Novel heteroleptic complexes of titanium(IV) derived from 2-hydroxyacetophenone: synthesis, characterization, antibacterial and molecular docking studies

A few new and versatile complexes of titanium(IV) derived from 2-hydroxyacetophenone of the types {[(Ap)Ti(OPr ⁱ )_2?n (L₂) _n ] (2a, 2e and 2f)}, {[(Ap)Ti(L₁OR)(L₂)] (2b–2d, 2g–2i)} have been synthesized by the reaction of the precursor [(Ap)Ti(OPr ⁱ )₂] with different 2-heteroaryl methyl ketone oximes and alkoxyalkanols in various molar ratios in refluxing toluene yielded mono nuclear heteroleptic derivatives, {where, n = 1–2, HAp = 2-hydroxyacetophenone, Pr ⁱ  = isopropyl, L₁ = O–CH₂–CH₂?, R = CH₃, C₂H₅, C₄H₉ and HL₂=HONC(Me)py-2, HONC(Me)fu-2}. All these newly synthesized complexes were characterized by elemental analysis, mass, UV, FT-IR and NMR (¹H, ¹³C) spectral studies. The mass spectra of the newly synthesized molecules indicate their monomeric state. Spectral studies suggest the bonding between metal and ligands in a tetra coordinated fashion. Thermogravimetric analyses indicate the multistep decomposition of complexes resulting TiO₂ as the end product at 600 °C. Antibacterial activities of these complexes were also exercised. Complex 2e is equipotent to the standard drug against Pseudomonas aeruginosa and Escherichia coli. A keen molecular docking study revealed lesser docking scores of some of these complexes than that of the standard drug gentamicin.     

Acute and subchronic dermal toxicity of Vitex negundo essential oil

Vitex negundo is a common herb in different herbal formulation. The potential acute and sub-chronic dermal toxicities were evaluated as per OECD (Organization for Economic Cooperation and Development) guidelines 402 and 411, respectively. Both sexes of Wistar rats were exposed to Vitex negundo oil of 2000?mg/kg body weight for acute dermal toxicity, whereas in the dermal sub-chronic toxicity study, rats were exposed to Vitex negundo oil 250, 500 and 1000?mg/kg body weight, respectively, for five times a week for 90?d. In acute and sub-chronic toxicity studies, all animals were normal without any behavioral, serum biochemistry, hematology, necroscopical and histopathological changes. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) of Vitex negundo oil were 250 and 1000?mg/kg/day, respectively. Vitex negundo oil is under the category 5 (Unclassified) according to the Globally Harmonized System, with an LD₅₀ value of over 2000?mg/kg.     

Improvement of Sleep Disturbance and Insomnia Following Parathyroidectomy for Primary Hyperparathyroidism

Background

The aim of the present study was to investigate the incidence of sleep disturbance and insomnia in patients with primary hyperparathyroidism (PHPT), and to evaluate the effect of parathyroidectomy.

Methods

A questionnaire was prospectively administered to adult patients with PHPT who underwent curative parathyroidectomy over an 11-month period. The questionnaire, administered preoperatively and 6 months postoperatively, included the Insomnia Severity Index (ISI) and eight additional questions regarding sleep pattern. Total ISI scores range from 0 to 28, with >7 signifying sleep difficulties and scores >14 indicating clinical insomnia.

Results

Of 197 eligible patients undergoing parathyroidectomy for PHPT, 115 (58.3 %) completed the preoperative and postoperative questionnaires. The mean age was 60.0 ± 1.2 years and 80.0 % were women. Preoperatively, 72 patients (62.6 %) had sleep difficulties, and 29 patients (25.2 %) met the criteria for clinical insomnia. Clinicopathologic variables were not predictive of clinical insomnia. There was a significant reduction in mean ISI score after parathyroidectomy (10.3 ± 0.6 vs 6.2 ± 0.5, p < 0.0001). Postoperatively, 79 patients (68.7 %) had an improved ISI score. Of the 29 patients with preoperative clinical insomnia, 21 (72.4 %) had resolution after parathyroidectomy. Preoperative insomnia patients had an increase in total hours slept after parathyroidectomy (5.4 ± 0.3 vs 6.1 ± 0.3 h, p = 0.02), whereas both insomnia patients and non-insomnia patients had a decrease in the number of awakenings (3.7 ± 0.4 vs 1.9 ± 0.2 times, p = 0.0001).

Conclusions

Sleep disturbances and insomnia are common in patients with PHPT, and the majority of patients will improve after curative parathyroidectomy.     

Evaluating the Potential Impact of Pharmacist Counseling on Medication Adherence Using a Simulation Activity

Objective. To evaluate the impact of counseling in a simulated medication adherence activity.Design. Students were randomized into 2 groups: patient medication monograph only (PMMO) and patient medication monograph with counseling (PMMC). Both groups received a fictitious medication and monograph. Additionally, the PMMC group received brief counseling. A multiple-choice, paper-based survey instrument was used to evaluate simulated food-drug interactions, adherence, and perceptions regarding the activity’s value and impact on understanding adherence challenges.Assessment. Ninety-two students participated (PMMC, n=45; and PMMO, n=47). Overall, a significantly higher incidence of simulated food-drug interactions occurred in the PMMO group (30%) vs the PMMC group (22%) (p=0.02). Doses taken without simulated food-drug interactions were comparable: 46.2% (PMCC) vs 41.9% (PMMO) (p=0.19). The average number of missed doses were 3.2 (PMMC) vs 2.8 (PMMO) (p=0.55). Approximately 70% of the students found the activity to be valuable and 89% believed it helped them better understand adherence challenges.Conclusion. This activity demonstrated the challenges and important role of counseling in medication adherence.     

Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 10⁵ plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.     

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

The 3C-like protease (3CL^pro) of SARS-CoV-2 is considered an excellent target for COVID-19 antiviral drug development because it is essential for viral replication and has a cleavage specificity distinct from human proteases. However, drug development for 3CL^pro has been hindered by a lack of cell-based reporter assays that can be performed in a BSL-2 setting. Current efforts to identify 3CL^pro inhibitors largely rely upon in vitro screening, which fails to account for cell permeability and cytotoxicity of compounds, or assays involving replication-competent virus, which must be performed in a BSL-3 facility. To address these limitations, we have developed a novel cell-based luciferase complementation reporter assay to identify inhibitors of SARS-CoV-2 3CL^pro in a BSL-2 setting. The assay is based on a lentiviral vector that co-expresses 3CL^pro and two luciferase fragments linked together by a 3CL^pro cleavage site. 3CL^pro-mediated cleavage results in a loss of complementation and low luciferase activity, whereas inhibition of 3CL^pro results in 10-fold higher levels of luciferase activity. The luciferase reporter assay can easily distinguish true 3CL^pro inhibition from cytotoxicity, a powerful feature that should reduce false positives during screening. Using the assay, we screened 32 small molecules for activity against SARS-CoV-2 3CL^pro, including HIV protease inhibitors, HCV protease inhibitors, and various other compounds that have been reported to inhibit SARS-CoV-2 3CL^pro. Of these, only five exhibited significant inhibition of 3CL^pro in cells: GC376, boceprevir, Z-FA-FMK, calpain inhibitor XII, and GRL-0496. This assay should greatly facilitate efforts to identify more potent inhibitors of SARS-CoV-2 3CL^pro.