Steady Concentration Research Articles

Review on Transdermal Drug Delivery System

Transdermal drug delivery system is an essential part of novel drug distribution system. The topically administered medications in the form of patches which when applied to the skin deliver the drug .For operative TDDS the drug are easily able to penetrate the skin and easily reach the target site. TDDS avoids the first pass metabolism, less frequency of administration, reduction gastrointestinal side effects. Adverse effects are minimized due to steady and optimum blood concentration. It has greater bioavailability and efficacy of drug. The human skin is multi-layered organ composed of many histological layers. Skin is the largest organ in the body. Its major functions are protection of major or vital internal organs for the external influences, temperature regulations, control of water output and sensation. Polymer should be chemically non-reactive, should not decompose on storage, should be non-toxic, cost should not be high. E.g. - cellulose derivatives, zein, gelatin etc. Backing films play a vital role in the transdermal patch and the role of the film is to protect the active layer. Transdermal patches can be evaluated by interaction studies thickness, weight uniformity, drug content, in vitro study,moisture content, swelling index basic component of TDDS.

Development of physiologically-based gut absorption model for probabilistic prediction of environmental chemical bioavailability.

Absorption in the gastrointestinal tract is a key factor determining the bioavailability of chemicals after oral exposure but is frequently assumed to have a conservative value of 100% for environmental chemicals, particularly in the context of high-throughput toxicokinetics for in vitro-to-in vivo extrapolation (IVIVE). For pharmaceutical compounds, the physiologically based advanced compartmental absorption and transit (ACAT) model has been used extensively to predict gut absorption but has not generally been applied to environmental chemicals. Here we develop a probabilistic environmental compart­mental absorption and transit (PECAT) model, adapting the ACAT model to environmental chemicals. We calibrated the model parameters to human in vivo, ex vivo, and in vitro datasets of drug permeability and fractional absorption by con­sidering two key factors: (1) differences between permeability in Caco-2 cells and in vivo permeability in the jejunum, and (2) differences in in vivo permeability across different gut segments. Incorporating these factors probabilistically, we found that given Caco-2 permeability measurements, predictions of the PECAT model are consistent with the (limited) available gut absorption data for environmental chemicals. However, the substantial chemical-to-chemical variability observed in the cal­ibration data often led to wide probabilistic confidence bounds in the predicted fraction absorbed and resulting steady state blood concentration. Thus, while the PECAT model provides a statistically rigorous, physiologically based approach for incor­porating in vitro data on gut absorption into toxicokinetic modeling and IVIVE, it also highlights the need for more accurate in vitro models and data for measuring gut segment-specific in vivo permeability of environmental chemicals.

Impacts of atmospheric CO2 increase and Amazon deforestation on the regional climate: A water budget modelling study

AbstractGlobal air temperature increase has caused changes in the global climate such as droughts, floods and severe events. Land cover shifts and the increase in greenhouse gas emissions can intensify these impacts. Therefore, the application of Specific Warming Level 2 (SWL2) technique has been considered to evaluate the global warming issue in various climate scales, which may induce different responses in the climate system. The objective of this study is to evaluate the impacts of a doubling of current atmospheric CO2 concentrations as well as the influence of deforestation of the Amazon Forest on the climate of South America. In this study, the CPTEC‐BAM1.2 global model was used to simulate these processes. The first scenario of simulations considered doubled atmospheric CO2 concentration (2XCO2 = 776 ppm) and the second scenario is the total conversion of the Amazon Forest to pasture (DEF). In the third scenario both CO2 and deforestation are considered simultaneously (2XCO2 + DEF). A control simulation considers the natural Amazon Forest shape and a steady CO2 concentration of 388 ppm. Results suggest that the temperature increased in all scenarios, the highest increment in the 2XCO2 + DEF experiment (5.4°C in 2XCO2 + DEF, 5.1°C in DEF and 3.2°C in 2XCO2). The model simulated drastic negative rainfall anomalies in each of three scenarios (2XCO2 + DEF: −2.1 mm day−1, 2XCO2: −1.3 mm day−1 and DEF: −0.9 mm day−1). Besides less precipitation and evapotranspiration, shifts in moisture transport were identified in each of the three scenarios. The effect of doubled atmospheric CO2 produces results similar to deforestation for hydrological water budget changes, and total pasture conversion may intensify such changes.

