent, were scrutinized. Patient demographics, drug treatment and adverse reactions were recorded. Using the Bayesian Confidence Propagation Neural Network (BCPNN) method, the information component (IC) was calculated.RESULTS: Among a total of 225 reports of ED, 59 involved antihypertensive drugs including ARB (9 cases) as suspected agents. A positive IC value was found indicating that ED was reported more often in association with antihypertensive drugs classes, except for angiotensin-converting enzyme inhibitors, compared with all other drugs in the database. Positive dechallenge was reported in 43 cases (72%).DISCUSSION: All classes of major antihypertensive drugs including ARB were implicated as suspected agents in cases of ED. Few risk factors were identified. The relatively high reporting of ED in association with ARB is in contrast with previous studies, suggesting that ARB have neither a positive nor any effect on ED. This discrepancy suggests that further studies are warrnted on this potential adverse reaction to ARB.
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| 3. |
- Ekman, Elisabet, et al.
(författare)
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Povidonöverkänslighet extremt ovanlig eller underskattad? Tidigare ansågs hjälpämnet povidon varjen toxiskt eller allergent
- 2007
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Ingår i: Läkartidningen. - 0023-7205. ; 104:17, s. 1318-1319
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Tidskriftsartikel (refereegranskat)abstract
- Povidon är en polymer som används som stabiliseringsmedel i många läkemedel och vissa kosmetika. Povidon har ansetts vara atoxiskt och inte allergiframkallande. Vi beskriver ett fall av överkänslighet mot povidon som nyligen rapporterats till biverkningsenheten i Lund. Vi har även gjort en litteratursökning och sammanfattar tidigare publicerade fall. Allergi mot povidon har dokumenterats med pricktest, och i några fall har man påvisat specifika IgE-antikroppar.
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| 4. |
- Giraldi, A, et al.
(författare)
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Effects of diabetes on neurotransmission in rat vaginal smooth muscle
- 2001
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Ingår i: International Journal of Impotence Research. - : Springer Science and Business Media LLC. - 1476-5489 .- 0955-9930. ; 13:2, s. 58-66
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to characterize the effect of experimental diabetes on neurotransmission in rat vagina. Female Sprague-Dawley rats were divided into two groups: non-diabetic controls (NDM, n=38) and diabetics (DM, n=38). DM was produced by intraperitoneal injection of streptozotocin. Eight weeks later the animals were killed, the distal part of the vagina was removed, and smooth muscle strips were prepared for functional organ bath experiments and for measurement of nitric oxide synthase (NOS) activity. In DM preparations, the EC(50) value for noradrenaline (NA) was significantly increased (P<0.05) and the maximal contractile response decreased (P=0.001). In preparations precontracted with NA, the NO donor SNAP and calcitonin gene-related peptide (CGRP) caused concentration-dependent relaxations, which were significantly decreased (P<0.001) in the DM group. Electrical stimulation of nerves (EFS) caused frequency-dependent contractions, which were significantly lower in DM than in NDM strips (P<0.001). SNAP and CGRP concentration-dependently inhibited EFS evoked contractions in both NDM and DM preparations. The inhibition was significantly lower (P<0.05) in the DM group. In NDM preparations precontracted with NA, EFS evoked frequency-dependent relaxations; such relaxations were inhibited or reduced in DM. Treatment with the NOS inhibitor, L-NOARG 0.1 mM, abolished relaxations in all preparations or produced contraction in DM preparations. Calcium-dependent NOS activity was not significantly different in the DM and NDM groups. However, the DM animals showed a small but significant increase in calcium-independent NOS-activity (P<0.05). Diabetes interferes with adrenergic-, cholinergic- and NANC-neurotransmitter mechanisms in the smooth muscle of the rat vagina. The changes in the nitrergic neurotransmission are not due to reduction in NOS-activity, but seem to be due to interference with later steps in the L-arginine/NO/guanylate cyclase/cGMP system.
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| 5. |
- Giraldi, A, et al.
