Simultaneous Co-administration Research Articles

Dual Antibiotic Approach: Synthesis and Antibacterial Activity of Antibiotic-Antimicrobial Peptide Conjugates.

In recent years, bacterial resistance to conventional antibiotics has become a major concern in the medical field. The global misuse of antibiotics in clinics, personal use, and agriculture has accelerated this resistance, making infections increasingly difficult to treat and rendering new antibiotics ineffective more quickly. Finding new antibiotics is challenging due to the complexity of bacterial mechanisms, high costs and low financial incentives for the development of new molecular scaffolds, and stringent regulatory requirements. Additionally, innovation has slowed, with many new antibiotics being modifications of existing drugs rather than entirely new classes. Antimicrobial peptides (AMPs) are a valid alternative to small-molecule antibiotics offering several advantages, including broad-spectrum activity and a lower likelihood of inducing resistance due to their multifaceted mechanisms of action. However, AMPs face challenges such as stability issues in physiological conditions, potential toxicity to human cells, high production costs, and difficulties in large-scale manufacturing. A reliable strategy to overcome the drawbacks associated with the use of small-molecule antibiotics and AMPs is combination therapy, namely the simultaneous co-administration of two or more antibiotics or the synthesis of covalently linked conjugates. This review aims to provide a comprehensive overview of the literature on the development of antibiotic-AMP conjugates, with a particular emphasis on critically analyzing the design and synthetic strategies employed in their creation. In addition to the synthesis, the review will also explore the reported antibacterial activity of these conjugates and, where available, examine any data concerning their cytotoxicity.

Yttrium oxide nanoparticles ameliorates calcium hydroxide and calcium titanate nanoparticles induced genomic DNA and mitochondrial damage, ROS generation and inflammation

Calcium hydroxide (Ca(OH)2NPs), calcium titanate (CaTiO3NPs) and yttrium oxide (Y2O3NPs) nanoparticles are prevalent in many industries, including food and medicine, but their small size raises concerns about potential cellular damage and genotoxic effects. However, there are very limited studies available on their genotoxic effects. Hence, this was done to investigate the effects of multiple administration of Ca(OH)2NPs, CaTiO3NPs or/and Y2O3NPs on genomic DNA stability, mitochondrial membrane potential integrity and inflammation induction in mouse brain tissues. Mice were orally administered Ca(OH)2NPs, CaTiO3NPs or/and Y2O3NPs at a dose level of 50 mg/kg b.w three times a week for 2 weeks. Genomic DNA integrity was studied using Comet assay and the level of reactive oxygen species (ROS) within brain cells was analyzed using 2,7 dichlorofluorescein diacetate dye. The expression level of Presenilin-1, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) genes and the integrity of the mitochondrial membrane potential were also detected. Oral administration of Ca(OH)2NPs caused the highest damage to genomic DNA and mitochondrial membrane potential, less genomic DNA and mitochondrial damage was induced by CaTiO3NPs administration while administration of Y2O3NPs did not cause any remarkable change in the integrity of genomic DNA and mitochondrial membrane potential. Highest ROS generation and upregulation of presenilin-1, TNF-α and IL-6 genes were also observed within the brain cells of mice administrated Ca(OH)2NPs but Y2O3NPs administration almost caused no changes in ROS generation and genes expression compared to the negative control. Administration of CaTiO3NPs alone slightly increased ROS generation and the expression level of TNF-α and IL-6 genes. Moreover, no remarkable changes in the integrity of genomic DNA and mitochondrial DNA potential, ROS level and the expression level of presenilin-1, TNF-α and IL-6 genes were noticed after simultaneous coadministration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs. Coadministration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs mitigated Ca(OH)2NPs and CaTiO3NPs induced ROS generation, genomic DNA damage and inflammation along with restoring the integrity of mitochondrial membrane potential through Y2O3NPs scavenging free radicals ability. Therefore, further studies are recommended to study the possibility of using Y2O3NPs to alleviate Ca(OH)2NPs and CaTiO3NPs induced genotoxic effects.

