Sr Care Pharm. 2022 Sep 1;37(9):394-398. doi: 10.4140/TCP.n.2022.394.

ABSTRACT

Clinical pharmacists with experience may identify prescribing patterns resulting in iatrogenic disease, which is commonly encountered in geriatric populations where polypharmacy is common. Serotonin toxicity is one toxidrome clinicians may identify, where specific medications are used in treatment. As a result of their pharmacology training, pharmacists may identify toxidromes caused by medications that other clinicians may overlook. Pharmacogenomic (PGx) testing can provide added insight into a potentially iatrogenic cause for serotonin toxicity, because testing can elucidate how well an individual patient may metabolize serotonergic medications. Using PGx as a resource in addition to clinical experience, pharmacists can better guide therapy in the geriatric, polypharmacy population to avoid serotonin toxicity.

PMID:36038994 | DOI:10.4140/TCP.n.2022.394

Clin Transl Allergy. 2022 Aug;12(8):e12173. doi: 10.1002/clt2.12173.

NO ABSTRACT

PMID:36036237 | DOI:10.1002/clt2.12173

STAR Protoc. 2022 Aug 18;3(3):101560. doi: 10.1016/j.xpro.2022.101560. eCollection 2022 Sep 16.

ABSTRACT

The methods for the culture and cardiomyocyte differentiation of human embryonic stem cells, and later human induced pluripotent stem cells (hiPSC), have moved from a complex and uncontrolled systems to simplified and relatively robust protocols, using the knowledge and cues gathered at each step. HiPSC-derived cardiomyocytes have proven to be a useful tool in human disease modelling, drug discovery, developmental biology, and regenerative medicine. In this protocol review, we will highlight the evolution of protocols associated with hPSC culture, cardiomyocyte differentiation, sub-type specification, and cardiomyocyte maturation. We also discuss protocols for somatic cell direct reprogramming to cardiomyocyte-like cells.

PMID:36035804 | PMC:PMC9405110 | DOI:10.1016/j.xpro.2022.101560

Front Pharmacol. 2022 Aug 12;13:929262. doi: 10.3389/fphar.2022.929262. eCollection 2022.

ABSTRACT

The gut microbiota and its metabolites have become a hotspot of recent research. Trimethylamine N-oxide (TMAO) metabolized by the gut microbiota is closely related to many diseases such as cardiovascular disease, chronic kidney disease, type 2 diabetes, etc. Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from non-communicable diseases. Recently, increasing focus has been put on the role of TMAO in the development and progress of chronic kidney disease. The level of TMAO in patients with chronic kidney disease is significantly increased, and a high level of TMAO deteriorates chronic kidney disease. This article describes the relationship between TMAO and chronic kidney disease and the research progress of drugs targeted TMAO, providing a reference for the development of anti-chronic kidney disease drugs targeted TMAO.

PMID:36034781 | PMC:PMC9411716 | DOI:10.3389/fphar.2022.929262

Front Pharmacol. 2022 Aug 11;13:950831. doi: 10.3389/fphar.2022.950831. eCollection 2022.

ABSTRACT

Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2) is a two-domain transmembrane protein-coding gene located on chromosome 3, the protein expressed by which acts as the membrane receptor of semaphorin and vascular endothelial growth factor during the development of axons and blood vessels. Although several research evidences at the cellular and clinical levels have associated DCBLD2 with tumorigenesis, nothing is known regarding this gene from a pan-cancer standpoint. In this study, we systematically analyzed the influence of DCBLD2 on prognosis, cancer staging, immune characteristics, and drug sensitivity in a variety of cancers based on a unified and standardized pan-cancer dataset. In addition, we performed GO enrichment analyses and KEGG analyses of DCBLD2-related genes and DCBLD2-binding proteins. Our results showed that DCBLD2 is a potential oncogenic, immunological as well as a prognostic biomarker in terms of pan-cancer, and is expected to contribute to the improvement of tumor prognosis and the development of targeted therapy.

