The aim of this study was to assess the utility of inexpensive techniques in evaluating the interactions of risperidone (Ris) with different traditional π-acceptors, with subsequent application of ...the findings into a Ris pharmaceutical formulation with improved therapeutic properties. Molecular docking calculations were performed using Ris and its different charge-transfer complexes (CT) with picric acid (PA), 2,3-dichloro-5,6-dicyanop-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-pquinon (BL), and tetrachloro-p-quinon (CL), as donors, and three receptors (serotonin, dopamine, and adrenergic) as acceptors to study the comparative interactions among them. To refine the docking results and further investigate the molecular processes of receptor-ligand interactions, a molecular dynamics simulation was run with output obtained from AutoDock Vina. Among all investigated complexes, the (Ris) (PA)-serotonin (CTcS) complex showed the highest binding energy. Molecular dynamics simulation of the 100 ns run revealed that both the Ris-serotonin (RisS) and CTcS complexes had a stable conformation; however, the CTcS complex was more stable.
Necroptosis is a tightly adjusted inflammatory necrotizing cell death signaling pathway that participates in pathogenesis of discrete diseases as rheumatoid arthritis (RA). Irisin is a myokine with ...immuno-modulatory effect. Evaluation of irisin efficiency as a novel therapeutic agent in experimentally induced RA via modulating immuno-inflammatory, necroptotic molecular and biochemical signaling pathways.
RA was induced in 30 female Wister albino rats by a single subcutaneous injection of collagen-II with incomplete Freund's adjuvant (CII-IFA) followed by booster immunization dose 10 days later. After 14 days of the injection, arthritis chronic phase was precipitated. 15 rats were treated by S.C irisin injection daily for 4 weeks. Joint tissue homogenate RIPK-3, MLKL, HMGB1, MCP1, IL-6, CHIT1, MDA, and PN levels were assessed calorimetrically. However, TNF-α mRNA expression level was evaluated by the qrt-PCR technique.
The results showed that irisin significantly decreases the level of all assessed biochemical parameters, except MDA, which was significantly increased in comparison with the correspondent values in the arthritic group with no treatment (ttt).
Irisin exhibits therapeutic anti-inflammatory and antioxidant effects via modulating immuno-inflammatory, necroptotic molecular, and biochemical signaling pathways in experimentally induced RA in rats.
RA: rheumatoid arthritis; RIPK3: receptor-interacting protein kinase 1; MLKL: mixed lineage kinase domain-like protein; HMGB1: High-mobility group protein box 1; MCP1: Monocyte chemoattractant protein 1; IL-6: Interleukin 6; CHIT1: Chitotriosidase; MDA: Malondialdehyde; PN: Peroxynitrite; TNF-α: Tumor Necrosis Factor; qrt-PCR: quantitative real-time reverse transcription PCR; CII-IFA: collagen-II with incomplete Freund's adjuvant; ttt: treatment
Note: TNF-α gene (NCBI GenBank Nucleotide accession # NM_012675.3); The housekeeping gene GAPDH (NCBI GenBank Nucleotide accession # NM_017008.4)
The commitment of the existent study was to develop a mucoadhesive
in situ
gel systems of vitamin B12 for the management of dry eye disease. The gels were prepared using pluronic F-127 and either of ...chitosan, carbapol 971P, sodium alginate, or hydroxy propyl methyl cellulose. Drug-excipients compatibility was investigated by means of differential scanning calorimetry and Fourier transform infrared spectroscopy. The gels were characterized for pH, clarity, gelling capacity, viscosity, and adhesion. In vitro release of vitamin B12 from the selected gels was investigated. In vivo effectiveness of the selected gel was determined in rabbit models using Schirmer’s and fluorescein tests. The compatibility studies revealed the possibility of incidence of drug/polymer interaction in some formulations. F2-containing pluronic F127 and hydroxypropyl methyl cellulose showed the most appropriate physical characterization and in vitro release profile. The prepared gels showed prolonged drug release with drug release mechanism of combined diffusion and erosion. The in vivo study revealed good effectiveness of the prepared mucoadhesive
in situ
gel system of vitamin B12 in the treatment of dry eye disease that was comparable to that of the marketed drops.
