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The Journal of Clinical Psychiatry Jun 2024To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. In this... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.
To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD () were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35). For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant ( = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% ( = .076), and response rates were 39.8% and 27.2% ( = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 ( = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups. The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies. ClinicalTrials.gov identifier: NCT04688164.
Topics: Humans; Depressive Disorder, Major; Male; Adult; Female; Double-Blind Method; Middle Aged; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Treatment Outcome; Drug Therapy, Combination
PubMed: 38917366
DOI: 10.4088/JCP.24m15265 -
PloS One 2024Acute ischemic stroke (AIS) is a significant global health issue, directly impacting mortality and disability. The Totaled Health Risks in Vascular Events (THRIVE) score...
Prognostic value of combining 24-hour ASPECTS and hemoglobin to red cell distribution width ratio to the THRIVE score in predicting in-hospital mortality among ischemic stroke patients treated with intravenous thrombolysis.
BACKGROUND
Acute ischemic stroke (AIS) is a significant global health issue, directly impacting mortality and disability. The Totaled Health Risks in Vascular Events (THRIVE) score is appreciated for its simplicity and ease of use to predict stroke clinical outcomes; however, it lacks laboratory and neuroimaging data, which limits its ability to predict outcomes precisely. Our study evaluates the impact of integrating the 24-hour Alberta Stroke Program Early CT Score (ASPECTS) and hemoglobin-to-red cell distribution width (HB/RDW) ratio into the THRIVE score using the multivariable fractional polynomial (MFP) method (combined THRIVE-MFP model) compared to the THRIVE-c model. We aim to assess their added value in predicting in-hospital mortality (IHM) prognosis.
MATERIALS AND METHODS
A retrospective study from January 2015 to July 2022 examined consecutive AIS patients receiving intravenous thrombolysis. Data on THRIVE scores, 24-hour ASPECTS, and HB/RDW levels were collected upon admission. The model was constructed using logistic regression and the MFP method. The prognostic value was determined using the area under the receiver operating characteristic curve (AuROC). Ischemic cerebral lesions within the middle cerebral artery territory were evaluated with non-contrast computed tomography (NCCT) after completing 24 hours of intravenous thrombolysis (24-hour ASPECTS).
RESULTS
Among a cohort of 345 patients diagnosed with AIS who received intravenous thrombolysis, 65 individuals (18.8%) experienced IHM. The combined THRIVE-MFP model was significantly superior to the THRIVE-c model in predicting IHM (AuROC 0.980 vs. 0.876, p<0.001), 3-month mortality (AuROC 0.947 vs. 0.892, p<0.001), and 3-month poor functional outcome (AuROC 0.910 vs. 0.853, p<0.001).
CONCLUSION
The combined THRIVE-MFP model showed excellent predictive performance, enhancing physicians' ability to stratify patient selection for intensive neurological monitoring and guiding treatment decisions. Incorporating 24-hour ASPECTS on NCCT and HB/RDW proved valuable in mortality prediction, particularly for hospitals with limited access to advanced neuroimaging resources.
Topics: Humans; Female; Ischemic Stroke; Male; Aged; Hospital Mortality; Prognosis; Hemoglobins; Retrospective Studies; Erythrocyte Indices; Middle Aged; Thrombolytic Therapy; Aged, 80 and over; ROC Curve
PubMed: 38917218
DOI: 10.1371/journal.pone.0304765 -
PloS One 2024Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the...
Orexin receptor 2 agonist activates diaphragm and genioglossus muscle through stimulating inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons in rodents.
Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the pre-Bötzinger complex, which are critical for the generation of inspiratory rhythm, and phrenic and hypoglossal motoneurons. Herein, we assessed the effects of OX2R-selective agonists TAK-925 (danavorexton) and OX-201 on respiratory function. In in vitro electrophysiologic analyses using rat medullary slices, danavorexton and OX-201 showed tendency and significant effect, respectively, in increasing the frequency of inspiratory synaptic currents of inspiratory neurons in the pre-Bötzinger complex. In rat medullary slices, both danavorexton and OX-201 significantly increased the frequency of inspiratory synaptic currents of hypoglossal motoneurons. Danavorexton and OX-201 also showed significant effect and tendency, respectively, in increasing the frequency of burst activity recorded from the cervical (C3-C5) ventral root, which contains axons of phrenic motoneurons, in in vitro electrophysiologic analyses from rat isolated brainstem-spinal cord preparations. Electromyogram recordings revealed that intravenous administration of OX-201 increased burst frequency of the diaphragm and burst amplitude of the genioglossus muscle in isoflurane- and urethane-anesthetized rats, respectively. In whole-body plethysmography analyses, oral administration of OX-201 increased respiratory activity in free-moving mice. Overall, these results suggest that OX2R-selective agonists enhance respiratory function via activation of the diaphragm and genioglossus muscle through stimulation of inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons. OX2R-selective agonists could be promising drugs for various conditions with respiratory dysfunction.