To ascertain the plasma concentration of propofol to achieve bispectral index-guided sedation using a target-controlled infusion in patients undergoing elective surgeries under neuraxial anaesthesia.

Sedation improves patient satisfaction, comfort and acceptance of regional anaesthesia. Propofol using bispectral index (BIS)/target-controlled infusion (TCI) system can be an optimal method of sedation, as it combines objective measurement of sedation using BIS along with maintenance of a steady plasma concentration of propofol with the TCI device. The aim of this study was to ascertain the dose and safety of propofol using BIS/TCI system for sedation in patients undergoing surgeries under neuraxial anaesthesia. One hundred and seven adult patients, undergoing elective surgical procedures under spinal or combined spinal epidural anaesthesia, were recruited. Propofol infusion was started with TCI at an initial target plasma concentration (Cpt) of 1.2 μg/mL, and after equilibration between Cpt and effect site concentration (Ce), propofol was then adjusted in increments and/or decrements of 0.2 μg/mL in order to maintain a BIS value between 60 and 80. The average time to reach BIS = 80 after starting infusion was 7.32 ± 3.13 minutes. The objective was to calculate mean Cpt value maintaining BIS between 60 and 80 and to observe recovery time and complications. Mean Cpt value was 1.13 ± 0.17 mg/mL with 95% confidence interval (1.10-1.16 μg/mL). In 85% of patients, a BIS value of 60-80 was maintained at Cpt ≤ 1.2 μg/mL. No patient had severe complications requiring stoppage of infusion. Propofol sedation using BIS/TCI system can provide safe and convenient sedation during neuraxial anaesthesia at very low plasma concentration, Cpt ≤ 1.2 μg/mL in majority of patients. There were no periprocedural complications, and recovery was rapid.

Multiparametric Magnetic Resonance Imaging and Metabolic Characterization of Patient-Derived Xenograft Models of Clear Cell Renal Cell Carcinoma.

Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are needed to evaluate novel imaging and therapeutic approaches targeting metabolism. We characterized 5 PDX from high-grade or metastatic ccRCC by multiparametric magnetic resonance imaging (MRI) and steady state metabolic profiling and flux analysis. Similar to MRI of clinical ccRCC, T2-weighted images of orthotopic tumors of most PDX were homogeneous. The increased hyperintense (cystic) areas observed in one PDX mimicked the cystic phenotype typical of some RCC. The negligible hypointense (necrotic) areas of PDX grown under the highly vascularized renal capsule are beneficial for preclinical studies. Mean apparent diffusion coefficient (ADC) values were equivalent to those of ccRCC in human patients. Hyperpolarized (HP) [1-13C]pyruvate MRI of PDX showed high glycolytic activity typical of high-grade primary and metastatic ccRCC with considerable intra- and inter-tumoral variability, as has been observed in clinical HP MRI of ccRCC. Comparison of steady state metabolite concentrations and metabolic flux in [U-13C]glucose-labeled tumors highlighted the distinctive phenotypes of two PDX with elevated levels of numerous metabolites and increased fractional enrichment of lactate and/or glutamate, capturing the metabolic heterogeneity of glycolysis and the TCA cycle in clinical ccRCC. Culturing PDX cells and reimplanting to generate xenografts (XEN), or passaging PDX in vivo, altered some imaging and metabolic characteristics while transcription remained like that of the original PDX. These findings show that PDX are realistic models of ccRCC for imaging and metabolic studies but that the plasticity of metabolism must be considered when manipulating PDX for preclinical studies.

Evaluation of N-alkanes as Faecal Markers to Estimate Diet Composition, Feed Intake, and Digestibility in European Bison (Bison bonasus)