PMID:36034778 | PMC:PMC9403722 | DOI:10.3389/fphar.2022.950831

Innov Pharm. 2021 Sep 22;12(4). doi: 10.24926/iip.v12i4.4341. eCollection 2021.

ABSTRACT

Pharmacogenomics (PGx) melds well with polypharmacy as another tool to identify medication related problems (MRPs) more specifically so they may be solved most effectively. PGx can pre-emptively assist in medication selection, medication dosing or identify better medications for patients already taking a medication. PGx can also confirm suspect medications of causing MRPs such as adverse drug reactions (ADRs) or drug interactions. In this case, PGx testing confirmed presence of a serious human leukocyte antigen (HLA) drug reaction with eosinophilia and systemic symptoms (DRESS) after a suspect medication had been stopped.

PMID:36033112 | PMC:PMC9401381 | DOI:10.24926/iip.v12i4.4341

Innov Pharm. 2021 Sep 22;12(4). doi: 10.24926/iip.v12i4.4034. eCollection 2021.

ABSTRACT

Background: Conversion disorder (CD) is a relatively common psychiatric disorder likely encountered by clinical pharmacists but probably not easily identified by pharmacists. Case Summary: This is a patient case where a patient with a tremor was referred to the pharmacist led, polypharmacy, pharmacogenomics (PGx) service to rule out a PGx cause due to medication metabolism. No pharmacologic or PGx cause was found for the tremor which helped support and confirm a diagnosis of CD. Practice Implications: By working collaboratively with psychiatrists, neurologists, physical medicine colleagues, clinical pharmacists may add value to patient care by assisting with diagnoses and appropriate treatment.

PMID:36033110 | PMC:PMC9401363 | DOI:10.24926/iip.v12i4.4034

Front Immunol. 2022 Aug 11;13:942765. doi: 10.3389/fimmu.2022.942765. eCollection 2022.

ABSTRACT

BACKGROUND: Prior studies have highlighted that novel programmed cell death (PCD) modalities, including ferroptosis, pyroptosis, and necroptosis, are correlated with tumor progression and antitumor immunity. Nonetheless, comprehensive analysis of tumor microenvironment (TME) profiles mediated by the crosstalk of distinct PCD forms has not been conducted in breast cancer (BC).

METHODS: Here, we curated 34 identified PCD-associated genes (PCDAGs) and applied the consensus clustering algorithm to establish PCD-mediated tumor patterns in BC. Subsequently, based on prognostic differentially expressed genes extracted from distinct PCD-mediated patterns, we applied the LASSO algorithm to construct CD_Score. Furthermore, the correlation analysis between CD_Score and TME features, molecular subtypes, clinicopathological characteristics, drug response, and immunotherapeutic efficacy was performed.

RESULTS: Three distinct PCD-clusters were determined among 2,038 BC samples, which did not only display different clinical outcomes but highly correlated to the established immunological tumor phenotypes: "desert," "excluded," and "inflamed" immune profiles. Based on the CD_Score derived from the PCD-related gene signature, BC patients could be stratified into CD_Score-low and -high group, of which the former displayed satisfactory survival outcome and enhanced immune infiltration. Further exploration identified that the CD_Score-high group significantly correlated with elevated neoantigen load and higher mutation frequency in SMGs (e.g., TP53 and MAP3K1) and reduced expression of immune checkpoint proteins.

CONCLUSIONS: This research is the first to emphasize the close relationship between distinct cell death modalities and the diversity and complexity of immune infiltration in TME. We established the CD_Score, which could help enhance our cognition of TME features and facilitate the clinical application of immunotherapy.

PMID:36032140 | PMC:PMC9403178 | DOI:10.3389/fimmu.2022.942765

Mol Genet Metab. 2022 Aug 12;137(1-2):140-145. doi: 10.1016/j.ymgme.2022.08.002. Online ahead of print.

ABSTRACT

OBJECTIVE: Pharmacogenomics (PGx) characterizes genetic variation in medication response. 85-95% of the population carries actionable PGx variants. No prior studies have demonstrated the application and feasibility of PGx in prenatal testing. We assessed parental desire for PGx findings from fetal exome sequencing (ES), evaluated PGx variants, and reviewed implications for medically complex neonates.

METHODS: A prospective cohort undergoing ES for nonimmune hydrops fetalis were offered PGx results as a secondary finding. Seven pharmacogenes with Level A evidence, defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, were tested and reported to patients and referring providers. Medication administration records were reviewed.

RESULTS: Most participants (36/40, 90%) desired PGx testing. 32/36 (89%) had potentially actionable PGx diplotypes in six genes: CYP2C19 (20/36, 56%), CYP2C9 (16/36, 44%), CYP2D6 (10/36, 28%), SLCO1B1 (13/36, 36%), TPMT (6/36, 17%), UGT1A1 (4/36, 11%). 12/13 (92%) live births had PGx variants. Neonatal chart review indicated that three medications with CPIC Level A evidence were administered to four neonates. None of the patients received a medication that aligned with an actionable pharmacogenetic variant as defined by Level A CPIC guidance.

CONCLUSION: Most participants opted to receive PGx results. 89% had actionable variants, consistent with population estimates. Obtaining fetal PGx data is feasible for medically complex neonates. Further studies are needed for broad clinical application of PGx in fetuses with major congenital abnormalities. Our study demonstrates the potential of PGx as useful preemptive clinical information that could be obtained at the time of fetal exome sequencing for other indications.

CLINICALTRIALS: gov Registration: NCT03911531.

PMID:36029725 | DOI:10.1016/j.ymgme.2022.08.002

J Crohns Colitis. 2022 Aug 27:jjac127. doi: 10.1093/ecco-jcc/jjac127. Online ahead of print.

ABSTRACT

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).

METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.

RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).

CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

PMID:36029471 | DOI:10.1093/ecco-jcc/jjac127

Biomed Pharmacother. 2022 Aug 23;154:113555. doi: 10.1016/j.biopha.2022.113555. Online ahead of print.

ABSTRACT

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a bioactive compound, a natural anthraquinone aglycone, present mainly in herbaceous species of the families Fabaceae, Polygonaceae and Rhamnaceae, with a physiological role in protection against abiotic stress in vegetative tissues. Emodin is mainly used in traditional Chinese medicine to treat sore throats, carbuncles, sores, blood stasis, and damp-heat jaundice. Pharmacological research in the last decade has revealed other potential therapeutic applications such as anticancer, neuroprotective, antidiabetic, antioxidant and anti-inflammatory. The present study aimed to summarize recent studies on bioavailability, preclinical pharmacological effects with evidence of molecular mechanisms, clinical trials and clinical pitfalls, respectively the therapeutic limitations of emodin. For this purpose, extensive searches were performed using the PubMed/Medline, Scopus, Google scholar, TRIP database, Springer link, Wiley and SciFinder databases as a search engines. The in vitro and in vivo studies included in this updated review highlighted the signaling pathways and molecular mechanisms of emodin. Because its bioavailability is low, there are limitations in clinical therapeutic use. In conclusion, for an increase in pharmacotherapeutic efficacy, future studies with carrier molecules to the target, thus opening up new therapeutic perspectives.

PMID:36027610 | DOI:10.1016/j.biopha.2022.113555

J Hypertens. 2022 Jun 1;40(Suppl 1):e311. doi: 10.1097/01.hjh.0000838772.03800.3c.

ABSTRACT

OBJECTIVE: Inadequate adherence to anti-hypertensive prescription is one of the major obstacles for blood pressure control in patients with arterial hypertension. It is estimated that 40% of patients with hypertension have partial or absent compliance, with more than 80% of non-adherence when blood pressure targets are not achieved. However, in clinical practice the assessment of therapeutic adherence is still challenging. The available methods for the assessment of anti-hypertensive compliance are costly, low accurate or time consuming.

