| 1. |
- Aziz, Mohd Yusmaidie, 1984, et al.
(författare)
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Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation
- 2018
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549. ; 107:5, s. 1461-1467
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Tidskriftsartikel (refereegranskat)abstract
- The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by liquid chromatography-tandem mass spectrometry as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 mu M(29), K-i = 0.68 mu M (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 mu M (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were k(inact) = 0.024 min(-1) (30) and K-I = 1.63 mu M(17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and K-i values of 0.057 mu M (17) and 0.043 mu M (3), respectively. M1 and M5 metabolites did not show any inhibitory properties within the limits of assay used. Average (95th percentile) simulated in vivo areas under the curve of midazolam increased 2.2-fold (3.7-fold) on the third which is the last day of piperaquine dosing, whereas for its metabolite M2, areas under the curve of midazolam increased 7.7-fold (13-fold). (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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| 2. |
- Aziz, Mohd Yusmaidie, 1984, et al.
(författare)
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LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma
- 2017
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232. ; 1063, s. 253-258
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma. Results: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508 nM with a runtime of 7.0 min per sample. The method was applied to clinical samples from healthy volunteers. Conclusion: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo.
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| 3. |
- Bamia, Christina, et al.
(författare)
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Dietary patterns and survival of older Europeans : the EPIC-Elderly Study (European Prospective Investigation into Cancer and Nutrition)
- 2007
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Ingår i: Public Health Nutrition. - : Cambridge University Press. - 1368-9800 .- 1475-2727. ; 10:6, s. 590-598
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the association of a posteriori dietary patterns with overall survival of older Europeans.Design and setting: This is a multi-centre cohort study. Cox regression analysis was used to investigate the association of the prevailing, a posteriori-derived, plant-based dietary pattern with all-cause mortality in a population of subjects who were 60 years or older at recruitment to the European Prospective Investigation into Cancer and Nutrition (EPIC-Elderly cohort). Analyses controlled for all known potential risk factors.Subjects: In total, 74 607 men and women, 60 years or older at enrolment and without previous coronary heart disease, stroke or cancer, with complete information about dietary intakes and potentially confounding variables, and with known survival status as of December 2003, were included in the analysis.Results: An increase in the score which measures the adherence to the plant-based diet was associated with a lower overall mortality, a one standard deviation increment corresponding to a statistically significant reduction of 14% (95% confidence interval 5–23%). In country-specific analyses the apparent association was stronger in Greece, Spain, Denmark and The Netherlands, and absent in the UK and Germany.Conclusions: Greater adherence to the plant-based diet that was defined a posteriori in this population of European elders is associated with lower all-cause mortality. This dietary score is moderately positively correlated with the Modified Mediterranean Diet Score that has been constructed a priori and was also shown to be beneficial for the survival of the same EPIC-Elderly cohort.
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| 4. |
- Bienvenu, Emile, et al.
(författare)
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A rapid and selective HPLC-UV method for the quantitation of efavirenz in plasma from patients on concurrent HIV/AIDS and tuberculosis treatments.
- 2013
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Ingår i: Biomedical chromatography : BMC. - : Wiley. - 1099-0801 .- 0269-3879. ; 27:11, s. 1554-9
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Tidskriftsartikel (refereegranskat)abstract
- Owing to heterogeneity in therapeutic response, efavirenz is of research and clinical interest. There is a need to quantitate it using noncostly and selective methods. A method for efavirenz quantitation in plasma containing HIV and tuberculosis drugs was developed. Chromatographic separation was carried out using a C18 column. The mobile phase consisted of 0.1% formic acid and acetonitrile, and was pumped at a flow rate of 0.3 mL/min. Efavirenz and ritonavir (internal standard) were monitored at 247 nm. Plasma proteins were precipitated by centrifugation. The analysis time was 6 min. The response was linear (r=0.9997). The accuracy ranged between 98 and 115% (intraday) and between 99 and 117% (interday). The precision ranged from 1.670 to 4.087% (intraday) and from 3.447 to 13.347% (interday). Recovery ranged from 98 to 132%. Stability ranged between 99 and 123%. The selectivity was proven by analysis of drugs used for the management of HIV/AIDS and tuberculosis. Plasma sample analysis showed an efavirenz retention time of 5.57 min and a peak plasma concentration of 2.4 µg/mL occurring at 2 h. This method is rapid and selective, and thus suitable for monitoring efavirenz in patients with HIV/AIDS alone or co-infected with tuberculosis in a less resourced setting.
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| 5. |
- Birgersson, Sofia, 1976, et al.
(författare)
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A high-throughput LC-MS/MS assay for quantification of artesunate and its metabolite dihydroartemisinin in human plasma and saliva.
- 2014
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Ingår i: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 6:18, s. 2357-69
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Saliva is an alternative sampling matrix to plasma, offering a noninvasive technique, but requires a highly sensitive bioanalytical method. MATERIALS & METHODS: An API 3000 triple quadrupole mass spectrometer with an electrospray ionization source operated in the positive ion mode was used for the analysis. RESULTS: A high-throughput LC-MS/MS method using SPE for the quantification of artesunate and dihydroartemisinin in plasma and saliva has been optimized and validated according to US FDA guidelines. For both analytes the LLOQ was determined to 5 ng/ml and the calibration range was 5-1000 ng/ml for artesunate and 5-2000 ng/ml for dihydroartemisinin. CONCLUSION: For the first time, a bioanalytical method for determination of artesunate and dihydroartemisinin in human saliva has been described, showing possible applicability in clinical saliva samples in addition to plasma samples.
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| 6. |
- Boeing, Heiner, et al.
(författare)
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Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study
- 2006
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 17:7, s. 957-969
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992-1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83-1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92-1.02) and RR = 0.89 (95% CI: 0.78-1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (< 120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake.
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| 7. |
- Eckernäs, Emma, 1992, et al.
(författare)
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Development and application of a highly sensitive LC-MS/MS method for simultaneous quantification of N,N-dimethyltryptamine and two of its metabolites in human plasma.
- 2022
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Ingår i: Journal of pharmaceutical and biomedical analysis. - : Elsevier BV. - 1873-264X .- 0731-7085. ; 212
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Tidskriftsartikel (refereegranskat)abstract
- A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated. Chromatography was performed using a diphenyl column with gradient elution (0.1% formic acid in methanol/water). The mass spectrometer was operated in multiple reaction monitoring mode. A methanolic solution containing internal standards 2-methylindole 3-acetic acid and deuterated DMT, was added to plasma samples, followed by protein precipitation with acetonitrile. The samples were centrifuged and supernatants transferred to new tubes and evaporated to dryness before reconstitution in aqueous mobile phase. The method was validated with regards to accuracy, precision, sensitivity, selectivity, recovery, matrix effects, stability, carry-over and dilution integrity. The validated linear range was 0.25-200nM for DMT and 15-250nM for DMT N-oxide. For the endogenous compound indole-3-acetic acid a different approach was taken due to its significant presence in blank samples. The change in signal response from a blank sample was used when constructing the calibration curve with linearity demonstrated between elevations of 500-5000nM above the blank. Applicability of the described method was demonstrated through analysis of plasma samples from healthy volunteers having received intravenous injections of DMT. The presented method for rapid and sensitive quantification of DMT and its metabolites in human plasma can be applied to future studies aiming to characterize DMT disposition and its relationship to immediate psychedelic or long-term antidepressive effects.
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| 8. |
- Eckernäs, Emma, 1992, et al.
(författare)
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N, N-dimethyltryptamine forms oxygenated metabolites via CYP2D6-an in vitro investigation
- 2023
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Ingår i: Xenobiotica. - 0049-8254. ; 53:8-9, s. 515-522
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Tidskriftsartikel (refereegranskat)abstract
- N, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT. This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high-resolution mass spectrometry for metabolite identification.DMT was rapidly metabolised by CYP2D6, while stable with all other investigated CYP enzymes. The metabolism of DMT in HLM was reduced after inclusion of harmine and SKF-525A whereas quinidine did not affect the metabolic rate, likely due to MAO-A residues present in HLM. Analysis of the CYP2D6 incubates showed formation of mono-, di- and tri-oxygenated metabolites, likely as a result of hydroxylation on the indole core. More research is needed to investigate the role of this metabolic pathway in vivo and any pharmacological activity of the proposed metabolites. Our findings may impact on safety issues following intake of ayahuasca in slow CYP2D6 metabolizers or with concomitant use of CYP2D6 inhibitors.
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| 9. |
- Ericsson, Therese, 1984, et al.
(författare)
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Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies.
- 2014
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 44:7, s. 615-626
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Tidskriftsartikel (refereegranskat)abstract
- 1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug–drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC–MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro–in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.
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| 10. |
- Fahey, Michael T., et al.
(författare)
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Identifying dietary patterns using a normal mixture model: application to the EPIC study
- 2012
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 1470-2738 .- 0143-005X. ; 66:1, s. 89-94
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Tidskriftsartikel (refereegranskat)abstract
- Background Finite mixture models posit the existence of a latent categorical variable and can be used for probabilistic classification. The authors illustrate the use of mixture models for dietary pattern analysis. An advantage of this approach is taking classification uncertainty into account. Methods Participants were a random sample of women from the European Prospective Investigation into Cancer. Food consumption was measured using dietary questionnaires. Mixture models identified latent classes in food consumption data, which were interpreted as dietary patterns. Results Among various assumptions examined, models allowing the variance of foods to vary within and between classes fit better than alternatives assuming constant variance (the K-means method of cluster analysis also makes the latter assumption). An eight-class model was best fitting and five patterns validated well in a second random sample. Patterns with lower classification uncertainty tended to be better validated. One pattern showed low consumption of foods despite being associated with moderate body mass index. Conclusion Mixture modelling for dietary pattern analysis has advantages over both factor and cluster analysis. In contrast to these other methods, it is easy to estimate pattern prevalence, to describe patterns and to use patterns to predict disease taking classification uncertainty into account. Owing to substantial error in food consumptions, any analysis will usually find some patterns that cannot be well validated. While knowledge of classification uncertainty may aid pattern evaluation, any method will better identify patterns from food consumptions measured with less error. Mixture models may be useful to identify individuals who under-report food consumption.
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