Drug metabolism and personalized therapy最新文献

Objectives: Determine the frequency of actionable mutations in non-small cell lung cancer (NSCLC) and their correlation with overall survival (OS) and the site of metastases.

Methods: We performed a descriptive cross-sectional study at the Hospital de Especialidades Eugenio Espejo, Ecuador, between 2017 and 2020. Demographic, pathological, and molecular alterations in epidermal growth factor (EGFR), Anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), Programmed death-ligand 1 (PD-L1) expression, and clinical data detailed in patients' medical records with metastatic NSCLC were collected and analyzed. Seventy-nine stage IV patients had NSCLC; adenocarcinoma histology represents 56 (70.9%). The predominant mutation was in EGFR (22.8%); the most common variant was the deletion of exon 19 (72.2%). The most common metastatic site was in the contralateral lung (22.3%); however, this variable showed no significant correlation to the molecular markers (p=0.057). The overall survival (OS) and the status of molecular markers are not statistically significant (p=0.27). OS was better for non-mutated EGFR than for mutated EGFR (p=0.012). However, the frequency values are unrelated to contralateral lung metastasis or survival.

Conclusions: Our frequency mutations are concordant with those found in other studies in Latin America. EGFR was the most common biomarker mutation, and there was a better OS in EGFR non-mutated patient.

Pharmacogenetics (PGx)-guided prescribing is an evidence-based precision medicine strategy. Although the past two decades have reported significant advancements in both the quality and quantity of PGx research studies, they are seldom done in developing countries like Bangladesh. This review identified and summarized PGx studies conducted in the Bangladeshi population by searching PubMed and Google Scholar. Additionally, a quality evaluation of the identified studies was also carried out. Eleven PGx studies were identified that looked at the effects of genetic variants on blood thinners (CYP2C9, VKORC1, and ITGB3), cancer drugs (TPMT, MTHFR, DPYD, ERCC1, GSTP1, XPC, XRCC1, TP53, XPD, and ABCC4), statins (COQ2, CYP2D6, and CYP3A5), and prednisolone (ABCB1, CYP3A5, and NR3C1) in the Bangladeshi population. Most studies were of low to moderate quality. Although the identified studies demonstrated the potential for PGx testing, the limited PGx literature in the Bangladeshi population poses a significant challenge in the widespread implementation of PGx testing in Bangladesh.

Introduction: Medicinal plants and herbs are the most important part of the Ayurveda. The term Rasayana in Charaka Samhita confers long life, youthfulness, strong body, freedom from diseases and the plants mentioned in Rsayana possess antiaging property. Aging is the collective term used for the complex detrimental physiological changes that reduce the functional ability of the cell. Oxidative stress, telomeres shortening, inflammation, and mitochondrial dysfunction are the main factors that regulate the aging process. Chronological aging is an irreversible process but the factors causing biological aging can be controlled. Ayurvedic herbs are better for the management of age-related problems. There are several natural bioactive agents present in plants that can delay the aging process in humans. They trigger actions like enhancing gene longevity and telomerase activity, ROS scavenging furthermore regeneration of tissues.

Content: The plants mentioned in the Rasayana of Ayurveda have antiaging potential and can be used to solve modern problems related to aging. Some Ayurvedic plants and their antiaging potential has explained in this review. The main causes of aging, medicinal plants and their use as potential antiaging mediator are covered in this study.

Summary: The process of aging is still an enigma. It is a complex, irretrievable, dynamic process that involves a number of factors and is subject to a number of environmental and genetic influences. Rasayana aspect has not been much investigated in clinical trials. Aging is considered to result from free radical damage. According to Charaka, Rasayana drugs open the partially or fully blocked channels. Many Rasayanas show free radical scavenging activity and has the potential to mitigate the effects of aging. It gives an overview of the significance of Ayurvedic medicinal plants as a source of inspiration and the use of these plants as remedies for antiaging.

Outlook: This study briefly outlooks the causes of aging and how medicinal plants can be used to reverse the aging process. In this study, we discussed the antiaging potential and mechanistic roles of Ayurvedic herbs. These herbs have the properties to slow down the natural process of aging and can successfully manage common age-related problems.

Objectives: Extrapyramidal symptoms (EPS) are one of the most prominent side effects of haloperidol. Variability of EPS severity may be associated with the genetic factors, affecting both haloperidol pharmacokinetics (e.g., CYP2D6) and pharmacodynamics (e.g., DRD2, ANKK1). We conducted a 3-week prospective study to investigate the associations of ANKK1/DRD2 TaqIA (rs1800497), DRD2 -141C Ins/Del (rs1799732) polymorphisms and CYP2D6 metabolic phenotype on the efficacy of haloperidol treatment and severity of EPS in patients with schizophrenia spectrum disorders.

Methods: In total, 57 inpatients with schizophrenia spectrum disorders (24 (42.1%)) females; age -46.7 (11.8) years (M(SD)) of European ancestry were enrolled. BARS and SAS scales were used to assess EPS. PANSS and CGI scales - to assess the efficacy of haloperidol treatment. Genotyping was performed by real-time PCR. CYP2D6 metabolic phenotype was predicted by the CYP2D6 *3, *4, *5, *6, *9, *10, *41 and xN genotypes.

Results: Minor C allele of TaqIA was associated with higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21 and minor Del allele of -141C Ins/Del - with more prominent clinical improvement by CGI scale (p=0.007) but not by PANSS. These differences were observed only in extensive CYP2D6 metabolizers, although no associations with the metabolic type itself were found. General linear model showed that the combination of TaqIA genotype and metabolic type was significantly associated with BARS score on day 21 (p=0.013).

