In advanced medication, drug-loaded polymeric nanoparticles (NPs) appeared as a novel drug delivery system with lots of advantages over conventional medicines. Despite all the advantages, NPs do not ...gain popularity for manufacturing hurdles. The study focused on the formulation difficulties and implementation of statistical design to establish an effective model for manufacturing NPs. In this study, physico-chemical properties of the drug and polymer (PLGA) were incorporated to understand the mechanistic insights of nanoformulations. Primarily, the process controlling parameters were screened by Plackett-Burman design and the critical process parameters (Cpp) were further fabricated by Box-Behnken design (BBD). The TLM-PLGA-NPs (telmisartan loaded PLGA NPs) exhibited particle size, encapsulation efficiency and zeta potential of 232.4 nm, 79.21% and -9.92 mV respectively. The NPs represented drug loading of 76.31%. Korsmeyer-Peppas model (
= 0.925) appeared to be the best fitted model for
release kinetics of NPs. The model identified Fickian diffusion of TLM from the polymeric nanoparticles. The ANOVA results of variables indicate that BBD is a suitable model for the development of polymeric NPs. The study successfully identified and evaluated the correlation of significant parameters that were directly or indirectly influencing the formulations which deliberately produce desired nanoparticles with the help of statistical design.
Importance: Consumers purchase a wide variety of consumer products and come into contact with these products on a daily basis. Manufacturers invest deeply in developing new products or improving ...existing products, in order to produce a positive impact on the lives of consumers. Objective: The goal of this study was to determine the impact of over-the-counter skin care products on the quality of life (QoL) of female consumers. Design and Measures: A QoL instrument developed for consumer products (the Farage QoL with an added Skin Care Module) was used to assess the impact of a 28-day facial skin care regimen using commercially available products formulated to improve elasticity, firmness and hydration, and to correct age- and sun-related skin color. Responses were collected prior to study commencement, at completion of the product usage stage, and after a period of withdrawal of the product with reversion to a basic skin care regimen. Participants: Two main study groups from Australia included 89 new mothers, i.e., women with children 2 years and under (mean age ± SD was 34 ± 4.8), and a national representative sample of 91 women (45 ± 12). An additional test group from China consisted of 40 younger cosmetic users (25 ± 4.3). The Skin Care Module was not included in the instrument for the third group. Results: After 28-days of usage, both test groups in the main study showed significant improvement in three of five items in the Skin Care Module (improved feelings of empowerment, happiness and self-esteem). Improvements persisted after 2 weeks of product withdrawal. In the main QoL instrument, the New Mothers group showed significant improvement in the Well-Being domain, driven by improvements in the Self-Image and Self Competence subdomains. The National Representative group showed improvements in the Energy and Vitality domain, driven by improvements in the Personal Pleasure, Physical State and Routine Activity subdomains. The additional group in the China study showed results similar to the New Mothers group. Conclusions and Relevance: A quality and efficacious skin care regimen can have a positive impact on the QoL of consumers. Differences in responses of the test groups were likely related to differences in the mean age and differences in time available to look after themselves.
We consider the conditional randomization test as a way to account for covariate imbalance in randomized experiments. The test accounts for covariate imbalance by comparing the observed test ...statistic to the null distribution of the test statistic conditional on the observed covariate imbalance. We prove that the conditional randomization test has the correct significance level and introduce original notation to describe covariate balance more formally. Through simulation, we verify that conditional randomization tests behave like more traditional forms of covariate adjustment but have the added benefit of having the correct conditional significance level. Finally, we apply the approach to a randomized product marketing experiment where covariate information was collected after randomization.
Vibrio cholerae non-O1, non-O139 was isolated from natural surface waters from different sites sampled in diarrhea endemic zones in Kolkata, India. Twenty-one of these isolates were randomly selected ...and included in the characterization. The multiserogroup isolates were compared by their virulence traits with a group of clinical non-O1, non-O139 isolates from the same geographic area. Of the 21 environmental isolates, 6 and 14 strains belonged to Heiberg groups I and II, respectively. Three of the environmental isolates showed resistance to 2,2-diamine-6,7-diisopropylpteridine phosphate. All of the non-O1, non-O139 strains were positive for toxR, and except for one environmental isolate, none of them were positive for tcpA in the PCR assay. None of the isolates were positive for genes encoding cholera toxin (ctxA), heat-stable toxin (est), heat-labile toxin (elt), and Shiga toxin variants (stx) of Escherichia coli. Additionally, except for one environmental isolate (PC32), all were positive for the gene encoding El Tor hemolysin (hly). The culture supernatants of 86% (18 of 21) of the environmental isolates showed a distinct cytotoxic effect on HeLa cells, and some of these strains also produced cell-rounding factor. The lipase, protease, and cell-associated hemagglutination activities and serum resistance properties of the environmental and clinical isolates did not differ much. However, seven environmental isolates exhibited very high hemolytic activities (80 to 100%), while none of the clinical strains belonged to this group. The environmental isolates manifested three adherence patterns, namely, carpet-like, diffuse, and aggregative adherence, and the clinical isolates showed diffuse adherence on HeLa cells. Of the 11 environmental isolates tested for enteropathogenic potential, 8 (73%) induced positive fluid accumulation (>=100) in a mouse model, and the reactivities of these isolates were comparable to those of clinical strains of non-O1, non-O139 and toxigenic O139 V. cholerae. Comparison of the counts of the colonized environmental and clinical strains in the mouse intestine showed that the organisms of both groups had similar colonizing efficiencies. These findings indicate the presence of potentially pathogenic V. cholerae non-O1, non-O139 strains in surface waters of the studied sites in Kolkata.