DESIGN AND METHOD: We designed a prospective observational study to evaluate the therapeutic adherence to inhibitors of renin-angiotensin-aldosterone system (RAAS) in patients with hypertension through serial measurement of aldosterone-to-direct renin ratio (ARR), before and after treatment.We enrolled 80 patients, including 40 patients with arterial hypertension and 40 healthy controls. Patients with arterial hypertension underwent three visits: at baseline and 2 and 8 weeks after initiation of RAAS inhibitors. Patients of the control group underwent two visits: at baseline and after 2 weeks. At each visit we collected blood specimens for hormonal assays and therapeutic drug monitoring, used as gold standard for therapeutic adherence. We used delta ARR (ARR), defined as the relative change in ARR before and after treatment, for assessment of therapeutic compliance.

RESULTS: After initiation of RAAS inhibitor, aldosterone significantly decreased and renin levels significantly increased, with consequent ARR reduction. The use ARR provided high accuracy for determination of therapeutic compliance, with an area under the curve (AUC) of 0.900 and 0.886, at 2 and 8 weeks respectively. A cut-off of -48% of ARR was adopted, providing 90% sensitivity and 75% specificity, both at 2 and 8 weeks.

CONCLUSIONS: The ARR measurement, is an innovative, cheap and highly sensitive method to predict compliance to RAAS inhibitors in patients with hypertension. We hence propose the implementation of ARR as screening test for identification of patients suspected to be non-adherent, reserving therapeutic drug monitoring for non-adherence confirmation.

PMID:36027462 | DOI:10.1097/01.hjh.0000838772.03800.3c

J Hypertens. 2022 Jun 1;40(Suppl 1):e200-e201. doi: 10.1097/01.hjh.0000837484.58272.76.

ABSTRACT

OBJECTIVE: Current guidelines recommend to withdraw interfering antihypertensive drugs before to perform a screening test for primary aldosteronism (PA). Recent studies suggested that diagnostic work-up of PA might be performed without withdrawing mineralocorticoid receptor antagonist (MRA) treatment in selected patients, especially when severe hypertension and hypokalemia are difficult to control.We designed a prospective study to evaluate the effects of MRA treatment on aldosterone to renin ratio (ARR) in patients with PA.

DESIGN AND METHOD: We prospectively recruited 121 patients with confirmed PA and started on canrenone treatment. Eighteen patients were enrolled in a short-term treatment cohort to assess the effects of MRA on aldosterone to renin ratio (ARR) and potassium after 2 and 8 weeks of canrenone therapy. One hundred and two patients were recruited in the long-term treatment cohort to evaluate the effects of canrenone on ARR after 2 to 12 months of MRA therapy.

RESULTS: Plasma renin activity and potassium displayed a significant increase, and ARR showed a significant reduction compared with baseline in patients with PA after MRA initiation. These effects were observed both after a short- and a long-term treatment with canrenone, and were progressively more significant after longer periods of therapy and with greater doses of MRA. We demonstrated that canrenone assumption severely impacts on the rate of false-negative screening tests for PA, which raised from 16.7% to 72.5% after 2 weeks and 7-12 months of MRA treatment, respectively.

CONCLUSIONS: ARR testing for PA screening should not be performed under MRA therapy.

PMID:36027140 | DOI:10.1097/01.hjh.0000837484.58272.76

Front Genet. 2022 Aug 9;13:960731. doi: 10.3389/fgene.2022.960731. eCollection 2022.

