Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease.

AIMS: This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease. METHODS: Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12. RESULTS: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. CONCLUSION: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.

A Phase 2a, Double-Blind, Placebo-controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma.

Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma.Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/µl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; n = 40) or placebo (n = 41). Inhaled corticosteroids and long-acting ß2-agonist were tapered down and then discontinued. The last four doses of AZD1419 were given without maintenance medication, followed by a 40-week observation period. Primary endpoint was time to loss of asthma control (LOC).Measurements and Main Results: AZD1419 induced a T-helper cell type 1-type IFN response with a sustained reduction in markers of type 2 inflammation. However, there were no statistically significant differences between AZD1419 and placebo for time to LOC, proportion of patients with LOC, changes in Asthma Control Questionnaire-five-item version, exacerbations, reliever use, FEV1, peak expiratory flow, or fractional exhaled nitric oxide (FeNO). LOC was predicted by an early rise in FeNO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 n = 11, placebo n = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419.Conclusions: AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on FeNO is possible for patients with well-controlled asthma.

Functionalized graphene oxide tablets for sample preparation of drugs in biological fluids: Extraction of ritonavir, a HIV protease inhibitor, from human saliva and plasma using LC-MS/MS.

In this work, graphene oxide-based tablets (GO-Tabs) were prepared by applying a thin layer of functionalized GO on a polyethylene substrate. The GO was functionalized with amine groups (-NH2 ) by poly(ethylene glycol)bis(3-aminopropyl) terminated (GO-NH2 -PEG-NH2 ). The functionalized GO-Tabs were used for the extraction of ritonavir (RTV) in human saliva samples. RTV in plasma and saliva samples was analyzed using LC-MS/MS. Gradient LC system with MS/MS in the positive-ion mode [electrospray ionization (ESI+)] was used. The transitions m/z 721 → 269.0 and m/z 614 → 421 were used for RTV and the internal standard indinavir, respectively. This study determined the human immunodeficiency virus protease inhibitor RTV in human saliva samples using functionalized GO-Tab and LC-MS/MS, and the method was validated. The standard calibration curve for plasma and saliva samples was constructed from 5.0 to 2000 nmol L-1 . The limit of detection was 0.1 nmol L-1 , and the limit of quantification was 5.0 nmol L-1 in both plasma and saliva matrices. The intra- and inter-assay precision values were found to be between 1.5 and 5.8%, and the accuracy values ranged from 88.0 to 108% utilizing saliva and plasma samples. The extraction recovery was more than 80%, and the presented functionalized GO-Tabs could be reused for more than 10 extractions without deterioration in recovery.

Vortex-assisted natural deep eutectic solvent microextraction using response surface methodology optimization for determination of orthophosphate in water samples by molybdenum blue method.

A new, rapid, and efficient microextraction technique named vortex-assisted natural deep eutectic solvent microextraction has been developed for the preconcentration and determination of orthophosphate in real water samples. The method is based on the formation of the phosphomolybdenium blue complex followed by proposed microextraction procedure and subsequent spectrophotometric determination in a microcell. Screening study for the optimal composition of natural deep eutectic solvent was initially performed with different solvents, including choline chloride as hydrogen bond acceptor and different hydrogen bond donors. A ternary mixture of glucose-choline chloride-water was used as the most efficient extraction solvent. Response surface methodology based on the central composite design was used to optimize experimental parameters. Under optimal conditions, the calibration graph for orthophosphate determination was linear over the range of 2.0-80.0 µg/L (correlation coefficient of 0.9971) with a detection limit of 0.2 µg/L. The repeatability, reproducibility, and relative error values of the method were below 7%, indicating acceptable precision and accuracy. This approach, using natural deep eutectic solvent as an eco-friendly solvent with high solubilization power and vortex mixing as an alternative energy source, represents a promising choice for a green separation and preconcentration methodology for determination of orthophosphate in real water samples.

Graphene Oxide Tablets for Sample Preparation of Drugs in Biological Fluids: Determination of Omeprazole in Human Saliva for Liquid Chromatography Tandem Mass Spectrometry.