There is a lack of knowledge on the European bison (Bison bonasus L. 1758) foraging behavior that is essential to develop an appropriate feeding strategy for each specific situation (captive or wild). Utilization of faecal markers may allow us to fill this gap, accommodating animal welfare and intensive labour issues that are major limitations of traditional techniques. This study aimed to evaluate the potential of n-alkane markers (C25 to C33) to estimate diet composition, feed intake its digestibility on three captive maleBison bonasus fed on known amounts of straw, and a beeswax labelled concentrate feed. Feeds and faecal samples were taken daily during 10 days. Prior to calculations, faecal concentrations were corrected for incomplete faecal recovery (FR). Results indicated that 4–5 days were sufficient for these markers to reach a steady concentration in bison faeces. Accurate estimates of diet composition and feed intake were obtained not differing from known values. Results suggest that faecal recovery of n-alkanes in bison are incomplete and tend to increase with carbon-chain length. Apparent dry-matter digestibility (DMDap) estimates were affected by the n-alkane (C27, C29,C31, and C33) used in the calculations. Estimates of DMDap obtained with application of FR corrections were 6.3% higher than those without correction. Results indicate that feeding a known amount of beeswax labelled supplement can be successfully used to estimate composition, feed intake, and its digestibility, requiring the application of n-alkane FR data.

Application of a count data model to evaluate the anti-metastatic efficacy of QAP14 in 4T1 breast cancer allografts

Dopamine D1 receptor (D1DR) is proved to be a promising target to prevent tumor metastasis, and our previous studies showed that QAP14, a potent anti-cancer agent, exerted inhibitory effect on lung metastasis via D1DR activation. Therefore, the purpose of the study was to establish count data models to quantitatively characterize the disease progression of lung metastasis and assess the anti-metastatic effect of QAP14. Data of metastatic progression were collected in 4T1 tumor-bearing mice. Generalized Poisson distribution best described the variability of metastasis counts among the individuals. An empirical PK/PD model was developed to establish mathematical relationships between steady plasma concentrations of QAP14 and metastasis growth dynamics. The latency period of metastasis was estimated to be 12 days after tumor implantation. Our model structure also fitted well to other D1DR agonists (fenoldopam and l-stepholidine) which had inhibitory impact on breast cancer lung metastasis likewise. QAP14 40 mg/kg showed the best inhibitory efficacy, for it provided the longest prolongation of metastasis-free periods compared with fenoldopam or l-stepholidine. This study provides a quantitative method to describe the lung metastasis progression of 4T1 allografts, as well as an alternative PD model structure to evaluate anti-metastatic efficacy.

PSXIII-B-18 Temporal Expression of Interleukin 6: Myokine Protein Abundance in Primary Bovine Satellite Cells from 11-Month-old Beef Steers

Abstract Myokine abundance and function have not been thoroughly evaluated in beef cattle. Many myokines have been shown to have a substantial impact on the health and well-being of mammals. While interleukin 6 (IL-6) is a known immune cytokine, it is also classified as a myokine and in mice is produced from muscle contraction post-exercise. IL-6 is linked to muscle hypertrophy through the action of increasing glucose uptake and stimulating satellite cell proliferation. The objective of this study is to characterize temporal IL-6 production by cultured primary bovine satellite cells (BSCs) in 11-month-old beef steers. IL-6 abundance was quantified in in vitro cultured undifferentiated primary BSCs isolated from 11-month-old steers. This experiment had 3 experimental replicates where cells were plated in triplicate with 10% Fetal Bovine Serum in DMEM. At 70% confluency the growth media was changed, and this was classified as time zero. The media then remained unchanged and was collected temporally at 0, 12, 24, and 48 hours. Media was assayed using Bovine IL-6 ELISA’s to quantify myokine abundance. Cells were also harvested for mRNA extraction and analyses at a future time. We are in the initial stages of the analyses, though preliminary data indicate no difference in IL-6 abundance between the BSC pools isolated from different steers. Temporally, we report that at hour 0 there is undetectable IL-6 concentration, but at 12, 24, and 48 hours there is a steady concentration of IL-6 released into the growth media by the BSCs. This confirms that IL-6 is being produced by BSCs from post-weaned, beef steers. We conclude that myokine; IL-6 is involved in post-natal skeletal muscle growth of beef cattle.

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

IntroductionExposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. MethodsThis was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22–26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2–4 months) of the boosting effect. ResultsThe mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%–192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. ConclusionPharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation.

The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at Cmax, Ctrough, and Caverage, or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.

Graphene Oxide and Metal-Organic Framework-Based Breathable Barrier Membranes for Toxic Vapors.