Poor mood, lack of pleasure, reduced focus, remorse, unpleasant thoughts, and sleep difficulties are all symptoms of depression. The only approved treatment for children and adolescents with major ...depressive disorder (MDD) is fluoxetine hydrochloride (FXN), a serotonin selective reuptake inhibitor antidepressant. MDD is the most common cause of disability worldwide. In the present research, picric acid (PA); dinitrobenzene; p-nitro benzoic acid; 2,6-dichloroquinone-4-chloroimide; 2,6-dibromoquinone-4-chloroimide; and 7,7′,8,8′-tetracyanoquinodimethane were used to make 1:1 FXN charge-transfer compounds in solid and liquid forms. The isolated complexes were then characterized by elemental analysis, conductivity, infrared, Raman, and 1H-NMR spectra, thermogravimetric analysis, scanning electron microscopy, and X-ray powder diffraction. Additionally, a molecular docking investigation was conducted on the donor moiety using FXN alone and the resulting charge transfer complex (FXN)(PA) as an acceptor to examine the interactions against two protein receptors (serotonin or dopamine). Interestingly, the (FXN)(PA) complex binds to both serotonin and dopamine more effectively than the FXN drug alone. Furthermore, (FXN)(PA)–serotonin had a greater binding energy than FXN–serotonin. Theoretical data were also generated by density functional theory simulations, which aided the molecular geometry investigation and could be beneficial to researchers in the future.
Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, ...may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated
,
,
,
,
,
, and
but did not affect
or
expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.
Haloperidol (HPL) is a typical antipsychotic drug used to treat acute psychotic conditions, delirium, and schizophrenia. Solid charge transfer (CT) products of HPL with ...7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have not been reported till date. Therefore, we conducted this study to investigate the donor-acceptor CT interactions between HPL (donor) and TCNQ and PA (π-acceptors) in liquid and solid states. The complete spectroscopic and analytical analyses deduced that the stoichiometry of these synthesized complexes was 1:1 molar ratio. Molecular docking calculations were performed for HPL as a donor and the resulting CT complexes with TCNQ and PA as acceptors with two protein receptors, serotonin and dopamine, to study the comparative interactions among them, as they are important neurotransmitters that play a large role in mental health. A molecular dynamics simulation was ran for 100 ns with the output from AutoDock Vina to refine docking results and better examine the molecular processes of receptor-ligand interactions. When compared to the reactant donor, the CT complex (HPL)(TCNQ) interacted with serotonin and dopamine more efficiently than HPL only. CT complex (HPL)(TCNQ) with dopamine (CTtD) showed the greatest binding energy value among all. Additionally, CTtD complex established more a stable interaction with dopamine than HPL-dopamine.
The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, ...the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.
Institutions must have access to antibiograms to monitor changes in antimicrobial resistance and direct empirical antibiotic therapy. The first facility-specific cumulative antibiogram was launched ...in the ICU in 2019. Consequently, many antibiogram-operation-related actions have been adopted in the institution based on reported data. This study aimed to analyze the cumulative antibiogram reports for multiple intensive care units (ICUs) for 2020, and compare the antimicrobial susceptibility testing (AST) patterns between the 2019 and 2020 years in an academic medical center.
This cross-sectional study was performed of routine bacterial culture and AST data extracted from a laboratory information system in a 2252-bed capacity hospital. Only the first diagnostic isolate of a given species per patient per year was included in the study. Interpretation and reporting were done in accordance with the applicable Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing guidelines.
Of the 46,791 clinical isolates, the Gram-negative bacilli isolation rate witnessed a significant increase: 35,670 isolates in 2020 versus. 33,652 isolates in 2019. Klebsiella pneumoniae showed a statistically significant increase, mainly in pediatric, emergency, and cardiothoracic ICUs (p < 0.001). Neonatal and pediatric ICUs showed statistically significant increases in Pseudomonas aeruginosa and Proteus mirabilis isolates (p < 0.001). A statistically significant decrease was noted in the prevalence of Acinetobacter, Escherichia coli, Burkholderia cepacia, and Enterobacter cloacae. The sensitivities of K. pneumoniae and E. coli to imipenem and tigecycline significantly improved (p < 0.001). The sensitivity to colistin was significantly decreased (p < 0.001). The sensitivity of P. aeruginosa isolates to colistin and carbapenems was improved (p < 0.001). We reported a statistically significant decrease in all Gram-positive cocci (11,121 in 2020 versus. 11,528 in 2019). Staphylococcus aureus showed a statistically significant increase (p < 0.001), particularly in the medical ICU.
