| 1. |
- Rendel, Filip, et al.
(author)
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Effects of Di-Isononyl Phthalate on Neuropeptide Y Expression in Differentiating Human Neuronal Cells
- 2017
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In: Basic & Clinical Pharmacology & Toxicology. - : Blackwell Publishing. - 1742-7835 .- 1742-7843. ; 120:3, s. 218-323
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Journal article (peer-reviewed)abstract
- Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian brain important for behavioural consequences of stress and energy metabolism. We have addressed possible effects of the phthalate DiNP on NPY expression in human SH‐SY5Y cells, a neuronal in vitro differentiation model. Pico‐ to nanomolar doses of DiNP and its metabolite MiNP resulted in decreased NPY mRNA and peptide expression in retinoid‐differentiated cells. Thus, dys‐regulated NPY may be an adverse outcome for exposure to low doses of DiNP in human beings.
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| 2. |
- Abelson, Klas, et al.
(author)
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The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat
- 2004
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In: Basic & Clinical Pharmacology & Toxicology. - : Blackwell. - 1742-7835 .- 1742-7843. ; 94:4, s. 153-60
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Journal article (peer-reviewed)abstract
- Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinalacetylcholine. The cholinergic receptor system interacts with several other receptor types, such as a2-adrenergic receptors.To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigatedin detail. This study was initiated to investigate the effects of the a2-adrenergic receptor agonists clonidine and rilmenidineand the a2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinalmicrodialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or withoutnicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptorswere investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholinerelease. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade atten-uated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, allligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curveand rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested a2-adrenergicreceptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, andthat they possess binding affinity to nicotinic receptors in vitro. The binding of a2-adrenergic receptor ligands to nicotinicreceptors might affect the intraspinal release of acetylcholine.
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| 3. |
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| 4. |
- Alenmyr, Lisa, et al.
(author)
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Effect of Mucosal TRPV1 Inhibition in Allergic Rhinitis.
- 2012
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 110, s. 264-268
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Journal article (peer-reviewed)abstract
- Transient receptor potential vanilloid-1 (TRPV1) has been implicated as a mediator of itch in allergic rhinitis. To address this possibility, we synthesized a TRPV1 blocker (SB-705498) for nasal administration in patients with seasonal allergic rhinitis. The pharmacological activity of SB-705498 was confirmed on human TRPV1-expressing HEK293 cells, using fluorometric calcium imaging, and in patients with allergic rhinitis subjected to nasal capsaicin challenges. The effect of SB-705498 was studied in patients with seasonal allergic rhinitis subjected to daily allergen challenges for seven days, using a double-blind, placebo-controlled, randomized and cross-over design. SB-705498 was delivered by nasal lavage 10 min. before each allergen challenge. Primary end-point was total nasal symptom score on days 5 to 7. Nasal peak inspiratory flow and eosinophil cationic protein content in nasal lavages were also monitored. Daily topical applications of SB-705498 at a concentration that inhibited capsaicin-induced nasal symptoms had no effect on total symptom score, nasal peak inspiratory flow and eosinophil cationic protein levels in allergen-challenged patients with seasonal allergic rhinitis. The individual symptom nasal itch or sneezes was also not affected. These findings may indicate that TRPV1 is not a key mediator of the symptoms in allergic rhinitis. However, additional studies, using drug formulations with a prolonged duration of action, should be conducted before TRPV1 is ruled out as a drug target in allergic rhinitis.
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| 5. |
- Alenmyr, Lisa, et al.
(author)
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TRPV4-mediated calcium influx and ciliary activity in human native airway epithelial cells.
