Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers

PubMed Central

Xi, Jinxiang; Zhang, Ze; Si, Xiuhua A

2015-01-01

Background Although direct nose-to-brain drug delivery has multiple advantages, its application is limited by the extremely low delivery efficiency (<1%) to the olfactory region where drugs can enter the brain. It is crucial to developing new methods that can deliver drug particles more effectively to the olfactory region. Materials and methods We introduced a delivery method that used magnetophoresis to improve olfactory delivery efficiency. The performance of the proposed method was assessed numerically in an image-based human nose model. Influences of the magnet layout, magnet strength, drug-release position, and particle diameter on the olfactory dosage were examined. Results and discussion Results showed that particle diameter was a critical factor in controlling the motion of nasally inhaled ferromagnetic drug particles. The optimal particle size was found to be approximately 15 μm for effective magnetophoretic guidance while avoiding loss of particles to the walls in the anterior nose. Olfactory delivery efficiency was shown to be sensitive to the position and strength of magnets and the release position of drug particles. The results of this study showed that clinically significant olfactory doses (up to 45%) were feasible using the optimal combination of magnet layout, selective drug release, and microsphere-carrier diameter. A 64-fold-higher delivery of dosage was predicted in the magnetized nose compared to the control case, which did not have a magnetic field. However, the sensitivity of olfactory dosage to operating conditions and the unstable nature of magnetophoresis make controlled guidance of nasally inhaled aerosols still highly challenging. PMID:25709443

Optimization of gene delivery methods in Xenopus laevis kidney (A6) and Chinese hamster ovary (CHO) cell lines for heterologous expression of Xenopus inner ear genes

PubMed Central

Ramirez-Gordillo, Daniel; Trujillo-Provencio, Casilda; Knight, V. Bleu; Serrano, Elba E.

2014-01-01

The Xenopus inner ear provides a useful model for studies of hearing and balance because it shares features with the mammalian inner ear, and because amphibians are capable of regenerating damaged mechanosensory hair cells. The structure and function of many proteins necessary for inner ear function have yet to be elucidated and require methods for analysis. To this end, we seek to characterize Xenopus inner ear genes outside of the animal model through heterologous expression in cell lines. As part of this effort, we aimed to optimize physical (electroporation), chemical (lipid-mediated; Lipofectamine™ 2000, Metafectene® Pro), and biological (viral-mediated; BacMam virus Cellular Lights™ Tubulin-RFP) gene delivery methods in amphibian (Xenopus; A6) cells and mammalian (Chinese hamster ovary (CHO)) cells. We successfully introduced the commercially available pEGFP-N3, pmCherry-N1, pEYFP-Tubulin, and Cellular Lights™ Tubulin-RFP fluorescent constructs to cells and evaluated their transfection or transduction efficiencies using the three gene delivery methods. In addition, we analyzed the transfection efficiency of a novel construct synthesized in our laboratory by cloning the Xenopus inner ear calcium-activated potassium channel β1 subunit, then subcloning the subunit into the pmCherry-N1 vector. Every gene delivery method was significantly more effective in CHO cells. Although results for the A6 cell line were not statistically significant, both cell lines illustrate a trend towards more efficient gene delivery using viral-mediated methods; however the cost of viral transduction is also much higher. Our findings demonstrate the need to improve gene delivery methods for amphibian cells and underscore the necessity for a greater understanding of amphibian cell biology. PMID:21959846

WE-AB-209-10: Optimizing the Delivery of Sequential Fluence Maps for Efficient VMAT Delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craft, D; Balvert, M

2016-06-15

Purpose: To develop an optimization model and solution approach for computing MLC leaf trajectories and dose rates for high quality matching of a set of optimized fluence maps to be delivered sequentially around a patient in a VMAT treatment. Methods: We formulate the fluence map matching problem as a nonlinear optimization problem where time is discretized but dose rates and leaf positions are continuous variables. For a given allotted time, which is allocated across the fluence maps based on the complexity of each fluence map, the optimization problem searches for the best leaf trajectories and dose rates such that themore » original fluence maps are closely recreated. Constraints include maximum leaf speed, maximum dose rate, and leaf collision avoidance, as well as the constraint that the ending leaf positions for one map are the starting leaf positions for the next map. The resulting model is non-convex but smooth, and therefore we solve it by local searches from a variety of starting positions. We improve solution time by a custom decomposition approach which allows us to decouple the rows of the fluence maps and solve each leaf pair individually. This decomposition also makes the problem easily parallelized. Results: We demonstrate method on a prostate case and a head-and-neck case and show that one can recreate fluence maps to high degree of fidelity in modest total delivery time (minutes). Conclusion: We present a VMAT sequencing method that reproduces optimal fluence maps by searching over a vast number of possible leaf trajectories. By varying the total allotted time given, this approach is the first of its kind to allow users to produce VMAT solutions that span the range of wide-field coarse VMAT deliveries to narrow-field high-MU sliding window-like approaches.« less

Optimizing Retransmission Threshold in Wireless Sensor Networks

PubMed Central

Bi, Ran; Li, Yingshu; Tan, Guozhen; Sun, Liang

2016-01-01

The retransmission threshold in wireless sensor networks is critical to the latency of data delivery in the networks. However, existing works on data transmission in sensor networks did not consider the optimization of the retransmission threshold, and they simply set the same retransmission threshold for all sensor nodes in advance. The method did not take link quality and delay requirement into account, which decreases the probability of a packet passing its delivery path within a given deadline. This paper investigates the problem of finding optimal retransmission thresholds for relay nodes along a delivery path in a sensor network. The object of optimizing retransmission thresholds is to maximize the summation of the probability of the packet being successfully delivered to the next relay node or destination node in time. A dynamic programming-based distributed algorithm for finding optimal retransmission thresholds for relay nodes along a delivery path in the sensor network is proposed. The time complexity is OnΔ·max1≤i≤n{ui}, where ui is the given upper bound of the retransmission threshold of sensor node i in a given delivery path, n is the length of the delivery path and Δ is the given upper bound of the transmission delay of the delivery path. If Δ is greater than the polynomial, to reduce the time complexity, a linear programming-based (1+pmin)-approximation algorithm is proposed. Furthermore, when the ranges of the upper and lower bounds of retransmission thresholds are big enough, a Lagrange multiplier-based distributed O(1)-approximation algorithm with time complexity O(1) is proposed. Experimental results show that the proposed algorithms have better performance. PMID:27171092

Optimizing hidden layer node number of BP network to estimate fetal weight

NASA Astrophysics Data System (ADS)

Su, Juan; Zou, Yuanwen; Lin, Jiangli; Wang, Tianfu; Li, Deyu; Xie, Tao

2007-12-01

The ultrasonic estimation of fetal weigh before delivery is of most significance for obstetrical clinic. Estimating fetal weight more accurately is crucial for prenatal care, obstetrical treatment, choosing appropriate delivery methods, monitoring fetal growth and reducing the risk of newborn complications. In this paper, we introduce a method which combines golden section and artificial neural network (ANN) to estimate the fetal weight. The golden section is employed to optimize the hidden layer node number of the back propagation (BP) neural network. The method greatly improves the accuracy of fetal weight estimation, and simultaneously avoids choosing the hidden layer node number with subjective experience. The estimation coincidence rate achieves 74.19%, and the mean absolute error is 185.83g.

Development of ocular drug delivery systems using molecularly imprinted soft contact lenses.

PubMed

Tashakori-Sabzevar, Faezeh; Mohajeri, Seyed Ahmad

2015-05-01

Recently, significant advances have been made in order to optimize drug delivery to ocular tissues. The main problems in ocular drug delivery are poor bioavailability and uncontrollable drug delivery of conventional ophthalmic preparations (e.g. eye drops). Hydrogels have been investigated since 1965 as new ocular drug delivery systems. Increase of hydrogel loading capacity, optimization of drug residence time on the ocular surface and biocompatibility with the eye tissue has been the main focus of previous studies. Molecular imprinting technology provided the opportunity to fulfill the above-mentioned objectives. Molecularly imprinted soft contact lenses (SCLs) have high potentials as novel drug delivery systems for the treatment of eye disorders. This technique is used for the preparation of polymers with specific binding sites for a template molecule. Previous studies indicated that molecular imprinting technology could be successfully applied for the preparation of SCLs as ocular drug delivery systems. Previous research, particularly in vivo studies, demonstrated that molecular imprinting is a versatile and effective method in optimizing the drug release behavior and enhancing the loading capacity of SCLs as new ocular drug delivery systems. This review highlights various potentials of molecularly imprinted contact lenses in enhancing the drug-loading capacity and controlling the drug release, compared to other ocular drug delivery systems. We have also studied the effects of contributing factors such as the type of comonomer, template/functional monomer molar ratio, crosslinker concentration in drug-loading capacity, and the release properties of molecularly imprinted hydrogels.

Optimizing Prednisolone Loading into Distiller's Dried Grain Kafirin Microparticles, and In vitro Release for Oral Delivery.

PubMed

Lau, Esther T L; Johnson, Stuart K; Williams, Barbara A; Mikkelsen, Deirdre; McCourt, Elizabeth; Stanley, Roger A; Mereddy, Ram; Halley, Peter J; Steadman, Kathryn J

2017-05-19

Kafirin microparticles have potential as colon-targeted delivery systems because of their ability to protect encapsulated material from digestive processes of the upper gastrointestinal tract (GIT). The aim was to optimize prednisolone loading into kafirin microparticles, and investigate their potential as an oral delivery system. Response surface methodology (RSM) was used to predict the optimal formulation of prednisolone loaded microparticles. Prednisolone release from the microparticles was measured in simulated conditions of the GIT. The RSM models were inadequate for predicting the relationship between starting quantities of kafirin and prednisolone, and prednisolone loading into microparticles. Compared to prednisolone released in the simulated gastric and small intestinal conditions, no additional drug release was observed in simulated colonic conditions. Hence, more insight into factors affecting drug loading into kafirin microparticles is required to improve the robustness of the RSM model. This present method of formulating prednisolone-loaded kafirin microparticles is unlikely to offer clinical benefits over commercially available dosage forms. Nevertheless, the overall amount of prednisolone released from the kafirin microparticles in conditions simulating the human GIT demonstrates their ability to prevent the release of entrapped core material. Further work developing the formulation methods may result in a delivery system that targets the lower GIT.

Blended Learning

ERIC Educational Resources Information Center

Halan, Deepak

2005-01-01

Blended learning basically refers to using several methods for teaching. It can be thought to be a learning program where more than one delivery mode is being used with the ultimate goal of optimizing the learning result and cost of program delivery. Examples of blended learning could be the combination of technology-based resources and…

The magnetofection method: using magnetic force to enhance gene delivery.

PubMed

Plank, Christian; Schillinger, Ulrike; Scherer, Franz; Bergemann, Christian; Rémy, Jean-Serge; Krötz, Florian; Anton, Martina; Lausier, Jim; Rosenecker, Joseph

2003-05-01

In order to enhance and target gene delivery we have previously established a novel method, termed magnetofection, which uses magnetic force acting on gene vectors that are associated with magnetic particles. Here we review the benefits, the mechanism and the potential of the method with regard to overcoming physical limitations to gene delivery. Magnetic particle chemistry and physics are discussed, followed by a detailed presentation of vector formulation and optimization work. While magnetofection does not necessarily improve the overall performance of any given standard gene transfer method in vitro, its major potential lies in the extraordinarily rapid and efficient transfection at low vector doses and the possibility of remotely controlled vector targeting in vivo.

Optimal Delivery of Aerosols to Infants During Mechanical Ventilation

PubMed Central

Azimi, Mandana; Hindle, Michael

2014-01-01

Abstract Purpose: The objective of this study was to determine optimal aerosol delivery conditions for a full-term (3.6 kg) infant receiving invasive mechanical ventilation by evaluating the effects of aerosol particle size, a new wye connector, and timing of aerosol delivery. Methods: In vitro experiments used a vibrating mesh nebulizer and evaluated drug deposition fraction and emitted dose through ventilation circuits containing either a commercial (CM) or new streamlined (SL) wye connector and 3-mm endotracheal tube (ETT) for aerosols with mass median aerodynamic diameters of 880 nm, 1.78 μm, and 4.9 μm. The aerosol was released into the circuit either over the full inhalation cycle (T1 delivery) or over the first half of inhalation (T2 delivery). Validated computational fluid dynamics (CFD) simulations and whole-lung model predictions were used to assess lung deposition and exhaled dose during cyclic ventilation. Results: In vitro experiments at a steady-state tracheal flow rate of 5 L/min resulted in 80–90% transmission of the 880-nm and 1.78-μm aerosols from the ETT. Based on CFD simulations with cyclic ventilation, the SL wye design reduced depositional losses in the wye by a factor of approximately 2–4 and improved lung delivery efficiencies by a factor of approximately 2 compared with the CM device. Delivery of the aerosol over the first half of the inspiratory cycle (T2) reduced exhaled dose from the ventilation circuit by a factor of 4 compared with T1 delivery. Optimal lung deposition was achieved with the SL wye connector and T2 delivery, resulting in 45% and 60% lung deposition for optimal polydisperse (∼1.78 μm) and monodisperse (∼2.5 μm) particle sizes, respectively. Conclusions: Optimization of selected factors and use of a new SL wye connector can substantially increase the lung delivery efficiency of medical aerosols to infants from current values of <1–10% to a range of 45–60%. PMID:24299500

Biological optimization systems for enhancing photosynthetic efficiency and methods of use

DOEpatents

Hunt, Ryan W.; Chinnasamy, Senthil; Das, Keshav C.; de Mattos, Erico Rolim

2012-11-06

Biological optimization systems for enhancing photosynthetic efficiency and methods of use. Specifically, methods for enhancing photosynthetic efficiency including applying pulsed light to a photosynthetic organism, using a chlorophyll fluorescence feedback control system to determine one or more photosynthetic efficiency parameters, and adjusting one or more of the photosynthetic efficiency parameters to drive the photosynthesis by the delivery of an amount of light to optimize light absorption of the photosynthetic organism while providing enough dark time between light pulses to prevent oversaturation of the chlorophyll reaction centers are disclosed.

Localized Cell and Drug Delivery for Auditory Prostheses

PubMed Central

Hendricks, Jeffrey L.; Chikar, Jennifer A.; Crumling, Mark A.; Raphael, Yehoash; Martin, David C.

2011-01-01

Localized cell and drug delivery to the cochlea and central auditory pathway can improve the safety and performance of implanted auditory prostheses (APs). While generally successful, these devices have a number of limitations and adverse effects including limited tonal and dynamic ranges, channel interactions, unwanted stimulation of non-auditory nerves, immune rejection, and infections including meningitis. Many of these limitations are associated with the tissue reactions to implanted auditory prosthetic devices and the gradual degeneration of the auditory system following deafness. Strategies to reduce the insertion trauma, degeneration of target neurons, fibrous and bony tissue encapsulation, and immune activation can improve the viability of tissue required for AP function as well as improve the resolution of stimulation for reduced channel interaction and improved place-pitch and level discrimination. Many pharmaceutical compounds have been identified that promote the viability of auditory tissue and prevent inflammation and infection. Cell delivery and gene therapy have provided promising results for treating hearing loss and reversing degeneration. Currently, many clinical and experimental methods can produce extremely localized and sustained drug delivery to address AP limitations. These methods provide better control over drug concentrations while eliminating the adverse effects of systemic delivery. Many of these drug delivery techniques can be integrated into modern auditory prosthetic devices to optimize the tissue response to the implanted device and reduce the risk of infection or rejection. Together, these methods and pharmaceutical agents can be used to optimize the tissue-device interface for improved AP safety and effectiveness. PMID:18573323

Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations.

PubMed

Barua, Neil U; Gill, Steven S; Love, Seth

2014-03-01

Convection-enhanced delivery (CED) describes a direct method of drug delivery to the brain through intraparenchymal microcatheters. By establishing a pressure gradient at the tip of the infusion catheter in order to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods-bypass of the blood-brain barrier, targeted distribution through large brain volumes and minimization of systemic side effects. Despite showing early promise, CED is yet to fulfill its potential as a mainstream strategy for the treatment of neurological disease. Substantial research effort has been dedicated to optimize the technology for CED and identify the parameters, which govern successful drug distribution. It seems likely that successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate preclinical models. In this review, we consider the factors most likely to influence the success or failure of CED, and review its application to the treatment of high-grade glioma, Parkinson's disease (PD) and Alzheimer's disease (AD). © 2013 International Society of Neuropathology.

Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vandewouw, Marlee M., E-mail: marleev@mie.utoronto

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target. Methods: The authors’ method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, aremore » used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.« less

SU-F-P-28: A Method of Maximize the Noncoplanar Beam Orientations and Assure the Beam Delivery Clearance for Stereotactic Body Radiation Therapy (SBRT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, J

2016-06-15

Purpose: Develop a method to maximize the noncoplanar beam orientations and assure the beam delivery clearance for SBRT, therefore, optimize the dose conformality to the target, increase the dose sparing to the critical normal organs and reduce the hot spots in the body. Methods: A SBRT body frame (Elekta, Stockholm, Sweden) was used for patient immobilization and target localization. The SBRT body frame has CT fiducials on its side frames. After patient’s CT scan, the radiation treatment isocenter was defined and its coordinators referring to the body frame was calculated in the radiation treatment planning process. Meanwhile, initial beam orientationsmore » were designed based on the patient target and critical organ anatomy. The body frame was put on the linear accelerator couch and positioned to the calculated isocenter. Initially designed beam orientations were manually measured by tuning the body frame position on the couch, the gantry and couch angles. The finalized beam orientations were put into the treatment planning for dosimetric calculations. Results: Without patient presence, an optimal set of beam orientations were designed and validated. The radiation treatment plan was optimized and guaranteed for delivery clearance. Conclusion: The developed method is beneficial and effective in SBRT treatment planning for individual patient. It first allows maximizing the achievable noncoplanar beam orientation space, therefore, optimize the treatment plan for specific patient. It eliminates the risk that a plan needs to be modified due to the gantry and couch collision during patient setup.« less

Andy Walker | NREL

Science.gov Websites

efficiency and renewable energy projects. His patent on the Renewable Energy Optimization (REO) method of distribution function for time-series simulation Analytical and numerical optimization Project delivery with System Operations and Maintenance: 2nd Edition, 2016, NREL/Sandia/Sunspec Alliance SuNLaMP PV O&M

Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems--enhancement of oral bioavailability.

PubMed

Hashem, Fahima M; Al-Sawahli, Majid M; Nasr, Mohamed; Ahmed, Osama A A

2015-01-01

Poor water solubility of a drug is a major challenge in drug delivery research and a main cause for limited bioavailability and pharmacokinetic parameters. This work aims to utilize custom fractional factorial design to assess the development of self-nanoemulsifying drug delivery systems (SNEDDS) and solid nanosuspensions (NS) in order to enhance the oral delivery of atorvastatin (ATR). According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components: oleic acid, Tween 80, and propylene glycol. In addition, 12 runs of NS were formulated by the antisolvent precipitation-ultrasonication method. Optimized formulations of SNEDDS and solid NS, deduced from the design, were characterized. Optimized SNEDDS formula exhibited mean globule size of 73.5 nm, zeta potential magnitude of -24.1 mV, and 13.5 μs/cm of electrical conductivity. Optimized solid NS formula exhibited mean particle size of 260.3 nm, 7.4 mV of zeta potential, and 93.2% of yield percentage. Transmission electron microscopy showed SNEDDS droplets formula as discrete spheres. The solid NS morphology showed flaky nanoparticles with irregular shapes using scanning electron microscopy. The release behavior of the optimized SNEDDS formula showed 56.78% of cumulative ATR release after 10 minutes. Solid NS formula showed lower rate of release in the first 30 minutes. Bioavailability estimation in Wistar albino rats revealed an augmentation in ATR bioavailability, relative to ATR suspension and the commercial tablets, from optimized ATR SNEDDS and NS formulations by 193.81% and 155.31%, respectively. The findings of this work showed that the optimized nanocarriers enhance the oral delivery and pharmacokinetic profile of ATR.

Guaranteed epsilon-optimal treatment plans with the minimum number of beams for stereotactic body radiation therapy

NASA Astrophysics Data System (ADS)

Yarmand, Hamed; Winey, Brian; Craft, David

2013-09-01

Stereotactic body radiation therapy (SBRT) is characterized by delivering a high amount of dose in a short period of time. In SBRT the dose is delivered using open fields (e.g., beam’s-eye-view) known as ‘apertures’. Mathematical methods can be used for optimizing treatment planning for delivery of sufficient dose to the cancerous cells while keeping the dose to surrounding organs at risk (OARs) minimal. Two important elements of a treatment plan are quality and delivery time. Quality of a plan is measured based on the target coverage and dose to OARs. Delivery time heavily depends on the number of beams used in the plan as the setup times for different beam directions constitute a large portion of the delivery time. Therefore the ideal plan, in which all potential beams can be used, will be associated with a long impractical delivery time. We use the dose to OARs in the ideal plan to find the plan with the minimum number of beams which is guaranteed to be epsilon-optimal (i.e., a predetermined maximum deviation from the ideal plan is guaranteed). Since the treatment plan optimization is inherently a multi-criteria-optimization problem, the planner can navigate the ideal dose distribution Pareto surface and select a plan of desired target coverage versus OARs sparing, and then use the proposed technique to reduce the number of beams while guaranteeing epsilon-optimality. We use mixed integer programming (MIP) for optimization. To reduce the computation time for the resultant MIP, we use two heuristics: a beam elimination scheme and a family of heuristic cuts, known as ‘neighbor cuts’, based on the concept of ‘adjacent beams’. We show the effectiveness of the proposed technique on two clinical cases, a liver and a lung case. Based on our technique we propose an algorithm for fast generation of epsilon-optimal plans.

Noncoplanar VMAT for nasopharyngeal tumors: Plan quality versus treatment time

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wild, Esther, E-mail: e.wild@dkfz.de; Bangert, Mark; Nill, Simeon

Purpose: The authors investigated the potential of optimized noncoplanar irradiation trajectories for volumetric modulated arc therapy (VMAT) treatments of nasopharyngeal patients and studied the trade-off between treatment plan quality and delivery time in radiation therapy. Methods: For three nasopharyngeal patients, the authors generated treatment plans for nine different delivery scenarios using dedicated optimization methods. They compared these scenarios according to dose characteristics, number of beam directions, and estimated delivery times. In particular, the authors generated the following treatment plans: (1) a 4π plan, which is a not sequenced, fluence optimized plan that uses beam directions from approximately 1400 noncoplanar directionsmore » and marks a theoretical upper limit of the treatment plan quality, (2) a coplanar 2π plan with 72 coplanar beam directions as pendant to the noncoplanar 4π plan, (3) a coplanar VMAT plan, (4) a coplanar step and shoot (SnS) plan, (5) a beam angle optimized (BAO) coplanar SnS IMRT plan, (6) a noncoplanar BAO SnS plan, (7) a VMAT plan with rotated treatment couch, (8) a noncoplanar VMAT plan with an optimized great circle around the patient, and (9) a noncoplanar BAO VMAT plan with an arbitrary trajectory around the patient. Results: VMAT using optimized noncoplanar irradiation trajectories reduced the mean and maximum doses in organs at risk compared to coplanar VMAT plans by 19% on average while the target coverage remains constant. A coplanar BAO SnS plan was superior to coplanar SnS or VMAT; however, noncoplanar plans like a noncoplanar BAO SnS plan or noncoplanar VMAT yielded a better plan quality than the best coplanar 2π plan. The treatment plan quality of VMAT plans depended on the length of the trajectory. The delivery times of noncoplanar VMAT plans were estimated to be 6.5 min in average; 1.6 min longer than a coplanar plan but on average 2.8 min faster than a noncoplanar SnS plan with comparable treatment plan quality. Conclusions: The authors’ study reconfirms the dosimetric benefits of noncoplanar irradiation of nasopharyngeal tumors. Both SnS using optimized noncoplanar beam ensembles and VMAT using an optimized, arbitrary, noncoplanar trajectory enabled dose reductions in organs at risk compared to coplanar SnS and VMAT. Using great circles or simple couch rotations to implement noncoplanar VMAT, however, was not sufficient to yield meaningful improvements in treatment plan quality. The authors estimate that noncoplanar VMAT using arbitrary optimized irradiation trajectories comes at an increased delivery time compared to coplanar VMAT yet at a decreased delivery time compared to noncoplanar SnS IMRT.« less

Sci—Thur PM: Planning and Delivery — 03: Automated delivery and quality assurance of a modulated electron radiation therapy plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Connell, T; Papaconstadopoulos, P; Alexander, A

2014-08-15

Modulated electron radiation therapy (MERT) offers the potential to improve healthy tissue sparing through increased dose conformity. Challenges remain, however, in accurate beamlet dose calculation, plan optimization, collimation method and delivery accuracy. In this work, we investigate the accuracy and efficiency of an end-to-end MERT plan and automated-delivery workflow for the electron boost portion of a previously treated whole breast irradiation case. Dose calculations were performed using Monte Carlo methods and beam weights were determined using a research-based treatment planning system capable of inverse optimization. The plan was delivered to radiochromic film placed in a water equivalent phantom for verification,more » using an automated motorized tertiary collimator. The automated delivery, which covered 4 electron energies, 196 subfields and 6183 total MU was completed in 25.8 minutes, including 6.2 minutes of beam-on time with the remainder of the delivery time spent on collimator leaf motion and the automated interfacing with the accelerator in service mode. The delivery time could be reduced by 5.3 minutes with minor electron collimator modifications and the beam-on time could be reduced by and estimated factor of 2–3 through redesign of the scattering foils. Comparison of the planned and delivered film dose gave 3%/3 mm gamma pass rates of 62.1, 99.8, 97.8, 98.3, and 98.7 percent for the 9, 12, 16, 20 MeV, and combined energy deliveries respectively. Good results were also seen in the delivery verification performed with a MapCHECK 2 device. The results showed that accurate and efficient MERT delivery is possible with current technologies.« less

Aerosol delivery and humidification with the Boussignac continuous positive airway pressure device.

PubMed

Thille, Arnaud W; Bertholon, Jean-François; Becquemin, Marie-Hélène; Roy, Monique; Lyazidi, Aissam; Lellouche, François; Pertusini, Esther; Boussignac, Georges; Maître, Bernard; Brochard, Laurent

2011-10-01

A simple method for effective bronchodilator aerosol delivery while administering continuing continuous positive airway pressure (CPAP) would be useful in patients with severe bronchial obstruction. To assess the effectiveness of bronchodilator aerosol delivery during CPAP generated by the Boussignac CPAP system and its optimal humidification system. First we assessed the relationship between flow and pressure generated in the mask with the Boussignac CPAP system. Next we measured the inspired-gas humidity during CPAP, with several humidification strategies, in 9 healthy volunteers. We then measured the bronchodilator aerosol particle size during CPAP, with and without heat-and-moisture exchanger, in a bench study. Finally, in 7 patients with acute respiratory failure and airway obstruction, we measured work of breathing and gas exchange after a β(2)-agonist bronchodilator aerosol (terbutaline) delivered during CPAP or via standard nebulization. Optimal humidity was obtained only with the heat-and-moisture exchanger or heated humidifier. The heat-and-moisture exchanger had no influence on bronchodilator aerosol particle size. Work of breathing decreased similarly after bronchodilator via either standard nebulization or CPAP, but P(aO(2)) increased significantly only after CPAP aerosol delivery. CPAP bronchodilator delivery decreases the work of breathing as effectively as does standard nebulization, but produces a greater oxygenation improvement in patients with airway obstruction. To optimize airway humidification, a heat-and-moisture exchanger could be used with the Boussignac CPAP system, without modifying aerosol delivery.

Strategies of experiment standardization and response optimization in a rat model of hemorrhagic shock and chronic hypertension.

PubMed

Reynolds, Penny S; Tamariz, Francisco J; Barbee, Robert Wayne

2010-04-01

Exploratory pilot studies are crucial to best practice in research but are frequently conducted without a systematic method for maximizing the amount and quality of information obtained. We describe the use of response surface regression models and simultaneous optimization methods to develop a rat model of hemorrhagic shock in the context of chronic hypertension, a clinically relevant comorbidity. Response surface regression model was applied to determine optimal levels of two inputs--dietary NaCl concentration (0.49%, 4%, and 8%) and time on the diet (4, 6, 8 weeks)--to achieve clinically realistic and stable target measures of systolic blood pressure while simultaneously maximizing critical oxygen delivery (a measure of vulnerability to hemorrhagic shock) and body mass M. Simultaneous optimization of the three response variables was performed though a dimensionality reduction strategy involving calculation of a single aggregate measure, the "desirability" function. Optimal conditions for inducing systolic blood pressure of 208 mmHg, critical oxygen delivery of 4.03 mL/min, and M of 290 g were determined to be 4% [NaCl] for 5 weeks. Rats on the 8% diet did not survive past 7 weeks. Response surface regression model and simultaneous optimization method techniques are commonly used in process engineering but have found little application to date in animal pilot studies. These methods will ensure both the scientific and ethical integrity of experimental trials involving animals and provide powerful tools for the development of novel models of clinically interacting comorbidities with shock.

Developments in the formulation and delivery of spray dried vaccines.

PubMed

Kanojia, Gaurav; Have, Rimko Ten; Soema, Peter C; Frijlink, Henderik; Amorij, Jean-Pierre; Kersten, Gideon

2017-10-03

Spray drying is a promising method for the stabilization of vaccines, which are usually formulated as liquids. Usually, vaccine stability is improved by spray drying in the presence of a range of excipients. Unlike freeze drying, there is no freezing step involved, thus the damage related to this step is avoided. The edge of spray drying resides in its ability for particles to be engineered to desired requirements, which can be used in various vaccine delivery methods and routes. Although several spray dried vaccines have shown encouraging preclinical results, the number of vaccines that have been tested in clinical trials is limited, indicating a relatively new area of vaccine stabilization and delivery. This article reviews the current status of spray dried vaccine formulations and delivery methods. In particular it discusses the impact of process stresses on vaccine integrity, the application of excipients in spray drying of vaccines, process and formulation optimization strategies based on Design of Experiment approaches as well as opportunities for future application of spray dried vaccine powders for vaccine delivery.

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Nutrition Screening and Therapy Within a Surgical Enhanced Recovery Pathway.

PubMed

Wischmeyer, Paul E; Carli, Franco; Evans, David C; Guilbert, Sarah; Kozar, Rosemary; Pryor, Aurora; Thiele, Robert H; Everett, Sotiria; Grocott, Mike; Gan, Tong J; Shaw, Andrew D; Thacker, Julie K M; Miller, Timothy E; Hedrick, Traci L; McEvoy, Matthew D; Mythen, Michael G; Bergamaschi, Roberto; Gupta, Ruchir; Holubar, Stefan D; Senagore, Anthony J; Abola, Ramon E; Bennett-Guerrero, Elliott; Kent, Michael L; Feldman, Liane S; Fiore, Julio F

2018-06-01

Perioperative malnutrition has proven to be challenging to define, diagnose, and treat. Despite these challenges, it is well known that suboptimal nutritional status is a strong independent predictor of poor postoperative outcomes. Although perioperative caregivers consistently express recognition of the importance of nutrition screening and optimization in the perioperative period, implementation of evidence-based perioperative nutrition guidelines and pathways in the United States has been quite limited and needs to be addressed in surgery-focused recommendations. The second Perioperative Quality Initiative brought together a group of international experts with the objective of providing consensus recommendations on this important topic with the goal of (1) developing guidelines for screening of nutritional status to identify patients at risk for adverse outcomes due to malnutrition; (2) address optimal methods of providing nutritional support and optimizing nutrition status preoperatively; and (3) identifying when and how to optimize nutrition delivery in the postoperative period. Discussion led to strong recommendations for implementation of routine preoperative nutrition screening to identify patients in need of preoperative nutrition optimization. Postoperatively, nutrition delivery should be restarted immediately after surgery. The key role of oral nutrition supplements, enteral nutrition, and parenteral nutrition (implemented in that order) in most perioperative patients was advocated for with protein delivery being more important than total calorie delivery. Finally, the role of often-inadequate nutrition intake in the posthospital setting was discussed, and the role of postdischarge oral nutrition supplements was emphasized.

Treatment planning, optimization, and beam delivery technqiues for intensity modulated proton therapy

NASA Astrophysics Data System (ADS)

Sengbusch, Evan R.

Physical properties of proton interactions in matter give them a theoretical advantage over photons in radiation therapy for cancer treatment, but they are seldom used relative to photons. The primary barriers to wider acceptance of proton therapy are the technical feasibility, size, and price of proton therapy systems. Several aspects of the proton therapy landscape are investigated, and new techniques for treatment planning, optimization, and beam delivery are presented. The results of these investigations suggest a means by which proton therapy can be delivered more efficiently, effectively, and to a much larger proportion of eligible patients. An analysis of the existing proton therapy market was performed. Personal interviews with over 30 radiation oncology leaders were conducted with regard to the current and future use of proton therapy. In addition, global proton therapy market projections are presented. The results of these investigations serve as motivation and guidance for the subsequent development of treatment system designs and treatment planning, optimization, and beam delivery methods. A major factor impacting the size and cost of proton treatment systems is the maximum energy of the accelerator. Historically, 250 MeV has been the accepted value, but there is minimal quantitative evidence in the literature that supports this standard. A retrospective study of 100 patients is presented that quantifies the maximum proton kinetic energy requirements for cancer treatment, and the impact of those results with regard to treatment system size, cost, and neutron production is discussed. This study is subsequently expanded to include 100 cranial stereotactic radiosurgery (SRS) patients, and the results are discussed in the context of a proposed dedicated proton SRS treatment system. Finally, novel proton therapy optimization and delivery techniques are presented. Algorithms are developed that optimize treatment plans over beam angle, spot size, spot spacing, beamlet weight, the number of delivered beamlets, and the number of delivery angles. These methods are evaluated via treatment planning studies including left-sided whole breast irradiation, lung stereotactic body radiotherapy, nasopharyngeal carcinoma, and whole brain radiotherapy with hippocampal avoidance. Improvements in efficiency and efficacy relative to traditional proton therapy and intensity modulated photon radiation therapy are discussed.

Novel microemulsion-based gel formulation of tazarotene for therapy of acne.

PubMed

Patel, Mrunali Rashmin; Patel, Rashmin Bharatbhai; Parikh, Jolly R; Patel, Bharat G

2016-12-01

The objective of this study was to develop and evaluate a novel microemulsion based gel formulation containing tazarotene for targeted topical therapy of acne. Psudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and co-surfactant for microemulsion formation. The optimized microemulsion formulation containing 0.05% tazarotene was formulated by spontaneous microemulsification method consisting of 10% Labrafac CC, mixed emulsifiers 15% Labrasol-Cremophor-RH 40 (1:1), 15% Capmul MCM, and 60% distilled water (w/w) as an external phase. All plain and tazarotene-loaded microemulsions were clear and showed physicochemical parameters for desired topical delivery and stability. The permeation profiles of tazarotene through rat skin from optimized microemulsion formulation followed the Higuchi model for controlled permeation. Microemulsion-based gel was prepared by incorporating Carbopol®971P NF in optimized microemulsion formulation having suitable skin permeation rate and skin uptake. Microemulsion-based gel showed desired physicochemical parameters and demonstrated advantage over marketed formulation in improving the skin tolerability of tazarotene indicating its potential in improving its topical delivery. The developed microemulsion-based gel may be a potential drug delivery vehicle for targeted topical delivery of tazarotene in the treatment of acne.

Transethosomal gels as carriers for the transdermal delivery of colchicine: statistical optimization, characterization, and ex vivo evaluation

PubMed Central

Abdulbaqi, Ibrahim M; Darwis, Yusrida; Assi, Reem Abou; Khan, Nurzalina Abdul Karim

2018-01-01

Introduction Colchicine is used for the treatment of gout, pseudo-gout, familial Mediterranean fever, and many other illnesses. Its oral administration is associated with poor bioavailability and severe gastrointestinal side effects. The drug is also known to have a low therapeutic index. Thus to overcome these drawbacks, the transdermal delivery of colchicine was investigated using transethosomal gels as potential carriers. Methods Colchicine-loaded transethosomes (TEs) were prepared by the cold method and statistically optimized using three sets of 24 factorial design experiments. The optimized formulations were incorporated into Carbopol 940® gel base. The prepared colchicine-loaded transethosomal gels were further characterized for vesicular size, dispersity, zeta potential, drug content, pH, viscosity, yield, rheological behavior, and ex vivo skin permeation through Sprague Dawley rats’ back skin. Results The results showed that the colchicine-loaded TEs had aspherical irregular shape, nanometric size range, and high entrapment efficiency. All the formulated gels exhibited non-Newtonian plastic flow without thixotropy. Colchicine-loaded transethosomal gels were able to significantly enhance the skin permeation parameters of the drug in comparison to the non-ethosomal gel. Conclusion These findings suggested that the transethosomal gels are promising carriers for the transdermal delivery of colchicine, providing an alternative route for drug administration. PMID:29670336

MO-FG-CAMPUS-TeP2-05: Optimizing Stereotactic Radiosurgery Treatment of Multiple Brain Metastasis Lesions with Individualized Rotational Arc Trajectories

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, P; Xing, L; Ma, L

Purpose: Radiosurgery of multiple (n>4) brain metastasis lesions requires 3–4 noncoplanar VMAT arcs with excessively high monitor units and long delivery time. We investigated whether an improved optimization technique would decrease the needed arc numbers and increase the delivery efficiency, while improving or maintaining the plan quality. Methods: The proposed 4pi arc space optimization algorithm consists of two steps: automatic couch angle selection followed by aperture generation for each arc with optimized control points distribution. We use a greedy algorithm to select the couch angles. Starting from a single coplanar arc plan we search through the candidate noncoplanar arcs tomore » pick a single noncoplanar arc that will bring the best plan quality when added into the existing treatment plan. Each time, only one additional noncoplanar arc is considered making the calculation time tractable. This process repeats itself until desired number of arc is reached. The technique is first evaluated in coplanar arc delivery scheme with testing cases and then applied to noncoplanar treatments of a case with 12 brain metastasis lesions. Results: Clinically acceptable plans are created within minutes. For the coplanar testing cases the algorithm yields singlearc plans with better dose distributions than that of two-arc VMAT, simultaneously with a 12–17% reduction in the delivery time and a 14–21% reduction in MUs. For the treatment of 12 brain mets while Paddick conformity indexes of the two plans were comparable the SCG-optimization with 2 arcs (1 noncoplanar and 1 coplanar) significantly improved the conventional VMAT with 3 arcs (2 noncoplanar and 1 coplanar). Specifically V16 V10 and V5 of the brain were reduced by 11%, 11% and 12% respectively. The beam delivery time was shortened by approximately 30%. Conclusion: The proposed 4pi arc space optimization technique promises to significantly reduce the brain toxicity while greatly improving the treatment efficiency.« less

Drop-on-Demand Sample Delivery for Studying Biocatalysts in Action at XFELs

PubMed Central

Fuller, Franklin D.; Gul, Sheraz; Chatterjee, Ruchira; Burgie, Ernest S.; Young, Iris D.; Lebrette, Hugo; Srinivas, Vivek; Brewster, Aaron S.; Michels-Clark, Tara; Clinger, Jonathan A.; Andi, Babak; Ibrahim, Mohamed; Pastor, Ernest; de Lichtenberg, Casper; Hussein, Rana; Pollock, Christopher J.; Zhang, Miao; Stan, Claudiu A.; Kroll, Thomas; Fransson, Thomas; Weninger, Clemens; Kubin, Markus; Aller, Pierre; Lassalle, Louise; Bräuer, Philipp; Miller, Mitchell D.; Amin, Muhamed; Koroidov, Sergey; Roessler, Christian G.; Allaire, Marc; Sierra, Raymond G.; Docker, Peter T.; Glownia, James M.; Nelson, Silke; Koglin, Jason E.; Zhu, Diling; Chollet, Matthieu; Song, Sanghoon; Lemke, Henrik; Liang, Mengning; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Zouni, Athina; Messinger, Johannes; Bergmann, Uwe; Boal, Amie K.; Bollinger, J. Martin; Krebs, Carsten; Högbom, Martin; Phillips, George N.; Vierstra, Richard D.; Sauter, Nicholas K.; Orville, Allen M.; Kern, Jan; Yachandra, Vittal K.; Yano, Junko

2017-01-01

X-ray crystallography at X-ray free-electron laser (XFEL) sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy (XES), both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing new insights into the interplay between the protein structure/dynamics and chemistry at an active site. Implementing such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly impacts the data quality. We present here a new, robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method. PMID:28250468

Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers.

PubMed

Fuller, Franklin D; Gul, Sheraz; Chatterjee, Ruchira; Burgie, E Sethe; Young, Iris D; Lebrette, Hugo; Srinivas, Vivek; Brewster, Aaron S; Michels-Clark, Tara; Clinger, Jonathan A; Andi, Babak; Ibrahim, Mohamed; Pastor, Ernest; de Lichtenberg, Casper; Hussein, Rana; Pollock, Christopher J; Zhang, Miao; Stan, Claudiu A; Kroll, Thomas; Fransson, Thomas; Weninger, Clemens; Kubin, Markus; Aller, Pierre; Lassalle, Louise; Bräuer, Philipp; Miller, Mitchell D; Amin, Muhamed; Koroidov, Sergey; Roessler, Christian G; Allaire, Marc; Sierra, Raymond G; Docker, Peter T; Glownia, James M; Nelson, Silke; Koglin, Jason E; Zhu, Diling; Chollet, Matthieu; Song, Sanghoon; Lemke, Henrik; Liang, Mengning; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Zouni, Athina; Messinger, Johannes; Bergmann, Uwe; Boal, Amie K; Bollinger, J Martin; Krebs, Carsten; Högbom, Martin; Phillips, George N; Vierstra, Richard D; Sauter, Nicholas K; Orville, Allen M; Kern, Jan; Yachandra, Vittal K; Yano, Junko

2017-04-01

X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly affects the data quality. We present here a robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.

Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers

DOE PAGES

Fuller, Franklin D.; Gul, Sheraz; Chatterjee, Ruchira; ...

2017-02-27

X-ray crystallography at X-ray free-electron laser (XFEL) sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy (XES), both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing new insights into the interplay between the protein structure/dynamics and chemistry at an active site. However, implementing such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly impacts the data quality. We present here a new, robust way of delivering controlled sample amountsmore » on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.« less

Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuller, Franklin D.; Gul, Sheraz; Chatterjee, Ruchira

X-ray crystallography at X-ray free-electron laser (XFEL) sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy (XES), both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing new insights into the interplay between the protein structure/dynamics and chemistry at an active site. However, implementing such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly impacts the data quality. We present here a new, robust way of delivering controlled sample amountsmore » on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.« less

A novel software and conceptual design of the hardware platform for intensity modulated radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Dan; Ruan, Dan; O’Connor, Daniel

Purpose: To deliver high quality intensity modulated radiotherapy (IMRT) using a novel generalized sparse orthogonal collimators (SOCs), the authors introduce a novel direct aperture optimization (DAO) approach based on discrete rectangular representation. Methods: A total of seven patients—two glioblastoma multiforme, three head & neck (including one with three prescription doses), and two lung—were included. 20 noncoplanar beams were selected using a column generation and pricing optimization method. The SOC is a generalized conventional orthogonal collimators with N leaves in each collimator bank, where N = 1, 2, or 4. SOC degenerates to conventional jaws when N = 1. For SOC-basedmore » IMRT, rectangular aperture optimization (RAO) was performed to optimize the fluence maps using rectangular representation, producing fluence maps that can be directly converted into a set of deliverable rectangular apertures. In order to optimize the dose distribution and minimize the number of apertures used, the overall objective was formulated to incorporate an L2 penalty reflecting the difference between the prescription and the projected doses, and an L1 sparsity regularization term to encourage a low number of nonzero rectangular basis coefficients. The optimization problem was solved using the Chambolle–Pock algorithm, a first-order primal–dual algorithm. Performance of RAO was compared to conventional two-step IMRT optimization including fluence map optimization and direct stratification for multileaf collimator (MLC) segmentation (DMS) using the same number of segments. For the RAO plans, segment travel time for SOC delivery was evaluated for the N = 1, N = 2, and N = 4 SOC designs to characterize the improvement in delivery efficiency as a function of N. Results: Comparable PTV dose homogeneity and coverage were observed between the RAO and the DMS plans. The RAO plans were slightly superior to the DMS plans in sparing critical structures. On average, the maximum and mean critical organ doses were reduced by 1.94% and 1.44% of the prescription dose. The average number of delivery segments was 12.68 segments per beam for both the RAO and DMS plans. The N = 2 and N = 4 SOC designs were, on average, 1.56 and 1.80 times more efficient than the N = 1 SOC design to deliver. The mean aperture size produced by the RAO plans was 3.9 times larger than that of the DMS plans. Conclusions: The DAO and dose domain optimization approach enabled high quality IMRT plans using a low-complexity collimator setup. The dosimetric quality is comparable or slightly superior to conventional MLC-based IMRT plans using the same number of delivery segments. The SOC IMRT delivery efficiency can be significantly improved by increasing the leaf numbers, but the number is still significantly lower than the number of leaves in a typical MLC.« less

Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics

PubMed Central

Fatouh, Ahmed M; Elshafeey, Ahmed H; Abdelbary, Ahmed

2017-01-01

Purpose Agomelatine is a novel antidepressant drug suffering from an extensive first-pass metabolism leading to a diminished absolute bioavailability. The aim of the study is: first to enhance its absolute bioavailability, and second to increase its brain delivery. Methods To achieve these aims, the nasal route was adopted to exploit first its avoidance of the hepatic first-pass metabolism to increase the absolute bioavailability, and second the direct nose-to-brain pathway to enhance the brain drug delivery. Solid lipid nanoparticles were selected as a drug delivery system to enhance agomelatine permeability across the blood–brain barrier and therefore its brain delivery. Results The optimum solid lipid nanoparticles have a particle size of 167.70 nm ±0.42, zeta potential of −17.90 mV ±2.70, polydispersity index of 0.12±0.10, entrapment efficiency % of 91.25%±1.70%, the percentage released after 1 h of 35.40%±1.13% and the percentage released after 8 h of 80.87%±5.16%. The pharmacokinetic study of the optimized solid lipid nanoparticles revealed a significant increase in each of the plasma peak concentration, the AUC(0–360 min) and the absolute bioavailability compared to that of the oral suspension of Valdoxan® with the values of 759.00 ng/mL, 7,805.69 ng⋅min/mL and 44.44%, respectively. The optimized solid lipid nanoparticles gave a drug-targeting efficiency of 190.02, which revealed more successful brain targeting by the intranasal route compared with the intravenous route. The optimized solid lipid nanoparticles had a direct transport percentage of 47.37, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery. Conclusion The intranasal administration of agomelatine solid lipid nanoparticles has effectively enhanced both the absolute bioavailability and the brain delivery of agomelatine. PMID:28684900

Adaptive intensity modulated radiotherapy for advanced prostate cancer

NASA Astrophysics Data System (ADS)

Ludlum, Erica Marie

The purpose of this research is to develop and evaluate improvements in intensity modulated radiotherapy (IMRT) for concurrent treatment of prostate and pelvic lymph nodes. The first objective is to decrease delivery time while maintaining treatment quality, and evaluate the effectiveness and efficiency of novel one-step optimization compared to conventional two-step optimization. Both planning methods are examined at multiple levels of complexity by comparing the number of beam apertures, or segments, the amount of radiation delivered as measured by monitor units (MUs), and delivery time. One-step optimization is demonstrated to simplify IMRT planning and reduce segments (from 160 to 40), MUs (from 911 to 746), and delivery time (from 22 to 7 min) with comparable plan quality. The second objective is to examine the capability of three commercial dose calculation engines employing different levels of accuracy and efficiency to handle high--Z materials, such as metallic hip prostheses, included in the treatment field. Pencil beam, convolution superposition, and Monte Carlo dose calculation engines are compared by examining the dose differences for patient plans with unilateral and bilateral hip prostheses, and for phantom plans with a metal insert for comparison with film measurements. Convolution superposition and Monte Carlo methods calculate doses that are 1.3% and 34.5% less than the pencil beam method, respectively. Film results demonstrate that Monte Carlo most closely represents actual radiation delivery, but none of the three engines accurately predict the dose distribution when high-Z heterogeneities exist in the treatment fields. The final objective is to improve the accuracy of IMRT delivery by accounting for independent organ motion during concurrent treatment of the prostate and pelvic lymph nodes. A leaf-shifting algorithm is developed to track daily prostate position without requiring online dose calculation. Compared to conventional methods of adjusting patient position, adjusting the multileaf collimator (MLC) leaves associated with the prostate in each segment significantly improves lymph node dose coverage (maintains 45 Gy compared to 42.7, 38.3, and 34.0 Gy for iso-shifts of 0.5, 1 and 1.5 cm). Altering the MLC portal shape is demonstrated as a new and effective solution to independent prostate movement during concurrent treatment.

