-
Nature Reviews. Drug Discovery Jul 2023Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural... (Review)
Review
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
Topics: Humans; Deuterium; Drug Discovery; Chemistry, Pharmaceutical
PubMed: 37277503
DOI: 10.1038/s41573-023-00703-8 -
Signal Transduction and Targeted Therapy Oct 2023Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and... (Review)
Review
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
Topics: Humans; Precision Medicine; Microbiota; Gastrointestinal Microbiome; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37806986
DOI: 10.1038/s41392-023-01619-w -
Journal of Affective Disorders Oct 2023The concurrent assessment of weight and affective psychopathology outcomes relevant to the psychopharmacology of major eating disorders (EDs), namely anorexia nervosa... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The concurrent assessment of weight and affective psychopathology outcomes relevant to the psychopharmacology of major eating disorders (EDs), namely anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED), warrants systematic review and meta-analysis of randomized controlled trials (RCTs).
METHODS
PubMed, Scopus, and ClinicalTrials.gov were inquired from inception through August 31st, 2022, for RCTs documenting any psychopharmacological intervention for EDs diagnosed according to validated criteria and reporting weight and psychopathology changes. Adopted keywords were: "anorexia nervosa," "bulimia nervosa," "binge eating disorder," "antidepressant," "antipsychotic," and "mood stabilizer." No language restriction applied.
RESULTS
5122 records were identified, and 203 full-texts were reviewed. Sixty-two studies entered the qualitative synthesis (AN = 22, BN = 23, BED = 17), of which 22 entered the meta-analysis (AN = 9, BN = 10, BED = 3). Concerning BMI increase in AN, olanzapine outperformed placebo (Hedges'g = 0.283, 95%C·I. = 0.051-0.515, I = 0 %; p = .017), whereas fluoxetine failed (Hedges'g = 0.351, 95%C.I. = -0.248 to 0.95, I = 63.37 %; p = .251). Fluoxetine not significantly changed weight (Hedges'g = 0.147, 95%C.I. = -0.157-0.451, I = 0 %; p = .343), reducing binging (Hedges'g = 0.203, 95%C.I. = 0.007-0.399, I = 0 %; p = .042), and purging episodes (Hedges'g = 0.328, 95%C.I. = -0.061-0.717, I = 58.97 %; p = .099) in BN. Lisdexamfetamine reduced weight (Hedges'g = 0.259, 95%C.I. = 0.071-0.446, I = 0 %; p = .007) and binging (Hedges'g = 0.571, 95%C.I. = 0.282-0.860, I = 53.84 %; p < .001) in BED.
LIMITATIONS
Small sample size, short duration, and lack of reliable operational definitions affect most of the included sponsored RCTs.
CONCLUSIONS
The efficacy of different drugs varies across different EDs, warranting additional primary studies recording broad psychopathological and cardiometabolic outcomes besides weight, especially against established psychotherapy interventions.
Topics: Humans; Fluoxetine; Psychopharmacology; Randomized Controlled Trials as Topic; Feeding and Eating Disorders; Bulimia Nervosa; Binge-Eating Disorder; Anorexia Nervosa; Antipsychotic Agents
PubMed: 37393954
DOI: 10.1016/j.jad.2023.06.068 -
JAMA Network Open Oct 2023Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia.
OBJECTIVE
To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).
DESIGN, SETTING, AND PARTICIPANTS
This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.
INTERVENTIONS
Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.
MAIN OUTCOMES AND MEASURES
The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.
RESULTS
A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.
CONCLUSIONS AND RELEVANCE
In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.
Topics: Male; Humans; Adult; Pharmacogenetics; Schizophrenia; Treatment Outcome
PubMed: 37801319
DOI: 10.1001/jamanetworkopen.2023.35518 -
Cancer Cell Apr 2024Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor...
Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and β-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.
Topics: Humans; Biological Specimen Banks; Pharmacogenetics; Precision Medicine; Liver Neoplasms; Organoids; Phenylurea Compounds; Quinolines
PubMed: 38593780
DOI: 10.1016/j.ccell.2024.03.004 -
Pharmacological Research Apr 2024Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of...
Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.