In this study, a novel sort of sample preparation sorbent was developed, by preparing thin layer graphene oxide tablets (GO-Tabs) utilizing a mixture of graphene oxide and polyethylene glycol on a polyethylene substrate. The GO-Tabs were used for extraction and concentration of omeprazole (OME) in human saliva samples. The determination of OME was carried out using liquid chromatography-tandem mass spectrometry (LC⁻MS/MS) under gradient LC conditions and in the positive ion mode (ESI+) with mass transitions of m/z 346.3→198.0 for OME and m/z 369.98→252.0 for the internal standard. Standard calibration for the saliva samples was in the range of 2.0⁻2000 nmol L-1. Limits of detection and quantification were 0.05 and 2.0 nmol L-1, respectively. Method validation showed good method accuracy and precision; the inter-day precision values ranged from 5.7 to 8.3 (%RSD), and the accuracy of determinations varied from -11.8% to 13.3% (% deviation from nominal values). The extraction recovery was 60%, and GO-Tabs could be re-used for more than ten extractions without deterioration in recovery. In this study, the determination of OME in real human saliva samples using GO-Tab extraction was validated.

Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples.

This study presents the use of molecularly imprinted polymer (MIP) as packing material for microextraction by packed syringe (MEPS) to achieve higher extraction selectivity. Pentycaine was used as template for MIP. Development and validation of the determination of lidocaine, ropivacaine, mepivacaine and bupivacaine in human plasma and urine samples utilizing MIP-MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. The MEPS MIP-cartridge could be used for 100 extractions before it was discarded. The extraction recovery ranged from 60 to 80%. The correlation coefficients values were >0.999 for all assays using lidocaine, ropivacaine, mepivacaine and bupivacaine in the calibration range 5-2000 nmol/L. The accuracy of the studied compounds, given as a percentage variation from the nominal concentration values, ranged from -4.9 to 8.4% using plasma and urine samples. The between-batch precision, given as the relative standard deviation, at three different concentrations (quality control samples) was ranged from -4.7 to 14.0% and from 1.8 to 12.7% in plasma and urine, respectively. The lower limit of quantification and limit of detection of the studied substances were 5.0 and 1.0 nm, respectively.

Opinion and Sentiment Analysis of Palliative Care in the Era of COVID-19.

During the COVID-19 pandemic, the value of palliative care has become more evident than ever. The current study quantitatively investigated the perceptions of palliative care emerging from the pandemic experience by analyzing a total of 26,494 English Tweets collected between 1 January 2020 and 1 January 2022. Such an investigation was considered invaluable in the era of more people sharing and seeking healthcare information on social media, as well as the emerging roles of palliative care. Using a web scraping method, we reviewed 6000 randomly selected Tweets and identified four themes in the extracted Tweets: (1) Negative Impact of the Pandemic on Palliative Care; (2) Positive Impact of the Pandemic on Palliative Care; (3) Recognized Benefits of Palliative Care; (4) Myth of Palliative Care. Although a large volume of Tweets focused on the negative impact of COVID-19 on palliative care as expected, we found almost the same volume of Tweets that were focused on the positive impact of COVID-19 on palliative care. We also found a smaller volume of Tweets associated with myths about palliative care. Using these manually classified Tweets, we trained machine learning (ML) algorithms to automatically classify the remaining tweets. The automatic classification of Tweets was found to be effective in classifying the negative impact of the COVID-19.

Deep eutectic solvent based ultrasound assisted emulsification microextraction for preconcentration and voltammetric determination of aflatoxin B1 in cereal samples.

A new and simple deep eutectic solvent based ultrasound-assisted emulsification microextraction (DES-UAEME) procedure has been developed for preconcentration and voltammetric determination of aflatoxin B1 (AFB1) in cereal products. The method is based on the acetonitrile-based extraction of AFB1 from homogenized cereal samples followed by a DES-UAEME procedure for subsequent differential pulse voltammetry (DPV) determination in a microcell. A DES composed of choline chloride and urea (ChCl-Ur) was used as the extraction solvent and electrolyte for DPV detection. Various parameters affecting the extraction efficiency of AFB1 were evaluated and optimized. Under optimum conditions the calibration graph was linear in the range of 0.2-80.0 µg L-1 (R2 = 0.9966) and the limit of detection (3Sb) was estimated to be 0.05 µg L-1. The intra-day and inter-day precision (RSD%) for determination of 5.0 µg L-1 AFB1 were 3.4% and 3.9%, respectively. The proposed method was also successfully applied for preconcentration and determination of AFB1 in different cereal samples and good relative recoveries were obtained over a range of 94 to 104%.

Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials.