Noncoplanar VMAT for nasopharyngeal tumors: Plan quality versus treatment time.

PubMed

Wild, Esther; Bangert, Mark; Nill, Simeon; Oelfke, Uwe

2015-05-01

The authors investigated the potential of optimized noncoplanar irradiation trajectories for volumetric modulated arc therapy (VMAT) treatments of nasopharyngeal patients and studied the trade-off between treatment plan quality and delivery time in radiation therapy. For three nasopharyngeal patients, the authors generated treatment plans for nine different delivery scenarios using dedicated optimization methods. They compared these scenarios according to dose characteristics, number of beam directions, and estimated delivery times. In particular, the authors generated the following treatment plans: (1) a 4π plan, which is a not sequenced, fluence optimized plan that uses beam directions from approximately 1400 noncoplanar directions and marks a theoretical upper limit of the treatment plan quality, (2) a coplanar 2π plan with 72 coplanar beam directions as pendant to the noncoplanar 4π plan, (3) a coplanar VMAT plan, (4) a coplanar step and shoot (SnS) plan, (5) a beam angle optimized (BAO) coplanar SnS IMRT plan, (6) a noncoplanar BAO SnS plan, (7) a VMAT plan with rotated treatment couch, (8) a noncoplanar VMAT plan with an optimized great circle around the patient, and (9) a noncoplanar BAO VMAT plan with an arbitrary trajectory around the patient. VMAT using optimized noncoplanar irradiation trajectories reduced the mean and maximum doses in organs at risk compared to coplanar VMAT plans by 19% on average while the target coverage remains constant. A coplanar BAO SnS plan was superior to coplanar SnS or VMAT; however, noncoplanar plans like a noncoplanar BAO SnS plan or noncoplanar VMAT yielded a better plan quality than the best coplanar 2π plan. The treatment plan quality of VMAT plans depended on the length of the trajectory. The delivery times of noncoplanar VMAT plans were estimated to be 6.5 min in average; 1.6 min longer than a coplanar plan but on average 2.8 min faster than a noncoplanar SnS plan with comparable treatment plan quality. The authors' study reconfirms the dosimetric benefits of noncoplanar irradiation of nasopharyngeal tumors. Both SnS using optimized noncoplanar beam ensembles and VMAT using an optimized, arbitrary, noncoplanar trajectory enabled dose reductions in organs at risk compared to coplanar SnS and VMAT. Using great circles or simple couch rotations to implement noncoplanar VMAT, however, was not sufficient to yield meaningful improvements in treatment plan quality. The authors estimate that noncoplanar VMAT using arbitrary optimized irradiation trajectories comes at an increased delivery time compared to coplanar VMAT yet at a decreased delivery time compared to noncoplanar SnS IMRT.

Radiolabeling of Nanoparticles and Polymers for PET Imaging

PubMed Central

Stockhofe, Katharina; Postema, Johannes M.; Schieferstein, Hanno; Ross, Tobias L.

2014-01-01

Nanomedicine has become an emerging field in imaging and therapy of malignancies. Nanodimensional drug delivery systems have already been used in the clinic, as carriers for sensitive chemotherapeutics or highly toxic substances. In addition, those nanodimensional structures are further able to carry and deliver radionuclides. In the development process, non-invasive imaging by means of positron emission tomography (PET) represents an ideal tool for investigations of pharmacological profiles and to find the optimal nanodimensional architecture of the aimed-at drug delivery system. Furthermore, in a personalized therapy approach, molecular imaging modalities are essential for patient screening/selection and monitoring. Hence, labeling methods for potential drug delivery systems are an indispensable need to provide the radiolabeled analog. In this review, we describe and discuss various approaches and methods for the labeling of potential drug delivery systems using positron emitters. PMID:24699244

An Optimizing Space Data-Communications Scheduling Method and Algorithm with Interference Mitigation, Generalized for a Broad Class of Optimization Problems

NASA Technical Reports Server (NTRS)

Rash, James L.

2010-01-01

NASA's space data-communications infrastructure, the Space Network and the Ground Network, provide scheduled (as well as some limited types of unscheduled) data-communications services to user spacecraft via orbiting relay satellites and ground stations. An implementation of the methods and algorithms disclosed herein will be a system that produces globally optimized schedules with not only optimized service delivery by the space data-communications infrastructure but also optimized satisfaction of all user requirements and prescribed constraints, including radio frequency interference (RFI) constraints. Evolutionary search, a class of probabilistic strategies for searching large solution spaces, constitutes the essential technology in this disclosure. Also disclosed are methods and algorithms for optimizing the execution efficiency of the schedule-generation algorithm itself. The scheduling methods and algorithms as presented are adaptable to accommodate the complexity of scheduling the civilian and/or military data-communications infrastructure. Finally, the problem itself, and the methods and algorithms, are generalized and specified formally, with applicability to a very broad class of combinatorial optimization problems.

Solubilization and Stability of Mitomycin C Solutions Prepared for Intravesical Administration.

PubMed

Myers, Alan L; Zhang, Yan-Ping; Kawedia, Jitesh D; Zhou, Ximin; Sobocinski, Stacey M; Metcalfe, Michael J; Kramer, Mark A; Dinney, Colin P N; Kamat, Ashish M

2017-06-01

Mitomycin C (MMC) is an antitumor agent that is often administered intravesically to treat bladder cancer. Pharmacologically optimized studies have suggested varying methods to optimize delivery, with drug concentration and solution volume being the main drivers. However, these MMC concentrations (e.g. 2.0 mg/mL) supersede its solubility threshold, raising major concerns of inferior drug delivery. In this study, we seek to confirm that the pharmacologically optimized MMC concentrations are achievable in clinical practice through careful modifications of the solution preparation methods. MMC admixtures (1.0 and 2.0 mg/mL) were prepared in normal saline using conventional and alternative compounding methods. Conventional methodology resulted in poorly soluble solutions, with many visible particulates and crystallates. However, special compounding methods, which included incubation of solutions at 50 °C for 50 min followed by storage at 37 °C, were sufficient to solubilize drug. Chemical degradation of MMC solutions was determined over 6 h using high-performance liquid chromatography (HPLC) analytics, while physical stability was tested in parallel. Immediately following the 50 min incubation, both MMC solutions exhibited approximately 5-7% drug degradation. Based on the measured concentrations and linear regression of degradation plots, additional storage of these solutions at 37 °C for 5 h retained chemical stability criterion (< 10% overall drug loss). No physical changes were observed in any solutions at any test time points. We recommend that the described alternative preparation methods may improve intravesicular delivery of MMC in this urological setting, and advise that clinicians employing these changes should closely monitor patients for MMC toxicities and pharmacodynamics (change in clinical outcomes) that result from the potential enhancement of MMC exposure in the bladder.

Spiking neural network simulation: memory-optimal synaptic event scheduling.

PubMed

Stewart, Robert D; Gurney, Kevin N

2011-06-01

Spiking neural network simulations incorporating variable transmission delays require synaptic events to be scheduled prior to delivery. Conventional methods have memory requirements that scale with the total number of synapses in a network. We introduce novel scheduling algorithms for both discrete and continuous event delivery, where the memory requirement scales instead with the number of neurons. Superior algorithmic performance is demonstrated using large-scale, benchmarking network simulations.

Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection.

PubMed

Soudy, R; Byeon, N; Raghuwanshi, Y; Ahmed, S; Lavasanifar, A; Kaur, K

2017-01-01

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting peptides, peptides generally suffer from poor pharmacokinetics, enzymatic instability, and weak receptor affinity, and they need further structural modification before successful translation to clinics is possible. The current review gives an overview of the different engineering strategies that have been developed for peptide structure optimization to confer selectivity and stability. We also provide an update on the methods used for peptide ligand identification, and peptide- receptor interactions. Additionally, some applications for the use of peptides in targeted delivery of chemotherapeutics and diagnostics over the past 5 years are summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Controlling subcellular delivery to optimize therapeutic effect

PubMed Central

Mossalam, Mohanad; Dixon, Andrew S; Lim, Carol S

2010-01-01

This article focuses on drug targeting to specific cellular organelles for therapeutic purposes. Drugs can be delivered to all major organelles of the cell (cytosol, endosome/lysosome, nucleus, nucleolus, mitochondria, endoplasmic reticulum, Golgi apparatus, peroxisomes and proteasomes) where they exert specific effects in those particular subcellular compartments. Delivery can be achieved by chemical (e.g., polymeric) or biological (e.g., signal sequences) means. Unidirectional targeting to individual organelles has proven to be immensely successful for drug therapy. Newer technologies that accommodate multiple signals (e.g., protein switch and virus-like delivery systems) mimic nature and allow for a more sophisticated approach to drug delivery. Harnessing different methods of targeting multiple organelles in a cell will lead to better drug delivery and improvements in disease therapy. PMID:21113240

Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer.

PubMed

Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P; Bridges, Charles R

2017-01-01

Despite progress in clinical treatment, cardiovascular diseases are still the leading cause of morbidity and mortality worldwide. Therefore, novel therapeutic approaches are needed, targeting the underlying molecular mechanisms of disease with improved outcomes for patients. Gene therapy is one of the most promising fields for the development of new treatments for the advanced stages of cardiovascular diseases. The establishment of clinically relevant methods of gene transfer remains one of the principal limitations on the effectiveness of gene therapy. Recently, there have been significant advances in direct and transvascular gene delivery methods. The ideal gene transfer method should be explored in clinically relevant large animal models of heart disease to evaluate the roles of specific molecular pathways in disease pathogenesis. Characteristics of the optimal technique for gene delivery include low morbidity, an increased myocardial transcapillary gradient, esxtended vector residence time in the myocytes, and the exclusion of residual vector from the systemic circulation after delivery to minimize collateral expression and immune response. Here we describe myocardial gene transfer techniques with molecular cardiac surgery with recirculating delivery in a large animal model of post ischemic heart failure.

Developments in the formulation and delivery of spray dried vaccines

PubMed Central

Kanojia, Gaurav; Have, Rimko ten; Soema, Peter C.; Frijlink, Henderik; Amorij, Jean-Pierre; Kersten, Gideon

2017-01-01

ABSTRACT Spray drying is a promising method for the stabilization of vaccines, which are usually formulated as liquids. Usually, vaccine stability is improved by spray drying in the presence of a range of excipients. Unlike freeze drying, there is no freezing step involved, thus the damage related to this step is avoided. The edge of spray drying resides in its ability for particles to be engineered to desired requirements, which can be used in various vaccine delivery methods and routes. Although several spray dried vaccines have shown encouraging preclinical results, the number of vaccines that have been tested in clinical trials is limited, indicating a relatively new area of vaccine stabilization and delivery. This article reviews the current status of spray dried vaccine formulations and delivery methods. In particular it discusses the impact of process stresses on vaccine integrity, the application of excipients in spray drying of vaccines, process and formulation optimization strategies based on Design of Experiment approaches as well as opportunities for future application of spray dried vaccine powders for vaccine delivery. PMID:28925794

Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

PubMed Central

Upadhyay, Ravi Kant

2014-01-01

Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

Fundamental Study of the Delivery of Nanoiron to DNAPL Source Zones in Naturally Heterogeneous Field Systems

DTIC Science & Technology

2012-09-01

121 Published text books , book chapters, and theses.........................................................................125...optimize the rate and method of injection (e.g. direct push, hydraulic fracture ), or to optimize the nanoiron properties for specific site geology...expected that higher injection rates will increase the radius of influence by decreasing the efficiency of all three attachment mechanisms (diffusion

Suprachoroidal Drug Delivery to the Back of the Eye Using Hollow Microneedles

PubMed Central

Patel, Samirkumar R.; Lin, Angela S. P.; Edelhauser, Henry F.

2011-01-01

Purpose In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. Methods A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. Results Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800–1,000 μm and applied pressures of 250–300 kPa provided most reliable delivery. Conclusions Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye. PMID:20857178

Study of vesicle size distribution dependence on pH value based on nanopore resistive pulse method

NASA Astrophysics Data System (ADS)

Lin, Yuqing; Rudzevich, Yauheni; Wearne, Adam; Lumpkin, Daniel; Morales, Joselyn; Nemec, Kathleen; Tatulian, Suren; Lupan, Oleg; Chow, Lee

2013-03-01

Vesicles are low-micron to sub-micron spheres formed by a lipid bilayer shell and serve as potential vehicles for drug delivery. The size of vesicle is proposed to be one of the instrumental variables affecting delivery efficiency since the size is correlated to factors like circulation and residence time in blood, the rate for cell endocytosis, and efficiency in cell targeting. In this work, we demonstrate accessible and reliable detection and size distribution measurement employing a glass nanopore device based on the resistive pulse method. This novel method enables us to investigate the size distribution dependence of pH difference across the membrane of vesicles with very small sample volume and rapid speed. This provides useful information for optimizing the efficiency of drug delivery in a pH sensitive environment.

SU-F-T-540: Comprehensive Fluence Delivery Optimization with Multileaf Collimation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weppler, S; Villarreal-Barajas, J; Department of Medical Physics, Tom Baker Cancer Center, Calgary, Alberta

2016-06-15

Purpose: Multileaf collimator (MLC) leaf sequencing is performed via commercial black-box implementations, on which a user has limited to no access. We have developed an explicit, generic MLC sequencing model to serve as a tool for future investigations of fluence map optimization, fluence delivery optimization, and rotational collimator delivery methods. Methods: We have developed a novel, comprehensive model to effectively account for a variety of transmission and penumbra effects previously treated on an ad hoc basis in the literature. As the model is capable of quantifying a variety of effects, we utilize the asymmetric leakage intensity across each leaf tomore » deliver fluence maps with pixel size smaller than the narrowest leaf width. Developed using linear programming and mixed integer programming formulations, the model is implemented using state of the art open-source solvers. To demonstrate the versatility of the algorithm, a graphical user interface (GUI) was developed in MATLAB capable of accepting custom leaf specifications and transmission parameters. As a preliminary proof-ofconcept, we have sequenced the leaves of a Varian 120 Leaf Millennium MLC for five prostate cancer patient fields and one head and neck field. Predetermined fluence maps have been processed by data smoothing methods to obtain pixel sizes of 2.5 cm{sup 2}. The quality of output was analyzed using computer simulations. Results: For the prostate fields, an average root mean squared error (RMSE) of 0.82 and gamma (0.5mm/0.5%) of 91.4% were observed compared to RMSE and gamma (0.5mm/0.5%) values of 7.04 and 34.0% when the leakage considerations were omitted. Similar results were observed for the head and neck case. Conclusion: A model to sequence MLC leaves to optimality has been proposed. Future work will involve extensive testing and evaluation of the method on clinical MLCs and comparison with black-box leaf sequencing algorithms currently used by commercial treatment planning systems.« less

Optimized Delivery System Achieves Enhanced Endomyocardial Stem Cell Retention

PubMed Central

Behfar, Atta; Latere, Jean-Pierre; Bartunek, Jozef; Homsy, Christian; Daro, Dorothee; Crespo-Diaz, Ruben J.; Stalboerger, Paul G.; Steenwinckel, Valerie; Seron, Aymeric; Redfield, Margaret M.; Terzic, Andre

2014-01-01

Background Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results Stem cell retention was simulated in silico using one and three-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol – a nickel and titanium alloy displaying shape memory and super-elasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared to a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle, without impact on biocompatibility or safety. Conclusions Modeling guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention. PMID:24326777

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 2(3) factorial design and in vivo evaluation in rabbits.

PubMed

Soliman, Sara M; Abdelmalak, Nevine S; El-Gazayerly, Omaima N; Abdelaziz, Nabaweya

2016-06-01

Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2(3) full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48 ± 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 ± 0.13) mg/cm(2)/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 - α) 464.17 ± 113.15 ng h/ml compared with 209.02 ± 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.

Optimal resource allocation strategy for two-layer complex networks

NASA Astrophysics Data System (ADS)

Ma, Jinlong; Wang, Lixin; Li, Sufeng; Duan, Congwen; Liu, Yu

2018-02-01

We study the traffic dynamics on two-layer complex networks, and focus on its delivery capacity allocation strategy to enhance traffic capacity measured by the critical value Rc. With the limited packet-delivering capacity, we propose a delivery capacity allocation strategy which can balance the capacities of non-hub nodes and hub nodes to optimize the data flow. With the optimal value of parameter αc, the maximal network capacity is reached because most of the nodes have shared the appropriate delivery capacity by the proposed delivery capacity allocation strategy. Our work will be beneficial to network service providers to design optimal networked traffic dynamics.

Design and characterization of calcium alginate microparticles coated with polycations as protein delivery system.

PubMed

Zarate, J; Virdis, L; Orive, G; Igartua, M; Hernández, R M; Pedraz, J L

2011-01-01

Bovine serum albumin (BSA) loaded calcium alginate microparticles (MPs) produced in this study by a w/o emulsification and external gelation method exhibited spherical and fairly smooth and porous morphology with 1.052 ± 0.057 µm modal particle size. The high permeability of the calcium alginate hydrogel lead to a potent burst effect and too fast protein release. To overcome these problems, MPs were coated with polycations, such as chitosan, poly-L-lysine and DEAE-dextran. Our results demonstrated that coated MPs showed slower release and were able to significantly reduce the release of BSA in the first hour. Therefore, this method can be applied to prepare coated alginate MPs which could be an optimal system for the controlled release of biotherapeutic molecules. Nevertheless, further studies are needed to optimize delivery properties which could provide a sustained release of proteins.

Inherent smoothness of intensity patterns for intensity modulated radiation therapy generated by simultaneous projection algorithms

NASA Astrophysics Data System (ADS)

Xiao, Ying; Michalski, Darek; Censor, Yair; Galvin, James M.

2004-07-01

The efficient delivery of intensity modulated radiation therapy (IMRT) depends on finding optimized beam intensity patterns that produce dose distributions, which meet given constraints for the tumour as well as any critical organs to be spared. Many optimization algorithms that are used for beamlet-based inverse planning are susceptible to large variations of neighbouring intensities. Accurately delivering an intensity pattern with a large number of extrema can prove impossible given the mechanical limitations of standard multileaf collimator (MLC) delivery systems. In this study, we apply Cimmino's simultaneous projection algorithm to the beamlet-based inverse planning problem, modelled mathematically as a system of linear inequalities. We show that using this method allows us to arrive at a smoother intensity pattern. Including nonlinear terms in the simultaneous projection algorithm to deal with dose-volume histogram (DVH) constraints does not compromise this property from our experimental observation. The smoothness properties are compared with those from other optimization algorithms which include simulated annealing and the gradient descent method. The simultaneous property of these algorithms is ideally suited to parallel computing technologies.

Improving delivery routes using combined heuristic and optimization in a consumer goods distribution company

NASA Astrophysics Data System (ADS)

Wibisono, E.; Santoso, A.; Sunaryo, M. A.

2017-11-01

XYZ is a distributor of various consumer goods products. The company plans its delivery routes daily and in order to obtain route construction in a short amount of time, it simplifies the process by assigning drivers based on geographic regions. This approach results in inefficient use of vehicles leading to imbalance workloads. In this paper, we propose a combined method involving heuristic and optimization to obtain better solutions in acceptable computation time. The heuristic is based on a time-oriented, nearest neighbor (TONN) to form clusters if the number of locations is higher than a certain value. The optimization part uses a mathematical modeling formulation based on vehicle routing problem that considers heterogeneous vehicles, time windows, and fixed costs (HVRPTWF) and is used to solve routing problem in clusters. A case study using data from one month of the company’s operations is analyzed, and data from one day of operations are detailed in this paper. The analysis shows that the proposed method results in 24% cost savings on that month, but it can be as high as 54% in a day.

Spot-Scanning Proton Arc (SPArc) Therapy: The First Robust and Delivery-Efficient Spot-Scanning Proton Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Xuanfeng, E-mail: Xuanfeng.ding@beaumont.org; Li, Xiaoqiang; Zhang, J. Michele

Purpose: To present a novel robust and delivery-efficient spot-scanning proton arc (SPArc) therapy technique. Methods and Materials: A SPArc optimization algorithm was developed that integrates control point resampling, energy layer redistribution, energy layer filtration, and energy layer resampling. The feasibility of such a technique was evaluated using sample patients: 1 patient with locally advanced head and neck oropharyngeal cancer with bilateral lymph node coverage, and 1 with a nonmobile lung cancer. Plan quality, robustness, and total estimated delivery time were compared with the robust optimized multifield step-and-shoot arc plan without SPArc optimization (Arc{sub multi-field}) and the standard robust optimized intensity modulatedmore » proton therapy (IMPT) plan. Dose-volume histograms of target and organs at risk were analyzed, taking into account the setup and range uncertainties. Total delivery time was calculated on the basis of a 360° gantry room with 1 revolutions per minute gantry rotation speed, 2-millisecond spot switching time, 1-nA beam current, 0.01 minimum spot monitor unit, and energy layer switching time of 0.5 to 4 seconds. Results: The SPArc plan showed potential dosimetric advantages for both clinical sample cases. Compared with IMPT, SPArc delivered 8% and 14% less integral dose for oropharyngeal and lung cancer cases, respectively. Furthermore, evaluating the lung cancer plan compared with IMPT, it was evident that the maximum skin dose, the mean lung dose, and the maximum dose to ribs were reduced by 60%, 15%, and 35%, respectively, whereas the conformity index was improved from 7.6 (IMPT) to 4.0 (SPArc). The total treatment delivery time for lung and oropharyngeal cancer patients was reduced by 55% to 60% and 56% to 67%, respectively, when compared with Arc{sub multi-field} plans. Conclusion: The SPArc plan is the first robust and delivery-efficient proton spot-scanning arc therapy technique, which could potentially be implemented into routine clinical practice.« less

Optimized preparation of in situ forming microparticles for the parenteral delivery of vinpocetine.

PubMed

Li, Jizhong; Chen, Fei; Hu, Chanjuan; He, Ling; Yan, Keshu; Zhou, Liying; Pan, Weisan

2008-06-01

A spherical symmetric design-response surface methodology was applied to optimize the preparation of vinpocetine-loaded poly(D,L-lactide-co-glycolide) PLGA in situ forming microparticles (ISM system). The influence of the ratio of PLGA to vinpocetine (w/w), the concentration of Tween 80 (w/v) and the volume of propylene glycol on the burst release, medium particle diameter and size distribution was evaluated. Scan electron microscopy of the optimized in situ microparticles exhibited spherical shape, and vinpocetine-loading mainly inside the microparticles. The data showed that the release of vinpocetine from in situ microparticles in vitro and in vivo lasted about 40 d. In vivo pharmacokinetic characteristics of the optimized in situ microparticles was assessed after they were intramuscularly injected into rats. HPLC method was used to determine the plasma concentration of vinpocetine. The absolute bioavailability of vinpocetine in the microparticles was 27.6% in rats, which suggested that PLGA in situ microparticles were a valuable system for the delivery of vinpocetine.

Transient gene expression in epidermal cells of plant leaves by biolistic DNA delivery.

PubMed

Ueki, Shoko; Magori, Shimpei; Lacroix, Benoît; Citovsky, Vitaly

2013-01-01

Transient gene expression is a useful approach for studying the functions of gene products. In the case of plants, Agrobacterium infiltration is a method of choice for transient introduction of genes for many species. However, this technique does not work efficiently in some species, such as Arabidopsis thaliana. Moreover, the infection of Agrobacterium is known to induce dynamic changes in gene expression patterns in the host plants, possibly affecting the function and localization of the proteins to be tested. These problems can be circumvented by biolistic delivery of the genes of interest. Here, we present an optimized protocol for biolistic delivery of plasmid DNA into epidermal cells of plant leaves, which can be easily performed using the Bio-Rad Helios gene gun system. This protocol allows efficient and reproducible transient expression of diverse genes in Arabidopsis, Nicotiana benthamiana and N. tabacum, and is suitable for studies of the biological function and subcellular localization of the gene products directly in planta. The protocol also can be easily adapted to other species by optimizing the delivery gas pressure.

TU-G-BRB-01: Continuous Path Optimization for Non-Coplanar Variant SAD IMRT Delivery Using C-Arm Machines.

PubMed

Ruan, D; Dong, P; Low, D; Sheng, K

2012-06-01

To develop and investigate a continuous path optimization methodology to traverse prescribed non-coplanar IMRT beams with variant SADs, by orchestrating the couch and gantry movement with zero-collision, minimal patient motion consequence and machine travel time. We convert the given collision zone definition and the prescribed beam location/angles to a tumor-centric coordinate, and represent the traversing path as a continuous open curve. We proceed to optimize a composite objective function consisting of (1) a strong attraction energy to ensure all prescribed beams are en-route, (2) a penalty for patient-motion inducing couch motion, and (3) a penalty for travel-time inducing overall path-length. Feasibility manifold is defined as complement to collision zone and the optimization is performed with a level set representation evolved with variational flows. The proposed method has been implemented and tested on clinically derived data. In the absence of any existing solutions for the same problem, we validate by: (1) visual inspecting the generated path rendered in the 3D tumor-centric coordinates, and (2) comparing with a traveling-salesman (TSP) solution obtained from relaxing the variant SADs and continuous collision-avoidance requirement. The proposed method has generated delivery paths that are smooth and intuitively appealing. Under relaxed settings, our results outperform the generic TSP solutions and agree with specially tuned versions. We have proposed a novel systematic approach that automatically determines the continuous path to cover non-coplanar, varying SAD IMRT beams. The proposed approach accommodates patient-specific collision zone definition and ensures its avoidance continuously. The differential penalty to couch and gantry motions allows customizable tradeoff between patient geometry stability and delivery efficiency. This development paves the path to achieve safe, accurate and efficient non-coplanar IMRT delivery with the advanced robotic controls in new-generation C-arm systems, enabling practical harvesting of the dose benefit offered by non-coplanar, variant SAD IMRT treatment. © 2012 American Association of Physicists in Medicine.

Could Revision of the Embryology Influence Our Cesarean Delivery Technique: Towards an Optimized Cesarean Delivery for Universal Use

PubMed Central

Stark, Michael; Mynbaev, Ospan; Vassilevski, Yuri; Rozenberg, Patrick

2016-01-01

Until today, there is no standardized Cesarean Section method and many variations exist. The main variations concern the type of abdominal incision, usage of abdominal packs, suturing the uterus in one or two layers, and suturing the peritoneal layers or leaving them open. One of the questions is the optimal location of opening the uterus. Recently, omission of the bladder flap was recommended. The anatomy and histology as results from the embryological knowledge might help to solve this question. The working thesis is that the higher the incision is done, the more damage to muscle tissue can take place contrary to incision in the lower segment, where fibrous tissue prevails. In this perspective, a call for participation in a two-armed prospective study is included, which could result in an optimal, evidence-based Cesarean Section for universal use. PMID:28078171

CyberArc: a non-coplanar-arc optimization algorithm for CyberKnife

NASA Astrophysics Data System (ADS)

Kearney, Vasant; Cheung, Joey P.; McGuinness, Christopher; Solberg, Timothy D.

2017-07-01

The goal of this study is to demonstrate the feasibility of a novel non-coplanar-arc optimization algorithm (CyberArc). This method aims to reduce the delivery time of conventional CyberKnife treatments by allowing for continuous beam delivery. CyberArc uses a 4 step optimization strategy, in which nodes, beams, and collimator sizes are determined, source trajectories are calculated, intermediate radiation models are generated, and final monitor units are calculated, for the continuous radiation source model. The dosimetric results as well as the time reduction factors for CyberArc are presented for 7 prostate and 2 brain cases. The dosimetric quality of the CyberArc plans are evaluated using conformity index, heterogeneity index, local confined normalized-mutual-information, and various clinically relevant dosimetric parameters. The results indicate that the CyberArc algorithm dramatically reduces the treatment time of CyberKnife plans while simultaneously preserving the dosimetric quality of the original plans.

CyberArc: a non-coplanar-arc optimization algorithm for CyberKnife.

PubMed

Kearney, Vasant; Cheung, Joey P; McGuinness, Christopher; Solberg, Timothy D

2017-06-26

The goal of this study is to demonstrate the feasibility of a novel non-coplanar-arc optimization algorithm (CyberArc). This method aims to reduce the delivery time of conventional CyberKnife treatments by allowing for continuous beam delivery. CyberArc uses a 4 step optimization strategy, in which nodes, beams, and collimator sizes are determined, source trajectories are calculated, intermediate radiation models are generated, and final monitor units are calculated, for the continuous radiation source model. The dosimetric results as well as the time reduction factors for CyberArc are presented for 7 prostate and 2 brain cases. The dosimetric quality of the CyberArc plans are evaluated using conformity index, heterogeneity index, local confined normalized-mutual-information, and various clinically relevant dosimetric parameters. The results indicate that the CyberArc algorithm dramatically reduces the treatment time of CyberKnife plans while simultaneously preserving the dosimetric quality of the original plans.

A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting.

PubMed

Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

2012-01-01

The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.

Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization.

PubMed

Caffrey, Leah M; deRonde, Brittany M; Minter, Lisa M; Tew, Gregory N

2016-10-10

A fundamental understanding of how polymer structure impacts internalization and delivery of biologically relevant cargoes, particularly small interfering ribonucleic acid (siRNA), is of critical importance to the successful design of improved delivery reagents. Herein we report the use of ring-opening metathesis polymerization (ROMP) methods to synthesize two series of guanidinium-rich protein transduction domain mimics (PTDMs): one based on an imide scaffold that contains one guanidinium moiety per repeat unit, and another based on a diester scaffold that contains two guanidinium moieties per repeat unit. By varying both the degree of polymerization and, in effect, the relative number of cationic charges in each PTDM, the performances of the two ROMP backbones for siRNA internalization were evaluated and compared. Internalization of fluorescently labeled siRNA into Jurkat T cells demonstrated that fluorescein isothiocyanate (FITC)-siRNA internalization had a charge content dependence, with PTDMs containing approximately 40 to 60 cationic charges facilitating the most internalization. Despite this charge content dependence, the imide scaffold yielded much lower viabilities in Jurkat T cells than the corresponding diester PTDMs with similar numbers of cationic charges, suggesting that the diester scaffold is preferred for siRNA internalization and delivery applications. These developments will not only improve our understanding of the structural factors necessary for optimal siRNA internalization, but will also guide the future development of optimized PTDMs for siRNA internalization and delivery.

Falcon: automated optimization method for arbitrary assessment criteria

DOEpatents

Yang, Tser-Yuan; Moses, Edward I.; Hartmann-Siantar, Christine

2001-01-01

FALCON is a method for automatic multivariable optimization for arbitrary assessment criteria that can be applied to numerous fields where outcome simulation is combined with optimization and assessment criteria. A specific implementation of FALCON is for automatic radiation therapy treatment planning. In this application, FALCON implements dose calculations into the planning process and optimizes available beam delivery modifier parameters to determine the treatment plan that best meets clinical decision-making criteria. FALCON is described in the context of the optimization of external-beam radiation therapy and intensity modulated radiation therapy (IMRT), but the concepts could also be applied to internal (brachytherapy) radiotherapy. The radiation beams could consist of photons or any charged or uncharged particles. The concept of optimizing source distributions can be applied to complex radiography (e.g. flash x-ray or proton) to improve the imaging capabilities of facilities proposed for science-based stockpile stewardship.

Cell-specific transmembrane injection of molecular cargo with gold nanoparticle-generated transient plasmonic nanobubbles

PubMed Central

Lukianova-Hleb, Ekaterina Y.; Wagner, Daniel S.; Brenner, Malcolm K.; Lapotko, Dmitri O.

2012-01-01

Optimal cell therapies require efficient, selective and rapid delivery of molecular cargo into target cells without compromising their viability. Achieving these goals ex vivo in bulk heterogeneous multi-cell systems such as human grafts is impeded by low selectivity and speed of cargo delivery and by significant damage to target and non-target cells. We have developed a cell level approach for selective and guided trans-membrane injection of extracellular cargo into specific target cells using transient plasmonic nanobubbles (PNB) as cell-specific nano-injectors. As a technical platform for this method we developed a laser flow cell processing system. The PNB injection method and flow system were tested in heterogeneous cell suspensions of target and non-target cells for delivery of Dextran-FITC dye into squamous cell carcinoma HN31 cells and transfection of human T-cells with a green fluorescent protein-encoding plasmid. In both models the method demonstrated single cell type selectivity, high efficacy of delivery (96% both for HN31 cells T-cells), speed of delivery (nanoseconds) and viability of treated target cells (96% for HN31 cells and 75% for T-cells). The PNB injection method may therefore be beneficial for real time processing of human grafts without removal of physiologically important cells. PMID:22521612

Cell-specific transmembrane injection of molecular cargo with gold nanoparticle-generated transient plasmonic nanobubbles.

PubMed

Lukianova-Hleb, Ekaterina Y; Wagner, Daniel S; Brenner, Malcolm K; Lapotko, Dmitri O

2012-07-01

Optimal cell therapies require efficient, selective and rapid delivery of molecular cargo into target cells without compromising their viability. Achieving these goals ex vivo in bulk heterogeneous multi-cell systems such as human grafts is impeded by low selectivity and speed of cargo delivery and by significant damage to target and non-target cells. We have developed a cell level approach for selective and guided transmembrane injection of extracellular cargo into specific target cells using transient plasmonic nanobubbles (PNB) as cell-specific nano-injectors. As a technical platform for this method we developed a laser flow cell processing system. The PNB injection method and flow system were tested in heterogeneous cell suspensions of target and non-target cells for delivery of Dextran-FITC dye into squamous cell carcinoma HN31 cells and transfection of human T-cells with a green fluorescent protein-encoding plasmid. In both models the method demonstrated single cell type selectivity, high efficacy of delivery (96% both for HN31 cells T-cells), speed of delivery (nanoseconds) and viability of treated target cells (96% for HN31 cells and 75% for T-cells). The PNB injection method may therefore be beneficial for real time processing of human grafts without removal of physiologically important cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Development and optimization of methotrexate-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery applications.

PubMed

Tahir, Nayab; Madni, Asadullah; Balasubramanian, Vimalkumar; Rehman, Mubashar; Correia, Alexandra; Kashif, Prince Muhammad; Mäkilä, Ermei; Salonen, Jarno; Santos, Hélder A

2017-11-25

Lipid-polymer hybrid nanoparticles (LPHNPs) are emerging platforms for drug delivery applications. In the present study, methotrexate loaded LPHNPs consisted of PLGA and Lipoid S100 were fabricated by employing a single-step modified nanoprecipitation method combined with self-assembly. A three factor, three level Box Behnken design using Design-Expert ® software was employed to access the influence of three independent variables on the particle size, drug entrapment and percent drug release. The optimized formulation was selected through numeric optimization approach. The results were supported with the ANOVA analysis, regression equations and response surface plots. Transmission electron microscope images indicated the nanosized and spherical shape of the LPHNPs with fair size distribution. The nanoparticles ranged from 176 to 308nm, which increased with increased polymer concentration. The increase in polymer and lipid concentration also increased the drug entrapment efficiency. The in vitro drug release was in range 70.34-91.95% and the release mechanism follow the Higuchi model (R 2 =0.9888) and Fickian diffusion (n<0.5). The in vitro cytotoxicity assay and confocal microscopy of the optimized formulation demonstrate the good safety and better internalization of the LPHNPs. The cell antiproliferation showed the spatial and controlled action of the nanoformulation as compared to the plain drug solution. The results suggest that LPHNPs can be a promising delivery system envisioned to safe, stable and potentially controlled delivery of methotrexate to the cancer cells to achieve better therapeutic outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical modification: the key to clinical application of RNA interference?

PubMed Central

Corey, David R.

2007-01-01

RNA interference provides a potent and specific method for controlling gene expression in human cells. To translate this potential into a broad new family of therapeutics, it is necessary to optimize the efficacy of the RNA-based drugs. As discussed in this Review, it might be possible to achieve this optimization using chemical modifications that improve their in vivo stability, cellular delivery, biodistribution, pharmacokinetics, potency, and specificity. PMID:18060019

Formulation and evaluation of optimized oxybenzone microsponge gel for topical delivery.

PubMed

Pawar, Atmaram P; Gholap, Aditya P; Kuchekar, Ashwin B; Bothiraja, C; Mali, Ashwin J

2015-01-01

Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 3(2) factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10-0.22 µm. The optimized formulation possesses the particle size and entrapment efficiency of 72 ± 0.77 µm and 96.9 ± 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity.

A personalized medicine approach to the design of dry powder inhalers: Selecting the optimal amount of bypass.

PubMed

Kopsch, Thomas; Murnane, Darragh; Symons, Digby

2017-08-30

In dry powder inhalers (DPIs) the patient's inhalation manoeuvre strongly influences the release of drug. Drug release from a DPI may also be influenced by the size of any air bypass incorporated in the device. If the amount of bypass is high less air flows through the entrainment geometry and the release rate is lower. In this study we propose to reduce the intra- and inter-patient variations of drug release by controlling the amount of air bypass in a DPI. A fast computational method is proposed that can predict how much bypass is needed for a specified drug delivery rate for a particular patient. This method uses a meta-model which was constructed using multiphase computational fluid dynamic (CFD) simulations. The meta-model is applied in an optimization framework to predict the required amount of bypass needed for drug delivery that is similar to a desired target release behaviour. The meta-model was successfully validated by comparing its predictions to results from additional CFD simulations. The optimization framework has been applied to identify the optimal amount of bypass needed for fictitious sample inhalation manoeuvres in order to deliver a target powder release profile for two patients. Copyright © 2017 Elsevier B.V. All rights reserved.

In Vitro Evaluation of Eslicarbazepine Delivery via Enteral Feeding Tubes.

PubMed

Reindel, Kristin; Zhao, Fang; Hughes, Susan; Dave, Vivek S

2017-12-01

Purpose: The feasibility of preparing an eslicarbazepine acetate suspension using Aptiom tablets for administration via enteral feeding tubes was evaluated. Methods: Eslicarbazepine acetate suspension (40 mg/mL) was prepared using Aptiom tablets after optimizing the tablet crushing methods and the vehicle composition. A stability-indicating high-performance liquid chromatography (HPLC) method was developed to monitor the eslicarbazepine stability in the prepared suspension. Three enteric feeding tubes of various composition and dimensions were evaluated for the delivery of the suspensions. The suspension was evaluated for the physical and chemical stability for 48 hours. Results: The reproducibility and consistency of particle size reduction was found to be best with standard mortar/pestle. The viscosity analysis and physical stability studies showed that ORA-Plus:water (50:50 v/v) was optimal for suspending ability and flowability of suspension through the tubes. The developed HPLC method was found to be stability indicating and suitable for the assay of eslicarbazepine acetate in the prepared suspension. The eslicarbazepine concentrations in separately prepared suspensions were within acceptable range (±3%), indicating accuracy and reproducibility of the procedure. The eslicarbazepine concentrations in suspensions before and after delivery through the enteric feeding tubes were within acceptable range (±4%), indicating absence of any physical/chemical interactions of eslicarbazepine with the tubes and a successful delivery of eslicarbazepine dosage via enteric feeding tubes. The stability study results showed that eslicarbazepine concentration in the suspension remained unchanged when stored at room temperature for 48 hours. Conclusion: The study presents a convenient procedure for the preparation of a stable suspension of eslicarbazepine acetate (40 mg/mL) using Aptiom tablets, for administration via enteral feeding tubes.

Shortening Delivery Times of Intensity Modulated Proton Therapy by Reducing Proton Energy Layers During Treatment Plan Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Water, Steven van de, E-mail: s.vandewater@erasmusmc.nl; Kooy, Hanne M.; Heijmen, Ben J.M.

2015-06-01

Purpose: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan. Methods and Materials: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system “Erasmus-iCycle.” The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust “time-efficient plan” (with energy layer reduction) with a robust “standard clinical plan” (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases.more » Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds. Results: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases. Conclusions: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs.« less

Periodic Heterogeneous Vehicle Routing Problem With Driver Scheduling

NASA Astrophysics Data System (ADS)

Mardiana Panggabean, Ellis; Mawengkang, Herman; Azis, Zainal; Filia Sari, Rina

2018-01-01

The paper develops a model for the optimal management of logistic delivery of a given commodity. The company has different type of vehicles with different capacity to deliver the commodity for customers. The problem is then called Periodic Heterogeneous Vehicle Routing Problem (PHVRP). The goal is to schedule the deliveries according to feasible combinations of delivery days and to determine the scheduling of fleet and driver and routing policies of the vehicles. The objective is to minimize the sum of the costs of all routes over the planning horizon. We propose a combined approach of heuristic algorithm and exact method to solve the problem.

A modular approach to intensity-modulated arc therapy optimization with noncoplanar trajectories

NASA Astrophysics Data System (ADS)

Papp, Dávid; Bortfeld, Thomas; Unkelbach, Jan

2015-07-01

Utilizing noncoplanar beam angles in volumetric modulated arc therapy (VMAT) has the potential to combine the benefits of arc therapy, such as short treatment times, with the benefits of noncoplanar intensity modulated radiotherapy (IMRT) plans, such as improved organ sparing. Recently, vendors introduced treatment machines that allow for simultaneous couch and gantry motion during beam delivery to make noncoplanar VMAT treatments possible. Our aim is to provide a reliable optimization method for noncoplanar isocentric arc therapy plan optimization. The proposed solution is modular in the sense that it can incorporate different existing beam angle selection and coplanar arc therapy optimization methods. Treatment planning is performed in three steps. First, a number of promising noncoplanar beam directions are selected using an iterative beam selection heuristic; these beams serve as anchor points of the arc therapy trajectory. In the second step, continuous gantry/couch angle trajectories are optimized using a simple combinatorial optimization model to define a beam trajectory that efficiently visits each of the anchor points. Treatment time is controlled by limiting the time the beam needs to trace the prescribed trajectory. In the third and final step, an optimal arc therapy plan is found along the prescribed beam trajectory. In principle any existing arc therapy optimization method could be incorporated into this step; for this work we use a sliding window VMAT algorithm. The approach is demonstrated using two particularly challenging cases. The first one is a lung SBRT patient whose planning goals could not be satisfied with fewer than nine noncoplanar IMRT fields when the patient was treated in the clinic. The second one is a brain tumor patient, where the target volume overlaps with the optic nerves and the chiasm and it is directly adjacent to the brainstem. Both cases illustrate that the large number of angles utilized by isocentric noncoplanar VMAT plans can help improve dose conformity, homogeneity, and organ sparing simultaneously using the same beam trajectory length and delivery time as a coplanar VMAT plan.

Formulation, optimization and characterization of cationic polymeric nanoparticles of mast cell stabilizing agent using the Box-Behnken experimental design.

PubMed

Gajra, Balaram; Patel, Ravi R; Dalwadi, Chintan

2016-01-01

The present research work was intended to develop and optimize sustained release of biodegradable chitosan nanoparticles (CSNPs) as delivery vehicle for sodium cromoglicate (SCG) using the circumscribed Box-Behnken experimental design (BBD) and evaluate its potential for oral permeability enhancement. The 3-factor, 3-level BBD was employed to investigate the combined influence of formulation variables on particle size and entrapment efficiency (%EE) of SCG-CSNPs prepared by ionic gelation method. The generated polynomial equation was validated and desirability function was utilized for optimization. Optimized SCG-CSNPs were evaluated for physicochemical, morphological, in-vitro characterizations and permeability enhancement potential by ex-vivo and uptake study using CLSM. SCG-CSNPs exhibited particle size of 200.4 ± 4.06 nm and %EE of 62.68 ± 2.4% with unimodal size distribution having cationic, spherical, smooth surface. Physicochemical and in-vitro characterization revealed existence of SCG in amorphous form inside CSNPs without interaction and showed sustained release profile. Ex-vivo and uptake study showed the permeability enhancement potential of CSNPs. The developed SCG-CSNPs can be considered as promising delivery strategy with respect to improved permeability and sustained drug release, proving importance of CSNPs as potential oral delivery system for treatment of allergic rhinitis. Hence, further studies should be performed for establishing the pharmacokinetic potential of the CSNPs.

Assessment of regional management strategies for controlling seawater intrusion

USGS Publications Warehouse

Reichard, E.G.; Johnson, T.A.

2005-01-01

Simulation-optimization methods, applied with adequate sensitivity tests, can provide useful quantitative guidance for controlling seawater intrusion. This is demonstrated in an application to the West Coast Basin of coastal Los Angeles that considers two management options for improving hydraulic control of seawater intrusion: increased injection into barrier wells and in lieu delivery of surface water to replace current pumpage. For the base-case optimization analysis, assuming constant groundwater demand, in lieu delivery was determined to be most cost effective. Reduced-cost information from the optimization provided guidance for prioritizing locations for in lieu delivery. Model sensitivity to a suite of hydrologic, economic, and policy factors was tested. Raising the imposed average water-level constraint at the hydraulic-control locations resulted in nonlinear increases in cost. Systematic varying of the relative costs of injection and in lieu water yielded a trade-off curve between relative costs and injection/in lieu amounts. Changing the assumed future scenario to one of increasing pumpage in the adjacent Central Basin caused a small increase in the computed costs of seawater intrusion control. Changing the assumed boundary condition representing interaction with an adjacent basin did not affect the optimization results. Reducing the assumed hydraulic conductivity of the main productive aquifer resulted in a large increase in the model-computed cost. Journal of Water Resources Planning and Management ?? ASCE.