- 2014
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 114:2, s. 210-216
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Journal article (peer-reviewed)abstract
- The transient receptor potential, vanilloid 4 (TRPV4), is a calcium permeable ion channel expressed in airway epithelial cells. Based on studies of cell lines and animals, TRPV4 has been suggested to play a role in the regulation of ciliary beat frequency (CBF). Whether the same is true for human ciliated epithelial cells is not known. Therefore, the aim was to examine the expression and function of TRPV4 in human native nasal epithelial cells. Expression of TRPV4 mRNA in nasal epithelial cells and in the cell lines BEAS2B and 16HBE was confirmed by quantitative real-time PCR. A marked apical TRPV4 immunoreactivity was observed in nasal epithelial cells using immunocytochemistry. Responses to pharmacological modulation of TRPV4 were assessed with calcium imaging and CBF measurements. The TRPV4 agonist GSK1016790A produced concentration-dependent calcium responses in TRPV4-expressing HEK293, BEAS2B and 16HBE cells, and the TRPV4 antagonist HC067047 caused a rightward shift of the GSK1016790A concentration-response curves. Nasal epithelial cells responded to the TRPV4 agonist GSK1016790A with increased intracellular calcium signals and increased CBF, followed by cessation of ciliary beating and cell death. These effects were prevented or inhibited by the TRPV4 antagonist HC067047, the TRP channel blocker ruthenium red or removal of extracellular calcium. We conclude that TRPV4 is expressed in human primary nasal epithelial cells and modulates epithelial calcium levels and CBF. Thus, TRPV4 may participate in mucociliary clearance and airway protection. However, exaggerated activation of TRPV4 may result in epithelial cell death. This article is protected by copyright. All rights reserved.
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| 6. |
- Allmyr, Mats, et al.
(author)
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Human Exposure to Triclosan via Toothpaste does not change CYP3A4 Activity or Plasma Concentrations of Thyroid Hormones
- 2009
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 105:5, s. 339-344
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Journal article (peer-reviewed)abstract
- Triclosan is an antibacterial compound commonly used in cosmetics and personal care products for everyday use. As previously shown, triclosan is found in the plasma, urine and milk from large parts of different human populations. Recent studies have revealed that triclosan is able to activate the human pregnane X receptor in vitro and thus possibly affecting metabolism of drugs in humans via the induction of CYP3A4. Besides, triclosan has been shown to affect thyroid hormonal levels in rats in vivo. In the present study, we investigated if an everyday exposure to triclosan via triclosan-containing toothpaste for 14 days in 12 adult humans caused an increase in plasma 4 beta-hydroxycholesterol, indicative of CYP3A4 induction, and/or alterations in thyroid hormonal status. The plasma triclosan concentrations increased from 0.009-0.81 ng/g to 26-296 ng/g (ranges) upon exposure. Despite this, there were no significant changes in plasma levels of either plasma 4 beta-hydroxycholesterol or thyroid hormones during the exposure. This indicates that the normal use of triclosan-containing toothpaste is not likely to alter metabolism of drugs via CYP3A4 induction or cause adverse events because of thyroid disturbances in humans.
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| 7. |
- Alsiö, Johan, et al.
(author)
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Impact of nandrolone decanoate on gene expression in endocrine systems related to the adverse effects of anabolic androgenic steroids
- 2009
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 105:5, s. 307-314
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Journal article (peer-reviewed)abstract
- Elite athletes, body builders and adolescents misuse anabolic-androgenic steroids (AAS) in order to increase muscle mass or to enhance physical endurance and braveness. The high doses misused are associated with numerous adverse effects. The purpose of this study was to evaluate the impact of chronic supratherapeutic AAS treatment on circulating hormones and gene expression in peripheral tissues related to such adverse effects. Quantitative real-time PCR was used to measure expression levels of in total 37 genes (including peptide hormones, cell membrane receptors, nuclear receptors, steroid synthesising enzymes and other enzymes) in the pituitary, testes, adrenals, adipose tissue, kidneys and liver of male Sprague-Dawley rats after 14-day administration of the AAS nandrolone decanoate, 3 or 15 mg/kg. Plasma glucose and levels of adrenocorticotropic hormone (ACTH), adiponectin, corticosterone, ghrelin, insulin and leptin were also measured. We found several expected effects on the hypothalamic-pituitary-gonadal axis, while the treatment also caused a number of other not previously identified changes in circulating factors and gene transcription levels such as the dose-dependent reduction of the beta(3)-adrenergic receptor in adipose tissue, reduction of both circulating and mRNA levels of adiponectin, up-regulation of both hydroxymethylglutaryl-CoA-reductase, the rate-limiting enzyme in de novo synthesis of cholesterol, and the receptor for ACTH in the adrenals. The results provide evidence for wide ranging effects of AAS on the hypothalamic-pituitary-adrenal axis, adipose tissue and substrates of the renal control of blood pressure.
