| 1. |
- Theakstone, Ashton G., et al.
(författare)
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Vibrational spectroscopy for the triage of traumatic brain injury computed tomography priority and hospital admissions
- 2022
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 39:11-12, s. 773-783
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Tidskriftsartikel (refereegranskat)abstract
- Computed tomography (CT) brain imaging is routinely used to support clinical decision-making in patients with traumatic brain injury (TBI). Only 7% of scans, however, demonstrate evidence of TBI. The other 93% of scans contribute a significant cost to the healthcare system and a radiation risk to patients. There may be better strategies to identify which patients, particularly those with mild TBI, are at risk of deterioration and require hospital admission. We introduce a blood serum liquid biopsy that utilizes attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy with machine learning algorithms as a decision-making tool to identify which patients with mild TBI will most likely present with a positive CT scan. Serum samples were obtained from patients (n = 298) patients who had acquired a TBI and were enrolled in CENTER-TBI and from asymptomatic control patients (n = 87). Injury patients (all severities) were stratified against non-injury controls. The cohort with mild TBI was further examined by stratifying those who had at least one CT abnormality against those who had no CT abnormalities. The test performed exceptionally well in classifications of patients with mild injury versus non-injury controls (sensitivity = 96.4% and specificity = 98.0%) and also provided a sensitivity of 80.2% when stratifying mild patients with at least one CT abnormality against those without. The results provided illustrate the test ability to identify four of every five CT abnormalities and show great promise to be introduced as a triage tool for CT priority in patients with mild TBI.
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| 2. |
- Amilon, Carl, et al.
(författare)
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Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy
- 2022
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Ingår i: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 24:3
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Tidskriftsartikel (refereegranskat)abstract
- (Carl Amilon and Mikael Boberg contributed equally to this work) Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.
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| 3. |
- Asimus, Sara, 1976, et al.
(författare)
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Artemisinin--a possible CYP2B6 probe substrate?
- 2009
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Ingår i: Biopharmaceutics & drug disposition. - : Wiley. - 1099-081X .- 0142-2782. ; 30:5, s. 265-75
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To compare in vitro metabolism rates for artemisinin and the CYP2B6 substrates, bupropion, propofol and efavirenz in human liver microsomes. METHODS: Rate constants of artemisinin, bupropion, propofol and efavirenz metabolism by human liver microsomes from a panel of 12 donors, with different levels of CYP2B6 activity, were estimated in WinNonlin. Correlations between the metabolic rate constant for artemisinin and the other CYP2B6 substrates were examined. RESULTS: Artemisinin and propofol depletion data in human liver microsomes were described by first order kinetic models. For bupropion and efavirenz, metabolite formation data were incorporated in the model. Rate constants varied considerably for all substrates. There was a high degree of correlation of rate constants between substrates (r> or =0.87, p<0.001). CONCLUSIONS: The rate of in vitro metabolism of artemisinin was correlated significantly to that of bupropion, propofol and efavirenz, suggesting artemisinin to be a potential alternative marker to assess CYP2B6 activity. Further studies characterizing the metabolic fate of artemisinin are needed in order to evaluate its utility as an in vitro and in vivo CYP2B6 probe substrate, since CYP2B6 might not be the only CYP isoform involved in the depletion of artemisinin.
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| 4. |
- Asimus, Sara, 1976, et al.
(författare)
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Artemisinin and CYP2A6 activity in healthy subjects.
- 2007
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 64:3, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6. METHODS: Twelve healthy male Vietnamese subjects were given coumarin or nicotine in randomized sequence before and after 5 days of a repeated oral administration of artemisinin during two different treatment periods 1 month apart. Sequential blood samples were drawn at baseline 7 days prior to artemisinin treatment and on the first and fifth day of artemisinin treatment during both treatment periods. Plasma concentrations of 7-hydroxycoumarin glucuronide (7-OHCG), nicotine, cotinine and artemisinin were analysed by high-performance liquid chromatography and those of coumarin and 7-hydroxycoumarin (7-OHC) were determined by liquid chromatography-tandem mass spectrometry. Urine, collected in two time intervals on the days of coumarin intake, was treated with beta-glucuronidase and analysed for 7-OHC levels. RESULTS: Artemisinin [Formula: see text] values decreased significantly to 23% [95% confidence interval (CI) 18%-28%] on the fifth day of artemisinin administration as compared with the first. The sum of renally excreted 7-OHC and 7-OHCG increased by 1.55-fold (adjusted 95% CI 1.08-2.23) in the 3- to 8-h interval compared to baseline 7 days before. The 7-OHCG/7-OHC plasma [Formula: see text] ratio increased by 1.72-fold (adjusted 95% CI 1.16-2.54) following 5 days of artemisinin intake. There was no significant change in the cotinine/nicotine AUC(0-11 hr) ratio between study days. CONCLUSION: Artemisinin significantly increased the sum of renally excreted 7-OHC and 7-OHCG in one of the two collection intervals, suggesting an induction of CYP2A6. A significant increase in the 7-OHCG to 7-OHC [Formula: see text] ratio indicates artemisinin to be an inducer of glucuronidation.
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| 5. |
- Asimus, Sara, 1976, et al.
(författare)
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Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects.
