J Int Med Res. 2023 Nov;51(11):3000605231214065. doi: 10.1177/03000605231214065.

ABSTRACT

Adverse drug reactions represent a major health burden because they cause notable patient morbidity and mortality. From this viewpoint, several strategies have been developed to prevent or reduce adverse drug reactions. One such strategy is the use of pharmacogenomics. Interindividual variability in drug response and adverse effects is mainly attributable to genetic variation in enzymes such as sulfotransferases and cytochrome P450s. The current narrative review discusses the relationship between the structure and activity of drugs. Specifically, the activity of drugs can be increased and/or their adverse effects can be reduced by altering specific positions in their structures.

PMID:38019107 | DOI:10.1177/03000605231214065

BMC Psychiatry. 2023 Nov 28;23(1):888. doi: 10.1186/s12888-023-05390-8.

ABSTRACT

BACKGROUND: Despite numerous national depression care guidelines (DCGs), suboptimal antidepressant treatment may occur. We examined DCG concordance and depression treatment outcomes in psychiatric settings.

METHODS: We evaluated treatment received and outcomes of 128 psychiatric out- and inpatients participating in the PEGAD (Pharmacoepidemiology and Pharmacogenetics of Antidepressant Treatment for Depressive Disorders) study at baseline, two weeks, and eight weeks using interviews and questionnaires. Inclusion criteria were ICD-10 diagnosis of a depressive disorder, a Patient Health Questionnaire-9 symptom (PHQ-9) score ≥ 10, and a new antidepressant prescribed. The primary outcome of the study was within-individual change in PHQ-9 scores.

RESULTS: At baseline, patients had predominately recurrent (83%) and in 19% treatment-resistant depression (TRD). The median preceding duration of the current episode was 6.5 months. At eight weeks, 85% of the patients (n = 107) used a DCG-concordant antidepressant dose. However, due to the scarcity of antidepressant combinations and augmentations, fewer TRD than non-TRD patients (25% vs. 84%, p < 0.005) received adequate antidepressant treatment. Additionally, one-third of the patients received inadequate follow-up. Overall, only 53% received treatment compatible with DCG recommendations for adequate pharmacotherapy and follow-up. The mean decline in PHQ-9 scores (-3.8 ± SD 5.7) was significant (p < 0.0005). Nearly 40% of the patients reached a subthreshold level of depression (PHQ-9 < 10), predicted by a lower baseline PHQ-9 score, recurrent depression, and female sex. However, 45% experienced no significant clinical improvement (PHQ-9 score reduction < 20%).

CONCLUSIONS: Our findings suggest that inadequate treatment continues to occur in psychiatric care settings, particularly for TRD patients.

PMID:38017416 | DOI:10.1186/s12888-023-05390-8

bioRxiv. 2023 Nov 15:2023.11.14.567143. doi: 10.1101/2023.11.14.567143. Preprint.

ABSTRACT

A web application, GTExome, is described that quickly identifies, classifies, and models missense mutations in commonly expressed human proteins. GTExome can be used to categorize genomic mutation data with tissue specific expression data from the Genotype-Tissue Expression (GTEx) project. Commonly expressed missense mutations in proteins from a wide range of tissue types can be selected and assessed for modeling suitability. Information about the consequences of each mutation is provided to the user including if disulfide bonds, hydrogen bonds, or salt bridges are broken, buried prolines introduced, buried charges are created or lost, charge is swapped, a buried glycine is replaced, or if the residue that would be removed is a proline in the cis configuration. Also, if the mutation site is in a binding pocket the number of pockets and their volumes are reported. The user can assess this information and then select from available experimental or computationally predicted structures of native proteins to create, visualize, and download a model of the mutated protein using Fast and Accurate Side-chain Protein Repacking (FASPR). For AlphaFold modeled proteins, confidence scores for native proteins are provided. Using this tool, we explored a set of 9,666 common missense mutations from a variety of tissues from GTEx and show that most mutations can be modeled using this tool to facilitate studies of proteinprotein and protein-drug interactions. The open-source tool is freely available at https://pharmacogenomics.clas.ucdenver.edu/gtexome/.

AUTHOR SUMMARY: GTExome greatly simplifies the process of studying the three-dimensional structures of proteins containing missense mutations that are critical to understanding human health. In contrast to current state-of-the-art methods, users with no external software or specialized training can rapidly produce three-dimensional structures of any possible mutation in nearly any protein in the human exome. Accomplishing this requires reliance on AlphaFold based structural models. We therefore compared the protein models created by GTExome where possible to known experimental structures. We find that by avoiding specific mutations, the majority of proteins are amenable to being modeled by GTExome with similar results to the direct use of AlphaFold.