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| 8. |
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| 9. |
- Andersson, Morgan, et al.
(author)
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Effects of a topical microemulsion in house dust mite allergic rhinitis.
- 2011
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 108:2, s. 146-148
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Journal article (peer-reviewed)abstract
- We have previously demonstrated that a topical microemulsion can attenuate symptoms and signs of seasonal allergic rhinitis. This likely reflects that the microemulsion interferes with the interaction between the allergen and the mucosa. Whether or not the finding translates to conditions caused by other inhaled agents such as house dust mite allergen is unknown. Patients with perennial allergic rhinitis caused by house dust mite were subjected to topical microemulsion treatment in a randomized, double-blinded and crossover design with isotonic saline as control. Morning symptoms were monitored, change from baseline was assessed and the treatments were compared. On the first days of the isotonic saline and microemulsion runs, before any treatment was given, total nasal symptoms were scored to 2.8 and 3.1 (range 0-9), respectively. Nasal symptoms were reduced by intervention with the microemulsion: the change from baseline was consistent for the microemulsion and the difference between the microemulsion and isotonic saline reached statistical significance in favour of the former. We conclude that intervention with a microemulsion may reduce symptoms of house dust mite allergic rhinitis at natural allergen exposure. Our findings suggest the possibility that topical microemulsions can be a useful option to reduce nasal mucosal exposure to allergen in perennial allergic rhinitis..
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| 10. |
- Andersson, Marine L, et al.
(author)
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High Prevalence of Drug-Drug Interactions in Primary Health Care is Caused by Prescriptions from other Healthcare Units.
- 2018
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 122:5, s. 512-516
-
Journal article (peer-reviewed)abstract
- Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary healthcare centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4-month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX. Interactions were classified with respect to the workplace of the prescriber, and the prevalence of interactions according to origin was analysed. We found that the drug interactions were significantly more common when the drugs were prescribed from different healthcare centres, compared with drugs prescribed from the patients' primary healthcare centre only. One explanation for this increased risk of drug interactions could be that the prescribers at different primary healthcare centres do not share the same information concerning the total medication list of the patient.
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| 11. |
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| 12. |
- Andersson, Sven, et al.
(author)
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Reduction of Homocysteine in Elderly with Heart Failure Improved Vascular Function and Blood Pressure Control but did Not Affect Inflammatory Activity.
- 2005
-
In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843. ; 97:5, s. 306-310
-
Journal article (peer-reviewed)abstract
- We have previously shown that hyperhomocysteinaemia is common in elderly heart failure patients, and is associated with endothelial dysfunction, impaired vasodilatory capacity and a low-grade inflammation. In the present study we examined if supplementation with B6, B12 and folate could normalize the hyperhomocysteinaemia and if so, in turn, would improve the associated parameters. This was an open study without placebo control on heart failure patients with plasma homocysteine > 15 microM. Measurements of cutaneous vascular reactivity, blood pressure, inflammatory activity and endothelial function were performed before and after intervention with intra-individual comparisons. The treatment reduced homocysteine to near normal values and enhanced the hyperaemic response to acetylcholine related to the response to heat. The mean arterial blood pressure and pulse rate was reduced. There was no effect on inflammatory activity, plasma levels of von Willebrand factor, subjective health quality or the hyperaemic responses to sodium nitroprusside or local warming. Hyperhomocysteinaemia in heart failure patients is multifactorial in origin. Folate deficiency, inflammatory activity and reduced renal function could be contributing. It is suggested that supplementation with B-vitamins can improve the vasodilatory capacity and reduce the blood pressure but additional studies are required to confirm this.