Case Study on Optimal Routing in Logistics Network by Priority-based Genetic Algorithm

NASA Astrophysics Data System (ADS)

Wang, Xiaoguang; Lin, Lin; Gen, Mitsuo; Shiota, Mitsushige

Recently, research on logistics caught more and more attention. One of the important issues on logistics system is to find optimal delivery routes with the least cost for products delivery. Numerous models have been developed for that reason. However, due to the diversity and complexity of practical problem, the existing models are usually not very satisfying to find the solution efficiently and convinently. In this paper, we treat a real-world logistics case with a company named ABC Co. ltd., in Kitakyusyu Japan. Firstly, based on the natures of this conveyance routing problem, as an extension of transportation problem (TP) and fixed charge transportation problem (fcTP) we formulate the problem as a minimum cost flow (MCF) model. Due to the complexity of fcTP, we proposed a priority-based genetic algorithm (pGA) approach to find the most acceptable solution to this problem. In this pGA approach, a two-stage path decoding method is adopted to develop delivery paths from a chromosome. We also apply the pGA approach to this problem, and compare our results with the current logistics network situation, and calculate the improvement of logistics cost to help the management to make decisions. Finally, in order to check the effectiveness of the proposed method, the results acquired are compared with those come from the two methods/ software, such as LINDO and CPLEX.

Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

NASA Astrophysics Data System (ADS)

Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

2014-02-01

It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

Silk-elastin-like protein polymer matrix for intraoperative delivery of an oncolytic vaccinia virus

PubMed Central

Price, Daniel L.; Li, Pingdong; Chen, Chun-Hao; Wong, Danni; Yu, Zhenkun; Chen, Nanhai G.; Yu, Yong A.; Szalay, Aladar A.; Cappello, Joseph; Fong, Yuman; Wong, Richard J.

2016-01-01

Background Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Methods Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. Results GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. Conclusion The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. PMID:25244076

Epidemiology, Etiology, Diagnosis, and Management of Placenta Accreta

PubMed Central

Garmi, Gali; Salim, Raed

2012-01-01

Placenta accreta is a severe pregnancy complication and is currently the most common indication for peripartum hysterectomy. It is becoming an increasingly common complication mainly due to the increasing rate of cesarean delivery. Main risk factor for placenta accreta is a previous cesarean delivery particularly when accompanied with a coexisting placenta previa. Antenatal diagnosis seems to be a key factor in optimizing maternal outcome. Diagnosis can be achieved by ultrasound in the majority of cases. Women with placenta accreta are usually delivered by a cesarean section. In order to avoid an emergency cesarean and to minimize complications of prematurity it is acceptable to schedule cesarean at 34 to 35 weeks. A multidisciplinary team approach and delivery at a center with adequate resources, including those for massive transfusion are both essential to reduce neonatal and maternal morbidity and mortality. The optimal management after delivery of the neonate is vague since randomized controlled trials and large cohort studies are lacking. Cesarean hysterectomy is probably the preferable treatment. In carefully selected cases, when fertility is desired, conservative management may be considered with caution. The current review discusses the epidemiology, predisposing factors, pathogenesis, diagnostic methods, clinical implications and management options of this condition. PMID:22645616

Optimization of Personnel Assignment Problem Based on Traveling Time by Using Hungarian Methods: Case Study on the Central Post Office Bandung

NASA Astrophysics Data System (ADS)

Supian, Sudradjat; Wahyuni, Sri; Nahar, Julita; Subiyanto

2018-01-01

In this paper, traveling time workers from the central post office Bandung in delivering the package to the destination location was optimized by using Hungarian method. Sensitivity analysis against data changes that may occur was also conducted. The sampled data in this study are 10 workers who will be assigned to deliver mail package to 10 post office delivery centers in Bandung that is Cikutra, Padalarang, Ujung Berung, Dayeuh Kolot, Asia- Africa, Soreang, Situ Saeur, Cimahi, Cipedes and Cikeruh. The result of this research is optimal traveling time from 10 workers to 10 destination locations. The optimal traveling time required by the workers is 387 minutes to reach the destination. Based on this result, manager of the central post office Bandung can make optimal decisions to assign tasks to their workers.

Repeated applications of a transdermal patch: analytical solution and optimal control of the delivery rate.

PubMed

Simon, L

2007-10-01

The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.

Nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease

PubMed Central

Fonseca-Santos, Bruno; Gremião, Maria Palmira Daflon; Chorilli, Marlus

2015-01-01

Alzheimer’s disease is a neurological disorder that results in cognitive and behavioral impairment. Conventional treatment strategies, such as acetylcholinesterase inhibitor drugs, often fail due to their poor solubility, lower bioavailability, and ineffective ability to cross the blood–brain barrier. Nanotechnological treatment methods, which involve the design, characterization, production, and application of nanoscale drug delivery systems, have been employed to optimize therapeutics. These nanotechnologies include polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and liquid crystals. Each of these are promising tools for the delivery of therapeutic devices to the brain via various routes of administration, particularly the intranasal route. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease. PMID:26345528

High content analysis platform for optimization of lipid mediated CRISPR-Cas9 delivery strategies in human cells.

PubMed

Steyer, Benjamin; Carlson-Stevermer, Jared; Angenent-Mari, Nicolas; Khalil, Andrew; Harkness, Ty; Saha, Krishanu

2016-04-01

Non-viral gene-editing of human cells using the CRISPR-Cas9 system requires optimized delivery of multiple components. Both the Cas9 endonuclease and a single guide RNA, that defines the genomic target, need to be present and co-localized within the nucleus for efficient gene-editing to occur. This work describes a new high-throughput screening platform for the optimization of CRISPR-Cas9 delivery strategies. By exploiting high content image analysis and microcontact printed plates, multi-parametric gene-editing outcome data from hundreds to thousands of isolated cell populations can be screened simultaneously. Employing this platform, we systematically screened four commercially available cationic lipid transfection materials with a range of RNAs encoding the CRISPR-Cas9 system. Analysis of Cas9 expression and editing of a fluorescent mCherry reporter transgene within human embryonic kidney cells was monitored over several days after transfection. Design of experiments analysis enabled rigorous evaluation of delivery materials and RNA concentration conditions. The results of this analysis indicated that the concentration and identity of transfection material have significantly greater effect on gene-editing than ratio or total amount of RNA. Cell subpopulation analysis on microcontact printed plates, further revealed that low cell number and high Cas9 expression, 24h after CRISPR-Cas9 delivery, were strong predictors of gene-editing outcomes. These results suggest design principles for the development of materials and transfection strategies with lipid-based materials. This platform could be applied to rapidly optimize materials for gene-editing in a variety of cell/tissue types in order to advance genomic medicine, regenerative biology and drug discovery. CRISPR-Cas9 is a new gene-editing technology for "genome surgery" that is anticipated to treat genetic diseases. This technology uses multiple components of the Cas9 system to cut out disease-causing mutations in the human genome and precisely suture in therapeutic sequences. Biomaterials based delivery strategies could help transition these technologies to the clinic. The design space for materials based delivery strategies is vast and optimization is essential to ensuring the safety and efficacy of these treatments. Therefore, new methods are required to rapidly and systematically screen gene-editing efficacy in human cells. This work utilizes an innovative platform to generate and screen many formulations of synthetic biomaterials and components of the CRISPR-Cas9 system in parallel. On this platform, we watch genome surgery in action using high content image analysis. These capabilities enabled us to identify formulation parameters for Cas9-material complexes that can optimize gene-editing in a specific human cell type. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

SU-E-T-539: Fixed Versus Variable Optimization Points in Combined-Mode Modulated Arc Therapy Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kainz, K; Prah, D; Ahunbay, E

2014-06-01

Purpose: A novel modulated arc therapy technique, mARC, enables superposition of step-and-shoot IMRT segments upon a subset of the optimization points (OPs) of a continuous-arc delivery. We compare two approaches to mARC planning: one with the number of OPs fixed throughout optimization, and another where the planning system determines the number of OPs in the final plan, subject to an upper limit defined at the outset. Methods: Fixed-OP mARC planning was performed for representative cases using Panther v. 5.01 (Prowess, Inc.), while variable-OP mARC planning used Monaco v. 5.00 (Elekta, Inc.). All Monaco planning used an upper limit of 91more » OPs; those OPs with minimal MU were removed during optimization. Plans were delivered, and delivery times recorded, on a Siemens Artiste accelerator using a flat 6MV beam with 300 MU/min rate. Dose distributions measured using ArcCheck (Sun Nuclear Corporation, Inc.) were compared with the plan calculation; the two were deemed consistent if they agreed to within 3.5% in absolute dose and 3.5 mm in distance-to-agreement among > 95% of the diodes within the direct beam. Results: Example cases included a prostate and a head-and-neck planned with a single arc and fraction doses of 1.8 and 2.0 Gy, respectively. Aside from slightly more uniform target dose for the variable-OP plans, the DVHs for the two techniques were similar. For the fixed-OP technique, the number of OPs was 38 and 39, and the delivery time was 228 and 259 seconds, respectively, for the prostate and head-and-neck cases. For the final variable-OP plans, there were 91 and 85 OPs, and the delivery time was 296 and 440 seconds, correspondingly longer than for fixed-OP. Conclusion: For mARC, both the fixed-OP and variable-OP approaches produced comparable-quality plans whose delivery was successfully verified. To keep delivery time per fraction short, a fixed-OP planning approach is preferred.« less

Feasibility of haloperidol-anchored albumin nanoparticles loaded with doxorubicin as dry powder inhaler for pulmonary delivery.

PubMed

Varshosaz, Jaleh; Hassanzadeh, Farshid; Mardani, Amin; Rostami, Mahboubeh

2015-03-01

Haloperidol (Hal) is a ligand that can target sigma 2 receptors over-expressed in non-small cell lung cancer. Hal targeted nanoparticles of bovine serum albumin (BSA) were prepared for pulmonary delivery of doxorubicin (DOX). The conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and (1)H nuclear magnetic resonance ((1)H NMR) spectroscopic methods. Nanoparticles were prepared by desolvation method from BSA-Hal and were loaded with DOX. They were characterized for their morphology, particle size, zeta potential, drug loading and release efficiency. The optimized nanoparticles were spray-dried using trehalose, l-leucin and mannitol as dry powder inhaler (DPI) in different inlet temperatures between 80 and 120°C. The obtained nanocomposites were characterized for their aerodynamic diameter, specific surface area (cm(2)/g) and fine particle fraction (FPF) by a Cascade Impactor device. The optimized nanoparticles showed particle size of 218 nm, zeta potential of -25.4 mV, drug entrapment efficiency of 89% and release efficiency of 56% until 2 h. After spray drying of these nanoparticles, the best results were obtained from mannitol with an inlet temperature of 80°C which produced a mean aerodynamic diameter of 4.58 μm, FPF of 66% and specific surface area of 6302.99 cm(2)/g. The obtained results suggest that the designed DPI could be a suitable inhaler for targeted delivery of DOX in pulmonary delivery.

Pharmacoinformatic approaches to understand complexation of dendrimeric nanoparticles with drugs

NASA Astrophysics Data System (ADS)

Jain, Vaibhav; Bharatam, Prasad V.

2014-02-01

Nanoparticle based drug delivery systems are gaining popularity due to their wide spectrum advantages over traditional drug delivery systems; among them, dendrimeric nano-vectors are the most widely explored carriers for pharmaceutical and biomedical applications. The precise mechanism of encapsulation of drug molecules inside the dendritic matrix, delivery of drugs into specific cells, interactions of nano-formulation with biological targets and proteins, etc. present a substantial challenge to the scientific understanding of the subject. Computational methods complement experimental techniques in the design and optimization of drug delivery systems, thus minimizing the investment in drug design and development. Significant progress in computer simulations could facilitate an understanding of the precise mechanism of encapsulation of bioactive molecules and their delivery. This review summarizes the pharmacoinformatic studies spanning from quantum chemical calculations to coarse-grained simulations, aimed at providing better insight into dendrimer-drug interactions and the physicochemical parameters influencing the binding and release mechanism of drugs.

Optimization of perfluoro nano-scale emulsions: the importance of particle size for enhanced oxygen transfer in biomedical applications.

PubMed

Fraker, Christopher A; Mendez, Armando J; Inverardi, Luca; Ricordi, Camillo; Stabler, Cherie L

2012-10-01

Nano-scale emulsification has long been utilized by the food and cosmetics industry to maximize material delivery through increased surface area to volume ratios. More recently, these methods have been employed in the area of biomedical research to enhance and control the delivery of desired agents, as in perfluorocarbon emulsions for oxygen delivery. In this work, we evaluate critical factors for the optimization of PFC emulsions for use in cell-based applications. Cytotoxicity screening revealed minimal cytotoxicity of components, with the exception of one perfluorocarbon utilized for emulsion manufacture, perfluorooctylbromide (PFOB), and specific w% limitations of PEG-based surfactants utilized. We optimized the manufacture of stable nano-scale emulsions via evaluation of: component materials, emulsification time and pressure, and resulting particle size and temporal stability. The initial emulsion size was greatly dependent upon the emulsion surfactant tested, with pluronics providing the smallest size. Temporal stability of the nano-scale emulsions was directly related to the perfluorocarbon utilized, with perfluorotributylamine, FC-43, providing a highly stable emulsion, while perfluorodecalin, PFD, coalesced over time. The oxygen mass transfer, or diffusive permeability, of the resulting emulsions was also characterized. Our studies found particle size to be the critical factor affecting oxygen mass transfer, as increased micelle size resulted in reduced oxygen diffusion. Overall, this work demonstrates the importance of accurate characterization of emulsification parameters in order to generate stable, reproducible emulsions with the desired bio-delivery properties. Copyright © 2012 Elsevier B.V. All rights reserved.

Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

PubMed Central

Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

2014-01-01

Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, J

Purpose: The aim of this work is to study the dosimetric impact of leaf interdigitation in prostate cancer dynamic IMRT treatment planning. Methods: Fifteen previously treated prostate cancer patients were replanned for dynamic IMRT (dMLC) with and without leaf interdigitation using Monaco 3.3 TPS on the Elekta Synergy linear accelerator. The prescription dose of PTV was 70Gy/35 fractions. Various dosimetric variables, such as PTV coverage, OAR sparing, delivery efficiency and optimization time, were evaluated for each plan. Results: Interdigitation did not improve the coverage, HI and CI for PTV. Regarding OARs, sparing was equivalent with and without interdigitation. Interdigitation shownmore » an increase in MUs and segments. It was worth noting that leaf interdigitation saved the optimization time. Conclusion: This study shows that leaf interdigitation does not improve plan quality when performing dMLC treatment plan for prostate cancer. However, it influences delivery efficiency and optimization time. Interdigitation may gain efficiency for dosimetrist when designing the prostate cancer dMLC plans.« less

A method to incorporate leakage and head scatter corrections into a tomotherapy inverse treatment planning algorithm

NASA Astrophysics Data System (ADS)

Holmes, Timothy W.

2001-01-01

A detailed tomotherapy inverse treatment planning method is described which incorporates leakage and head scatter corrections during each iteration of the optimization process, allowing these effects to be directly accounted for in the optimized dose distribution. It is shown that the conventional inverse planning method for optimizing incident intensity can be extended to include a `concurrent' leaf sequencing operation from which the leakage and head scatter corrections are determined. The method is demonstrated using the steepest-descent optimization technique with constant step size and a least-squared error objective. The method was implemented using the MATLAB scientific programming environment and its feasibility demonstrated for 2D test cases simulating treatment delivery using a single coplanar rotation. The results indicate that this modification does not significantly affect convergence of the intensity optimization method when exposure times of individual leaves are stratified to a large number of levels (>100) during leaf sequencing. In general, the addition of aperture dependent corrections, especially `head scatter', reduces incident fluence in local regions of the modulated fan beam, resulting in increased exposure times for individual collimator leaves. These local variations can result in 5% or greater local variation in the optimized dose distribution compared to the uncorrected case. The overall efficiency of the modified intensity optimization algorithm is comparable to that of the original unmodified case.

Formulation and Evaluation of Optimized Oxybenzone Microsponge Gel for Topical Delivery

PubMed Central

Pawar, Atmaram P.; Gholap, Aditya P.; Kuchekar, Ashwin B.; Bothiraja, C.; Mali, Ashwin J.

2015-01-01

Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 32 factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10–0.22 µm. The optimized formulation possesses the particle size and entrapment efficiency of 72 ± 0.77 µm and 96.9 ± 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity. PMID:25789176

Nanoparticles Prepared From N,N-Dimethyl-N-Octyl Chitosan as the Novel Approach for Oral Delivery of Insulin: Preparation, Statistical Optimization and In-vitro Characterization

PubMed Central

Shamsa, Elnaz Sadat; Mahjub, Reza; Mansoorpour, Maryam; Rafiee-Tehrani, Morteza; Abedin Dorkoosh, Farid

2018-01-01

In this study, N,N-Dimethyl-N-Octyl chitosan was synthesized. Nanoparticles containing insulin were prepared using PEC method and were statistically optimized using the Box-Behnken response surface methodology. The independent factors were considered to be the insulin concentration, concentration and pH of the polymer solution, while the dependent factors were characterized as the size, zeta potential, PdI and entrapment efficiency. The optimized nanoparticles were morphologically studied using SEM. The cytotoxicity of the nanoparticles on the Caco-2 cell culture was studied using the MTT cytotoxicity assay method, while the permeation of the insulin nanoparticles across the Caco-2 cell monolayer was also determined. The optimized nanoparticles posed appropriate physicochemical properties. The SEM morphological studies showed spherical to sub-spherical nanoparticles with no sign of aggregation. The in-vitro release study showed that 95.5 ± 1.40% of the loaded insulin was released in 400 min. The permeability studies revealed significant enhancement in the insulin permeability using nanoparticles prepared from octyl chitosan at 240 min (11.3 ± 0.78%). The obtained data revealed that insulin nanoparticles prepared from N,N-Dimethyl-N-Octyl chitosan can be considered as the good candidate for oral delivery of insulin compared to nanoparticles prepared from N,N,N-trimethyl chitosan.

Technical Aspects of Fecal Microbial Transplantation (FMT).

PubMed

Bhutiani, N; Schucht, J E; Miller, K R; McClave, Stephen A

2018-06-09

Fecal microbial transplantation (FMT) has become established as an effective therapeutic modality in the treatment of antibiotic-refractory recurrent Clostridium difficile colitis. A number of formulations and methods of delivery of FMT are currently available, each with distinct advantages. This review aims to review donor and patient selection for FMT as well as procedural aspects of FMT to help guide clinical practice. FMT can be obtained in fresh, frozen, lyophilized, and capsule-based formulations for delivery by oral ingestion, nasoenteric tube, colonoscopy, or enema (depending on the formulation used). Choosing the optimal method relies heavily on patient-related factors, including underlying pathology and severity of illness. As potential applications for FMT expand, careful donor screening and patient selection are critical to minimizing risk to patients and physicians. FMT represents an excellent therapeutic option for treatment of recurrent Clostridium difficile colitis and holds promise as a possible treatment modality in a variety of other conditions. The wide array of delivery methods allows for its application in various disease states in both the inpatient and outpatient setting.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

PubMed

Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

2017-04-01

Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Transethosomal gels as carriers for the transdermal delivery of colchicine: statistical optimization, characterization, and ex vivo evaluation.

PubMed

Abdulbaqi, Ibrahim M; Darwis, Yusrida; Assi, Reem Abou; Khan, Nurzalina Abdul Karim

2018-01-01

Colchicine is used for the treatment of gout, pseudo-gout, familial Mediterranean fever, and many other illnesses. Its oral administration is associated with poor bioavailability and severe gastrointestinal side effects. The drug is also known to have a low therapeutic index. Thus to overcome these drawbacks, the transdermal delivery of colchicine was investigated using transethosomal gels as potential carriers. Colchicine-loaded transethosomes (TEs) were prepared by the cold method and statistically optimized using three sets of 24 factorial design experiments. The optimized formulations were incorporated into Carbopol 940 ® gel base. The prepared colchicine-loaded transethosomal gels were further characterized for vesicular size, dispersity, zeta potential, drug content, pH, viscosity, yield, rheological behavior, and ex vivo skin permeation through Sprague Dawley rats' back skin. The results showed that the colchicine-loaded TEs had aspherical irregular shape, nanometric size range, and high entrapment efficiency. All the formulated gels exhibited non-Newtonian plastic flow without thixotropy. Colchicine-loaded transethosomal gels were able to significantly enhance the skin permeation parameters of the drug in comparison to the non-ethosomal gel. These findings suggested that the transethosomal gels are promising carriers for the transdermal delivery of colchicine, providing an alternative route for drug administration.

A novel software and conceptual design of the hardware platform for intensity modulated radiation therapy.

PubMed

Nguyen, Dan; Ruan, Dan; O'Connor, Daniel; Woods, Kaley; Low, Daniel A; Boucher, Salime; Sheng, Ke

2016-02-01

To deliver high quality intensity modulated radiotherapy (IMRT) using a novel generalized sparse orthogonal collimators (SOCs), the authors introduce a novel direct aperture optimization (DAO) approach based on discrete rectangular representation. A total of seven patients-two glioblastoma multiforme, three head & neck (including one with three prescription doses), and two lung-were included. 20 noncoplanar beams were selected using a column generation and pricing optimization method. The SOC is a generalized conventional orthogonal collimators with N leaves in each collimator bank, where N = 1, 2, or 4. SOC degenerates to conventional jaws when N = 1. For SOC-based IMRT, rectangular aperture optimization (RAO) was performed to optimize the fluence maps using rectangular representation, producing fluence maps that can be directly converted into a set of deliverable rectangular apertures. In order to optimize the dose distribution and minimize the number of apertures used, the overall objective was formulated to incorporate an L2 penalty reflecting the difference between the prescription and the projected doses, and an L1 sparsity regularization term to encourage a low number of nonzero rectangular basis coefficients. The optimization problem was solved using the Chambolle-Pock algorithm, a first-order primal-dual algorithm. Performance of RAO was compared to conventional two-step IMRT optimization including fluence map optimization and direct stratification for multileaf collimator (MLC) segmentation (DMS) using the same number of segments. For the RAO plans, segment travel time for SOC delivery was evaluated for the N = 1, N = 2, and N = 4 SOC designs to characterize the improvement in delivery efficiency as a function of N. Comparable PTV dose homogeneity and coverage were observed between the RAO and the DMS plans. The RAO plans were slightly superior to the DMS plans in sparing critical structures. On average, the maximum and mean critical organ doses were reduced by 1.94% and 1.44% of the prescription dose. The average number of delivery segments was 12.68 segments per beam for both the RAO and DMS plans. The N = 2 and N = 4 SOC designs were, on average, 1.56 and 1.80 times more efficient than the N = 1 SOC design to deliver. The mean aperture size produced by the RAO plans was 3.9 times larger than that of the DMS plans. The DAO and dose domain optimization approach enabled high quality IMRT plans using a low-complexity collimator setup. The dosimetric quality is comparable or slightly superior to conventional MLC-based IMRT plans using the same number of delivery segments. The SOC IMRT delivery efficiency can be significantly improved by increasing the leaf numbers, but the number is still significantly lower than the number of leaves in a typical MLC.

Designing food delivery systems: challenges related to the in vitro methods employed to determine the fate of bioactives in the gut.

PubMed

Arranz, Elena; Corredig, Milena; Guri, Anilda

2016-08-10

An in depth understanding of the underpinning mechanisms that relate to food disruption and processing in the gastrointestinal tract is necessary to achieve optimal intake of nutrients and their bioefficacy. Although in vivo trials can provide insights on physiological responses of nutrients, in vitro assays are often applied as tools to understand specific mechanisms, or as prescreening methods to determine the factors associated with the uptake of food components in the gastrointestinal tract. In vitro assays are also often utilized to design novel or improved food delivery systems. In this review the available approaches to study delivery and uptake of food bioactives and the associated challenges are discussed. For an in depth understanding of food processing in the gastrointestinal tract, it is necessary to apply multidisciplinary methodologies, at the interface between materials science, chemistry, physics and biology.

Analysis of low molecular weight acids by monolithic immobilized pH gradient-based capillary isoelectric focusing coupled with mass spectrometry.

PubMed

Wang, Tingting; Fekete, Agnes; Gaspar, Andras; Ma, Junfeng; Liang, Zhen; Yuan, Huiming; Zhang, Lihua; Schmitt-Kopplin, Philippe; Zhang, Yukui

2011-02-01

A novel method for the separation and detection of low molecular weight (LMW) acids was developed using monolithic immobilized pH gradient-based capillary isoelectric focusing coupled with mass spectrometry. Two main parameters, focusing conditions and delivery buffer conditions, which might affect separation efficiency, were optimized with the focusing time of 7 min at 350 V/cm and the delivery buffer of 50% (v/v) acetonitrile in 10 mmol/L ammonium formate (pH 3.0). Under these conditions, the linear correlation between the volume of delivery solvent and the pK(a) of the model components was observed. In addition, the separation mechanism of LMW acids was proposed as well. We suppose that this method may provide a useful tool for the characterization of LMW components (e.g. natural organic matter of different origins). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Space Launch System Mission Flexibility Assessment

NASA Technical Reports Server (NTRS)

Monk, Timothy; Holladay, Jon; Sanders, Terry; Hampton, Bryan

2012-01-01

The Space Launch System (SLS) is envisioned as a heavy lift vehicle that will provide the foundation for future beyond low Earth orbit (LEO) missions. While multiple assessments have been performed to determine the optimal configuration for the SLS, this effort was undertaken to evaluate the flexibility of various concepts for the range of missions that may be required of this system. These mission scenarios include single launch crew and/or cargo delivery to LEO, single launch cargo delivery missions to LEO in support of multi-launch mission campaigns, and single launch beyond LEO missions. Specifically, we assessed options for the single launch beyond LEO mission scenario using a variety of in-space stages and vehicle staging criteria. This was performed to determine the most flexible (and perhaps optimal) method of designing this particular type of mission. A specific mission opportunity to the Jovian system was further assessed to determine potential solutions that may meet currently envisioned mission objectives. This application sought to significantly reduce mission cost by allowing for a direct, faster transfer from Earth to Jupiter and to determine the order-of-magnitude mass margin that would be made available from utilization of the SLS. In general, smaller, existing stages provided comparable performance to larger, new stage developments when the mission scenario allowed for optimal LEO dropoff orbits (e.g. highly elliptical staging orbits). Initial results using this method with early SLS configurations and existing Upper Stages showed the potential of capturing Lunar flyby missions as well as providing significant mass delivery to a Jupiter transfer orbit.

Solving multi-customer FPR model with quality assurance and discontinuous deliveries using a two-phase algebraic approach.

PubMed

Chiu, Yuan-Shyi Peter; Chou, Chung-Li; Chang, Huei-Hsin; Chiu, Singa Wang

2016-01-01

A multi-customer finite production rate (FPR) model with quality assurance and discontinuous delivery policy was investigated in a recent paper (Chiu et al. in J Appl Res Technol 12(1):5-13, 2014) using differential calculus approach. This study employs mathematical modeling along with a two-phase algebraic method to resolve such a specific multi-customer FPR model. As a result, the optimal replenishment lot size and number of shipments can be derived without using the differential calculus. Such a straightforward method may assist practitioners who with insufficient knowledge of calculus in learning and managing the real multi-customer FPR systems more effectively.

Disruptive Technology: Saving Money and Inspiring Engagement in Professional Staff.

PubMed

McPherson, Penne; Talbot, Elizabeth

Competent, efficient, and cost-effective delivery of professional development is a challenge in health care. Collaboration of teaching methodologies with academia and acute care offers fresh perspectives and delivery methods that can facilitate optimal outcomes. One multihospital system introduced the academic "flipped classroom" model to its acute care setting and integrated it into professional development requirements. The concept of the flipped classroom requires independent student engagement prior to classroom activities versus the traditional classroom lecture model. Results realized a cost savings in 2 years of $28,737 in addition to positive employee engagement.

Optimizing Safety, Fidelity and Usability of an Intelligent Clinical Support Tool (ICST) For Acute Hospital Care: an Australian Case Study Using a Multi-Method Delphi Process.

PubMed

Botti, Mari; Redley, Bernice; Nguyen, Lemai; Coleman, Kimberley; Wickramasinghe, Nilmini

2015-01-01

This research focuses on a major health priority for Australia by addressing existing gaps in the implementation of nursing informatics solutions in healthcare. It serves to inform the successful deployment of IT solutions designed to support patient-centered, frontline acute healthcare delivery by multidisciplinary care teams. The outcomes can guide future evaluations of the contribution of IT solutions to the efficiency, safety and quality of care delivery in acute hospital settings.

Development and optimization of transferrin-conjugated nanostructured lipid carriers for brain delivery of paclitaxel using Box-Behnken design.

PubMed

Emami, Jaber; Rezazadeh, Mahboubeh; Sadeghi, Hojjat; Khadivar, Khashayar

2017-05-01

The treatment of brain cancer remains one of the most difficult challenges in oncology. The purpose of this study was to develop transferrin-conjugated nanostructured lipid carriers (Tf-NLCs) for brain delivery of paclitaxel (PTX). PTX-loaded NLCs (PTX-NLCs) were prepared using solvent evaporation method and the impact of various formulation variables were assessed using Box-Behnken design. Optimized PTX-NLC was coupled with transferrin as targeting ligand and in vitro cytotoxicity of it was investigated against U-87 brain cancer cell line. As a result, 14.1 mg of cholesterol, 18.5 mg of triolein, and 0.5% poloxamer were used to prepare the optimal formulation. Mean particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL), mean release time (MRT) of adopted formulation were confirmed to be 205.4 ± 11 nm, 25.7 ± 6.22 mV, 91.8 ± 0.5%, 5.38 ± 0.03% and 29.3 h, respectively. Following conjugation of optimized PTX-NLCs with transferrin, coupling efficiency was 21.3 mg transferrin per mmol of stearylamine; PS and MRT were increased while ZP, EE and DL decreased non-significantly. Tf-PTX-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the Tf-PTX-NLCs could potentially be exploited as a delivery system in brain cancer cells.

Direct aperture optimization: a turnkey solution for step-and-shoot IMRT.

PubMed

Shepard, D M; Earl, M A; Li, X A; Naqvi, S; Yu, C

2002-06-01

IMRT treatment plans for step-and-shoot delivery have traditionally been produced through the optimization of intensity distributions (or maps) for each beam angle. The optimization step is followed by the application of a leaf-sequencing algorithm that translates each intensity map into a set of deliverable aperture shapes. In this article, we introduce an automated planning system in which we bypass the traditional intensity optimization, and instead directly optimize the shapes and the weights of the apertures. We call this approach "direct aperture optimization." This technique allows the user to specify the maximum number of apertures per beam direction, and hence provides significant control over the complexity of the treatment delivery. This is possible because the machine dependent delivery constraints imposed by the MLC are enforced within the aperture optimization algorithm rather than in a separate leaf-sequencing step. The leaf settings and the aperture intensities are optimized simultaneously using a simulated annealing algorithm. We have tested direct aperture optimization on a variety of patient cases using the EGS4/BEAM Monte Carlo package for our dose calculation engine. The results demonstrate that direct aperture optimization can produce highly conformal step-and-shoot treatment plans using only three to five apertures per beam direction. As compared with traditional optimization strategies, our studies demonstrate that direct aperture optimization can result in a significant reduction in both the number of beam segments and the number of monitor units. Direct aperture optimization therefore produces highly efficient treatment deliveries that maintain the full dosimetric benefits of IMRT.

Novel Starch-PVA Polymer for Microparticle Preparation and Optimization Using Factorial Design Study

PubMed Central

Chattopadhyay, Helen; De, Amit Kumar; Datta, Sriparna

2015-01-01

The aim of our present work was to optimize the ratio of a very novel polymer, starch-polyvinyl alcohol (PVA), for controlled delivery of Ornidazole. Polymer-coated drug microparticles were prepared by emulsion method. Microscopic study, scanning electron microscopic study, and atomic force microscopic study revealed that the microparticles were within 10 micrometers of size with smooth spherical shape. The Fourier transform infrared spectroscopy showed absence of drug polymer interaction. A statistical 32 full factorial design was used to study the effect of different concentration of starch and PVA on the drug release profile. The three-dimensional plots gave us an idea about the contribution of each factor on the release kinetics. Hence this novel polymer of starch and polyvinyl alcohol can be utilized for control release of the drug from a targeted delivery device. PMID:27347511

Economic Model Predictive Control of Bihormonal Artificial Pancreas System Based on Switching Control and Dynamic R-parameter.

PubMed

Tang, Fengna; Wang, Youqing

2017-11-01

Blood glucose (BG) regulation is a long-term task for people with diabetes. In recent years, more and more researchers have attempted to achieve automated regulation of BG using automatic control algorithms, called the artificial pancreas (AP) system. In clinical practice, it is equally important to guarantee the treatment effect and reduce the treatment costs. The main motivation of this study is to reduce the cure burden. The dynamic R-parameter economic model predictive control (R-EMPC) is chosen to regulate the delivery rates of exogenous hormones (insulin and glucagon). It uses particle swarm optimization (PSO) to optimize the economic cost function and the switching logic between insulin delivery and glucagon delivery is designed based on switching control theory. The proposed method is first tested on the standard subject; the result is compared with the switching PID and the switching MPC. The effect of the dynamic R-parameter on improving the control performance is illustrated by comparing the results of the EMPC and the R-EMPC. Finally, the robustness tests on meal change (size and timing), hormone sensitivity (insulin and glucagon), and subject variability are performed. All results show that the proposed method can improve the control performance and reduce the economic costs. The simulation results verify the effectiveness of the proposed algorithm on improving the tracking performance, enhancing robustness, and reducing economic costs. The method proposed in this study owns great worth in practical application.

Optimizing Wartime Materiel Delivery: An Overview of DoD containerization. Volume 3. Annotated Bibliography

DOT National Transportation Integrated Search

1988-10-01

This annotated bibliography, Volume III of the study entitled, Optimizing Wartime Materiel Delivery: An overview of DOD Containerization Efforts, documents studies related to containerization. Several objectives of the study were defined. These inclu...

WE-AB-209-09: Optimization of Rotational Arc Station Parameter Optimized Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, P; Xing, L; Ungun, B

Purpose: To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of improving VMAT in both plan quality and delivery efficiency. Methods: The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based Proximal Operator Graph Solver (POGS) within seconds. Apertures with zero or low weight were thrown out. Tomore » avoid being trapped in a local minimum, a stochastic gradient descent method was employed which also greatly increased the convergence rate of the objective function. The above procedure repeated until the plan could not be improved any further. A weighting factor associated with the total plan MU also indirectly controlled the complexities of aperture shapes. The number of apertures for VMAT and SPORT was confined to 180. The SPORT allowed the coexistence of multiple apertures in a single SP. The optimization technique was assessed by using three clinical cases (prostate, H&N and brain). Results: Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. Prostate case: the volume of the 50% prescription dose was decreased by 22% for the rectum. H&N case: SPORT improved the mean dose for the left and right parotids by 15% each. Brain case: the doses to the eyes, chiasm and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the H&N case. Conclusion: The superior dosimetric quality and delivery efficiency presented here indicates that SPORT is an intriguing alternative treatment modality.« less

Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery.

PubMed

El Zaafarany, Ghada M; Awad, Gehanne A S; Holayel, Samar M; Mortada, Nahed D

2010-09-15

Transfersomes are highly efficient edge activator (EA)-based ultraflexible vesicles capable of, non-invasively, trespassing skin by virtue of their high, self-optimizing deformability. This investigation presents different approaches for the optimization of Transfersomes for enhanced transepidermal delivery of Diclofenac sodium (DS). Different methods of preparation, drug and lipid concentrations and vesicle compositions were employed, resulting in ultraflexible vesicles with diverse membrane characteristics. Evaluation of Transfersomes was implemented in terms of their shapes, sizes, entrapment efficiencies (EE%), relative deformabilities and in vitro skin permeation. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% (Span 85>Span 80>Na cholate>Na deoxycholate>Tween 80). Whereas, those prepared using 85:15% (w/w) ratio showed highest deformability (Tween 80 was superior to bile salts and spans). Transfersomes were proved significantly superior in terms of, the amount of drug deposited in the skin and the amount permeated, with an enhancement ratio of 2.45, when compared to a marketed product. The study proved that the type and concentration of EA, as well as, the method of preparation had great influences on the properties of Transfersomes. Hence, optimized Transfersomes can significantly increase transepidermal flux and prolong the release of DS, when applied non-occlusively. Copyright 2010 Elsevier B.V. All rights reserved.

Platelet-Rich Plasma in Bone Regeneration: Engineering the Delivery for Improved Clinical Efficacy

PubMed Central

Rodriguez, Isaac A.; Growney Kalaf, Emily A.; Bowlin, Gary L.; Sell, Scott A.

2014-01-01

Human bone is a tissue with a fairly remarkable inherent capacity for regeneration; however, this regenerative capacity has its limitations, and defects larger than a critical size lack the ability to spontaneously heal. As such, the development and clinical translation of effective bone regeneration modalities are paramount. One regenerative medicine approach that is beginning to gain momentum in the clinical setting is the use of platelet-rich plasma (PRP). PRP therapy is essentially a method for concentrating platelets and their intrinsic growth factors to stimulate and accelerate a healing response. While PRP has shown some efficacy in both in vitro and in vivo scenarios, to date its use and delivery have not been optimized for bone regeneration. Issues remain with the effective delivery of the platelet-derived growth factors to a localized site of injury, the activation and temporal release of the growth factors, and the rate of growth factor clearance. This review will briefly describe the physiological principles behind PRP use and then discuss how engineering its method of delivery may ultimately impact its ability to successfully translate to widespread clinical use. PMID:25050347

Pantoprazole Sodium Loaded Microballoons for the Systemic Approach: In Vitro and In Vivo Evaluation.

PubMed

Gupta, Pravin; Kumar, Manish; Kaushik, Darpan

2017-09-01

Purpose: Various floating and pulsatile drug delivery systems suffer from variations in the gastric transit time affecting the bioavailability of drugs. The objective of the study was to develop Pantoprazole Sodium (PAN) microballoons that may prolong the gastric residence time and could enhance the drug bioavailability. Methods: Microballoons were prepared using Eudragit ® L100 by adopting emulsion solvent diffusion method with non-effervescent approach, in vitro studies were performed and the in vivo evaluation was carried out employing ethanol induced ulceration method. Optimization and validation were carried out through Design Expert ® software. Results: The results demonstrate an increase in percentage yield, buoyancy, encapsulation efficacy and swelling. Particles were in the size range 80-100 µm following zero order release pattern. SEM study revealed their rough surface with spherical shape, internal cavity and porous walls. DSC thermo gram confirms the encapsulation of drug in amorphous form. Significant anti ulcer activity was observed for the prepared microballoons. The calculated ulcer index and protection were 0.20±0.05 and 97.43 % respectively for LRS-O (optimized formulation). Conclusion: This kind of pH dependent drug delivery may provide an efficient dosage regimen with enhanced patient compliance.

Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

PubMed Central

Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-bin

2016-01-01

Background The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Materials and methods Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. Results The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. Conclusion SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability. PMID:27418807

Molecularly Imprinted Polymers: Novel Discovery for Drug Delivery.

PubMed

Dhanashree, Surve; Priyanka, Mohite; Manisha, Karpe; Vilasrao, Kadam

2016-01-01

Molecularly imprinted polymers (MIP) are novel carriers synthesized by imprinting of a template over a polymer. This paper presents the recent application of MIP for diagnostic and therapeutic drug delivery. MIP owing to their 3D polymeric structures and due to bond formation with the template serves as a reservoir of active causing stimuli sensitive, enantioselective, targetted and/or controlled release. The review elaborates about key factors for optimization of MIP, controlled release by MIP for various administration routes various forms like patches, contact lenses, nanowires along with illustrations. To overcome the limitation of organic solvent usage causing increased cost, water compatible MIP and use of supercritical fluid technology for molecular imprinting were developed. Novel methods for developing water compatible MIP like pickering emulsion polymerization, co-precipitation method, cyclodextrin imprinting, surface grafting, controlled/living radical chain polymerization methods are described with illustration in this review. Various protein imprinting methods like bulk, epitope and surface imprinting are described along with illustrations. Further, application of MIP in microdevices as biomimetic sensing element for personalized therapy is elaborated. Although development and application of MIP in drug delivery is still at its infancy, constant efforts of researchers will lead to a novel intelligent drug delivery with commercial value. Efforts should be directed in developing solid oral dosage forms consisting of MIP for therapeutic protein and peptide delivery and targeted release of potent drugs addressing life threatening disease like cancer. Amalgamation of bio-engineering and pharmaceutical techniques can make these future prospects into reality.

Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins

PubMed Central

Klyachko, Natalia L; Haney, Matthew J; Zhao, Yuling; Manickam, Devika S; Mahajan, Vivek; Suresh, Poornima; Hingtgen, Shawn D; Mosley, R Lee; Gendelman, Howard E; Kabanov, Alexander V; Batrakova, Elena V

2013-01-01

Aims Active targeted transport of the nanoformulated redox enzyme, catalase, in macrophages attenuates oxidative stress and as such increases survival of dopaminergic neurons in animal models of Parkinson’s disease. Optimization of the drug formulation is crucial for the successful delivery in living cells. We demonstrated earlier that packaging of catalase into a polyion complex micelle (‘nanozyme’) with a synthetic polyelectrolyte block copolymer protected the enzyme against degradation in macrophages and improved therapeutic outcomes. We now report the manufacture of nanozymes with superior structure and therapeutic indices. Methods Synthesis, characterization and therapeutic efficacy of optimal cell-based nanoformulations are evaluated. Results A formulation design for drug carriers typically works to avoid entrapment in monocytes and macrophages focusing on small-sized nanoparticles with a polyethylene glycol corona (to provide a stealth effect). By contrast, the best nanozymes for delivery in macrophages reported in this study have a relatively large size (~200 nm), which resulted in improved loading capacity and release from macrophages. Furthermore, the cross-linking of nanozymes with the excess of a nonbiodegradable linker ensured their low cytotoxicity, and efficient catalase protection in cell carriers. Finally, the ‘alternatively activated’ macrophage phenotype (M2) utilized in these studies did not promote further inflammation in the brain, resulting in a subtle but statistically significant effect on neuronal regeneration and repair in vivo. Conclusion The optimized cross-linked nanozyme loaded into macrophages reduced neuroinflammatory responses and increased neuronal survival in mice. Importantly, the approach for nanoformulation design for cell-mediated delivery is different from the common requirements for injectable formulations. PMID:24237263

A quantitative study of IMRT delivery effects in commercial planning systems for the case of oesophagus and prostate tumours.

PubMed

Seco, J; Clark, C H; Evans, P M; Webb, S

2006-05-01

This study focuses on understanding the impact of intensity-modulated radiotherapy (IMRT) delivery effects when applied to plans generated by commercial treatment-planning systems such as Pinnacle (ADAC Laboratories Inc.) and CadPlan/Helios (Varian Medical Systems). These commercial planning systems have had several version upgrades (with improvements in the optimization algorithm), but the IMRT delivery effects have not been incorporated into the optimization process. IMRT delivery effects include head-scatter fluence from IMRT fields, transmission through leaves and the effect of the rounded shape of the leaf ends. They are usually accounted for after optimization when leaf sequencing the "optimal" fluence profiles, to derive the delivered fluence profile. The study was divided into two main parts: (a) analysing the dose distribution within the planning-target volume (PTV), produced by each of the commercial treatment-planning systems, after the delivered fluence had been renormalized to deliver the correct dose to the PTV; and (b) studying the impact of the IMRT delivery technique on the surrounding critical organs such as the spinal cord, lungs, rectum, bladder etc. The study was performed for tumours of (i) the oesophagus and (ii) the prostate and pelvic nodes. An oesophagus case was planned with the Pinnacle planning system for IMRT delivery, via multiple-static fields (MSF) and compensators, using the Elekta SL25 with a multileaf collimator (MLC) component. A prostate and pelvic nodes IMRT plan was performed with the Cadplan/Helios system for a dynamic delivery (DMLC) using the Varian 120-leaf Millennium MLC. In these commercial planning systems, since IMRT delivery effects are not included into the optimization process, fluence renormalization is required such that the median delivered PTV dose equals the initial prescribed PTV dose. In preparing the optimum fluence profile for delivery, the PTV dose has been "smeared" by the IMRT delivery techniques. In the case of the oesophagus, the critical organ, spinal cord, received a greater dose than initially planned, due to the delivery effects. The increase in the spinal cord dose is of the order of 2-3 Gy. In the case of the prostate and pelvic nodes, the IMRT delivery effects led to an increase of approximately 2 Gy in the dose delivered to the secondary PTV, the pelvic nodes. In addition to this, the small bowel, rectum and bladder received an increased dose of the order of 2-3 Gy to 50% of their total volume. IMRT delivery techniques strongly influence the delivered dose distributions for the oesophagus and prostate/pelvic nodes tumour sites and these effects are not yet accounted for in the Pinnacle and the CadPlan/Helios planning systems. Currently, they must be taken into account during the optimization stage by altering the dose limits accepted during optimization so that the final (sequenced) dose is within the constraints.

Ultrafast optical pulse delivery with fibers for nonlinear microscopy

PubMed Central

Kim, Daekeun; Choi, Heejin; Yazdanfar, Siavash; So, Peter T. C.

2008-01-01

Nonlinear microscopies including multiphoton excitation fluorescence microscopy and multiple-harmonic generation microscopy have recently gained popularity for cellular and tissue imaging. The optimization of these imaging methods for minimally invasive use will require optical fibers to conduct light into tight space where free space delivery is difficult. The delivery of high peak power laser pulses with optical fibers is limited by dispersion resulting from nonlinear refractive index responses. In this paper, we characterize a variety of commonly used optical fibers in terms of how they affect pulse profile and imaging performance of nonlinear microscopy; the following parameters are quantified: spectral bandwidth and temporal pulse width, two-photon excitation efficiency, and optical resolution. A theoretical explanation for the measured performance of these is also provided. PMID:18816597

A 4D-optimization concept for scanned ion beam therapy.

PubMed

Graeff, Christian; Lüchtenborg, Robert; Eley, John Gordon; Durante, Marco; Bert, Christoph

2013-12-01

Scanned carbon beam therapy offers advantageous dose distributions and an increased biological effect. Treating moving targets is complex due to sensitivity to range changes and interplay. We propose a 4D treatment planning concept that considers motion during particle number optimization. The target was subdivided into sectors, one for each motion phase of a 4D-CT. Each sector was non-rigidly transformed to its motion phase and there targeted by a dedicated raster field (RST). Therefore, the resulting 4D-RST compensated target motion and range changes. A 4D treatment control system (TCS) was needed for synchronized delivery to the measured patient motion. 4D-optimized plans were simulated for 9 NSCLC lung cancer patients and compared to static irradiation at end-exhale. A prototype TCS was implemented and successfully tested in a film experiment. The 4D-optimized treatment plan resulted in only slightly lower dose coverage of the target compared to static optimization, with V 95% of 97.9% (median, range 96.5-99.4%) vs. 99.3% (98.5-99.8%), with negligible overdose. The conformity number was comparable at 88.2% (85.1-92.5%) vs. 85.2% (79.9-91.2%) for 4D and static, respectively. We implemented and tested a 4D treatment plan optimization method resulting in highly conformal dose delivery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Optimization and evaluation of gastroretentive ranitidine HCl microspheres by using design expert software.