PMID:38014287 | PMC:PMC10680684 | DOI:10.1101/2023.11.14.567143

Clin Transl Sci. 2023 Nov 27. doi: 10.1111/cts.13692. Online ahead of print.

ABSTRACT

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data and explore clinical outcomes of PGx implementation in underserved populations. Black and Latino patients were recruited from an outpatient clinic and underwent PGx testing. Feasibility measures included enrollment metrics and actionable genotype frequencies. The primary clinical outcome was patient medication treatment satisfaction 6 months after testing. Implementation outcomes included the number of healthcare provider encounters and medication changes within the 6-month follow-up. Effectiveness outcomes included medication adherence, patient-perceived test value, and time spent discussing medications with providers. Ninety-nine patients completed the study. Proton-pump inhibitors were the most frequent PGx drug class prescribed at baseline (61%) followed by nonsteroidal anti-inflammatory drugs (36%). Patients with an actionable genotype constituted 96% of the population, while 28% had an actionable genotype related to their PGx drug. Patient treatment satisfaction significantly increased over the 6 months after PGx testing. In addition, medication adherence and the number of provider encounters significantly increased over the study period. In a pilot study, preemptive PGx testing was feasible in primary care clinics, improved patient treatment satisfaction and adherence and increased the number of provider encounters in medically underserved patients. Future clinical trials are warranted to assess the long-term effects of PGx testing in a larger diverse patient population. This article is protected by copyright. All rights reserved.

PMID:38013396 | DOI:10.1111/cts.13692

Pharmacol Res Perspect. 2023 Dec;11(6):e01150. doi: 10.1002/prp2.1150.

ABSTRACT

Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.

PMID:38013228 | DOI:10.1002/prp2.1150

JAMA Netw Open. 2023 Nov 1;6(11):e2345132. doi: 10.1001/jamanetworkopen.2023.45132.

ABSTRACT

IMPORTANCE: Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD).

OBJECTIVES: To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine.

EXPOSURE: Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d).

MAIN OUTCOME AND MEASURE: The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression.

RESULTS: In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome.

CONCLUSIONS AND RELEVANCE: In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

PMID:38010652 | PMC:PMC10682837 | DOI:10.1001/jamanetworkopen.2023.45132

Clin Pharmacol Ther. 2023 Nov 27. doi: 10.1002/cpt.3112. Online ahead of print.

ABSTRACT

Methadone and buprenorphine/naloxone are opioid agonist therapies for opioid use disorder treatment. Genetic factors contribute to individual differences in opioid response; however, little is known regarding genetic associations with clinical outcomes in people receiving opioid agonist therapies. Participants diagnosed with opioid use disorder, principally consisting of prescription opioids (licit or illicit), were randomized to methadone or buprenorphine/naloxone for 24 weeks of daily treatment (NCT03033732). Urine was collected at 12 biweekly study visits and analyzed for non-treatment opioids. Variants in genes involved in methadone metabolism (CYP2B6, CYP2C19, and CYP3A4), buprenorphine metabolism (CYP3A4 and UGT2B7), and μ-opioid receptor function (OPRM1) were genotyped and analyzed for their association with the number of non-treatment opioid-free urine screens. Primary analyses focused on the last 12 weeks (6 study visits, post-titration) of treatment among those reporting White ethnicity. Additional sensitivity and exploratory analyses were performed. Among methadone-treated participants (n=52), the OPRM1 rs1799971 AA genotype (vs. G-genotypes, i.e., having one or two G alleles ) was associated with greater opioid-free urine screens (Incidence Rate Ratio=5.24, 95%CI=2.43, 11.26, p=0.000023); longitudinal analyses showed a significant genotype-by-time interaction over the full 24 weeks (12 study visits, β=-0.28, 95% CI=-0.45, -0.11, p=0.0015). Exploratory analyses suggest an OPRM1 rs1799971 genotype effect on retention. No evidence of association was found between other genetic variants, including in metabolic variants, and non-treatment opioid-free urine screens in the methadone or buprenorphine/naloxone arms. Those with the OPRM1 rs1799971 G-genotypes may have a poorer response to methadone maintenance treatment, an effect that persisted through 24 weeks of treatment.

PMID:38009933 | DOI:10.1002/cpt.3112

Clin Pharmacol Drug Dev. 2023 Nov 27. doi: 10.1002/cpdd.1343. Online ahead of print.

