Support Care Cancer. 2022 Jan 11. doi: 10.1007/s00520-022-06818-9. Online ahead of print.

ABSTRACT

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure.

METHODS: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs).

RESULTS: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426).

CONCLUSION: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.

PMID:35018520 | DOI:10.1007/s00520-022-06818-9

Int J Infect Dis. 2022 Jan 8:S1201-9712(22)00004-2. doi: 10.1016/j.ijid.2022.01.003. Online ahead of print.

ABSTRACT

OBJECTIVE: No population PK model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH based on therapeutic drug monitoring (TDM) implementation in Indonesian TB patients.

MATERIALS AND METHODS: INH concentrations, N-Acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model.

RESULTS: A total of 107 TB patients (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping.

CONCLUSIONS: We established the population PK model for INH in Indonesian TB patients using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian TB patients.

PMID:35017103 | DOI:10.1016/j.ijid.2022.01.003

J Eat Disord. 2022 Jan 11;10(1):6. doi: 10.1186/s40337-022-00529-6.

ABSTRACT

BACKGROUND: Orthorexia nervosa (ON) is characterized by an excessive, obsessive concern with healthy eating generating psychological complications and even malnutrition at a caloric and protein level. Current evidence suggests that people with greater food knowledge are the most likely to be affected, placing nutrition students as a populational risk group. Since there are no nationwide studies dealing with orthorexia nervosa in this risk group, the present pilot study intends to identify risk factors for orthorexia nervosa in a sample of Nutrition and Dietetics students in Chile.

METHOD: A descriptive cross-sectional pilot study was done on 90 Nutrition and Dietetics students from a Chilean university, representing 70% of its population. The ORTHO-11-ES instrument was applied to determine ON risk, along with consulting about attitudinal, physical-clinical and social variables. Statistical tests were performed in GraphPad PRISM 8.0®, applying probability ratios and personal correlation, between the sociodemographic variables and the risk of orthorexia nervosa. This study was approved by the university Ethics Committee based on the Helsinki Declaration.

RESULTS: 23.3% of the studied population was at risk of suffering ON. Associated variables were being in the second year of their major (OR 2.22), coming from a charter school (OR 3.00) and cohabitation being limited to ≤ 1 person (OR 2.47). Particularly, declared physical activity limits are associated to the risk of suffering ON (Sedentary OR 2.42, Heavy OR 3.53), as well as time spent on the social network Instagram (< 1 h OR 2.77, > 3 h OR 1.80).

CONCLUSIONS: There is an ON risk prevalence of 23.3% in the present pilot sample under study, indicating that years of study, cohabitation, secondary educational establishment, physical activity and Instagram use constitute associated factors for the studied condition. Some results vary from international evidence, describing a dual nature in the variables for Instagram time and declared physical activity for ON risk. This study needs replication in more representative samples and longitudinal character with control groups which can confirm the studied elements as ON risk factors. Orthorexia nervosa (ON) is an expression created to indicate a possible new eating disorder characterized by excessive and obsessive preoccupation with healthy eating. Some of its most distinctive traits include marked anxiety over food, exaggerated fear over the appearance of some diseases and shame about physical appearance. This ultimately impacts food choice, planning, acquisition, preparation and consumption, creating psychological complications along with some associated with malnutrition. Considering that Nutrition students are an at-risk group, the present pilot study evaluated its prevalence and associated factors in a specific sample in Chile. Conditions associated with the risk of orthorexia nervosa identified in the present study include: number of hours spent using Instagram, limited cohabitation, extreme physical activity, and number of years in the major. These results should be taken cautiously, with their association confirmed in follow-up studies.

PMID:35016711 | DOI:10.1186/s40337-022-00529-6

Drug Metab Pharmacokinet. 2021 Dec 4;43:100436. doi: 10.1016/j.dmpk.2021.100436. Online ahead of print.

ABSTRACT

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15∗3 and NUDT15∗2 genotypes were at a 10-15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15∗3 and NUDT15∗2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.

PMID:35016134 | DOI:10.1016/j.dmpk.2021.100436

Eur Neuropsychopharmacol. 2022 Jan 8;55:112-157. doi: 10.1016/j.euroneuro.2021.12.005. Online ahead of print.

