| 1. |
- Arbring, Kerstin, et al.
(författare)
-
Comparison of prothrombin time (INR) results and main characteristics of patients on warfarin treatment in primary health care centers and anticoagulation clinics
- 2013
-
Ingår i: BMC Health Services Research. - : BioMed Central. - 1472-6963. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundOral anticoagulant therapy is used to prevent thrombosis in patients with atrial fibrillation (AF), venous thrombosis and prosthetic heart valves. The introduction of new therapies emphasizes the need to discern the best practice for the patients remaining on warfarin treatment. This study compares patient characteristics and therapeutic control in two settings managing warfarin treatment: Swedish primary health care centers (PHCC) and specialized anticoagulation clinics (ACC).MethodsProthrombin time (PT) test results reported as International Normalized Ratio (INR) were collected for five consecutive days from patients on warfarin treatment; 564 PHCC and 927 ACC patients. Therapeutic control was calculated as PT test results in relation to intended therapeutic range (TR). Mann–Whitney Rank Sum Test and Chi2 test were used for statistical comparisons.ResultsThe PHCC patients were older than the ACC patients, 76 v. 70 years (p<0.01) with a predominance of men in both groups. The reasons for treating differed between the groups. Seventy-two percent of PHCC patients and 66% of ACC patients had a PT-INR within the intended TR (p<0.05). Men generally had better results than women (72% v. 63%, p<0.001) and particularly in the PHCC group v. the ACC group (78% v. 69%, p<0.01).PT-INR above intended TR was significantly more common in the ACC setting, (p<0.05), for women overall (p<0.01), for women in the PHCC setting, and for ACC men (p<0.05).ConclusionsIn this study both settings achieved good therapeutic control of warfarin treatment with a minor advantage for PHCC over ACC, and better results for men, especially in the PHCC setting. As patient characteristics differ between the PHCC and ACC, it is important to conduct further randomized studies to discern the best practice locally for warfarin management also after the introduction of new drugs.
|
|
| 2. |
|
|
| 3. |
- Arbring, Kerstin, 1961-
(författare)
-
Two worlds, one goal : A Clinician’s Perspective on Laboratory Analyses in Anticoagulant Treatment
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Almost precisely a century ago, in the 1920s and 1930s, cattle bled to death in North America after being fed moldy hay containing sweet clover, the yellow Melilotus officinalis, and the white Melilotus albus. The toxic substance in the hay inhibiting blood coagulation was identified and named dicumarol. Further development resulted in warfarin, an oral anticoagulant that has been used for over 70 years and still is, even though newer direct-acting oral anticoagulants (DOACs) are mainly replacing it. For some patients, warfarin is still the drug of choice. A safe warfarin treatment needs repeated blood sample analysis (PT-INR), and with the new DOACs come new laboratory challenges. The aim of this thesis was to investigate ways laboratory methods can contribute to improving oral anticoagulant treatment. Paper I explores genetic variants of the enzyme targeted by warfarin, VKORC1. The result shows that the haplotype VKORC1*2 is the most important of the VKORC1 haplotypes for warfarin dosage, with a lower dose requirement. The VKORC1*2 haplotype was also related to more unstable PT-INR levels. Paper II describes a cross-section study comparing warfarin treatment control, as PT-INRs within the intended therapeutic range, in primary health care centers (PHCCs) and specialized anticoagulation clinics (ACCs). Both settings showed good therapeutic control, with at least as good therapeutic control in the PHCCs as in the ACCs. Today, almost all warfarin treatment in our region is centralized to ACCs. Paper III focuses on the modification of a point-of-care PT method. A ratio of PT from two different dilutions of each patient sample was calculated and used as an indirect measure of DOAC activity. There were close correlations between the PT ratio and drug concentrations measured at the hospital laboratory. The detection level varies between DOACs and may limit its use in some situations. Paper IV evaluated the MRX PT DOAC, an assay based on the PT ratio principle. It was found to be able to detect potentially interfering DOAC levels in plasma samples. Confirmatory testing is recommended, as is sensitivity improvement for the detection of specific interferences.
|
|
| 4. |
- Bastami, Salumeh, et al.
(författare)
-
Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.
|
|
| 5. |
- Bastami, Salumeh, et al.
(författare)
-
Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Postoperative Morphine Consumption
- 2014
-
Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 115:5, s. 423-431
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 6. |
- Bastami, Salumeh, et al.
(författare)
-
Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
- 2013
-
Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:5, s. 1022-1033
-
Tidskriftsartikel (refereegranskat)abstract
- Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.
|
|
| 7. |
- Bastami, Salumeh, et al.
(författare)
-
Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
- 2014
-
Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 238, s. 125-132
-
Tidskriftsartikel (refereegranskat)abstract
- The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50 mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.
|
|
| 8. |
- Bastami, Salumeh, 1967-
(författare)
-
Practical and clinical use of opioids
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pain is a common symptom of a number of conditions including cancer and one of the most frequent reasons for seeking healthcare. Acute and chronic pain result in considerable discomfort with a detrimental impact on the quality of life. Opioids are the mainstay of pain management for many patients with severe pain. Opioids are, unfortunately, also commonly abused drugs, and are well-represented in forensic toxicology investigations.Side effects related to the central nervous system are the major reasons fordiscontinuation of opioid treatment. In this thesis, we tested the hypothesis that local analgesic treatment by opioids, without the usual opioid-related side effects, could be a potential alternative to systemic opioid treatment. We examined the analgesic effect of topically applied morphine in a randomized, double blind, cross over study in patients with painful leg ulcers. Significant reduction of pain was obtained after application of both morphine and placebo gel. Morphine reduced pain more than placebo but the difference was not statistically significant. However, morphine could reduce pain considerably more than placebo in those cases where VAS (Visual analog scale) was higher initially.Another issue with opioid therapy is the substantial individual variability in response to opioids including morphine and tramadol. We investigated the significance of UGT2B7, CYP2D6, OPRM1 and ABCB1 polymorphisms for pharmacokinetic and pharmacodynamic properties of morphine and tramadol. We showed that genetic variants in CYP2D6 and UGT2B7 have an important role in the metabolism of tramadol and morphine respectively. While the role of SNPs in ABCB1 remained unclear, genetic variants in OPRM1 gene were correlated with the required dose of morphine. Taken together, these findings suggest that genotypes should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results.Opioids, besides their analgesic properties, have other pharmacological effects including effects on immune system. We evaluated potential differences between commonly used opiates with regard to their effect on the immune system. We found an inhibition of cytokine release, in the order of potency as follows: tramadol > ketobemidone >morphine >fentanyl. All opioids with the exception of fentanyl were capable of inhibiting production of mRNAs for TNF-alpha and IL-8. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of opioids and to improve opioid treatment strategies in patients with cancer.Here, we have found that individual genotype matters and affects the individual response. Further research is warranted to tailor individualized treatment. Personalized medicine has increased in importance and will hopefully in the near future become standard procedure to improve and predict the outcome of treatment by opioids.
|
|
| 9. |
- Bastami, Salumeh, et al.
(författare)
-
Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial : a pilot study
- 2012
-
Ingår i: International Wound Journal. - : Blackwell Publishing. - 1742-4801 .- 1742-481X. ; 9:4, s. 419-427
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.
|
|
| 10. |
- Chenna Narendra, Sudeep, et al.
(författare)
-
Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
- 2015
-
Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 10:10, s. e0141863-
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.
|
|