PubMed

Hooda, Aashima; Nanda, Arun; Jain, Manish; Kumar, Vikash; Rathee, Permender

2012-12-01

The current study involves the development and optimization of their drug entrapment and ex vivo bioadhesion of multiunit chitosan based floating system containing Ranitidine HCl by ionotropic gelation method for gastroretentive delivery. Chitosan being cationic, non-toxic, biocompatible, biodegradable and bioadhesive is frequently used as a material for drug delivery systems and used to transport a drug to an acidic environment where it enhances the transport of polar drugs across epithelial surfaces. The effect of various process variables like drug polymer ratio, concentration of sodium tripolyphosphate and stirring speed on various physiochemical properties like drug entrapment efficiency, particle size and bioadhesion was optimized using central composite design and analyzed using response surface methodology. The observed responses were coincided well with the predicted values given by the optimization technique. The optimized microspheres showed drug entrapment efficiency of 74.73%, particle size 707.26 μm and bioadhesion 71.68% in simulated gastric fluid (pH 1.2) after 8 h with floating lag time 40s. The average size of all the dried microspheres ranged from 608.24 to 720.80 μm. The drug entrapment efficiency of microspheres ranged from 41.67% to 87.58% and bioadhesion ranged from 62% to 86%. Accelerated stability study was performed on optimized formulation as per ICH guidelines and no significant change was found in drug content on storage. Copyright © 2012 Elsevier B.V. All rights reserved.

Rate-programming of nano-particulate delivery systems for smart bioactive scaffolds in tissue engineering.

PubMed

Izadifar, Mohammad; Haddadi, Azita; Chen, Xiongbiao; Kelly, Michael E

2015-01-09

Development of smart bioactive scaffolds is of importance in tissue engineering, where cell proliferation, differentiation and migration within scaffolds can be regulated by the interactions between cells and scaffold through the use of growth factors (GFs) and extra cellular matrix peptides. One challenge in this area is to spatiotemporally control the dose, sequence and profile of release of GFs so as to regulate cellular fates during tissue regeneration. This challenge would be addressed by rate-programming of nano-particulate delivery systems, where the release of GFs via polymeric nanoparticles is controlled by means of the methods of, such as externally-controlled and physicochemically/architecturally-modulated so as to mimic the profile of physiological GFs. Identifying and understanding such factors as the desired release profiles, mechanisms of release, physicochemical characteristics of polymeric nanoparticles, and externally-triggering stimuli are essential for designing and optimizing such delivery systems. This review surveys the recent studies on the desired release profiles of GFs in various tissue engineering applications, elucidates the major release mechanisms and critical factors affecting release profiles, and overviews the role played by the mathematical models for optimizing nano-particulate delivery systems. Potentials of stimuli responsive nanoparticles for spatiotemporal control of GF release are also presented, along with the recent advances in strategies for spatiotemporal control of GF delivery within tissue engineered scaffolds. The recommendation for the future studies to overcome challenges for developing sophisticated particulate delivery systems in tissue engineering is discussed prior to the presentation of conclusions drawn from this paper.

Delivery of Clinical Preventive Services in Family Medicine Offices

PubMed Central

Crabtree, Benjamin F.; Miller, William L.; Tallia, Alfred F.; Cohen, Deborah J.; DiCicco-Bloom, Barbara; McIlvain, Helen E.; Aita, Virginia A.; Scott, John G.; Gregory, Patrice B.; Stange, Kurt C.; McDaniel, Reuben R.

2005-01-01

BACKGROUND This study aimed to elucidate how clinical preventive services are delivered in family practices and how this information might inform improvement efforts. METHODS We used a comparative case study design to observe clinical preventive service delivery in 18 purposefully selected Midwestern family medicine offices from 1997 to 1999. Medical records, observation of outpatient encounters, and patient exit cards were used to calculate practice-level rates of delivery of clinical preventive services. Field notes from direct observation of clinical encounters and prolonged observation of the practice and transcripts from in-depth interviews of practice staff and physicians were systematically examined to identify approaches to delivering clinical preventive services recommended by the US Preventive Services Task Force. RESULTS Practices developed individualized approaches for delivering clinical preventive services, with no one approach being successful across practices. Clinicians acknowledged a 3-fold mission of providing acute care, managing chronic problems, and prevention, but only some made prevention a priority. The clinical encounter was a central focus for preventive service delivery in all practices. Preventive services delivery rates often appeared to be influenced by competing demands within the clinical encounter (including between different preventive services), having a physician champion who prioritized prevention, and economic concerns. CONCLUSIONS Practice quality improvement efforts that assume there is an optimal approach for delivering clinical preventive services fail to account for practices’ propensity to optimize care processes to meet local contexts. Interventions to enhance clinical preventive service delivery should be tailored to meet the local needs of practices and their patient populations. PMID:16189059

Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates.

PubMed

Abdelaziz, Hadeer M; Gaber, Mohamed; Abd-Elwakil, Mahmoud M; Mabrouk, Moustafa T; Elgohary, Mayada M; Kamel, Nayra M; Kabary, Dalia M; Freag, May S; Samaha, Magda W; Mortada, Sana M; Elkhodairy, Kadria A; Fang, Jia-You; Elzoghby, Ahmed O

2018-01-10

There is progressive evolution in the use of inhalable drug delivery systems (DDSs) for lung cancer therapy. The inhalation route offers many advantages, being non-invasive method of drug administration as well as localized delivery of anti-cancer drugs to tumor tissue. This article reviews various inhalable colloidal systems studied for tumor-targeted drug delivery including polymeric, lipid, hybrid and inorganic nanocarriers. The active targeting approaches for enhanced delivery of nanocarriers to lung cancer cells were illustrated. This article also reviews the recent advances of inhalable microparticle-based drug delivery systems for lung cancer therapy including bioresponsive, large porous, solid lipid and drug-complex microparticles. The possible strategies to improve the aerosolization behavior and maintain the critical physicochemical parameters for efficient delivery of drugs deep into lungs were also discussed. Therefore, a strong emphasis is placed on the approaches which combine the merits of both nanocarriers and microparticles including inhalable nanocomposites and nanoaggregates and on the optimization of such formulations using the proper techniques and carriers. Finally, the toxicological behavior and market potential of the inhalable anti-cancer drug delivery systems are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

SU-F-BRB-12: A Novel Haar Wavelet Based Approach to Deliver Non-Coplanar Intensity Modulated Radiotherapy Using Sparse Orthogonal Collimators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, D; Ruan, D; Low, D

2015-06-15

Purpose: Existing efforts to replace complex multileaf collimator (MLC) by simple jaws for intensity modulated radiation therapy (IMRT) resulted in unacceptable compromise in plan quality and delivery efficiency. We introduce a novel fluence map segmentation method based on compressed sensing for plan delivery using a simplified sparse orthogonal collimator (SOC) on the 4π non-coplanar radiotherapy platform. Methods: 4π plans with varying prescription doses were first created by automatically selecting and optimizing 20 non-coplanar beams for 2 GBM, 2 head & neck, and 2 lung patients. To create deliverable 4π plans using SOC, which are two pairs of orthogonal collimators withmore » 1 to 4 leaves in each collimator bank, a Haar Fluence Optimization (HFO) method was used to regulate the number of Haar wavelet coefficients while maximizing the dose fidelity to the ideal prescription. The plans were directly stratified utilizing the optimized Haar wavelet rectangular basis. A matching number of deliverable segments were stratified for the MLC-based plans. Results: Compared to the MLC-based 4π plans, the SOC-based 4π plans increased the average PTV dose homogeneity from 0.811 to 0.913. PTV D98 and D99 were improved by 3.53% and 5.60% of the corresponding prescription doses. The average mean and maximal OAR doses slightly increased by 0.57% and 2.57% of the prescription doses. The average number of segments ranged between 5 and 30 per beam. The collimator travel time to create the segments decreased with increasing leaf numbers in the SOC. The two and four leaf designs were 1.71 and 1.93 times more efficient, on average, than the single leaf design. Conclusion: The innovative dose domain optimization based on compressed sensing enables uncompromised 4π non-coplanar IMRT dose delivery using simple rectangular segments that are deliverable using a sparse orthogonal collimator, which only requires 8 to 16 leaves yet is unlimited in modulation resolution. This work is supported in part by Varian Medical Systems, Inc. and NIH R43 CA18339.« less

Three dimensional intensity modulated brachytherapy (IMBT): dosimetry algorithm and inverse treatment planning.

PubMed

Shi, Chengyu; Guo, Bingqi; Cheng, Chih-Yao; Esquivel, Carlos; Eng, Tony; Papanikolaou, Niko

2010-07-01

The feasibility of intensity modulated brachytherapy (IMBT) to improve dose conformity for irregularly shaped targets has been previously investigated by researchers by means of using partially shielded sources. However, partial shielding does not fully explore the potential of IMBT. The goal of this study is to introduce the concept of three dimensional (3D) intensity modulated brachytherapy and solve two fundamental issues regarding the application of 3D IMBT treatment planning: The dose calculation algorithm and the inverse treatment planning method. A 3D IMBT treatment planning system prototype was developed using the MATLAB platform. This system consists of three major components: (1) A comprehensive IMBT source calibration method with dosimetric inputs from Monte Carlo (EGSnrc) simulations; (2) a "modified TG-43" (mTG-43) dose calculation formalism for IMBT dosimetry; and (3) a physical constraint based inverse IMBT treatment planning platform utilizing a simulated annealing optimization algorithm. The model S700 Axxent electronic brachytherapy source developed by Xoft, Inc. (Fremont, CA), was simulated in this application. Ten intracavitary accelerated partial breast irradiation (APBI) cases were studied. For each case, an "isotropic plan" with only optimized source dwell time and a fully optimized IMBT plan were generated and compared to the original plan in various dosimetric aspects, such as the plan quality, planning, and delivery time. The issue of the mechanical complexity of the IMBT applicator is not addressed in this study. IMBT approaches showed superior plan quality compared to the original plans and tht isotropic plans to different extents in all studied cases. An extremely difficult case with a small breast and a small distance to the ribs and skin, the IMBT plan minimized the high dose volume V200 by 16.1% and 4.8%, respectively, compared to the original and the isotropic plans. The conformity index for the target was increased by 0.13 and 0.04, respectively. The maximum dose to the skin was reduced by 56 and 28 cGy, respectively, per fraction. Also, the maximum dose to the ribs was reduced by 104 and 96 cGy, respectively, per fraction. The mean dose to the ipsilateral and contralateral breasts and lungs were also slightly reduced by the IMBT plan. The limitations of IMBT are the longer planning and delivery time. The IMBT plan took around 2 h to optimize, while the isotropic plan optimization could reach the global minimum within 5 min. The delivery time for the IMBT plan is typically four to six times longer than the corresponding isotropic plan. In this study, a dosimetry method for IMBT sources was proposed and an inverse treatment planning system prototype for IMBT was developed. The improvement of plan quality by 3D IMBT was demonstrated using ten APBI case studies. Faster computers and higher output of the source can further reduce plan optimization and delivery time, respectively.

Prolonged Hypocalcemic Effect by Pulmonary Delivery of Calcitonin Loaded Poly(Methyl Vinyl Ether Maleic Acid) Bioadhesive Nanoparticles

PubMed Central

Varshosaz, J.; Minaiyan, M.; Forghanian, M.

2014-01-01

The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe2+ and Zn2+ ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 μg·kg−1), iv solution of sCT (5 μg·kg−1), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly. PMID:24701588

Role of Cigarette Sensory Cues in Modifying Puffing Topography

PubMed Central

Rees, Vaughan W.; Kreslake, Jennifer M.; Wayne, Geoffrey Ferris; O Connor, Richard J.; Cummings, K. Michael; Connolly, Gregory N.

2012-01-01

Background Human puffing topography promotes tobacco dependence by ensuring nicotine delivery, but the factors that determine puffing behavior are not well explained by existing models. Chemosensory cues generated by variations in cigarette product design features may serve as conditioned cues to allow the smoker to optimize nicotine delivery by adjusting puffing topography. Internal tobacco industry research documents were reviewed to understand the influence of sensory cues on puffing topography, and to examine how the tobacco industry has designed cigarettes, including modified risk tobacco products (MRTPs), to enhance puffing behavior to optimize nicotine delivery and product acceptability. Methods Relevant internal tobacco industry documents were identified using systematic searching with key search terms and phrases, and then snowball sampling method was applied to establish further search terms. Results Modern cigarettes are designed by cigarette manufacturers to provide sensory characteristics that not only maintain appeal, but provide cues which inform puffing intensity. Alterations in the chemosensory cues provided in tobacco smoke play an important role in modifying smoking behavior independently of the central effects of nicotine. Conclusions An associative learning model is proposed to explain the influence of chemosensory cues on variation in puffing topography. These cues are delivered via tobacco smoke and are moderated by design features and additives used in cigarettes. The implications for regulation of design features of modified risk tobacco products, which may act to promote intensive puffing while lowering risk perceptions, are discussed. PMID:22365895

Factors affecting optimal linear endovenous energy density for endovenous laser ablation in incompetent lower limb truncal veins - A review of the clinical evidence.

PubMed

Cowpland, Christine A; Cleese, Amy L; Whiteley, Mark S

2017-06-01

Objectives The objective is to identify the factors that affect the optimal linear endovenous energy density (LEED) to ablate incompetent truncal veins. Methods We performed a literature review of clinical studies, which reported truncal vein ablation rates and LEED. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) flow diagram documents the search strategy. We analysed 13 clinical papers which fulfilled the criteria to be able to compare results of great saphenous vein occlusion as defined by venous duplex ultrasound, with the LEED used in the treatment. Results Evidence suggests that the optimal LEED for endovenous laser ablation of the great saphenous vein is >80 J/cm and <100 J/cm in terms of optimal closure rates with minimal side-effects and complications. Longer wavelengths targeting water might have a lower optimal LEED. A LEED <60 J/cm has reduced efficacy regardless of wavelength. The optimal LEED may vary with vein diameter and may be reduced by using specially shaped fibre tips. Laser delivery technique and type as well as the duration time of energy delivery appear to play a role in determining LEED. Conclusion The optimal LEED to ablate an incompetent great saphenous vein appears to be >80 J/cm and <95 J/cm based on current evidence for shorter wavelength lasers. There is evidence that longer wavelength lasers may be effective at LEEDs of <85 J/cm.

TH-CD-209-10: Scanning Proton Arc Therapy (SPArc) - The First Robust and Delivery-Efficient Spot Scanning Proton Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, X; Li, X; Zhang, J

Purpose: To develop a delivery-efficient proton spot-scanning arc therapy technique with robust plan quality. Methods: We developed a Scanning Proton Arc(SPArc) optimization algorithm integrated with (1)Control point re-sampling by splitting control point into adjacent sub-control points; (2)Energy layer re-distribution by assigning the original energy layers to the new sub-control points; (3)Energy layer filtration by deleting low MU weighting energy layers; (4)Energy layer re-sampling by sampling additional layers to ensure the optimal solution. A bilateral head and neck oropharynx case and a non-mobile lung target case were tested. Plan quality and total estimated delivery time were compared to original robust optimizedmore » multi-field step-and-shoot arc plan without SPArc optimization (Arcmulti-field) and standard robust optimized Intensity Modulated Proton Therapy(IMPT) plans. Dose-Volume-Histograms (DVH) of target and Organ-at-Risks (OARs) were analyzed along with all worst case scenarios. Total delivery time was calculated based on the assumption of a 360 degree gantry room with 1 RPM rotation speed, 2ms spot switching time, beam current 1nA, minimum spot weighting 0.01 MU, energy-layer-switching-time (ELST) from 0.5 to 4s. Results: Compared to IMPT, SPArc delivered less integral dose(−14% lung and −8% oropharynx). For lung case, SPArc reduced 60% of skin max dose, 35% of rib max dose and 15% of lung mean dose. Conformity Index is improved from 7.6(IMPT) to 4.0(SPArc). Compared to Arcmulti-field, SPArc reduced number of energy layers by 61%(276 layers in lung) and 80%(1008 layers in oropharynx) while kept the same robust plan quality. With ELST from 0.5s to 4s, it reduced 55%–60% of Arcmulti-field delivery time for the lung case and 56%–67% for the oropharynx case. Conclusion: SPArc is the first robust and delivery-efficient proton spot-scanning arc therapy technique which could be implemented in routine clinic. For modern proton machine with ELST close to 0.5s, SPArc would be a popular treatment option for both single and multi-room center.« less

SU-E-T-268: Differences in Treatment Plan Quality and Delivery Between Two Commercial Treatment Planning Systems for Volumetric Arc-Based Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, S; Zhang, H; Zhang, B

2015-06-15

Purpose: To clinically evaluate the differences in volumetric modulated arc therapy (VMAT) treatment plan and delivery between two commercial treatment planning systems. Methods: Two commercial VMAT treatment planning systems with different VMAT optimization algorithms and delivery approaches were evaluated. This study included 16 clinical VMAT plans performed with the first system: 2 spine, 4 head and neck (HN), 2 brain, 4 pancreas, and 4 pelvis plans. These 16 plans were then re-optimized with the same number of arcs using the second treatment planning system. Planning goals were invariant between the two systems. Gantry speed, dose rate modulation, MLC modulation, planmore » quality, number of monitor units (MUs), VMAT quality assurance (QA) results, and treatment delivery time were compared between the 2 systems. VMAT QA results were performed using Mapcheck2 and analyzed with gamma analysis (3mm/3% and 2mm/2%). Results: Similar plan quality was achieved with each VMAT optimization algorithm, and the difference in delivery time was minimal. Algorithm 1 achieved planning goals by highly modulating the MLC (total distance traveled by leaves (TL) = 193 cm average over control points per plan), while maintaining a relatively constant dose rate (dose-rate change <100 MU/min). Algorithm 2 involved less MLC modulation (TL = 143 cm per plan), but greater dose-rate modulation (range = 0-600 MU/min). The average number of MUs was 20% less for algorithm 2 (ratio of MUs for algorithms 2 and 1 ranged from 0.5-1). VMAT QA results were similar for all disease sites except HN plans. For HN plans, the average gamma passing rates were 88.5% (2mm/2%) and 96.9% (3mm/3%) for algorithm 1 and 97.9% (2mm/2%) and 99.6% (3mm/3%) for algorithm 2. Conclusion: Both VMAT optimization algorithms achieved comparable plan quality; however, fewer MUs were needed and QA results were more robust for Algorithm 2, which more highly modulated dose rate.« less

Using mobile technology to optimize disease surveillance and healthcare delivery at mass gatherings: a case study from India's Kumbh Mela

PubMed Central

Kazi, Dhruv S.; Greenough, P. Gregg; Madhok, Rishi; Heerboth, Aaron; Shaikh, Ahmed; Leaning, Jennifer; Balsari, Satchit

2017-01-01

Abstract Background Planning for mass gatherings often includes temporary healthcare systems to address the needs of attendees. However, paper-based record keeping has traditionally precluded the timely application of collected clinical data for epidemic surveillance or optimization of healthcare delivery. We evaluated the feasibility of harnessing ubiquitous mobile technologies for conducting disease surveillance and monitoring resource utilization at the Allahabad Kumbh Mela in India, a 55-day festival attended by over 70 million people. Methods We developed an inexpensive, tablet-based customized disease surveillance system with real-time analytic capabilities, and piloted it at five field hospitals. Results The system captured 49 131 outpatient encounters over the 3-week study period. The most common presenting complaints were musculoskeletal pain (19%), fever (17%), cough (17%), coryza (16%) and diarrhoea (5%). The majority of patients received at least one prescription. The most common prescriptions were for antimicrobials, acetaminophen and non-steroidal anti-inflammatory drugs. There was great inter-site variability in caseload with the busiest hospital seeing 650% more patients than the least busy hospital, despite identical staffing. Conclusions Mobile-based health information solutions developed with a focus on user-centred design can be successfully deployed at mass gatherings in resource-scarce settings to optimize care delivery by providing real-time access to field data. PMID:27694349

Polycation nanostructured lipid carrier, a novel nonviral vector constructed with triolein for efficient gene delivery.

PubMed

Zhang, Zhiwen; Sha, Xianyi; Shen, Anle; Wang, Yongzhong; Sun, Zhaogui; Gu, Zheng; Fang, Xiaoling

2008-06-06

A novel nonviral gene transfer vector was developed by modifying nanostructured lipid carrier (NLC) with cetylated polyethylenimine (PEI). Polycation nanostructured lipid carrier (PNLC) was prepared using the emulsion-solvent evaporation method. Its in vitro gene transfer properties were evaluated in the human lung adenocarcinoma cell line SPC-A1 and Chinese Hamster Ovary (CHO) cells. Enhanced transfection efficiency of PNLC was observed after the addition of triolein to the PNLC formulation and the transfection efficiency of the optimized PNLC was comparable to that of Lipofectamine 2000. In the presence of 10% serum the transfection efficiency of the optimal PNLC was not significantly changed in either cell line, whereas that of Lipofectamine 2000 was greatly decreased in both. Thus, PNLC is an effective nonviral gene transfer vector and the gene delivery activity of PNLC was enhanced after triolein was included into the PNLC formulation.

Optimal economic order quantity for buyer-distributor-vendor supply chain with backlogging derived without derivatives

NASA Astrophysics Data System (ADS)

Teng, Jinn-Tsair; Cárdenas-Barrón, Leopoldo Eduardo; Lou, Kuo-Ren; Wee, Hui Ming

2013-05-01

In this article, we first complement an inappropriate mathematical error on the total cost in the previously published paper by Chung and Wee [2007, 'Optimal the Economic Lot Size of a Three-stage Supply Chain With Backlogging Derived Without Derivatives', European Journal of Operational Research, 183, 933-943] related to buyer-distributor-vendor three-stage supply chain with backlogging derived without derivatives. Then, an arithmetic-geometric inequality method is proposed not only to simplify the algebraic method of completing prefect squares, but also to complement their shortcomings. In addition, we provide a closed-form solution to integral number of deliveries for the distributor and the vendor without using complex derivatives. Furthermore, our method can solve many cases in which their method cannot, because they did not consider that a squared root of a negative number does not exist. Finally, we use some numerical examples to show that our proposed optimal solution is cheaper to operate than theirs.

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, Peter; Storer, R. Ian; Sabnis, Yogesh A.

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Aptamer-loaded Gold Nanoconstructs for Targeted Cancer Therapy

NASA Astrophysics Data System (ADS)

Dam, Duncan Hieu Minh

Traditional cancer treatments, including chemotherapy, often cause severe side effects in patients. Targeted therapy where tumor cells are targeted via biomarkers overexpressed on the cell surface has been shown to reduce such adverse effects. Monoclonal antibodies (mAbs) are currently the most common chemotherapeutic agents that bind with high affinity to these cancer markers. However, poor intratumoral uptake of mAb and release of drugs from mAb carriers have been the biggest challenge for this delivery method. As a result, recent work has focused on other strategies to improve the efficacy of drug delivery in targeted therapy. Among potential carriers for drug delivery, gold nanoparticles (AuNPs) have emerged as one of the most promising vehicles. This thesis describes the development of a drug delivery nanoconstruct that can both target cancer cells and induce therapeutic effects. The nanoconstructs are composed of gold nanostars (AuNS) as delivery vehicles loaded with the DNA aptamer AS1411 that can target the ubiquitous shuttle protein nucleolin (NCL) in various cancer cell types. The gold nanocarrier stabilizes the oligonucleotides for intracellular delivery and promotes high loading densities of the oligonucleotide drugs. We have investigated the interactions of the nanoconstruct with different subcellular compartments of the cancer cells. This physical phenomenon has shown to correlate with the biological activities such as apoptosis and cell death that happen in the cancer cells after incubation with the nanoconstructs. A thorough screening of the nanoconstructs in 13 different cancer cell lines is conducted to narrow down the potential targets for in vivo study. Before testing the in vivo efficacy, we evaluate the toxicity of the nanoconstructs in non-tumor animals, which confirms its safety for further in vivo applications. The accumulation of the nanoconstructs in two different cancerous tumors, however, suggests that further optimization of the design is required. Thus, we introduced an improved nanoconstruct with higher loading of AS1411 on the surface of AuNS. The significant enhancement in the loading of the Apt increases the cellular uptake as well as the in vitro efficacy of the nanoconstruct in both fibrosarcoma and pancreatic cancer cells. To further optimize the design of the nanoconstruct, we create a conjugation method in which the loading of AS1411 can be effectively controlled at various pH conditions. This method can potentially be applied for any DNA or RNA; however, the stability of oligonucleotides is unknown as a function of pH. Therefore, we also evaluate how pH conditions can affect the loading densities and structural integrity of a range of different oligonucleotides (single stranded DNA, hairpin DNA, duplexes, quadruplexes) on AuNS. The ultimate goal of this process is to identify a set of design principles to optimize oligonucleotide loading based on the local chemical environment around the nanoparticle.

Wireless Sensor Network Quality of Service Improvement on Flooding Attack Condition

NASA Astrophysics Data System (ADS)

Hartono, R.; Widyawan; Wibowo, S. B.; Purnomo, A.; Hartatik

2018-03-01

There are two methods of building communication using wireless media. The first method is building a base infrastructure as an intermediary between users. Problems that arise on this type of network infrastructure is limited space to build any network physical infrastructure and also the cost factor. The second method is to build an ad hoc network between users who will communicate. On ad hoc network, each user must be willing to send data from source to destination for the occurrence of a communication. One of network protocol in Ad Hoc, Ad hoc on demand Distance Vector (AODV), has the smallest overhead value, easier to adapt to dynamic network and has small control message. One AODV protocol’s drawback is route finding process’ security for sending the data. In this research, AODV protocol is optimized by determining Expanding Ring Search (ERS) best value. Random topology is used with variation in the number of nodes: 25, 50, 75, 100, 125 and 150 with node’s speed of 10m/s in the area of 1000m x 1000m on flooding network condition. Parameters measured are Throughput, Packet Delivery Ratio, Average Delay and Normalized Routing Load. From the test results of AODV protocol optimization with best value of Expanding Ring Search (ERS), throughput increased by 5.67%, packet delivery ratio increased by 5.73%, and as for Normalized Routing Load decreased by 4.66%. ERS optimal value for each node’s condition depending on the number of nodes on the network.

Investigation of microemulsion system for transdermal delivery of itraconazole

PubMed Central

Chudasama, Arpan; Patel, Vineetkumar; Nivsarkar, Manish; Vasu, Kamala; Shishoo, Chamanlal

2011-01-01

A new oil-in-water microemulsion-based (ME) gel containing 1% itraconazole (ITZ) was developed for topical delivery. The solubility of ITZ in oils and surfactants was evaluated to identify potential excipients. The microemulsion existence ranges were defined through the construction of the pseudoternary phase diagrams. The optimized microemulsion was characterized for its morphology and particle size distribution. The optimized microemulsion was incorporated into polymeric gels of Lutrol F127, Xanthan gum, and Carbopol 934 for convenient application and evaluated for pH, drug content, viscosity, and spreadability. In vitro drug permeation of ME gels was determined across excised rat skins. Furthermore, in vitro antimycotic inhibitory activity of the gels was conducted using agar-cup method and Candida albicans as a test organism. The droplet size of the optimized microemulsion was found to be <100 nm. The optimized Lutrol F 127 ME gel showed pH in the range of 5.68±0.02 and spreadability of 5.75±1.396 gcm/s. The viscosity of ME gel was found to be 1805.535±542.4 mPa s. The permeation rate (flux) of ITZ from prepared ME gel was found to be 4.234 μg/cm/h. The release profile exhibited diffusion controlled mechanism of drug release from ME ITZ gel. The developed ME gels were nonirritant and there was no erythema or edema. The antifungal activity of ITZ showed the widest zone of inhibition with Lutrol F127 ME gel. These results indicate that the studied ME gel may be a promising vehicle for topical delivery of ITZ. PMID:22171289

Irreversible electroporation of stage 3 locally advanced pancreatic cancer: optimal technique and outcomes

PubMed Central

2015-01-01

Objective Irreversible electroporation (IRE) of stage 3 pancreatic adenocarcinoma has been used to provide quality of life time in patients who have undergone appropriate induction therapy. The optimal technique has been reported within the literature, but not in video form. IRE of locally advanced pancreatic cancer is technically demanding requiring precision ultrasound use for continuous imaging in multiple needle placements and during IRE energy delivery. Methods Appropriate patients with locally advanced pancreatic cancer should have undergone appropriate induction chemotherapy for a reasonable duration. The safe and effective technique for irreversible electroporation is preformed through an open approach with the emphasis on intra-operative ultrasound and intra-operative electroporation management. Results The technique of open irreversible electroporation of the pancreas involves bracketing the target tumor with IRE probes and any and all invaded vital structures including the celiac axis, superior mesenteric artery (SMA), superior mesenteric-portal vein, and bile duct with continuous intraoperative ultrasound imaging through a caudal to cranial approach. Optimal IRE delivery requires a change in amperage of at least 12 amps from baseline tissue conductivity in order to achieve technical success. Multiple pull-backs are necessary since the IRE ablation probe lengths are 1 cm and thus needed to achieve technical success along the caudal to cranial plane. Conclusions Irreversible electroporation in combination with multi-modality therapy for locally advanced pancreatic carcinoma is feasible for appropriate patients with locally advanced cancer. Technical demands are high and require the highest quality ultrasound for precise spacing measurements and optimal delivery to ensure adequate change in tissue resistance. PMID:29075594

Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

PubMed Central

Feng, Shun; Zhu, Lijun; Huang, Zhisheng; Wang, Haojia; Li, Hong; Zhou, Hua; Lu, Linlin; Wang, Ying; Liu, Zhongqiu; Liu, Liang

2017-01-01

Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration. PMID:28670109

Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

PubMed Central

Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

2017-01-01

Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors. PMID:28287120

Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model.

PubMed

Ware, Matthew J; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A; Corr, Stuart J

2017-03-13

Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

NASA Astrophysics Data System (ADS)

Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

2017-03-01

Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

Synthesis of thiolated chitosan and preparation nanoparticles with sodium alginate for ocular drug delivery.

PubMed

Zhu, Xuan; Su, Meiqin; Tang, Shaoheng; Wang, Lingsong; Liang, Xinfang; Meng, Feihong; Hong, Ying; Xu, Zhiran

2012-01-01

The goal of the present study was to synthesize mucoadhesive polymer - thiolated chitosan (TCS) from chitosan (CS), then prepared CS/TCS-sodium alginate nanoparticles (CS/TCS-SA NPs), determined which was more potential for ocular drug delivery. A new method for preparing TCS was developed, and the characteristics were determined using Fourier transform infrared spectroscopy and the degree of thiol immobilized was measured by Ellman's reagent. Human corneal epithelium (HCE) cells were incubated with different concentrations of TCS for 48 h to determine the cell viabilities. CS/TCS-SA NPs were prepared and optimized by a modified ionic gelation method. The particle sizes, zeta potentials, Scanning electron microscopy images, mucoadhesion, in vitro cell uptake and in vivo studies of the two types of NP were compared. The new method enabled a high degree of thiol substitution of TCS, up to 1,411.01±4.02 μmol/g. In vitro cytocompatibility results suggest that TCS is nontoxic. Compared to CS-SA NPs, TCS-SA NPs were more stable, with higher mucoadhesive properties and could deliver greater amounts of drugs into HCE cells in vitro and cornea in vivo. TCS-SA NPs have better delivery capability, suggesting they have good potential for ocular drug delivery applications.

Spray-Dried Thiolated Chitosan-Coated Sodium Alginate Multilayer Microparticles for Vaginal HIV Microbicide Delivery.

PubMed

Meng, Jianing; Agrahari, Vivek; Ezoulin, Miezan J; Purohit, Sudhaunshu S; Zhang, Tao; Molteni, Agostino; Dim, Daniel; Oyler, Nathan A; Youan, Bi-Botti C

2017-05-01

It is hypothesized that novel thiolated chitosan-coated multilayer microparticles (MPs) with enhanced drug loading are more mucoadhesive than uncoated MPs and safe in vivo for vaginal delivery of topical anti-HIV microbicide. Formulation optimization is achieved through a custom experimental design and the alginate (AG) MPs cores are prepared using the spray drying method. The optimal MPs are then coated with the thiolated chitosan (TCS) using a layer-by-layer method. The morphological analysis, in situ drug payload, in vitro drug release profile, and mucoadhesion potential of the MPs are carried out using scanning electron microscopy, solid-state 31 P NMR spectroscopy, UV spectroscopy, fluorescence imaging and periodic acid Schiff method, respectively. The cytotoxicity and preclinical safety of MPs are assessed on human vaginal (VK2/E6E7) and endocervical (End1/E6E7) epithelial cell lines and in female C57BL/6 mice, respectively. The results show that the MPs are successfully formulated with an average diameter ranging from 2 to 3 μm with a drug loading of 7-12% w/w. The drug release profile of these MPs primarily follows the Baker-Lonsdale and Korsmeyer-Peppas models. The MPs exhibit high mucoadhesion (20-50 folds) compared to native AGMPs. The multilayer MPs are noncytotoxic. Histological and immunochemical analysis of the mice genital tract shows neither signs of damage nor inflammatory cell infiltrate. These data highlight the potential use of TCS-coated AG-based multilayer MPs templates for the topical vaginal delivery of anti-HIV/AIDS microbicides.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

PubMed

Emami, J; Mohiti, H; Hamishehkar, H; Varshosaz, J

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design

PubMed Central

Emami, J.; Mohiti, H.; Hamishehkar, H.; Varshosaz, J.

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7® software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide. PMID:26430454

Ultrasound-mediated drug delivery for cardiovascular disease

PubMed Central

Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail; Holland, Christy K

2014-01-01

Introduction Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. Areas covered The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. Expert opinion These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments. PMID:23448121

Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery

PubMed Central

Ronaldson, Patrick T; Davis, Thomas P

2012-01-01

The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

Microfluidics for producing poly (lactic-co-glycolic acid)-based pharmaceutical nanoparticles.

PubMed

Li, Xuanyu; Jiang, Xingyu

2017-12-24

Microfluidic chips allow the rapid production of a library of nanoparticles (NPs) with distinct properties by changing the precursors and the flow rates, significantly decreasing the time for screening optimal formulation as carriers for drug delivery compared to conventional methods. The batch-to-batch reproducibility which is essential for clinical translation is achieved by precisely controlling the precursors and the flow rate, regardless of operators. Poly (lactic-co-glycolic acid) (PLGA) is the most widely used Food and Drug Administration (FDA)-approved biodegradable polymers. Researchers often combine PLGA with lipids or amphiphilic molecules to assemble into a core/shell structure to exploit the potential of PLGA-based NPs as powerful carriers for cancer-related drug delivery. In this review, we discuss the advantages associated with microfluidic chips for producing PLGA-based functional nanocomplexes for drug delivery. These laboratory-based methods can readily scale up to provide sufficient amount of PLGA-based NPs in microfluidic chips for clinical studies and industrial-scale production. Copyright © 2017. Published by Elsevier B.V.

Advances in Progenitor Cell Therapy Using Scaffolding Constructs for Central Nervous System Injury

PubMed Central

Walker, Peter A.; Aroom, Kevin R.; Jimenez, Fernando; Shah, Shinil K.; Harting, Matthew T.; Gill, Brijesh S.

2010-01-01

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Current clinical therapy is focused on optimization of the acute/subacute intracerebral milieu, minimizing continued cell death, and subsequent intense rehabilitation to ameliorate the prolonged physical, cognitive, and psychosocial deficits that result from TBI. Adult progenitor (stem) cell therapies have shown promise in pre-clinical studies and remain a focus of intense scientific investigation. One of the fundamental challenges to successful translation of the large body of pre-clinical work is the delivery of progenitor cells to the target location/organ. Classically used vehicles such as intravenous and intra arterial infusion have shown low engraftment rates and risk of distal emboli. Novel delivery methods such as nanofiber scaffold implantation could provide the structural and nutritive support required for progenitor cell proliferation, engraftment, and differentiation. The focus of this review is to explore the current state of the art as it relates to current and novel progenitor cell delivery methods. PMID:19644777

Biomimetic proteolipid vesicles for targeting inflamed tissues

NASA Astrophysics Data System (ADS)

Molinaro, R.; Corbo, C.; Martinez, J. O.; Taraballi, F.; Evangelopoulos, M.; Minardi, S.; Yazdi, I. K.; Zhao, P.; De Rosa, E.; Sherman, M. B.; de Vita, A.; Toledano Furman, N. E.; Wang, X.; Parodi, A.; Tasciotti, E.

2016-09-01

A multitude of micro- and nanoparticles have been developed to improve the delivery of systemically administered pharmaceuticals, which are subject to a number of biological barriers that limit their optimal biodistribution. Bioinspired drug-delivery carriers formulated by bottom-up or top-down strategies have emerged as an alternative approach to evade the mononuclear phagocytic system and facilitate transport across the endothelial vessel wall. Here, we describe a method that leverages the advantages of bottom-up and top-down strategies to incorporate proteins derived from the leukocyte plasma membrane into lipid nanoparticles. The resulting proteolipid vesicles--which we refer to as leukosomes--retained the versatility and physicochemical properties typical of liposomal formulations, preferentially targeted inflamed vasculature, enabled the selective and effective delivery of dexamethasone to inflamed tissues, and reduced phlogosis in a localized model of inflammation.

An Ant Colony Optimization and Hybrid Metaheuristics Algorithm to Solve the Split Delivery Vehicle Routing Problem

DTIC Science & Technology

2015-01-01

programming formulation of traveling salesman problems , Journal of the ACM, 7(4), 326-329. Montemanni, R., Gambardella, L. M., Rizzoli, A.E., Donati. A.V... salesman problem . BioSystem, 43(1), 73-81. Dror, M., Trudeau, P., 1989. Savings by split delivery routing. Transportation Science, 23, 141- 145. Dror, M...An Ant Colony Optimization and Hybrid Metaheuristics Algorithm to solve the Split Delivery Vehicle Routing Problem Authors: Gautham Rajappa

Optimization of an efficient transcuticular delivery system for control of citrus huanglongbing

USDA-ARS?s Scientific Manuscript database

We experimentally develop and optimize a transcuticular nano-delivery system for enhancing permeation of effective compound against HLB disease through citrus cuticle into the phloem by foliar spray or bark application. The results showed that two kinds of nanoemulsions (W/O and O/W) with the smalle...

Optimizing Wartime Materiel Delivery: An Overview of DoD containerization. Volume 2. Framework for Action to Address DoD Containerization Issues

DOT National Transportation Integrated Search

1988-10-01

This second volume of the study entitled, Optimizing Wartime Materiel Delivery: An Overview of DOD Containerization Efforts, -outlines a framework for action to address containerization issues identified in Volume I. The objectives of the study inclu...

Trajectory Modulated Arc Therapy: A Fully Dynamic Delivery With Synchronized Couch and Gantry Motion Significantly Improves Dosimetric Indices Correlated With Poor Cosmesis in Accelerated Partial Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Jieming; Atwood, Todd; Eyben, Rie von

2015-08-01

Purpose: To develop planning and delivery capabilities for linear accelerator–based nonisocentric trajectory modulated arc therapy (TMAT) and to evaluate the benefit of TMAT for accelerated partial breast irradiation (APBI) with the patient in prone position. Methods and Materials: An optimization algorithm for volumetrically modulated arc therapy (VMAT) was generalized to allow for user-defined nonisocentric TMAT trajectories combining couch rotations and translations. After optimization, XML scripts were automatically generated to program and subsequently deliver the TMAT plans. For 10 breast patients in the prone position, TMAT and 6-field noncoplanar intensity modulated radiation therapy (IMRT) plans were generated under equivalent objectives andmore » constraints. These plans were compared with regard to whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose. Results: For TMAT APBI, nonisocentric collision-free horizontal arcs with large angular span (251.5 ± 7.9°) were optimized and delivered with delivery time of ∼4.5 minutes. Percentage changes of whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose for TMAT relative to IMRT were −10.81% ± 6.91%, −27.81% ± 7.39%, −14.82% ± 9.67%, and 39.40% ± 10.53% (P≤.01). Conclusions: This is a first demonstration of end-to-end planning and delivery implementation of a fully dynamic APBI TMAT. Compared with IMRT, TMAT resulted in marked reduction of the breast tissue volume irradiated at high doses.« less

pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery.

PubMed

Koetting, Michael Clinton; Guido, Joseph Frank; Gupta, Malvika; Zhang, Annie; Peppas, Nicholas A

2016-01-10

Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-responsive poly(itaconic acid-co-N-vinyl-2-pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro-scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 μg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 μg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically-degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1h in intestinal conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

Discovery and Delivery of Synergistic Chemotherapy Drug Combinations to Tumors

NASA Astrophysics Data System (ADS)

Camacho, Kathryn Militar

Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped. Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects. Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts. The advantages of multi-drug incorporation in nano-vehicles are many: improved accumulation in tumor tissue via the enhanced permeation and retention effect, limited uptake in healthy tissue, and controlled exposure of tumor tissue to optimal synergistic drug ratios. To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: liposomes and polymer-drug conjugates. Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios. Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model. Furthermore, versatile drug incorporation methods investigated here can be broadly applied to various agents. Findings from our research can potentially widen the therapeutic window of chemotherapy combinations by emphasizing investigations of optimal drug ratios rather than maximum drug doses and by identifying appropriate nanoparticles for their delivery. Application of these concepts can ultimately help capture the full therapeutic potential of combination regimens.

A continuous arc delivery optimization algorithm for CyberKnife m6.

PubMed

Kearney, Vasant; Descovich, Martina; Sudhyadhom, Atchar; Cheung, Joey P; McGuinness, Christopher; Solberg, Timothy D

2018-06-01

This study aims to reduce the delivery time of CyberKnife m6 treatments by allowing for noncoplanar continuous arc delivery. To achieve this, a novel noncoplanar continuous arc delivery optimization algorithm was developed for the CyberKnife m6 treatment system (CyberArc-m6). CyberArc-m6 uses a five-step overarching strategy, in which an initial set of beam geometries is determined, the robotic delivery path is calculated, direct aperture optimization is conducted, intermediate MLC configurations are extracted, and the final beam weights are computed for the continuous arc radiation source model. This algorithm was implemented on five prostate and three brain patients, previously planned using a conventional step-and-shoot CyberKnife m6 delivery technique. The dosimetric quality of the CyberArc-m6 plans was assessed using locally confined mutual information (LCMI), conformity index (CI), heterogeneity index (HI), and a variety of common clinical dosimetric objectives. Using conservative optimization tuning parameters, CyberArc-m6 plans were able to achieve an average CI difference of 0.036 ± 0.025, an average HI difference of 0.046 ± 0.038, and an average LCMI of 0.920 ± 0.030 compared with the original CyberKnife m6 plans. Including a 5 s per minute image alignment time and a 5-min setup time, conservative CyberArc-m6 plans achieved an average treatment delivery speed up of 1.545x ± 0.305x compared with step-and-shoot plans. The CyberArc-m6 algorithm was able to achieve dosimetrically similar plans compared to their step-and-shoot CyberKnife m6 counterparts, while simultaneously reducing treatment delivery times. © 2018 American Association of Physicists in Medicine.

Drug delivery systems with modified release for systemic and biophase bioavailability.

PubMed

Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine

PubMed Central

Chintalapudi, Ramprasad; Murthy, T. E. G. K.; Lakshmi, K. Rajya; Manohar, G. Ganesh

2015-01-01

Background: The aim of the present study was to formulate and optimize the self-emulsifying drug delivery systems (SEDDS) of nevirapine (NVP) by use of 22 factorial designs to enhance the oral absorption of NVP by improving its solubility, dissolution rate, and diffusion profile. SEDDS are the isotropic mixtures of oil, surfactant, co-surfactant and drug that form oil in water microemulsion when introduced into the aqueous phase under gentle agitation. Materials and Methods: Solubility of NVP in different oils, surfactants, and co-surfactants was determined for the screening of excipients. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations with the help of data obtained through the maximum micro emulsion region containing combinations of oil, surfactant, and co-surfactant. The formulations of SEDDS were optimized by 22 factorial designs. Results: The optimum formulation of SEDDS contains 32.5% oleic acid, 44.16% tween 20, and 11.9% polyethylene glycol 600 as oil, surfactant, and co-surfactant respectively. The SEDDS was evaluated for the following drug content, self-emulsification time, rheological properties, zeta potential, in vitro diffusion studies, thermodynamic stability studies, and in vitro dissolution studies. An increase in dissolution was achieved by SEDDS compared to pure form of NVP. Conclusion: Overall, this study suggests that the dissolution and oral bioavailability of NVP could be improved by SEDDS technology. PMID:26682191

Formulation and evaluation of atenolol floating bioadhesive system using optimized polymer blends

PubMed Central

Siddam, Haritha; Kotla, Niranjan G.; Maddiboyina, Balaji; Singh, Sima; Sunnapu, Omprakash; Kumar, Anil; Sharma, Dinesh

2016-01-01

Introduction: Oral sustained release gastro retentive dosage forms offer several advantages for drugs having absorption from the upper gastrointestinal tract to improve the bioavailability of medications which have narrow absorption window. The aim of the study was to develop a floating bioadhesive drug delivery system exhibiting a unique combination of floatation and bioadhesion to prolong the residence in the stomach using atenolol as a model drug. Methods: Prior to compression, polymeric blend(s) were evaluated for flow properties. The tablets were prepared by direct compression method using bioadhesive polymer like Carbopol 934P and hydrophilic polymers like HPMC K4M, HPMC K15M, and HPMC K100M. The prepared tablets were evaluated for physical characteristics, bioadhesive strength, buoyancy lag time, swelling index and in vitro drug release studies. Results: The mean bioadhesive strength was found to be in the range of 16.2 to 52.1 gm. The optimized blend (F11) showed 92.3% drug releases after 24 hrs. Whilst, increase in concentration of carbopol 934P, bioadhesive strength and swelling index was increased with slow release. The n values of optimized formulations were found in the range of 0.631-0.719 indicating non-fickian anomalous type transport mechanism. Conclusion: The study aided in developing an ideal once-a-day gastro retentive floating drug delivery system with improved floating, swelling and bioadhesive characteristics with better bioavailability. PMID:27051631

Preferred delivery method and acceptability of Wheat-Soy Blend (WSB++) as a daily complementary food supplement in northwest Bangladesh.