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| 13. |
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| 14. |
- Aronsson, Patrik, 1983, et al.
(author)
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Assessment and Characterization of Purinergic Contractions and Relaxations in the Rat Urinary Bladder.
- 2010
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In: Basic & clinical pharmacology & toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 107:1, s. 603-613
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Journal article (peer-reviewed)abstract
- The aim of the present study was to assess the purinoceptor functional responses of the urinary bladder by using isolated rat urinary bladder strip preparations. ATP elicited a transient bladder contraction followed by a sustained relaxation and ADP, UDP and UTP generated predominantly potent relaxations (relaxatory potencies: ADP = ATP > UDP = UTP). The ATP contractions were desensitized with the P2X(1/3) purinoceptor agonist/desensitizer alpha,beta-meATP and reduced by the P2 purinoceptor antagonist PPADS but unaffected by the P2 purinoceptor antagonist suramin. Electrical field stimulation (1-60 Hz) evoked frequency-dependent bladder contractions that were decreased by incubation with alpha,beta-meATP but not further decreased by PPADS. Suramin antagonized relaxations generated by UDP but not those by ADP, ATP or UTP. PPADS antagonized and tended to antagonize UTP and UDP relaxations, respectively, but did neither affect ADP nor ATP relaxations. ADP relaxations were insensitive to the P2Y(1) purinoceptor antagonist MRS 2179 and the ATP-sensitive potassium channel antagonist glibenclamide. The ATP relaxations were inhibited by the P1 purinoceptor antagonist 8-p-sulfophenyltheophylline but unaffected by the A2A adenosine receptor antagonist 8-(3-chlorostyryl)caffeine and glibenclamide. Adenosine evoked relaxations that were antagonized by the A2B adenosine receptor antagonist PSB 1115. Thus, in the rat urinary bladder purinergic contractions are elicited predominantly by stimulation of the P2X(1) purinoceptors, while UDP/UTP-sensitive P2Y purinoceptor(s) and P1 purinoceptors of the A2B adenosine receptor subtype are involved in bladder relaxation.
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| 15. |
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| 16. |
- Axelsson, Magnus A. B., et al.
(author)
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Retrospective identification of new psychoactive substances in patient samples submitted for clinical drug analysis
- 2022
-
In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 131:5, s. 420-434
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Journal article (peer-reviewed)abstract
- New psychoactive substances (NPS) are life threatening through unpredictable toxicity and limited analytical options for clinicians. We present the retrospective identification of NPS in raw data from a liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based multidrug panel analysis on 14 367 clinical oral fluid samples requested during 2019 mainly by psychiatric and addiction care clinics. Retrospectively analysed NPS included 48 notified originally in 2019 by the European Union Early Warning System (EU EWS) and 28 frequently reported in Sweden. Of 88 included NPS, 34 (mitragynine, flualprazolam, 3F/4F-α-P(i)HP, etizolam, 4F-MDMB-BINACA, cyproheptadine, 5F-MDMB-PICA, isotonitazene, isohexedrone, MDPEP, N-ethylpentedrone, tianeptine, flubromazolam, 4′-methylhexedrone, α-P(i)HP, eutylone, mephedrone, N-ethylhexedrone, 5F-MDMB-PINACA, ADB-BUTINACA, 3-methoxy PCP, 4F-furanylfentanyl, 4F-isobuturylfentanyl, acrylfentanyl, furanylfentanyl, clonazolam, norfludiazepam, 3F-phenmetrazine, 3-MMC, 4-methylpentedrone, BMDP, ethylphenidate, methylone and α-PVP) were identified as 219 findings in 84 patients. Eight NPS notified in 2019 were identified, five before EWS release. NPS occurred in 1.20% of all samples and 1.53% of samples containing traditional drugs, and in 1.87% of all patients and 2.88% of patients using traditional drugs. NPS use was more common in men and polydrug users. Legal (not scheduled) NPS were more used than comparable illegal ones. Retrospective identification could be useful when prioritizing NPS for clinical routine analysis and when studying NPS epidemiology. © 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.