BACKGROUND: Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. METHODS: Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. FINDINGS: In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0-4h) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237). INTERPRETATION: AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. FUNDING: AstraZeneca.

Synthesis of chitosan based magnetic molecularly imprinted polymers for selective separation and spectrophotometric determination of histamine in tuna fish.

A novel chitosan molecularly imprinted polymers (CHI/MIPs) coated on Fe3O4 magnetic nanoparticles (MNPs) for selective solid phase extraction (SPE) of histamine (His) was synthesized by cross-linking of CHI with (3-Glycidyloxypropyl) trimethoxysilane (GPTMS) in the presence of His as the template molecule, and GPTMS/MNPS. Synthesized sorbent was characterized by scanning electron microscopy, X-ray diffraction, FT-IR and via adsorption kinetics and adsorption isotherms. The application of this sorbent was investigated in preconcentration and spectrophotometric determination of His by charge transfer complexation. The method is based on the adsorption of His on CHI/MMIPs and subsequent reaction of desorbed His with 2,3-Dichloro 5,6-dicyano-p-benzoquinone (DDQ) reagent for final spectrophotometric detection. The experimental parameters affecting separation efficiency and spectrophotometric determination were optimized. Under optimum conditions and at an analytical wavelength of 468nm, the calibration plot is linear in the 5.0-160.0ngmL-1 concentration range, and the limit of detection (estimated at S/N=3) is 1.5ngmL-1. The intra-day and inter-day precisions are in the range from 2.9 to 4.1%. The method was successfully applied for determination of His in spiked tuna fish samples where it gave recoveries ranging from 94.3 to 107.0%.

Novel carboxymethyl cellulose-polyvinyl alcohol blend films stabilized by Pickering emulsion incorporation method.

The aim of this study was to investigate the possibility of increasing the antimicrobial and antioxidant properties of biodegradable active films stabilized via Pickering emulsions. The blend films were prepared from carboxymethyl cellulose (CMC) and polyvinyl alcohol (PVA), emulsified with oleic acid (OL) and incorporated with rosemary essential oil (REO). Formation of Pickering emulsion was confirmed by scanning electron microscopy (SEM), optical microscopy, mean droplet size and emulsion stability. Morphological, optical, physical, mechanical, thermal, antifungal and antioxidant properties of the films incorporated with different concentrations of REO (0.5, 1.5 and 3%) were determined. The results showed an increase in UV absorbance and elongation at break but, a decrease in tensile strength and thermal stability of the films. Interestingly, films containing REO exhibited considerable antioxidant and antimicrobial properties. In vitro microbial tests exhibited 100% fungal inhibition against Penicillium digitatum in the films containing 3% REO. In addition, no fungal growth were observed after 60days of storage at 25°C in bread slices were stored with active films incorporated with 3% REO, could attributed to the slow and regular release of REO caused by Pickering emulsions. The results of this study suggest that Pickering emulsion is a very promising method, which significantly affects antioxidant and antimicrobial activities of the films.

Preparation and characterization of active emulsified films based on chitosan-carboxymethyl cellulose containing zinc oxide nano particles.

Active nanocomposites based on carboxymethyl cellulose-chitosan-oleic acid (CMC-CH-OL) incorporated with different concentrations (0.5-2wt.%) of zinc oxide nanoparticles (ZnO NPs) were produced by casting method. The effects of ZnO NPs on the morphological, mechanical, thermal, physical and antifungal properties of the films were studied. New interaction between ZnO NPs and polymer matrix were confirmed by Fourier Transform infrared. After addition of ZnO NPs, tensile strength, lightness (L*) and thermal stability decreased however, elongation at break, contact angle, a* (greenness) and b* (yellowness) of the nanocomposite films increased in comparison to the films without nano-filler. UV transmittance at 280nm decreased from 17.3% to 0.2, 0.1 and 0.1 for the nanocomposite films containing 0.5, 1 and 2wt.% ZnO NPs, respectively, suggesting higher UV blocking properties. Disc diffusion test showed considerable antifungal properties of the active nanocomposite films against Aspergillus niger, especially in CMC-CH-OL-ZnO 2wt.% by more than 40% fungal growth inhibition.

Influence of poly(ethylene glycol)-alpha-cyclodextrin complexes on stabilization and transdermal permeation of ascorbic acid.