NO ABSTRACT

PMID:38009725 | DOI:10.1002/cpdd.1343

Pharmacogenomics. 2023 Nov 27. doi: 10.2217/pgs-2023-0188. Online ahead of print.

ABSTRACT

With the aim of integrating clinical pharmacology with pharmacogenomics and providing a platform to gather clinicians, academicians, diagnostic laboratory personnel and scientists from related domains, the International Conference on Clinical Pharmacology and Pharmacogenomics 2023 (ICCPP 2023) was jointly organized by the Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, India and the CANSEARCH research platform in Pediatric Oncology and Hematology, University of Geneva, Geneva, Switzerland. The conference was held on 31 August and 1 September 2023, as a continued Indo-Swiss scientific exchange event series. In this report we describe the proceedings of this conference for the benefit of peers who could not attend the conference but are interested in knowing about the scientific program in detail.

PMID:38009368 | DOI:10.2217/pgs-2023-0188

J Hypertens. 2023 Nov 17. doi: 10.1097/HJH.0000000000003613. Online ahead of print.

ABSTRACT

OBJECTIVE: Hypertension is linked to gut dysbiosis. Here, the impact of the angiotensin receptor antagonist irbesartan on the gut microbiota of spontaneously hypertensive rats (SHR) were investigated. In addition, we assessed their contribution to its antihypertensive effect.

METHODS: Eight-week-old Wistar-Kyoto (WKY) rats and SHR were administered irbesartan for 8 weeks. Fecal microbiota transplantation (FMT) was performed from SHR treated with irbesartan or untreated SHR to recipient untreated SHR. The preventive effect of Lactobacillus on hypertension in SHR was evaluated. Blood pressure (BP) was calculated using a tail-sleeve sphygmomanometer. To better assess the composition of the gut microbiota, the V3-V4 region of the 16S rRNA gene was amplified while short-chain fatty acids (SCFAs) in feces were tested by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS).

RESULTS: Irbesartan restored gut dysbiosis, increased the abundance of Lactobacillus, and improved anti-inflammatory ability, antioxidative ability, intestinal integrity, and intestinal inflammation in SHR. The microbiota in SHR-treated irbesartan could reduce BP and improve antioxidative ability and gut integrity in SHR. Lactobacillus johnsonii (L. johnsonii) and Lactobacillus reuteri (L. reuteri) reduced BP, restored gut dysbiosis and improved anti-inflammatory ability, antioxidative ability, intestinal integrity in SHR. Most notably, irbesartan, L. johnsonii, and L. reuteri can significantly increase SCFA content in SHR feces.

CONCLUSION: The current study demonstrated that irbesartan treatment ameliorated gut dysbiosis in SHR. Irbesartan induced alterations in gut microbiota, with increased prevalence of Lactobacillus.

PMID:38009301 | DOI:10.1097/HJH.0000000000003613

Curr Drug Metab. 2023 Nov 24. doi: 10.2174/0113892002255240231117072211. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs.

OBJECTIVES: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs.

METHOD: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher's exact test compared the allele frequencies between the populations.

RESULTS: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa. The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir.

CONCLUSION: These results show a possibility of kidney protection and an increase in bilirubin in this population.

PMID:38008947 | DOI:10.2174/0113892002255240231117072211

Cancer Cell Int. 2023 Nov 26;23(1):295. doi: 10.1186/s12935-023-03135-x.

ABSTRACT

BACKGROUND: Colorectal cancer is a highly prevalent and deadly. The most common metastatic site is the liver. We performed a whole exome sequencing analysis of a series of metachronous colorectal cancer liver metastases (mCLM) and matched non-malignant liver tissues to investigate the genomic profile of mCLM and explore associations with the patients' prognosis and therapeutic modalities.

METHODS: DNA samples from mCLM and non-malignant liver tissue pairs (n = 41) were sequenced using whole exome target enrichment and their germline and somatic genetic variability, copy number variations, and mutational signatures were assessed for associations with relapse-free (RFS) and overall survival (OS).