Garments protective against chemical warfare agents (CWAs) or accidently released toxic chemicals must block the transport of toxic gases/vapors for a substantial time and allow moisture transport for breathability. These demands are challenging: either the barriers block CWAs effectively but have poor breathability or barriers have excellent breathability but cannot block CWAs well. Existing protective garments employ large amounts of active carbon, making them quite heavy. Metal-organic framework (MOF)-based adsorbents are being investigated as sorbents for CWAs. Breathable laminate of graphene oxide (GO) flakes supported on a porous membrane reduces permeation rates of CWA simulants substantially. We developed a multilayered membrane-based flexible barrier: GO laminate-based membrane over a MOF nanocrystal-filled expanded polytetrafluorethylene (ePTFE) membrane having submicrometer pores. The GO laminate-based layer developed a steady breakthrough concentration level almost 2 orders of magnitude below the usual breakthrough level. This highly reduced level of CWA was blocked by the MOF nanocrystal-filled membrane substrate layer over a highly extended period. We demonstrated the blocking of CWAs, mustard (HD), soman (GD), a sarin simulant [dimethyl methyl phosphonate (DMMP)], and ammonia for an extended period while the moisture transmission rate was substantial. The times for complete blockage of ammonia, HD, GD, and DMMP were 2750 min, 1075 min, 176 min, and 7 days, respectively. This remarkable performance resulted from a very low steady-state penetrant permeation through GO-laminate membrane and substantial penetrant sorption by MOF nanocrystals; furthermore, both layers show high moisture vapor transmission.

Bioanalytical Method Development and Validation of Levetiracetam, Pantoprazole and Therapeutic Activity of Levetiracetam

Background: Levetiracetam is an antiepileptic drug prescribed in the treatment of patients with seizures. This study aimed to develop a bioanalytical (HPLC) high­ performance liquid chromatography method for monitoring drug plasma levels in subjects with levetiracetam and pantoprazole as comedication.
 Method: A Bioanalytical Method Development and Validation were done through High­ Performance Liquid Chromatography was developed to analyze the plasma level concentration of levetiracetam in subjects. The plasma concentrations were analyzed in 65 epileptic subjects given 250 to 1000 mg/dose of levetiracetam ranging in males 4550.72ng/mL and females 2586.48ng/mL. 
 Results: The validation parameters were processed as ICH guidelines with linearity of levetiracetamwhereY=57.978X+6.6141andforpantoprazoleY=20.047X+102followedwith Inter dayandintradayprecisionon250ng/ml,450ng/ml,650ng/mlforlevetiracetamwhere
 %RSD are 0.02,0.09,0.03,0.02,0.07 and 0.02 respectively, where the pantoprazole %RSD are 0.05,0.02,0.01,0.02,0.05, and0.03respectively. Therapeutic Drug Monitoring for levetiracetam with pantoprazole as comedication showed significant results where the mean serum concentration for 65 subjects who undergoing medication for period of time with achieved steady state serum concentration. The therapeutic range was found to be 25 male and 12 female subjects, further 28 subjects of both genders were under sub-therapeutic activity with no dose correction requirement.
 Conclusion: The method proposed to measure levetiracetam concentration was convenient, reproducible, and specific. Therefore, randomized, controlled studies in a larger population are awaited with a wide range of dosing (250­1000mg) to correlate with the total serum concentration of the population and multiple comedications for dose adjustments to maintain the maximum safe concentration in the subject.

A sensitive and robust bioanalytical assay for pharmacokinetic analysis of ROR1xCD3 bispecific T cell engager (NVG-111) in a first-in-human study.

