| 1. |
- Elens, Laure, et al.
(författare)
-
Genetic Predisposition to Poor Opioid Response in Preterm Infants : Impact of KCNJ6 and COMT Polymorphisms on Pain Relief after Endotracheal Intubation
- 2016
-
Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:4, s. 525-533
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, Val 158 Met) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n 17) or morphine (n 17). Methods: Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes. Results: Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank 7.5, P 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank 14.4, P 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy. Conclusion: We conclude that the KCNJ6 -1250A and COMT 158 Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
|
|
| 2. |
- Matic, Maja, et al.
(författare)
-
Effect of UGT2B7-900G > A (-842G > A; rs7438135) on morphine glucuronidation in preterm newborns: results from a pilot cohort
- 2014
-
Ingår i: Pharmacogenomics. - 1462-2416 .- 1744-8042. ; 15:12, s. 1589-1597
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Assess association between UGT2B7 polymorphism -900G>A (rs7438135, also known as -842G>A) with morphine kinetics in preterm newborns undergoing mechanical ventilation. Materials & methods: Thirty-four infants were enrolled in a randomized clinical trial and allocated to rapid sequence intubation with remifentanil (1 mu g/kg) or morphine (0.3 mg/kg). The latter group was included in our study. Results: Morphine plasma concentrations at 20 min post intubation were associated with postnatal age (p = 0.017) and UGT2B7 -900G>A (p = 0.036). UGT2B7 -900A allele carriers (n = 13) had lower morphine levels compared with UGT2B7 -900G/G patients (n = 2). Morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations were only found to be associated with gestational and postnatal age. However, -900A allele carriers had a higher morphine-3-glucuronide: morphine metabolic ratio compared with patients genotyped as -900G/G (p = 0.005), as determined by linear regression. Conclusion: Our small pilot study illustrates that in addition to gestational and postnatal age, the UGT2B7 -900G>A polymorphism significantly alters morphine pharmacokinetics in preterm infants.
|
|
| 3. |
- Oosten, Astrid W, et al.
(författare)
-
A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.
- 2017
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 56:7, s. 733-746
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.METHODS: Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.RESULTS: A one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m(2) increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m(2). The clearance of morphine or its metabolites was not found to be correlated with treatment failure.CONCLUSION: The influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369.
|
|