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| 17. |
- Azarbayjani, Faranak, et al.
(author)
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Increased susceptibility to phenytoin teratogenicity : Excessive generation of reactive oxygen species or impaired antioxidant defense?
- 2006
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 99:4, s. 305-311
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Journal article (peer-reviewed)abstract
- Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.
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| 18. |
- Bastami, Salumeh, et al.
(author)
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Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Postoperative Morphine Consumption
- 2014
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 115:5, s. 423-431
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Journal article (peer-reviewed)abstract
- Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in both effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7,OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine-induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsies as morphine is also a very commonly abused drug. Blood samples were collected from 40 patients following abdominal hysterectomy, 24hr after initiation of analgesia through a patient-controlled analgesia (PCA) pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsies found positive for morphine in routine forensic analysis. Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. The dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood. Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients. We conclude that gene polymorphisms contribute significantly to the variation in morphine concentrations observed in individual patients.
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| 19. |
- Bengtsson, Christine, et al.
(author)
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Effect of Medication on Microvascular Vasodilatation in Patients with Systemic Lupus Erythematosus
- 2010
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 107:6, s. 919-924
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate the microvascular responses in the skin, to local heat, iontophoretically administered acetylcholine and to sodium nitroprusside in relation to cardiovascular damage in patients with systemic lupus erythematosus (SLE) and matched controls. We also wanted to examine if the ongoing medication in SLE patients influenced this vascular response. We investigated 30 women with SLE and compared them with 20 age and sex-matched controls. The cutaneous blood flow response to local heat (+44 degrees C), iontophoretically administered endothelium-dependent (acetylcholine), as well as independent (sodium nitroprusside) vasodilatation, was measured by laser Doppler flowmetry. Clinical data and medication were retrieved from the clinical database and patient records. The cutaneous microvascular reactivity did not differ between SLE patients and a group of matched controls nor did it correlate with cardiovascular damage [assessed by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)]. However, patients on antimalarial drugs (hydroxychloroquine n = 8 and chloroquine diphosphate n = 3) responded more strongly to sodium nitroprusside (endothelium-independent vasodilatation) compared with those without antimalarial drugs (p < 0.01). The response to acetylcholine was higher among patients on warfarin compared with those without (p < 0.05), whereas glucocorticoid use (>= 5 mg daily) was associated with reduced response to acetylcholine (p < 0.05). Smokers in general tended to have a lower response to acetylcholine (p = 0.064). Smoking SLE patients versus non-smoking SLE patients had a significantly lower response to acetylcholine (p = 0.01). Medication with antimalarial drugs-enhanced endothelium-independent vasodilatation, while glucocorticoid use was associated with reduction and warfarin-treatment with enhancement of endothelium-dependent vasodilatation. Therefore, despite there is no difference in microvascular endothelium-dependent vasodilatation, other factors such as medication and smoking may affect vasodilatation in SLE patients.
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| 20. |
- Bergmann, Troels K., et al.
(author)
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Impact of ABCB1 Variants on Neutrophil Depression : A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer
- 2012
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 110:2, s. 199-204
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Journal article (peer-reviewed)abstract
- The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Bjorklund, Geir, et al.
(author)
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Mercury exposure and its effects on fertility and pregnancy outcome
- 2019
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In: Basic & Clinical Pharmacology & Toxicology. - : WILEY. - 1742-7835 .- 1742-7843. ; 125:4, s. 317-327
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Research review (peer-reviewed)abstract
- Mercury (Hg), a highly toxic environmental pollutant, shows harmfulness which still represents a big concern for human health, including hazards to fertility and pregnancy outcome. Research has shown that Hg could induce impairments in the reproductive function, cellular deformation of the Leydig cells and the seminiferous tubules, and testicular degeneration as well as abnormal menstrual cycles. Some studies investigated spontaneous abortion and complicated fertility outcome due to occupational Hg exposure. Moreover, there is a relation between inhaled Hg vapour and reproductive outcome. This MiniReview evaluates the hypothesis that exposure to Hg may increase the risk of reduced fertility, spontaneous abortion and congenital deficits or abnormalities.
