Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management

Interindividual variability in analgesic effects of nonsteroidal anti‐inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel. CYP2C8*1 (0.806),*2 (0.164), *3 (0.018), and *4 (0.012) alleles were identified. Genotype frequencies were distributed as homozygous wild type (66.7%), heterozygous (27.8%), and homozygous variant/compound heterozygous (5.4%), respectively. CYP2C9*1 (0.824), *2 (0.027), *3 (0.012), *5 (0.009), *6 (0.009), *8 (0.042), *9 (0.061), and *11(0.015) were observed with extensive (68.5%), intermediate (18.1%) and poor predicted metabolizers (0.6%), respectively. Fifty‐two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. Although the distribution of the CYP2C9 (p = 0.0515) phenotypes was marginally significantly in high and low ED users; some CYP2C8 and CYP2C9 allelic combinations observed in 15.2% (25) of the cohort are associated with higher risks for analgesic failure. CYP2C8 and CYP2C9 preemptive genotyping could potentially enable clinicians to identify patients with impaired metabolic phenotypes.     

Guidelines of the French Society of Otorhinolaryngology (SFORL): Nonsteroidal anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version

ObjectivesTo present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections.MethodsBased on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or “expert opinion”. The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group.ResultsThe main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20–30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3–5 or “Evaluation Enfant Douleur” (EVENDOL) child pain score 4–7) and insufficiently relieved by first-line paracetamol (residual VAS ≥ 3 or EVENDOL ≥ 4); o pain is moderate to intense (VAS 5–7 or EVENDOL 7–10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6 h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72 h.     

Ketorolac use and anastomotic leak in patients with esophageal cancer

ObjectivesRecent evidence has shown an association between postoperative ketorolac use and anastomotic leak in patients undergoing intestinal and colorectal operations, but this relationship has been minimally explored after esophagectomy. As the use of nonopioid pain control and enhanced recovery protocols is increasingly prioritized, determination of a possible correlation between perioperative ketorolac use and leak is essential.MethodsRecords of patients undergoing esophagectomy for adenocarcinoma at a single institution from 2006 to 2018 reviewed for occurrence of anastomotic leak. Institutional pharmacy records were queried for ketorolac administration during the surgical case through the time of discharge. Multivariable logistic regression was used to determine the relationship between ketorolac administration and anastomotic leak.ResultsA total of 1019 patients met inclusion criteria, the majority of whom were male (907, 89%) with a median age of 62 years. Patients predominantly presented with locoregionally advanced disease and were treated with initial chemoradiation. Ketorolac was administered to 686 patients (67%); use was observed to increase over the study period from 49% in 2006 to 92% in 2016. Conversely, anastomotic leak occurred in 87 patients (9%) overall and decreased over time from 15% (11/72) in 2006 to 2% (2/83) in 2018. Upon multivariable analysis, neither ketorolac administration evaluated as a categoric variable (odds ratio, 0.99; P = .958) or as a continuous variable using dose (odds ratio, 1.00; P = .843) demonstrated an association with anastomotic leak.ConclusionsKetorolac in the postoperative period after esophagectomy has become an integral component of enhanced recovery pathways and does not appear to be associated with anastomotic leak.     

Aspirin and nonaspirin nonsteroidal antiinflammatory drug use and occurrence of colorectal adenoma in Black American women

Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women.     

Metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) by Streptomyces griseolus CYP105A1 and its variants

In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4′-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3′-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4′-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites.