Influence of Simvastatin as Augmentative Therapy in the Treatment of Generalized Anxiety Disorder: A Pilot Randomized, Placebo-Controlled Study.

BACKGROUND: Preliminary evidence is promising regarding the anxiolytic effects of statins in animal models of anxiety. Hence, this study aimed to evaluate the efficacy of simvastatin augmentation versus placebo in the treatment of patients with generalized anxiety disorder (GAD) with residual symptoms despite treatment with selective serotonin reuptake inhibitors (SSRIs). METHODS: A double-blind, 8-week controlled trial was conducted from August 2018 to December 2019 in an outpatient psychiatry clinic in Hamadan, Iran. A total of 138 patients with a diagnosis of GAD were assessed for eligibility. Of them, 84 patients who met the study criteria were randomly assigned either to the adjuvant simvastatin (20 mg/day) or to the placebo group. Standard medication consisting of SSRIs was consistent 2 months prior to and during the study. The severity of anxiety symptoms for each patient was assessed based on the Hamilton Anxiety Rating Scale (HAM-A) score at baseline, week 4, and week 8 after treatment. Additionally, blood lipid values were assessed at baseline and on completion of the study. RESULTS: Thirty-three out of 42 patients in the intervention group and 35 out of 42 patients in the control group completed the 8 weeks of the study period. Compared to the placebo group, in the simvastatin group cholesterol, triglycerides, and low-density lipoprotein significantly decreased, and high-density lipoprotein significantly increased over time. General linear model analysis demonstrated that although over time a higher decrease in mean HAM-A scores was observed in the intervention group compared to the control group, this difference was not statistically significant (p = 0.11). In addition, at the end of the study, the number of responders and remitters was comparable in the two groups. CONCLUSIONS: The results from this clinical study did not support the potential efficacy of adjunctive simvastatin in the treatment of patients with GAD. Thus, large-scale and long-term clinical trials are required to more accurately assess the potential efficacy of statins in the treatment of patients with anxiety disorders.

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products.

The importance of new effective treatment methodologies for human immunodeficiency virus (HIV) is undeniable for the medical society. Viral protein U (Vpu), one of the disparaged accessory proteins of HIV, is responsible for the dissemination of viral particles, and HIV mutants lacking Vpu protein have remarkably reduced pathogenicity. Here, we explored the marine natural products to find the leading structures which can potentially inhibit the activity of Vpu in silico. To fulfill this goal, we set up a virtual screening based on molecular docking to evaluate the binding capacity of different marine products to Vpu. For validation, we used molecular dynamics simulation and monitored the root mean square deviation value and binding interactions. The results were intriguing when we realized that the hit compounds (phlorotannins) had previously been identified as reverse transcriptase and HIV protease inhibitors. This research inaugurates a new road to combat HIV by multifaceted mode of action of these marine natural products without putting the normal cells in jeopardy (with their safe toxicological profile).

Metronidazole aryloxy, carboxy and azole derivatives: Synthesis, anti-tumor activity, QSAR, molecular docking and dynamics studies.

A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed the most potent cytotoxic activity (IC50s less than 100 µg/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.

Design, Synthesis, and Biological Activity of New Triazole and Nitro-Triazole Derivatives as Antifungal Agents.

In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi. Nitrotriazole derivatives showed excellent and desirable antifungal activity against most of the tested fungi. Among the synthesized compounds, 5a-d and 5g, possessing nitrotriazole moiety, showed maximum antifungal activity, in particular against several fluconazole-resistant fungi.

Amino-7,8-dihydro-4H-chromenone derivatives as potential inhibitors of acetylcholinesterase and butyrylcholinesterase for Alzheimer's disease management; in vitro and in silico study.