Topics: Animals; Diaphragm; Motor Neurons; Orexin Receptors; Rats; Phrenic Nerve; Mice; Male; Hypoglossal Nerve; Rats, Sprague-Dawley; Inhalation; Medulla Oblongata; Isoquinolines; Pyridines
PubMed: 38917189
DOI: 10.1371/journal.pone.0306099 -
PloS One 2024Young calves are more susceptible to cold than older animals due to their limited ability to regulate body temperature and lack of fat reserves and may have difficulty...
Young calves are more susceptible to cold than older animals due to their limited ability to regulate body temperature and lack of fat reserves and may have difficulty consuming the energy needed to cope with the cold by maintaining body temperature and meeting their metabolic needs, especially when fed constant levels of waste milk (WM) with less solids, which can be detrimental to health and future performance. An alternative to overcome this problem is increasing the milk's solids content to the existing volume by using different sources [milk replacer powder (MR) or transition milk (TM)]. Thus, we aimed to evaluate the effects of increasing the total solids of WM via MR (WM+MR) or TM (WM+TM) on the performance, feeding behavior, and health-related variables of cold-stressed dairy calves during pre- and post-weaning. We hypothesized that feeding WM supplemented with MR or TM as potential liquid feed enhancers would improve milk dry matter and energy intake of the calves with a positive impact on body development and have no negative impact on feeding behavior and health. Additionally, we hypothesized that MR would not differ from TM. As a sample size calculation at 80% power using power analysis (PROC POWER) in SAS 9.4, a total of 51 Holstein-Friesian vigorous male calves [vigor score 21-27; 17 per treatment; 4-d old; body weight (BW) = 40.0 ± 0.63 kg (mean ± SD)] were selected, assigned randomly to treatments, and housed in individual pens in an outdoor barn. Irrespective of the type of treatment, all calves were fed 6 kg/d liquid feed from d 1 to d 53 of the experiment. In a step-down weaning program, calves received 0.5 kg liquid feed from d 54 to d 60. All calves were weaned on d 61 and remained in the study until d 101 as post-weaning evaluation. The calves had ad libitum access to starter feed and fresh drinking water across the experiment. Intake, growth, and behavior data were analyzed using a general linear mixed model and health data were analyzed using mixed logistic regression, mixed linear regression, and survival analysis models in SAS. We found that supplementation was responsible for a greater dry matter intake (DMI; P = 0.004), superior average BW (P = 0.037), and increased crude protein (CP; P = 0.001) and crude fat (CF; P = 0.001) intakes, with the most favorable outcomes observed for the WM+TM group when compared with WM+MR. Animals fed WM (control group; CON) showed a smaller average daily gain during the first 40-d of life (P = 0.026), showing slight changes during the whole period of evaluation when compared with the supplemented groups (SUP; WM+MR and WM+TM). No difference between MR- and TM-SUP groups, probability of having abnormal appearance (P = 0.032) and pneumonia occurrence (P = 0.022) was reduced in the SUP than in CON animals, with no effect on diarrhea among treatment groups (P = 0.461). Using milk supplements added to WM is an alternative to improve the intake, performance, and health of young calves under cold stress. Our findings showed that SUP animals outperformed the CON group in terms of DMI, average BW, and intake of CP and CF, with the TM-SUP group displaying the most favorable outcomes. Moreover, the SUP groups demonstrated reduced odds of experiencing abnormal appearance and pneumonia, highlighting the positive impact of supplementation on calf health.
Topics: Animals; Cattle; Milk; Animal Feed; Feeding Behavior; Dietary Supplements; Animals, Newborn; Cold Temperature; Weaning; Female; Male; Milk Substitutes; Powders
PubMed: 38917166
DOI: 10.1371/journal.pone.0305227 -
PloS One 2024Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure....
Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure. The rise of multidrug-resistant strains of S. typhi exacerbates this challenge, severely compromising conventional treatment efficacy due to over activity of efflux pumps. In our study, a comprehensive exploration of two fundamental aspects to combat MDR in S. typhi is carried out; i.e. employing advanced bioinformatics analyses and AlphaFold AI, We successfully identified and characterised a putative homologue, ABC-TPA, reminiscent of the P-glycoprotein (P-gp) known for its role in multidrug resistance in diverse pathogens. This discovery provides a critical foundation for understanding the potential mechanisms driving antibiotic resistance in S. typhi. Furthermore, employing computational methodologies, We meticulously assessed the potential of lignans, specifically Schisandrin A, B, and C, as promising Efflux Pump Inhibitors (EPIs) against the identified P-gp homologue in S. typhi. Noteworthy findings revealed robust binding interactions of Schisandrin A and B with the target protein, indicating substantial inhibitory capabilities. In contrast, Schisandrin C exhibited instability, showing varied effectiveness among the evaluated lignans. Pharmacokinetics and toxicity predictions underscored the favourable attributes of Schisandrin A, including prolonged action duration. Furthermore, high systemic stability and demanished toxicity profile of SA and SB present their therapeutic efficacy against MDR. This comprehensive investigation not only elucidates potential therapeutic strategies against MDR strains of S. typhi but also highlights the relevance of computational approaches in identifying and evaluating promising candidates. These findings lay a robust foundation for future empirical studies to address the formidable challenges antibiotic resistance poses in this clinically significant infectious diseases.
Topics: Salmonella typhi; Drug Resistance, Multiple, Bacterial; Lignans; Anti-Bacterial Agents; Bacterial Proteins; Humans; Microbial Sensitivity Tests; Computational Biology
PubMed: 38917154
DOI: 10.1371/journal.pone.0303285 -
PloS One 2024Human immunodeficiency virus (HIV) and antiretroviral treatment (ART) are both associated with hypercoagulability. Altered clot properties could be a potential mechanism...
BACKGROUND
Human immunodeficiency virus (HIV) and antiretroviral treatment (ART) are both associated with hypercoagulability. Altered clot properties could be a potential mechanism thereof. We aimed to investigate the association of HIV and ART, with fibrinogen and plasma clot properties in a group of Black South Africans.
METHODS
At baseline, 151 newly diagnosed people living with HIV (PLWH) and 176 controls were recruited. Some PLWH subsequently commenced with ARTs (n = 70) while others remained ART-naïve (n = 81). Fibrinogen and clot properties (turbidity assay) were investigated from baseline to 5-year follow-up. A sub-group of 21 women (n = 10 ART-treated; n = 11 ART-naïve) with HIV was systematically selected and matched with 12 controls, and additional clot properties (rheometry, permeability and fibre diameter) were investigated.
RESULTS
Fibrinogen was lower in the HIV groups compared to the controls, while % γ' fibrinogen was higher. PLWH had shorter lag times and lower maximum absorbance than the controls (p<0.05). Their CLTs on the other hand were longer. Most variables increased over time in all groups, but differences in the degree of change over time was observed for lag time (p = 0.024) and permeability (p = 0.03). Participants who commenced with ART had a tendency of delayed clot formation (p = 0.08) and increased clot permeability (p = 0.005).
CONCLUSION
PLWH had lower total fibrinogen concentration and formed less dense clots. They also formed clots that were more difficult to lyse, which likely not resulted from altered clot properties. ART use (NNRTI's) had a moderately protective effect, delaying clot formation, and increasing clot permeability.
Topics: Humans; Female; HIV Infections; South Africa; Adult; Fibrinogen; Black People; Male; Blood Coagulation; Middle Aged; Case-Control Studies; African People
PubMed: 38917149
DOI: 10.1371/journal.pone.0305826 -
PloS One 2024Neutrophil proteinase 3 (PR3) is an important drug target for inflammatory lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Drug...
Neutrophil proteinase 3 (PR3) is an important drug target for inflammatory lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Drug discovery efforts targeting PR3 require active enzyme for in vitro characterization, such as inhibitor screening, enzymatic assays, and structural studies. Recombinant expression of active PR3 overcomes the need for enzyme supplies from human blood and in addition allows studies on the influence of mutations on enzyme activity and ligand binding. Here, we report the expression of recombinant PR3 (rPR3) using a baculovirus expression system. The purification and activation process described resulted in highly pure and active PR3. The activity of rPR3 in the presence of commercially available inhibitors was compared with human PR3 by using a fluorescence-based enzymatic assay. Purified rPR3 had comparable activity to the native human enzyme, thus being a suitable alternative for enzymatic studies in vitro. Further, we established a surface plasmon resonance-based assay to determine binding affinities and kinetics of PR3 ligands. These methods provide valuable tools for early drug discovery aiming towards treatment of lung inflammation.
Topics: Humans; Myeloblastin; Ligands; Recombinant Proteins; Animals; Sf9 Cells; Surface Plasmon Resonance; Protein Binding; Baculoviridae; Kinetics; Gene Expression; Spodoptera
PubMed: 38917138
DOI: 10.1371/journal.pone.0294827 -
PloS One 2024This study evaluates the impact of dietary supplementation of the blue-green alga Arthrospira platensis NIOF17/003 nanoparticles (AN) on the growth performance,...
