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Kugelberg, Fredrik
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Publications (10 of 63) Show all publications
Haage, P., Kronstrand, R., Josefsson, M., Calistri, S., van Schaik, R. H., Green, H. & Kugelberg, F. (2018). Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype. Pharmacology Research & Perspectives, 6(4), Article ID e00419.
Open this publication in new window or tab >>Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
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2018 (English)In: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 6, no 4, article id e00419Article in journal (Refereed) Published
Abstract [en]

Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-152586 (URN)10.1002/prp2.419 (DOI)000442994300006 ()29992026 (PubMedID)2-s2.0-85052511964 (Scopus ID)
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2018-12-03Bibliographically approved
Karlsson, L., Zackrisson, A. L., Josefsson, M., Carlsson, B., Green, H. & Kugelberg, F. . (2015). Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.. The Pharmacogenomics Journal, 15(2), 165-71
Open this publication in new window or tab >>Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.
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2015 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 2, p. 165-71Article in journal (Refereed) Published
Abstract [en]

We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-116540 (URN)10.1038/tpj.2014.50 (DOI)000351780200008 ()25245581 (PubMedID)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2018-01-11
Nilsson, G., Kugelberg, F., Ahlner, J. & Kronstrand, R. (2015). Validation of an LC-MS/MS method for the determination of zopiclone, N-desmethylzopiclone and 2-amino-5-chloropyridine in whole blood and its application to estimate the original zopiclone concentration in stored specimens. International journal of legal medicine (Print), 129(2), 269-277
Open this publication in new window or tab >>Validation of an LC-MS/MS method for the determination of zopiclone, N-desmethylzopiclone and 2-amino-5-chloropyridine in whole blood and its application to estimate the original zopiclone concentration in stored specimens
2015 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 129, no 2, p. 269-277Article in journal (Refereed) Published
Abstract [en]

2-amino-5-chloropyridine (ACP) is a degradation product of zopiclone (ZOP) and may be formed when blood specimens are stored. ZOP instability in blood makes interpretation of concentrations difficult especially in cases of prolonged sample storage. This study investigated how ACP could be used to estimate the original concentration of ZOP in authentic samples. For that purpose, an analytical LC-MS/MS method for the quantitation of ACP, ZOP and the metabolite Ndesmethylzopiclone (NDZOP) in blood was validated. The method was then applied to investigate ACP formation, ZOP and NDZOP degradation in stored ZOP post-dosed authentic whole blood and two mathematical models were used to calculate the original concentration of ZOP. During storage, ACP was formed in amounts equimolar to the ZOP and NDZOP degradation. Results from samples in which ACP had been formed were used to test two models to estimate the original ZOP concentration. The correlation tests of the models showed strong correlations to the original ZOP concentration (r=0.960 and r=0.955) with p<0.01. This study showed that the equimolar degradation of ZOP and NDZOP to ACP could be used to estimate the original concentration of the unstable ZOP.

Place, publisher, year, edition, pages
Springer, 2015
Keywords
Degradation; Forensic toxicology; 2-amino-5-chloropyridine; Zopiclone; LC-MS/MS
National Category
Medical and Health Sciences Forensic Science
Identifiers
urn:nbn:se:liu:diva-105820 (URN)10.1007/s00414-014-1049-2 (DOI)000350032800007 ()25069820 (PubMedID)
Note

The article title of this article was in Manuscript: LC-MS/MS determination of 2-amino-5-chloropyridine to estimate the original zopiclone concentration in stored whole blood.

Available from: 2014-04-08 Created: 2014-04-08 Last updated: 2017-12-05Bibliographically approved
Kronstrand, R., Thelander, G., Lindstedt, D., Roman, M. & Kugelberg, F. (2014). Fatal intoxications associated with the designer opioid AH-7921. Journal of Analytical Toxicology, 38(8), 599-604
Open this publication in new window or tab >>Fatal intoxications associated with the designer opioid AH-7921
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2014 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 38, no 8, p. 599-604Article in journal (Refereed) Published
Abstract [en]

AH-7921 (3,4-dichloro-N-[(1-dimethylamino) cyclohexylmethyl] benzamide) is a designer opioid with similar to 80% of morphines m-agonist activity. Over a 6-month period, we encountered nine deaths where AH-7921 was involved and detected in blood from the deceased. Shortly after the last death, on August 1 2013, AH-7921 was scheduled as a narcotic and largely disappeared from the illicit market in Sweden. AH-7921 was measured by a selective liquid chromatography- MS-MS method and the concentrations of AH-7921 ranged from 0.03 to 0.99 mu g/g blood. Six of our cases had other drugs of abuse on board and most had other medications such as benzodiazepines, antidepressants and analgesics. However, the other medicinal drugs encountered were present in postmortem therapeutic concentrations and unlikely to have contributed to death. In addition to the parent compound, we identified six possible metabolites where two N-demethylated dominated and four mono-hydroxylated were found in trace amounts in the blood. In conclusion, deaths with AH-7921 seem to occur both at low and high concentrations, probably a result of different tolerance to the drug. Hence, it is reasonable to assume that no sharp dividing line exists between lethal and non-lethal concentrations. Further, poly-drug use did not seem to be a major contributing factor for the fatal outcome.