In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the management of Alzheimer's disease (AD). The target compounds were evaluated against AChE and BChE in vitro, and 4k exhibited good potency against BChE (IC50 = 0.65 ± 0.13 µM) compared with donepezil used as a positive control. Kinetic studies revealed that compound 4k exhibited a competitive-type inhibition with a Ki value of 0.55 µM. Molecular docking and molecular dynamics simulations further supported the rationality of our design strategy, as 4k showed promising binding interactions with the active sites of BChE. Overall, our findings highlight the potential of amino-7,8-dihydro-4H-chromenone derivatives as promising candidates for developing novel therapeutics targeting cholinesterase in managing AD.

Synthesis, Antioxidant, Cytotoxicity, Induce Apoptosis Investigation and Docking Study of New Halogenated Dihydropyrano[3,2-b]Chromene-3-Carbonitrile Derivatives on MCF-7 Breast Cancer Cell Line.

Background: Chromene derivatives showed numerous biological activities. In the current study, the antioxidant, cytotoxicity, and apoptosis properties of halogenated dihydropyrano[3,2-b]chromene-3-carbonitrile derivatives (HDCCD) on MCF-7 cell line have been examined. Objectives: This study's principal point was synthesizing new halogenated pyranochromene derivatives and assessing their cytotoxic effects and apoptosis potential on MCF-7 breast cancer cell line by flow cytometry. Methods: Initially, 6-chloro- and 6-bromo-3-hydroxychromone compounds were prepared. In the next step, a series of HDCCD were synthesized by a one-pot three-component reaction of these two compounds, aromatic aldehydes, and malononitrile, in the presence of triethylamine in EtOH at reflux conditions. These compounds were fully characterized by standard spectroscopic techniques (IR, 1H, and 13C NMR) and elemental analyses. The potential of the antioxidant activity was determined by using ferric reducing antioxidant power assay (FRAP). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) were used to evaluate metabolic activity. The nitric oxide (NO) and malondialdehyde (MDA) biomarkers of the exposed cells were evaluated on the cells and their supernatant. To quantify apoptotic death of MCF-7 breast cancer cells treated by the compounds at their IC50 concentrations, Annexin V-FITC apoptosis detection kit was utilized. Molecular docking of compounds (6a-j) into the Cyclin-dependent kinase 6 (PDB code: 4EZ5) was carried out, and the probable binding mode of compounds 6e and 6j was determined. Results: A dose-response relationship was seen in all the compounds. Most of them induced cytotoxic effects on the cells. Nitrite concentration of the culture media of the cells was decreased compared to the control. Malondialdehyde levels of the cells were below the range of the control by the addition of 6b, 6d, 6e, 6f, and 6g compounds on the cells, while the addition of the 6a, 6c, 6h, 6i, and 6j compounds increased the MDA level compared to the control. Flow cytometric analysis showed that most of the exposed cells were in the early and late apoptotic stage, and a few of them were in the necrotic stage. Conclusions: It could be concluded that HDCCD (6a-j) was toxic and caused death in the cells by apoptosis. The compounds have lipophilic characteristics, so they can easily pass the cell membrane. As confirmed by LDH results, it can be concluded that the cytotoxicity is connected with apoptosis rather than necrosis, endorsed by flowcytometry analysis afterward.

The clinical and paraclinical effectiveness of four-hour infusion vs. half-hour infusion of high-dose ampicillin-sulbactam in treatment of critically ill patients with sepsis or septic shock: An assessor-blinded randomized clinical trial.

PURPOSE: This study was conducted to determine whether critically ill patients admitted to the intensive care unit (ICU) with sepsis and septic shock may benefit from extended infusion of ampicillin/sulbactam compared with those receiving intermittent infusion. MATERIAL AND METHODS: This randomized assessor-blinded clinical trial was conducted in the ICUs of Nemazee and Shahid Rajaee hospital, Shiraz, Iran, from August 2019 to August 2021. The participants randomly received 9 g Ampicillin/Sulbactam every 8 h by either extended (infused over 4 h) or intermittent (infused over 30 min) intravenous infusion if their estimated glomerular filtration rate based on Cockrorft-Gault formula was higher than 60 ml/min. RESULTS: Totally, 136 patients were enrolled and allocated to the intervention and control groups, each with 68 patients. Clinical cure was significantly higher in the extended group (P = 0.039), but ICU and hospital length of stay did not differ between the groups (P = 0.87 and 0.83, respectively). The ICU (P = 0.031) and hospital (P = 0.037) mortality rates in the extended infusion group were significantly lower than those in the intermittent infusion group. CONCLUSION: These data should be replicated in larger clinical trials before providing any recommendation in favor of this method of administration in clinical practice.

