METHODS: The cold pressor pain responses of 148 opioid dependent patients receiving MMT were evaluated using the cold pressor test (CPT). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR)-genotyping.
RESULTS: Of the 148 subjects, 77 (52.0%) were carriers of CYP2B6*6 allele. CYP2B6*6 allele carriers had shorter cold pain threshold and pain tolerance times than non-carriers of CYP2B6*6 allele (21.05s vs 33.69s, p=0.036 and 27.15s vs 44.51s, p=0.020, respectively). Pain intensity scores of the CYP2B6*6 allele carriers was 67.55, whereas that of the CYP2B6*6 allele non-carriers was 64.86 (p=0.352).
CONCLUSION: Our study indicates that the CYP2B6*6 allele is associated with a lower pain threshold and lower pain tolerance among males with opioid dependence on MMT. The CYP2B6*6 allele may provide a mechanistic explanation for clinical observations of heightened pain sensitivity among opioid dependent patients receiving MMT.
RESULTS: The mRNA expression of PPARα was significantly induced in HCT116 cells following treatment with chrysin for 36 h, but the mRNA expression of PPARα was inhibited, when the cells were treated with a combination of chrysin and MK886 (PPARα inhibitor). This phenomenon proved that the incorporation of MK886 lowers the expression levels of PPARα, thus enabling us to study the function of PPARα. The cell population of the G0/G1 phase significantly increased in chrysin-treated cells, which was accompanied by a decrease in the percentage of S phase cell population after 12 h of treatment. However, treatments of HCT116 cells with chrysin only or a combination of chrysin and MK886 did not show the opposite situation in the G0/G1 and S phase cell populations, indicating that the expression of PPARα may not be associated with the cell cycle in the treated cells. The migration rate in chrysin-treated HCT116 cells was reduced significantly after 24 and 36 h of treatments. However, the activity was revived, when the expression of PPARα was inhibited, indicating that the migration activity of chrysin-treated cells is likely correlated with the expression of PPARα. Comparison of the CYP2S1 and CYP1B1 mRNA expression in chrysin only treated, and a combination of chrysin and MK886-treated HCT116 cells for 24 and 36 h showed a significant difference in the expression levels, indicating that PPARα inhibitor could also modify the expression of CYP2S1 and CYP1B1.
CONCLUSION: The study indicates that PPARα may play an essential role in regulating the migration activity, and the expression of CYP2S1 and CYP1B1 in chrysin-treated colorectal cancer cells.
OBJECTIVE: This study sought to detect CYP2B6 and OPRM1 variants and their genotypes, as major contributors to inter-variability in methadone responsiveness and methadone dose requirements.
METHODS: We carried out a prospective experimental one-phase pharmacogenetic study in four addiction clinics in Malaysia. Patients on stable methadone maintenance therapy were recruited. The prevalence of the CYP2B6 and OPRM1 polymorphisms was determined using a nested polymerase chain reaction (PCR), followed by genotyping. A two-step multiplex PCR method was developed to simultaneously detect the 26 SNPs in these two genes.
RESULTS: 120 males were recruited for this study. The patients were between 21and 59 years old, although the majority of the patients were in their 30s. C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1 were found to be polymorphic, and the allelic frequencies of each were calculated. We further detected eight new haplotypes.
CONCLUSION: C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1were found to be polymorphic. The new haplotypes may give a new insight on methadone clinics.
AIM: This is a planned interim analysis of pathfinder™3, an international, open-label, Phase 3 trial evaluating the efficacy and safety (including immunogenicity) of N8-GP administered before, during and after major surgery in severe haemophilia A patients aged ≥12 years.
METHODS: Sixteen patients who underwent 18 major surgical procedures (including synovectomy, joint replacement and ankle arthrodesis) were included here. Postoperative assessments were conducted daily for days 1-6, and once for days 7-14. Primary endpoint was N8-GP haemostatic efficacy, assessed after completion of surgery using a four-point scale ('excellent', 'good', 'moderate', 'none').
RESULTS: Haemostasis was successful (rated 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures and rated as 'moderate' (5.6%) for one surgery in a patient with multiple comorbidities who needed an intraoperative N8-GP dose (20.7 IU kg-1 ). In the postoperative period, three bleeds occurred (one during days 1-6; two during days 7-14); all were successfully treated with N8-GP. Mean N8-GP consumption on day of surgery was 80.0 IU kg-1 ; patients received a mean of 1.7 doses (median: 2, range: 1-3). No safety concerns were identified.
CONCLUSION: The data showed that N8-GP was effective and well tolerated for the prevention and treatment of bleeds during major surgery; such FVIII products with extended half-lives may modify current treatment schedules, enabling fewer infusions and earlier patient discharge.
Methods: The nanoemulsions were formulated using a high-pressure homogenization technique and were characterized for their physicochemical properties.
Results: The characterizations revealed a particle size of 100.32±0.75 nm, polydispersity index of 0.18±0.01, zeta potential of -46.9±1.39 mV, viscosity of 1.24±0.34 cps, and osmolality of 285.33±0.58 mOsm/kg, indicating that the nanoemulsion has compatibility for parenteral application. CLN was physicochemically stable within 6 months of storage at 4°C, and the transmission electron microscopy revealed that the CLN droplets were almost spherical in shape. The in vitro release of CLN profile followed a sustained release pattern. The pharmacokinetic profile of CLN showed a significantly higher Cmax, area under the curve (AUC)0-
t
, prolonged half-life, and lower total plasma clearance, indicating that the systemic concentration of cefuroxime was higher in CLN-treated rats as compared to cefuroxime-free treated rats. A similar profile was obtained for the biodistribution of cefuroxime in the brain, in which CLN showed a significantly higher Cmax, AUC0-
t
, prolonged half-life, and lower clearance as compared to free cefuroxime solution.
Conclusion: Overall, CLN showed excellent physicochemical properties, fulfilled the requirements for parenteral administration, and presented improved in vivo pharmacokinetic profile, which reflected its practical approach to enhance cefuroxime delivery to the brain.
METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.
RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.
CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation.
Methods: Light-induced damage to the retina was created by exposure of adult albino Sprague-Dawley rats to intense light for 24 hours. A single dose of Cx43MP, Cx43MP-NPs, or saline was injected intravitreally at 2 hours after onset of light damage. Fluorescein isothiocyanate (FITC)-labelled Cx43MP-NPs were intravitreally injected to confirm delivery into the retina. Electroretinogram (ERG) recordings were performed at 24 hours, 1 week, and 2 weeks post cessation of light damage. The retinal and choroidal layers were analyzed in vivo using optical coherence tomography (OCT) and immunohistochemistry was performed on harvested tissues using glial fibrillary acidic protein (GFAP), leukocyte common antigen (CD45), and Cx43 antibodies.
Results: FITC was visualized 30 minutes after injection in the ganglion cell layer and in the choroid. Cx43MP and Cx43MP-NP treatments improved a-wave and b-wave function of the ERG compared with saline-injected eyes at 1 week and 2 weeks post treatment, and prevented photoreceptor loss by 2 weeks post treatment. Inflammation was also reduced and this was in parallel with downregulation of Cx43 expression.
Conclusions: The slow release of Cx43MP incorporated into NPs is more effective at treating retinal injury than a single dose of native Cx43MP in solution by reducing inflammation and maintaining both retinal structure and function. This NP preparation has clinical relevance as it reduces possible ocular complications associated with repeated intravitreal injections.