RESULTS: Our genetic analysis could stratify all patients into existing targeted therapeutic regimens. The most commonly mutated genes in mCLM were TP53, APC, and KRAS together with PIK3CA and several passenger genes like ABCA13, FAT4, PCLO, and UNC80. Patients with somatic alterations in genes from homologous recombination repair, Notch, and Hedgehog pathways had significantly prolonged RFS, while those with altered MYC pathway genes had poor RFS. Additionally, alterations in the JAK-STAT pathway were prognostic of longer OS. Patients bearing somatic variants in VIPR2 had significantly shorter OS and those with alterations in MUC16 prolonged OS. Carriage of the KRAS-12D variant was associated with shortened survival in our and external datasets. On the other hand, tumor mutation burden, mismatch repair deficiency, microsatellite instability, mutational signatures, or copy number variation in mCLM had no prognostic value.

CONCLUSIONS: The results encourage further molecular profiling for personalized treatment of colorectal cancer liver metastases discerning metachronous from synchronous scenarios.

PMID:38008721 | DOI:10.1186/s12935-023-03135-x

Stud Health Technol Inform. 2023 Nov 23;308:359-364. doi: 10.3233/SHTI230860.

ABSTRACT

In this study, screening, confirmation and validation of mismatch allele-specific (AS) forward (F)-primers are executed to establish a quadruplex amplification analysis (real-time PCR) for discrimination of CYP2D6*10, ADRB1, NPPA and CYP3A5*3 genotypes associated with hypertensive pharmacogenomics. To significantly distinguish heterozygote and homozygote, ΔCq (differences in threshold cycles between the wild-type F-primer amplification assay and the mutant-type F-primer amplification assay) was utilized to determine outcomes. Detection of plasmid by uniplex real-time PCR was used to screen the mismatch AS F-primers. Robustness assessment and agreement analysis were employed to confirm and validate initially selected F-primers, respectively. Robustness assessment confirmed that except of ADRB1 (0.7-0.9), amplification efficiency ranged from 0.9 to 1.1. No statistically significant difference was found between the analysis and NGS. Therefore, the optimized F-primer as polymorphism recognition molecules can benefit the genotyping guiding drug delivery in anti-hypertension treatment.

PMID:38007760 | DOI:10.3233/SHTI230860

Genet Med. 2023 Nov 22:101033. doi: 10.1016/j.gim.2023.101033. Online ahead of print.

ABSTRACT

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

PMID:38007624 | DOI:10.1016/j.gim.2023.101033

Atherosclerosis. 2023 Nov 10;386:117382. doi: 10.1016/j.atherosclerosis.2023.117382. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The lipid profile is consistently associated with coronary artery disease (CAD) and ischemic stroke (IS). However, the lipoprotein subfractions have not been deeply explored in stroke subtypes, especially in IS outcome.

METHODS: We performed two-sample Mendelian randomization (MR) analysis using 92 lipid traits measured by nuclear magnetic resonance in 115,000 subjects from the UK Biobank. Data for genetic associations with IS, its subtypes, and long-term outcome (LTO) were obtained from three cohorts of European ancestry: GIGASTROKE (73,652 cases, 1,234,808 controls), GODS (n = 1791) and GISCOME (n = 6165). Results obtained using CARDIoGRAMPlusC4D were used to identify differences with CAD.

RESULTS: Genetically determined low concentration of medium high-density lipoprotein (HDL) particles (odds ratio (OR) = 0.92, 95% CI 0.88-0.96; p = 3.6 × 10-4) and its cholesterol content (OR = 0.92, 95% CI 0.88-0.96; p = 1.9 × 10-4) showed causal associations with an increased risk of stroke. Genetic predisposition to high apolipoprotein (apo)B to apoA-I ratio was causally associated with an increased risk of IS (OR = 1.12, 95% CI 1.06-1.18, p = 1.1 × 10-4), and a highly suggestive association was found between non-esterified cholesterol in low-density lipoprotein (LDL) and increased risk of atherothrombotic stroke (LAS) (OR = 1.35, 95% CI 1.10-1.66; p = 4.0 × 10-3). Low cholesterol in small and medium LDL was suggestively associated with poor LTO.

CONCLUSIONS: Our results support that low medium HDL concentration was causally associated with an increased stroke risk, while high levels of non-esterified cholesterol in LDL were suggestively associated with an increased risk of LAS and with a better LTO.

PMID:38006695 | DOI:10.1016/j.atherosclerosis.2023.117382

Drug Alcohol Depend. 2023 Nov 20;253:111033. doi: 10.1016/j.drugalcdep.2023.111033. Online ahead of print.

