-
Clinical and Translational Science Jun 2024Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression...
Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression constitutes the most common mental disorder in the US, and while antidepressant therapy can help, the current trial -and error approach can require patients to endure multiple medication trials before finding one that is effective. Tailoring the fit of pharmacogenetic testing with prescribers' needs across a variety of settings could help to establish a generalizable value proposition to improve likelihood of adoption. We conducted a study to explore the value proposition for health systems using pharmacogenetic testing for mental health medications through prescribers' real-world experiences using implementation science concepts and systematic interviews with prescribers and administrators from four health care systems. To identify a value proposition, we organized the themes according to the Triple Aim framework, a leading framework for health care policy which asserts that high-value care should focus on three key metrics: (1) better health care quality and (2) population-level outcomes with (3) reduced per capita costs. Primary care providers whom we interviewed said that they value pharmacogenetic testing because it would provide more information about medications that they can prescribe, expanding their ability to identify medications that best-fit patients and reducing their reliance on referrals to specialists; they said that this capacity would help meet patients' needs for access to mental health care through primary care. At the same time, prescribers expressed differing views about how pharmacogenetic testing can help with quality of care and whether their views about out-of-pocket cost would prevent them from offering it. Thus, implementation should focus on integrating pharmacogenetic testing into primary care and using strategies to support prescribers' interactions with patients.
Topics: Humans; Pharmacogenomic Testing; Primary Health Care; Antidepressive Agents; Depressive Disorder, Major; Quality of Health Care
PubMed: 38898561
DOI: 10.1111/cts.13837 -
The Lancet. Child & Adolescent Health Jul 2024The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions.
METHODS
For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393).
FINDINGS
Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m (-1·21 to -0·19) with molindone to 2·03 kg/m (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone.
INTERPRETATION
Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations.
FUNDING
UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.
Topics: Humans; Antipsychotic Agents; Child; Adolescent; Network Meta-Analysis; Randomized Controlled Trials as Topic; Mental Disorders; Heart Rate; Blood Pressure
PubMed: 38897716
DOI: 10.1016/S2352-4642(24)00098-1 -
Revista Do Colegio Brasileiro de... 2024valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of...
INTRODUCTION
valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of the abdominal wall are studied.
METHOD
sixty Wistar rats were allocated into two groups: experimental (VPA) and control (0.9% sodium chloride), treated daily, starting three days before the intervention and until euthanasia. Under anesthesia, a median laparotomy was performed and repaired with two synthetic layers. Assessments took place 3, 7 and 14 days after surgery. The integrity of the wounds, the quality of the inflammatory reaction, the intensity of the leukocyte infiltrate, collagen synthesis, the intensity of angiogenesis and the presence of myofibroblasts were studied.
RESULTS
there was dehiscence of the PMA plane in 11 of the 30 animals (p=0.001) in the experimental group. There was no difference in the quality and intensity of the inflammatory reaction. Immunohistochemistry revealed, in the experimental group, less collagen I (p3=0.003, p7=0.013 and p14=0.001) and more collagen III (p3=0.003, p7=0.013 and p14= 0.001). Collagen evaluated by Sirus Supra Red F3BA showed, in the experimental group, less collagen at all three times (p<0.001) with less collagen I and collagen III (p<0.001). A lower number of vessels was found on the 3rd day (p<0.001) and on the 7th day (p=0.001) and did not affect the number of myofibroblasts.
CONCLUSION
VPA showed dehiscence of the PMA plane, with less deposition of total collagen and collagen I, less angiogenic activity, without interfering with the number of myofibroblasts.
Topics: Animals; Rats, Wistar; Wound Healing; Rats; Abdominal Wall; Valproic Acid; Male; Abdominal Muscles
PubMed: 38896636
DOI: 10.1590/0100-6991e-20243676-en -
Science Advances Jun 2024Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells....
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.
Topics: Tryptophan; Humans; Drug Resistance, Neoplasm; Neoplastic Stem Cells; Pancreatic Neoplasms; Cell Line, Tumor; Animals; Mice; Gene Expression Regulation, Neoplastic; Carcinoma, Pancreatic Ductal; Gemcitabine; Deoxycytidine; RNA-Binding Proteins; Indoleamine-Pyrrole 2,3,-Dioxygenase
PubMed: 38896624
DOI: 10.1126/sciadv.adj8650 -
Brain and Behavior Jun 2024Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc)....
INTRODUCTION
Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks.
METHODS
MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow-up analyses.
RESULTS
Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time.
CONCLUSION
Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.
Topics: Humans; Ketamine; Male; Depressive Disorder, Major; Nucleus Accumbens; Adult; Female; Habenula; Magnetic Resonance Imaging; Middle Aged; Antidepressive Agents; Anhedonia
PubMed: 38894648
DOI: 10.1002/brb3.3511 -
Clinical and Translational Science Jun 2024Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These...
Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA-B75 serotype markers-HLA-B*15:11 and HLA-B*15:21-which are prevalent in several Asian countries. However, a reliable method for identifying HLA-B75 serotype markers is still not available. We developed an in-house quantitative PCR (qPCR) for HLA-B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA-typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA-screened samples tested for HLA-B*15:02 at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%-100.00%) and a specificity of 100% (95% confidence interval = 95.07%-100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA-B75 markers not being HLA-B*15:02 (two samples with HLA-B*15:11 and five samples with HLA-B*15:21). In conclusion, this qPCR method could be useful for identifying HLA-B75 carriers at risk of carbamazepine-induced reactions in Asian populations where carriers of HLA-B*15:02, HLA-B*15:11, or HLA-B*15:21 are common.
Topics: Humans; Carbamazepine; HLA-B15 Antigen; Real-Time Polymerase Chain Reaction; Thailand; Anticonvulsants; Asian People; Pharmacogenetics; Serogroup; Sensitivity and Specificity; Alleles
PubMed: 38894615
DOI: 10.1111/cts.13867 -
Sensors (Basel, Switzerland) Jun 2024Quasi-bound state in the continuum (QBIC) can effectively enhance the interaction of terahertz (THz) wave with matter due to the tunable high-Q property, which has a...
Quasi-bound state in the continuum (QBIC) can effectively enhance the interaction of terahertz (THz) wave with matter due to the tunable high-Q property, which has a strong potential application in the detection of low-concentration biological samples in the THz band. In this paper, a novel THz metamaterial sensor with a double-chain-separated resonant cavity structure based on QBIC is designed and fabricated. The process of excitation of the QBIC mode is verified and the structural parameters are optimized after considering the ohmic loss by simulations. The simulated refractive index sensitivity of the sensor is up to 544 GHz/RIU, much higher than those of recently reported THz metamaterial sensors. The sensitivity of the proposed metamaterial sensor is confirmed in an experiment by detecting low-concentration lithium citrate (LC) and bovine serum albumin (BSA) solutions. The limits of detection (LoDs) are obtained to be 0.0025 mg/mL (12 μM) for LC and 0.03125 mg/mL (0.47 μM) for BSA, respectively, both of which excel over most of the reported results in previous studies. These results indicate that the proposed THz metamaterial sensor has excellent sensing performances and can well be applied to the detection of low-concentration biological samples.
Topics: Serum Albumin, Bovine; Biosensing Techniques; Limit of Detection; Animals; Terahertz Radiation; Cattle; Terahertz Spectroscopy; Refractometry; Lithium Compounds; Citric Acid
PubMed: 38894440
DOI: 10.3390/s24113649 -
Sensors (Basel, Switzerland) Jun 2024L-tryptophan is an amino acid that is essential to the metabolism of humans. Therefore, there is a high interest for its detection in biological fluids including blood,...
L-tryptophan is an amino acid that is essential to the metabolism of humans. Therefore, there is a high interest for its detection in biological fluids including blood, urine, and saliva for medical studies, but also in food products. Towards this goal, we report on a new electrochemiluminescence (ECL) method for L-tryptophan detection involving the in situ production of hydrogen peroxide at the surface of boron-doped diamond (BDD) electrodes. We demonstrate that the ECL response efficiency is directly related to HO production at the electrode surface and propose a mechanism for the ECL emission of L-tryptophan. After optimizing the analytical conditions, we show that the ECL response to L-tryptophan is directly linear with concentration in the range of 0.005 to 1 µM. We achieved a limit of detection of 0.4 nM and limit of quantification of 1.4 nM in phosphate buffer saline (PBS, pH 7.4). Good selectivity against other indolic compounds (serotonin, 3-methylindole, tryptamine, indole) potentially found in biological fluids was observed, thus making this approach highly promising for quantifying L-tryptophan in a broad range of aqueous matrices of interest.
Topics: Tryptophan; Boron; Electrodes; Diamond; Electrochemical Techniques; Luminescent Measurements; Humans; Limit of Detection; Biosensing Techniques; Hydrogen Peroxide
PubMed: 38894416
DOI: 10.3390/s24113627 -
Molecules (Basel, Switzerland) Jun 2024Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities,...
Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (, , , and ) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.
Topics: Receptors, sigma; Haloperidol; Humans; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Structure-Activity Relationship; Molecular Structure; Cell Survival; Ligands; Cell Proliferation; Drug Screening Assays, Antitumor
PubMed: 38893570
DOI: 10.3390/molecules29112697 -
Molecules (Basel, Switzerland) May 2024Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.
Topics: Animals; Zebrafish; Anticonvulsants; Disease Models, Animal; Pentylenetetrazole; Epilepsy; Seizures; Electroencephalography; Valproic Acid; Larva; Brain; Inositol
PubMed: 38893448
DOI: 10.3390/molecules29112572