Arthrospira platensis nanoparticles dietary supplementation improves growth performance, steroid hormone balance, and reproductive productivity of Nile tilapia (Oreochromis niloticus) broodstock.
This study evaluates the impact of dietary supplementation of the blue-green alga Arthrospira platensis NIOF17/003 nanoparticles (AN) on the growth performance, whole-body biochemical compositions, blood biochemistry, steroid hormonal, and fry production efficiency of Nile tilapia (Oreochromis niloticus) broodstock, during the spawning season. After a 21-day preparation period to equip the females and ensure that their ovaries were filled with eggs, mating between the mature females and males took place in a 3:1 ratio during a 14-day spawning cycle. A total of 384 tilapia broodstock 288 females and 96 males with an initial body weight of 450.53±0.75, were divided into four groups; AN0: a basal diet as a control group with no supplementation of Arthrospira platensis, and the other three groups (AN2, AN4, and AN6) were diets supplemented with nanoparticles of A. platensis at levels of 2, 4, and 6 g kg─1 diet, respectively. The results found that fish-fed group AN6 showed the highest significant differences in weight gain (WG), final weight (FW), feed conversion ratio (FCR), protein efficiency ratio (PER), and feed efficiency ratio (FER). Females fed the AN6 diet showed the highest significant fat content. Compared to the AN0 group, fish fed on the supplemented diets showed significant improvement (p < 0.05) in triglyceride, glucose, and aspartate aminotransferase (AST). A gradual increase in AN inclusion level resulted in a gradual increase in the concentrations of luteinizing hormone (LH), and follicle-stimulating hormone (FSH), testosterone, progesterone, and prolactin. The rates (%) of increase in fry production for females fed supplemented diets were 10.5, 18.6, and 32.2% for AN2, AN4, and AN6, respectively, compared to the control group. This work concluded that the inclusion levels of 6 g kg─1 of A. platensis nanoparticles in the diet of Nile tilapia broodstock significantly improved the growth performances, steroid hormone concentrations, and increased the fry production efficiency by 32.2%, respectively. These findings revealed that A. platensis nanoparticles resulted in a significantly enhanced female' reproductive productivity of Nile tilapia broodstock.
Topics: Animals; Dietary Supplements; Nanoparticles; Female; Reproduction; Spirulina; Cichlids; Male; Animal Feed; Gonadal Steroid Hormones
PubMed: 38917116
DOI: 10.1371/journal.pone.0299480 -
PloS One 2024N-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is...
OBJECTIVE
N-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is still unclear. The purpose of this study is to investigate the effect of intestinal microbiota alteration on the pharmacokinetics of NBP and its related mechanisms.
METHODS
After treatment with antibiotics and probiotics, plasma NBP concentrations in SD rats were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The effect of intestinal microbiota changes on NBP pharmacokinetics was compared. Intestinal microbiota changes after NBP treatment were analyzed by 16S rRNA sequencing. Expressions of CYP3A1 mRNA and protein in the liver and small intestine tissues under different intestinal flora conditions were determined by qRT-PCR and Western Blot. KEGG analysis was used to analyze the effect of intestinal microbiota changes on metabolic pathways.
RESULTS
Compared to the control group, the values of Cmax, AUC0-8, AUC0-∞, t1/2 in the antibiotic group increased by 56.1% (P<0.001), 56.4% (P<0.001), 53.2% (P<0.001), and 24.4% (P<0.05), respectively. In contrast, the CL and Tmax values decreased by 57.1% (P<0.001) and 28.6% (P<0.05), respectively. Treatment with antibiotics could reduce the richness and diversity of the intestinal microbiota. CYP3A1 mRNA and protein expressions in the small intestine of the antibiotic group were 61.2% and 66.1% of those of the control group, respectively. CYP3A1 mRNA and protein expressions in the liver were 44.6% and 63.9% of those in the control group, respectively. There was no significant change in the probiotic group. KEGG analysis showed that multiple metabolic pathways were significantly down-regulated in the antibiotic group. Among them, the pathways of drug metabolism, bile acid biosynthesis and decomposition, and fatty acid synthesis and decomposition were related to NBP biological metabolism.
CONCLUSION
Antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism.
Topics: Animals; Gastrointestinal Microbiome; Anti-Bacterial Agents; Rats; Benzofurans; Rats, Sprague-Dawley; Male; Cytochrome P-450 CYP3A; Liver; Intestine, Small
PubMed: 38917098
DOI: 10.1371/journal.pone.0297713 -
Journal of Medicinal Chemistry Jun 2024G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and...
G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)--phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.
PubMed: 38917049
DOI: 10.1021/acs.jmedchem.3c02164