PubMed

Shamim, Abu Ahmed; Hanif, Abu A M; Merrill, Rebecca D; Campbell, Rebecca K; Kumkum, Mehnaz Alam; Shaikh, Saijuddin; de Pee, Saskia; Ahmed, Tahmeed; Parveen, Monira; Mehra, Sucheta; Klemm, Rolf D W; Labrique, Alain B; West, Keith P; Christian, Parul

2015-01-01

Fortified blended foods (FBFs) are widely used to prevent undernutrition in early childhood in food-insecure settings. We field tested enhanced Wheat Soy Blend (WSB++)-a FBF fortified with micronutrients, milk powder, sugar, and oil-in preparation for a complementary food supplement (CFS) trial in rural northwestern Bangladesh. Formative work was conducted to determine the optimal delivery method (cooked vs. not) for this CFS, to examine mothers' child feeding practices with and acceptance of the WSB++, and to identify potential barriers to adherence. Our results suggest WSB++ is an acceptable CFS in rural Bangladesh and the requirement for mothers to cook WSB++ at home is unlikely to be a barrier to its daily use as a CFS in this population.

DOE Optimization of Nano-based Carrier of Pregabalin as Hydrogel: New Therapeutic & Chemometric Approaches for Controlled Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Arafa, Mona G.; Ayoub, Bassam M.

2017-01-01

Niosomes entrapping pregabalin (PG) were prepared using span 60 and cholesterol in different molar ratios by hydration method, the remaining PG from the hydrating solution was separated from vesicles by freeze centrifugation. Optimization of nano-based carrier of pregabalin (PG) was achieved. Quality by Design strategy was successfully employed to obtain PG-loaded niosomes with the desired properties. The optimal particle size, drug release and entrapment efficiency were attained by Minitab® program using design of experiment (DOE) that predicted the best parameters by investigating the combined effect of different factors simultaneously. Pareto chart was used in the screening step to exclude the insignificant variables while response surface methodology (RSM) was used in the optimization step to study the significant factors. Best formula was selected to prepare topical hydrogels loaded with niosomal PG using HPMC and Carbopol 934. It was verified, by means of mechanical and rheological tests, that addition of the vesicles to the gel matrix affected significantly gel network. In vitro release and ex vivo permeation experiments were carried out. Delivery of PG molecules followed a Higuchi, non Fickian diffusion. The present work will be of interest for pharmaceutical industry as a controlled transdermal alternative to the conventional oral route.

DOE Optimization of Nano-based Carrier of Pregabalin as Hydrogel: New Therapeutic & Chemometric Approaches for Controlled Drug Delivery Systems

PubMed Central

Arafa, Mona G.; Ayoub, Bassam M.

2017-01-01

Niosomes entrapping pregabalin (PG) were prepared using span 60 and cholesterol in different molar ratios by hydration method, the remaining PG from the hydrating solution was separated from vesicles by freeze centrifugation. Optimization of nano-based carrier of pregabalin (PG) was achieved. Quality by Design strategy was successfully employed to obtain PG-loaded niosomes with the desired properties. The optimal particle size, drug release and entrapment efficiency were attained by Minitab® program using design of experiment (DOE) that predicted the best parameters by investigating the combined effect of different factors simultaneously. Pareto chart was used in the screening step to exclude the insignificant variables while response surface methodology (RSM) was used in the optimization step to study the significant factors. Best formula was selected to prepare topical hydrogels loaded with niosomal PG using HPMC and Carbopol 934. It was verified, by means of mechanical and rheological tests, that addition of the vesicles to the gel matrix affected significantly gel network. In vitro release and ex vivo permeation experiments were carried out. Delivery of PG molecules followed a Higuchi, non Fickian diffusion. The present work will be of interest for pharmaceutical industry as a controlled transdermal alternative to the conventional oral route. PMID:28134262

Placenta accreta spectrum: accreta, increta, and percreta.

PubMed

Silver, Robert M; Barbour, Kelli D

2015-06-01

Placenta accreta can lead to hemorrhage, resulting in hysterectomy, blood transfusion, multiple organ failure, and death. Accreta has been increasing steadily in incidence owing to an increase in the cesarean delivery rate. Major risk factors are placenta previa in women with prior cesarean deliveries. Obstetric ultrasonography can be used to diagnose placenta accreta antenatally, which allows for scheduled delivery in a multidisciplinary center of excellence for accreta. Controversies exist regarding optimal management, including optimal timing of delivery, surgical approach, use of adjunctive measures, and conservative (uterine-sparing) therapy. We review the definition, risk factors, diagnosis, management, and controversies regarding placenta accreta. Copyright © 2015 Elsevier Inc. All rights reserved.

Challenging the 4- to 5-minute rule: from perimortem cesarean to resuscitative hysterotomy.

PubMed

Rose, Carl H; Faksh, Arij; Traynor, Kyle D; Cabrera, Daniel; Arendt, Katherine W; Brost, Brian C

2015-11-01

Although perimortem delivery has been recorded in the medical literature for millennia, the procedural intent has evolved to the current fetocentric approach, predicating timing of delivery following maternal cardiopulmonary arrest to optimize neonatal outcome. We suggest a call to action to reinforce the concept that if the uterus is palpable at or above the umbilicus, preparations for delivery should be made simultaneous with initiation of maternal resuscitative efforts; if maternal condition is not rapidly reversible, hysterotomy with delivery should be performed regardless of fetal viability or elapsed time since arrest. Cognizant of the difficulty in determining precise timing of arrest in clinical practice, if fetal status is already compromised further delay while attempting to assess fetal heart rate, locating optimal surgical equipment, or transporting to an operating room will result in unnecessary worsening of both maternal and fetal condition. Even if intrauterine demise has already occurred, maternal resuscitative efforts will typically be markedly improved following delivery with uterine decompression. Consequently we suggest that perimortem cesarean delivery be renamed "resuscitative hysterotomy" to reflect the mutual optimization of resuscitation efforts that would potentially provide earlier and more substantial benefit to both mother and baby. Copyright © 2015 Elsevier Inc. All rights reserved.

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine.

PubMed

Upadhyay, Mansi; Adena, Sandeep Kumar Reddy; Vardhan, Harsh; Pandey, Sureshwar; Mishra, Brahmeshwar

2018-03-01

The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg). The IPN microbeads were optimized by Box-Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle. Ionotropic gelation method utilizing metal ion calcium (Ca 2+ ) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box-Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively. The particle size and % drug entrapment of the optimized batch was 494.37 ± 1.4 µm and 81.39 ± 2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12 h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP. Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.

Optimization of territory control of the mail carrier by using Hungarian methods

NASA Astrophysics Data System (ADS)

Supian, S.; Wahyuni, S.; Nahar, J.; Subiyanto

2018-03-01

In this paper, the territory control of the mail carrier from the central post office Bandung in delivering the package to the destination location was optimized by using Hungarian method. Sensitivity analysis against data changes that may occur was also conducted. The sampled data in this study are the territory control of 10 mail carriers who will be assigned to deliver mail package to 10 post office delivery centers in Bandung. The result of this research is the combination of territory control optimal from 10 mail carriers as follows: mail carrier 1 to Cikutra, mail carrier 2 to Ujung Berung, mail carrier 3 to Dayeuh Kolot, mail carrier 4 to Padalarang, mail carrier 5 to Situ Saeur, mail carrier 6 to Cipedes, mail carrier 7 to Cimahi, mail carrier 8 to Soreang, mail carrier 9 to Asia-Afrika, mail carrier 10 to Cikeruh. Based on this result, manager of the central post office Bandung can make optimal decisions to assign tasks to their mail carriers.

Optimal design of implants for magnetically mediated hyperthermia: A wireless power transfer approach

NASA Astrophysics Data System (ADS)

Lang, Hans-Dieter; Sarris, Costas D.

2017-09-01

In magnetically mediated hyperthermia (MMH), an externally applied alternating magnetic field interacts with a mediator (such as a magnetic nanoparticle or an implant) inside the body to heat up the tissue in its proximity. Producing heat via induced currents in this manner is strikingly similar to wireless power transfer (WPT) for implants, where power is transferred from a transmitter outside of the body to an implanted receiver, in most cases via magnetic fields as well. Leveraging this analogy, a systematic method to design MMH implants for optimal heating efficiency is introduced, akin to the design of WPT systems for optimal power transfer efficiency. This paper provides analytical formulas for the achievable heating efficiency bounds as well as the optimal operating frequency and the implant material. Multiphysics simulations validate the approach and further demonstrate that optimization with respect to maximum heating efficiency is accompanied by minimizing heat delivery to healthy tissue. This is a property that is highly desirable when considering MMH as a key component or complementary method of cancer treatment and other applications.

Development of drug delivery systems based on nanostructured porous silicon loaded with the anti-tumoral drug emodin adsorbed on silver nanoparticles

NASA Astrophysics Data System (ADS)

Hernández, Margarita; Recio, Gonzalo; Sevilla, Paz; Torres-Costa, Vicente; García-Ramos, José V.; Domingo, Concepción; Martín-Palma, Raúl J. J.

2012-10-01

A study of the fluorescence and Raman spectra of a new and complex drug delivery system formed by emodin adsorbed on silver nanoparticles embedded into a matrix of porous silicon is here reported. Several experimental methods of inclusion of the drug-silver set inside the pores, without previous functionalization of porous silicon, have been tested in order to optimize the conditions for the fluorescence detection of emodin. In this sense, we have also added bovine serum albumin to the system, finding that the presence of the protein enhances the fluores-cence signal from emodin.

Improving the Computational Effort of Set-Inversion-Based Prandial Insulin Delivery for Its Integration in Insulin Pumps

PubMed Central

León-Vargas, Fabian; Calm, Remei; Bondia, Jorge; Vehí, Josep

2012-01-01

Objective Set-inversion-based prandial insulin delivery is a new model-based bolus advisor for postprandial glucose control in type 1 diabetes mellitus (T1DM). It automatically coordinates the values of basal–bolus insulin to be infused during the postprandial period so as to achieve some predefined control objectives. However, the method requires an excessive computation time to compute the solution set of feasible insulin profiles, which impedes its integration into an insulin pump. In this work, a new algorithm is presented, which reduces computation time significantly and enables the integration of this new bolus advisor into current processing features of smart insulin pumps. Methods A new strategy was implemented that focused on finding the combined basal–bolus solution of interest rather than an extensive search of the feasible set of solutions. Analysis of interval simulations, inclusion of physiological assumptions, and search domain contractions were used. Data from six real patients with T1DM were used to compare the performance between the optimized and the conventional computations. Results In all cases, the optimized version yielded the basal–bolus combination recommended by the conventional method and in only 0.032% of the computation time. Simulations show that the mean number of iterations for the optimized computation requires approximately 3.59 s at 20 MHz processing power, in line with current features of smart pumps. Conclusions A computationally efficient method for basal–bolus coordination in postprandial glucose control has been presented and tested. The results indicate that an embedded algorithm within smart insulin pumps is now feasible. Nonetheless, we acknowledge that a clinical trial will be needed in order to justify this claim. PMID:23294789

Drug-targeting methodologies with applications: A review

PubMed Central

Kleinstreuer, Clement; Feng, Yu; Childress, Emily

2014-01-01

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

Terbinafine Hydrochloride Trans-ungual Delivery via Nanovesicular Systems: In Vitro Characterization and Ex Vivo Evaluation.

PubMed

Elsherif, Noha Ibrahim; Shamma, Rehab Nabil; Abdelbary, Ghada

2017-02-01

Treating a nail infection like onychomycosis is challenging as the human nail plate acts as a formidable barrier against all drug permeation. Available oral and topical treatments have several setbacks. Terbinafine hydrochloride (TBH), belonging to the allylamine class, is mainly used for treatment of onychomycosis. This study aims to formulate TBH in a nanobased spanlastic vesicular carrier that enables and enhances the drug delivery through the nail. The nanovesicles were formulated by ethanol injection method, using either Span® 60 or Span® 65, together with Tween 80 or sodium deoxycholate as an edge activator. A full factorial design was implemented to study the effect of different formulation and process variables on the prepared TBH-loaded spanlastic nanovesicles. TBH entrapment efficiency percentages, particle size diameter, percentage drug released after 2 h and 8 h were selected as dependent variables. Optimization was performed using Design-Expert® software to obtain an optimized formulation with high entrapment efficiency (62.35 ± 8.91%), average particle size of 438.45 ± 70.5 nm, and 29.57 ± 0.93 and 59.53 ± 1.73% TBH released after 2 and 8 h, respectively. The optimized formula was evaluated using differential scanning calorimetry and X-ray diffraction and was also morphologically examined using transmission electron microscopy. An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation. In conclusion, the results confirmed that spanlastics exhibit promising results for the trans-ungual delivery of TBH.

SU-E-J-150: Impact of Intrafractional Prostate Motion On the Accuracy and Efficiency of Prostate SBRT Delivery: A Retrospective Analysis of Prostate Tracking Log Files

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiang, H; Hirsch, A; Willins, J

2014-06-01

Purpose: To measure intrafractional prostate motion by time-based stereotactic x-ray imaging and investigate the impact on the accuracy and efficiency of prostate SBRT delivery. Methods: Prostate tracking log files with 1,892 x-ray image registrations from 18 SBRT fractions for 6 patients were retrospectively analyzed. Patient setup and beam delivery sessions were reviewed to identify extended periods of large prostate motion that caused delays in setup or interruptions in beam delivery. The 6D prostate motions were compared to the clinically used PTV margin of 3–5 mm (3 mm posterior, 5 mm all other directions), a hypothetical PTV margin of 2–3 mmmore » (2 mm posterior, 3 mm all other directions), and the rotation correction limits (roll ±2°, pitch ±5° and yaw ±3°) of CyberKnife to quantify beam delivery accuracy. Results: Significant incidents of treatment start delay and beam delivery interruption were observed, mostly related to large pitch rotations of ≥±5°. Optimal setup time of 5–15 minutes was recorded in 61% of the fractions, and optimal beam delivery time of 30–40 minutes in 67% of the fractions. At a default imaging interval of 15 seconds, the percentage of prostate motion beyond PTV margin of 3–5 mm varied among patients, with a mean at 12.8% (range 0.0%–31.1%); and the percentage beyond PTV margin of 2–3 mm was at a mean of 36.0% (range 3.3%–83.1%). These timely detected offsets were all corrected real-time by the robotic manipulator or by operator intervention at the time of treatment interruptions. Conclusion: The durations of patient setup and beam delivery were directly affected by the occurrence of large prostate motion. Frequent imaging of down to 15 second interval is necessary for certain patients. Techniques for reducing prostate motion, such as using endorectal balloon, can be considered to assure consistently higher accuracy and efficiency of prostate SBRT delivery.« less

Modelling and multi-parametric control for delivery of anaesthetic agents.

PubMed

Dua, Pinky; Dua, Vivek; Pistikopoulos, Efstratios N

2010-06-01

This article presents model predictive controllers (MPCs) and multi-parametric model-based controllers for delivery of anaesthetic agents. The MPC can take into account constraints on drug delivery rates and state of the patient but requires solving an optimization problem at regular time intervals. The multi-parametric controller has all the advantages of the MPC and does not require repetitive solution of optimization problem for its implementation. This is achieved by obtaining the optimal drug delivery rates as a set of explicit functions of the state of the patient. The derivation of the controllers relies on using detailed models of the system. A compartmental model for the delivery of three drugs for anaesthesia is developed. The key feature of this model is that mean arterial pressure, cardiac output and unconsciousness of the patient can be simultaneously regulated. This is achieved by using three drugs: dopamine (DP), sodium nitroprusside (SNP) and isoflurane. A number of dynamic simulation experiments are carried out for the validation of the model. The model is then used for the design of model predictive and multi-parametric controllers, and the performance of the controllers is analyzed.

Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

NASA Astrophysics Data System (ADS)

Li, Bin; Luo, Xiao; Deng, Binbin; Giancola, Jolynn B.; McComb, David W.; Schmittgen, Thomas D.; Dong, Yizhou

2016-02-01

Lipid-like nanoparticles (LLNs) have shown great potential for RNA delivery. Lipid-like compounds are key components in LLNs. In this study, we investigated the effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Our results showed that position change of functional groups on lipid-like compounds can dramatically improve delivery efficiency. We then optimized formulation ratios of TNT-b10 LLNs, a lead material, increasing delivery efficiency over 2-fold. More importantly, pegylated TNT-b10 LLNs is stable for over four weeks and is over 10-fold more efficient than that of its counterpart TNT-a10 LLNs. Additionally, the optimal formulation O-TNT-b10 LLNs is capable of delivering mRNA encoding luciferase in vivo. These results provide useful insights into the design of next generation LLNs for mRNA delivery.

Preconception care: delivery strategies and packages for care

PubMed Central

2014-01-01

The notion of preconception care aims to target the existing risks before pregnancy, whereby resources may be used to improve reproductive health and optimize knowledge before conceiving. The preconception period provides an opportunity to intervene earlier to optimize the health of potential mothers (and fathers) and to prevent harmful exposures from affecting the developing fetus. These interventions include birth spacing and preventing teenage pregnancy, promotion of contraceptive use, optimization of weight and micronutrient status, prevention and management of infectious diseases, and screening for and managing chronic conditions. Given existing interventions and the need to organize services to optimize delivery of care in a logical and effective manner, interventions are frequently co-packaged or bundled together. This paper highlights packages of preconception interventions that can be combined and co-delivered to women through various delivery channels and provides a logical framework for development of such packages in varying contexts. PMID:25415178

Planning and delivery of four-dimensional radiation therapy with multileaf collimators

NASA Astrophysics Data System (ADS)

McMahon, Ryan L.

This study is an investigation of the application of multileaf collimators (MLCs) to the treatment of moving anatomy with external beam radiation therapy. First, a method for delivering intensity modulated radiation therapy (IMRT) to moving tumors is presented. This method uses an MLC control algorithm that calculates appropriate MLC leaf speeds in response to feedback from real-time imaging. The algorithm does not require a priori knowledge of a tumor's motion, and is based on the concept of self-correcting DMLC leaf trajectories . This gives the algorithm the distinct advantage of allowing for correction of DMLC delivery errors without interrupting delivery. The algorithm is first tested for the case of one-dimensional (1D) rigid tumor motion in the beam's eye view (BEV). For this type of motion, it is shown that the real-time tracking algorithm results in more accurate deliveries, with respect to delivered intensity, than those which ignore motion altogether. This is followed by an appropriate extension of the algorithm to two-dimensional (2D) rigid motion in the BEV. For this type of motion, it is shown that the 2D real-time tracking algorithm results in improved accuracy (in the delivered intensity) in comparison to deliveries which ignore tumor motion or only account for tumor motion which is aligned with MLC leaf travel. Finally, a method is presented for designing DMLC leaf trajectories which deliver a specified intensity over a moving tumor without overexposing critical structures which exhibit motion patterns that differ from that of the tumor. In addition to avoiding overexposure of critical organs, the method can, in the case shown, produce deliveries that are superior to anything achievable using stationary anatomy. In this regard, the method represents a systematic way to include anatomical motion as a degree of freedom in the optimization of IMRT while producing treatment plans that are deliverable with currently available technology. These results, combined with those related to the real-time MLC tracking algorithm, show that an MLC is a promising tool to investigate for the delivery of four-dimensional radiation therapy.

Silk-elastin-like protein polymer matrix for intraoperative delivery of an oncolytic vaccinia virus.

PubMed

Price, Daniel L; Li, Pingdong; Chen, Chun-Hao; Wong, Danni; Yu, Zhenkun; Chen, Nanhai G; Yu, Yong A; Szalay, Aladar A; Cappello, Joseph; Fong, Yuman; Wong, Richard J

2016-02-01

Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. © 2014 Wiley Periodicals, Inc.

Novel isotretinoin microemulsion-based gel for targeted topical therapy of acne: formulation consideration, skin retention and skin irritation studies

NASA Astrophysics Data System (ADS)

Patel, Mrunali R.; Patel, Rashmin B.; Parikh, Jolly R.; Patel, Bharat G.

2016-04-01

Isotretinoin was formulated in novel microemulsion-based gel formulation with the aim of improving its solubility, skin tolerability, therapeutic efficacy, skin-targeting efficiency and patient compliance. Microemulsion was formulated by the spontaneous microemulsification method using 8 % isopropyl myristate, 24 % Labrasol, 8 % plurol oleique and 60 % water as an external phase. All plain and isotretinoin-loaded microemulsions were clear and showed physicochemical parameters for the desired topical delivery and stability. The permeation profiles of isotretinoin through rat skin from selected microemulsion formulation followed zero-order kinetics. Microemulsion-based gel was prepared by incorporating Carbopol®971 in optimized microemulsion formulation having suitable skin permeation rate and skin uptake. Microemulsion-based gel showed desired physicochemical parameters and demonstrated advantage over marketed formulation in improving the skin tolerability of isotretinoin, indicating its potential in improving topical delivery of isotretinoin. The developed microemulsion-based gel may be a potential drug delivery vehicle for targeted topical delivery of isotretinoin in the treatment of acne.

[In vitro transdermal delivery of the active fraction of xiangfusiwu decoction based on principal component analysis].

PubMed

Li, Zhen-Hao; Liu, Pei; Qian, Da-Wei; Li, Wei; Shang, Er-Xin; Duan, Jin-Ao

2013-06-01

The objective of the present study was to establish a method based on principal component analysis (PCA) for the study of transdermal delivery of multiple components in Chinese medicine, and to choose the best penetration enhancers for the active fraction of Xiangfusiwu decoction (BW) with this method. Improved Franz diffusion cells with isolated rat abdomen skins were carried out to experiment on the transdermal delivery of six active components, including ferulic acid, paeoniflorin, albiflorin, protopine, tetrahydropalmatine and tetrahydrocolumbamine. The concentrations of these components were determined by LC-MS/MS, then the total factor scores of the concentrations at different times were calculated using PCA and were employed instead of the concentrations to compute the cumulative amounts and steady fluxes, the latter of which were considered as the indexes for optimizing penetration enhancers. The results showed that compared to the control group, the steady fluxes of the other groups increased significantly and furthermore, 4% azone with 1% propylene glycol manifested the best effect. The six components could penetrate through skin well under the action of penetration enhancers. The method established in this study has been proved to be suitable for the study of transdermal delivery of multiple components, and it provided a scientific basis for preparation research of Xiangfusiwu decoction and moreover, it could be a reference for Chinese medicine research.

Gold Nanoparticle Mediated Laser Transfection for Efficient siRNA Mediated Gene Knock Down

PubMed Central

Heinemann, Dag; Schomaker, Markus; Kalies, Stefan; Schieck, Maximilian; Carlson, Regina; Escobar, Hugo Murua; Ripken, Tammo; Meyer, Heiko; Heisterkamp, Alexander

2013-01-01

Laser based transfection methods have proven to be an efficient and gentle alternative to established molecule delivery methods like lipofection or electroporation. Among the laser based methods, gold nanoparticle mediated laser transfection bears the major advantage of high throughput and easy usability. This approach uses plasmon resonances on gold nanoparticles unspecifically attached to the cell membrane to evoke transient and spatially defined cell membrane permeabilization. In this study, we explore the parameter regime for gold nanoparticle mediated laser transfection for the delivery of molecules into cell lines and prove its suitability for siRNA mediated gene knock down. The developed setup allows easy usage and safe laser operation in a normal lab environment. We applied a 532 nm Nd:YAG microchip laser emitting 850 ps pulses at a repetition rate of 20.25 kHz. Scanning velocities of the laser spot over the sample of up to 200 mm/s were tested without a decline in perforation efficiency. This velocity leads to a process speed of ∼8 s per well of a 96 well plate. The optimal particle density was determined to be ∼6 particles per cell using environmental scanning electron microscopy. Applying the optimized parameters transfection efficiencies of 88% were achieved in canine pleomorphic adenoma ZMTH3 cells using a fluorescent labeled siRNA while maintaining a high cell viability of >90%. Gene knock down of d2-EGFP was demonstrated and validated by fluorescence repression and western blot analysis. On basis of our findings and established mathematical models we suppose a mixed transfection mechanism consisting of thermal and multiphoton near field effects. Our findings emphasize that gold nanoparticle mediated laser transfection provides an excellent tool for molecular delivery for both, high throughput purposes and the transfection of sensitive cells types. PMID:23536802

Optimization of lens layout for THz signal free-space delivery

NASA Astrophysics Data System (ADS)

Yu, Jimmy; Zhou, Wen

2018-03-01

We investigate how to extend the air-space distance for Terahertz (THz) signal by using optimized lens layout. After a delivery over 129.6 cm air-space we realize the BER of 10 Gb/s QPSK signal at 450 GHz smaller than 1 ×10-4 with this optimized lens layout. If only two lenses are employed, the BER is higher than forward error correction (FEC) threshold at the input power of 15 dBm into the photodiode.

Development of a gastroretentive pulsatile drug delivery platform.

PubMed

Thitinan, Sumalee; McConville, Jason T

2012-04-01

To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag-time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag-time controlling layer. The lag-time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. By varying the composition of the lag-time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Simulation study of electric-guided delivery of 0.4µm monodisperse and polydisperse aerosols to the ostiomeatal complex.

PubMed

Xi, Jinxiang; Yuan, Jiayao Eddie; Si, Xiuhua April

2016-05-01

Despite the high prevalence of rhinosinusitis, current inhalation therapy shows limited efficacy due to extremely low drug delivery efficiency to the paranasal sinuses. Novel intranasal delivery systems are needed to enhance targeted delivery to the sinus with therapeutic dosages. An optimization framework for intranasal drug delivery was developed to target polydisperse charged aerosols to the ostiomeatal complex (OMC) with electric guidance. The delivery efficiency of a group of charged aerosols recently reported in the literature was numerically assessed and optimized in an anatomically accurate nose-sinus model. Key design variables included particle charge number, particle size and distribution, electrode strength, and inhalation velocity. Both monodisperse and polydisperse aerosol profiles were considered. Results showed that the OMC delivery efficiency was highly sensitive to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric-guidance and point drug release, focused deposition with significantly enhanced dosage in the OMC can be achieved. For 0.4 µm charged aerosols, an OMC delivery efficiency of 51.6% was predicted for monodisperse aerosols and 34.4% for polydisperse aerosols. This difference suggested that the aerosol profile exerted a notable effect on intranasal deliveries. Sensitivity analysis indicated that the OMC deposition fraction was highly sensitive to the charge and size of particles and was less sensitive to the inhalation velocity considered in this study. Experimental studies are needed to validate the numerically optimized designs. Further studies are warranted to investigate the targeted OMC delivery with both electric and acoustics controls, the latter of which has the potential to further deliver the drug particles into the sinus cavity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple anatomy optimization of accumulated dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V.; Moore, Joseph A.

Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dosemore » variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.« less

A novel adaptive needle insertion sequencing for robotic, single needle MR-guided high-dose-rate prostate brachytherapy

NASA Astrophysics Data System (ADS)

Borot de Battisti, M.; de Senneville, B. Denis; Hautvast, G.; Binnekamp, D.; Lagendijk, J. J. W.; Maenhout, M.; Moerland, M. A.

2017-05-01

MR-guided high-dose-rate (HDR) brachytherapy has gained increasing interest as a treatment for patients with localized prostate cancer because of the superior value of MRI for tumor and surrounding tissues localization. To enable needle insertion into the prostate with the patient in the MR bore, a single needle MR-compatible robotic system involving needle-by-needle dose delivery has been developed at our institution. Throughout the intervention, dose delivery may be impaired by: (1) sub-optimal needle positioning caused by e.g. needle bending, (2) intra-operative internal organ motion such as prostate rotations or swelling, or intra-procedural rectum or bladder filling. This may result in failure to reach clinical constraints. To assess the first aforementioned challenge, a recent study from our research group demonstrated that the deposited dose may be greatly improved by real-time adaptive planning with feedback on the actual needle positioning. However, the needle insertion sequence is left to the doctor and therefore, this may result in sub-optimal dose delivery. In this manuscript, a new method is proposed to determine and update automatically the needle insertion sequence. This strategy is based on the determination of the most sensitive needle track. The sensitivity of a needle track is defined as its impact on the dose distribution in case of sub-optimal positioning. A stochastic criterion is thus presented to determine each needle track sensitivity based on needle insertion simulations. To assess the proposed sequencing strategy, HDR prostate brachytherapy was simulated on 11 patients with varying number of needle insertions. Sub-optimal needle positioning was simulated at each insertion (modeled by typical random angulation errors). In 91% of the scenarios, the dose distribution improved when the needle was inserted into the most compared to the least sensitive needle track. The computation time for sequencing was less than 6 s per needle track. The proposed needle insertion sequencing can therefore assist in delivering an optimal dose in HDR prostate brachytherapy.

Drug delivery optimization through Bayesian networks.

PubMed Central

Bellazzi, R.

1992-01-01

This paper describes how Bayesian Networks can be used in combination with compartmental models to plan Recombinant Human Erythropoietin (r-HuEPO) delivery in the treatment of anemia of chronic uremic patients. Past measurements of hematocrit or hemoglobin concentration in a patient during the therapy can be exploited to adjust the parameters of a compartmental model of the erythropoiesis. This adaptive process allows more accurate patient-specific predictions, and hence a more rational dosage planning. We describe a drug delivery optimization protocol, based on our approach. Some results obtained on real data are presented. PMID:1482938

3D Monte Carlo model with direct photon flux recording for optimal optogenetic light delivery

NASA Astrophysics Data System (ADS)

Shin, Younghoon; Kim, Dongmok; Lee, Jihoon; Kwon, Hyuk-Sang

2017-02-01

Configuring the light power emitted from the optical fiber is an essential first step in planning in-vivo optogenetic experiments. However, diffusion theory, which was adopted for optogenetic research, precluded accurate estimates of light intensity in the semi-diffusive region where the primary locus of the stimulation is located. We present a 3D Monte Carlo model that provides an accurate and direct solution for light distribution in this region. Our method directly records the photon trajectory in the separate volumetric grid planes for the near-source recording efficiency gain, and it incorporates a 3D brain mesh to support both homogeneous and heterogeneous brain tissue. We investigated the light emitted from optical fibers in brain tissue in 3D, and we applied the results to design optimal light delivery parameters for precise optogenetic manipulation by considering the fiber output power, wavelength, fiber-to-target distance, and the area of neural tissue activation.

Development of a chitosan based double layer-coated tablet as a platform for colon-specific drug delivery

PubMed Central

Kim, Min Soo; Yeom, Dong Woo; Kim, Sung Rae; Yoon, Ho Yub; Kim, Chang Hyun; Son, Ho Yong; Kim, Jin Han; Lee, Sangkil; Choi, Young Wook

2017-01-01

A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD. PMID:28053506

SU-E-T-295: Simultaneous Beam Sampling and Aperture Shape Optimization for Station Parameter Optimized Radiation Therapy (SPORT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarepisheh, M; Li, R; Xing, L

Purpose: Station Parameter Optimized Radiation Therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital LINACs, in which the station parameters of a delivery system, (such as aperture shape and weight, couch position/angle, gantry/collimator angle) are optimized altogether. SPORT promises to deliver unprecedented radiation dose distributions efficiently, yet there does not exist any optimization algorithm to implement it. The purpose of this work is to propose an optimization algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: We build a mathematical model whose variables are beam angles (including non-coplanar and/or even nonisocentric beams) andmore » aperture shapes. To solve the resulting large scale optimization problem, we devise an exact, convergent and fast optimization algorithm by integrating three advanced optimization techniques named column generation, gradient method, and pattern search. Column generation is used to find a good set of aperture shapes as an initial solution by adding apertures sequentially. Then we apply the gradient method to iteratively improve the current solution by reshaping the aperture shapes and updating the beam angles toward the gradient. Algorithm continues by pattern search method to explore the part of the search space that cannot be reached by the gradient method. Results: The proposed technique is applied to a series of patient cases and significantly improves the plan quality. In a head-and-neck case, for example, the left parotid gland mean-dose, brainstem max-dose, spinal cord max-dose, and mandible mean-dose are reduced by 10%, 7%, 24% and 12% respectively, compared to the conventional VMAT plan while maintaining the same PTV coverage. Conclusion: Combined use of column generation, gradient search and pattern search algorithms provide an effective way to optimize simultaneously the large collection of station parameters and significantly improves quality of resultant treatment plans as compared with conventional VMAT or IMRT treatments.« less

The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery.

PubMed

Ljung, R

2010-05-01

The optimal mode of delivery of a haemophilia carrier expecting a child is still a matter of uncertainty and debate. The aim of this commentary/review is to suggest that normal vaginal delivery should be the recommended mode of delivery for the majority of carriers, based on review of studies on obstetric aspects of haemophilia. About 2.0-4.0% of all haemophilia boys born in countries with a good standard of health care will suffer from ICH during the neonatal period. This is an average figure including all modes of delivery and regardless of whether the carrier status of the mother or the haemophilia status of the foetus was known or not at the time of delivery. On the basis of current literature, one may conclude that the risk of serious bleeding in the neonate affected with haemophilia is small in conjunction with normal vaginal delivery. It should be possible to further reduce the low frequency of complications if appropriate precautions are taken when planning the delivery in pregnant woman with known carrier status, if the sex of the foetus is known and, even more, when the haemophilia status of the foetus is known. Instrumental delivery such as use of vacuum extraction and foetal scalp monitors must be avoided at delivery of carriers.

Real-time evaluation of two light delivery systems for photodynamic disinfection of Candida albicans biofilm in curved root canals.

PubMed

Sabino, C P; Garcez, A S; Núñez, S C; Ribeiro, M S; Hamblin, M R

2015-08-01

Antimicrobial photodynamic therapy (APDT) combined with endodontic treatment has been recognized as an alternative approach to complement conventional root canal disinfection methods on bacterial biofilms. We developed an in  vitro model of bioluminescent Candida albicans biofilm inside curved dental root canals and investigated the microbial reduction produced when different light delivery methods are employed. Each light delivery method was evaluated in respect to the light distribution provided inside curved root canals. After conventional endodontic preparation, teeth were sterilized before canals were contaminated by a bioluminescent strain of C. albicans (CEC789). Methylene blue (90 μM) was introduced into the canals and then irradiated (λ = 660 nm, P = 100 mW, beam diameter = 2 mm) with laser tip either in contact with pulp chamber or within the canal using an optical diffuser fiber. Light distribution was evaluated by CCD camera, and microbial reduction was monitored through bioluminescence imaging. Our findings demonstrated that the bioluminescent C. albicans biofilm model had good reproducibility and uniformity. Light distribution in dental tissue was markedly dependent on the light delivery system, and this strategy was directly related to microbial destruction. Both light delivery systems performed significant fungal inactivation. However, when irradiation was performed with optical diffuser fiber, microbial burden reduction was nearly 100 times more effective. Bioluminescence is an interesting real-time analysis to endodontic C. albicans biofilm inactivation. APDT showed to be an effective way to inactivate C. albicans biofilms. Diffuser fibers provided optimized light distribution inside curved root canals and significantly increased APDT efficiency.

Real-time evaluation of two light delivery systems for photodynamic disinfection of Candida albicans biofilm in curved root canals

PubMed Central

Sabino, C. P.; Garcez, A. S.; Núñez, S. C.; Ribeiro, M. S.; Hamblin, M. R.

2014-01-01

Antimicrobial photodynamic therapy (APDT) combined with endodontic treatment has been recognized as an alternative approach to complement conventional root canal disinfection methods on bacterial biofilms. We developed an in vitro model of bioluminescent Candida albicans biofilm inside curved dental root canals and investigated the microbial reduction produced when different light delivery methods are employed. Each light delivery method was evaluated in respect to the light distribution provided inside curved root canals. After conventional endodontic preparation, teeth were sterilized before canals were contaminated by a bioluminescent strain of C. albicans (CEC789). Methylene blue (90 µM) was introduced into the canals and then irradiated (λ=660 nm, P=100 mW, beam diameter=2 mm) with laser tip either in contact with pulp chamber or within the canal using an optical diffuser fiber. Light distribution was evaluated by CCD camera, and microbial reduction was monitored through bioluminescence imaging. Our findings demonstrated that the bioluminescent C. albicans biofilm model had good reproducibility and uniformity. Light distribution in dental tissue was markedly dependent on the light delivery system, and this strategy was directly related to microbial destruction. Both light delivery systems performed significant fungal inactivation. However, when irradiation was performed with optical diffuser fiber, microbial burden reduction was nearly 100 times more effective. Bioluminescence is an interesting real-time analysis to endodontic C. albicans biofilm inactivation. APDT showed to be an effective way to inactivate C. albicans biofilms. Diffuser fibers provided optimized light distribution inside curved root canals and significantly increased APDT efficiency. PMID:25060900

A practical approach to automate randomized design of experiments for ligand-binding assays.

PubMed

Tsoi, Jennifer; Patel, Vimal; Shih, Judy

2014-03-01

Design of experiments (DOE) is utilized in optimizing ligand-binding assay by modeling factor effects. To reduce the analyst's workload and error inherent with DOE, we propose the integration of automated liquid handlers to perform the randomized designs. A randomized design created from statistical software was imported into custom macro converting the design into a liquid-handler worklist to automate reagent delivery. An optimized assay was transferred to a contract research organization resulting in a successful validation. We developed a practical solution for assay optimization by integrating DOE and automation to increase assay robustness and enable successful method transfer. The flexibility of this process allows it to be applied to a variety of assay designs.

Targeted delivery of growth factors in ischemic stroke animal models.

PubMed

Rhim, Taiyoun; Lee, Minhyung

2016-01-01

Ischemic stroke is caused by reduced blood supply and leads to loss of brain function. The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth. However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems. To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery. Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route.

Future therapeutic directions; new medications and insulin delivery in a changing world for effective diabetes management.

PubMed

Modi, Pankaj

2009-09-01

Insulin remains a key to the management of diabetes. The early addition of insulin to oral therapy in type-2 patients is recognized as an effective option that can help improve glycemic control and reduces the complications and contribute to more favorable outcomes. Controlling blood glucose levels within acceptable limits is crucial to the long-term health of patients with diabetes. The benefits of patient education and chronic disease management tools cannot be underestimated as many patients will require education and help in initiation of insulin therapy to achieve glycemic targets. The wide choice of insulin formulations and the ever-expanding range of delivery methods are now available. These methods made insulin administration easier, less painful, more discreet, and more accurate than ever before thus providing important tools to overcome barriers to insulin initiation and improve achievement of glycemic goals. In addition, exciting developments in newer therapeutics have increased the potential for optimal glycemic control. This review discusses how these approaches can help patients manage their diabetes effectively by considering new insulin formulations and delivery devices and newer therapeutics.

Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

NASA Astrophysics Data System (ADS)

Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

2016-01-01

Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

Correlation of spatial intensity distribution of light reaching the retina and restoration of vision by optogenetic stimulation

NASA Astrophysics Data System (ADS)

Shivalingaiah, Shivaranjani; Gu, Ling; Mohanty, Samarendra K.

2011-03-01

Stimulation of retinal neuronal cells using optogenetics via use of chanelrhodopsin-2 (ChR2) and blue light has opened up a new direction for restoration of vision with respect to treatment of Retinitis pigmentosa (RP). In addition to delivery of ChR2 to specific retinal layer using genetic engineering, threshold level of blue light needs to be delivered onto the retina for generating action potential and successful behavioral outcome. We report measurement of intensity distribution of light reaching the retina of Retinitis pigmentosa (RP) mouse models and compared those results with theoretical simulations of light propagation in eye. The parameters for the stimulating source positioning in front of eye was determined for optimal light delivery to the retina. In contrast to earlier viral method based delivery of ChR2 onto retinal ganglion cells, in-vivo electroporation method was employed for retina-transfection of RP mice. The behavioral improvement in mice with Thy1-ChR2-YFP transfected retina, expressing ChR2 in retinal ganglion cells, was found to correlate with stimulation intensity.

Influence of robust optimization in intensity-modulated proton therapy with different dose delivery techniques

PubMed Central

Liu, Wei; Li, Yupeng; Li, Xiaoqiang; Cao, Wenhua; Zhang, Xiaodong

2012-01-01

Purpose: The distal edge tracking (DET) technique in intensity-modulated proton therapy (IMPT) allows for high energy efficiency, fast and simple delivery, and simple inverse treatment planning; however, it is highly sensitive to uncertainties. In this study, the authors explored the application of DET in IMPT (IMPT-DET) and conducted robust optimization of IMPT-DET to see if the planning technique’s sensitivity to uncertainties was reduced. They also compared conventional and robust optimization of IMPT-DET with three-dimensional IMPT (IMPT-3D) to gain understanding about how plan robustness is achieved. Methods: They compared the robustness of IMPT-DET and IMPT-3D plans to uncertainties by analyzing plans created for a typical prostate cancer case and a base of skull (BOS) cancer case (using data for patients who had undergone proton therapy at our institution). Spots with the highest and second highest energy layers were chosen so that the Bragg peak would be at the distal edge of the targets in IMPT-DET using 36 equally spaced angle beams; in IMPT-3D, 3 beams with angles chosen by a beam angle optimization algorithm were planned. Dose contributions for a number of range and setup uncertainties were calculated, and a worst-case robust optimization was performed. A robust quantification technique was used to evaluate the plans’ sensitivity to uncertainties. Results: With no uncertainties considered, the DET is less robust to uncertainties than is the 3D method but offers better normal tissue protection. With robust optimization to account for range and setup uncertainties, robust optimization can improve the robustness of IMPT plans to uncertainties; however, our findings show the extent of improvement varies. Conclusions: IMPT’s sensitivity to uncertainties can be improved by using robust optimization. They found two possible mechanisms that made improvements possible: (1) a localized single-field uniform dose distribution (LSFUD) mechanism, in which the optimization algorithm attempts to produce a single-field uniform dose distribution while minimizing the patching field as much as possible; and (2) perturbed dose distribution, which follows the change in anatomical geometry. Multiple-instance optimization has more knowledge of the influence matrices; this greater knowledge improves IMPT plans’ ability to retain robustness despite the presence of uncertainties. PMID:22755694

Interbody fusion cage design using integrated global layout and local microstructure topology optimization.

PubMed

Lin, Chia-Ying; Hsiao, Chun-Ching; Chen, Po-Quan; Hollister, Scott J

2004-08-15

An approach combining global layout and local microstructure topology optimization was used to create a new interbody fusion cage design that concurrently enhanced stability, biofactor delivery, and mechanical tissue stimulation for improved arthrodesis. To develop a new interbody fusion cage design by topology optimization with porous internal architecture. To compare the performance of this new design to conventional threaded cage designs regarding early stability and long-term stress shielding effects on ingrown bone. Conventional interbody cage designs mainly fall into categories of cylindrical or rectangular shell shapes. The designs contribute to rigid stability and maintain disc height for successful arthrodesis but may also suffer mechanically mediated failures of dislocation or subsidence, as well as the possibility of bone resorption. The new optimization approach created a cage having designed microstructure that achieved desired mechanical performance while providing interconnected channels for biofactor delivery. The topology optimization algorithm determines the material layout under desirable volume fraction (50%) and displacement constraints favorable to bone formation. A local microstructural topology optimization method was used to generate periodic microstructures for porous isotropic materials. Final topology was generated by the integration of the two-scaled structures according to segmented regions and the corresponding material density. Image-base finite element analysis was used to compare the mechanical performance of the topology-optimized cage and conventional threaded cage. The final design can be fabricated by a variety of Solid Free-Form systems directly from the image output. The new design exhibited a narrower, more uniform displacement range than the threaded cage design and lower stress at the cage-vertebra interface, suggesting a reduced risk of subsidence. Strain energy density analysis also indicated that a higher portion of total strain energy density was transferred into the new bone region inside the new designed cage, indicating a reduced risk of stress shielding. The new design approach using integrated topology optimization demonstrated comparable or better stability by limited displacement and reduced localized deformation related to the risk of subsidence. Less shielding of newly formed bone was predicted inside the new designed cage. Using the present approach, it is also possible to tailor cage design for specific materials, either titanium or polymer, that can attain the desired balance between stability, reduced stress shielding, and porosity for biofactor delivery.

A Blended Education Program Based on Critical Thinking and Its Effect on Personality Type and Attribution Style of the Students

ERIC Educational Resources Information Center

Mosalanejad, Leili; Alipor, Ahmad; Zandi, Bahman

2010-01-01

Blended learning is a mixture of the various learning strategies and delivery methods that will optimize the learning experience of the user. This research evaluated psychological effect of blended learning on student. This research is a quasi-experimental study. 41 students participated in two groups and they registered in the course of…

Data for Flipped Classroom Design: Using Student Feedback to Identify the Best Components from Online and Face-to-Face Classes

ERIC Educational Resources Information Center

Crews, Thad; Butterfield, Jeff

2014-01-01

Colleges and universities have seen considerable enrollment growth in online courses during the past decade. However, online modalities are not optimal for all subject areas or students. There is growing interest in hybrid, blended, and flipped instruction as a way to incorporate the best of different delivery methods. This study investigates and…

Synthesis and Characterization of Silver-Doped Mesoporous Bioactive Glass and Its Applications in Conjunction with Electrospinning

PubMed Central

Ciraldo, Francesca E.; Goldmann, Wolfgang H.

2018-01-01

Since they were first developed in 2004, mesoporous bioactive glasses (MBGs) rapidly captured the interest of the scientific community thanks to their numerous beneficial properties. MBGs are synthesised by a combination of the sol–gel method with the chemistry of surfactants to obtain highly mesoporous (pore size from 5 to 20 nm) materials that, owing to their high surface area and ordered structure, are optimal candidates for controlled drug-delivery systems. In this work, we synthesised and characterised a silver-containing mesoporous bioactive glass (Ag-MBG). It was found that Ag-MBG is a suitable candidate for controlled drug delivery, showing a perfectly ordered mesoporous structure ideal for the loading of drugs together with optimal bioactivity, sustained release of silver from the matrix, and fast and strong bacterial inhibition against both Gram-positive and Gram-negative bacteria. Silver-doped mesoporous glass particles were used in three electrospinning-based techniques to produce PCL/Ag-MBG composite fibres, to coat bioactive glass scaffolds (via electrospraying), and for direct sol electrospinning. The results obtained in this study highlight the versatility and efficacy of Ag-substituted mesoporous bioactive glass and encourage further studies to characterize the biological response to Ag-MBG-based antibacterial controlled-delivery systems for tissue-engineering applications. PMID:29710768

Synthesis and factorial design applied to a novel chitosan/sodium polyphosphate nanoparticles via ionotropic gelation as an RGD delivery system.

PubMed

Kiilll, Charlene Priscila; Barud, Hernane da Silva; Santagneli, Sílvia Helena; Ribeiro, Sidney José Lima; Silva, Amélia M; Tercjak, Agnieszka; Gutierrez, Junkal; Pironi, Andressa Maria; Gremião, Maria Palmira Daflon

2017-02-10

Chitosan nanoparticles have been extensively studied for both drug and protein/peptide delivery. The aim of this study was to develop an optimized chitosan nanoparticle, by ionotropic gelation method, using 3 2 full factorial design with a novel polyanion, sodium polyphosphate, well known under the trade name Graham salt. The effects of these parameters on the particle size, zeta potential, and morphology and association efficiency were investigated. The optimized nanoparticles showed an estimated size of 166.20±1.95nm, a zeta potential of 38.7±1.2mV and an efficacy of association of 97.0±2.4%. The Atomic Force Microscopy (AFM) and Scanning Electronic Microscopy (SEM) revealed spherical nanoparticles with uniform size. Molecular interactions among the components of the nanoparticles and peptide were evaluated by Fourier Transform Infrared Spectra (FTIR) and Differential Scanning Calorimetry (DSC). The obtained results indicated that, the developed nanoparticles demonstrated high biocompatible, revealing no or low toxicity in the human cancer cell line (Caco-2). In conclusion, this work provides parameters that contribute to production of chitosan nanoparticles and sodium polyphosphate with desirable size, biocompatible and enabling successful use for protein/peptides delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development and in vivo evaluation of self-microemulsion as delivery system for α-mangostin.