In spite of having a remarkable anti tumor activity against a wide variety of cancers, the clinical effectiveness of the major chemotherapeutic drug paclitaxel is often limited by the issues of drug ...resistance that hampers the therapeutic effectiveness of the drug. The combination of proton pump inhibitor with paclitaxel is an effective approach to overcome therapeutic resistance caused by the acidic microenvironment (Warburg effect) in tumor. In the present study a new simple, precise and selective liquid chromatography tandem mass spectrometry method was developed for quantification of paclitaxel and lansoprazole using esomeprazole as an internal standard and applied for the pharmacokinetic study of investigational paclitaxel - lansoprazole loaded PLGA nanoparticles. The developed method quantifies both the drugs simultaneously irrespective of their dissimilar stability concerns. The detection was exercised with multiple reaction-monitoring mode in positive ionization that yielded highly intense response of parent-product (m/z) transition pair 854.4 → 286.1, 370.1 → 251.9 and 346 → 198 for paclitaxel, lansoprazole and Esomeprazole respectively. The chromatographic separation was achieved using phenomenex Kinetex 5 μ C18 100A 50 × 3.0 mm column and a gradient mobile phase combination of ammonium acetate in deionized water (pH 6.8, 2 mM, w/v) and acetonitrile spiked with formic acid (1:1000, v/v
). This method showed good linearity over a concentration range of 10–320 ng/mL and 100–3200 ng/mL with correlation coefficient (R2) 0.98 and 0.94 for paclitaxel and lansoprazole respectively. Using liquid liquid extraction process both the drugs were extracted from rat plasma. The intra- and inter-day precision and accuracy values were within the variability limits and both the analytes were found to be stable throughout the freeze-thaw, auto-sampler, bench top and long term stability studies. The liquid chromatography tandem mass spectrometry method was successfully validated in accordance with United States Food and Drug administration guidelines and the results were within the acceptable limits. The liquid chromatography tandem mass spectrometry method was successfully utilized for the pharmacokinetic investigation of experimental paclitaxel - lansoprazole loaded PLGA nanoparticles in rat plasma.
Development and validation of LC-MS/MS method for simultaneous detection of PTX-LAN in preclinical pharmacokinetics of a newly developed chemotherapeutics. Display omitted
•The first developed bioanalytical method for simultaneous detection of paclitaxel and lansoprazole•The validated method quantifies dissimilar analytes simultaneously.•The method offers a sensitive, accurate and precise measurement of analytes in a wide calibration range.•The method utilized minimum amount of plasma for pharmacokinetics determination.
Paclitaxel (PTX) is a major chemotherapeutic drug that is effective against a wide variety of cancers, particularly breast, ovarian and lung cancer. For a weakly basic chemotherapeutic drug such as ...PTX, the development of the acidic tumor microenvironment (Warburg effect) has a remarkable impact on therapeutic resistance. The present approach takes advantage of the acidic tumor microenvironment by incorporating lansoprazole (LAN), a proton pump inhibitor (PPI), with PTX as a potent therapeutic combination that is capable of reversing PTX resistance. To deliver optimal amounts of the drugs to neoplastic cells, a nano drug delivery system was selected. To design the nanoformulation process in a limited framework, typical formulation parameters were optimized and validated by the application of response surface methodology (RSM) using Box-Behnken design (BBD). On the basis of critical quality aspects, the experimental design helped to determine the optimal particle size (243.7 nm), zeta potential (−9.14 mV) and encapsulation efficiencies (88.91% and 80.35% for PTX and LAN respectively). The optimized formulation (PTX-LAN-PLGA-NPs) exhibited sustained
in vitro
release profiles over 384 hours for both the encapsulated drugs. The Korsmeyer-Peppas model was found to be the best fitted model for the release kinetics, where the release mechanism follows Fickian diffusion. In
in vitro
anti-tumor efficacy experiments using Michigan Cancer Foundation-7 (MCF-7) breast cancer cells, the PTX-LAN-PLGA-NPs exhibited a steep decrease in cell viability compared to the pure drugs. Taken together, the results strongly support that incorporation of PTX and LAN in nanoparticles (NPs) is a promising approach for cancer chemotherapy.