Pharmacological agents for the prevention of colistin-induced nephrotoxicity.

BACKGROUND: Colistin is a polymyxin antibiotic which has been used for treatment of Gram-negative infections, but it was withdrawn due to its nephrotoxicity. However, colistin has gained its popularity in recent years due to the reemergence of multidrug resistant Gram-negative infections and drug-induced toxicity is considered as the main obstacle for using this valuable antibiotic. RESULTS: In total, 30 articles, including 29 animal studies and one clinical trial were included in this study. These compounds, including aged black garlic extract, albumin fragments, alpha lipoic acid, astaxanthin, baicalein, chrysin, cilastatin, colchicine, curcumin, cytochrome c, dexmedetomidine, gelofusine, grape seed proanthocyanidin extract, hesperidin, luteolin, lycopene, melatonin, methionine, N-acetylcysteine, silymarin, taurine, vitamin C, and vitamin E exhibited beneficial effects in most of the published works. CONCLUSIONS: In this review, the authors have attempted to review the available literature on the use of several compounds for prevention or attenuation of colistin-induced nephrotoxicity. Most of the studied compounds were potent antioxidants, and it seems that using antioxidants concomitantly can have a protective effect during the colistin exposure.

Synthesis and In Vitro Cytotoxicity of Novel Halogenated Dihydropyrano[3,2-b]Chromene Derivatives.

Lung and breast cancers are among the most common cancers. In the present work, initially, 6-bromo-; and 6-chloro-3-hydroxychromone compounds were prepared. In the next step, a series of 8-bromo-; and 8-chloro-dihyropyrano[3,2-b]chromene derivatives were synthesized by one-pot three component reaction of these two compounds, aromatic aldehydes, and ethyl cyanoacetate in the presence of triethylamine in EtOH at reflux conditions. The synthesized compounds were tested for their in vitro cytotoxic activity against A549 (lung cancer) and MCF-7 (breast cancer) cell lines. It was found that some compounds have high to moderate cytotoxicity, which makes them potential candidates for further studies. This study can be the basis for further studies to design and synthesis potent anticancer compounds and investigating their mechanism of action.

The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: a randomized double blinded placebo-controlled clinical trial.

AIM OF THE STUDY: This study was conducted to investigate the positive effect of silymarin on liver enzymes and antioxidant status in trauma patients with elevated liver enzymes due to trauma-induced liver injury, admitted to the intensive care unit. MATERIAL AND METHODS: This one-year, randomized, double-blinded, placebo-controlled clinical trial was conducted on 90 trauma patients. The participants were assigned to either receiving Livergol tablets containing 140 mg of silymarin or 140 mg of placebo three times daily for 14 days. Liver enzymes, including aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), were measured at baseline and days 3, 7, 9 and 14 after intervention. Also, antioxidant markers were measured at baseline and day 14 after treatment. RESULTS: Receiving silymarin supplement significantly lowered the liver enzymes, compared to placebo (p < 0.05). The mean serum level of malondialdehyde (MDA) was significantly decreased and the mean serum levels of total antioxidant capacity (TAC) and thiol groups were significantly increased in the silymarin group from baseline to day 14. In the placebo group, mean serum levels of MDA and thiol groups were significantly increased, while serum level of TAC was not significantly changed at day 14, compared to baseline. Also, the mean serum level of MDA was significantly lower, while the serum levels of thiol groups and TAC were significantly higher in the silymarin group. CONCLUSIONS: Silymarin supplementation significantly improved some antioxidant markers (TAC and thiol) and decreased liver enzymes in patients with trauma-induced liver injury.

