RESUMO
BACKGROUND: Androgen receptor signaling is crucial to prostate cancer aggressiveness. Members of the solute carrier family of the organic anion transporting peptides (SLCO) are potential regulators of androgen availability in prostate tissue. It remains unknown whether genetic variations in SLCOs contribute to the differences in prostate cancer aggressiveness in African Americans (AA) and European Americans (EA). METHODS: SNPs in 11 SLCO members were selected, with addition of 139 potentially functional SNPs and 128 ancestry informative markers. A total of 1,045 SNPs were genotyped and analyzed in 993 AAs and 1,057 EAs from the North Carolina-Louisiana Prostate Cancer Project. Expression and cellular localization of SLCOs were examined using qRT-PCR, IHC, and in situ RNA hybridization in independent sets of prostate cancer cases. RESULTS: Significant associations with prostate cancer characteristics were found for SNPs in SLCO2A1 and SLCO5A1. The associations differed by race (P interaction < 0.05). SNPs in SLCO2A1 were associated with reduced tumor aggressiveness and low Gleason score in AAs; whereas, SNPs in SLCO5A1 were associated with high clinical stage in EAs. In prostate tissue, SLCO2A1 and SLCO5A1 were the most expressed SLCOs at the mRNA level and were expressed predominantly in prostate endothelial and epithelial cells at the protein level, respectively. CONCLUSIONS: SLCO2A1 and SLCO5A1 play important but different roles in prostate cancer aggressiveness in AAs versus EAs. IMPACT: The finding calls for consideration of racial differences in biomarker studies of prostate cancer and for investigations on functions of SLCO2A1 and SLCO5A1 in prostate cancer.
Assuntos
Transportadores de Ânions Orgânicos/sangue , Neoplasias da Próstata/sangue , Adulto , Negro ou Afro-Americano , Idoso , Alelos , Biomarcadores Tumorais/sangue , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/mortalidade , População BrancaRESUMO
OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of a single 50-mg oral dose of diclofenac potassium for oral solution (OS) in a pediatric cohort with a diagnosis of episodic migraine; the 3-month safety trial following an outpatient dosing period was also evaluated. BACKGROUND: Children and adolescents often experience migraine pain that is poorly controlled, which may affect their emotional and psychological well-being. Diclofenac potassium for OS is approved for the treatment of migraine with aura (MWA) or migraine without aura (MWoA) in adults 18 years of age or older. It is formulated in a soluble buffered powder that provides more rapid absorption than the tablet formulations of diclofenac potassium. In a randomized, double-blind, crossover trial, more adult patients were pain-free at 2 hours post-dose following treatment with diclofenac potassium for OS than those who received the diclofenac tablet formulation or placebo. METHODS: This was a Phase 4 open-label study that took place at 2 US sites. Participants 12-17 years of age with a diagnosis of episodic MWA or MWoA for ≥3 months and ≤14 headaches per month were enrolled in the study. Participants received one 50-mg dose of diclofenac potassium for OS under fasted conditions on day 1. Blood samples were collected for PK analysis within 15 minutes pre-dose and at 5, 10, 15, 20, 30, 40, and 60 minutes post-dose, and at 2, 4, and 6 hours post-dose. Safety evaluations were performed after the initial dose and at the end of study on day 90; adverse events were monitored throughout the study. After completing the PK assessments, participants were given a 3-month supply (27 packets) of diclofenac potassium for OS (50-mg doses) for their migraine attacks. Participants were advised to take diclofenac potassium for OS at the onset of a migraine. They were told to take no more than 2 doses daily and not to use it more than 3 days/week. RESULTS: Twenty-five participants completed the study; 84% were females and 96% were white or Caucasian, with a mean age of 15.5 years and a mean weight of 63.1 kg. Diclofenac was rapidly absorbed with a median time to maximum concentration of 15 minutes and a mean peak plasma concentration of 1412 (±846.2) ng/mL. Diclofenac had a half-life of 66.8 (±9.2) minutes. The mean area under the concentration-time curve from zero to the last measurable time point was 82,920.0 (±25,327.6) minutes × ng/mL, and the mean area under the concentration-time curve from time zero to infinity was 84,388.8 (±25,993.6) minutes × ng/mL. Participants took the study drug an average of 10 times over 79 days, with an overall total drug exposure of 506 mg. No deaths or discontinuations due to an AE were reported during the study. The most frequently reported treatment emergent adverse events were arthralgia and motion sickness, each of which occurred in 2 (8%) of the participants. CONCLUSIONS: Diclofenac potassium for OS exhibited a favorable pharmacokinetic and safety profile in 12- to 17-year-old patients with a diagnosis of episodic MWA or MWoA.