Influence of Genetic Polymorphisms on the Response to Tramadol, Ibuprofen, and the Combination in Patients With Moderate to Severe Pain After Dental Surgery.

PURPOSE: We aimed to elucidate the influence on analgesic effect of genetic polymorphisms in enzymes responsible for biotransformation of tramadol and ibuprofen or other possible genes involved in their mechanism of action. METHODS: The study population comprised 118 patients from a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial that assessed the analgesic efficacy and tolerability of a single dose of ibuprofen (arginine)/tramadol 400/37.5 mg compared with ibuprofen arginine 400 mg alone, tramadol 50 mg alone, and placebo in patients with moderate to severe pain after dental surgery. We analyzed 32 polymorphisms in the cytochrome P450 (CYP) enzymes COMT, ABCB1, SLC22A1, OPRM1, and SLC22A1. FINDINGS: We did not find any statistically significant difference among CYP2C9 phenotypes related to ibuprofen response, although CYP2C9 poor metabolizers had a longer effect (higher pain relief at 6 hours). Likewise, we did not find any statistically significant difference among PTGS2 genotypes, contradicting previously publications. IMPLICATIONS: There was not a clear effect of CYP2D6 phenotype on tramadol response, although CYP2D6 poor metabolizers had a slower analgesic effect. Concerning the transport of CYP2D6, we observed a better response in individuals carrying ABCB1 mutated alleles, which might correlate with higher tramadol plasma levels. Finally, we found a statistically significant better response in patients carrying the OPRM1 A118G G allele, which contradicts the previous reports. Measuring the active metabolite O-desmethyl-tramadol formation would be of great importance to better evaluate this association because O-desmethyl-tramadol has a higher µ-opioid receptor affinity compared with the parent drug. EudraCT.ema.europa.eu identifier: 2013-004637-33.

Grading the potential safety risk of medications used in hospital care.

OBJECTIVE: The aim of this study was to stratify medications used in hospital  care according to their potential risk. METHOD: The RAND/UCLA Appropriateness Method was used. Anatomical Therapeutic Chemical subgroups were classified according to their potential risk. A literature search, bulletins, and alerts issued by patient safety organizations were used to identify the potential safety risk of  these subgroups. Nine experts in patient/medication safety were selected to score the subgroups for their appropriateness in the classification. Two evaluation rounds were conducted: the first by email and the second by a  panel meeting. RESULTS: A total of 298 Anatomical Therapeutic Chemical subgroups were  evaluated. They were classified into three scenarios (low, medium, and high  risk). In the first round, 266 subgroups were classified as appropriate to the  assigned scenario, 32 were classified as uncertain, and none were classified as  inappropriate. In the second round, all subgroups were classified as appropriate.  The most frequent subgroups in the low-risk scenario belonged to  group A "Alimentary tract and metabolism" (44%); the most frequent in the  medium-risk scenario belonged to group J "Antiinfectives for systemic use"  (32%); and the most frequent in the high-risk scenario belonged to group L  "Antineoplastic and immunomodulating agents" (29%) and group N "Nervous  system" (26%). CONCLUSIONS: Based on the RAND/UCLA appropriateness method, Anatomical  Therapeutic Chemical subgroups used in hospital care were classified according  to their potential risk (low, medium, or high). These lists can be incorporated  into a risk-scoring tool for future patient/medication safety studies.