Place, publisher, year, edition, pages
Oxford University Press, 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-112182 (URN)10.1093/jat/bku057 (DOI)000343324100022 ()25217553 (PubMedID)
Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2018-01-11Bibliographically approved
Karlsson, L., Andersson, M., Kronstrand, R. & Kugelberg, F. (2014). Mephedrone, Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice. Basic & Clinical Pharmacology & Toxicology, 115(5), 411-416
Open this publication in new window or tab >>Mephedrone, Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice
2014 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, p. 411-416Article in journal (Refereed) Published
Abstract [en]

During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so-called bath salts include mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose-response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.

Place, publisher, year, edition, pages
Wiley: 12 months, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-112616 (URN)10.1111/bcpt.12253 (DOI)000344015300006 ()24739011 (PubMedID)
Note

Funding Agencies|National Board of Forensic Medicine in Sweden; Forensic Science Center of Linkoping University; Lions Research Foundation

Available from: 2014-12-08 Created: 2014-12-05 Last updated: 2017-12-05
Bastami, S., Haage, P., Kronstrand, R., Kugelberg, F., Zackrisson, A.-L. & Uppugunduri, S. (2014). Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose. Forensic Science International, 238, 125-132
Open this publication in new window or tab >>Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
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2014 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, p. 125-132Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Tramadol; Pharmacokinetics; Pharmacodynamics; CYP2D6; ABCB1; OPRM1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106838 (URN)10.1016/j.forsciint.2014.03.003 (DOI)000334580700025 ()24709712 (PubMedID)
Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-11-09Bibliographically approved
Nilsson, G., Kugelberg, F., Ahlner, J. & Kronstrand, R. (2014). Quantitative Analysis of Zopiclone, N-desmethylzopiclone, Zopiclone N-oxide and 2-Amino-5-chloropyridine in Urine Using LC-MS-MS. Journal of Analytical Toxicology, 38(6), 327-334
Open this publication in new window or tab >>Quantitative Analysis of Zopiclone, N-desmethylzopiclone, Zopiclone N-oxide and 2-Amino-5-chloropyridine in Urine Using LC-MS-MS
2014 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 38, no 6, p. 327-334Article in journal (Refereed) Published
Abstract [en]

A simple LC-MS/MS method was validated to allow determination of zopiclone (ZOP), Ndesmethylzopiclone (NDZOP), zopiclone N-oxide (ZOPNO) and 2-amino-5 chloropyridine (ACP) in urine at concentrations up to 3000 ng/mL within 3.5 min. This method was used for quantitative analysis of the analytes in authentic urine samples obtained 10 h after oral administration of zopiclone (Imovane®) and in aliquots of the same urine samples after different storage conditions. Additionally, pH of each studied urine sample was measured over time. The results showed that formation of ACP occurred at elevated pH and/or temperature by degradation of ZOP, NDZOP and ZOPNO. This method was also applied to samples obtained from two female victims of drug-facilitated assault. One sample had been exposed to long-term storage conditions at different temperatures and at pH>8.2, which resulted in high concentrations of ACP. The other sample, which was exposed to pH <6.5, showed no formation of ACP. ACP is formed both from ZOP and from its metabolites NDZOP and ZOPNO depending on the pH of the urine, time of storage and/or the temperature conditions. For correct interpretation in forensic cases ZOP, its major metabolites and ACP should be analyzed. When ACP is identified in urine the concentrations of ZOP, NDZOP and ZOPNO should be interpreted with great caution.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy F, 2014
Keywords
Degradation; Forensic toxicology; Zopiclone; LC-MS-MS
National Category
Clinical Medicine Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-105819 (URN)10.1093/jat/bku042 (DOI)000340069000004 ()
Available from: 2014-04-08 Created: 2014-04-08 Last updated: 2018-01-11Bibliographically approved
Karlsson, L., Green, H., Zackrisson, A. L., Bengtsson, F., Jakobsen Falk, I., Carlsson, B., . . . Kugelberg, F. (2013). ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. International journal of legal medicine (Print), 127(3), 579-586
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram
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2013 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, no 3, p. 579-586Article in journal (Refereed) Published
Abstract [en]

P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood–brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
ABCB1, Citalopram, Forensic material, Genotype, Postmortem, Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93390 (URN)10.1007/s00414-013-0849-0 (DOI)000318247100006 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
Boiso, S., Zackrisson, A. L., Jakobsen Falk, I., Karlsson, L., Carlsson, B., Tillmar, A., . . . Green, H. (2013). ABCB1 gene polymorphisms are associated with suicide in forensic autopsies. Pharmacogenetics & Genomics, 23(9), 463-469
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
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2013 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed) Published
Abstract [en]

Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

Place, publisher, year, edition, pages
Lippincott, Williams and Wilkins, 2013
Keywords
ABCB1, autopsy, forensic material, genotype, postmortem, sex, suicide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97235 (URN)10.1097/FPC.0b013e328363a9bf (DOI)000323220200002 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||Swedish Cancer Society||

Available from: 2013-09-06 Created: 2013-09-05 Last updated: 2017-12-06
Karlsson, L., Carlsson, B., Hiemke, C., Ahlner, J., Bengtsson, F., Schmitt, U. & Kugelberg, F. C. (2013). Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment. European Neuropsychopharmacology, 23(11), 1636-1644
Open this publication in new window or tab >>Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment
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2013 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 11, p. 1636-1644Article in journal (Refereed) Published
Abstract [en]

Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp.

Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. Results: In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls.

Conclusions: The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Citalopram, enantiomers, escitalopram, mice knockout, P-glycoprotein
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76122 (URN)10.1016/j.euroneuro.2013.01.003 (DOI)000328014700033 ()
Available from: 2012-03-28 Created: 2012-03-28 Last updated: 2017-12-07Bibliographically approved
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