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| 25. |
- Björklund, Geir, et al.
(author)
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Neurotoxic effects of mercury exposure in dental personnel
- 2019
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In: Basic & Clinical Pharmacology & Toxicology. - : WILEY. - 1742-7835 .- 1742-7843. ; 124:5, s. 568-574
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Research review (peer-reviewed)abstract
- Numerous studies have reported neurobehavioural effects in dental personnel occupationally exposed to chronic low levels of mercury (Hg). Hg exposure from dental work may also induce various chronic conditions such as elevation of amyloid protein expression, deterioration of microtubules and increase or inhibition of transmitter release at motor nerve terminal endings. Therefore, clinical studies of Hg toxicity in dentistry may provide new knowledge about disturbed metal homeostasis in neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and mood disorders. The purpose of this MiniReview is to evaluate the evidence of possible relevance between Hg exposure in dentistry and idiopathic disturbances in motor functions, cognitive skills and affective reactions, as well as dose-response relationships.
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| 26. |
- Björn, Niclas, et al.
(author)
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ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
- 2018
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In: Basic & Clinical Pharmacology & Toxicology. - : WILEY. - 1742-7835 .- 1742-7843. ; 123:3, s. 277-287
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Journal article (peer-reviewed)abstract
- The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.
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| 27. |
- Björn, Niclas, et al.
(author)
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The association of four genetic variants with myelosuppression in gemcitabine-treated Japanese is not evident in gemcitabine/carboplatin-treated Swedes
- 2022
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In: Basic & Clinical Pharmacology & Toxicology. - : John Wiley & Sons. - 1742-7835 .- 1742-7843. ; 130:4, s. 513-521
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Journal article (peer-reviewed)abstract
- Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real-time PCR. The relationships between the risk alleles and low toxicity (non-ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3-4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.
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| 28. |
- Bouchene, Salim, 1984-, et al.
(author)
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A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat
- 2018
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 123:4, s. 407-422
-
Journal article (peer-reviewed)abstract
- Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.
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| 29. |
- Buhl, Mads, et al.
(author)
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Circulating Free Fatty Acids do not Contribute to the Acute Systemic Inflammatory Response. An Experimental Study in Porcine Endotoxaemia
- 2009
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 105:5, s. 319-326
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Journal article (peer-reviewed)abstract
- Intensive insulin therapy, aiming for strict normoglycaemia, is associated with increased survival in critically ill patients. Insulin therapy concomitantly reduces plasma-free fatty acids. Recent studies indicate that free fatty acids mediate inflammation. In addition to plasma glucose and free fatty acid-lowering effects, insulin also has anti-inflammatory properties. This study was designed to study the pro-inflammatory effects of two free fatty acid concentrations during acute endotoxaemia and controlled comparable levels of plasma glucose and insulin. Twenty pigs were anaesthetized and mechanically ventilated. Pigs were randomized to two different, constant Intralipid (R) infusion rates, throughout observation. All pigs were administered continuous intravenous infusion of endotoxin and subjected to controlled levels of p-glucose (4.5 mmol/l) and insulin by use of a hyperinsulinaemic euglycaemic clamp. Changes in circulating tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, leucocytes, insulin, glucose, free fatty acids, triglycerides, albumin, blood gases, temperature, and, haemodynamic function were monitored. Immediately following killing, biopsies were taken from heart and kidney. Biopsies were analysed for protein content of TNF-alpha, IL-6, IL-8 and IL-10. Sustained elevated and significantly different plasma levels of free fatty acids were demonstrated between groups (mean free fatty acid concentrations, 1.62 mM versus 0.58 mM, p < 0.0002). Endotoxaemia induced a steep increase in plasma TNF-alpha, IL-6 and leucocytes, however, without differences between the low- and high-free fatty acid groups. Cytokine content in heart and kidney tissue was not modified by free fatty acids. Compared with the response obtained at lower free fatty acid levels, high free fatty acid levels did not exacerbate the inflammatory response to acute endotoxaemia. Our results do not support the role of free fatty acids as a significant pro-inflammatory mediator.