e19505 Background: Receptor tyrosine kinase-like Orphan Receptor-1 (ROR1) is widely expressed on hematological and solid tumors. NVG-111, a first in class humanized tandem scFv ROR1xCD3 bispecific antibody elicits potent killing of ROR1+ tumor cells in vitro and in vivo. This bispecific T-cell engager (TCE) is being evaluated in a first in human, Phase I trial in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The predicted therapeutic dose and steady state serum concentrations of NVG-111 were estimated by allometric scaling using relevant doses from a murine PK study. To assess free drug levels in patients following 21 days of continuous infusion of NVG-111, a bespoke, sensitive pharmacokinetics (PK) assay with high levels of specificity and sensitivity was developed. Methods: Anti-idiotype (anti-ID) antibodies directed to anti-ROR1 (αROR1-ID) and anti-CD3 (αCD3-ID) were generated by mouse immunization or by phage display from customized libraries. A proof-of-concept sandwich ELISA assay was developed using αCD3-ID to capture NVG-111 and detection by biotinylated hROR1-streptavidin-HRP. Gyrolab and Quanterix Simoa high sensitivity ELISA platforms were used to detect NVG-111 by αCD3-ID capture and αROR1-ID detection. The mesoscale discovery electrochemiluminescence assay (MSD-ECLA) was developed using a reversed format; NVG-111 capture with αROR1-ID and detection with αCD3-ID. Results: Allometric scaling predicted a theoretically relevant therapeutic dose and steady state serum concentration of 1ng/mL NVG-111 in humans, which was just at the level of sensitivity of a conventional ELISA under non-matrix conditions. Transferring the format to Quanterix Simoa had limited success due to high background levels in all configurations evaluated. The Gyrolab platform increased sensitivity to 75pg/mL, but suboptimal individual human sera matrix selectivity limited assay validity. Assessment of MSD-ECLA provided the best signal/noise, enhanced human disease and healthy sera selectivity, and a dynamic sensitivity range of 250pg/mL to 32ng/mL, which enabled the development of a GCLP qualified PK assay. The MSD-ECLA assay was employed to measure NVG-111 concentrations in CLL or MCL subjects dosed with 0.3-30µg/day NVG-111. MSD-ECLA detected drug in patients receiving NVG-111, with a range of steady-state serum concentrations (Cavg.ss) of 168-610pg/mL. This was in-line with the predicted drug levels from the single species allometric scaling, albeit with observed levels being marginally lower than expected. Conclusions: Development, custom optimization and validation of a highly sensitive MSD-ECLA PK assay has enabled GCLP-compliant measurement of circulating NVG-111 in CLL or MCL patients treated with at least 10µg/day cIV NVG-111.

New long-acting injectable microspheres prepared by IVL-DrugFluidic™ system: 1-month and 3-month in vivo drug delivery of leuprolide

The microspheres for 1-month (PLGA-based) and 3-month (PLA-based) drug releases of leuprolide were manufactured using an IVL-DrugFluidic™ system and their morphology, particle size and distribution, and encapsulation efficiency were compared with the commercialized products. In vivo test was also conducted to monitor the amount of leuprolide and testosterone in plasma after a single subcutaneous injection in male Sprague–Dawley (SD) rats and male Beagle dogs. The median diameter, span value, drug loading, and encapsulation efficiency of PLGA-based microspheres (63.29 μm, 0.26, 13.15%, and 78.90%, respectively) and PLA-based microspheres (80.28 μm, 0.21, 14.42%, and 86.50%, respectively) demonstrated narrow particle size distribution (monodispersed) and efficient drug loading/encapsulation efficiency. Both the microspheres exhibited a desired time-dependent drug release profile and reduced initial burst release by 16-fold in SD rats and 240-fold in Beagle dogs compared to Leuplin DPS®. Moreover, the testosterone level in plasma was suppressed to < 0.50 ng/mL after 28 days with a steady plasma drug concentration. The results suggested that newly developed leuprolide-loaded microspheres produced by the IVL-DrugFluidic™ system could provide extended drug release with advantages such as reduced initial burst release and testosterone level suppression, along with steady plasma drug concentration, over the existing products.

Low-density lipoprotein cholesterol increased significantly after short-term discontinuation of atorvastatin, but did not correlate with plasma drug concentrations