PubMed

Xu, Wen-Ke; Jiang, Hui; Yang, Kui; Wang, Ya-Qin; Zhang, Qian; Zuo, Jian

2017-03-01

α-Mangostin (MG) is a versatile bioactive compound isolated from mangosteen and possesses significant pharmacokinetic shortages. To augment the potential clinical efficacy, MG-loaded self-microemulsion (MG-SME) was designed and prepared in this study, and its potential as a drug loading system was evaluated based on the pharmacokinetic performance and tissue distribution feature. The formula of MG-SME was optimized by an orthogonal test under the guidance of ternary phase diagram, and the prepared MG-SME was characterized by encapsulation efficiency, size distribution, and morphology. Optimized high performance liquid chromatography method was employed to determine concentrations of MG and characterize the pharmacokinetic and tissue distribution features of MG in rodents. It was found that diluted MG-SME was characterized as spherical particles with a mean diameter of 24.6 nm and an encapsulation efficiency of 87.26%. The delivery system enhanced the area under the curve of MG by 4.75 times and increased the distribution in lymphatic organs. These findings suggested that SME as a nano-sized delivery system efficiently promoted the digestive tract absorption of MG and modified its distribution in tissues. The targeting feature and high oral bioavailability of MG-SME promised a good clinical efficacy, especially for immune diseases. Copyright © 2017. Published by Elsevier Taiwan.

A fluorescence-based imaging approach to pharmacokinetic analysis of intracochlear drug delivery.

PubMed

Ayoob, Andrew M; Peppi, Marcello; Tandon, Vishal; Langer, Robert; Borenstein, Jeffrey T

2018-04-05

Advances in microelectromechanical systems (MEMS) technologies are enhancing the development of intracochlear delivery devices for the treatment of hearing loss with emerging pharmacological therapies. Direct intracochlear delivery addresses the limitations of systemic and intratympanic delivery. However, optimization of delivery parameters for these devices requires pharmacokinetic assessment of the spatiotemporal drug distribution inside the cochlea. Robust methods of measuring drug concentration in the perilymph have been developed, but lack spatial resolution along the tonotopic axis or require complex physiological measurements. Here we describe an approach for quantifying distribution of fluorescent drug-surrogate probe along the cochlea's sensory epithelium with high spatial resolution enabled by confocal fluorescence imaging. Fluorescence from FM 1-43 FX, a fixable endocytosis marker, was quantified using confocal fluorescence imaging of whole mount sections of the organ of Corti from cochleae resected and fixed at several time points after intracochlear delivery. Intracochlear delivery of FM 1-43 FX near the base of the cochlea produces a base-apex gradient of fluorescence in the row of inner hair cells after 1 h post-delivery that is consistent with diffusion-limited transport along the scala tympani. By 3 h post-delivery there is approximately an order of magnitude decrease in peak average fluorescence intensity, suggesting FM 1-43 FX clearance from both the perilymph and inner hair cells. The increase in fluorescence intensity at 72 h post-delivery compared to 3 h post-delivery may implicate a potential radial transport pathway into the scala media. Copyright © 2018 Elsevier B.V. All rights reserved.

Penalization of aperture complexity in inversely planned volumetric modulated arc therapy

PubMed Central

Younge, Kelly C.; Matuszak, Martha M.; Moran, Jean M.; McShan, Daniel L.; Fraass, Benedick A.; Roberts, Donald A.

2012-01-01

Purpose: Apertures obtained during volumetric modulated arc therapy (VMAT) planning can be small and irregular, resulting in dosimetric inaccuracies during delivery. Our purpose is to develop and integrate an aperture-regularization objective function into the optimization process for VMAT, and to quantify the impact of using this objective function on dose delivery accuracy and optimized dose distributions. Methods: An aperture-based metric (“edge penalty”) was developed that penalizes complex aperture shapes based on the ratio of MLC side edge length and aperture area. To assess the utility of the metric, VMAT plans were created for example paraspinal, brain, and liver SBRT cases with and without incorporating the edge penalty in the cost function. To investigate the dose calculation accuracy, Gafchromic EBT2 film was used to measure the 15 highest weighted apertures individually and as a composite from each of two paraspinal plans: one with and one without the edge penalty applied. Films were analyzed using a triple-channel nonuniformity correction and measurements were compared directly to calculations. Results: Apertures generated with the edge penalty were larger, more regularly shaped and required up to 30% fewer monitor units than those created without the edge penalty. Dose volume histogram analysis showed that the changes in doses to targets, organs at risk, and normal tissues were negligible. Edge penalty apertures that were measured with film for the paraspinal plan showed a notable decrease in the number of pixels disagreeing with calculation by more than 10%. For a 5% dose passing criterion, the number of pixels passing in the composite dose distributions for the non-edge penalty and edge penalty plans were 52% and 96%, respectively. Employing gamma with 3% dose/1 mm distance criteria resulted in a 79.5% (without penalty)/95.4% (with penalty) pass rate for the two plans. Gradient compensation of 3%/1 mm resulted in 83.3%/96.2% pass rates. Conclusions: The use of the edge penalty during optimization has the potential to markedly improve dose delivery accuracy for VMAT plans while still maintaining high quality optimized dose distributions. The penalty regularizes aperture shape and improves delivery efficiency. PMID:23127107

Optimization of Chitosan and Cellulose Acetate Phthalate Controlled Delivery of Methylprednisolone for Treatment of Inflammatory Bowel Disease.

PubMed

Jagdale, Swati; Chandekar, Apoorva

2017-06-01

Purpose: Inflammatory bowel disease (IBD) is a chronic, relapsing and often life-long disorder. The best way to tackle IBD is to develop a site targeted drug delivery. Methylprednisolone is a potent anti-inflammatory steroid. The relative potency of methylprednisolone to hydrocortisone is at least four is to one. The aim of the present research was to develop a colon targeted drug delivery for treatment of IBD. Methods: Compression coated drug delivery system was designed and optimised. Core tablet contained drug, croscarmellose sodium (CCS-superdisintegrant), avicel (binder) and dicalcium phosphate (diluent). Design of experiment with 3 2 factorial design was applied for optimization of compression coated delivery. Chitosan and cellulose acetate phthalate were chosen as independent variables. Swelling index, hardness and % drug release were dependant variables. Results: Core tablet (C5 batch) containing 2.15% CCS showed disintegration in less than 10sec. FTIR, UV and DSC study had shown absence of any significant physical and chemical interaction between drug and polymers. F8 was found to be optimised formulation. F8 contained 35% chitosan and 17.5% cellulose acetate phthalate. It showed drug release of 86.3% ± 6.1%, hardness 6.5 ± 1.5 and lag time 7 hrs. Simulated media drug release was 97.51 ± 8.6% with 7.5 hrs lag time. The results confirmed that the lag time was highly affected by the coating of the polymers as well as the concentration of the superdisintegrant used in core tablet. Conclusion: In-vitro and in-vivo results confirmed a potential colon targeted drug therapy for treatment of IBD.

The care delivery experience of hospitalized patients with complex chronic disease.

PubMed

Kuluski, Kerry; Hoang, Sylvia N; Schaink, Alexis K; Alvaro, Celeste; Lyons, Renee F; Tobias, Roy; Bensimon, Cécile M

2013-12-01

This study investigated what is important in care delivery from the perspective of hospital inpatients with complex chronic disease, a currently understudied population. One-on-one semi-structured interviews were conducted with inpatients at a continuing care/rehabilitation hospital (n = 116) in Canada between February and July 2011. The study design was mixed methods and reports on patient characteristics and care delivery experiences. Basic descriptive statistics were run using SPSS version 17, and thematic analysis on the transcripts was conducted using NVivo9 software. Patients had an average of 5 morbidities and several illness symptoms including activity of daily living impairments, physical pain and emotional disturbance. Three broad themes (each with one or more subthemes) were generated from the data representing important components of care delivery: components of the care plan (a comprehensive assessment, supported transitions and a bio-psycho-social care package); care capacity and quality (optimal staff to patient ratios, quicker response times, better patient-provider communication and consistency between providers) and the patient-provider relationships (characterized by respect and dignity). As health systems throughout the industrialized world move to sustain health budgets while optimizing quality of care, it is critical to better understand this population, so that appropriate metrics, services and policies can be developed. The study has generated a body of evidence on the important components of care delivery from the perspectives of a diverse group of chronically ill individuals who have spent a considerable amount of time in the health-care system. Moving forward, exploration around the appropriate funding models and skill mix is needed to move the evidence into changed practice. © 2013 John Wiley & Sons Ltd.

Optimization of Chitosan and Cellulose Acetate Phthalate Controlled Delivery of Methylprednisolone for Treatment of Inflammatory Bowel Disease

PubMed Central

Jagdale, Swati; Chandekar, Apoorva

2017-01-01

Purpose: Inflammatory bowel disease (IBD) is a chronic, relapsing and often life-long disorder. The best way to tackle IBD is to develop a site targeted drug delivery. Methylprednisolone is a potent anti-inflammatory steroid. The relative potency of methylprednisolone to hydrocortisone is at least four is to one. The aim of the present research was to develop a colon targeted drug delivery for treatment of IBD. Methods: Compression coated drug delivery system was designed and optimised. Core tablet contained drug, croscarmellose sodium (CCS-superdisintegrant), avicel (binder) and dicalcium phosphate (diluent). Design of experiment with 32 factorial design was applied for optimization of compression coated delivery. Chitosan and cellulose acetate phthalate were chosen as independent variables. Swelling index, hardness and % drug release were dependant variables. Results: Core tablet (C5 batch) containing 2.15% CCS showed disintegration in less than 10sec. FTIR, UV and DSC study had shown absence of any significant physical and chemical interaction between drug and polymers. F8 was found to be optimised formulation. F8 contained 35% chitosan and 17.5% cellulose acetate phthalate. It showed drug release of 86.3% ± 6.1%, hardness 6.5 ± 1.5 and lag time 7 hrs. Simulated media drug release was 97.51 ± 8.6% with 7.5 hrs lag time. The results confirmed that the lag time was highly affected by the coating of the polymers as well as the concentration of the superdisintegrant used in core tablet. Conclusion: In-vitro and in-vivo results confirmed a potential colon targeted drug therapy for treatment of IBD. PMID:28761822

Public-private delivery of insecticide-treated nets: a voucher scheme in Volta Region, Ghana

PubMed Central

Kweku, Margaret; Webster, Jayne; Taylor, Ian; Burns, Susan; Dedzo, McDamien

2007-01-01

Background Coverage of vulnerable groups with insecticide-treated nets (ITNs) in Ghana, as in the majority of countries of sub-Saharan Africa is currently low. A voucher scheme was introduced in Volta Region as a possible sustainable delivery system for increasing this coverage through scale-up to other regions. Successful scale-up of public health interventions depends upon optimal delivery processes but operational research for delivery processes in large-scale implementation has been inadequate. Methods A simple tool was developed to monitor numbers of vouchers given to each health facility, numbers issued to pregnant women by the health staff, and numbers redeemed by the distributors back to the management agent. Three rounds of interviews were undertaken with health facility staff, retailers and pregnant women who had attended antenatal clinic (ANC). Results During the one year pilot 25,926 vouchers were issued to eligible women from clinics, which equates to 50.7% of the 51,658 ANC registrants during this time period. Of the vouchers issued 66.7% were redeemed by distributors back to the management agent. Initially, non-issuing of vouchers to pregnant women was mainly due to eligibility criteria imposed by the midwives; later in the year it was due to decisions of the pregnant women, and supply constraints. These in turn were heavily influenced by factors external to the programme: current household ownership of nets, competing ITN delivery strategies, and competition for the limited number of ITNs available in the country from major urban areas of other regions. Conclusion Both issuing and redemption of vouchers should be monitored as factors assumed to influence voucher redemption had an influence on issuing, and vice versa. More evidence is needed on how specific contextual factors influence the success of voucher schemes and other models of delivery of ITNs. Such an evidence base will facilitate optimal strategic decision making so that the delivery model with the best probability of success within a given context is implemented. Rigorous monitoring has an important role to play in the successful scaling-up of delivery of effective public health interventions. PMID:17274810

Design and Optimization of Floating Drug Delivery System of Acyclovir

PubMed Central

Kharia, A. A.; Hiremath, S. N.; Singhai, A. K.; Omray, L. K.; Jain, S. K.

2010-01-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t50%) and 70% (t70%) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t50% and t70% indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. PMID:21694992

Design and optimization of floating drug delivery system of acyclovir.

PubMed

Kharia, A A; Hiremath, S N; Singhai, A K; Omray, L K; Jain, S K

2010-09-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.

The effect of nanoparticle size on theranostic systems: the optimal particle size for imaging is not necessarily optimal for drug delivery

NASA Astrophysics Data System (ADS)

Dreifuss, Tamar; Betzer, Oshra; Barnoy, Eran; Motiei, Menachem; Popovtzer, Rachela

2018-02-01

Theranostics is an emerging field, defined as combination of therapeutic and diagnostic capabilities in the same material. Nanoparticles are considered as an efficient platform for theranostics, particularly in cancer treatment, as they offer substantial advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of theranostic nanoplatforms raises an important question: Is the optimal particle for imaging also optimal for therapy? Are the specific parameters required for maximal drug delivery, similar to those required for imaging applications? Herein, we examined this issue by investigating the effect of nanoparticle size on tumor uptake and imaging. Anti-epidermal growth factor receptor (EGFR)-conjugated gold nanoparticles (GNPs) in different sizes (diameter range: 20-120 nm) were injected to tumor bearing mice and their uptake by tumors was measured, as well as their tumor visualization capabilities as tumor-targeted CT contrast agent. Interestingly, the results showed that different particles led to highest tumor uptake or highest contrast enhancement, meaning that the optimal particle size for drug delivery is not necessarily optimal for tumor imaging. These results have important implications on the design of theranostic nanoplatforms.

High throughput RNAi assay optimization using adherent cell cytometry

PubMed Central

2011-01-01

Background siRNA technology is a promising tool for gene therapy of vascular disease. Due to the multitude of reagents and cell types, RNAi experiment optimization can be time-consuming. In this study adherent cell cytometry was used to rapidly optimize siRNA transfection in human aortic vascular smooth muscle cells (AoSMC). Methods AoSMC were seeded at a density of 3000-8000 cells/well of a 96well plate. 24 hours later AoSMC were transfected with either non-targeting unlabeled siRNA (50 nM), or non-targeting labeled siRNA, siGLO Red (5 or 50 nM) using no transfection reagent, HiPerfect or Lipofectamine RNAiMax. For counting cells, Hoechst nuclei stain or Cell Tracker green were used. For data analysis an adherent cell cytometer, Celigo® was used. Data was normalized to the transfection reagent alone group and expressed as red pixel count/cell. Results After 24 hours, none of the transfection conditions led to cell loss. Red fluorescence counts were normalized to the AoSMC count. RNAiMax was more potent compared to HiPerfect or no transfection reagent at 5 nM siGLO Red (4.12 +/-1.04 vs. 0.70 +/-0.26 vs. 0.15 +/-0.13 red pixel/cell) and 50 nM siGLO Red (6.49 +/-1.81 vs. 2.52 +/-0.67 vs. 0.34 +/-0.19). Fluorescence expression results supported gene knockdown achieved by using MARCKS targeting siRNA in AoSMCs. Conclusion This study underscores that RNAi delivery depends heavily on the choice of delivery method. Adherent cell cytometry can be used as a high throughput-screening tool for the optimization of RNAi assays. This technology can accelerate in vitro cell assays and thus save costs. PMID:21518450

[Methods and Applications to estimate the conversion factor of Resource-Based Relative Value Scale for nurse-midwife's delivery service in the national health insurance].

PubMed

Kim, Jinhyun; Jung, Yoomi

2009-08-01

This paper analyzed alternative methods of calculating the conversion factor for nurse-midwife's delivery services in the national health insurance and estimated the optimal reimbursement level for the services. A cost accounting model and Sustainable Growth Rate (SGR) model were developed to estimate the conversion factor of Resource-Based Relative Value Scale (RBRVS) for nurse-midwife's services, depending on the scope of revenue considered in financial analysis. The data and sources from the government and the financial statements from nurse-midwife clinics were used in analysis. The cost accounting model and SGR model showed a 17.6-37.9% increase and 19.0-23.6% increase, respectively, in nurse-midwife fee for delivery services in the national health insurance. The SGR model measured an overall trend of medical expenditures rather than an individual financial status of nurse-midwife clinics, and the cost analysis properly estimated the level of reimbursement for nurse-midwife's services. Normal vaginal delivery in nurse-midwife clinics is considered cost-effective in terms of insurance financing. Upon a declining share of health expenditures on midwife clinics, designing a reimbursement strategy for midwife's services could be an opportunity as well as a challenge when it comes to efficient resource allocation.

Development, optimization and evaluation of polymeric electrospun nanofiber: A tool for local delivery of fluconazole for management of vaginal candidiasis.

PubMed

Sharma, Rahul; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-01-01

The present study is designed to explore the localized delivery of fluconazole using mucoadhesive polymeric nanofibers. Drug-loaded polymeric nanofibers were fabricated by the electrospinning method using polyvinyl alcohol (PVA) as the polymeric constituent. The prepared nanofibers were found to be uniform, non-beaded and non-woven, with the diameter of the fibers ranging from 150 to 180 nm. Further drug release studies indicate a sustained release of fluconazole over a period of 6 h. The results of studies on anti-microbial activity indicated that drug-loaded polymeric nanofibers exhibit superior anti-microbial activity against Candida albicans, when compared to the plain drug.

Optimal topologies for maximizing network transmission capacity

NASA Astrophysics Data System (ADS)

Chen, Zhenhao; Wu, Jiajing; Rong, Zhihai; Tse, Chi K.

2018-04-01

It has been widely demonstrated that the structure of a network is a major factor that affects its traffic dynamics. In this work, we try to identify the optimal topologies for maximizing the network transmission capacity, as well as to build a clear relationship between structural features of a network and the transmission performance in terms of traffic delivery. We propose an approach for designing optimal network topologies against traffic congestion by link rewiring and apply them on the Barabási-Albert scale-free, static scale-free and Internet Autonomous System-level networks. Furthermore, we analyze the optimized networks using complex network parameters that characterize the structure of networks, and our simulation results suggest that an optimal network for traffic transmission is more likely to have a core-periphery structure. However, assortative mixing and the rich-club phenomenon may have negative impacts on network performance. Based on the observations of the optimized networks, we propose an efficient method to improve the transmission capacity of large-scale networks.

Cartilage-targeting drug delivery: can electrostatic interactions help?

PubMed

Bajpayee, Ambika G; Grodzinsky, Alan J

2017-03-01

Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge-charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.

A New TS Algorithm for Solving Low-Carbon Logistics Vehicle Routing Problem with Split Deliveries by Backpack-From a Green Operation Perspective.

PubMed

Xia, Yangkun; Fu, Zhuo; Tsai, Sang-Bing; Wang, Jiangtao

2018-05-10

In order to promote the development of low-carbon logistics and economize logistics distribution costs, the vehicle routing problem with split deliveries by backpack is studied. With the help of the model of classical capacitated vehicle routing problem, in this study, a form of discrete split deliveries was designed in which the customer demand can be split only by backpack. A double-objective mathematical model and the corresponding adaptive tabu search (TS) algorithm were constructed for solving this problem. By embedding the adaptive penalty mechanism, and adopting the random neighborhood selection strategy and reinitialization principle, the global optimization ability of the new algorithm was enhanced. Comparisons with the results in the literature show the effectiveness of the proposed algorithm. The proposed method can save the costs of low-carbon logistics and reduce carbon emissions, which is conducive to the sustainable development of low-carbon logistics.

Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

PubMed Central

Li, Bo; Wang, Hai; Qiu, Guixing; Su, Xinlin

2016-01-01

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration. PMID:28070506

Maternal and neonatal factors associated with mode of delivery under a universal newborn hearing screening programme in Lagos, Nigeria

PubMed Central

Olusanya, Bolajoko O; Solanke, Olumuyiwa A

2009-01-01

Background Emerging evidence from a recent pilot universal newborn hearing screening (UNHS) programme suggests that the burden of obstetric complications associated with mode of delivery is not limited to maternal and perinatal mortality but may also include outcomes that undermine optimal early childhood development of the surviving newborns. However, the potential pathways for this association have not been reported particularly in the context of a resource-poor setting. This study therefore set out to establish the pattern of delivery and the associated neonatal outcomes under a UNHS programme. Methods A cross-sectional study in which all consenting mothers who delivered in an inner-city tertiary maternity hospital in Lagos, Nigeria from May 2005 to December 2007 were enrolled during the UNHS programme. Socio-demographic, obstetric and neonatal factors independently associated with vaginal, elective and emergency caesarean deliveries were determined using multinomial logistic regression analyses. Results Of the 4615 mothers enrolled, 2584 (56.0%) deliveries were vaginal, 1590 (34.4%) emergency caesarean and 441 (9.6%) elective caesarean section. Maternal age, parity, social class and all obstetric factors including lack of antenatal care, maternal HIV and multiple gestations were associated with increased risk of emergency caesarean delivery compared with vaginal delivery. Only parity, lack of antenatal care and prolonged/obstructed labour were associated with increased risk of emergency compared with elective caesarean delivery. Infants delivered by vaginal method or by emergency caesarean section were more likely to be associated with the risk of sensorineural hearing loss but less likely to be associated with hyperbilirubinaemia compared with infants delivered by elective caesarean section. Emergency caesarean delivery was also associated with male gender, low five-minute Apgar scores and admission into special care baby unit compared with vaginal or elective caesarean delivery. Conclusions The vast majority of caesarean delivery in this population occur as emergencies and are associated with socio-demographic factors as well as several obstetric complications. Mode of delivery is also associated with the risk of sensorineural hearing loss and other adverse birth outcomes that lie on the causal pathways for potential developmental deficits. PMID:19732443

Blood-brain barrier structure and function and the challenges for CNS drug delivery.

PubMed

Abbott, N Joan

2013-05-01

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.

Transport spatial model for the definition of green routes for city logistics centers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pamučar, Dragan, E-mail: dpamucar@gmail.com; Gigović, Ljubomir, E-mail: gigoviclj@gmail.com; Ćirović, Goran, E-mail: cirovic@sezampro.rs

This paper presents a transport spatial decision support model (TSDSM) for carrying out the optimization of green routes for city logistics centers. The TSDSM model is based on the integration of the multi-criteria method of Weighted Linear Combination (WLC) and the modified Dijkstra algorithm within a geographic information system (GIS). The GIS is used for processing spatial data. The proposed model makes it possible to plan routes for green vehicles and maximize the positive effects on the environment, which can be seen in the reduction of harmful gas emissions and an increase in the air quality in highly populated areas.more » The scheduling of delivery vehicles is given as a problem of optimization in terms of the parameters of: the environment, health, use of space and logistics operating costs. Each of these input parameters was thoroughly examined and broken down in the GIS into criteria which further describe them. The model presented here takes into account the fact that logistics operators have a limited number of environmentally friendly (green) vehicles available. The TSDSM was tested on a network of roads with 127 links for the delivery of goods from the city logistics center to the user. The model supports any number of available environmentally friendly or environmentally unfriendly vehicles consistent with the size of the network and the transportation requirements. - Highlights: • Model for routing light delivery vehicles in urban areas. • Optimization of green routes for city logistics centers. • The proposed model maximizes the positive effects on the environment. • The model was tested on a real network.« less

Development of a novel niosomal system for oral delivery of Ginkgo biloba extract

PubMed Central

Jin, Ye; Wen, Jingyuan; Garg, Sanjay; Liu, Da; Zhou, Yulin; Teng, Lirong; Zhang, Weiyu

2013-01-01

Background The aim of this study was to develop an optimal niosomal system to deliver Ginkgo biloba extract (GbE) with improved oral bioavailability and to replace the conventional GbE tablets. Methods In this study, the film dispersion-homogenization method was used to prepare GbE niosomes. The resulting GbE niosome suspension was freeze-dried or spray-dried to improve the stability of the niosomes. GbE-loaded niosomes were formulated and characterized in terms of their morphology, particle size, zeta potential, entrapment efficiency, and angle of repose, and differential scanning calorimetry analysis was performed. In vitro release and in vivo distribution studies were also carried out. Results The particle size of the optimal delivery system prepared with Tween 80, Span 80, and cholesterol was about 141 nm. There was a significant difference (P < 0.05) in drug entrapment efficiency between the spray-drying method (about 77.5%) and the freeze-drying method (about 50.1%). The stability study revealed no significant change in drug entrapment efficiency for the GbE niosomes at 4°C and 25°C after 3 months. The in vitro release study suggested that GbE niosomes can prolong the release of flavonoid glycosides in phosphate-buffered solution (pH 6.8) for up to 48 hours. The in vivo distribution study showed that the flavonoid glycoside content in the heart, lung, kidney, brain, and blood of rats treated with the GbE niosome carrier system was greater than in the rats treated with the oral GbE tablet (P < 0.01). No flavonoid glycosides were detected in the brain tissue of rats given the oral GbE tablets, but they were detected in the brain tissue of rats given the GbE niosomes. Conclusion Niosomes are a promising oral system for delivery of GbE to the brain. PMID:23378764

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

PubMed

Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Systematic Assessment of Strategies for Lung-targeted Delivery of MicroRNA Mimics

PubMed Central

Schlosser, Kenny; Taha, Mohamad; Stewart, Duncan J.

2018-01-01

There is considerable interest in the use of synthetic miRNA mimics (or inhibitors) as potential therapeutic agents in pulmonary vascular disease; however, the optimal delivery method to achieve high efficiency, selective lung targeting has not been determined. Here, we sought to investigate the relative merits of different lung-targeted strategies for delivering miRNA mimics in rats. Methods: Tissue levels of a synthetic miRNA mimic, cel-miR-39-3p (0.5 nmol in 50 µL invivofectamine/PBS vehicle) were compared in male rats (n=3 rats/method) after delivery by commonly used lung-targeting strategies including intratracheal liquid instillation (IT-L), intratracheal aerosolization with (IT-AV) or without ventilator assistance (IT-A), intranasal liquid instillation (IN-L) and intranasal aerosolization (IN-A). Intravenous (IV; via jugular vein), intraperitoneal (IP) and subcutaneous (SC) delivery served as controls. Relative levels of cel-miR-39 were quantified by RT-qPCR. Results: At 2 h post delivery, IT-L showed the highest lung mimic level, which was significantly higher than levels achieved by all other methods (from ~10- to 10,000-fold, p<0.05). Mimic levels remained detectable in the lung 24 h after delivery, but were 10- to 100-fold lower. The intrapulmonary distribution of cel-miR-39 was comparable when delivered as either a liquid or aerosol, with evidence of mimic distribution to both the left and right lung lobes and penetration to distal regions. All lung-targeted strategies showed lung-selective mimic uptake, with mimic levels 10- to 100-fold lower in heart and 100- to 10,000-fold lower in liver, kidney and spleen. In contrast, IV, SC and IP routes showed comparable or higher mimic levels in non-pulmonary tissues. Conclusions: miRNA uptake in the lungs differed markedly by up to 4 orders of magnitude, demonstrating that the choice of delivery strategy could have a significant impact on potential therapeutic outcomes in preclinical investigations of miRNA-based drug candidates. PMID:29507615

European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update.

PubMed

Sweet, David G; Carnielli, Virgilio; Greisen, Gorm; Hallman, Mikko; Ozek, Eren; Plavka, Richard; Saugstad, Ola Didrik; Simeoni, Umberto; Speer, Christian P; Vento, Máximo; Visser, Gerard H A; Halliday, Henry L

2017-01-01

Advances in the management of respiratory distress syndrome (RDS) ensure that clinicians must continue to revise current practice. We report the third update of the European Guidelines for the Management of RDS by a European panel of expert neonatologists including input from an expert perinatal obstetrician based on available literature up to the beginning of 2016. Optimizing the outcome for babies with RDS includes consideration of when to use antenatal steroids, and good obstetric practice includes methods of predicting the risk of preterm delivery and also consideration of whether transfer to a perinatal centre is necessary and safe. Methods for optimal delivery room management have become more evidence based, and protocols for lung protection, including initiation of continuous positive airway pressure and titration of oxygen, should be implemented from soon after birth. Surfactant replacement therapy is a crucial part of the management of RDS, and newer protocols for surfactant administration are aimed at avoiding exposure to mechanical ventilation, and there is more evidence of differences among various surfactants in clinical use. Newer methods of maintaining babies on non-invasive respiratory support have been developed and offer potential for greater comfort and less chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease although minimizing the time spent on mechanical ventilation using caffeine and if necessary postnatal steroids are also important considerations. Protocols for optimizing the general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome. © 2016 S. Karger AG, Basel.

Ethosomes and Transfersomes: Principles, Perspectives and Practices.

PubMed

Garg, Varun; Singh, Harmanpreet; Bimbrawh, Sneha; Singh, Sachin Kumar; Gulati, Monica; Vaidya, Yogyata; Kaur, Prabhjot

2017-01-01

The success story of liposomes in the treatment of systemic infectious diseases and various carcinomas lead the scientists to the innovation of elastic vesicles to achieve similar success through transdermal route. In this direction, ethosomes and transfersomes were developed with the objective to design the vesicles that could pass through the skin. However, there is a lack of systematic review outlining the principles, method of preparation, latest advancement and applications of ethosomes and transfersomes. This review covers various aspects that would be helpful to scientists in understanding advantages of these vesicular systems and designing a unique nano vesicular delivery system. Structured search of bibliographic databases for previously published peer-reviewed research papers was explored and data was culminated in terms of principle of these vesicular delivery systems, composition, mechanism of actions, preparation techniques, methods for their characterization and their application. A total of 182 papers including both, research and review articles, were included in this review in order to make the article comprehensive and readily understandable. The mechanism of action and composition of ethosomes and transfersomes was extensively discussed. Various methods of preparation such as, rotary film evaporation method, reverse phase evaporation method, vortex/ sonication method, ethanol injection method, freeze thaw methods, along with their advantages has been discussed. It was also discussed that both these elastic nanocarriers offer unique advantages of ferrying the drug across membranes, sustaining drug release as well as protecting the encapsulated bio actives from external environment. The enhanced bioavailability and skin penetration of ethosomes as compared to conventional vesicular delivery systems is attributed to the presence of ethanol in the bilayers while that for transfersomes accrues due to their elasticity along with their ability to retain their shape because of the presence of edge activators. Successful delivery of synthetic drugs as well as phytomedicines has been extensively reported through these vesicles. Though these vesicular systems offer a good potential for rational drug delivery, a thoughtfully designed process is required to optimize the process variables involved. Industrial scale production of efficacious, safe, cost effective and stable formulations of both these delivery systems appears to be a pre-requisite to ensure their utility as the trans-dermal vehicles. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Methods for Optimizing CRISPR-Cas9 Genome Editing Specificity

PubMed Central

Tycko, Josh; Myer, Vic E.; Hsu, Patrick D.

2016-01-01

Summary Advances in the development of delivery, repair, and specificity strategies for the CRISPR-Cas9 genome engineering toolbox are helping researchers understand gene function with unprecedented precision and sensitivity. CRISPR-Cas9 also holds enormous therapeutic potential for the treatment of genetic disorders by directly correcting disease-causing mutations. Although the Cas9 protein has been shown to bind and cleave DNA at off-target sites, the field of Cas9 specificity is rapidly progressing with marked improvements in guide RNA selection, protein and guide engineering, novel enzymes, and off-target detection methods. We review important challenges and breakthroughs in the field as a comprehensive practical guide to interested users of genome editing technologies, highlighting key tools and strategies for optimizing specificity. The genome editing community should now strive to standardize such methods for measuring and reporting off-target activity, while keeping in mind that the goal for specificity should be continued improvement and vigilance. PMID:27494557

Research on simulation based material delivery system for an automobile company with multi logistics center

NASA Astrophysics Data System (ADS)

Luo, D.; Guan, Z.; Wang, C.; Yue, L.; Peng, L.

2017-06-01

Distribution of different parts to the assembly lines is significant for companies to improve production. Current research investigates the problem of distribution method optimization of a logistics system in a third party logistic company that provide professional services to an automobile manufacturing case company in China. Current research investigates the logistics leveling the material distribution and unloading platform of the automobile logistics enterprise and proposed logistics distribution strategy, material classification method, as well as logistics scheduling. Moreover, the simulation technology Simio is employed on assembly line logistics system which helps to find and validate an optimization distribution scheme through simulation experiments. Experimental results indicate that the proposed scheme can solve the logistic balance and levels the material problem and congestion of the unloading pattern in an efficient way as compared to the original method employed by the case company.

Optimizing Chemotherapy Dose and Schedule by Norton-Simon Mathematical Modeling

PubMed Central

Traina, Tiffany A.; Dugan, Ute; Higgins, Brian; Kolinsky, Kenneth; Theodoulou, Maria; Hudis, Clifford A.; Norton, Larry

2011-01-01

Background To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14 - 7). Results The model predicted that 7 days of treatment followed by a 7-day rest (7 - 7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development. PMID:20519801

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

PubMed Central

Rashid, Rehmana; Kim, Dong Wuk; Yousaf, Abid Mehmood; Mustapha, Omer; Din, Fakhar ud; Park, Jong Hyuck; Yong, Chul Soon; Oh, Yu-Kyoung; Youn, Yu Seok; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility. PMID:26491288

Fabrication, Physicochemical Characterization, and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics.

PubMed

Shah, Viral; Choudhury, Bijaya Krushna

2017-11-01

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.

SU-C-204-02: Improved Patient-Specific Optimization of the Stopping Power Calibration for Proton Therapy Planning Using a Single Proton Radiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rinaldi, I; Ludwig Maximilian University, Garching, DE; Heidelberg University Hospital, Heidelberg, DE

2015-06-15

Purpose: We present an improved method to calculate patient-specific calibration curves to convert X-ray computed tomography (CT) Hounsfield Unit (HU) to relative stopping powers (RSP) for proton therapy treatment planning. Methods: By optimizing the HU-RSP calibration curve, the difference between a proton radiographic image and a digitally reconstructed X-ray radiography (DRR) is minimized. The feasibility of this approach has previously been demonstrated. This scenario assumes that all discrepancies between proton radiography and DRR originate from uncertainties in the HU-RSP curve. In reality, external factors cause imperfections in the proton radiography, such as misalignment compared to the DRR and unfaithful representationmore » of geometric structures (“blurring”). We analyze these effects based on synthetic datasets of anthropomorphic phantoms and suggest an extended optimization scheme which explicitly accounts for these effects. Performance of the method is been tested for various simulated irradiation parameters. The ultimate purpose of the optimization is to minimize uncertainties in the HU-RSP calibration curve. We therefore suggest and perform a thorough statistical treatment to quantify the accuracy of the optimized HU-RSP curve. Results: We demonstrate that without extending the optimization scheme, spatial blurring (equivalent to FWHM=3mm convolution) in the proton radiographies can cause up to 10% deviation between the optimized and the ground truth HU-RSP calibration curve. Instead, results obtained with our extended method reach 1% or better correspondence. We have further calculated gamma index maps for different acceptance levels. With DTA=0.5mm and RD=0.5%, a passing ratio of 100% is obtained with the extended method, while an optimization neglecting effects of spatial blurring only reach ∼90%. Conclusion: Our contribution underlines the potential of a single proton radiography to generate a patient-specific calibration curve and to improve dose delivery by optimizing the HU-RSP calibration curve as long as all sources of systematic incongruence are properly modeled.« less

Possibility of Exosome-Based Therapeutics and Challenges in Production of Exosomes Eligible for Therapeutic Application.

PubMed

Yamashita, Takuma; Takahashi, Yuki; Takakura, Yoshinobu

2018-01-01

Exosomes are cell-derived vesicles with a diameter 30-120 nm. Exosomes contain endogenous proteins and nucleic acids; delivery of these molecules to exosome-recipient cells causes biological effects. Exosomes derived from some types of cells such as mesenchymal stem cells and dendritic cells have therapeutic potential and may be biocompatible and efficient agents against various disorders such as organ injury. However, there are many challenges for the development of exosome-based therapeutics. In particular, producing exosomal formulations is the major barrier for therapeutic application because of their heterogeneity and low productivity. Development and optimization of producing methods, including methods for isolation and storage of exosome formulations, are required for realizing exosome-based therapeutics. In addition, improvement of therapeutic potential and delivery efficiency of exosomes are important for their therapeutic application. In this review, we summarize current knowledge about therapeutic application of exosomes and discuss some challenges in their successful use.

Blueberry (Vaccinium corymbosum L.).

PubMed

Song, Guo-Qing

2015-01-01

Vaccinium consists of approximately 450 species, of which highbush blueberry (Vaccinium corymbosum) is one of the three major Vaccinium fruit crops (i.e., blueberry, cranberry, and lingonberry) domesticated in the twentieth century. In blueberry the adventitious shoot regeneration using leaf explants has been the most desirable regeneration system to date; Agrobacterium tumefaciens-mediated transformation is the major gene delivery method and effective selection has been reported using either the neomycin phosphotransferase II gene (nptII) or the bialaphos resistance (bar) gene as selectable markers. The A. tumefaciens-mediated transformation protocol described in this chapter is based on combining the optimal conditions for efficient plant regeneration, reliable gene delivery, and effective selection. The protocol has led to successful regeneration of transgenic plants from leaf explants of four commercially important highbush blueberry cultivars for multiple purposes, providing a powerful approach to supplement conventional breeding methods for blueberry by introducing genes of interest.

WE-D-BRD-01: Innovation in Radiation Therapy Delivery: Advanced Digital Linac Features

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xing, L; Wong, J; Li, R

2014-06-15

Last few years has witnessed significant advances in linac technology and therapeutic dose delivery method. Digital linacs equipped with high dose rate FFF beams have been clinically implemented in a number of hospitals. Gated VMAT is becoming increasingly popular in treating tumors affected by respiratory motion. This session is devoted to update the audience with these technical advances and to present our experience in clinically implementing the new linacs and dose delivery methods. Topics to be covered include, technical features of new generation of linacs from different vendors, dosimetric characteristics and clinical need for FFF-beam based IMRT and VMAT, respiration-gatedmore » VMAT, the concept and implementation of station parameter optimized radiation therapy (SPORT), beam level imaging and onboard image guidance tools. Emphasis will be on providing fundamental understanding of the new treatment delivery and image guidance strategies, control systems, and the associated dosimetric characteristics. Commissioning and acceptance experience on these new treatment delivery technologies will be reported. Clinical experience and challenges encountered during the process of implementation of the new treatment techniques and future applications of the systems will also be highlighted. Learning Objectives: Present background knowledge of emerging digital linacs and summarize their key geometric and dosimetric features. SPORT as an emerging radiation therapy modality specifically designed to take advantage of digital linacs. Discuss issues related to the acceptance and commissioning of the digital linacs and FFF beams. Describe clinical utility of the new generation of digital linacs and their future applications.« less

Diffusion profile of macromolecules within and between human skin layers for (trans)dermal drug delivery.

PubMed

Römgens, Anne M; Bader, Dan L; Bouwstra, Joke A; Baaijens, Frank P T; Oomens, Cees W J

2015-10-01

Delivering a drug into and through the skin is of interest as the skin can act as an alternative drug administration route for oral delivery. The development of new delivery methods, such as microneedles, makes it possible to not only deliver small molecules into the skin, which are able to pass the outer layer of the skin in therapeutic amounts, but also macromolecules. To provide insight into the administration of these molecules into the skin, the aim of this study was to assess the transport of macromolecules within and between its various layers. The diffusion coefficients in the epidermis and several locations in the papillary and reticular dermis were determined for fluorescein dextran of 40 and 500 kDa using a combination of fluorescent recovery after photobleaching experiments and finite element analysis. The diffusion coefficient was significantly higher for 40 kDa than 500 kDa dextran, with median values of 23 and 9 µm(2)/s in the dermis, respectively. The values only marginally varied within and between papillary and reticular dermis. For the 40 kDa dextran, the diffusion coefficient in the epidermis was twice as low as in the dermis layers. The adopted method may be used for other macromolecules, which are of interest for dermal and transdermal drug delivery. The knowledge about diffusion in the skin is useful to optimize (trans)dermal drug delivery systems to target specific layers or cells in the human skin. Copyright © 2015 Elsevier Ltd. All rights reserved.

Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k: Formulation, optimization, in-vitro and in-vivo antidiabetic evaluation.

PubMed

Garg, Varun; Kaur, Puneet; Singh, Sachin Kumar; Kumar, Bimlesh; Bawa, Palak; Gulati, Monica; Yadav, Ankit Kumar

2017-11-15

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of polypeptide-k (PPK) is reported with the aim to achieve its oral delivery. Box-Behnken design (BBD) was adopted to develop and optimize the composition of SNEDDS. Oleoyl polyoxyl-6 glycerides (A), Tween 80 (B), and diethylene glycol monoethyl ether (C) were used as oil, surfactant and co-surfactant, respectively as independent variables. The effect of variation in their composition was observed on the mean droplet size (y1), polydispersity index (PDI) (y2), % drug loading (y3) and zeta potential (y4). As per the optimal design, seventeen SNEDDS prototypes were prepared. The optimized composition of SNEDDS formulation was 25% v/v Oleoyl polyoxyl-6 glycerides, 37% v/v Tween 80, 38% v/v diethylene glycol monoethyl ether, and 3% w/v PPK. The optimized formulation revealed values of y1, y2, y3, and y4 as 31.89nm, 0.16, 73.15%, and -15.65mV, respectively. Further the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, disintegration and dissolution properties. Both, liquid and solid-SNEDDS have shown release of >90% within 10min. The formulation was found stable with change in pH, dilution, temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline PPK was observed in amorphous state in solid SNEDDS when characterized through DSC and PXRD studies. The biochemical, hematological and histopathological results of streptozotocin induced diabetic rats shown promising antidiabetic potential of PPK loaded in SNEDDS at its both the doses (i.e. 400mg/kg and 800mg/kg) as compared to its naïve form at both the doses. The study revealed successful formulation of SNEDDS for oral delivery of PPK. Copyright © 2017 Elsevier B.V. All rights reserved.

Increased cutaneous wound healing effect of biodegradable liposomes containing madecassoside: preparation optimization, in vitro dermal permeation, and in vivo bioevaluation.

PubMed

Li, Zehao; Liu, Meifeng; Wang, Huijuan; Du, Song

2016-01-01

Madecassoside (MA) is highly potent in treating skin disorders such as wounds and psoriasis. However, the topical wound healing effect of MA was hampered by its poor membrane permeability. In order to overcome this shortcoming, MA liposomes were designed and prepared by a double-emulsion method to enhance transdermal and wound healing effects. In this study, response surface methodology was adopted to yield the optimal preparation conditions of MA double-emulsion liposomes with average particle size of 151 nm and encapsulation efficiency of 70.14%. Moreover, MA double-emulsion liposomes demonstrated superior stability and homogeneous appearance in 5 months; their leakage rate was <12% even at 37°C and <5% at 4°C within 1 month. In vitro skin permeation, skin distribution, and burn wound healing of MA liposomal formulations were conducted for the first time to evaluate MA delivery efficiency and wound healing effect. The transdermal property and wound cure effect of MA double-emulsion liposomes were superior to those of MA film dispersion liposomes, and both the methods were endowed with an excellent performance by polyethylene glycol modification. In conclusion, double-emulsion liposome formulation was an applicable and promising pharmaceutical preparation for enhancing MA delivery toward wound healing effect and improving wound-healing progress.

Objective Lens Optimized for Wavefront Delivery, Pupil Imaging, and Pupil Ghosting

NASA Technical Reports Server (NTRS)

Olzcak, Gene

2009-01-01

An interferometer objective lens (or diverger) may be used to transform a collimated beam into a diverging or converging beam. This innovation provides an objective lens that has diffraction-limited optical performance that is optimized at two sets of conjugates: imaging to the objective focus and imaging to the pupil. The lens thus provides for simultaneous delivery of a high-quality beam and excellent pupil resolution properties.

The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance.

PubMed

Selen, Arzu; Dickinson, Paul A; Müllertz, Anette; Crison, John R; Mistry, Hitesh B; Cruañes, Maria T; Martinez, Marilyn N; Lennernäs, Hans; Wigal, Tim L; Swinney, David C; Polli, James E; Serajuddin, Abu T M; Cook, Jack A; Dressman, Jennifer B

2014-11-01

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

PubMed Central

Shelate, Pragna; Dave, Divyang

2016-01-01

The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability.

PubMed

Dangre, Pankaj; Gilhotra, Ritu; Dhole, Shashikant

2016-10-01

The present investigation is aimed to design a statistically optimized self-microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 ± 1.64 s; globule size, 196.81 ± 1.29 nm; zeta potential, -9.34 ± 1.2 mV, and polydispersity index, 0.354 ± 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF-O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug.

Optimized spray drying process for preparation of one-step calcium-alginate gel microspheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Popeski-Dimovski, Riste

Calcium-alginate micro particles have been used extensively in drug delivery systems. Therefore we establish a one-step method for preparation of internally gelated micro particles with spherical shape and narrow size distribution. We use four types of alginate with different G/M ratio and molar weight. The size of the particles is measured using light diffraction and scanning electron microscopy. Measurements showed that with this method, micro particles with size distribution around 4 micrometers can be prepared, and SEM imaging showed that those particles are spherical in shape.

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

PubMed Central

Behara, Srinivas R.B.; Farkas, Dale R.; Hindle, Michael; Longest, P. Worth

2013-01-01

Purpose The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device. Methods DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices. Results The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI. Conclusions High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD < 1.5 µm, FPF<5µm/ED > 90%, and ED > 80%. PMID:23949304

Optimization of a Diaphragm for a Micro-Shock Tube-Based Drug Delivery Method

PubMed Central

Rathod, Vivek T.; Mahapatra, Debiprosad Roy

2017-01-01

This paper presents the design optimization of diaphragms for a micro-shock tube-based drug delivery device. The function of the diaphragm is to impart the required velocity and direction to the loosely held drug particles on the diaphragm through van der Waals interaction. The finite element model-based studies involved diaphragms made up of copper, brass and aluminium. The study of the influence of material and geometric parameters serves as a vital tool in optimizing the magnitude and direction of velocity distribution on the diaphragm surface. Experiments carried out using a micro-shock tube validate the final deformed shape of the diaphragms determined from the finite element simulation. The diaphragm yields a maximum velocity of 335 m/s for which the maximum deviation of the velocity vector is 0.62°. Drug particles that travel to the destination target tissue are simulated using the estimated velocity distribution and angular deviation. Further, a theoretical model of penetration helps in the prediction of the drug particle penetration in the skin tissue like a target, which is found to be 0.126 mm. The design and calibration procedure of a micro-shock tube device to alter drug particle penetration considering the skin thickness and property are presented. PMID:28952503

Optimizing delivery of recovery-oriented online self-management strategies for bipolar disorder: a review.