A validated LC-MS/MS method for determination of Molnupiravir and Favipiravir in human plasma; Assessment of the remarkable potential synergistic effect against SARS-CoV-2 Infection: Application to a pharmacokinetic study in healthy Egyptian volunteers

Several clinical trials were carried out to find the route for an efficient therapy against SARS-CoV-2 infection. Mono- and dual therapy of various antivirals were investigated and found to have a clinical benefit in infected patients. Some of these antivirals are Molnupiravir (MOL) and Favipiravir (FAV), both drugs were evaluated for combined antiviral activity in some recent clinical trials. In this study, an efficient, simple, and rapid LC-MS/MS method for simultaneous determination of N-hydroxycytidine (NHC), MOL active metabolite, and FAV in human plasma of healthy volunteers was developed. Plasma protein precipitation was performed using acetonitrile. Compounds’ separation was achieved using Agilent Zorbax Eclipse plus C18, 4.6 × 150 mm, 3.5 µm and an isocratic elution of a mobile phase composed of methanol − 0.2 % acetic acid (10:90, v/v) at a flow rate of 0.5 mL/min using pyrazinamide as an internal standard (IS). Drugs were quantified using API 6500 + Qtrap mass spectrometer employing a selective ion mode combining a positive and negative ESI interface. The bioanalytical method was validated in accordance with the US-FDA bioanalytical guidance. The calibration range for both NHC and FAV was 10.0–––10000.0 ng/mL computed via weighted linear regression approach (1/x2). The proposed method could be applied to support the upcoming clinical studies for therapeutic drug monitoring of patients undergoing dual combination therapy as the latter combination proved more efficacious and powerful tool for the complete treatment of SARS-CoV-2 cases. Finally, the suggested bioanalytical method was efficiently utilized in human pharmacokinetic study of NHC and FAV, after simultaneous co-administration, in healthy volunteers.

Genotoxicity and oxidative stress induction by calcium hydroxide, calcium titanate or/and yttrium oxide nanoparticles in mice

Intensive uses of Calcium hydroxide (Ca(OH)2NPs), calcium titanate (CaTiO3NPs) and yttrium oxide (Y2O3NPs) nanoparticles increase their environmental release and human exposure separately or together through contaminated air, water and food. However, too limited data are available on their genotoxicity. Therefore, this study explored the effect of Ca(OH)2NPs, CaTiO3NPs or/and Y2O3NPs administration on the genotoxicityand oxidative stress induction in mice hepatic tissue. Mice were orally administered Ca(OH)2NPs, CaTiO3NPs and Y2O3NPs separately or simultaneously together at a dose level of 50 mg/kg b.w. for two successive weeks (3 days per week). Marked induction of DNA damage noticed after oral administration of Ca(OH)2NPs or CaTiO3NPs alone together with high Ca(OH)2NPs induced reactive oxygen species (ROS) generation and a slight CaTiO3NPs induced ROS production were highly decreased after simultaneous coadministration of administration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs up to the negative control level. Oral administration of Y2O3NPs alone also did not cause observable changes in the genomic DNA integrity and the ROS generation level compared to the negative control levels. Similarly, significant elevations in P53 gene expression and high reductions in Kras and HSP-70 genes expression were observed only after administration of Ca(OH)2NPs alone, while, remarkable increases in the Kras and HSP-70 genes expression and non-significant changes in p53 gene expression were noticed after administration of CaTiO3NPs and Y2O3NPs separately or simultaneously together with Ca(OH)2NPs. Conclusion: Ca(OH)2NPs exhibited the highest genotoxic effect through oxidative stress induction and disruption of apoptotic (p53 and Kras) and protective (HSP-70) genes expression. Slight DNA damage was noticed after CaTiO3NPs administration. However, administration of Y2O3NPs alone was non-genotoxic and coadministration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs restored genomic DNA integrity and normal expression of apoptotic p53 and protective HSP-70 genes disrupted by Ca(OH)2NPs and CaTiO3NPs. Thus co-administration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs is recommended to counter Ca(OH)2NPs and CaTiO3NPs induced genotoxicity and oxidative stress.

A validated LC-MS/MS bioanalytical method for the pharmacokinetic interaction study of the effect of some co-administered COVID-19 protocol drugs on pholcodine containing antitussive mixture

The symptoms of the viral infection COVID-19, which range from mild to severe, can include fever, coughing, sore throats, malaise, headaches, and a loss of taste or smell. Fever and cough are the most typical symptoms of COVID-19, and in more severe cases, it can make breathing difficult. Hence, in this in-vivo study, we studied the effect of the simultaneous co-administration of COVID-19 treatment drugs (azithromycin, dexamethasone, and hydroxychloroquine) on the pharmacokinetics of the antitussive drugs combination: pholcodine, pseudoephedrine and paracetamol in rats. For the simultaneous determination of pholcodine, pseudoephedrine, and paracetamol in rat plasma, a UPLC-MS/MS technique was developed and approved. a mobile phase made up of 0.15% aqueous formic acid: acetonitrile (20:80, v/v) was used using an Xterra C18 MS column (3.5 m, 4.6 × 50 mm). The detection procedure involved the employment of a multiple reaction monitoring mode utilizing triple-quadrupole tandem mass spectrometer. The concentration range for pholcodine, pseudoephedrine, and paracetamol was linear across 12–1000 ng/ml, 10–550 ng/ml, and 400–30000 ng/ mL, respectively. The results show that the coefficient of variation is satisfactory at quality control samples for all the mentioned drugs, confirming the accuracy and precision of the method. This approach was successfully implemented in a rat drug-drug pharmacokinetic interaction study to determine whether the co-administration of COVID-19 protocol medications would affect the bioavailability of pholcodine, pseudoephedrine and paracetamol. It was found that azithromycin, dexamethasone, and hydroxychloroquine co-administration significantly affect the bioavailability of these drugs, increasing their systemic exposure as a result and this could potentially lead to increasing adverse effects. Therefore, healthcare professionals should consider the potential drug-drug interaction when prescribing these medications to COVID-19 patients.

Estimation of genomic and mitochondrial DNA integrity in the renal tissue of mice administered with acrylamide and titanium dioxide nanoparticles

The Kidneys remove toxins from the blood and move waste products into the urine. However, the accumulation of toxins and fluids in the body leads to kidney failure. For example, the overuse of acrylamide and titanium dioxide nanoparticles (TiO2NPs) in many food and consumer products increases human exposure and risks; however, there are almost no studies available on the effect of TiO2NPs coadministration with acrylamide on the integrity of genomic and mitochondrial DNA. Accordingly, this study was conducted to estimate the integrity of genomic and mitochondrial DNA in the renal tissue of mice given acrylamide and TiO2NPs. To achieve this goal, mice were administrated orally TiO2NPs or/and acrylamide at the exposure dose levels (5 mg/kg b.w) and (3 mg/kg b.w), respectively, five times per week for two consecutive weeks. Concurrent oral administration of TiO2NPs with acrylamide caused remarkable elevations in the tail length, %DNA in tail and tail moment with higher fragmentation incidence of genomic DNA compared to those detected in the renal tissue of mice given TiO2NPs alone. Simultaneous coadministration of TiO2NPs with acrylamide also caused markedly high elevations in the reactive oxygen species (ROS) production and p53 expression level along with a loss of mitochondrial membrane potential and high decreases in the number of mitochondrial DNA copies and expression level of β catenin gene. Therefore, from these findings, we concluded that concurrent coadministration of acrylamide with TiO2NPs augmented TiO2NPs induced genomic DNA damage and mitochondrial dysfunction through increasing intracellular ROS generation, decreasing mitochondrial DNA Copy, loss of mitochondrial membrane potential and altered p53 and β catenin genes expression. Therefore, further studies are recommended to understand the biological and toxic effects resulting from TiO2NPs with acrylamide coadministration.

Fabrication and functional attributes of nanotherapeutically engineered system for co-administration of adapalene and lycopene for enhanced acne management: an in vitro and in vivo investigation

BackgroundAcne vulgaris is caused due to several different biological, environmental and specific pathological factors, resulting in secretion of unregulated amount of sebum by the sebaceous glands. Acne is thought to be a minor, self-restraint, puberty leading and hormone-induced cosmetic disorder. It significantly affects the quality of life leading to social disengagement, anxiety, depression, necessitating its therapeutic management in due course of time. Thus, despite not being fatal it has social and mental impact on individual’s life. Pathogenesis of acne is complex and multifactorial involving diverse physiological, environmental factors and significant role of propionibacterium acne. Retinoids have been used as preferred first-line therapy for treatment of acne, but they have many limitations. Adapalene has found to be acting synergistically with other drugs like benzoyl peroxide, salicylic acid, clindamycin, etc., and various other topical antioxidants.ResultsThe study investigates the formulation and characterization of novel nanostructured lipid vesicles (NLVs) co-loaded with adapalene and lycopene, through topical gel. The high-pressure homogenization method was used to prepare nanostructured lipid vesicles followed by incorporation into hydrophilic gel vehicle. This novel system was scientifically tested for various evaluation parameters like size and vesicle size distribution, polydispersity index, drug entrapment efficiency and in vitro drug release characteristics, along with rheological behavior of formulation gel. Skin permeation and biodistribution characteristics through skin were also evaluated, and better localization of drug in dermis and reduced systemic penetration were the key observation in prepared formulation.ConclusionThe simultaneous co-administration of lycopene resulted in an additive effect in therapeutic management of acne. It can be predicted that this novel NLVs-based gel along with synergistic effect of lycopene will definitely result in better therapeutic efficacy and reduced systemic adverse effects of adapalene. This combination can be explored as future alternative for acne therapy.

Model predictive control using MISO approach for drug co-administration in anesthesia

In this paper, a model predictive control system for the depth of hypnosis is proposed and analyzed. This approach considers simultaneous co-administration of the hypnotic and analgesic drugs and their effect on the Bispectral Index Scale (BIS). The control scheme uses the nonlinear multiple-input–single-output (MISO) model to predict the remifentanil influence over the propofol hypnotic effect. Then, it exploits a generalized model predictive control algorithm and a ratio between the two drugs in order to provide the optimal dosage for the desired BIS level, taking into account the typical constraints of the process. The proposed approach has been extensively tested in simulation, using a set of patients described by realistic nonlinear pharmacokinetic/pharmacodynamic models, which are representative of a wide population. Additionally, an exhaustive robustness evaluation considering inter- and intra-patient variability has been included, which demonstrates the effectiveness of the analyzed control structure.

Multivalent cations interactions with fluoroquinolones or tetracyclines: A cross-sectional study.

IntroductionOral fluoroquinolones and tetracyclines are known to interact with divalent or trivalent cation-containing compounds (DTCCs) via chelation. The objective of this study is to describe the prevalence of these drug-drug interactions (DDIs) in an inpatient setting.MethodsA cross-sectional study of prospectively collected data were conducted at an academic tertiary care hospital. We included hospitalized adults who were receiving oral fluoroquinolones or tetracyclines with DTCCs in 2019. Our hospital uses electronic health records for medication ordering and handwritten medication administration records (MARs). The primary study outcome was the percentage of simultaneous administration of fluoroquinolones or tetracyclines with DTCCs, and the secondary outcome was the percentage of inappropriate separation time.ResultsAmong patients who received oral fluoroquinolones or tetracyclines, 47 patients (26.6%) were co-administered DTCCs and included in this study. Ciprofloxacin (n = 29; 61.7%) was the most commonly interacting antibiotic, followed by moxifloxacin (n = 12; 25.5%) and doxycycline (n = 6; 12.8%). The interacting DTCCs included iron-containing products and calcium-containing products, and half of the patients (n = 24; 51%) received DTCCs once daily. Most patients (n = 35; 74.5%) were found to receive oral fluoroquinolones or tetracyclines at the same time as DTCCs, while one (2.1%) received inappropriately separated DTCCs.ConclusionsDespite being a very known contraindicated DDI, the prevalence of simultaneous co-administration of oral fluoroquinolones or tetracyclines with polyvalent cations was extremely high in a hospital with handwritten MARs. Antimicrobial stewardship programs should target this DDI, and future studies should evaluate the impact of different practical solutions to this problem in different clinical settings.

CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy

The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ+ TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

P049 A new preclinical rationale for first-line therapy of ulcerative colitis

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory condition with no known medical cure. 5-Aminosalicylic acid (5-ASA [mesalazine]) represents the cornerstone of first-line therapy for mild-to-moderate UC. Sulfasalazine (SASP) is the original agent in this class of drugs. Meta-analyses of patients with mild-to-moderately active UC comparing 5-ASA to placebo showed 5-ASA to be significantly superior to placebo. However, about two-thirds of patients treated with 5-ASA fail to enter clinical remission. It is therefore most important to identify strategies to accelerate and maximise the therapeutic effects of 5-ASA. Therapeutic intervention against NFκB activation is a useful strategy for treatment of UC. The 4-alkanoylaminobenzamide PM0503 inhibits the breakdown of the NFκB inhibitor IκBβ, and SASP/5-ASA inhibits the breakdown of IκBα. This elicited a hypothesis of a possible synergistic action and converging effect on NFκB signalling. In the present study, we investigated the effect of combining SASP/5-ASA with PM0503 in experimental colitis. Methods SASP and PM0503 alone or in combination were administered for 5 days to Balb/c mice with colitis triggered by 5% dextran sulphate sodium (DSS). Blood in the stool, stool consistency and body weight loss were evaluated daily on a 0–4 point scale. The disease activity index (DAI) was calculated by summarising the total score of these three parameters. Results Addition of 5% DSS in the drinking water for 5 days produced reproducible symptoms of colitis. PM0503 was shown to inhibit DSS induced colitis by reducing mean DAI at day 5 from 6.9 in controls to 1.7 (a 75% decrease). Mean DAI recorded with SASP treatment at optimal doses in the same series of experiments was 4.4 (a 36% decrease). Furthermore, and most important, lower doses of PM0503 acted synergistically with SASP in ameliorating DSS-induced disease severity. The combination of PM0503 and SASP using suboptimal doses having minimal beneficial effects as monotherapies, showed more than 50% disease inhibition at day 5. In addition, no toxicity was observed with PM0503 alone or in combination with SASP. Conclusion Our findings offer a preclinical rationale for simultaneous coadministration of PM0503 and a 5-ASA agent such as SASP or 5-ASA as first-line treatment for patients with UC.

Attenuation of neurological deficit by a novel ethanolamine derivative in rats after brain trauma.

Objectives: To prove that our novel ethanolamine derivative (FDES) can normalize overall movement and exploratory activity of rats with traumatic brain injury (TBI) owing to its peculiar properties.Materials and methods: TBI was modeled using controlled cortical impact injury (CCI) model method. The resulting neurological deficit, efficacy of the novel agent and other reference agents used were assayed in tests which evaluated overall movements and exploratory behavior of the rats. Finally, scopolamine in equimolar dose was used to estimate the role of cholinergic system in the efficacy of our agent. The tests included: limb-placing, open field, elevated plus maze, cylinder, and beam walking tests.Results: Intraperitoneal administration of FDES at a dose of 10 mg/kg led to improvement of fore- and hind-limb functions of rats with traumatic brain injury as was shown in “Limb placing”, “Open field” “Cylinder” and “Beam walking” tests. The new agent had no effects on traumatized rats behavior in the “Elevated Plus Maze” test. Simultaneous co-administration of scopolamine with FDES reduced the beneficial effects of the latter in rats with trauma.Conclusion: The neuroprotective effects of new agent were manifested in the reduction of motor deficiencies, and exploratory activity in the CCI model rats. In comparison with choline alfoscerate and citicoline, FDES showed more beneficial effects as were observed in most of the tests, and did not negatively influence the traumatized rats psychologically. Notably, it is possible that the neuroprotective influence of the new agent is mediated by its actions on the cholinergic system.

Coenzyme Q10 ameliorates cadmium induced reproductive toxicity in male rats.

This study aimed at investigating the protective role of CoQ10 against cadmium (Cd)-induced reproductive toxicity in male rats. Adult male Wistar rats were exposed to an acute dose of Cd (25 mg/kg bwt; Cd group), Cd+CoQ10 (25 mg/kg bwt Cd+10 mg CoQ10; Cd-Q10 group) and distilled water (control) in vivo for 15 consecutive days and semen quality was assessed. A significant reduction was noted in sperm concentration, progressive motility, morphology and DNA integrity in both Cd- and Cd-Q10 groups in comparison to control indicating Cd-induced testicular lipid per oxidation (LPO) and decline in indigenous antioxidant defense system as measured by total antioxidant capacity (TAC) (p<0.05). However, simultaneous co-administration of CoQ10 along with Cd (Cd-Q10 group) was able to improve sperm concentration, motility, progressive motility, morphology, DNA integrity, and testicular TAC as well as lower LPO compared to Cd group (p<0.05). Results indicate that used dose of CoQ10 is capable of moderately ameliorating reproductive toxicity of Cd by improving semen quality and reducing testicular oxidative stress.

Study of Interactions between Amlodipine and Quercetin on Human Serum Albumin: Spectroscopic and Modeling Approaches.

The aim of this study was to analyze the binding interactions between a common antihypertensive drug (amlodipine besylate—AML) and the widely distributed plant flavonoid quercetin (Q), in the presence of human serum albumin (HSA). Fluorescence analysis was implemented to investigate the effect of ligands on albumin intrinsic fluorescence and to define the binding and quenching properties. Further methods, such as circular dichroism and FT-IR, were used to obtain more details. The data show that both of these compounds bind to Sudlow’s Site 1 on HSA and that there exists a competitive interaction between them. Q is able to displace AML from its binding site and the presence of AML makes it easier for Q to bind. AML binds with the lower affinity and if the binding site is already occupied by Q, it binds to the secondary binding site inside the same hydrophobic pocket of Sudlow’s Site 1, with exactly the same affinity. Experimental data were complemented with molecular docking studies. The obtained results provide useful information about possible pharmacokinetic interactions upon simultaneous co-administration of the food/dietary supplement and the antihypertensive drug.

Effect of (–)-epicatechin-3-gallate and (–)-epigallocatechin-3-gallate on the binding of tegafur to human serum albumin as determined by spectroscopy, isothermal titration calorimetry, and molecular docking

Green tea has attracted great interest as a cancer prevention agent. Interactions of tea polyphenols with serum albumin may influence the efficacy of drugs. The interactions of (–)-epigallocatechin-3-gallate (EGCG), (–)-epicatechin-3-gallate (ECG), and tegafur (TF) alone or in combination with human serum albumin (HSA) at pH 7.4 and different temperatures were investigated by spectroscopic methods, isothermal titration calorimetry (ITC), and molecular docking. The binding affinities to HSA were ranked in the order of EGCG > ECG > TF, and the interactions were spontaneous and exothermic. Ternary system studies showed that the presence of one component hindered the binding of another component to HSA. The secondary structures of HSA were slightly altered in the presence of the ligands. Site marking experiments and molecular docking showed that EGCG and ECG mainly bound to subdomain IIA and ΙΙΙA while TF bound to subdomain ΙΙA and ΙB. Results indicated that the existence of ECG and EGCG would influence the binding of TF to HSA and can increase the free concentration of TF. Obtained results would provide beneficial information about possible interference upon simultaneous co-administration of the tea components and drugs.Communicated by Ramaswamy H. Sarma

Performance of closed-loop resuscitation of haemorrhagic shock with fluid alone or in combination with norepinephrine: an experimental study

BackgroundClosed-loop resuscitation can improve personalization of care, decrease workload and bring expert knowledge in isolated areas. We have developed a new device to control the administration of fluid or simultaneous co-administration of fluid and norepinephrine using arterial pressure.MethodWe evaluated the performance of our prototype in a rodent model of haemorrhagic shock. After haemorrhagic shock, rats were randomized to five experimental groups: three were resuscitated with fluid and two with co-administration of fluid and norepinephrine. Among groups resuscitated with fluid, one was resuscitated by a physician and two were resuscitated according to two different closed-loop algorithms. Among groups resuscitated with fluid and norepinephrine, one was resuscitated by a physician and the other one by the closed-loop device. The precision of arterial pressure during the resuscitation period was assessed using rising time, time passed in the target area and performance error calculations.ResultsGroups resuscitated with fluid had similar performances and passed as much time in the target area of 80–90 mmHg as the manual group [manual: 76.8% (67.9–78.2), closed-loop: 64.6% (45.7–72.9) and 80.9% (59.1–85.3)]. Rats resuscitated with fluid and norepinephrine using closed-loop passed similar time in target area than manual group [closed-loop: 74.4% (58.4–84.5) vs. manual: 60.1% (46.1–72.4)] but had shorter rising time to reach target area [160 s (106–187) vs. 434 s (254–1081)] than those resuscitated by a physician. Rats resuscitated with co-administration of fluid and norepinephrine required less fluid and had less hemodilution than rats resuscitated with fluid alone. Lactate decrease was similar between groups resuscitated with fluid alone and fluid with norepinephrine.ConclusionsThis study assessed extensively the performances of several algorithms for closed-loop resuscitation of haemorrhagic shock with fluid alone and with co-administration of fluid and norepinephrine. The performance of the closed-loop algorithms tested was similar to physician-guided treatment with considerable saving of work for the caregiver. Arterial pressure closed-loop guided algorithms can be extended to combined administration of fluid and norepinephrine.

Quetiapine prevents Aβ25-35-induced cell death in cultured neuron by enhancing brain-derived neurotrophic factor release from astrocyte.

β-Amyloid (Aβ)-induced neuronal toxicity is an early event in the pathogenesis of Alzheimer's disease. Quetiapine (QTP) is an atypical antipsychotic drug that has neuroprotectant properties, but little is known about its direct protective effects on neurons against the Aβ-induced cell toxicity. In the present study, we investigated the neuroprotective effects of QTP on Aβ25-35-induced cell death and the possible underlying mechanisms in primary cultures of neurons. Exposure of cortical neurons to 10 μM or more Aβ25-35 caused significant viability loss in a MTT assay, and the toxic effects were not significantly prevented by the simultaneous coadministration of QTP. However, pretreated astrocyte conditioned medium (ACM) with QTP (ACMQTP) for 24 h markedly protected the neurons against the amyloid-induced cell loss. Furthermore, we revealed that QTP increased both the release of brain-derived neurotrophic factor from cultured astrocytes and the phosphorylation of extracellular signal-regulated kinase after 24 h of treatment, which might be responsible for its protective effects on neurons. Consistent with the aforementioned findings, the protective effects of ACM on neurons could potentially be abolished by the extracellular signal-regulated kinase inhibitor and tropomyosin receptor kinase B receptor blocker. In conclusion, our data demonstrated that QTP exerted its neuroprotective effects against amyloid toxicity by enhancing the brain-derived neurotrophic factor release from astrocytes.

Influence of quercetin on the interaction of gliclazide with human serum albumin - spectroscopic and docking approaches.