Objetivo: Estratificar los medicamentos utilizados en el ámbito hospitalario según el riesgo de provocar daño al paciente.Método: Se utilizó la metodología RAND/UCLA para clasificar los subgrupos terapéuticos del código Anatómica, Terapéutica, Química según el  riesgo de provocar daño al paciente. Para ello se realizó una revisión de la  evidencia disponible en publicaciones, boletines y alertas de organismos de  seguridad del paciente. A continuación se seleccionaron nueve expertos en  seguridad del paciente/medicamento para evaluar la clasificación de los  subgrupos terapéuticos: una primera ronda de evaluación por vía telemática y  una segunda ronda en una reunión presencial en la que se presentaron y  discutieron los resultados de la primera.Resultados: Se evaluaron 298 subgrupos terapéuticos. Se clasificaron en tres  escenarios (riesgo bajo, medio y alto). En la primera ronda se clasificaron 266  subgrupos como adecuados al escenario asignado, 32 subgrupos fueron  clasificados como inciertos y ninguno fue clasificado como inapropiado. En la  segunda ronda, todos los subgrupos fueron clasificados como adecuados. Los  subgrupos más frecuentes en el escenario de riesgo bajo pertenecieron al Grupo  A: "Tracto alimentario y metabolismo" (44%), en el de riesgo medio al Grupo J:  "Antiinfecciosos para uso sistémico" (32%), y en el de riesgo alto al Grupo L:  "Agentes antineoplásicos e inmunomoduladores" (29%) y al Grupo N: "Sistema  nervioso" (26%).Conclusiones: La metodología RAND/UCLA ha permitido estratificar los  subgrupos utilizados en el ámbito hospitalario según el riesgo potencial de  provocar daño al paciente. Esta estratificación puede servir como herramienta  para futuros estudios de seguridad en la utilización de medicamentos.

Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study.

AIMS: This study was conducted to assess the bioequivalence between two 10-mg amlodipine tablet formulations. As secondary objectives, sex-related differences and tolerability profile were evaluated. METHODS: Thirty-six healthy volunteers (18 males and 18 females; age 20-32 years, weight 49.5-98.0 kg) were included in a randomised crossover study. Subjects were administered a single 10-mg oral dose of each formulation separated by a 14-day washout period. Plasma amlodipine levels were determined by a high performance liquid chromatographic method with tandem mass spectrometry detection. RESULTS: All subjects completed the study and 90% confidence intervals for relevant pharmacokinetic parameters were within the ranges defined by European and US Regulatory Authorities: the geometric mean and the 90% confidence interval test/reference ratios calculated from log-transformed values were 104.54 (101.46-107.72%) for AUC(0-infinity) and 100.32 (97.41-103.33%) for Cmax. There were no serious or severe adverse events. The tolerability profile appeared to be comparable for the two products. On average, bioavailability of amlodipine was slightly higher in females than in males, but these differences could be explained by the lower body weight of women. There were no sex-related differences in drug clearance. Bioequivalence was also demonstrated within each gender group. Amlodipine treatment produced a slight decrease of systolic blood pressure and an increased in heart rate, which were more pronounced in women. The incidence of adverse events was similar in men and women. CONCLUSIONS: The two formulations were considered bioequivalent. Although there were no relevant gender-related differences in the pharmacokinetics of amlodipine, women reached higher amlodipine concentrations most likely because of their lower body weight, and therefore, the reported pharmacodynamic effects were higher within this gender group.

Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions.

The aim of this study was to evaluate the effect of ibuprofen on gastric mucosa and enzymes involved in gastroprotection in healthy volunteers. Twenty-four Helicobacter pylori-negative subjects were randomized to treatment with ibuprofen or ibuprofen-arginate (each 600 mg/6 hr during 3 days). Endoscopies were performed 1 week before and after treatment. Biopsies were taken from the gastric antrum and corpus for determination of prostaglandin E2 (PGE2) by ELISA and cyclooxygenase (COX-1 and COX-2) and nitric oxide synthase (eNOS and iNOS) by western blot. All subjects had at least one gastric lesion except for two individuals taking ibuprofen-arginate. Ibuprofen-arginate caused a lower rate of clinical adverse reactions than ibuprofen. Subjects with gastric lesions or adverse reactions had lower PGE2 levels. COX-1, COX-2, eNOS, and iNOS were detectable in all subjects. The constitutive enzymes (COX-1 and eNOS) did not change after treatment. COX-2 was higher in corpus than antrum and it increased after ibuprofen treatment. iNOS tended to increase mildly in the corpus in subjects with adverse reactions or endoscopic lesions. There were no significant differences between ibuprofen and ibuprofen-arginate in PGE2, or enzymes.