- 2007
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Ingår i: Fundamental & Clinical Pharmacology. - : Wiley. - 0767-3981 .- 1472-8206. ; 21:3, s. 307-316
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy-five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1–5). A six-drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days −6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four-hour plasma concentrations of parent drugs and corresponding metabolites and 7-hydroxycoumarin urine concentrations were quantified by liquid chromatography-tandem mass spectrometry. The 1-hydroxymidazolam/midazolam 4-h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66-fold (98.75% CI: 2.10–3.36)], artemether [1.54 (1.14–2.09)] and dihydroartemisinin [1.25 (1.06–1.47)] compared with day −6. The S-4'-hydroxymephenytoin/S-mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47–1.94)] and arteether [1.33 (1.15–1.55)] compared with day −6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18–0.39)], arteether [0.70 (0.55–0.89)] and dihydroartemisinin [0.73 (0.59–0.90)] compared with day −6. The α-hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day −6 in the artemisinin [0.82 (0.70–0.96)] and dihydroartemisinin [0.83 (0.71–0.96)] groups, respectively. In the artemisinin-treated subjects this decrease was followed by a 1.34-fold (1.14–1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Bienvenu, Emile, et al.
(författare)
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Frequencies of Single Nucleotide Polymorphisms in Cytochrome P450 Genes in a Rwandan Population: Difference to Other African Populations
- 2013
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Ingår i: Current Pharmacogenomics and Personalized Medicine. - 1875-6921 .- 1875-6913. ; 11:3, s. 237-246
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Tidskriftsartikel (refereegranskat)abstract
- The cytochrome P450 (CYP450) enzymes play a key role for interindividual variability in drug response. No comprehensive pharmacogenetic data are yet available for the Rwandan population in regards to single nucleotide polymorphisms in CYP450s of major importance for personalized medicine. This study investigated the genotype and allele frequencies with respect to relevant SNPs for CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 genes in Rwandan subjects (n=80). Results were compared with data from South African and Cameroonian populations using Pearson's χ2 and Fisher's Exact statistical tests. Genetic variation was observed in 11 out of the 13 SNPs in the above CYP450 genes. There were significant differences in the distribution of the allelic variants when the Rwandan sample was compared to the Cameroonian and the South African groups, with respect to CYP2A6 1093G>A SNP (P=0.0033 and 0.019, respectively) and CYP3A4 -392A>G SNP (P=0.0001 and 0.0084, respectively). The distribution of the CYP1A2-163C>A SNP differed between the Rwandans and the South Africans (P=0.0001), and CYP3A5 6986A>G SNP between the Rwandan and the Cameroonian subjects (P=0.017). The polymorphisms CYP2B6 516G>T and 785A>G did not show significant differences (P>0.05) between the Rwandans, Cameroonians and South Africans in the distribution of the 516T and the 785G variants. This is the first study evaluating the allele and genotype frequencies of these key CYP450 genes in Rwandan subjects. The results demonstrate the need to further characterize individual African populations with respect to genetic variations in order for personalized medicine to be realized among Africans. These data will also help illuminate the future planning of pharmacodynamic studies aimed at associations of these pharmacogenetic variants with drug safety and efficacy in Rwanda. © 2013 Bentham Science Publishers.
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| 10. |
- Bienvenu, Emile, et al.
(författare)
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The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients
- 2014
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Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542. ; 102, s. 44-53
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Tidskriftsartikel (refereegranskat)abstract
- Efavirenz (EFV) exhibits interindividual pharmacokinetic variability caused by differences in cytochrome P450 (CYP) expression. Most tuberculosis (TB) drugs interact with the CYP metabolizing enzymes, while the clinical validity of genotyping in predicting EFV plasma levels in Rwandan subjects is not known. We investigated in patients co-infected with human immunodeficiency virus (HIV) and TB recruited in Rwanda the effects of 10 SNPs in five drug-metabolizing enzymes on EFV plasma levels and treatment response when patients are treated with EFV-containing therapy alone (n= 28) and when combined with rifampicin-based TB treatment (n= 62), and the validity of genotyping for CYP2B6 single nucleotide polymorphisms in predicting supra-therapeutic EFV levels. There was a significant difference between CYP1A2 -739T/G and T/T genotypes when patients were treated with EFV-containing therapy combined with rifampicin-based TB treatment, but not when EFV-containing therapy was alone. CYP2B6 516T/T genotype was associated with high EFV levels compared to other CYP2B6 516G>T genotypes in the presence and in the absence of rifampicin-based TB treatment. Predictive factors of EFV plasma levels in the presence of rifampicin-based TB treatment were CYP2A6 1093G>A, CYP2B6 516G>T, and CYP2B6 983T>C accounting for 27%, 43%, and 29% of the total variance in EFV levels, respectively. There was a high positive predictive value (PPV) (100%) for CYP2B6 516T/T and 983T/T genotypes in predicting EFV plasma levels above the therapeutic range, but this PPV decreased in the presence of rifampicin-based TB treatment. Rifampicin-based TB treatment was also shown to affect EFV plasma levels significantly, but did not affect the significant reduction of HIV-RNA copies. These results indicate that genotyping for CYP2B6 SNPs could be used as a tool in predicting supra-therapeutic EFV plasma levels, which could minimize adverse drug events. © 2013 Elsevier B.V.
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