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| 30. |
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| 31. |
- Burkina, Viktoriia, et al.
(author)
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Porcine cytochrome 2A19 and 2E1
- 2019
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In: Basic and Clinical Pharmacology and Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 124, s. 32-39
-
Research review (peer-reviewed)abstract
- Cytochrome P450 (CYP) is a major group of enzymes, which conduct Phase I metabolism. Among commonly used animal models, the pig has been suggested as the most suitable model for investigating drug metabolism in human beings. Moreover, porcine CYP2A19 and CYP2E1 are responsible for the biotransformation of both endogenous and exogenous compounds such as 3-methylindole (skatole), sex hormones and food compounds. However, little is known about the regulation of porcine CYP2A19 and CYP2E1. In this MiniReview, we summarise the current knowledge about the regulation of porcine CYP2A19 and CYP2E1 by environmental, biological and dietary factors. Finally, we reflect on the need for further research, to clarify the interaction between active feed components and the porcine CYP system.
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| 32. |
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| 33. |
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| 34. |
- Canaparo, Roberto, et al.
(author)
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Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples
- 2007
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 100:4, s. 240-248
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Journal article (peer-reviewed)abstract
- Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCBI) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.00 1, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
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| 35. |
- Cao, Hao
(author)
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Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
- 2016
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843.
-
Journal article (peer-reviewed)abstract
- Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed toDEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects fromDEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP mayhave detrimental effects on metabolic functions.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Cars, Thomas, et al.
(author)
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Extraction of Electronic Health Record Data in a Hospital Setting : Comparison of Automatic and Semi-Automatic Methods Using Anti-TNF Therapy as Model
- 2013
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 112:6, s. 392-400
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Journal article (peer-reviewed)abstract
- There is limited experience and methods for extractions of drug therapy data from electronic health records (EHR) in the hospital setting. We have therefore developed and evaluated completeness and consistency of an automatic versus a semi-automatic extraction procedure applied on prescribing and administration of the TNF inhibitor infliximab using a hospital EHR system in Karolinska University Hospital, Sweden. Using two different extraction methods (automatic and semi-automatic), all administered infusions of infliximab between 2007 and 2010 were extracted from a database linked to the EHR system. Extracted data included encrypted personal identity number (PIN), date of birth, sex, time of prescription/administration, healthcare units, prescribed/administered dose and time of admission/discharge. The primary diagnosis (ICD-10) for the treatment with infliximab was extracted by linking infliximab infusions to their corresponding treatment episode. A total of 13,590 infusions of infliximab were administered during the period of 2007 to 2010. Of those were 13,531 (99.6%) possible to link to a corresponding treatment episode, and a primary diagnosis was extracted for 13,530 infusions. Information on encrypted PIN, date of birth, time of prescription/administration, time of admission/discharge and healthcare unit was complete. Information about sex was missing in one patient only. Calculable information about dosage was extracted for 13,300 (98.3%) of all linked infusions. This methodological study showed the potential to extract drug therapy data in a hospital setting. The semi-automatic procedure produced an almost complete pattern of demographics, diagnoses and dosages for the treatment with infliximab.
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| 40. |
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| 41. |
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| 42. |
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| 43. |
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| 44. |
- Choong, Eva, et al.
(author)
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Sex difference in formation of propofol metabolites : a replication study
- 2013
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 113:2, s. 126-131
-
Journal article (peer-reviewed)abstract
- Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.
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| 45. |
- Dahl, Svein G., et al.
(author)
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Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic-Pharmacodynamic Models : A Conceptual Framework
- 2010
-
In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 106:1, s. 2-12
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Research review (peer-reviewed)abstract
- The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic-target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi-mechanistic models has been made, examples being chemotherapy-induced myelosuppression and glucose-endogenous insulin-antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the 'bridging' model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made.