An algorithm for coupling multibranch in vitro experiment to numerical physiology simulation for a hybrid cardiovascular model.

The hybrid cardiovascular modeling approach integrates an in vitro experiment with a computational lumped-parameter simulation, enabling direct physical testing of medical devices in the context of closed-loop physiology. The interface between the in vitro and computational domains is essential for properly capturing the dynamic interactions of the two. To this end, we developed an iterative algorithm capable of coupling an in vitro experiment containing multiple branches to a lumped-parameter physiology simulation. This algorithm identifies the unique flow waveform solution for each branch of the experiment using an iterative Broyden's approach. For the purpose of algorithm testing, we first used mathematical surrogates to represent the in vitro experiments and demonstrated five scenarios where the in vitro surrogates are coupled to the computational physiology of a Fontan patient. This testing approach allows validation of the coupling result accuracy as the mathematical surrogates can be directly integrated into the computational simulation to obtain the "true solution" of the coupled system. Our algorithm successfully identified the solution flow waveforms in all test scenarios with results matching the true solutions with high accuracy. In all test cases, the number of iterations to achieve the desired convergence criteria was less than 130. To emulate realistic in vitro experiments in which noise contaminates the measurements, we perturbed the surrogate models by adding random noise. The convergence tolerance achievable with the coupling algorithm remained below the magnitudes of the added noise in all cases. Finally, we used this algorithm to couple a physical experiment to the computational physiology model to demonstrate its real-world applicability.

The effect of different intensivist staffing patterns on the rate of potential drug-drug interactions in adult trauma intensive care units.

BACKGROUND: Drug-drug interactions (DDIs) have created alarming challenges for public health, especially in those admitted to intensive care units (ICUs). Many studies have shown that involvement of intensivists in the ICUs improves the outcome and decreases the treatment costs. The effect of academic versus non-academic (therapeutic) intensivist as well as hours of coverage and attendance of intensivist on potential DDIs (pDDIs) was evaluated in six adult trauma ICUs of a level one trauma center. METHODS: In this 6-month cross-sectional study, 200 patients were included. The DDIs were classified into five groups, including type A, B, C, D, and X. pDDIs were defined as interactions belonged to C, D and X categories. Patients in six adult ICUs with three different patterns of intensivist staffing models including type A (once-daily therapeutic intensivist visit followed by 24 h on-call), B (twice-daily academic intensivist visit, 8 h of attendance in ICU and 16 h on-call) and C (all criteria just like ICU type B, except for the presence of therapeutic instead of academic intensivist) were screened for pDDIs. RESULTS: In total, 3735 drug orders and 3869 drugs (193 different types) were screened and 1826 pDDIs were identified. Type C, D and X interactions accounted for 60.6%, 35.5%, and 3.9% of all pDDIs, respectively. The mean of pDDI per patient was significantly higher (p-value < 0.001) in the ICU type A than ICU types C and B. The frequency of pDDIs was the highest in the type A ICUs. A statistically significant relationship was observed between the number of prescribed drugs and ICU length of stay (p-value < 0.001 and p = 0.009, respectively). CONCLUSION: Different patterns of intensivist staffing affect pDDIs to varying degrees. In the studied ICUs academic versus therapeutic intensivist, twice versus once-daily visit, and 8 h attendance with16 h on-call versus 24 h on-call were associated with more reductions in pDDIs. PLAIN LANGUAGE SUMMARY: The impact of different intensivist staffing patterns in ICUs on the rate of potential drug-drug interactionsDrug-drug interactions (DDIs) have created alarming challenges for public health, especially in patients admitted to intensive care units (ICUs). Many studies have shown that involvement of intensivists in the ICUs improves the outcome and limits the costs. Considering the high incidence of potential DDIs (pDDIs) occurring for critically ill patients and the importance of ADRs caused by pDDIs in ICUs, the effect of the presence of an academic versus therapeutic intensivist, as well as the hour of coverage of intensivist on prevalence of pDDIs was evaluated in six adult trauma ICUs of a level one trauma center in Shiraz, Iran. We also determined the prevalence of pDDIs and their associated risk factors. To the best of our knowledge, this is the first study that has assessed the effect of various ICU physician staffing models on the incidence and pattern of pDDIs.