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Dam foundation Introduction Statin non-adherence remains a prevalent challenge in cardiovascular disease prevention and robust methods to monitor adherence are needed. Large variations in low-density-lipoprotein cholesterol (LDL-C) response to a given type and dose of statin have been reported. The LDL-C response to short-term discontinuation of statins is not well defined. Moreover, the relationship between the blood concentrations of statin metabolites and LDL-C, and how clinical factors interact, are unknown. Purpose To determine changes in LDL-C at an individual and group level during four-day discontinuation of atorvastatin, and to investigate whether clinical factors and atorvastatin metabolites concentration correlate with changes in LDL-C. Methods This clinical pharmacokinetic adherence study conducted in 2021, included 60 adult participants treated with atorvastatin 20 mg (n=20), 40 mg (n=20) or 80 mg (n=20). The participants were instructed to take atorvastatin daily between 07 and 10 am the week before study start, to ensure steady state drug concentrations. The last dose of atorvastatin was taken 24 hours prior to the first blood sampling (day zero). Atorvastatin doses were omitted until after blood sampling on the fourth day. The concentrations of atorvastatin metabolites (acid and lactone forms, including 2-OH- and 4-OH metabolite) were measured by a liquid chromatography–tandem mass spectrometry assay. Paired-samples T-tests, Spearman rank correlations and linear regression analyses were performed with SPSS. Results Mean age was 65 (SD 11) years, 18 (30%) were female, 45 (75%) had cardiovascular disease and 11 (18%) had diabetes mellitus. Mean LDL-C at steady state on day zero was 1.9 (SD 0.6) mmol/L. LDL-C increased on average by 0.5 (SD 0.3) mmol/L (30%) from day zero to day four, during the period with atorvastatin discontinuation. The increase of LDL-C was significant already after the first omitted dose (day one) (Figure 1). LDL-C increased from day zero to day four in 78 out of the 80 patients (97.5%). Higher Body Mass Index was significantly associated with lager increase in LDL-C during the four-day discontinuation (B 0.02, 95% CI 0.01 to 0.04, p=0.028), whereas age, sex, kidney function, cardiovascular disease and diabetes were not. Changes in atorvastatin plus metabolites concentration from day zero to day four were not associated with changes in LDL-C during discontinuation (Figure 2). This also applied if we assessed the individual atorvastatin metabolites. Conclusion Atorvastatin discontinuation for only four days resulted in a statistically significant 30% increase of LDL-C. Atorvastatin pharmacokinetics did not correlate with change in LDL-C during the discontinuation. Even short-term non-adherence may have unfavourable consequences, and deserves further attention.

Formulation and evaluation of sustained release tablets of propranolol hydrochloride

The main objective of sustained release drug delivery system is to provide a steady state blood plasma level concentration which is non-toxic and therapeutically active for a longer period of time. Owing its increased patient compliance and prolonged release of action in delivering drugs several benefits can be contemplated in delivering of sustained release dosage form[1]. Among various route of drug delivery Sustained release drug delivery is most widely preferred as it’s less frequency of dosing and controls the release of drugs. Natural polymers are biodegradable and nontoxic in nature with reduced side effects. It is also eco-friendly and safe to be administered as compared to synthetic polymers. The current work was based on preparation of sustained release tablets of Propranolol Hydrochloride using natural polymers like Gum Acacia, Hibiscus Rosasinesis and Microcrystalline cellulose. Presently much attention is being paid for formulation of sustained release tablets that contains matrix system. Direct compression method was used for formulation of sustained release tablets of Propranolol Hydrochloride. The prepared tablets were evaluated for different pre-formulation studies and in vitro dissolution studies were performed using USP-III dissolution apparatus. Dissolution studies of different formulations were evaluated for 24 hours at 370C.

Effects of combination treatment with metformin and berberine on hypoglycemic activity and gut microbiota modulation in db/db mice

BackgroundGut microbiota alterations could influence the metabolism of administered drugs, leading to their altered pharmacokinetics and pharmacodynamics. Despite that metformin and berberine has individually demonstrated their impacts on hypoglycemic activities and gut microbiota alterations in diabetic mice, investigation regarding the impact of their combination treatment in diabetic treatment has never been conducted. PurposeOur current study was proposed aiming to investigate the effect of combination use of metformin with berberine on hypoglycemic activity and identify the possible intestinal bacteria involved in their microbiota-medicated drug-drug interactions in db/db mice. Study DesignPharmacodynamics interactions between metformin and berberine were evaluated in six groups of db/db mice (db, M250, B250, B125, B250+M250, and B125+M250) with its wild type (WT) as control to receive 14 days treatment of vehicle, metformin at 250 mg/kg, berberine at 250/125 mg/kg, and metformin (250 mg/kg) 2 h after dosing berberine (250/125 mg/kg). MethodsOn day 13, insulin tolerance test (ITT) was conducted. On day 15, fasting serum samples were obtained for insulin concentration determination followed by intraperitoneal glucose tolerance test (ipGTT), homeostatic model assessment for insulin resistance (HOMA-IR) calculation, and feces collection for microbial 16S rRNA sequencing analyses. In addition, metformin steady state plasma concentrations on day 15 were measured by validated LC-MS/MS method. ResultsCombination treatment of metformin with berberine could further reduce in blood glucose in comparison to that of db/db diabetic control. Further microbial 16S rRNA sequencing analyses revealed that gut microbiota compositions were significantly changed with the abundance of Proteobacteria and Verrucomicrobia altered the most after metformin and berberine co-treatment compared to their monotherapy. In addition, steady state metformin concentrations in their combination treatment were significantly higher than that from metformin monotherapy. ConclusionCo-administration of metformin (250 mg/kg) with berberine (125 mg/kg) could not only further improve insulin sensitivity, but also demonstrate different alterations on gut microbial communities than that of their individual treatment in db/db mice.