ABSTRACT

Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.

PMID:35016057 | DOI:10.1016/j.euroneuro.2021.12.005

J Hum Genet. 2022 Jan 11. doi: 10.1038/s10038-021-01009-6. Online ahead of print.

ABSTRACT

Host genetic factors have been shown to play a role in SARs-CoV-2 infection in diverse populations. However, the genetic landscape differs among various ethnicities; therefore, we explored the host genetic factors associated with COVID-19 disease susceptivity and disease severity in a Thai population. We recruited and genotyped 212 unrelated COVID-19 Thai patients and 36 controls using AxiomTM Human Genotyping SARs-COV-2 array, including 847,384 single nucleotide polymorphisms related to SARs-COV-2 pathogenesis, immune response, and related comorbidity No SNPs passed the genome-wide significance threshold of p value <1 × 10-8. However, with a threshold of p value <1 × 10-5, a locus on chromosome 5q32 was found to have a suggestive association with COVID-19 disease susceptibility (p value 6.9 × 10-6; Q-Q plot λ = 0.805, odds ratio 0.02). Notably, IL17B is a gene located in this linkage disequilibrium block and is previously shown to play a part in inflammation and pneumonia. Additionally, a suggestive locus on chromosome 12q22, harboring EEA1 and LOC643339, was associated with COVID-19 disease severity (p value 1.3 × 10-6 - 4.4 × 10-6, Q-Q plot λ = 0.997, odds ratio 0.28-0.31). EEA1 is involved in viral entry into cells, while LOC643339 is a long non-coding RNA. In summary, our study suggested loci on chromosomes 5q32 and 12q22 to be linked to COVID-19 disease susceptibility and disease severity, respectively. The small sample size of this study may lessen the likelihood that the association found is real, but it could still be true. Further study with a larger cohort is required to confirm these findings.

PMID:35013560 | DOI:10.1038/s10038-021-01009-6

Cells. 2021 Dec 28;11(1):86. doi: 10.3390/cells11010086.

ABSTRACT

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.

PMID:35011648 | DOI:10.3390/cells11010086

Materials (Basel). 2021 Dec 21;15(1):16. doi: 10.3390/ma15010016.

ABSTRACT

In this work we developed a bi-functional Bacterial-Nano-Cellulose (BNC) carrier system for cell cultures of Chelidonium majus-a medicinal plant producing antimicrobial compounds. The porous BNC was biosynthesized for 3, 5 or 7 days by the non-pathogenic Komagataeibacter xylinus bacteria and used in three forms: (1) Without removal of K. xylinus cells, (2) partially cleaned up from the remaining K. xylinus cells using water washing and (3) fully purified with NaOH leaving no bacterial cells remains. The suspended C. majus cells were inoculated on the BNC pieces in liquid medium and the functionalized BNC was harvested and subjected to scanning electron microscopy observation and analyzed for the content of C. majus metabolites as well as to antimicrobial assays and tested for potential proinflammatory irritating activity in human neutrophils. The highest content and the most complex composition of pharmacologically active substances was found in 3-day-old, unpurified BNC, which was tested for its bioactivity. The assays based on the IL-1β, IL-8 and TNF-α secretion in an in vitro model showed an anti-inflammatory effect of this particular biomatrix. Moreover, 3-day-old-BNC displayed antimicrobial and antibiofilm activity against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The results of the research indicated a possible application of such modified composites, against microbial pathogens, especially in local surface infections, where plant metabolite-enriched BNC may be used as the occlusive dressing.

PMID:35009165 | DOI:10.3390/ma15010016

Int J Mol Sci. 2021 Dec 31;23(1):467. doi: 10.3390/ijms23010467.

ABSTRACT

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

PMID:35008894 | DOI:10.3390/ijms23010467

Int J Mol Sci. 2021 Dec 31;23(1):421. doi: 10.3390/ijms23010421.

