Molecules. 2021 Oct 14;26(20):6210. doi: 10.3390/molecules26206210.

ABSTRACT

Androstenedione is a steroidal hormone produced in male and female gonads, as well as in the adrenal glands, and it is known for its key role in the production of estrogen and testosterone. Androstenedione is also sold as an oral supplement, that is being utilized to increase testosterone levels. Simply known as "andro" by athletes, it is commonly touted as a natural alternative to anabolic steroids. By boosting testosterone levels, it is thought to be an enhancer for athletic performance, build body muscles, reduce fats, increase energy, maintain healthy RBCs, and increase sexual performance. Nevertheless, several of these effects are not yet scientifically proven. Though commonly used as a supplement for body building, it is listed among performance-enhancing drugs (PEDs) which is banned by the World Anti-Doping Agency, as well as the International Olympic Committee. This review focuses on the action mechanism behind androstenedione's health effects, and further side effects including clinical features, populations at risk, pharmacokinetics, metabolism, and toxicokinetics. A review of androstenedione regulation in drug doping is also presented.

PMID:34684800 | PMC:PMC8539210 | DOI:10.3390/molecules26206210

Nutrients. 2021 Oct 18;13(10):3649. doi: 10.3390/nu13103649.

ABSTRACT

This review aims to identify hospital food service strategies to improve food consumption among hospitalized patients. A systematic search that met the inclusion and exclusion criteria was manually conducted through Web of Science and Scopus by an author, and the ambiguities were clarified by two senior authors. The quality assessment was separately conducted by two authors, and the ambiguities were clarified with all the involved authors. Qualitative synthesis was used to analyze and summarized the findings. A total of 2432 articles were identified by searching the databases, and 36 studies were included. The majority of the studies applied menu modifications and meal composition interventions (n = 12, 33.3%), or included the implementation of the new food service system (n = 8, 22.2%), protected mealtimes, mealtime assistance and environmental intervention (n = 7, 19.4%), and attractive meal presentation (n = 3, 8.3%). Previous studies that used multidisciplinary approaches reported a significant improvement in food intake, nutritional status, patient satisfaction and quality of life (n = 6, 16.7%). In conclusion, it is suggested that healthcare institutions consider applying one or more of the listed intervention strategies to enhance their foodservice operation in the future.

PMID:34684649 | PMC:PMC8537902 | DOI:10.3390/nu13103649

Nutrients. 2021 Oct 12;13(10):3571. doi: 10.3390/nu13103571.

ABSTRACT

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.

PMID:34684572 | PMC:PMC8538640 | DOI:10.3390/nu13103571

Medicina (Kaunas). 2021 Oct 14;57(10):1107. doi: 10.3390/medicina57101107.

ABSTRACT

Cannabis products that contain the tetrahydrocannabinol (THC) cannabinoid are emerging as promising therapeutic agents for the treatment of medical conditions such as chronic pain. THC elicits psychoactive effects through modulation of dopaminergic neurons, thereby altering levels of dopamine in the brain. This case report highlights the complexity associated with medicinal cannabis and the health risks associated with its use. A 57-year-old male with Parkinson's disease was experiencing worsening tremors and vivid hallucinations despite therapy optimization attempts. It was discovered that the patient took cannabis for chronic back pain, and a pharmacogenomics (PGx) test indicated the presence of variants for the COMT and HTR2A genes. These variants could increase dopamine levels and predispose patients to visual hallucinations. Once the cannabis was discontinued, the patient's hallucinations began to slowly dissipate. Cannabis use continues to expand as it gains more acceptance legally and medicinally, but cannabis can affect the response to drugs. This patient case suggests that cannabis use in combination with dopamine-promoting drugs, especially in a patient with genetic variants, can increase the risk for vivid hallucinations. These conditions support the importance of considering herb-drug interactions and PGx data when performing a medication safety review.

PMID:34684144 | PMC:PMC8539120 | DOI:10.3390/medicina57101107

Medicina (Kaunas). 2021 Oct 1;57(10):1050. doi: 10.3390/medicina57101050.

ABSTRACT

Background and Objectives: Methotrexate is widely prescribed for the treatment of moderate-to-severe psoriasis. As drug survival encompasses efficacy, safety, and treatment satisfaction, such studies provide insights into successful drug treatments in the real-life scenario. The objective was to define methotrexate drug survival and reasons for discontinuation, along with factors associated with drug survival, in a cohort of adult patients with moderate-to-severe plaque psoriasis. Materials and Methods: Data on methotrexate treatment were extracted from our institutional registry. Drug survival was estimated by Kaplan-Meier analysis, and predictors of drug survival were analyzed by Cox proportional hazards regression. Results: We included 133 patients treated with methotrexate. Due to significant effects of the year of treatment initiation, drug survival analysis was performed for 117 patients who started methotrexate in 2010 or later. Median methotrexate drug survival was 11.0 months. Overall, 89% of patients discontinued treatment, with over half of these (51%) due to lack of efficacy. Significantly longer drug survival was seen for patients who discontinued treatment due to lack of efficacy versus drug safety (p = 0.049); when stratified by sex, this remained significant only for women (p = 0.002). The patient ABCC2 rs717620 genotype was significantly associated with drug survival in both univariate log-rank and multivariate Cox regression analyses, with variant T allele associated with longer drug survival (hazard ratio, 0.606; 95% confidence interval, 0.380-0.967; p = 0.036). Conclusions: We have identified the novel association of patient ABCC2 rs717620 genotype with methotrexate drug survival. This pharmacogenetic marker might thus help in the management of psoriasis patients in daily practice.

PMID:34684087 | PMC:PMC8539794 | DOI:10.3390/medicina57101050

Pharmaceutics. 2021 Oct 2;13(10):1604. doi: 10.3390/pharmaceutics13101604.

ABSTRACT

Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.

PMID:34683897 | PMC:PMC8540545 | DOI:10.3390/pharmaceutics13101604

Pharmaceutics. 2021 Sep 28;13(10):1573. doi: 10.3390/pharmaceutics13101573.

ABSTRACT

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine's metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.

PMID:34683865 | PMC:PMC8540141 | DOI:10.3390/pharmaceutics13101573

J Pers Med. 2021 Oct 15;11(10):1032. doi: 10.3390/jpm11101032.

ABSTRACT

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of autoimmune origin, in which inflammation and demyelination lead to neurodegeneration and progressive disability. Treatment is aimed at slowing down the course of the disease and mitigating its symptoms. One of the first-line treatments used in patients with MS is glatiramer acetate (GA). However, in clinical practice, a response rate of between 30% and 55% is observed. This variability in the effectiveness of the medication may be influenced by genetic factors such as polymorphisms in the genes involved in the pathogenesis of MS. Therefore, this review assesses the impact of genetic variants on the response to GA therapy in patients diagnosed with MS. The results suggest that a relationship exists between the effectiveness of the treatment with GA and the presence of polymorphisms in the following genes: CD86, CLEC16A, CTSS, EOMES, MBP, FAS, TRBC1, IL1R1, IL12RB2, IL22RA2, PTPRT, PVT1, ALOX5AP, MAGI2, ZAK, RFPL3, UVRAG, SLC1A4, and HLA-DRB1*1501. Consequently, the identification of polymorphisms in these genes can be used in the future as a predictive marker of the response to GA treatment in patients diagnosed with MS. Nevertheless, there is a lack of evidence for this and more validation studies need to be conducted to apply this information to clinical practice.

PMID:34683173 | PMC:PMC8540092 | DOI:10.3390/jpm11101032

J Pers Med. 2021 Oct 2;11(10):1002. doi: 10.3390/jpm11101002.

ABSTRACT

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5-7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46-1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68-1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.

PMID:34683143 | PMC:PMC8539387 | DOI:10.3390/jpm11101002

J Pers Med. 2021 Sep 23;11(10):946. doi: 10.3390/jpm11100946.

ABSTRACT

miRNAs play an important role in neurodegenerative diseases. Many miRNA-target gene interactions (MTI) have been experimentally confirmed and associated with Alzheimer's disease (AD). miRNAs may also be contained within extracellular vesicles (EVs), mediators of cellular communication and a potential source of circulating biomarkers in body fluids. Therefore, EV-associated miRNAs (EV-miRNAs) in peripheral blood could support earlier and less invasive AD diagnostics. We aimed to prioritize EV-related miRNA with AD-related genes and to identify the most promising candidates for novel AD biomarkers. A list of unique EV-miRNAs from the literature was combined with a known set of AD risk genes and enriched for MTI. Additionally, miRNAs associated with the AD phenotype were combined with all known target genes in MTI enrichment. Expression in different sample types was analyzed to identify AD-associated miRNAs with the greatest potential as AD circulating biomarkers. Four common MTI were observed between EV-miRNAs and AD-associated miRNAs: hsa-miR-375-APH1B, hsa-miR-107-CDC42SE2, hsa-miR-375-CELF2, and hsa-miR-107-IL6. An additional 61 out of 169 unique miRNAs (36.1%) and seven out of 84 unique MTI (8.3%), observed in the body fluids of AD patients, were proposed as very strong AD-circulating biomarker candidates. Our analysis summarized several potential novel AD biomarkers, but further studies are needed to evaluate their potential in clinical practice.

PMID:34683087 | PMC:PMC8538213 | DOI:10.3390/jpm11100946

J Pers Med. 2021 Sep 22;11(10):943. doi: 10.3390/jpm11100943.