Protein-binding interactions are displacement reactions which have been implicated as the causative mechanisms in many drug-drug interactions. Thus, the aim of presented study was to analyse human serum albumin-binding displacement interaction between two ligands, hypoglycaemic drug gliclazide and widely distributed plant flavonoid quercetin. Fluorescence analysis was used in order to investigate the effect of substances on intrinsic fluorescence of human serum albumin (HSA) and to define binding and quenching properties of ligand-albumin complexes in binary and ternary systems, respectively. Both ligands showed the ability to bind to HSA, although to a different extent. The displacement effect of one ligand from HSA by the other one has been described on the basis of the quenching curves and binding constants comparison for the binary and ternary systems. According to the fluorescence data analysis, gliclazide presents a substance with a lower binding capacity towards HSA compared with quercetin. Results also showed that the presence of quercetin hindered the interaction between HSA and gliclazide, as the binding constant for gliclazide in the ternary system was remarkably lower compared with the binary system. This finding indicates a possibility for an increase in the non-bound fraction of gliclazide which can lead to its more significant hypoglycaemic effect. Additionally, secondary and tertiary structure conformational alterations of HSA upon binding of both ligands were investigated using synchronous fluorescence, circular dichroism and FT-IR. Experimental data were complemented with molecular docking studies. Obtained results provide beneficial information about possible interference upon simultaneous co-administration of the food/dietary supplement and drug.

Da-Chaihu-Tang alters the pharmacokinetics of nifedipine in rats and a treatment regimen to avoid this.

To investigate the influence of co-administrated Da-Chaihu-Tang (DCT; a traditional Chinese formulation) on the pharmacokinetics of nifedipine, as well as the safe optimal dosing interval to avoid the adverse interactions. A single dose of DCT was administered with nifedipine simultaneously, 2 h before, 30 min before or 30 min after nifedipine administration. Pharmacokinetics of nifedipine with or without DCT were compared. The influences of DCT on nifedipine intestinal mucosal and hepatic metabolism were studied by using rat in-vitro everted jejunal sac model and hepatic microsomes. A simultaneous co-administration of DCT significantly increased the area under concentration-time curve from time zero to infinity (AUC0-inf ) of nifedipine. In-vitro mechanism investigations revealed that DCT inhibited both the intestinal and the hepatic metabolism of nifedipine. Further study on the optimal dosing interval for nifedipine and DCT revealed that administration of DCT 30 min before or after nifedipine did not significantly change the AUC of nifedipine. The bioavailability of nifedipine is significantly increased by a simultaneous oral co-administration of DCT. This increase is caused by the inhibitory effect of DCT on both the intestinal mucosal and the hepatic metabolism of nifedipine. The dose interval between DCT and nifedipine needs to be set for over 30 min to avoid such drug-drug interactions.

In Vitro and In Vivo Evaluation of the Effect of Puerarin on Hepatic Cytochrome P450-Mediated Drug Metabolism

Puerarin (8-β-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a major pharmacological component of Puerariae Radix, the root of Pueraria lobata. We investigated the effect of puerarin on hepatic cytochrome P450-mediated drug metabolism in rats and humans. The in vitro cytochrome P450 inhibitory effect of puerarin in human and rat liver microsomes was evaluated using the following model cytochrome P450 substrates: phenacetin for CYP1A, diclofenac for CYP2C, dextromethorphan for CYP2D, and testosterone for CYP3A. The in vivo pharmacokinetics of intravenous and oral buspirone, a probe substrate for CYP3A, was studied with single simultaneous intravenous coadministration of puerarin in rats. In the in vitro cytochrome P450 inhibition study, the rate of disappearance of testosterone was significantly reduced in the presence of 10 µM PU, while that of other cytochrome P450 substrates was not significantly affected in both human and rat liver microsomes, suggesting that puerarin inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and rat systems (IC50 = 15.5 ± 3.9 µM). After intravenous administration of buspirone with single simultaneous coadministration of intravenous puerarin at a dose of 10 mg/kg in rats, the total area under the plasma concentration-time curve from time zero to time infinity was increased while time-averaged total body clearance decreased. When buspirone was orally administered in rats with the 10 mg/kg intravenous puerarin coadministration, both total area under the plasma concentration-time curve from time zero to time infinity and the extent of absolute oral bioavailability were significantly increased. Therefore, results of the in vitro microsomal and in vivo pharmacokinetic studies suggest the possible inhibition of hepatic CYP3A-mediated drug metabolism by puerarin administration, potentially leading to metabolism-mediated herb-drug interactions with clinical significance.