Can First-Dose Therapeutic Drug Monitoring Predict the Steady State Area Under the Blood Concentration-Time Curve of Busulfan in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation?

Busulfan has high intra-individual variability and possible time-dependent changes in clearance, which complicates therapeutic drug monitoring (TDM), as first dose sampling may not predict the steady state concentrations. In this study, we aimed to use Bayesian pharmacokinetic parameters estimated from the first dose to predict the steady state AUC for busulfan. This observational study was conducted among pediatric patients at King Abdullah Specialist Children’s Hospital. From each patient, we collected six blood samples (2, 2.25, 2.5, 3, 4, and 6 h after the start of IV infusion of the first dose). A subset of patients were also sampled at the steady state. First, we modeled the data using only the first dose. The model was used to estimate the empirical Bayesian estimates of clearance for each individual patient, then we used the empirical Bayesian estimates of clearance to predict the AUC0–tau at steady state (i.e., predicted AUC0–tau). Steady state AUC0–tau was also calculated for patients sampled at steady state using the trapezoidal method using raw time concentration data; this was considered the reference AUC0–tau.. Then, we compared the AUC0–tau predicted using the Bayesian approach with the reference AUC0–tau values. We calculated bias and precision to assess predictability. In total we had 33 patients sampled after first dose and at steady state. Using the Bayesian approach to predict the AUC0–tau, bias was −2.8% and precision was 33%. This indicates that first dose concentrations cannot accurately predict steady state busulfan concentrations; therefore, follow-up TDM may be required for optimal dosing.

Solute Dispersion From a Continuous Release Source in a Vegetated Flow: An Analytical Study

AbstractSteady dispersion of solute in flows with submerged vegetation due to a continuous release source is a focus in water resources research. This paper presents a fully analytical effort for a complete description of the steady‐state concentration field. The analytically predicted vertical concentration profiles agree well with both experimental measurements and numerical simulation results. Relations between the steady dispersion for a continuous release source and the transient dispersion due to an instantaneous release source are also discussed. Results show that the mean concentration in the canopy layer is higher than that in the upper water layer and the steady concentration distribution approaches relative uniformity at a dimensionless downstream distance x = 0.5. The solute release position is shown highly remarkably affecting the way in which the downstream state is approached. Moreover, the vertical concentration profiles predicted by a spatially dependent four‐zone turbulent diffusivity model are better than those predicted by a constant single‐zone model. The obtained analytical results contribute essentially to our understanding of solute transport in water flows with submerged vegetation.

Wound-Microenvironment Engineering through Advanced-Dressing Bioprinting.

In patients with comorbidities, a large number of wounds become chronic, representing an overwhelming economic burden for healthcare systems. Engineering the microenvironment is a paramount trend to activate cells and burst-healing mechanisms. The extrusion bioprinting of advanced dressings was performed with novel composite bioinks made by blending adipose decellularized extracellular matrix with plasma and human dermal fibroblasts. Rheological and microstructural assessments of the composite hydrogels supported post-printing cell viability and proliferation over time. Embedded fibroblasts expressed steady concentrations of extracellular matrix proteins, including type 1, 3 and 4 collagens and fibronectin. ELISA assessments, multiplex protein arrays and ensuing bioinformatic analyses revealed paracrine activities corresponding to wound-healing activation through the modulation of inflammation and angiogenesis. The two modalities of advanced dressings, differing in platelet number, showed differences in the release of inflammatory and angiogenic cytokines, including interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conditioned media stimulated human-dermal-cell proliferation over time. Our findings open the door to engineering the microenvironment as a strategy to enhance healing.