ABSTRACT

Background and aims: Albeit several factors which influence the outcome of corona virus disease (COVID-19) are already known, genetic markers which may predict the outcome of the disease in hospitalized patients are still very sparse. Thus, in this study, we aimed to analyze whether the single-nucleotide polymorphism (SNP) rs5443 in the gene GNB3, which was associated with higher T cell responses in previous studies, might be a suitable biomarker to predict T cell responses and the outcome of COVID-19 in a comprehensive German cohort. Methods: We analyzed the influence of demographics, pre-existing disorders, laboratory parameters at the time of hospitalization, and GNB3 rs5443 genotype in a comprehensive cohort (N = 1570) on the outcome of COVID-19. In a sub cohort, we analyzed SARS-CoV-2-specific T cell responses and associated GNB3 rs5443 genotypes. We investigated the influence of all factors on COVID-19 fatality in multivariable analysis. Results: We found a younger patient age, normotension or absence of diabetes mellitus or cardiovascular diseases, normal blood cell counts, and low inflammatory markers at hospital admission were protective factors against fatal course of disease. In addition, the rs5443 TT genotype was significantly associated with protection against COVID-19 fatality (OR: 0.60, 95% CI: 0.40-0.92, p = 0.02). We also observed significantly increased SARS-CoV-2-specific T cell responses in rs5443 TT genotype carriers (p = 0.01). Although we observed a significant association of the factors described previously in univariate analysis, only a younger age of the patients, normal blood cell counts, and the GNB3 rs5443 TT genotype remained independent predictors against COVID-19 fatality in multivariable analysis. Conclusion: Immutable predictors for COVID-19 fatality are relatively rare. In this study we could show that the TT genotype of the SNP rs5443 in the gene GNB3 is associated with protection against COVID-19 fatality. It was as well correlated to higher SARS-CoV-2-specific T cell responses, which could result in a milder course of disease in those patients. Based on those observations we hereby provide a further prognostic biomarker, which might be used in routine diagnostics as a predictive factor for COVID-19 mortality already upon hospitalization.

PMID:36017493 | PMC:PMC9395599 | DOI:10.3389/fgene.2022.960731

Complex Psychiatry. 2021 Dec;7(3-4):60-70. doi: 10.1159/000518926. Epub 2021 Aug 24.

ABSTRACT

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute's Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

PMID:36017067 | PMC:PMC8740081 | DOI:10.1159/000518926

Pharmaceutics. 2022 Aug 21;14(8):1744. doi: 10.3390/pharmaceutics14081744.

ABSTRACT

Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl &lt; 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study's findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication's dose in accordance with renal function.

PMID:36015370 | DOI:10.3390/pharmaceutics14081744

Pharmaceutics. 2022 Aug 14;14(8):1692. doi: 10.3390/pharmaceutics14081692.

ABSTRACT

Melanoma is a skin cancer characterized by rapid growth and spread for which current therapies produce both resistance and increased risk of infection. To develop new anti-melanoma biocompatible species, the series of complexes Cu(N-N)(bzac)(X)⋅nH2O (N-N: 1,10-phenanthroline/2,2'-bipyridine, Hbzac: 1-phenyl-1,3-butanedione, X: NO3/ClO4, and n = 0, 1) was studied. Single-crystal X-ray diffraction revealed a mononuclear structure for all complexes. The ability of the complexes to scavenge or trap reactive oxygen species such as O2⋅- and HO⋅ was proved by EPR spectroscopy experiments. All complexes inhibited B16 murine melanoma cells in a dose-dependent and nanomolar range, but the complexes with 1,10-phenanthroline were more active. Moreover, comparative activity on B16 and healthy BJ cells revealed a therapeutic index of 1.27-2.24. Bioinformatic methods were used to calculate the drug-likeness, pharmacokinetic, pharmacogenomic, and pharmacodynamic profiles of the compounds. The results showed that all compounds exhibit drug-likeness features, as well as promising absorption, distribution, metabolism, and excretion (ADME) properties, and no toxicity. The pharmacodynamics results showed that the neutral species appear to be good candidates for antitumor molecular targets (Tyrosyl-DNA phosphodiesterase 1, DNA-(apurinic or apyrimidinic site) lyase or Kruppel-like factor 5). Furthermore, the pharmacogenomic results showed a good affinity of the copper(II) complexes for the human cytochrome. These results recommend complexes bearing 1,10-phenanthroline as good candidates for developing drugs to melanoma alternative treatment.