Topics: Humans; Spain; Europe; Pharmacology, Clinical; Pharmacogenetics; Pharmacology
PubMed: 38364957
DOI: 10.1016/j.phrs.2024.107104 -
Annual Review of Pharmacology and... Jan 2024I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have... (Review)
Review
I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: () discovery and characterization of the AHR/CYP1 axis, () pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, () standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and () discovery and characterization of the gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.
Topics: Humans; Animals; Mice; Genomics; Membrane Transport Proteins; Pharmacogenetics; Physicians
PubMed: 37788491
DOI: 10.1146/annurev-pharmtox-022323-082311 -
Molecules (Basel, Switzerland) Aug 2023is a plant genus within the Rutaceae family comprising over 17 species, which are widely distributed in Asia, Australia, and the Pacific Islands. Furthermore, these... (Review)
Review
is a plant genus within the Rutaceae family comprising over 17 species, which are widely distributed in Asia, Australia, and the Pacific Islands. Furthermore, these species have been used in traditional medicine to treat fever, pain, and dysentery. Several reports have also extensively studied the leaves, seeds, stembark, and bark of from 1965 to 2023 to explore their natural product composition. Various phytochemical studies have revealed the isolation of 413 compounds recorded, comprising coumarins, terpenoids, flavonoids, and aromatics, as well as alkaloids, which constitute the largest proportion (46.9%). These isolated compounds have long been known to exhibit different bioactivities, such as cytotoxic and anti-inflammatory properties. Cytotoxic activity has been observed against HCT 116, HeLa, HepG2, and other cell lines. Previous studies have also reported the presence of antifungal, hepatoprotective, antihyperlipidemic, antidiarrheal, and antioxidant effects. Therefore, this review provides a comprehensive overview of species, highlighting their phytochemistry, biological activities, and potential as a source of active natural compounds.
Topics: Murraya; Medicine, Traditional; Plant Extracts; Alkaloids; Rutaceae; Phytochemicals; Ethnopharmacology; Phytotherapy
PubMed: 37570872
DOI: 10.3390/molecules28155901 -
Pharmacological Reviews Nov 2023The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This... (Review)
Review
The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.
Topics: Humans; Pharmacology, Clinical; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Carrier Proteins; Ligands
PubMed: 37586884
DOI: 10.1124/pharmrev.121.000436 -
Drug Design, Development and Therapy 2023YiShen HuoXue decoction (YSHXD) is a formulation that has been used clinically for the treatment of renal fibrosis (RF) for many years. We aimed to clarify therapeutic...
PURPOSE
YiShen HuoXue decoction (YSHXD) is a formulation that has been used clinically for the treatment of renal fibrosis (RF) for many years. We aimed to clarify therapeutic effects of YSHXD against RF and potential pharmacological mechanisms.
MATERIALS AND METHODS
We used network pharmacology analysis and machine-learning to screen the core components and core targets of YSHXD against RF, followed by molecular docking and molecular dynamics simulations to confirm the reliability of the results. Finally, we validated the network pharmacology analysis experimentally in HK-2 cells and a rat model of RF established by unilateral ureteral ligation (UUO).
RESULTS
Quercetin, kaempferol, luteolin, beta-sitosterol, wogonin, stigmasterol, isorhamnetin, baicalein, and dihydrotanshinlactone progesterone were identified as the main active components of YSHXD in the treatment of unilateral ureteral ligation-induced RF, with IL-6, IL1β, TNF, AR, and PTGS2 as core target proteins. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of YSHXD predicted by network pharmacology analysis was confirmed in HK-2 cells and UUO rats. YSHXD downregulated NLRP3, ASC, NF-κBp65, Caspase-1, GSDMD, PTGS2, IL-1β, IL-6, IL-18, TNF-α, α-SMA and upregulated HGF, effectively alleviating the RF process.
CONCLUSION
YSHXD exerts important anti-inflammatory and anti-cellular inflammatory necrosis effects by inhibiting the NLRP3/caspase-1/GSDMD-mediated pyroptosis pathway, indicating that YSHXD represents a new strategy and complementary approach to RF therapy.
Topics: Animals; Rats; Pyroptosis; Cyclooxygenase 2; Interleukin-6; Molecular Docking Simulation; NLR Family, Pyrin Domain-Containing 3 Protein; Network Pharmacology; Reproducibility of Results; Caspases; Drugs, Chinese Herbal
PubMed: 37900883
DOI: 10.2147/DDDT.S420135