ABSTRACT

BACKGROUND: Patients with psychotic disorders who receive atypical antipsychotic drugs often develop metabolic abnormalities. The sterol regulatory element-binding factor 2 (SREBF2) gene and insulin-induced gene (INSIG) have important roles in lipid metabolism. A previous study indicated that risperidone stimulated both lipogenesis and cholesterogenesis through activation of SREBP2 expression and inhibition of INSIG2. The SREBF2 gene and INSIG2 polymorphisms have been reported to be associated with metabolic abnormalities.

OBJECTIVE: To investigate the association of the SREBF2 gene (rs1052717, rs2267439, and rs2267443) and INSIG2 (rs7566605, rs11123469, and rs17587100) polymorphisms and the presence of obesity and dyslipidemia in Thai psychotic disorder patients treated with risperidone.

METHODS: All 113 psychiatric patients using risperidone were evaluated for their lipid profile and screened for obesity criteria. We genotyped the SREBF2 gene and INSIG2 polymorphisms using TaqMan real-time polymerase chain reaction.

RESULTS: None of the studied SREBF2 gene and INSIG2 SNPs were associated with obesity in Thai psychotic disorder patients receiving risperidone. Nonetheless, the SREBF2 rs2267443 (G/A) A-allele carriers were at a higher risk for hypertriglyceridemia, whereas the INSIG2 rs11123469 (T/C) C-allele carriers had a lower risk for hypertriglyceridemia, after being adjusted for clinical characteristics using multiple logistic regression.

CONCLUSIONS: Our findings suggest that the SREBF2 gene rs2267443 (G/A) and the INSIG2 rs11123469 (T/C) polymorphisms are associated with dyslipidemia in Thai psychotic disorder patients treated with risperidone. Further studies with prospective designs and larger patient groups are needed.

PMID:34683084 | PMC:PMC8541118 | DOI:10.3390/jpm11100943

J Pers Med. 2021 Sep 22;11(10):941. doi: 10.3390/jpm11100941.

ABSTRACT

State-of-the-art research on the human genome has produced remarkable research achievements in pharmacogenomics and functional genomics, and these research results are making an invaluable contribution to the advancement of personalized medicine [...].

PMID:34683082 | PMC:PMC8541271 | DOI:10.3390/jpm11100941

Pharmaceuticals (Basel). 2021 Oct 18;14(10):1056. doi: 10.3390/ph14101056.

ABSTRACT

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02-2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05-3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63-3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance.

PMID:34681280 | PMC:PMC8538435 | DOI:10.3390/ph14101056

Pharmaceuticals (Basel). 2021 Sep 25;14(10):970. doi: 10.3390/ph14100970.

ABSTRACT

The advancement in therapy has provided a dramatic improvement in the rate of recovery among cancer patients. However, this improved survival is also associated with enhanced risks for cardiovascular manifestations, including hypertension, arrhythmias, and heart failure. The cardiotoxicity induced by chemotherapy is a life-threatening consequence that restricts the use of several chemotherapy drugs in clinical practice. This article addresses the prevalence of cardiotoxicity mediated by commonly used chemotherapeutic and immunotherapeutic agents. The role of susceptible genes and radiation therapy in the occurrence of cardiotoxicity is also reviewed. This review also emphasizes the protective role of antioxidants and future perspectives in anticancer drug-induced cardiotoxicities.

PMID:34681194 | PMC:PMC8539940 | DOI:10.3390/ph14100970

Genes (Basel). 2021 Oct 17;12(10):1632. doi: 10.3390/genes12101632.

ABSTRACT

Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression of the human telomerase gene (hTERT) in patients with ALL has been studied as a biomarker and could become a new therapeutic target. We evaluate the role of hTERT gene expression in ALL pediatric patients, through quantitative real-time PCR technique, and the possible correlation between hTERT expression and clinical variables: gender, age, white blood cells (WBC), gene fusions, and immunophenotyping. The analysis between healthy controls and ALL patients (N = 244) was statistically significant (p < 0.001), demonstrating hTERT overexpression in these patients. In comparison with the usual set of clinical variables, the data were not statistically significant (p > 0.05), indicating that hTERT is equally overexpressed among patients regardless of gender, age, gene fusions, and immunophenotyping. Moreover, patients who presented a higher hTERT expression level had a significant (p < 0.0001) lower overall survival rate. In summary, hTERT expression emerges as an important molecular pathway in leukemogenesis regardless patient's clinical variables, thus, the data here presented pointed it as a valuable biomarker in pediatric acute lymphoblastic leukemia and a promising target for new therapeutic and prognostic measures.

PMID:34681025 | PMC:PMC8535500 | DOI:10.3390/genes12101632

Genes (Basel). 2021 Sep 28;12(10):1537. doi: 10.3390/genes12101537.