PMID:36015318 | DOI:10.3390/pharmaceutics14081692

Pharmaceutics. 2022 Aug 4;14(8):1627. doi: 10.3390/pharmaceutics14081627.

ABSTRACT

The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary aim was to develop a population pharmacokinetic model for the metabolite showing the most associations with the abovementioned factors. A total of 29 patients were treated with intravenous infusion of ciprofloxacin and enrolled on this trial. Blood samples for pharmacokinetic analysis were taken at 1, 4, and 11.5 h following the completion of the infusion. Sex, age, body weight, height, serum creatinine and bilirubin levels, and creatinine clearance (CLCR) were recorded, and polymorphisms rs2032582 and rs1045642 in the ABCB1 gene, rs4148977 in the SLCO1A2 gene and rs762551 in the CYP1A2 gene were analyzed. A three-stage parent drug-metabolite population pharmacokinetic model was developed. Median (IQR) metabolite/parent ratios of the desethylene ciprofloxacin, formyl ciprofloxacin and oxociprofloxacin were 5.86 (4.09-9.87)%, 4.08 (3.38-6.92)% and 5.91 (3.42-13.65)%, respectively. The desethylene ciprofloxacin metabolic ratio was positively associated with height (r2 = 0.2277, p = 0.0089) and CLCR (r2 = 0.2023, p = 0.0144) and negatively associated with age (r2 = 0.2227, p = 0.0112). Males had a significantly higher oxociprofloxacin metabolic ratio than females (9.14 vs 3.42%, p = 0.0043). In the desethylene ciprofloxacin population PK model, the volume of distribution decreased with age, the parent drug-metabolite transfer rate constant increased with CLCR, and the metabolite elimination rate constant decreased with age and is increased in CYP1A2 rs762551 variant allele carriers. We therefore hypothesized that the CYP1A2 inhibition by ciprofloxacin is mediated by its metabolite desethylene ciprofloxacin.

PMID:36015253 | DOI:10.3390/pharmaceutics14081627

Pharmaceuticals (Basel). 2022 Aug 11;15(8):990. doi: 10.3390/ph15080990.

ABSTRACT

Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population.

PMID:36015138 | DOI:10.3390/ph15080990

Nutrients. 2022 Aug 10;14(16):3275. doi: 10.3390/nu14163275.

ABSTRACT

BACKGROUND: Vitamin D deficiency has been associated with the severity of COVID-19. The role of vitamin D in pregnant women with COVID-19 has been poorly investigated to date. The aim of this study was to evaluate the influence of vitamin D in affecting some clinical features in pregnancy between SARS-CoV-2 positive and negative patients.

METHODS: Vitamin D pathway related polymorphisms and 25-hydroxyvitamin D levels were quantified in pregnant women followed from the first to the third trimester of pregnancy. Vitamin D deficiency was considered with values ≤ 30 ng/mL.

RESULTS: In total, 160 women were enrolled: 23 resulted positive for at least one SARS-CoV-2 related test (molecular swab or antibody tests). Vitamin D-associated polymorphisms were able to affect vitamin D levels in SARS-CoV-2 negative and positive subjects: remarkably, all the VDR TaqICC genotype patients were negative for SARS-CoV-2. In a sub-population (118 patients), vitamin D levels correlated with pregnancy-related factors, such as alpha-fetoprotein levels. Third-trimester vitamin D levels were lower in preterm births compared to full-term pregnancy: this trend was highlighted for SARS-CoV-2 positive patients.

CONCLUSIONS: This is the first study demonstrating a role of vitamin D in affecting the clinical characteristics of pregnant women during the COVID-19 era. Further studies in larger and different cohorts of patients are required to confirm these findings.

PMID:36014781 | DOI:10.3390/nu14163275