ABSTRACT

Autophagy is an intracellular mechanism that maintains cellular homeostasis in different tissues. This process declines in cartilage due to aging, which is correlated with osteoarthritis (OA), a multifactorial and degenerative joint disease. Several studies show that microRNAs regulate different steps of autophagy but only a few of them participate in OA. Therefore, epigenetic modifications could represent a therapeutic opportunity during the development of OA. Besides, polyphenols are bioactive components with great potential to counteract diseases, which could reverse altered epigenetic regulation and modify autophagy in cartilage. This review aims to analyze epigenetic mechanisms that are currently associated with autophagy in OA, and to evaluate whether polyphenols are used to reverse the epigenetic alterations generated by aging in the autophagy pathway.

PMID:35008847 | DOI:10.3390/ijms23010421

Int J Mol Sci. 2021 Dec 29;23(1):378. doi: 10.3390/ijms23010378.

ABSTRACT

Eleven novel imide-tetrazoles were synthesized. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for antimicrobial activity using standard and clinical strains. Within the studied group, compounds 1-3 were recognized as leading structures with the most promising results in antimicrobial studies. Minimal inhibitory concentration values for compounds 1, 2, 3 were within the range of 0.8-3.2 μg/mL for standard and clinical Gram-positive and Gram-negative bacterial strains, showing in some cases higher activity than the reference Ciprofloxacin. Additionally, all three inhibited the growth of all clinical Staphylococci panels: Staphylococcus aureus (T5592; T5591) and Staphylococcus epidermidis (5253; 4243) with MIC values of 0.8 μg/mL. Selected compounds were examined in topoisomerase IV decatenation assay and DNA gyrase supercoiling assay, followed by suitable molecular docking studies to explore the possible binding modes. In summary, the presented transition from substrate imide-thioureas to imide-tetrazole derivatives resulted in significant increase of antimicrobial properties. The compounds 1-3 proposed here provide a promising basis for further exploration towards novel antimicrobial drug candidates.

PMID:35008805 | DOI:10.3390/ijms23010378

Int J Mol Sci. 2021 Dec 27;23(1):270. doi: 10.3390/ijms23010270.

ABSTRACT

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver-Burk plots, Ki and IC50 values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.

PMID:35008697 | DOI:10.3390/ijms23010270

Int J Mol Sci. 2021 Dec 22;23(1):73. doi: 10.3390/ijms23010073.

ABSTRACT

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

PMID:35008510 | DOI:10.3390/ijms23010073

Pharmacogenomics. 2022 Jan 10. doi: 10.2217/pgs-2021-0099. Online ahead of print.

ABSTRACT

Imaging and tissue biopsies represent the current gold standard for breast cancer diagnosis and patient management. However, these practices are time-consuming, expensive and require invasive procedures. Moreover, tissue biopsies do not capture spatial and temporal tumor heterogeneity. Conversely, liquid biopsy, which includes circulating tumor cells, circulating free nucleic acids and extracellular vesicles, is minimally invasive, easy to perform and can be repeated during a patient's follow-up. Increasing evidence also suggests that liquid biopsy can be used to efficiently screen and diagnose tumors at an early stage, and to monitor changes in the tumor molecular profile. In the present review, clinical applications and prospects are discussed.

PMID:35006002 | DOI:10.2217/pgs-2021-0099

Front Cardiovasc Med. 2021 Dec 24;8:726694. doi: 10.3389/fcvm.2021.726694. eCollection 2021.