(författare)
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Morphological and functional characterization of a rat vaginal smooth muscle sphincter
- 2002
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Ingår i: International Journal of Impotence Research. - : Springer Science and Business Media LLC. - 1476-5489 .- 0955-9930. ; 14:4, s. 271-282
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to gain information about adrenergic-, cholinergic- and nonadrenergic, non-cholinergic (NANC)- transmitter systems/mediators in the rat vagina, and to characterize its smooth muscles functionally. Tissue sections from vagina of Sprague Dawley rats were immunolabelled with antibodies against protein gene product 9.5 (PGP), synaptophysin (Syn), tyrosine hydroxylase (TH), vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Circularly cut vaginal smooth muscle preparations from the distal vagina were studied in organ baths. In the paravaginal tissue, a large number of PGP-, NOS-, TH-, VIP-immunoreactive (IR) and few CGRP-IR nerve trunks were observed, giving off branches to the smooth muscle wall. The smooth muscle wall was supplied by a large number of PGP-, Syn-, VAChT-, NPY-, NOS- and TH- IR nerve terminals, whilst only a moderate to few numbers of CGRP-, VIP- and PACAP-IR terminals were identified. Especially the distal part of the vaginal wall, where the circularly running smooth muscle was thickened into a distinct sphincter structure, was very richly innervated, predominantly by PGP- and NOS-IR terminals. Below and within the basal parts of the epithelium in the distal half of the vagina, a large number of PGP- and few NOS- and PACAP-IR varicose terminals were observed. The vaginal arteries were encircled by plexuses of nerve terminals. A large number of these were PGP-, Syn-, VAChT-, NOS-, TH-, NPY- and VIP-IR, and few were CGRP- and PACAP-IR. In isolated preparations of the distal vagina, electrical field stimulation (EFS) caused frequency-dependent contractions, which were reduced by sildenafil, tetrodotoxin (TTX) and phentolamine. In preparations contracted by norepinephrine (NA), EFS produced frequency-dependent relaxations. Pretreatment with the NOS-inhibitor N-G-nitro-L-arginine, TTX, or the inhibitor of soluble guanylate cyclase, ODQ, abolished the EFS relaxations. In NE precontracted preparations, cumulative addition of sildenafil caused concentration-dependent relaxation. Carbachol contracted the strips concentration-dependently from baseline. It can be concluded that the distal part of the rat vagina forms a distinct smooth muscle sphincter, which is richly innervated by adrenergic, cholinergic and NANC nerves. The present studies suggest that in the rat the L-arginine/NO-system not only plays an important role in the regulation of vaginal smooth muscle tone, but also affects blood flow, and may have sensory functions.
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| 6. |
- Pettersson, Jonas, et al.
(författare)
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Muscular exercise can cause highly pathological liver function tests in healthy men.
- 2008
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 65:2, s. 253-259
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Tidskriftsartikel (refereegranskat)abstract
- What is already known about this subject • The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. • Physical exercise can result in transient elevations of liver function tests. • There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds • Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. • Liver function tests are significantly increased for at least 7 days after weightlifting. • It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.
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| 7. |
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| 8. |
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| 9. |
- Werkström, Viktoria, et al.
(författare)
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Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction
- 1997
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 120:2, s. 312-318
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Tidskriftsartikel (refereegranskat)abstract
- 1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K+ channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 microM) evoked a relaxation amounting to 76 +/- 6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K+ channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12-72 microM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86 +/- 6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 microM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33 +/- 9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1-1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 microM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K+ channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin.
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| 10. |
- Werkström, Viktoria, et al.
(författare)
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Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation
- 1995
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Ingår i: British Journal of Pharmacology. - 1476-5381. ; 116:1, s. 1599-1604
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Tidskriftsartikel (refereegranskat)abstract
- 1 Non-adrenergic, non-cholinergic (NANC) relaxations induced by electrical field stimulation (EFS)were studied in pig isolated urethra. The mechanism for relaxation was characterized by measurement of cyclic nucleotides and by study of involvement of different subsets of voltage-operated calcium channels (VOCCs). 2 EFS evoked frequency-dependent and tetrodotoxin-sensitive relaxations in the presence of propranolol (1 yM), phentolamine (1 pM) and scopolamine (1 pM). At low frequencies (< 12 Hz), relaxations were rapid, whereas at high (> 12 Hz) frequencies distinct biphasic relaxations were evoked. The latter consisted of a rapidly developing first phase followed by a more long-lasting second phase. 3 Treatment with the NO-synthesis inhibitor N0-nitro-L-arginine (L-NOARG; 0.3 mM) inhibited relaxations at low frequencies of stimulation. At high frequencies (> 12 Hz) only the first relaxation phase was affected. 4 Measurement of cyclic nucleotides in preparations subjected to continuous nerve-stimulation, revealed an increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels from 1.3 ± 0.3 to 3.0±0.4 pmol mg'- protein (P<0.01). In the presence of L-NOARG, there was a significant decrease in cyclic GMP content to control. However, there was no increase in cyclic GMP content in response to EFS. Levels of cyclic AMP remained unchanged following EFS. 5 Treatment with the N-type VOCC-inhibitor, wo-conotoxin GVIA (0.1 FM) reduced NO-dependent relaxations, the effect being most pronounced at low frequencies (1-4 Hz) of stimulation. The NOindependent second phase of the relaxation, studied in the presence of L-NOARG (0.3 mM) at 16- 30 Hz, was however markedly reduced or abolished by w-conotoxin GVIA. w-Conotoxin MVIIC (1 pM)or w-agatoxin IVA (30 nM) had no effect on electrically evoked relaxations. 6 These results suggest that NANC-nerve derived urethral relaxation in the pig consists of two apparently independent components. One is mediated by NO and associated with an increase in cyclic GMP content. The other mediator is unknown and produces relaxations not associated with changes in levels of cyclic nucleotides. The release of this mediator seems to involve the N-type VOCC, since the relaxation was markedly reduced or abolished by w-conotoxin GVIA.
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