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The World Journal of Biological... Jun 2024For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and... (Review)
Review
BACKGROUND
For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging.
METHODS
In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)).
RESULTS
Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings.
CONCLUSION
All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.
PubMed: 38913780
DOI: 10.1080/15622975.2024.2366235 -
American Journal of Health-system... Jun 2024In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been...
In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
PubMed: 38912618
DOI: 10.1093/ajhp/zxae171 -
Frontiers in Pharmacology 2024
PubMed: 38910892
DOI: 10.3389/fphar.2024.1439276 -
Biological Trace Element Research Jun 2024Humans are exposed to various chemical elements that have been associated with the development and progression of diseases such as coronary artery disease (CAD). Unlike...
Humans are exposed to various chemical elements that have been associated with the development and progression of diseases such as coronary artery disease (CAD). Unlike previous research, we employed a multi-element approach to investigate CAD patients and those with comorbid conditions such as diabetes (CAD-DM2), high blood pressure (CAD-HBP), or high blood lipids (CAD-HBL). Plasma concentrations of 21 elements, including lithium (Li), boron (B), aluminum (Al), calcium (Ca), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), strontium (Sr), cadmium (Cd), tin (Sn), stibium (Sb), barium (Ba), and lead (Pb), were measured in CAD patients (n = 201) and healthy subjects (n = 110) using inductively coupled plasma-mass spectrometry (ICP-MS). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were utilized to analyze the ionomic profiles. Spearman correlation analysis was employed to identify the interaction patterns among individual elements. We found that levels of Ba, Li, Ni, Zn and Pb were elevated in the CAD group compared to the healthy group, while Sb, Ca, Cu, Ti, Fe, and Se were lower. Furthermore, the CAD-DM2 group exhibited higher levels of Ni and Cd, while the CAD-HBP group showed lower levels of Co and Mn. In the CAD-HBL group, Ti was increased, whereas Ba, Cr, Cu, Co, Mn, and Ni were reduced. In conclusion, ionomic profiles can be utilized to differentiate CAD patients from healthy individuals, potentially providing insights for future treatment or dietary interventions.
PubMed: 38910164
DOI: 10.1007/s12011-024-04227-z -
European Neuropsychopharmacology : the... Jun 2024
PubMed: 38909437
DOI: 10.1016/j.euroneuro.2024.05.003 -
Methods in Molecular Biology (Clifton,... 2024The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of...
The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the website contains data from 1784 population samples in more than 14 million individuals from 129 countries on the frequency of genes from different polymorphic regions including data for the human leukocyte antigen (HLA) system. In addition, over the last four years, AFND has also incorporated genotype raw data from 85,000 individuals comprising 215 population samples from 39 countries. Moreover, more population data sets containing next generation sequencing data spanning >3 million individuals have been added. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, epitope prediction algorithms for population coverage in vaccine development, population genetics, among many others. In this chapter, we present an update of the most used searching mechanisms as described in a previous volume and some of the latest developments included in AFND.
Topics: Humans; Gene Frequency; Databases, Genetic; Genetics, Population; HLA Antigens; Alleles; Computational Biology; Internet; Web Browser; Genotype; High-Throughput Nucleotide Sequencing
PubMed: 38907888
DOI: 10.1007/978-1-0716-3874-3_2 -
The Journal of Antimicrobial... Jun 2024
PubMed: 38905150
DOI: 10.1093/jac/dkae187 -
Pediatric Hematology and Oncology Jun 2024This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective...
This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009-2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs ( < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively ( < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters.
PubMed: 38904214
DOI: 10.1080/08880018.2024.2368007 -
Toxicological Sciences : An Official... Jun 2024Drug-induced liver injury (DILI) is the most common trigger for acute liver failure and the leading cause of attrition in drug development. In this study, we developed...
Drug-induced liver injury (DILI) is the most common trigger for acute liver failure and the leading cause of attrition in drug development. In this study, we developed an in-silico framework to screen drug-induced hepatocellular toxicity (INSIGHT) by integrating the post-treatment transcriptomic data from both rodent models and primary human hepatocytes. We first built an early prediction model using logistic regression with elastic net regularization for 123 compounds and established the INSIGHT framework that can screen for drug-induced hepatotoxicity. The 235 signature genes identified by INSIGHT were involved in metabolism, bile acid synthesis, and stress response pathways. Applying the INSIGHT to an independent transcriptomic dataset treated by 185 compounds predicted that 27 compounds show a high DILI risk, including zoxazolamine and emetine. Further integration with cell image data revealed that predicted DILI compounds can induce abnormal morphological changes in the endoplasmic reticulum (ER) and mitochondrion. Clustering analysis of the treatment-induced transcriptomic changes delineated distinct DILI mechanisms induced by these compounds. Our study presents a computational framework for a mechanistic understanding of long-term liver injury and the prospective prediction of DILI.
PubMed: 38902949
DOI: 10.1093/toxsci/kfae078 -
The British Journal of General Practice... Jun 2024Treatment of depression is common in primary care but not every antidepressant is effective in every patient. Adverse drug reactions are common, imposing a substantial...
BACKGROUND
Treatment of depression is common in primary care but not every antidepressant is effective in every patient. Adverse drug reactions are common, imposing a substantial burden on the patient and the NHS. Pharmacogenomics (PGx) utilises an individual's genetic makeup to predict their response to medications. By tailoring prescriptions to a person's genetic profile, PGx can significantly reduce adverse drug reactions, identify non-responders to medications, and enhance overall patient outcomes.
AIM
To see if PGx testing for antidepressants can be undertaken in general practice as part of 'usual care'; to increase GP and patient awareness of PGx testing; to alter patient treatment according to the results of testing; and to sustain these changes at 4 years.
METHOD
In 2019, 23 patients were recruited by GPs at the surgery. They consented and had cheek swabs to check their genetic profile to common antidepressants. Results were reviewed at 1 week by the GP and patient, treatment changes made and reviewed again at 4 years.
RESULTS
On the CYP2D pathway, 19/23 patients were extensive (normal) metabolisers, one intermediate and two poor. These two had their treatments changed. At 4-year review 19/23 were on appropriate treatment (two had been stopped) but two had inappropriate drug treatment. On CYP2C19 pathway, 10/23 were normal metabolisers, eight intermediate, zero poor but five ultrarapid (they had their treatment changed). At 4-year review, 20/23 were on appropriate treatment (two stopped) and one inappropriate.
CONCLUSION
PGx testing works in primary care, improving patient outcomes sustainably.
Topics: Humans; Quality Improvement; Antidepressive Agents; Primary Health Care; Pharmacogenetics; Female; Male; Depression; Middle Aged; Adult; General Practice; Pharmacogenomic Testing
PubMed: 38902050
DOI: 10.3399/bjgp24X737901