ABSTRACT

Aim: To explore the diverse target distribution and variable mechanisms of different fangjis prescriptions when treating arrhythmias based on the systems pharmacology. Methods: The active ingredients and their corresponding targets were acquired from the three fangjis [Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET)] and the arrhythmia-related genes were identified based on comprehensive database screening. Networks were constructed between the fangjis and arrhythmia and used to define arrhythmia modules. Common and differential gene targets were identified within the arrhythmia network modules and the cover rate (CR) matrix was applied to compare the contributions of the fangjis to the network and modules. Comparative pharmacogenetics analyses were then conducted to define the arrhythmia-related signaling pathways regulated by the fangjis prescriptions. Finally, the divergence and convergence points of the arrhythmia pathways were deciphered based on databases and the published literature. Results: A total of 187, 105, and 68 active ingredients and 1,139, 1,195, and 811 corresponding gene targets of the three fangjis were obtained and 102 arrhythmia-related genes were acquired. An arrhythmia network was constructed and subdivided into 4 modules. For the target distribution analysis, 65.4% of genes were regulated by the three fangjis within the arrhythmia network. ZT and GLT were more similar to each other, mainly regulated by module two, whereas HET was divided among all the modules. From the perspective of signal transduction, calcium-related pathways [calcium, cyclic guanosine 3',5'-monophosphate (cGMP)-PKG, and cyclic adenosine 3',5'-monophosphate (cAMP)] and endocrine system-related pathways (oxytocin signaling pathway and renin secretion pathways) were associated with all the three fangjis prescriptions. Nevertheless, heterogeneity existed between the biological processes and pathway distribution among the three prescriptions. GLT and HET were particularly inclined toward the conditions involving abnormal hormone secretion, whereas ZT tended toward renin-angiotensin-aldosterone system (RAAS) disorders. However, calcium signaling-related pathways prominently feature in the pharmacological activities of the decoctions. Experimental validation indicated that ZT, GLT, and HET significantly shortened the duration of ventricular arrhythmia (VA) and downregulated the expression of CALM2 and interleukin-6 (IL-6) messenger RNAs (mRNAs); GLT and HET downregulated the expression of CALM1 and NOS3 mRNAs; HET downregulated the expression of CRP mRNA. Conclusion: Comparing the various distributions of the three fangjis, pathways provide evidence with respect to precise applications toward individualized arrhythmia treatments.

PMID:35004871 | PMC:PMC8739471 | DOI:10.3389/fcvm.2021.726694

J Pediatr Pharmacol Ther. 2022;27(1):4-11. doi: 10.5863/1551-6776-27.1.4. Epub 2021 Dec 22.

NO ABSTRACT

PMID:35002553 | PMC:PMC8717621 | DOI:10.5863/1551-6776-27.1.4

Pharmacogenomics. 2022 Jan 10. doi: 10.2217/pgs-2021-0109. Online ahead of print.

ABSTRACT

Aim: We evaluated the clinical acceptance and feasibility of a pharmacist-guided personalized consult service following its transition from a mandatory (mPGx) to optional (oPGx) CYP2C9/VKORC1/CYP4F2 genotyping for warfarin. Methods: A total of 1105 patients were included. Clinical acceptance and feasibility outcomes were analyzed using bivariate and multivariable analyses. Results: After transitioning to optional genotyping, genotype testing was still ordered in a large segment of the eligible population (52.1%). Physician acceptance of pharmacist-recommended doses improved from 83.9% (mPGx) to 86.6% (oPGx; OR: 1.3; 95% CI: 1.1-1.5; p = 0.01) with a shorter median genotype result turnaround time (oPGX: 23.6 hr vs mPGX: 25.1 hr ; p < 0.01). Conclusion: Ordering of genotype testing and provider acceptance of dosing recommendations remained high after transitioning to optional genotyping.

PMID:35001645 | DOI:10.2217/pgs-2021-0109

Am J Health Syst Pharm. 2022 Jan 6:zxab489. doi: 10.1093/ajhp/zxab489. Online ahead of print.

ABSTRACT

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PMID:34999758 | DOI:10.1093/ajhp/zxab489

Eur J Cancer. 2022 Jan 5;162:148-157. doi: 10.1016/j.ejca.2021.12.009. Online ahead of print.

ABSTRACT

AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.

PATIENTS AND METHODS: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs.

RESULTS: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient.

CONCLUSION: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.

PMID:34998046 | DOI:10.1016/j.ejca.2021.12.009

Br J Clin Pharmacol. 2022 Jan 7. doi: 10.1111/bcp.15216. Online ahead of print.

ABSTRACT

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates, and infants, is limited by a paucity of good quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts, by complementary information about targeted and non-targeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a sub-division into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as well as type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, non-invasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (e.g. liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, like artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to identify complex phenotypes and subpopulations of patients to improve development of medicines for children with potential economic advantages.

PMID:34997627 | DOI:10.1111/bcp.15216