Development of statistically optimized, paclitaxel-lansoprazole, dual drug loaded PLGA nanoparticles as a promising tumor acidic microenvironment targeted chemotherapeutic approach.
In this study, the protective effects of Croton hookeri (CH) extract on renal injury were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single injection of STZ ...(45 mg/kg) to Sprague-Dawley rats. After 5 days, CH extract (200 mg/kg) was administered daily by oral gavage for 2 weeks. Administration of CH extracts significantly reduced blood glucose levels in STZ-induced diabetic rats. STZ-induced changes in total cholesterol, LDL, HDL, ALT, AST, BUN, and serum creatinine levels were significantly restored by treatment with CH extract. Abnormal levels of SOD, catalase, glutathione, and oxidized GSH (GSSG) in STZ-treated rats were also significantly recovered by CH extract treatment. CH extract markedly reduced the expression of collagen-1, fibronectin, and α-SMA in the kidney of STZ-induced diabetic rats. In particular, oxidative DNA damages, MDA, TGF-β, IL-1β, and IL-6 levels were significantly reduced in STZ-treated rats following treatment with CH extract, whereas IL-10 showed opposite trend. STZ-induced SIRT1, SIRT3 downregulation and cloudin-1 upregulation in the kidney were dramatically recovered by CH extract treatment. Our data suggest that CH extract protects against diabetic-induced nephropathy by inhibiting oxidative stress and inflammation. Therefore, it has potential as a food supplement to alleviate renal dysfunction caused by diabetes-induced nephropathy.
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•CH extracts protects streptozocin-induced diabetic nephropathy.•CH extracts reduces urinary excretion of kidney injury biomarkers.•CH extracts protects streptozocin-induced oxidative stress in the kidney.•CH extracts protects streptozocin-induced inflammation in the kidney.
Background: Proton Pump Inhibitors (PPI) are observed to be great healer in gastroesophageal reflux disorder (GERD) and duodenal ulcer. Quantification of the drugs in human plasma by validated ...bioanalytical method are very important to determine pharmacokinetic parameters for undergoing comparative study with standard available formulations to make the newer one commercially available. Objective: The objective of this study was to determine the relative bioavailability of Ilaprazole, a novel PPI comparing the test formulation to the reference one according to standard regulatory guidelines. Materials and Methods: The bioequivalence of two tablet formulations, one as reference and other as test containing 10 mg of ilaprazole CAS No. 172152-36-2 was studied in 12 healthy Indian volunteers. This was a single dose, twoperiod and randomized crossover study separated with a washout period of one week. Plasma samples for pharmacokinetic analysis were collected before dosing and at pre-specified time points after dosing. The concentration of ilaprazole in plasma was determined by a validated HPLC-UV method using theophylline as internal standard. The formulations were compared using the parameters Area under the plasma concentration-time curve (AUC 0-t ), Area under the plasma concentration-time curve from zero to infinity (AUC 0-͵), Peak plasma concentration (C max ), and time to reach peak plasma concentration (t max ). Results: Mean AUC 0-t of test and reference product were calculated to be 2627.793 ± 154.989 ng h ml−1 and 2555.905 ± 225.916 ng h ml−1 , with a C max of 347.459 ± 48.175 ng h ml−1 . While mean AUC 0-͵ of test and reference product were calculated to be 2733.334 ± 242.438 ng h ml−1 and 2728.716 ± 284.408 ng h ml−1 . Conclusion: The results of this investigation indicated no statistically significant differences between the logarithmic transformed AUC 0-͵ and C max values of the two preparations. The 90% confidence interval for the ratio of the logarithmic transformed AUC 0-t , AUC 0-͵ and C max were 2 within the bioequivalence limit of 80-125% and the relative bioavailability of test formulation was 102.81% to that of reference formulation. The results of this study in healthy human volunteers of 27.92 ± 5.12 yrs (average age), 171.28 ± 6.85 cm (average height) and 66.43 ± 5.21 kg (average weight) support the use of the 10 mg dose tablet newly formulated.
The increasing number of on-chip cores and a limited number of memory controllers pose a critical problem for off-chip memory bandwidth. In this work, we propose an adaptive hybrid switching strategy ...with a dual crossbar router to provide low latency paths between cache and memory controllers. The performance is further improved by finding the optimal number and placement of memory controllers using machine learning approach with low overheads. The proposed architecture improves the average bandwidth of the network by 21.03% and reduces the network energy and memory access latency by 12.60% and 20.45%, respectively as compared to the traditional NoC architecture.
•A hybrid switching strategy with dual crossbar routers that allow simultaneous use of both circuit and packet-switched paths.•An optimal number and placement of memory controllers in the network using machine learning approach.•An energy-efficient router architecture using power-efficient drowsy and power-gating techniques.•New experimental evaluations with various application-specific traffic scenarios in terms of throughput, latency, improvements.•A detailed analysis of scalability and a summary of proposed and existing works
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