The present study was conducted to investigate the effect of poly(ethylene glycol)-alpha-cyclodextrin (alpha-CD) complexes on stabilization and cutaneous permeation of ascorbic acid from specially prepared transdermal patches. Poly(ethylene glycol) citrate (6-armPEG) and its inclusion complex with alpha-CD were prepared and used for preparation of the transdermal patches. Duro-Tak 87-2979 was taken as an adhesive matrix in combination with ascorbic acid. A diffusion cell with an artificial membrane was used to evaluate the absorption of ascorbic acid from the patches. The influence of drug release of alpha-CD and two types of its PEG complexes (as the novel permeation enhancers) was tested. The 6-armPEG-alpha-CD complex consisting of a PEG-citric acid ester at a concentration of 0.08-0.1% (w/v) is a suitable stabilizer for ascorbic acid during UV assay. The release studies showed that the type of enhancer is important in diffusion of the drug across membrane. Furthermore, the diffusion of ascorbic acid was considerably enhanced in the presence of 6-armPEG-alpha-CD complex. Inclusion complexes of 6-armPEG with alpha-CD at a concentration of 0.08-0.1% (w/v) is a suitable stabilizer for UV method of assay. The present data suggest that 6-armPEG-alpha-CD complex is also useful in enhancing the release of ascorbic acid from the acrylic type pressure sensitive adhesives.

Synthesis and hydrolytic behavior of ibuprofen prodrugs and their PEGylated derivatives.

Polyethylene glycol (PEG) derivatives of ibuprofen were prepared by esterification of PEG monosuccinate with hydroxy ethyl ester (HEE), hydroxy ethylamide (HEA), and hydroxy ethyl thioester (HET) of ibuprofen. Hydrolysis of HEE-PEG, HEA-PEG, and HET-PEG were studied in vitro with or without esterases to investigate the applicability of these PEGylated prodrugs. The polymeric prodrugs released major fraction of the parent drug (ibuprofen) and a small fraction of hydroxy ethyl derivatives after 48 hr. In HET-PEG, the amount of drug release was higher than HEE-PEG and HEA-PEG. The difference between acidic and alkali buffered solutions was considerable. In human plasma, 50% of drug was released after 150 hr incubation at 37 degrees C from HET-PEG.

Liquid-phase microextraction of organophosphorus pesticides using supramolecular solvent as a carrier for ferrofluid.

A liquid-phase microextraction based on application of supramolecular solvent as a carrier for ferrofluid has been developed for the extraction and determination of three organophosphorus pesticides (OPPs). The ferrofluid was produced from combination of oleic acid coated magnetic particles and supramolecular solvent as the extractant solvent. Ferrofluid can be attracted by a magnet, and no centrifugation step was needed for phase separation. A response surface methodology (RSM) based on central composite design (CCD) was used for efficient optimization of the main variables in the extraction procedure. Under the optimum experimental conditions, the calibration curves found to be linear in the range of 0.5-400µgL(-1) with correlation coefficients ranging from 0.9967 to 0.9984. The intra-day and inter-day precision (RSD %) for 100 and 200µgL(-1) of each pesticides were in the range of 2.0-5.3% and 2.6-5.7%, respectively. The limit of detection (S/N=3), ranged from 0.1 to 0.35µgL(-1). The proposed method was successfully applied to the extraction and determination of organophosphorus pesticide residues in water and fruit juice samples.

Synthesis and hydrolytic behaviour of 2-mercaptoethyl ibuprofenate-polyethylene glycol conjugate as a novel transdermal prodrug.

Thiolated derivatives of ibuprofen and its polyethylene glycol ester were synthesized via condensation of 2-mercaptoethyl ibuprofenate with carboxy-terminated polyethylene glycol. The release of ibuprofen from this polymeric prodrug has been studied under conditions simulating those encountered in the skin. The polymeric prodrug of ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 4 to 23.9% hydrolysis at pH 8.5 (15% at pH 7.4) after 48 h at 37 degrees C. The polymer-drug conjugate was subjected to enzymatic hydrolysis in human plasma. The polymer showed considerable enzymatic hydrolysis (68% after 48 h). The results showed that the polymeric prodrug model of non-steroidal anti-inflammatory drugs (NSAIDs) described here can be used in topical formulations of NSAIDs. It is expected that the novel thiol derivative will have both enhanced transdermal penetration and stability to oxidation which make it a suitable candidate for transdermal formulations.