Nickel Ferrite (NiFe2O4) Nanoparticles as Magnetically Recyclable Nanocatalyst for Highly Efficient Synthesis of 4H-Chromene Derivatives.

An adapted one-pot route to nanocatalyst-assisted synthesis of 4H-chromenes via three component condensation reaction between dimedone, malononitrile, and a broad range of aryl aldehydes by the use of magnetic nickel ferrite nanoparticles is described. By this achievement, not only a novel route to highly efficient synthesis of these series of heterocycles was introduced but also the scope of these medicinally important products was developed via preparation of some novel products. Above all, a new application of nickel ferrite nanoparticles (NiFe2O4 NPs) as highly efficient, green and magnetically recyclable catalyst has been introduced. Overall, obtaining good to excellent yields of products, environmentally and economic benign procedure, easy handling, availability of starting materials, use of non-toxic solvents, and high recyclability of nano-catalyst could be countered as most important advantages of this methodology.

Omega-3 Supplementation in the Prevention of Contrast Induced Nephropathy in Patients Undergoing Elective Percutaneous Coronary Intervention: A Randomized Placebo-Controlled Trial.

Purpose: Contrast-induced nephropathy (CIN) is the third cause of hospital-acquired renal failure and is associated with significant morbidity and mortality. Several studies have revealed the protective role of omega-3 in prevention and treatment of some kidney injuries. This study was conducted to examine the effect of omega-3 supplementation on the markers of renal function and to evaluate its potential in the prevention of CIN in patients undergoing elective percutaneous coronary intervention (PCI). Methods: In this double-blind, randomized clinical trial, 85 eligible patients scheduled for PCI was randomly divided into omega-3 (a single 3750 mg dose of omega-3 as well as routine hydration therapy within 12 hours before PCI) or control (placebo plus routine hydration therapy) groups. Serum creatinine (SCr) and cystatin C levels were measured at baseline and 24 hours after PCI. Results: Our results indicated that post- PCI cystatin C levels were significantly decreased in the omega-3 group compared to the control group (P < 0.001). Although less upward manner was seen in the level of 24-hour creatinine in the omega-3 group, it did not reach the significance level (P = 0.008). Conclusion: The positive effect of omega-3 on cystatin C levels showed that it may have a protective role in the prevention of CIN in post-PCI patients with normal kidney function. However, to better assess this effect, it is highly recommended to design future studies with higher doses and longer duration of therapy with omega-3 plus long-term follow up.

Design, Synthesis, Biological Evaluation and Molecular Modeling Study of Novel Indolizine-1-Carbonitrile Derivatives as Potential Anti-Microbial Agents.

A novel one-pot two step tandem reaction for the synthesis of indolizine-1-carbonitrile derivatives (5a-i) was identified. The route comprises 1,3-dipolar cycloaddition reaction of aromatic aldehyde derivatives (1a-i), malononitrile (2) and 1-(2-(4-bromophenyl)-2-oxoethyl)-2-chloropyridin-1-ium (4) under ultrasound irradiation at room temperature in the presence of triethylamine at acetonitrile. The product compounds were tested against bacteria and fungi. It was revealed that compound 5b had the most antifungal activity (range MICs = 8-32 µg/mL) and compound 5g had the most antibacterial activity (range MICs = 16-256 µg/mL). Molecular docking of compounds (5a-i) into fungal 14α-demethylase and bacterial protein tyrosine phosphatase active sites were also performed and probable binding mode of compounds 5b and 5g were determined.