ABSTRACT

The genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. To commence, 176 outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center, were enrolled. Patient characteristics, blood test results, dietary vitamin K intake, and CYP2C9 and VKORC1 (-1639G>A) genotypes were recorded. CYP2C9 and VKORC1 (-1639G>A) genotyping revealed that 80% of the patients had CYP2C9 *1/*1 and VKORC1 mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake. eGFR exercised a significant impact on the maintenance doses, as an increase in eGFR of 10 mL/min/1.73 m2 escalated the warfarin maintenance dose by 0.6 mg. Reduced eGFR was related to lower warfarin maintenance doses, independent of VKORC1 and CYP2C9 genotypes in Japanese patients.

PMID:34680932 | PMC:PMC8535514 | DOI:10.3390/genes12101537

Genes (Basel). 2021 Sep 26;12(10):1511. doi: 10.3390/genes12101511.

ABSTRACT

This narrative review aims to provide an overview of the main Machine Learning (ML) techniques and their applications in pharmacogenetics (such as antidepressant, anti-cancer and warfarin drugs) over the past 10 years. ML deals with the study, the design and the development of algorithms that give computers capability to learn without being explicitly programmed. ML is a sub-field of artificial intelligence, and to date, it has demonstrated satisfactory performance on a wide range of tasks in biomedicine. According to the final goal, ML can be defined as Supervised (SML) or as Unsupervised (UML). SML techniques are applied when prediction is the focus of the research. On the other hand, UML techniques are used when the outcome is not known, and the goal of the research is unveiling the underlying structure of the data. The increasing use of sophisticated ML algorithms will likely be instrumental in improving knowledge in pharmacogenetics.

PMID:34680905 | PMC:PMC8535911 | DOI:10.3390/genes12101511

Biomedicines. 2021 Sep 26;9(10):1319. doi: 10.3390/biomedicines9101319.

ABSTRACT

(1) Background: Inter-tumour heterogeneity is one of cancer's most fundamental features. Patient stratification based on drug response prediction is hence needed for effective anti-cancer therapy. However, single-gene markers of response are rare and/or may fail to achieve a significant impact in the clinic. Machine Learning (ML) is emerging as a particularly promising complementary approach to precision oncology. (2) Methods: Here we leverage comprehensive Patient-Derived Xenograft (PDX) pharmacogenomic data sets with dimensionality-reducing ML algorithms with this purpose. (3) Results: Combining multiple gene alterations via ML leads to better discrimination between sensitive and resistant PDXs in 19 of the 26 analysed cases. Highly predictive ML models employing concise gene lists were found for three cases: paclitaxel (breast cancer), binimetinib (breast cancer) and cetuximab (colorectal cancer). Interestingly, each of these multi-gene ML models identifies some treatment-responsive PDXs not harbouring the best actionable mutation for that case. Thus, ML multi-gene predictors generally have much fewer false negatives than the corresponding single-gene marker. (4) Conclusions: As PDXs often recapitulate clinical outcomes, these results suggest that many more patients could benefit from precision oncology if ML algorithms were also applied to existing clinical pharmacogenomics data, especially those algorithms generating classifiers combining data-selected gene alterations.

PMID:34680436 | PMC:PMC8533095 | DOI:10.3390/biomedicines9101319

Biomedicines. 2021 Sep 22;9(10):1288. doi: 10.3390/biomedicines9101288.

ABSTRACT

Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or osteoarticular infections, treated either with one or two 1500 mg doses of dalbavancin. A liquid chromatography-tandem mass spectrometry method was used to measure total dalbavancin concentrations in plasma samples. The results were analyzed through a non-compartmental analysis (NCA). Breakpoint minimum inhibitory concentration (MIC) was used to calculate AUC/MIC and T > MIC parameters, adjusted by 93% protein binding. A total of 14 patients were enrolled, 11 with osteoarticular infection and 3 with ABSSSI. Long-term pharmacokinetics showed median T > MIC (0.125 mg/L) of 11.9 and 13.7 weeks for single and dual dose, respectively. Similarly, median AUC0-2w/MIC ratios of 20,590 and 31,366 were observed for single and dual dose regimens, respectively. No adverse events were observed, and treatment success was achieved in 12/14 patients. Failure was associated with the worst clinical conditions, bone infections, and single dose. The results of this study show that dalbavancin exposure exceeds previously suggested pharmacodynamic targets. Optimization of these targets is needed for the osteoarticular setting.

PMID:34680409 | PMC:PMC8533485 | DOI:10.3390/biomedicines9101288

Cancers (Basel). 2021 Oct 14;13(20):5165. doi: 10.3390/cancers13205165.

ABSTRACT

BACKGROUND: The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina's 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied.

RESULTS: SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores).

CONCLUSION: These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.

PMID:34680315 | PMC:PMC8533997 | DOI:10.3390/cancers13205165