ABSTRACT

Our paper evaluates the extent to which the brain disease model of addiction (BDMA) has contributed to reducing the prevalence of tobacco smoking and tobacco-related harm over the past 20 years. We discuss the ways in which genetic and neuroscience research on nicotine addiction have contributed to our understanding of tobacco smoking. We then examine the extent to which the BDMA has produced more effective treatments to assist smoking cessation. We also assess the degree to which the BDMA has contributed to the tobacco control policies that have produced substantial reductions in tobacco-related morbidity and mortality in the two decades since the model was first proposed by Alan Leshner. We also assess whether the BDMA has reduced the stigmatisation of people who smoke tobacco.

PMID:38006672 | DOI:10.1016/j.drugalcdep.2023.111033

Pharmaceutics. 2023 Nov 16;15(11):2629. doi: 10.3390/pharmaceutics15112629.

ABSTRACT

Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that certain guidelines are followed to enhance and ensure proper statistical modeling. This article presents a methodology for constructing a design space using process data, while avoiding the common pitfalls associated with retrospective data analysis. For this study, data from a real wet granulation process were collected to pragmatically illustrate all the concepts and methods developed in this article.

PMID:38004608 | DOI:10.3390/pharmaceutics15112629

Pharmaceutics. 2023 Nov 4;15(11):2587. doi: 10.3390/pharmaceutics15112587.

ABSTRACT

Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee quality and stability; this is the case, for example, with omeprazole. Omeprazole is used as a model drug due to the lack of a paediatric formulation meeting gastro-resistance requirements, which remains a challenge today. In this experimental study, the development of enteric polymer-coated pellets is proposed. It is proposed to use aqueous coating dispersions without the use of organic solvents, which are commonly used in fluidised bed coatings. To do this, the design of experiments method is used as a statistical tool for experiment creation and the subsequent analysis of the responses. In particular, this study uses a randomised full factorial design. The mean weight increases of the protective layer and the enteric coating are chosen as factors. Each factor is assigned two levels. Therefore, the design of the used experiments is a 22 + 1 central point. Overall, the obtained pellets can be an alternative to the compounding formulas of omeprazole that are currently used in the paediatric population, which do not meet the gastro-resistance specifications necessary to guarantee the therapeutic efficacy of this active ingredient.

PMID:38004567 | DOI:10.3390/pharmaceutics15112587

Pharmaceutics. 2023 Oct 28;15(11):2548. doi: 10.3390/pharmaceutics15112548.

ABSTRACT

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is part of the standard treatment of colorectal cancer (CRC). Severe adverse dose limiting reactions that impair treatment safety and lead to treatment suspension remain a relevant concern. Single-nucleotide polymorphisms (SNPs) in genes involved in the activation of capecitabine may alter the bioavailability of 5-FU and thereby affect therapy outcomes. The aim of this study was to evaluate the association of these SNPs with severe toxicity and treatment suspension in patients with CRC treated with capecitabine-based therapy. An ambispective cohort study was conducted, including 161 patients with CRC. SNPs were analyzed using real-time PCR with TaqMan® probes. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. CES1 rs71647871-A was associated with a severe hand-foot syndrome (p = 0.030; OR = 11.92; 95% CI = 1.46-73.47; GG vs. A). CDA rs1048977-CC (p = 0.030; OR = 2.30; 95% CI 1.09-5.00; T vs. CC) and capecitabine monotherapy (p = 0.003; OR = 3.13; 95% CI 1.49-6.81) were associated with treatment suspension due to toxicity. SNPs CES1 rs71647871 and CDA rs1048977 may act as potential predictive biomarkers of safety in patients with CRC under capecitabine-based adjuvant therapy.

PMID:38004528 | DOI:10.3390/pharmaceutics15112548

Pharmaceutics. 2023 Oct 27;15(11):2540. doi: 10.3390/pharmaceutics15112540.

ABSTRACT

The modalities for prescribing a psychotropic (dose and choice of molecule) are currently unsatisfactory, which can lead to a lack of efficacy of the treatment associated with prolonged exposure of the patient to the symptoms of his or her illness and the side effects of the molecule. In order to improve the quality of treatment prescription, a part of the current biomedical research is dedicated to the development of pharmacogenetic tools for individualized prescription. In this guideline, we will present the genes of interest with level 1 clinical recommendations according to PharmGKB for the two major families of psychotropics: antipsychotics and antidepressants. For antipsychotics, there are CYP2D6 and CYP3A4, and for antidepressants, CYP2B6, CYP2D6, and CYP2C19. The study will focus on describing the role of each gene, presenting the variants that cause functional changes, and discussing the implications for prescriptions in clinical practice.

PMID:38004520 | DOI:10.3390/pharmaceutics15112540