Medication Errors in Patients with Enteral Feeding Tubes in the Intensive Care Unit.

OBJECTIVE: Most patients admitted to Intensive Care Units (ICU) have problems in using oral medication or ingesting solid forms of drugs. Selecting the most suitable dosage form in such patients is a challenge. The current study was conducted to assess the frequency and types of errors of oral medication administration in patients with enteral feeding tubes or suffering swallowing problems. METHODS: A cross-sectional study was performed in the ICU of Shahid Sadoughi Hospital, Yazd, Iran. Patients were assessed for the incidence and types of medication errors occurring in the process of preparation and administration of oral medicines. FINDINGS: Ninety-four patients were involved in this study and 10,250 administrations were observed. Totally, 4753 errors occurred among the studied patients. The most commonly used drugs were pantoprazole tablet, piracetam syrup, and losartan tablet. A total of 128 different types of drugs and nine different oral pharmaceutical preparations were prescribed for the patients. Forty-one (35.34%) out of 116 different solid drugs (except effervescent tablets and powders) could be substituted by liquid or injectable forms. The most common error was the wrong time of administration. Errors of wrong dose preparation and administration accounted for 24.04% and 25.31% of all errors, respectively. CONCLUSION: In this study, at least three-fourth of the patients experienced medication errors. The occurrence of these errors can greatly impair the quality of the patients' pharmacotherapy, and more attention should be paid to this issue.

Biotransformation of acetoin to 2,3-butanediol: Assessment of plant and microbial biocatalysts.

2,3-Butanediol (2,3-BD) is a valuable bulk chemical owing to its extensive application in chemical and pharmaceutical industry with diverse applications in drug, cosmetics and food products. In the present study, the biotransformation of acetoin to 2,3-BD by five plant species (Brassica oleracea, Brassica rapa, Daucuscarota, Pastinaca sativa, and Raphnussativus) and five microorganisms (Aspergillusfoetidus, Penicillumcitrinum, Saccharomyces carlbergensis, Pichiafermentans, and Rhodotrulaglutinis) was investigated as a method for the production of 2,3-BD, which can serve as an alternative to the common pentoses and hexoses fermentation by microorganisms. The produced 2,3-BD stereoisomers were characterized and their total conversion yields were determined. The results showed that the examined plants can be used as a green factory for the production of all 2,3-BD stereoisomers, except B. rapa. In microorganisms, P. fermentans and S. carlbergensis produced (-)-2R,3R and mesobutanediol, while P. citrinum produced (+)-2S,3S and mesobutanediol. R. glutinis and A. foetidus produced all three isomers. In conclusion, efficient whole-cell biocatalysts from plants and microorganisms were determined in the bioconversion of acetoin to 2,3-BD. The profile of produced stereoisomers demonstrated that microorganisms produce more specific stereoisomers.

Design, Synthesis, and Antifungal Activity of New α-Aminophosphonates.

α-Aminophosphonates are bioisosteres of amino acids and have several pharmacological activities. These compounds have been synthesized by various routes from reaction between amine, aldehyde, and phosphite compounds. In order to synthesize α-aminophosphonates, catalytic effect of CuCl2 was compared with FeCl3. Also all designed structures as well as griseofulvin were docked into the active site of microtubule (1JFF), using Autodock program. The results showed that the reactions were carried out in the presence of CuCl2 in lower yields, and also the time of reaction was longer in comparison with FeCl3. The chemical structures of the new compounds were confirmed by spectral analyses. The compounds were investigated for antifungal activity against several fungi in comparison with griseofulvin. An indole-derived bis(α-aminophosphonates) with the best negative ΔG in docking study showed maximum antifungal activity against Microsporum canis, and other investigated compounds did not have a good antifungal activity.