The high susceptibility rates of Enterobacteriaceae toward colistin and tigecycline, should be cautiously considered in empiric therapy while looking for alternatives. The majority of isolates of Gram-positive cocci were coagulase negative staphylococci (CONS), we still need to confirm whether they are true pathogens or commensals before considering anti-staphylococcal agents in the empirical therapy. We underscored some corrective actions that might have improved the susceptibility rates, such as antibiotic cycling
Background:
Gabapentin is widely prescribed as an off-label drug for the treatment of various diseases, including drug and alcohol addiction. Approximately 83–95% of the usage of gabapentin is ...off-label, accounting for more than 90% of its sales in the market, which indicates an alarming situation of drug abuse. Such misuse of gabapentin has serious negative consequences. The safety of the use of gabapentin in pregnant women has always been a serious issue, as gabapentin can cross placental barriers. The impact of gabapentin on brain development in the fetus is not sufficiently investigated, which poses difficulties in clinical decisions regarding prescriptions.
Methods:
The consequences effect of prenatal gabapentin exposure on the development of ventral midbrain dopaminergic neurons were investigated using three-dimensional neuronal cell cultures. Time-mated Swiss mice were used to isolate embryos. The ventral third of the midbrain was removed and used to enrich the dopaminergic population in 3D cell cultures that were subsequently exposed to gabapentin. The effects of gabapentin on the viability, ATP release, morphogenesis and genes expression of ventral midbrain dopaminergic neurons were investigated.
Results:
Gabapentin treatment at the therapeutic level interfered with the neurogenesis and morphogenesis of vmDA neurons in the fetal brain by causing changes in morphology and alterations in the expression of key developmental genes, such as
Nurr1, Chl1, En1, Bdnf, Drd2,
and
Pitx3.
The TH + total neurite length and dominant neurite length were significantly altered. We also found that gabapentin could halt the metabolic state of these neuronal cells by blocking the generation of ATP.
Conclusion:
Our findings clearly indicate that gabapentin hampers the morphogenesis and development of dopaminergic neurons. This implies that the use of gabapentin could lead to serious complications in child-bearing women. Therefore, caution must be exercised in clinical decisions regarding the prescription of gabapentin in pregnant women.
Background
Adhesive capsulitis of the shoulder is a pain syndrome of progressive nature, associated with reduced active and passive range of motion of the gleno-humeral joint. Previous studies ...suggested an underlying synovial inflammatory process, followed by capsular hypertrophy and reactive fibrosis. The aim of our study was to investigate the influence of anterior shoulder joint capsule abnormal thickening and abnormal signal intensity on MRI, as important imaging biomarkers, for the diagnosis of as adhesive capsulitis.
Results
This cross sectional analytic study involved 28 patients with adhesive capsulitis ((17 males, 11 females, age range:23–65 years, mean age: 45.61 years ± 11.95) and 28 controls (14 males, 14 females; age range, 39 to 61 years; mean age 52.82 years ± 6.45;). The patients and the controls were reviewed by two radiologists with experience of more than 10 years, blinded to each other's results. Adhesive capsulitis was diagnosed based on clinical criteria of significant restricted passive motion of shoulder joint. The thickness and abnormal signal intensity of anterior glenohumeral joint capsule were evaluated at its thickest portion, positioned underneath the subscapularis muscle. Additionally, the formerly known MR characteristics of adhesive capsulitis, involving the thickness of humeral and glenoid portions of axillary recess, maximal thickness of axillary capsule, and thickness of coracohumeral ligament, were assessed. The estimation of abnormal hyperintensity of humeral and glenoid capsule in axillary recess, subcoracoid fat triangle obliteration and abnormal hyperintensity were also included in our study. All magnetic resonance imaging (MRI) quantitative values showed significant difference between adhesive capsulitis group and control group. Regarding qualitative values, only abnormal high signal intensity of the anterior portion of joint capsule, of the axillary portion of joint capsule and of glenoid portion of axillary capsule showed statisticaly significant difference between cases and controls. In receiver operating characteristic (ROC) curve study, the anterior capsule thickness revealed a high diagnostic value with an area under the curve (AUC) of 1.0. An anterior capsule thickness cut off value of at 2.45 mm showed a very high diagnostic performance, revealing a sensitivity of and specificity of 100%.
Conclusions
The anterior glenohumeral joint capsule abnormal thickening, and abnormal hyperintensity have a high diagnostic performance, in addition to the previously known abnormal MRI findings, in the evaluation of adhesive capsulitis.
PDF