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| 46. |
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| 47. |
- Dahlgren, David, et al.
(author)
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Evaluation and validation of chemotherapy‐specific diarrhoea and histopathology in rats
- 2022
-
In: Basic & Clinical Pharmacology & Toxicology. - : John Wiley & Sons. - 1742-7835 .- 1742-7843. ; 131:6, s. 536-546
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Journal article (peer-reviewed)abstract
- Chemotherapy-induced mucositis is characterized by diarrhoea and villous atrophy. However, it is not well-understood why diarrhoea arises, why it only occurs with some chemotherapeutics and how it is related to villus atrophy. The objectives in this study were to determine (i) the relationship between chemotherapy-induced diarrhoea and villus atrophy and to (ii) establish and validate a rat diarrhoea model with clinically relevant endpoints. Male Wistar Han IGS rats were treated with saline, doxorubicin, idarubicin, methotrexate, 5-fluorouracil, irinotecan or 5-fluorouracil+irinotecan. After 72 h, jejunal tissue was taken for morphological, apoptotic and proliferative analyses, and faecal water content and change in body weight were determined. All treatments except methotrexate caused a similar reduction (≈42%) in villus height, but none of them altered mucosal crypt cell proliferation or apoptosis. Doxorubicin, idarubicin, irinotecan and 5-fluorouracil+irinotecan caused body weight reduction, but only irinotecan and idarubicin caused diarrhoea. No direct correlation between diarrhoea and villus height or body weight loss was observed. Therefore, studies of the mechanisms for chemotherapy-induced diarrhoea should focus on functional factors. Finally, the irinotecan and idarubicin diarrhoea models established in this study will be useful in developing supportive treatments of this common and serious adverse effect in patients undergoing chemotherapy.
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| 48. |
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| 49. |
- Efsen, Eva, et al.
(author)
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Ramiprilate Inhibits Functional Matrix Metalloproteinase Activity in Crohns Disease Fistulas
- 2011
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In: Basic & Clinical Pharmacology & Toxicology. - : WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA. - 1742-7835 .- 1742-7843. ; 109:3, s. 208-216
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Journal article (peer-reviewed)abstract
- Increased expression of matrix metalloproteinase (MMP)-2, -3 and -9 has been demonstrated in Crohns disease fistulas, but it is unknown whether these enzymes are biologically active and represent a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue and examined the effect of inhibitors, including clinically available drugs that beside their main action also suppress MMPs. Fistula specimens were obtained by surgical excision from 22 patients with Crohns disease and from 10 patients with fistulas resulting from other causes. Colonic endoscopic biopsies from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene-diamine-tetraacetic acid (EDTA), the synthetic broad-spectrum inhibitor, GM6001, the angiotensin-converting enzyme (ACE) inhibitor, ramiprilate, and the tetracycline, doxycycline. In Crohns disease fistulas, about 50% of the total protease activity was attributable to MMP activity. The average total MMP activity was significantly higher (about 3.5-times) in Crohns fistulas (471 FU/mu g protein, range 49-2661) compared with non-Crohns fistulas [134 FU/mu g protein, range 0-495, (p andlt; 0.05)] and normal colon [153 FU/mu g protein, range 77-243, (p andlt; 0.01)]. MMP-3 activity was increased in Crohns fistulas (1.4 ng/ml, range 0-9.83) compared with non-Crohns fistulas, [0.32 ng/ml, range 0-2.66, (p andlt; 0.02)]. The same applied to MMP-9 activity [0.64 ng/ml, range 0-5.66 and 0.17 ng/ml, range 0-1.1, respectively (p andlt; 0.04)]. Ramiprilate significantly decreased the average total MMP activity level by 42% and suppressed the specific MMP-3 activity by 72%, which is comparable to the effect of GM6001 (87%). Moreover, MMP-9 activity was completely blunted by ramiprilate. Doxycycline had no effect on MMP activity. Increased functional MMP activity, notably MMP-3 and -9, is present in Crohns fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor.
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| 50. |
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