Conclusions: Our results highlight the importance of using both pharmacokinetic and pharmacodynamic genetic markers for predicting haloperidol treatment response to personalize schizophrenia spectrum disorders treatment.

Objectives: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats.

Methods: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method.

Results: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner.

Conclusions: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest C_max in the lung and T_max in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

Objectives: Rhinitis is classified into several types with allergic rhinitis (AR) being the most common. AR is among the inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), in which corticosteroids are administered to overcome the decrease in cortisol production. The treatment options available for AR vary with 1^st line treatment being intranasal corticosteroids (INCS). The responsiveness to corticosteroids is due to their binding to corticotropin-releasing hormone receptor-1 (CRHR1). Various studies have studied the responsiveness to corticosteroids treatment in patients with asthma and COPD in association with CRHR1 gene single nucleotide polymorphisms (SNPs).

Methods: In our study, we investigated the association of three SNPs of CRHR1 gene (rs242941, rs242940, and rs72834580) with symptoms improvement post-treatment in AR patients. Blood samples were collected from 103 patients for DNA extraction and gene sequencing. Those patients started to receive INCS for 8 weeks and their symptoms were assessed, through a questionnaire, before treatment and post-treatment to check for symptoms improvement.

Results: Our data showed that improvement of eye redness is significantly less following INCS treatment in patients with allele (C) (AOR=0.289, p-value-0.028, 95 % CI=0.096-0.873) and genotype (CC) (AOR=0.048, p-value-0.037, 95 % CI=0.003-0.832) of rs242941 SNP. There was no correlation with other genotypes, alleles, or haplotypes of the investigated SNPs.

Conclusions: Our findings show that there is no correlation between CRHR1 gene polymorphism and symptoms improvement following INCS treatment. Further studies are required to evaluate the association of INCS and symptoms improvement post-treatment with larger sample size.

Objectives: Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension.

Methods: Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction.

Results: The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008).

Conclusions: Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

Objectives: This real-world study was conducted to assess the adverse effects following immunization (AEFI) and immunogenicity of ChAdO×1 nCoV-19 vaccine in terms of neutralising antibody titers and to study the effects of covariates such as age, sex, comorbidities and prior COVID status on these outcomes. Also, the effectiveness of the vaccine based on interval between the two doses was also investigated.

Methods: A total of 512 participants (M/F=274/238) aged 35(18-87) years comprising a mixed population of healthcare workers, other frontline workers and general public were enrolled between March and May 2021. Records for adverse events if any were collected telephonically by following up with participants up to 6 months post first dose and graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 5. Blood samples for measuring antibody titers against the receptor binding domain (RBD) were collected serially using a convenient sampling strategy up to 6 months after the first dose. Data on breakthrough COVID infection was collected telephonically till December 2021.

Results: Incidence of local reactions was higher after first dose at 33.4 % (171/512) compared to those after second dose at 12.9 % (66/512). Commonest side effect observed was injection site pain after the first (87.1 %; 149/171) and second (87.9 %; 56/66) dose respectively. Among systemic reactions, fever was the most common manifestation followed by myalgia and headache. Female sex (p<0⸱001) and age less than 60 years (p<0⸱001) had significantly higher predilection for systemic toxicities. Age ≤60 years (p=0.024) and prior-COVID (p<0.001) were found to be significantly associated with higher antibody titers, however, no association was found between these variables and breakthrough COVID infection. Longer spacing between the doses (≥6 weeks) was found to offer better protection against breakthrough infection compared to a spacing of 4 weeks. All breakthroughs were mild-moderate in severity, not requiring hospitalization.

Conclusions: The ChAdOx1 nCov-19 vaccine is apparently safe and effective against SARS-CoV-2 virus infection. Prior COVID infection and younger age group achieve higher antibody titers, but no additional protection. Delaying the second dose up to at least 6 weeks is more effective compared to shorter spacing between doses.

Objectives: A study was conducted to develop and validate the warfarin pharmacogenetic dose optimization algorithm considering the clinical pharmacogenetic implementation consortium (CPIC) recommendations for the Asian ethnicity population.

Methods: The present prospective observational study recruited warfarin-receiving patients. We collected a three ml blood sample for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2 polymorphism assessment during the follow-up visits. Clinical history, sociodemographic and warfarin dose details were noted.

Results: The study recruited 300 patients (250 in derivation and 50 in validation timed cohort) receiving warfarin therapy. The baseline characteristics were similar in both cohorts. BMI, presence of comorbidity, VKORC1, CYP2C9*2, and CYP2C9*3 were identified as covariates significantly affecting the warfarin weekly maintenance dose (p<0.001 for all) and the same were included in warfarin pharmacogenetic dose optimization algorithm building. The algorithm built-in the present study showed a good correlation with Gage (r=0.57, p<0.0001), and IWPC (r=0.51, p<0.0001) algorithms, widely accepted in western side of the globe. The receiver operating characteristic curve analysis showed a sensitivity of 73 %, a positive predictive value of 96 %, and a specificity of 89 %. The algorithm correctly identified the validation cohort's warfarin-sensitive, intermediate reacting, and resistant patient populations.

Conclusions: Validation and comparisons of the warfarin pharmacogenetic dose optimization algorithm have made it ready for the clinical trial assessment.