PubMed

Leitan, Nuwan D; Michalak, Erin E; Berk, Lesley; Berk, Michael; Murray, Greg

2015-03-01

Self-management is emerging as a viable alternative to difficult-to-access psychosocial treatments for bipolar disorder (BD), and has particular relevance to recovery-related goals around empowerment and personal meaning. This review examines data and theory on BD self-management from a recovery-oriented perspective, with a particular focus on optimizing low-intensity delivery of self-management tools via the web. A critical evaluation of various literatures was undertaken. Literatures on recovery, online platforms, and self-management in mental health and BD are reviewed. The literature suggests that the self-management approach aligns with the recovery framework. However, studies have identified a number of potential barriers to the utilization of self-management programs for BD and it has been suggested that utilizing an online environment may be an effective way to surmount many of these barriers. Online self-management programs for BD are rapidly developing, and in parallel the recovery perspective is becoming the dominant paradigm for mental health services worldwide, so research is urgently required to assess the efficacy and safety of optimization methods such as professional and/or peer support, tailoring and the development of 'online communities'. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Combinatorial programming of human neuronal progenitors using magnetically-guided stoichiometric mRNA delivery.

PubMed

Azimi, Sayyed M; Sheridan, Steven D; Ghannad-Rezaie, Mostafa; Eimon, Peter M; Yanik, Mehmet Fatih

2018-05-01

Identification of optimal transcription-factor expression patterns to direct cellular differentiation along a desired pathway presents significant challenges. We demonstrate massively combinatorial screening of temporally-varying mRNA transcription factors to direct differentiation of neural progenitor cells using a dynamically-reconfigurable magnetically-guided spotting technology for localizing mRNA, enabling experiments on millimetre size spots. In addition, we present a time-interleaved delivery method that dramatically reduces fluctuations in the delivered transcription-factor copy-numbers per cell. We screened combinatorial and temporal delivery of a pool of midbrain-specific transcription factors to augment the generation of dopaminergic neurons. We show that the combinatorial delivery of LMX1A, FOXA2 and PITX3 is highly effective in generating dopaminergic neurons from midbrain progenitors. We show that LMX1A significantly increases TH -expression levels when delivered to neural progenitor cells either during proliferation or after induction of neural differentiation, while FOXA2 and PITX3 increase expression only when delivered prior to induction, demonstrating temporal dependence of factor addition. © 2018, Azimi et al.

Charging power optimization for nonlinear vibration energy harvesting systems subjected to arbitrary, persistent base excitations

NASA Astrophysics Data System (ADS)

Dai, Quanqi; Harne, Ryan L.

2018-01-01

The vibrations of mechanical systems and structures are often a combination of periodic and random motions. Emerging interest to exploit nonlinearities in vibration energy harvesting systems for charging microelectronics may be challenged by such reality due to the potential to transition between favorable and unfavorable dynamic regimes for DC power delivery. Therefore, a need exists to devise an optimization method whereby charging power from nonlinear energy harvesters remains maximized when excitation conditions are neither purely harmonic nor purely random, which have been the attention of past research. This study meets the need by building from an analytical approach that characterizes the dynamic response of nonlinear energy harvesting platforms subjected to combined harmonic and stochastic base accelerations. Here, analytical expressions are formulated and validated to optimize charging power while the influences of the relative proportions of excitation types are concurrently assessed. It is found that about a 2 times deviation in optimal resistive loads can reduce the charging power by 20% when the system is more prominently driven by harmonic base accelerations, whereas a greater proportion of stochastic excitation results in a 11% reduction in power for the same resistance deviation. In addition, the results reveal that when the frequency of a predominantly harmonic excitation deviates by 50% from optimal conditions the charging power reduces by 70%, whereas the same frequency deviation for a more stochastically dominated excitation reduce total DC power by only 20%. These results underscore the need for maximizing direct current power delivery for nonlinear energy harvesting systems in practical operating environments.

Redesigning Care Delivery with Patient Support Personnel: Learning from Accountable Care Organizations

PubMed Central

Gorbenko, Ksenia O.; Fraze, Taressa; Lewis, Valerie A.

2017-01-01

INTRODUCTION Accountable care organizations (ACOs) are a value-based payment model in the United States rooted in holding groups of healthcare providers financially accountable for the quality and total cost of care of their attributed population. To succeed in reaching their quality and efficiency goals, ACOs implement a variety of care delivery changes, including workforce redesign. Patient support personnel (PSP)—non-physician staff such as care coordinators, community health workers, and others—are critical to restructuring care delivery. Little is known about how ACOs are redesigning their patient support personnel in terms of responsibilities, location, and evaluation. METHODS We conducted semi-structured one-hour interviews with 25 executives at 16 distinct ACOs. The interviews were recorded, transcribed, and coded for themes, using a qualitative coding and analysis process. RESULTS ACOs deployed PSP to perform four clusters of responsibilities: care provision, care coordination, logistical help with transportation, and social and emotional support. ACOs deployed these personnel strategically across settings (primary care, inpatient services, emergency department, home care and community) depending on their population needs. Most ACOs used personnel with the same level of training across settings. Few ACOs planned to conduct a comprehensive evaluation of their PSP to optimize their value. DISCUSSION ACO strategies in workforce redesign indicate a shift from a physician-centered to a team-based approach. Employing personnel with varying levels of clinical training to perform different tasks can help further optimize care delivery. More robust evaluation of the deployment of PSP and their performance is needed to demonstrate cost-saving benefits of workforce redesign. PMID:28217305

Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein delivery and cell-based drug delivery as therapeutic strategies.

PubMed

Giordano, Carmen; Albani, Diego; Gloria, Antonio; Tunesi, Marta; Batelli, Sara; Russo, Teresa; Forloni, Gianluigi; Ambrosio, Luigi; Cigada, Alberto

2009-12-01

This review presents two intriguing multidisciplinary strategies that might make the difference in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The first proposed strategy is based on the controlled delivery of recombinant proteins known to play a key role in these neurodegenerative disorders that are released in situ by optimized polymer-based systems. The second strategy is the use of engineered cells, encapsulated and delivered in situ by suitable polymer-based systems, that act as drug reservoirs and allow the delivery of selected molecules to be used in the treatment of Alzheimer's and Parkinson's diseases. In both these scenarios, the design and development of optimized polymer-based drug delivery and cell housing systems for central nervous system applications represent a key requirement. Materials science provides suitable hydrogel-based tools to be optimized together with suitably designed recombinant proteins or drug delivering-cells that, once in situ, can provide an effective treatment for these neurodegenerative disorders. In this scenario, only interdisciplinary research that fully integrates biology, biochemistry, medicine and materials science can provide a springboard for the development of suitable therapeutic tools, not only for the treatment of Alzheimer's and Parkinson's diseases but also, prospectively, for a wide range of severe neurodegenerative disorders.

TU-CD-304-01: FEATURED PRESENTATION and BEST IN PHYSICS (THERAPY): Trajectory Modulated Arc Therapy: Development of Novel Arc Delivery Techniques Integrating Dynamic Table Motion for Extended Volume Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chin, E; Hoppe, R; Million, L

2015-06-15

Purpose: Integration of coordinated robotic table motion with inversely-planned arc delivery has the potential to resolve table-top delivery limitations of large-field treatments such as Total Body Irradiation (TBI), Total Lymphoid Irradiation (TLI), and Cranial-Spinal Irradiation (CSI). We formulate the foundation for Trajectory Modulated Arc Therapy (TMAT), and using Varian Developer Mode capabilities, experimentally investigate its practical implementation for such techniques. Methods: A MATLAB algorithm was developed for inverse planning optimization of the table motion, MLC positions, and gantry motion under extended-SSD geometry. To maximize the effective field size, delivery trajectories for TMAT TBI were formed with the table rotated atmore » 270° IEC and dropped vertically to 152.5cm SSD. Preliminary testing of algorithm parameters was done through retrospective planning analysis. Robotic delivery was programmed using custom XML scripting on the TrueBeam Developer Mode platform. Final dose was calculated using the Eclipse AAA algorithm. Initial verification of delivery accuracy was measured using OSLDs on a solid water phantom of varying thickness. Results: A comparison of DVH curves demonstrated that dynamic couch motion irradiation was sufficiently approximated by static control points spaced in intervals of less than 2cm. Optimized MLC motion decreased the average lung dose to 68.5% of the prescription dose. The programmed irradiation integrating coordinated table motion was deliverable on a TrueBeam STx linac in 6.7 min. With the couch translating under an open 10cmx20cm field angled at 10°, OSLD measurements along the midline of a solid water phantom at depths of 3, 5, and 9cm were within 3% of the TPS AAA algorithm with an average deviation of 1.2%. Conclusion: A treatment planning and delivery system for Trajectory Modulated Arc Therapy of extended volumes has been established and experimentally demonstrated for TBI. Extension to other treatment techniques such as TLI and CSI is readily achievable through the developed platform. Grant Funding by Varian Medical Systems.« less

Comparison of Genetic Algorithm and Hill Climbing for Shortest Path Optimization Mapping

NASA Astrophysics Data System (ADS)

Fronita, Mona; Gernowo, Rahmat; Gunawan, Vincencius

2018-02-01

Traveling Salesman Problem (TSP) is an optimization to find the shortest path to reach several destinations in one trip without passing through the same city and back again to the early departure city, the process is applied to the delivery systems. This comparison is done using two methods, namely optimization genetic algorithm and hill climbing. Hill Climbing works by directly selecting a new path that is exchanged with the neighbour's to get the track distance smaller than the previous track, without testing. Genetic algorithms depend on the input parameters, they are the number of population, the probability of crossover, mutation probability and the number of generations. To simplify the process of determining the shortest path supported by the development of software that uses the google map API. Tests carried out as much as 20 times with the number of city 8, 16, 24 and 32 to see which method is optimal in terms of distance and time computation. Based on experiments conducted with a number of cities 3, 4, 5 and 6 producing the same value and optimal distance for the genetic algorithm and hill climbing, the value of this distance begins to differ with the number of city 7. The overall results shows that these tests, hill climbing are more optimal to number of small cities and the number of cities over 30 optimized using genetic algorithms.

Concurrent Monte Carlo transport and fluence optimization with fluence adjusting scalable transport Monte Carlo

PubMed Central

Svatos, M.; Zankowski, C.; Bednarz, B.

2016-01-01

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship within a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead. PMID:27277051

Recommendations for Filler Material Composition and Delivery Method for Bench-Scale Testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardin, Ernest; Brady, Patrick Vane

This report supplements Joint Workplan on Filler Investigations for DPCs (SNL 2017) providing new and some corrected information for use in planning Phase 1 laboratory testing of slurry cements as possible DPC fillers. The scope description is to "Describe a complete laboratory testing program for filler composition, delivery, emplacement in surrogate canisters, and post-test examination. To the extent possible specify filler material and equipment sources." This report includes results from an independent expert review (Dr. Arun Wagh, retired from Argonne National Laboratory and contracted by Sandia) that helped to narrow the range of cement types for consideration, and to providemore » further guidance on mix variations to optimize injectability, durability, and other aspects of filler performance.« less

SU-E-T-197: Helical Cranial-Spinal Treatments with a Linear Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, J; Bernard, D; Liao, Y

2014-06-01

Purpose: Craniospinal irradiation (CSI) of systemic disease requires a high level of beam intensity modulation to reduce dose to bone marrow and other critical structures. Current helical delivery machines can take 30 minutes or more of beam-on time to complete these treatments. This pilot study aims to test the feasibility of performing helical treatments with a conventional linear accelerator using longitudinal couch travel during multiple gantry revolutions. Methods: The VMAT optimization package of the Eclipse 10.0 treatment planning system was used to optimize pseudo-helical CSI plans of 5 clinical patient scans. Each gantry revolution was divided into three 120° arcsmore » with each isocenter shifted longitudinally. Treatments requiring more than the maximum 10 arcs used multiple plans with each plan after the first being optimized including the dose of the others (Figure 1). The beam pitch was varied between 0.2 and 0.9 (couch speed 5- 20cm/revolution and field width of 22cm) and dose-volume histograms of critical organs were compared to tomotherapy plans. Results: Viable pseudo-helical plans were achieved using Eclipse. Decreasing the pitch from 0.9 to 0.2 lowered the maximum lens dose by 40%, the mean bone marrow dose by 2.1% and the maximum esophagus dose by 17.5%. (Figure 2). Linac-based helical plans showed dose results comparable to tomotherapy delivery for both target coverage and critical organ sparing, with the D50 of bone marrow and esophagus respectively 12% and 31% lower in the helical linear accelerator plan (Figure 3). Total mean beam-on time for the linear accelerator plan was 8.3 minutes, 54% faster than the tomotherapy average for the same plans. Conclusions: This pilot study has demonstrated the feasibility of planning pseudo-helical treatments for CSI targets using a conventional linac and dynamic couch movement, and supports the ongoing development of true helical optimization and delivery.« less

Development of Microemulsion Based Nabumetone Transdermal Delivery For Treatment of Arthritis.

PubMed

Jagdale, Swati; Deore, Gokul; Chabukswar, Anuruddha

2018-02-26

Background Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract , diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave idea for present research work for development of transdermal delivery. Objective Objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for treatment of arthritis. Method Oil, surfactant and co-surfactant were selected based on solubility study for the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel. Results Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50-200 nm size . Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160 nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16±2.10 % drug release through egg membrane and 99.15±2.73% drug release in ex-vivo study. Conclusion Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Formulation and evaluation of microemulsion-based hydrogel for topical delivery

PubMed Central

Sabale, Vidya; Vora, Sejal

2012-01-01

Background: The purpose of this study was to develop microemulsion-based hydrogel formulation for topical delivery of bifonazole with an objective to increase the solubility and skin permeability of the drug. Materials and Methods: Oleic acid was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulison systems. The pseudo-ternary phase diagrams for microemulsion regions were constructed using oleic acid as the oil, Tween 80 as the surfactant and isopropyl alcohol (IPA) as the cosurfactant. Various microemulsion formulations were prepared and optimized by 32 factorial design on the basis of percentage (%) transmittance, globule size, zeta potential, drug release, and skin permeability. The abilities of various microemulsions to deliver bifonazole through the skin were evaluated ex vivo using Franz diffusion cells fitted with rat skins. The Hydroxy Propyl Methyl Cellulose (HPMC) K100 M as a gel matrix was used to construct the microemulsion-based hydrogel for improving the viscosity of microemulsion for topical administration. The optimized microemulsion-based hydrogel was evaluated for viscosity, spreadability, skin irritancy, skin permeability, stability, and antifungal activity by comparing it with marketed bifonazole cream. Results: The mechanism of drug release from microemulsion-based hydrogel was observed to follow zero order kinetics. The studied optimized microemulsion-based hydrogel showed a good stability over the period of 3 months. Average globule size of optimized microemulsion (F5) was found to be 18.98 nm, zeta potential was found to be -5.56 mv, and permeability of drug from microemulsion within 8 h was observed 84%. The antifungal activity of microemulsion-based hydrogel was found to be comparable with marketed cream. Conclusion: The results indicate that the studied microemulsion-based hydrogel (F5) has a potential for sustained action of drug release and it may act as promising vehicle for topical delivery of ibuprofen. PMID:23373005

Optimized formulation of solid self-microemulsifying sirolimus delivery systems

PubMed Central

Cho, Wonkyung; Kim, Min-Soo; Kim, Jeong-Soo; Park, Junsung; Park, Hee Jun; Cha, Kwang-Ho; Park, Jeong-Sook; Hwang, Sung-Joo

2013-01-01

Background The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocapry late (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution). Conclusion The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration. PMID:23641156

Nanoethosomes mediated transdermal delivery of vinpocetine for management of Alzheimer's disease.

PubMed

Moghaddam, Atefeh Afshar; Aqil, Mohd; Ahmad, Farhan J; Ali, Mushir M; Sultana, Yasmin; Ali, Asgar

2015-12-01

To develop and statistically optimize nanoethosomal formulation for transdermal delivery of vinpocetine as an anti-Alzheimer's drug. Box-Behnken experimental design was applied for optimization of nanoethosomes. The independent variables were phospholipid (X 1 ), Tween 80 (X 2 ) and Ethanol (X 3 ) while entrapment efficiency (Y 1 ), particle sizes (Y 2 ), elasticity (Y 3 ) and flux (Y 4 ) were the dependent variables. Optimized nanoethosomal vinpocetine formulation with mean particle size 50.57 ± 26.11 nm showed 97.51 ± 0.86% entrapment efficiency, achieved mean transdermal flux 925.60 ± 39.80 µg/cm 2 /h and elasticity of 86.61 ± 2.88. Ex-vivo study of nanoethosomal formulation showed a significant increase flux and entrapment efficiency compared with control vinpocetine solution. Our results suggest that nanoethosome is an efficient carrier for transdermal delivery of vinpocetine as compared to its oral form.

Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine.

PubMed

Klinman, Dennis M; Yamamoto, Masaki; Tross, Debra; Tomaru, Koji

2009-12-01

The intentional release of anthrax spores in 2001 confirmed this pathogen's ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy.

Statistical optimization of tretinoin-loaded penetration-enhancer vesicles (PEV) for topical delivery.

PubMed

Bavarsad, Neda; Akhgari, Abbas; Seifmanesh, Somayeh; Salimi, Anayatollah; Rezaie, Annahita

2016-02-29

The aim of this study was to develop and optimize deformable liposome for topical delivery of tretinoin. Liposomal formulations were designed based on the full factorial design and prepared by fusion method. The influence of different ratio of soy phosphatidylcholine and transcutol (independent variables) on incorporation efficiency and drug release in 15 min and 24 h (responses) from liposomal formulations was evaluated. Liposomes were characterized for their vesicle size and Differential Scanning Calorimetry (DSC) was used to investigate changes in their thermal behavior. The penetration and retention of drug was determined using mouse skin. Also skin histology study was performed. Particle size of all formulations was smaller than 20 nm. Incorporation efficiency of liposomes was 79-93 %. Formulation F7 (25:5) showed maximum drug release. Optimum formulations were selected based on the contour plots resulted by statistical equations of drug release in 15 min and 24 h. Solubility properties of transcutol led to higher skin penetration for optimum formulations compared to tretinoin cream. There was no significant difference between the amount of drug retained in the skin by applying optimum formulations and cream. Histopatological investigation suggested optimum formulations could decrease the adverse effect of tretinoin in liposome compared to conventional cream. According to the results of the study, it is concluded that deformable liposome containing transcutol may be successfully used for dermal delivery of tretinoin.

Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases.

PubMed

Monteiro, Lis Marie; Löbenberg, Raimar; Cotrim, Paulo Cesar; Barros de Araujo, Gabriel Lima; Bou-Chacra, Nádia

2017-01-01

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z -average in the range of 100-300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z -averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z -average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology.

Liposomes containing glycocholate as potential oral insulin delivery systems: preparation, in vitro characterization, and improved protection against enzymatic degradation

PubMed Central

Niu, Mengmeng; Lu, Yi; Hovgaard, Lars; Wu, Wei

2011-01-01

Background: Oral delivery of insulin is challenging and must overcome the barriers of gastric and enzymatic degradation as well as low permeation across the intestinal epithelium. The present study aimed to develop a liposomal delivery system containing glycocholate as an enzyme inhibitor and permeation enhancer for oral insulin delivery. Methods: Liposomes containing sodium glycocholate were prepared by a reversed-phase evaporation method followed by homogenization. The particle size and entrapment efficiency of recombinant human insulin (rhINS)-loaded sodium glycocholate liposomes can be easily adjusted by tuning the homogenization parameters, phospholipid:sodium glycocholate ratio, insulin:phospholipid ratio, water:ether volume ratio, interior water phase pH, and the hydration buffer pH. Results: The optimal formulation showed an insulin entrapment efficiency of 30% ± 2% and a particle size of 154 ± 18 nm. A conformational study by circular dichroism spectroscopy and a bioactivity study confirmed the preserved integrity of rhINS against preparative stress. Transmission electron micrographs revealed a nearly spherical and deformed structure with discernable lamella for sodium glycocholate liposomes. Sodium glycocholate liposomes showed better protection of insulin against enzymatic degradation by pepsin, trypsin, and α-chymotrypsin than liposomes containing the bile salt counterparts of sodium taurocholate and sodium deoxycholate. Conclusion: Sodium glycocholate liposomes showed promising in vitro characteristics and have the potential to be able to deliver insulin orally. PMID:21822379

Theory and in vivo application of electroporative gene delivery.

PubMed

Somiari, S; Glasspool-Malone, J; Drabick, J J; Gilbert, R A; Heller, R; Jaroszeski, M J; Malone, R W

2000-09-01

Efficient and safe methods for delivering exogenous genetic material into tissues must be developed before the clinical potential of gene therapy will be realized. Recently, in vivo electroporation has emerged as a leading technology for developing nonviral gene therapies and nucleic acid vaccines (NAV). Electroporation (EP) involves the application of pulsed electric fields to cells to enhance cell permeability, resulting in exogenous polynucleotide transit across the cytoplasmic membrane. Similar pulsed electrical field treatments are employed in a wide range of biotechnological processes including in vitro EP, hybridoma production, development of transgenic animals, and clinical electrochemotherapy. Electroporative gene delivery studies benefit from well-developed literature that may be used to guide experimental design and interpretation. Both theory and experimental analysis predict that the critical parameters governing EP efficacy include cell size and field strength, duration, frequency, and total number of applied pulses. These parameters must be optimized for each tissue in order to maximize gene delivery while minimizing irreversible cell damage. By providing an overview of the theory and practice of electroporative gene transfer, this review intends to aid researchers that wish to employ the method for preclinical and translational gene therapy, NAV, and functional genomic research.

Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCowan, P. M., E-mail: pmccowan@cancercare.mb.ca; McCurdy, B. M. C.; Medical Physics Department, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9

Purpose: The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., “movie” mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID’s angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, lessmore » EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. Methods: Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into “frame-averaged” EPID images using MATLAB. Each frame-averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a ±1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac’s average gantry speed and the dose per fraction. Results: The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region’s mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment’s dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. Conclusions: The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors’ clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors’ required level of accuracy in the dose reconstruction.« less

Optimization of a Biomimetic Apatite Nanoparticle Delivery System for Non-viral Gene Transfection---a Simulated Body Fluid Approach

NASA Astrophysics Data System (ADS)

Das, Debobrato

Current methods for gene delivery utilize nanocarriers such as liposomes and viral vectors that may produce in vivo toxicity, immunogenicity, or mutagenesis. Moreover, these common high-cost systems have a low efficacy of gene-vehicle transport across the cell plasma membrane followed by inadequate release and weak intracellular stability of the genetic sequence. Thus, this study aims to maximize gene transfection while minimizing cytotoxicity by utilizing supersaturated blood-plasma ions derived from simulated body fluids (SBF). With favorable electrostatic interactions to create biocompatible calcium-phosphate nanoparticles (NPs) derived from biomimetic apatite (BA), results suggest that the SBF system, though naturally sensitive to reaction conditions, after optimization can serve as a tunable and versatile platform for the delivery of various types of nucleic acids. From a systematic exploration of the effects of nucleation pH, incubation temperature, and time on transfection efficiency, the study proposes distinct characteristic trends in SBF BA-NP morphology, cellular uptake, cell viability, and gene modulation. Specifically, with aggressive nucleation and growth of BA-NPs in solution (observed via scanning electron microscopy), the ensuing microenvironment imposes a more toxic cellular interaction (indicated by alamarBlue and BCA assays), limiting particle uptake (fluorescence experiments) and subsequent gene knockdown (quantitative loss of function assays). Controlled precipitation of BA-NPs function to increase particle accessibility by surrounding cells, and subsequently enhance uptake and transfection efficiency. By closely examining such trends, an optimal fabrication condition of pH 6.5-37C can be observed where particle growth is more tamed and less chaotic, providing improved, favorable cellular interactions that increase cell uptake and consequently maximize gene transfection, without compromising cellular viability.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Y. M., E-mail: ymingy@gmail.com; Bednarz, B.; Svatos, M.

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship withinmore » a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead.« less

Towards a hybrid energy efficient multi-tree-based optimized routing protocol for wireless networks.

PubMed

Mitton, Nathalie; Razafindralambo, Tahiry; Simplot-Ryl, David; Stojmenovic, Ivan

2012-12-13

This paper considers the problem of designing power efficient routing with guaranteed delivery for sensor networks with unknown geographic locations. We propose HECTOR, a hybrid energy efficient tree-based optimized routing protocol, based on two sets of virtual coordinates. One set is based on rooted tree coordinates, and the other is based on hop distances toward several landmarks. In HECTOR, the node currently holding the packet forwards it to its neighbor that optimizes ratio of power cost over distance progress with landmark coordinates, among nodes that reduce landmark coordinates and do not increase distance in tree coordinates. If such a node does not exist, then forwarding is made to the neighbor that reduces tree-based distance only and optimizes power cost over tree distance progress ratio. We theoretically prove the packet delivery and propose an extension based on the use of multiple trees. Our simulations show the superiority of our algorithm over existing alternatives while guaranteeing delivery, and only up to 30% additional power compared to centralized shortest weighted path algorithm.

Towards a Hybrid Energy Efficient Multi-Tree-Based Optimized Routing Protocol for Wireless Networks

PubMed Central

Mitton, Nathalie; Razafindralambo, Tahiry; Simplot-Ryl, David; Stojmenovic, Ivan

2012-01-01

This paper considers the problem of designing power efficient routing with guaranteed delivery for sensor networks with unknown geographic locations. We propose HECTOR, a hybrid energy efficient tree-based optimized routing protocol, based on two sets of virtual coordinates. One set is based on rooted tree coordinates, and the other is based on hop distances toward several landmarks. In HECTOR, the node currently holding the packet forwards it to its neighbor that optimizes ratio of power cost over distance progress with landmark coordinates, among nodes that reduce landmark coordinates and do not increase distance in tree coordinates. If such a node does not exist, then forwarding is made to the neighbor that reduces tree-based distance only and optimizes power cost over tree distance progress ratio. We theoretically prove the packet delivery and propose an extension based on the use of multiple trees. Our simulations show the superiority of our algorithm over existing alternatives while guaranteeing delivery, and only up to 30% additional power compared to centralized shortest weighted path algorithm. PMID:23443398

Optimized anion exchange column isolation of zirconium-89 ( 89Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Hara, Matthew J.; Murray, Nathaniel J.; Carter, Jennifer C.

Zirconium-89 ( 89Zr), produced by the (p, n) reaction from naturally monoisotopic yttrium ( natY), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its abilitymore » to quantitatively capture Zr from a load solution high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>10 5) and has been shown to remove Fe, an abundant contaminant in Y foils, from the 89Zr elution fraction. Finally, the method was evaluated using cyclotron bombarded Y foil targets; the method was shown to achieve >95% recovery of the 89Zr present in the foils. The anion exchange column method described here is intended to be the first 89Zr isolation stage in a dual-column purification process.« less

Optimized anion exchange column isolation of zirconium-89 ( 89Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform

DOE PAGES

O’Hara, Matthew J.; Murray, Nathaniel J.; Carter, Jennifer C.; ...

2018-02-24

Zirconium-89 ( 89Zr), produced by the (p, n) reaction from naturally monoisotopic yttrium ( natY), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its abilitymore » to quantitatively capture Zr from a load solution high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>10 5) and has been shown to remove Fe, an abundant contaminant in Y foils, from the 89Zr elution fraction. Finally, the method was evaluated using cyclotron bombarded Y foil targets; the method was shown to achieve >95% recovery of the 89Zr present in the foils. The anion exchange column method described here is intended to be the first 89Zr isolation stage in a dual-column purification process.« less

Influence of different prebiotics and mode of their administration on broiler chicken performance.

PubMed

Bednarczyk, M; Stadnicka, K; Kozłowska, I; Abiuso, C; Tavaniello, S; Dankowiakowska, A; Sławińska, A; Maiorano, G

2016-08-01

In the post-antibiotics era, prebiotics are proposed as alternatives to antibiotic growth promoters in poultry production. The goal of this study was to compare in ovo method of prebiotic delivery with in-water supplementation and with both methods combined (in ovo+in-water) in broiler chickens. Two trials were conducted. Trial 1 was carried out to optimize the doses of two prebiotics, DN (DiNovo®, extract of beta-glucans) and BI (Bi2tos, trans-galactooligosaccharides), for in ovo delivery. The estimated parameters were hatchability and bacteriological status of the newly hatched chicks. Prebiotics were dissolved in 0.2 ml of physiological saline, at the doses: 0.18, 0.88, 3.5 and 7.0 mg/embryo; control group (C) was injected in ovo with 0.2 ml of physiological saline. Trial 2 was conducted to evaluate effects of different prebiotics (DN, BI and raffinose family oligosaccharides (RFO)) delivered in ovo, in-water and in a combined way (in ovo+in-water) on broiler chickens performance. The results of the Trial 1 indicated that the optimal dose of DN and BI prebiotics delivered in ovo, that did not reduce chicks' hatchability, was 0.88 mg/embryo (DN) and 3.5 mg/embryo (BI). Both prebiotics numerically increased number of lactobacilli and bifidobacteria in chicken feces (P>0.05). In Trial 2, all prebiotics (DN, BI and RFO) significantly increased BW gain compared with the C group (P<0.05), especially during the first 21 days of life. However, feed intake and feed conversion ratio were increased upon prebiotics delivery irrespective of method used. Injection of prebiotics in ovo combined with in-water supplementation did not express synergistic effects on broilers performance compared with in ovo injection only. Taken together, those results confirm that single in ovo prebiotics injection into the chicken embryo can successfully replace prolonged in-water supplementation post hatching.

Planning 4D intensity-modulated arc therapy for tumor tracking with a multileaf collimator

NASA Astrophysics Data System (ADS)

Niu, Ying; Betzel, Gregory T.; Yang, Xiaocheng; Gui, Minzhi; Parke, William C.; Yi, Byongyong; Yu, Cedric X.

2017-02-01

This study introduces a practical four-dimensional (4D) planning scheme of IMAT using 4D computed tomography (4D CT) for planning tumor tracking with dynamic multileaf beam collimation. We assume that patients can breathe regularly, i.e. the same way as during 4D CT with an unchanged period and amplitude, and that the start of 4D-IMAT delivery can be synchronized with a designated respiratory phase. Each control point of the IMAT-delivery process can be associated with an image set of 4D CT at a specified respiratory phase. Target is contoured at each respiratory phase without a motion-induced margin. A 3D-IMAT plan is first optimized on a reference-phase image set of 4D CT. Then, based on the projections of the planning target volume in the beam’s eye view at different respiratory phases, a 4D-IMAT plan is generated by transforming the segments of the optimized 3D plan by using a direct aperture deformation method. Compensation for both translational and deformable tumor motion is accomplished, and the smooth delivery of the transformed plan is ensured by forcing connectivity between adjacent angles (control points). It is envisioned that the resultant plans can be delivered accurately using the dose rate regulated tracking method which handles breathing irregularities (Yi et al 2008 Med. Phys. 35 3955-62).This planning process is straightforward and only adds a small step to current clinical 3D planning practice. Our 4D planning scheme was tested on three cases to evaluate dosimetric benefits. The created 4D-IMAT plans showed similar dose distributions as compared with the 3D-IMAT plans on a single static phase, indicating that our method is capable of eliminating the dosimetric effects of breathing induced target motion. Compared to the 3D-IMAT plans with large treatment margins encompassing respiratory motion, our 4D-IMAT plans reduced radiation doses to surrounding normal organs and tissues.

Objective lens simultaneously optimized for pupil ghosting, wavefront delivery and pupil imaging

NASA Technical Reports Server (NTRS)

Olczak, Eugene G (Inventor)

2011-01-01

An objective lens includes multiple optical elements disposed between a first end and a second end, each optical element oriented along an optical axis. Each optical surface of the multiple optical elements provides an angle of incidence to a marginal ray that is above a minimum threshold angle. This threshold angle minimizes pupil ghosts that may enter an interferometer. The objective lens also optimizes wavefront delivery and pupil imaging onto an optical surface under test.

Half a billion surgical cases: Aligning surgical delivery with best-performing health systems

PubMed Central

Shrime, Mark G.; Daniels, Kimberly M.; Meara, John G.

2015-01-01

Background Surgical delivery varies 200-fold across countries. No direct correlation exists, however, between surgical delivery and health outcomes, making it difficult to pinpoint a goal for surgical scale-up. This report determines the amount of surgery that would be delivered worldwide if the world aligned itself with countries providing the best health outcomes. Methods Annual rates of surgical delivery have been published previously for 129 countries. Five health outcomes were plotted against reported surgical delivery. Univariate and multivariate polynomial regression curves were fit, and the optimal point on each regression curve was determined by solving for first-order conditions. The country closest to the optimum for each health outcome was taken as representative of the best-performing health system. Monetary inputs to and surgical procedures provided by these systems were scaled to the global population. Results For 3 of the 5 health outcomes, optima could be found. Globally, 315 million procedures currently are provided annually. If global delivery mirrored the 3 best-performing countries, between 360 million and 460 million cases would be provided annually. With population growth, this will increase to approximately half a billion cases by 2030. Health systems delivering these outcomes spend approximately 10% of their GDP on health. Conclusion This is the first study to provide empirical evidence for the surgical output that an ideal health system would provide. Our results project ideal delivery worldwide of approximately 550 million annual surgical cases by 2030. PMID:25934078

Ultrasound mediated nanoparticle drug delivery

NASA Astrophysics Data System (ADS)

Mullin, Lee B.

Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems. Ultrasound parameters are optimized to achieve maximum cell internalization of molecules and increased nanoparticle delivery to a cell layer on a coverslip. In-vivo studies demonstrate the possibility of using a lower dose of paclitaxel to slow tumor growth rates, increase doxorubicin concentration in tumor tissue, and enhance tumor delivery of fluorescent molecules through treatments that combine nanoparticles with ultrasound and microbubbles.

Application of in situ polymerization for design and development of oral drug delivery systems.

PubMed

Ngwuluka, Ndidi

2010-12-01

Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.

Controlled laser delivery into biological tissue via thin-film optical tunneling and refraction

NASA Astrophysics Data System (ADS)

Whiteside, Paul J. D.; Goldschmidt, Benjamin S.; Curry, Randy; Viator, John A.

2015-02-01

Due to the often extreme energies employed, contemporary methods of laser delivery utilized in clinical dermatology allow for a dangerous amount of high-intensity laser light to reflect off a multitude of surfaces, including the patient's own skin. Such techniques consistently represent a clear and present threat to both patients and practitioners alike. The intention of this work was therefore to develop a technique that mitigates this problem by coupling the light directly into the tissue via physical contact with an optical waveguide. In this manner, planar waveguides cladded in silver with thin-film active areas were used to illuminate agar tissue phantoms with nanosecond-pulsed laser light at 532nm. The light then either refracted or optically tunneled through the active area, photoacoustically generating ultrasonic waves within the phantom, whose peak-to-peak intensity directly correlated to the internal reflection angle of the beam. Consequently, angular spectra for energy delivery were recorded for sub-wavelength silver and titanium films of variable thickness. Optimal energy delivery was achieved for internal reflection angles ranging from 43 to 50 degrees, depending on the active area and thin film geometries, with titanium films consistently delivering more energy across the entire angular spectrum due to their relatively high refractive index. The technique demonstrated herein therefore not only represents a viable method of energy delivery for biological tissue while minimizing the possibility for stray light, but also demonstrates the possibility for utilizing thin films of high refractive index metals to redirect light out of an optical waveguide.

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): Formulation design and optimization studies

PubMed Central

Yang, Yu-Tsai; Di Pasqua, Anthony J.; Zhang, Yong; Sueda, Katsuhiko; Jay, Michael

2015-01-01

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID:24047113

Energy modulated electron therapy: Design, implementation, and evaluation of a novel method of treatment planning and delivery

NASA Astrophysics Data System (ADS)

Al-Yahya, Khalid

Energy modulated electron therapy (EMET) is a promising treatment modality that has the fundamental capabilities to enhance the treatment planning and delivery of superficially located targets. Although it offers advantages over x-ray intensity modulated radiation therapy (IMRT), EMET has not been widely implemented to the same level of accuracy, automation, and clinical routine as its x-ray counterpart. This lack of implementation is attributed to the absence of a remotely automated beam shaping system as well as the deficiency in dosimetric accuracy of clinical electron pencil beam algorithms in the presence of beam modifiers and tissue heterogeneities. In this study, we present a novel technique for treatment planning and delivery of EMET. The delivery is achieved using a prototype of an automated "few leaf electron collimator" (FLEC). It consists of four copper leaves driven by stepper motors which are synchronized with the x-ray jaws in order to form a series of collimated rectangular openings or "fieldlets". Based on Monte Carlo studies, the FLEC has been designed to serve as an accessory tool to the current accelerator equipment. The FLEC was constructed and its operation was fully automated and integrated with the accelerator through an in-house assembled control unit. The control unit is a portable computer system accompanied with customized software that delivers EMET plans after acquiring them from the optimization station. EMET plans are produced based on dose volume constraints that employ Monte Carlo pre-generated and patient-specific kernels which are utilized by an in-house developed optimization algorithm. The structure of the optimization software is demonstrated. Using Monte Carlo techniques to calculate dose allows for accurate modeling of the collimation system as well as the patient heterogeneous geometry and take into account their impact on optimization. The Monte Carlo calculations were validated by comparing them against output measurements with an ionization chamber. Comparisons with measurements using nearly energy-independent radiochromic films were performed to confirm the Monte Carlo calculation accuracy for 1-D and 2-D dose distributions. We investigated the clinical significance of EMET on cancer sites that are inherently difficult to plan with IMRT. Several parameters were used to analyze treatment plans where they show that EMET provides significant overall improvements over IMRT.

Solid lipid nanoparticles for pulmonary delivery of insulin.

PubMed

Liu, Jie; Gong, Tao; Fu, Hualin; Wang, Changguang; Wang, Xiuli; Chen, Qian; Zhang, Qin; He, Qin; Zhang, Zhirong

2008-05-22

Growing attention has been given to the potential of pulmonary route as an alternative for non-invasive systemic delivery of therapeutic agents. In this study, novel nebulizer-compatible solid lipid nanoparticles (SLNs) for pulmonary drug delivery of insulin were developed by reverse micelle-double emulsion method. The influences of the amount of sodium cholate (SC) and soybean phosphatidylcholine (SPC) on the deposition properties of the nanoparticles were investigated. Under optimal conditions, the entrapment delivery (ED), respirable fraction (RF) and nebulization efficiency (NE) of SLNs could reach 96.53, 82.11 and 63.28%, respectively, and Ins-SLNs remained stable during nebulization. Fasting plasma glucose level was reduced to 39.41% and insulin level was increased to approximately 170 microIU/ml 4h after pulmonary administration of 20 IU/kg Ins-SLNs. A pharmacological bioavailability of 24.33% and a relative bioavailability of 22.33% were obtained using subcutaneous injection as a reference. Incorporating fluorescent-labelled insulin into SLNs, we found that the SLNs were effectively and homogeneously distributed in the lung alveoli. These findings suggested that SLNs could be used as a potential carrier for pulmonary delivery of insulin by improving both in vitro and in vivo stability as well as prolonging hypoglycemic effect, which inevitably resulted in enhanced bioavailability.

Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB–siRNA conjugates

PubMed Central

Cuellar, Trinna L.; Barnes, Dwight; Nelson, Christopher; Tanguay, Joshua; Yu, Shang-Fan; Wen, Xiaohui; Scales, Suzie J.; Gesch, Julie; Davis, David; van Brabant Smith, Anja; Leake, Devin; Vandlen, Richard; Siebel, Christian W.

2015-01-01

Delivery of siRNA is a key hurdle to realizing the therapeutic promise of RNAi. By targeting internalizing cell surface antigens, antibody–siRNA complexes provide a possible solution. However, initial reports of antibody–siRNA complexes relied on non-specific charged interactions and have not been broadly applicable. To assess and improve this delivery method, we built on an industrial platform of therapeutic antibodies called THIOMABs, engineered to enable precise covalent coupling of siRNAs. We report that such coupling generates monomeric antibody–siRNA conjugates (ARCs) that retain antibody and siRNA activities. To broadly assess this technology, we generated a battery of THIOMABs against seven targets that use multiple internalization routes, enabling systematic manipulation of multiple parameters that impact delivery. We identify ARCs that induce targeted silencing in vitro and extend tests to target prostate carcinoma cells following systemic administration in mouse models. However, optimal silencing was restricted to specific conditions and only observed using a subset of ARCs. Trafficking studies point to ARC entrapment in endocytic compartments as a limiting factor, independent of the route of antigen internalization. Our broad characterization of multiple parameters using therapeutic-grade conjugate technology provides a thorough assessment of this delivery technology, highlighting both examples of success as well as remaining challenges. PMID:25550431

Development of transethosomes formulation for dermal fisetin delivery: Box-Behnken design, optimization, in vitro skin penetration, vesicles-skin interaction and dermatokinetic studies.

PubMed

Moolakkadath, Thasleem; Aqil, Mohd; Ahad, Abdul; Imam, Syed Sarim; Iqbal, Babar; Sultana, Yasmin; Mujeeb, Mohd; Iqbal, Zeenat

2018-05-07

The present study was conducted for the optimization of transethosomes formulation for dermal fisetin delivery. The optimization of the formulation was carried out using "Box-Behnken design". The independent variables were Lipoid S 100, ethanol and sodium cholate. The prepared formulations were characterized for vesicle size, entrapment efficiency and in vitro skin penetration study. The vesicles-skin interaction, confocal laser scanning microscopy and dermatokinetic studies were performed with optimized formulation. Results of the present study demonstrated that the optimized formulation presented vesicle size of 74.21 ± 2.65 nm, zeta potential of -11.0 mV, entrapment efficiency of 68.31 ± 1.48% and flux of 4.13 ± 0.17 µg/cm 2 /h. The TEM image of optimized formulation exhibited sealed and spherical shape vesicles. Results of thermoanalytical techniques demonstrated that the prepared transethosomes vesicles formulation had fluidized the rigid membrane of rat's skin for smoother penetration of fisetin transethosomes. The confocal study results presented well distribution and penetration of Rhodamine B loaded transethosomes vesicles formulation up to deeper layers of the rat's skin as compared to the Rhodamine B-hydro alcoholic solution. Present study data revealed that the developed transethosomes vesicles formulation was found to be a potentially useful drug carrier for fisetin dermal delivery.

A New TS Algorithm for Solving Low-Carbon Logistics Vehicle Routing Problem with Split Deliveries by Backpack—From a Green Operation Perspective

PubMed Central

Fu, Zhuo; Wang, Jiangtao

2018-01-01

In order to promote the development of low-carbon logistics and economize logistics distribution costs, the vehicle routing problem with split deliveries by backpack is studied. With the help of the model of classical capacitated vehicle routing problem, in this study, a form of discrete split deliveries was designed in which the customer demand can be split only by backpack. A double-objective mathematical model and the corresponding adaptive tabu search (TS) algorithm were constructed for solving this problem. By embedding the adaptive penalty mechanism, and adopting the random neighborhood selection strategy and reinitialization principle, the global optimization ability of the new algorithm was enhanced. Comparisons with the results in the literature show the effectiveness of the proposed algorithm. The proposed method can save the costs of low-carbon logistics and reduce carbon emissions, which is conducive to the sustainable development of low-carbon logistics. PMID:29747469

Polyelectrolyte Complex Optimization for Macrophage Delivery of Redox Enzyme Nanoparticles

PubMed Central

Zhao, Yuling; Haney, Matthew J.; Klyachko, Natalia L.; Li, Shu; Booth, Stephanie L.; Higginbotham, Sheila M.; Jones, Jocelyn; Zimmerman, Matthew C.; Mosley, R. Lee; Kabanov, Alexander V.; Gendelman, Howard E.; Batrakova, Elena V.

2011-01-01

Background We posit that cell-mediated drug delivery can improve transport of therapeutic enzymes to the brain and decrease inflammation and neurodegeneration induced during Parkinson’s disease. Our prior work demonstrated that macrophages loaded with nanoformulated catalase (“nanozyme”) protect the nigrostriatum in a murine model of Parkinson’s disease. Packaging of catalase into block ionomer complex with a synthetic polyelectrolyte block copolymers protects the enzyme degradation in macrophages. Methods We examined relationships between the composition and structure of block ionomer complexes, their physicochemical characteristics, and loadings, release rates, and catalase activity in bone marrow-derived macrophages. Results Formation of block-ionomer complexes resulted in improved aggregation stability. Block ionomer complexes with ε-polylisine, and poly-L-glutamic acid -poly(ethylene glycol) demonstrated the least cytotoxicity and high loading and release rates, however, did not efficiently protect catalase inside macrophages. Conclusion nanozymes with polyethyleneimine- and poly(L-lysine)10-poly(ethylene glycol) provided the best protection of enzymatic activity for cell-mediated drug delivery. PMID:21182416

Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

NASA Astrophysics Data System (ADS)

Hossain, Shaolie S.; Hossainy, Syed F. A.; Bazilevs, Yuri; Calo, Victor M.; Hughes, Thomas J. R.

2012-02-01

The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A three-dimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate.

The construction of a novel kind of non-viral gene delivery vector based on protein as core backbone.

PubMed

Li, D; Kong, Y; Yu, H; Lehtinen, A; Huang, H; Shen, F; Min, L; Zhou, J; Tang, G; Wang, Q

2008-04-01

A novel kind of non-viral gene delivery vector based on transferrin (Tf) as the core component was constructed with high transfection efficiency and low toxicity. The synthesis vector of Tf-PEI600 was confirmed by different physicochemical methods, including (1)H nuclear magnetic resonance, gel permeation chromatography, X-ray and thermogravimetric analysis. The cytotoxicity and gene delivery efficiency of the synthesized vector were verified by in vitro experiments. The agarose gel electrophoresis assay indicated that the novel copolymer Tf-PEI600 could efficiently condense plasmid DNA and the condensed nanoparticles exhibited a spherical shape. As the weight ratio of Tf-PEI600 to DNA reached 15.0, the particle size (about 200 nm) and the zeta potential (about 20 mV) of the nanoparticles became optimal for gene delivery. The methylthiazolyl tetrazolium (MTT) assay showed the cytotoxicity of Tf-PEI600 to be similar to that of PEI600 and much lower than that of PEI25kDa. In gene-delivery experiments with COS-7 cells and HepG2 cells, the Tf-PEI600 showed about a 30- to 53-fold higher efficiency than PEI600 and nearly equal to that of PEI25kDa. These data suggest that Tf-PEI600, with the advantages of low toxicity and high gene-delivery efficiency, might have great prospects in the practice of gene delivery. The core-shell structure of Tf-PEI600 also provided a novel strategy for the construction of non-viral gene delivery vectors.

Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda

PubMed Central

Jain, Vivek; Chang, Wei; Byonanebye, Dathan M.; Owaraganise, Asiphas; Twinomuhwezi, Ellon; Amanyire, Gideon; Black, Douglas; Marseille, Elliot; Kamya, Moses R.; Havlir, Diane V.; Kahn, James G.

2015-01-01

Background Evidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up. Methods Within a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing. Findings Among 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451–716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100–200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals. Conclusions In a Ugandan HIV clinic, ART delivery costs—including VL testing—for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions. PMID:26632823

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.

PubMed

Ghosh, Priyanka; Lee, DoMin; Kim, Kyung Bo; Stinchcomb, Audra L

2014-01-01

The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

Simultaneous beam sampling and aperture shape optimization for SPORT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarepisheh, Masoud; Li, Ruijiang; Xing, Lei, E-mail: Lei@stanford.edu

Purpose: Station parameter optimized radiation therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital linear accelerators, in which the station parameters of a delivery system, such as aperture shape and weight, couch position/angle, gantry/collimator angle, can be optimized simultaneously. SPORT promises to deliver remarkable radiation dose distributions in an efficient manner, yet there exists no optimization algorithm for its implementation. The purpose of this work is to develop an algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: The authors build a mathematical model with the fundamental station point parameters as the decisionmore » variables. To solve the resulting large-scale optimization problem, the authors devise an effective algorithm by integrating three advanced optimization techniques: column generation, subgradient method, and pattern search. Column generation adds the most beneficial stations sequentially until the plan quality improvement saturates and provides a good starting point for the subsequent optimization. It also adds the new stations during the algorithm if beneficial. For each update resulted from column generation, the subgradient method improves the selected stations locally by reshaping the apertures and updating the beam angles toward a descent subgradient direction. The algorithm continues to improve the selected stations locally and globally by a pattern search algorithm to explore the part of search space not reachable by the subgradient method. By combining these three techniques together, all plausible combinations of station parameters are searched efficiently to yield the optimal solution. Results: A SPORT optimization framework with seamlessly integration of three complementary algorithms, column generation, subgradient method, and pattern search, was established. The proposed technique was applied to two previously treated clinical cases: a head and neck and a prostate case. It significantly improved the target conformality and at the same time critical structure sparing compared with conventional intensity modulated radiation therapy (IMRT). In the head and neck case, for example, the average PTV coverage D99% for two PTVs, cord and brainstem max doses, and right parotid gland mean dose were improved, respectively, by about 7%, 37%, 12%, and 16%. Conclusions: The proposed method automatically determines the number of the stations required to generate a satisfactory plan and optimizes simultaneously the involved station parameters, leading to improved quality of the resultant treatment plans as compared with the conventional IMRT plans.« less

Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning.

PubMed

Liu, Shi; Wu, Yu; Wooten, H Omar; Green, Olga; Archer, Brent; Li, Harold; Yang, Deshan

2016-03-08

A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image-guided radiation therapy (MR-IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam-on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam-on time can be calculated using both the planned beam-on time and the decay-corrected dose rate. To predict the remain-ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of the proposed prediction algorithm is sufficient to support patient treatment appointment scheduling. This developed software tool is currently applied in use on a daily basis in our clinic, and could also be used as an important indicator for treatment plan complexity.

Optimizing utility owner participation in the project development and delivery process.

DOT National Transportation Integrated Search

2013-04-01

Coordination with utility owners during the project development and delivery process involves multiple : activities, such as requesting and collecting data about the location and characteristics of existing facilities to : identifying and analyzing u...

A novel method for biomaterial scaffold internal architecture design to match bone elastic properties with desired porosity.

PubMed

Lin, Cheng Yu; Kikuchi, Noboru; Hollister, Scott J

2004-05-01

An often-proposed tissue engineering design hypothesis is that the scaffold should provide a biomimetic mechanical environment for initial function and appropriate remodeling of regenerating tissue while concurrently providing sufficient porosity for cell migration and cell/gene delivery. To provide a systematic study of this hypothesis, the ability to precisely design and manufacture biomaterial scaffolds is needed. Traditional methods for scaffold design and fabrication cannot provide the control over scaffold architecture design to achieve specified properties within fixed limits on porosity. The purpose of this paper was to develop a general design optimization scheme for 3D internal scaffold architecture to match desired elastic properties and porosity simultaneously, by introducing the homogenization-based topology optimization algorithm (also known as general layout optimization). With an initial target for bone tissue engineering, we demonstrate that the method can produce highly porous structures that match human trabecular bone anisotropic stiffness using accepted biomaterials. In addition, we show that anisotropic bone stiffness may be matched with scaffolds of widely different porosity. Finally, we also demonstrate that prototypes of the designed structures can be fabricated using solid free-form fabrication (SFF) techniques.

A randomized trial of Foley balloon induction of labor trial in nulliparas (FIAT-N).

PubMed

Connolly, Katherine A; Kohari, Katherine S; Rekawek, Patricia; Smilen, Brooke S; Miller, Meredith R; Moshier, Erin; Factor, Stephanie H; Stone, Joanne L; Bianco, Angela T

2016-09-01

With an increasing rate of induction of labor, it is important to choose induction methods that are safe and efficient in achieving a vaginal delivery. The optimal method for inducing nulliparous women with an unfavorable cervix is not known. We sought to determine if induction of labor with simultaneous use of oxytocin and Foley balloon vs sequential use of Foley balloon followed by oxytocin decreases the time to delivery in nulliparous women. We conducted a randomized controlled trial of nulliparous women presenting for induction at a single institution from December 2013 through March 2015. After decision for induction was made by their primary provider, women with gestational age ≥24 weeks with a nonanomalous, singleton fetus in vertex presentation with intact membranes were offered participation. Exclusion criteria included history of uterine surgery, unexplained vaginal bleeding, latex allergy, or contraindication to vaginal delivery. Participants were randomized to either simultaneous (oxytocin and Foley balloon) or sequential (oxytocin after expulsion of Foley balloon) induction group. The primary outcome was time from induction to delivery. Secondary outcomes included mode of delivery, estimated blood loss, postpartum hemorrhage, chorioamnionitis, and composite neonatal outcome. Maternal and neonatal outcomes were collected via chart review. Analyses were done on an intention-to-treat basis. A total of 166 patients were enrolled; 82 in the simultaneous and 84 in the sequential group. There were no differences in baseline characteristics in the 2 groups. Patients who received simultaneous oxytocin with insertion of a Foley balloon delivered significantly earlier (15.92 vs 18.87 hours, P = .004) than those in the sequential group. There was no difference in rate of cesarean delivery, estimated blood loss, postpartum hemorrhage, chorioamnionitis, or composite neonatal outcome. Simultaneous use of oxytocin and Foley balloon for induction of labor results in a significantly shorter interval to delivery in nulliparas. Copyright © 2016 Elsevier Inc. All rights reserved.

Inadequacy of Plasma Acyclovir Levels at Delivery in Patients with Genital Herpes Receiving Oral Acyclovir Suppressive Therapy in Late Pregnancy

PubMed Central

Leung, Daniel T.; Henning, Paul A.; Wagner, Emily C.; Blasig, Audrey; Wald, Anna; Sacks, Stephen L.; Corey, Lawrence; Money, Deborah M.

2009-01-01

Objective: Acyclovir therapy in late pregnancy among women with recurrent genital herpes is effective in decreasing genital lesion frequency and subclinical viral shedding rates at delivery, thereby decreasing the need for caesarean delivery. Despite good adherence and increased dosing schedules, breakthrough lesions and viral shedding are still observed in some women at or near delivery. Anecdotal data suggests that low levels of HSV replication at delivery may result in transmission to the neonate. Therefore, defining optimal acyclovir dosing during labor and delivery is warranted. Our objectives were to determine actual acyclovir levels at delivery, and explore associations between acyclovir levels, duration of labour and time since last acyclovir dose. Methods: Twenty-seven patients were prescribed oral acyclovir 400 mg three times daily from 36 weeks gestation. Cord blood (venous and arterial) and maternal venous blood samples were collected at delivery, and acyclovir levels measured using capillary electrophoresis. Correlations between duration of labour and time since last acyclovir dose with acyclovir blood levels were calculated. Results: Acyclovir levels were below the published mean steady-state trough value (180 ng/ml) in 52% of venous cord, 55% of arterial cord, and 36% of maternal samples. There was a significant inverse correlation between time since last dose and venous cord (rs19=−0.57, p<0.015), arterial cord (rs16=−0.63, p<0.01), and maternal acyclovir levels (r10=−0.69, p<0.03). Conclusions: Oral dosing of acyclovir in late pregnancy may result in insufficient levels at delivery to prevent viral shedding. Alternative approaches should evaluate dosing through labor, perhaps intravenously, and its effect on viral shedding. PMID:20085679

WE-AB-209-12: Quasi Constrained Multi-Criteria Optimization for Automated Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, W.T.; Siebers, J.V.

Purpose: To introduce quasi-constrained Multi-Criteria Optimization (qcMCO) for unsupervised radiation therapy optimization which generates alternative patient-specific plans emphasizing dosimetric tradeoffs and conformance to clinical constraints for multiple delivery techniques. Methods: For N Organs At Risk (OARs) and M delivery techniques, qcMCO generates M(N+1) alternative treatment plans per patient. Objective weight variations for OARs and targets are used to generate alternative qcMCO plans. For 30 locally advanced lung cancer patients, qcMCO plans were generated for dosimetric tradeoffs to four OARs: each lung, heart, and esophagus (N=4) and 4 delivery techniques (simple 4-field arrangements, 9-field coplanar IMRT, 27-field non-coplanar IMRT, and non-coplanarmore » Arc IMRT). Quasi-constrained objectives included target prescription isodose to 95% (PTV-D95), maximum PTV dose (PTV-Dmax)< 110% of prescription, and spinal cord Dmax<45 Gy. The algorithm’s ability to meet these constraints while simultaneously revealing dosimetric tradeoffs was investigated. Statistically significant dosimetric tradeoffs were defined such that the coefficient of determination between dosimetric indices which varied by at least 5 Gy between different plans was >0.8. Results: The qcMCO plans varied mean dose by >5 Gy to ipsilateral lung for 24/30 patients, contralateral lung for 29/30 patients, esophagus for 29/30 patients, and heart for 19/30 patients. In the 600 plans computed without human interaction, average PTV-D95=67.4±3.3 Gy, PTV-Dmax=79.2±5.3 Gy, and spinal cord Dmax was >45 Gy in 93 plans (>50 Gy in 2/600 plans). Statistically significant dosimetric tradeoffs were evident in 19/30 plans, including multiple tradeoffs of at least 5 Gy between multiple OARs in 7/30 cases. The most common statistically significant tradeoff was increasing PTV-Dmax to reduce OAR dose (15/30 patients). Conclusion: The qcMCO method can conform to quasi-constrained objectives while revealing significant variations in OAR doses including mean dose reductions >5 Gy. Clinical implementation will facilitate patient-specific decision making based on achievable dosimetry as opposed to accept/reject models based on population derived objectives.« less

Buparvaquone loaded solid lipid nanoparticles for targeted delivery in theleriosis

PubMed Central

Soni, Maheshkumar P.; Shelkar, Nilakash; Gaikwad, Rajiv V.; Vanage, Geeta R.; Samad, Abdul; Devarajan, Padma V.

2014-01-01

Background: Buparvaquone (BPQ), a hydroxynaphthoquinone derivative, has been investigated for the treatment of many infections and is recommended as the gold standard for the treatment of theileriosis. Theileriosis, an intramacrophage infection is localized mainly in reticuloendotheileial system (RES) organs. The present study investigates development of solid lipid nanoparticles (SLN) of BPQ for targeted delivery to the RES. Materials and Methods: BPQ SLN was prepared using melt method by adding a molten mixture into aqueous Lutrol F68 solution (80°C). Larger batches were prepared up to 6 g of BPQ with GMS: BPQ, 2:1. SLN of designed size were obtained using ultraturrax and high pressure homogenizer. A freeze and thaw study was used to optimize type and concentration of cryoprotectant with Sf: Mean particle size, Si: Initial particle size <1.3. Differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and scanning electron microscope (SEM) study was performed on optimized formulation. Formulation was investigated for in vitro serum stability, hemolysis and cell uptake study. Pharmacokinetic and biodistribution study was performed in Holtzman rat. Results: Based on solubility in lipid; glyceryl monostearate (GMS) was selected for preparation of BPQ SLN. Batches of BPQ SLN were optimized for average particle size and entrapment efficiency at <100 mg solid content. A combination of Solutol HS-15 and Lutrol F68 at 2% w/v and greater enabled the desired Sf/Si < 1.3. Differential scanning calorimetry and powder X-ray diffraction revealed decrease in crystallinity of BPQ in BPQ SLN while, scanning electron microscope revealed spherical morphology. BPQ SLN revealed good stability at 4°C and 25°C. Low hemolytic potential (<8%) and in vitro serum stability up to 5 h was observed. Cytotoxicity of SLN to the U937 cell was low. The macrophage cell line revealed high (52%) uptake of BPQ SLN in 1 h suggesting the potential to RES uptake. SLN revealed longer circulation and biodistrbution study confirmed high RES uptake (75%) in RES organs like liver lung spleen etc. Conclusion: The high RES uptake suggests BPQ SLN as a promising approach for targeted and improved delivery in theileriosis. PMID:24459400

Adaptive Liver Stereotactic Body Radiation Therapy: Automated Daily Plan Reoptimization Prevents Dose Delivery Degradation Caused by Anatomy Deformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leinders, Suzanne M.; Delft University of Technology, Delft; Breedveld, Sebastiaan

Purpose: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. Methods and Materials: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientationsmore » were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. Results: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. Conclusions: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.« less

Optimization and characterization of gastroretentive floating drug delivery system using Box-Behnken design.

PubMed

Rapolu, Kishore; Sanka, Krishna; Vemula, Praveen Kumar; Aatipamula, Vinaydas; Mohd, Abdul Bari; Diwan, Prakash V

2013-12-01

One among many strategies to prolong gastric residence time and improve local effect of the metronidazole in stomach to eradicate Helicobacter pylori in the treatment of peptic ulcer was floating drug delivery system particularly effervescent gastroretentive tablets. The objective of this study was to prepare and evaluate, effervescent floating drug delivery system of a model drug, metronidazole. Effervescent floating drug delivery tablets were prepared by wet granulation method. A three-factor, three levels Box-Behnken design was adopted for the optimization. The selected independent variables were amount of hydroxypropyl methylcellulose K 15M (X1), sodium carboxy methylcellulose (X2) and NaHCO3 (X3). The dependent variables were floating lag time (YFLT), cumulative percentage of metronidazole released at 6th h (Y6) and cumulative percentage of metronidazole released at 12th h (Y12). Physical properties, drug content, in vitro floating lag time, total floating time and drug release behavior were assessed. YFLT range was found to be from 1.02 to 12.07 min. The ranges of other responses, Y6 and Y12 were 25.72 ± 2.85 to 77.14 ± 3.42 % and 65.47 ± 1.25 to 99.65 ± 2.28 %, respectively. Stability studies revealed that no significant change in in vitro floating lag time, total floating time and drug release behavior before and after storage. It can be concluded that a combination of hydroxypropyl methylcellulose K 15M, sodium carboxy methylcellulose and NaHCO3 can be used to increase the gastric residence time of the dosage form to improve local effect of metronidazole.

User input in iterative design for prevention product development: leveraging interdisciplinary methods to optimize effectiveness.

PubMed

Guthrie, Kate M; Rosen, Rochelle K; Vargas, Sara E; Guillen, Melissa; Steger, Arielle L; Getz, Melissa L; Smith, Kelley A; Ramirez, Jaime J; Kojic, Erna M

2017-10-01

The development of HIV-preventive topical vaginal microbicides has been challenged by a lack of sufficient adherence in later stage clinical trials to confidently evaluate effectiveness. This dilemma has highlighted the need to integrate translational research earlier in the drug development process, essentially applying behavioral science to facilitate the advances of basic science with respect to the uptake and use of biomedical prevention technologies. In the last several years, there has been an increasing recognition that the user experience, specifically the sensory experience, as well as the role of meaning-making elicited by those sensations, may play a more substantive role than previously thought. Importantly, the role of the user-their sensory perceptions, their judgements of those experiences, and their willingness to use a product-is critical in product uptake and consistent use post-marketing, ultimately realizing gains in global public health. Specifically, a successful prevention product requires an efficacious drug, an efficient drug delivery system, and an effective user. We present an integrated iterative drug development and user experience evaluation method to illustrate how user-centered formulation design can be iterated from the early stages of preclinical development to leverage the user experience. Integrating the user and their product experiences into the formulation design process may help optimize both the efficiency of drug delivery and the effectiveness of the user.

Simultaneous minimization of leaf travel distance and tongue-and-groove effect for segmental intensity-modulated radiation therapy.

PubMed

Dai, Jianrong; Que, William

2004-12-07

This paper introduces a method to simultaneously minimize the leaf travel distance and the tongue-and-groove effect for IMRT leaf sequences to be delivered in segmental mode. The basic idea is to add a large enough number of openings through cutting or splitting existing openings for those leaf pairs with openings fewer than the number of segments so that all leaf pairs have the same number of openings. The cutting positions are optimally determined with a simulated annealing technique called adaptive simulated annealing. The optimization goal is set to minimize the weighted summation of the leaf travel distance and tongue-and-groove effect. Its performance was evaluated with 19 beams from three clinical cases; one brain, one head-and-neck and one prostate case. The results show that it can reduce the leaf travel distance and (or) tongue-and-groove effect; the reduction of the leaf travel distance reaches its maximum of about 50% when minimized alone; the reduction of the tongue-and-groove reaches its maximum of about 70% when minimized alone. The maximum reduction in the leaf travel distance translates to a 1 to 2 min reduction in treatment delivery time per fraction, depending on leaf speed. If the method is implemented clinically, it could result in significant savings in treatment delivery time, and also result in significant reduction in the wear-and-tear of MLC mechanics.

A Glider-Assisted Link Disruption Restoration Mechanism in Underwater Acoustic Sensor Networks.

PubMed

Jin, Zhigang; Wang, Ning; Su, Yishan; Yang, Qiuling

2018-02-07

Underwater acoustic sensor networks (UASNs) have become a hot research topic. In UASNs, nodes can be affected by ocean currents and external forces, which could result in sudden link disruption. Therefore, designing a flexible and efficient link disruption restoration mechanism to ensure the network connectivity is a challenge. In the paper, we propose a glider-assisted restoration mechanism which includes link disruption recognition and related link restoring mechanism. In the link disruption recognition mechanism, the cluster heads collect the link disruption information and then schedule gliders acting as relay nodes to restore the disrupted link. Considering the glider's sawtooth motion, we design a relay location optimization algorithm with a consideration of both the glider's trajectory and acoustic channel attenuation model. The utility function is established by minimizing the channel attenuation and the optimal location of glider is solved by a multiplier method. The glider-assisted restoration mechanism can greatly improve the packet delivery rate and reduce the communication energy consumption and it is more general for the restoration of different link disruption scenarios. The simulation results show that glider-assisted restoration mechanism can improve the delivery rate of data packets by 15-33% compared with cooperative opportunistic routing (OVAR), the hop-by-hop vector-based forwarding (HH-VBF) and the vector based forward (VBF) methods, and reduce communication energy consumption by 20-58% for a typical network's setting.

A Glider-Assisted Link Disruption Restoration Mechanism in Underwater Acoustic Sensor Networks

PubMed Central

Wang, Ning; Su, Yishan; Yang, Qiuling

2018-01-01

Underwater acoustic sensor networks (UASNs) have become a hot research topic. In UASNs, nodes can be affected by ocean currents and external forces, which could result in sudden link disruption. Therefore, designing a flexible and efficient link disruption restoration mechanism to ensure the network connectivity is a challenge. In the paper, we propose a glider-assisted restoration mechanism which includes link disruption recognition and related link restoring mechanism. In the link disruption recognition mechanism, the cluster heads collect the link disruption information and then schedule gliders acting as relay nodes to restore the disrupted link. Considering the glider’s sawtooth motion, we design a relay location optimization algorithm with a consideration of both the glider’s trajectory and acoustic channel attenuation model. The utility function is established by minimizing the channel attenuation and the optimal location of glider is solved by a multiplier method. The glider-assisted restoration mechanism can greatly improve the packet delivery rate and reduce the communication energy consumption and it is more general for the restoration of different link disruption scenarios. The simulation results show that glider-assisted restoration mechanism can improve the delivery rate of data packets by 15–33% compared with cooperative opportunistic routing (OVAR), the hop-by-hop vector-based forwarding (HH-VBF) and the vector based forward (VBF) methods, and reduce communication energy consumption by 20–58% for a typical network’s setting. PMID:29414898

Nanovesicles for transdermal delivery of felodipine: Development, characterization, and pharmacokinetics

PubMed Central

Yusuf, Mohd; Sharma, Vijay; Pathak, Kamla

2014-01-01

Aim: The research traces development of nanovesicles to attain enhanced transdermal delivery of felodipine and also investigates parameters for optimization of variable membrane compositions containing soya- and egg lecithin and edge activator. Materials and Methods: Rotary evaporation sonication method was employed to obtain tranfersomal formulation that was characterized for vesicle shape and size, polydispersity index (PDI), zeta potential, entrapment and loading efficiency, deformability index and in vitro skin permeation. Results: Spherical nanovesicles of 75.71 ± 5.4 nm with PDI 0.228 and zeta potential of −49.8 were adjudged as the best formulation (MF8). MF8 displayed maximum entrapment and loading efficiency with a high deformability index of 119.68. In vitro permeation across rat skin by MF8 reported 256% enhancement in permeation (flux = 23.72 ± 0.64) when compared with transdermal control formulation and followed zero order kinetics (Case-II). Pharmacokinetic studies revealed that transdermal administration, in contrast to oral delivery provided relatively constant, sustained blood concentration with minimal plasma fluctuation, rapid and prolonged peak time. The relative bioavailability of felodipine was found 358.42% versus oral administration that was well supported by the outcomes of confocal laser scanning microscopic studies that suggested rapid permeation of drugs to across dermal layers. Conclusion: The results conclude that composition variation and method of preparation elicited significant effect on the vesicle characteristic and proved the transcendency of felodipine loaded transfersomes. PMID:25126525

Nanoparticle as a novel tool in hyperthermic intraperitoneal and pressurized intraperitoneal aerosol chemotheprapy to treat patients with peritoneal carcinomatosis

PubMed Central

Nowacki, Maciej; Peterson, Margarita; Kloskowski, Tomasz; McCabe, Eleanor; Guiral, Delia Cortes; Polom, Karol; Pietkun, Katarzyna; Zegarska, Barbara; Pokrywczynska, Marta; Drewa, Tomasz; Roviello, Franco; Medina, Edward A.; Habib, Samy L.; Zegarski, Wojciech

2017-01-01

The treatment of peritoneal surface malignances has changed considerably over the last thirty years. Unfortunately, the palliative is the only current treatment for peritoneal carcinomatosis (PC). Two primary intraperitoneal chemotherapeutic methods are used. The first is combination of cytoreductive surgery (CRS) and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC), which has become the gold standard for many cases of PC. The second is Pressurized IntraPeritoneal Aerosol Chemotheprapy (PIPAC), which is promising direction to minimally invasive as safedrug delivery. These methods were improved through multicenter studies and clinical trials that yield important insights and solutions. Major method development has been made through nanomedicine, specifically nanoparticles. Here, we are presenting the latest advances of nanoparticles and their application to precision diagnostics and improved treatment strategies for PC. These advances will likely develop both HIPEC and PIPAC methods that used for in vitro and in vivo studies. Several benefits of using nanoparticles will be discussed including: 1) Nanoparticles as drug delivery systems; 2) Nanoparticles and Near Infrred (NIR) Irradiation; 3) use of nanoparticles in perioperative diagnostic and individualized treatment planning; 4) use of nanoparticles as anticancer dressing’s, hydrogels and as active beeds for optimal reccurence prevention; and 5) finally the curent in vitro and in vivo studies and clinical trials of nanoparticles. The current review highlighted use of nanoparticles as novel tools in improving drug delivery to be effective for treatment patients with peritoneal carcinomatosis. PMID:29100461

Mixed Integer Programming Model and Incremental Optimization for Delivery and Storage Planning Using Truck Terminals

NASA Astrophysics Data System (ADS)

Sakakibara, Kazutoshi; Tian, Yajie; Nishikawa, Ikuko

We discuss the planning of transportation by trucks over a multi-day period. Each truck collects loads from suppliers and delivers them to assembly plants or a truck terminal. By exploiting the truck terminal as a temporal storage, we aim to increase the load ratio of each truck and to minimize the lead time for transportation. In this paper, we show a mixed integer programming model which represents each product explicitly, and discuss the decomposition of the problem into a problem of delivery and storage, and a problem of vehicle routing. Based on this model, we propose a relax-and-fix type heuristic in which decision variables are fixed one by one by mathematical programming techniques such as branch-and-bound methods.

A Decision-making Model for a Two-stage Production-delivery System in SCM Environment

NASA Astrophysics Data System (ADS)

Feng, Ding-Zhong; Yamashiro, Mitsuo

A decision-making model is developed for an optimal production policy in a two-stage production-delivery system that incorporates a fixed quantity supply of finished goods to a buyer at a fixed interval of time. First, a general cost model is formulated considering both supplier (of raw materials) and buyer (of finished products) sides. Then an optimal solution to the problem is derived on basis of the cost model. Using the proposed model and its optimal solution, one can determine optimal production lot size for each stage, optimal number of transportation for semi-finished goods, and optimal quantity of semi-finished goods transported each time to meet the lumpy demand of consumers. Also, we examine the sensitivity of raw materials ordering and production lot size to changes in ordering cost, transportation cost and manufacturing setup cost. A pragmatic computation approach for operational situations is proposed to solve integer approximation solution. Finally, we give some numerical examples.

Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate.

PubMed

Biswas, Nikhil; Sahoo, Ranjan Kumar

2016-02-01

The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h. Copyright © 2015 Elsevier B.V. All rights reserved.

Better delivery/pick up routes in the presence of uncertainty.

DOT National Transportation Integrated Search

2007-08-01

We consider the Courier Delivery Problem, a variant of the Vehicle Routing Problem with : time windows in which customers appear probabilistically and their service times are uncertain. : We use scenario-based stochastic optimization with recourse fo...

Nanosized sustained-release pyridostigmine bromide microcapsules: process optimization and evaluation of characteristics

PubMed Central

Tan, Qunyou; Jiang, Rong; Xu, Meiling; Liu, Guodong; Li, Songlin; Zhang, Jingqing

2013-01-01

Background Pyridostigmine bromide (3-[[(dimethylamino)-carbonyl]oxy]-1-methylpyridinium bromide), a reversible inhibitor of cholinesterase, is given orally in tablet form, and a treatment schedule of multiple daily doses is recommended for adult patients. Nanotechnology was used in this study to develop an alternative sustained-release delivery system for pyridostigmine, a synthetic drug with high solubility and poor oral bioavailability, hence a Class III drug according to the Biopharmaceutics Classification System. Novel nanosized pyridostigmine-poly(lactic acid) microcapsules (PPNMCs) were expected to have a longer duration of action than free pyridostigmine and previously reported sustained-release formulations of pyridostigmine. Methods The PPNMCs were prepared using a double emulsion-solvent evaporation method to achieve sustained-release characteristics for pyridostigmine. The preparation process for the PPNMCs was optimized by single-factor experiments. The size distribution, zeta potential, and sustained-release behavior were evaluated in different types of release medium. Results The optimal volume ratio of inner phase to external phase, poly(lactic acid) concentration, polyvinyl alcohol concentration, and amount of pyridostigmine were 1:10, 6%, 3% and 40 mg, respectively. The negatively charged PPNMCs had an average particle size of 937.9 nm. Compared with free pyridostigmine, PPNMCs showed an initial burst release and a subsequent very slow release in vitro. The release profiles for the PPNMCs in four different types of dissolution medium were fitted to the Ritger-Peppas and Weibull models. The similarity between pairs of dissolution profiles for the PPNMCs in different types of medium was statistically significant, and the difference between the release curves for PPNMCs and free pyridostigmine was also statistically significant. Conclusion PPNMCs prepared by the optimized protocol described here were in the nanometer range and had good uniformity, with significantly slower pyridostigmine release than from free pyridostigmine. This novel sustained-release delivery nanosystem for pyridostigmine might alleviate the need to identify new acetylcholinesterase inhibitors. PMID:23459707

Visualization of a variety of possible dosimetric outcomes in radiation therapy using dose-volume histogram bands.

PubMed

Trofimov, Alexei; Unkelbach, Jan; DeLaney, Thomas F; Bortfeld, Thomas

2012-01-01

Dose-volume histograms (DVH) are the most common tool used in the appraisal of the quality of a clinical treatment plan. However, when delivery uncertainties are present, the DVH may not always accurately describe the dose distribution actually delivered to the patient. We present a method, based on DVH formalism, to visualize the variability in the expected dosimetric outcome of a treatment plan. For a case of chordoma of the cervical spine, we compared 2 intensity modulated proton therapy plans. Treatment plan A was optimized based on dosimetric objectives alone (ie, desired target coverage, normal tissue tolerance). Plan B was created employing a published probabilistic optimization method that considered the uncertainties in patient setup and proton range in tissue. Dose distributions and DVH for both plans were calculated for the nominal delivery scenario, as well as for scenarios representing deviations from the nominal setup, and a systematic error in the estimate of range in tissue. The histograms from various scenarios were combined to create DVH bands to illustrate possible deviations from the nominal plan for the expected magnitude of setup and range errors. In the nominal scenario, the DVH from plan A showed superior dose coverage, higher dose homogeneity within the target, and improved sparing of the adjacent critical structure. However, when the dose distributions and DVH from plans A and B were recalculated for different error scenarios (eg, proton range underestimation by 3 mm), the plan quality, reflected by DVH, deteriorated significantly for plan A, while plan B was only minimally affected. In the DVH-band representation, plan A produced wider bands, reflecting its higher vulnerability to delivery errors, and uncertainty in the dosimetric outcome. The results illustrate that comparison of DVH for the nominal scenario alone does not provide any information about the relative sensitivity of dosimetric outcome to delivery uncertainties. Thus, such comparison may be misleading and may result in the selection of an inferior plan for delivery to a patient. A better-informed decision can be made if additional information about possible dosimetric variability is presented; for example, in the form of DVH bands. Copyright © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Comparative effectiveness of faecal microbiota transplant by route of administration.

PubMed

Gundacker, N D; Tamhane, A; Walker, J B; Morrow, C D; Rodriguez, J M

2017-08-01

The optimal route of delivery for faecal microbiota transplant (FMT) is unknown. This observational single-centre study analysed the two-week cure rates for all patients who received FMT from 2013 to 2016 according to route of delivery. Overall, nasogastric delivery of FMT was less effective than lower endoscopic delivery. When patients were stratified by illness severity, nasogastric delivery achieved similar cure rates in healthier individuals, whereas lower endoscopic delivery was preferred for relatively ill individuals. Nasogastric delivery may be less effective than lower endoscopic delivery; however, when taking the cost, preparation and potential risk into account, this difference may not be clinically significant for patients with mild disease. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

FUNCTIONAL NANOPARTICLES FOR MOLECULAR IMAGING GUIDED GENE DELIVERY

PubMed Central

Liu, Gang; Swierczewska, Magdalena; Lee, Seulki; Chen, Xiaoyuan

2010-01-01

Gene therapy has great potential to bring tremendous changes in treatment of various diseases and disorders. However, one of the impediments to successful gene therapy is the inefficient delivery of genes to target tissues and the inability to monitor delivery of genes and therapeutic responses at the targeted site. The emergence of molecular imaging strategies has been pivotal in optimizing gene therapy; since it can allow us to evaluate the effectiveness of gene delivery noninvasively and spatiotemporally. Due to the unique physiochemical properties of nanomaterials, numerous functional nanoparticles show promise in accomplishing gene delivery with the necessary feature of visualizing the delivery. In this review, recent developments of nanoparticles for molecular imaging guided gene delivery are summarized. PMID:22473061

Topical ketoprofen nanogel: artificial neural network optimization, clustered bootstrap validation, and in vivo activity evaluation based on longitudinal dose response modeling.

PubMed

Elkomy, Mohammed H; Elmenshawe, Shahira F; Eid, Hussein M; Ali, Ahmed M A

2016-11-01

This work aimed at investigating the potential of solid lipid nanoparticles (SLN) as carriers for topical delivery of Ketoprofen (KP); evaluating a novel technique incorporating Artificial Neural Network (ANN) and clustered bootstrap for optimization of KP-loaded SLN (KP-SLN); and demonstrating a longitudinal dose response (LDR) modeling-based approach to compare the activity of topical non-steroidal anti-inflammatory drug formulations. KP-SLN was fabricated by a modified emulsion/solvent evaporation method. Box-Behnken design was implemented to study the influence of glycerylpalmitostearate-to-KP ratio, Tween 80, and lecithin concentrations on particle size, entrapment efficiency, and amount of drug permeated through rat skin in 24 hours. Following clustered bootstrap ANN optimization, the optimized KP-SLN was incorporated into an aqueous gel and evaluated for rheology, in vitro release, permeability, skin irritation and in vivo activity using carrageenan-induced rat paw edema model and LDR mathematical model to analyze the time course of anti-inflammatory effect at various application durations. Lipid-to-drug ratio of 7.85 [bootstrap 95%CI: 7.63-8.51], Tween 80 of 1.27% [bootstrap 95%CI: 0.601-2.40%], and Lecithin of 0.263% [bootstrap 95%CI: 0.263-0.328%] were predicted to produce optimal characteristics. Compared with profenid® gel, the optimized KP-SLN gel exhibited slower release, faster permeability, better texture properties, greater efficacy, and similar potency. SLNs are safe and effective permeation enhancers. ANN coupled with clustered bootstrap is a useful method for finding optimal solutions and estimating uncertainty associated with them. LDR models allow mechanistic understanding of comparative in vivo performances of different topical formulations, and help design efficient dermatological bioequivalence assessment methods.

Optimization, Characterization and Commissioning of a Novel Uniform Scanning Proton Beam Delivery System

NASA Astrophysics Data System (ADS)

Mascia, Anthony Edward

Purpose: To develop and characterize the required detectors for uniform scanning optimization and characterization, and to develop the methodology and assess their efficacy for optimizing, characterizing and commissioning a novel proton beam uniform scanning system. Methods and Materials: The Multi Layer Ion Chamber (MLIC), a 1D array of vented parallel plate ion chambers, was developed in-house for measurement of longitudinal profiles. The Matrixx detector (IBA Dosimetry, Germany) and XOmat V film (Kodak, USA) were characterized for measurement of transverse profiles. The architecture of the uniform scanning system was developed and then optimized and characterized for clinical proton radiotherapy. Results: The MLIC detector significantly increased data collection efficiency without sacrificing data quality. The MLIC was capable of integrating an entire scanned and layer stacked proton field with one measurement, producing results with the equivalent spatial sampling of 1.0mm. The Matrixx detector and modified 1D water phantom jig improved data acquisition efficiency and complemented the film measurements. The proximal, central and distal proton field planes were measured using these methods, yielding better than 3% uniformity. The binary range modulator was programmed, optimized and characterized such that the proton field ranges were separated by approximately 5.0mm modulation width and delivered with an accuracy of 1.0mm in water. Several wobbling magnet scan patterns were evaluated and the raster pattern, spot spacing, scan amplitude and overscan margin were optimized for clinical use. Conclusion: Novel detectors and methods are required for clinically efficient optimization and characterization of proton beam scanning systems. Uniform scanning produces proton beam fields that are suited for clinical proton radiotherapy.

High-density sub-100-nm peptide-gold nanoparticle complexes improve vaccine presentation by dendritic cells in vitro.

PubMed

Lin, Adam Yuh; Lunsford, Jessica; Bear, Adham Sean; Young, Joseph Keith; Eckels, Phillip; Luo, Laureen; Foster, Aaron Edward; Drezek, Rebekah Anna

2013-02-12

Nanocarriers have been explored to improve the delivery of tumor antigens to dendritic cells (DCs). Gold nanoparticles are attractive nanocarriers because they are inert, non-toxic, and can be readily endocytosed by DCs. Here, we designed novel gold-based nanovaccines (AuNVs) using a simple self-assembling bottom-up conjugation method to generate high-peptide density delivery and effective immune responses with limited toxicity. AuNVs were synthesized using a self-assembling conjugation method and optimized using DC-to-splenocyte interferon-γ enzyme-linked immunosorbent spot assays. The AuNV design has shown successful peptide conjugation with approximately 90% yield while remaining smaller than 80 nm in diameter. DCs uptake AuNVs with minimal toxicity and are able to process the vaccine peptides on the particles to stimulate cytotoxic T lymphocytes (CTLs). These high-peptide density AuNVs can stimulate CTLs better than free peptides and have great potential as carriers for various vaccine types.

High-density sub-100-nm peptide-gold nanoparticle complexes improve vaccine presentation by dendritic cells in vitro

NASA Astrophysics Data System (ADS)

Lin, Adam Yuh; Lunsford, Jessica; Bear, Adham Sean; Young, Joseph Keith; Eckels, Phillip; Luo, Laureen; Foster, Aaron Edward; Drezek, Rebekah Anna

2013-02-01

Nanocarriers have been explored to improve the delivery of tumor antigens to dendritic cells (DCs). Gold nanoparticles are attractive nanocarriers because they are inert, non-toxic, and can be readily endocytosed by DCs. Here, we designed novel gold-based nanovaccines (AuNVs) using a simple self-assembling bottom-up conjugation method to generate high-peptide density delivery and effective immune responses with limited toxicity. AuNVs were synthesized using a self-assembling conjugation method and optimized using DC-to-splenocyte interferon-γ enzyme-linked immunosorbent spot assays. The AuNV design has shown successful peptide conjugation with approximately 90% yield while remaining smaller than 80 nm in diameter. DCs uptake AuNVs with minimal toxicity and are able to process the vaccine peptides on the particles to stimulate cytotoxic T lymphocytes (CTLs). These high-peptide density AuNVs can stimulate CTLs better than free peptides and have great potential as carriers for various vaccine types.

Biocompatible polymer microneedle for topical/dermal delivery of tranexamic acid.

PubMed

A Machekposhti, S; Soltani, M; Najafizadeh, P; Ebrahimi, S A; Chen, P

2017-09-10

Recently-introduced biocompatible polymeric microneedles offer an efficient method for drug delivery. Tranexamic acid is a novel drug for treating melasma that is administered both locally and orally and inhibits excessive melanin via melanocyte. The tranexamic acid biocompatible polymer microneedle used in this study was fabricated from PVP and methacrylic acid, using the lithography method. The required mechanical strength to pierce skin was attained by optimizing the ratio of PVP to methacrylic acid. Acute dermal toxicity was done, and drug diffusion in skin layers was simulated by calculating the diffusion coefficient of tranexamic acid in interstitial fluid (plasma). The biocompatible polymer microneedle was fabricated at 60°C. Needles could sustain 0.6N that is enough to pierce stratum corneum. 34% of the released drug was locally effective and the rest permeated through the skin. The pyramidal polymer microneedle in this study was fully released in skin in approx. 7h. This polymer microneedle has no dermal toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Benchmarking to improve the quality of cystic fibrosis care.

PubMed

Schechter, Michael S

2012-11-01

Benchmarking involves the ascertainment of healthcare programs with most favorable outcomes as a means to identify and spread effective strategies for delivery of care. The recent interest in the development of patient registries for patients with cystic fibrosis (CF) has been fueled in part by an interest in using them to facilitate benchmarking. This review summarizes reports of how benchmarking has been operationalized in attempts to improve CF care. Although certain goals of benchmarking can be accomplished with an exclusive focus on registry data analysis, benchmarking programs in Germany and the United States have supplemented these data analyses with exploratory interactions and discussions to better understand successful approaches to care and encourage their spread throughout the care network. Benchmarking allows the discovery and facilitates the spread of effective approaches to care. It provides a pragmatic alternative to traditional research methods such as randomized controlled trials, providing insights into methods that optimize delivery of care and allowing judgments about the relative effectiveness of different therapeutic approaches.

Modeling hospital surgical delivery process design using system simulation: optimizing patient flow and bed capacity as an illustration.

PubMed

Kumar, Sameer

2011-01-01

It is increasingly recognized that hospital operation is an intricate system with limited resources and many interacting sources of both positive and negative feedback. The purpose of this study is to design a surgical delivery process in a county hospital in the U.S where patient flow through a surgical ward is optimized. The system simulation modeling is used to address questions of capacity planning, throughput management and interacting resources which constitute the constantly changing complexity that characterizes designing a contemporary surgical delivery process in a hospital. The steps in building a system simulation model is demonstrated using an example of building a county hospital in a small city in the US. It is used to illustrate a modular system simulation modeling of patient surgery process flows. The system simulation model development will enable planners and designers how they can build in overall efficiencies in a healthcare facility through optimal bed capacity for peak patient flow of emergency and routine patients.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

PubMed

Okur, Neslihan Üstündağ; Özdemir, Derya İlem; Kahyaoğlu, Şennur Görgülü; Şenyiğit, Zeynep Ay; Aşıkoğlu, Makbule; Genç, Lütfi; Karasulu, H Yeşim

2015-01-01

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

Analytical Tools to Improve Optimization Procedures for Lateral Flow Assays

PubMed Central

Hsieh, Helen V.; Dantzler, Jeffrey L.; Weigl, Bernhard H.

2017-01-01

Immunochromatographic or lateral flow assays (LFAs) are inexpensive, easy to use, point-of-care medical diagnostic tests that are found in arenas ranging from a doctor’s office in Manhattan to a rural medical clinic in low resource settings. The simplicity in the LFA itself belies the complex task of optimization required to make the test sensitive, rapid and easy to use. Currently, the manufacturers develop LFAs by empirical optimization of material components (e.g., analytical membranes, conjugate pads and sample pads), biological reagents (e.g., antibodies, blocking reagents and buffers) and the design of delivery geometry. In this paper, we will review conventional optimization and then focus on the latter and outline analytical tools, such as dynamic light scattering and optical biosensors, as well as methods, such as microfluidic flow design and mechanistic models. We are applying these tools to find non-obvious optima of lateral flow assays for improved sensitivity, specificity and manufacturing robustness. PMID:28555034

Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation

PubMed Central

Çelik, Burak

2017-01-01

The aim of this study was to design and optimize risperidone (RIS) mucoadhesive buccal tablets for systemic delivery as an alternative route. Direct compression method was used for the preparation of buccal tablets, and screening studies were conducted with different polymers to determine their effects on tablet characteristics. Carbopol® (CP) and sodium alginate (SA) were selected as two polymer types for further optimization studies by applying response surface methodology. Tablet hardness (TH), ex vivo residence time (RT), and peak detachment force (DF) from buccal mucosa were selected as three important responses. Physicochemical compatibility of formulation excipients and RIS was evaluated by using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analysis. In vitro drug release profiles and release kinetics were investigated; swelling index and matrix erosion studies were conducted. Optimum formulation consisted of 16.4% CP and 20.3% SA, which provided 7.67±0.29 hour ex vivo RT, 45.52±4.85 N TH, and 2.12±0.17 N DF. FT-IR spectroscopy and DSC analysis revealed that there was no chemical interaction present between tablet ingredients. Cumulative RIS release of >90% was achieved after 8 hours of in vitro dissolution studies, which was supported by swelling and matrix erosion analysis. Mechanism of RIS release was fitted best to zero-order model, while release exponent (n) value of 0.77 demonstrated an anomalous (non-Fickian) release, indicating combined erosion and swelling mechanism. The results suggested that optimized buccal tablets of RIS would be a promising and alternative delivery system for the treatment of schizophrenia. PMID:29225461

Combined fluorimetric caspase 3/7 assay and bradford protein determination for assessment of polycation-mediated cytotoxicity.

PubMed

Larsen, Anna K; Hall, Arnaldur; Lundsgart, Henrik; Moghimi, S Moein

2013-01-01

Cationic polyplexes and lipoplexes are widely used as artificial systems for nucleic acid delivery into the cells, but they can also induce cell death. Mechanistic understanding of cell toxicity and biological side effects of these cationic entities is essential for optimization strategies and design of safe and efficient nucleic acid delivery systems. Numerous methods are presently available to detect and delineate cytotoxicity and cell death-mediated signals in cell cultures. Activation of caspases is part of the classical apoptosis program and increased caspase activity is therefore a well-established hallmark of programmed cell death. Additional methods to monitor cell death-related signals must, however, also be carried out to fully define the type of cell toxicity in play. These may include methods that detect plasma membrane damage, loss of mitochondrial membrane potential, phosphatidylserine exposure, and cell morphological changes (e.g., membrane blebbing, nuclear changes, cytoplasmic swelling, cell rounding). Here we describe a 96-well format protocol for detection of capsase-3/7 activity in cell lysates, based on a fluorescent caspase-3 assay, combined with a method to simultaneously determine relative protein contents in the individual wells.

Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases

PubMed Central

Löbenberg, Raimar; Cotrim, Paulo Cesar

2017-01-01

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z-average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z-averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology. PMID:28255558

Cluster Randomized Trial to Compare Spectacle Delivery Systems at Outreach Eye Camps in South India

PubMed Central

Ramasamy, Dhivya; Joseph, Sanil; Valaguru, Vijayakumar; Mitta, Vinod P.; Ravilla, Thulasiraj D; Cotch, Mary Frances

2014-01-01

Purpose To study the optimal method for delivery of spectacles at eye camps to maximize procurement and use. Methods A cluster randomized controlled trial, undertaken in the catchment districts of Aravind Eye Hospital – Theni, in the state of Tamil Nadu, India. Community eye camps (n = 21) were allocated to offer one of three types of service for purchase of spectacles to correct refractive error: (1) Issuance of a prescription only; (2) booking orders for spectacles with subsequent delivery; (3) on-the-spot fitting and dispensing of spectacles. Follow-up questionnaires were administered 6 weeks after interventions to assess patient outcomes. The primary outcome measured was spectacle procurement at follow-up 6 weeks post-screening. Secondary outcomes included use of and satisfaction with spectacles. Reasons for purchase/non-purchase were also assessed. Results Compared to those who were issued only a prescription and adjusting for distance from base hospital, spectacle procurement was significantly higher for those allowed to book spectacles for subsequent delivery (odds ratio, OR, 8.79, 95% confidence interval, CI, 4.61–16.78) and for those receiving spectacles on the spot (OR 13.97, 95% CI 8.12–24.05). Among those with spectacles at 6 weeks, spectacle use was nearly universal and satisfaction with spectacles varied between 92 and 94% among the three different dispensing modalities. Conclusion Making spectacles available on the spot is important to ensure procurement in a context where availability and access to dispensing opticians is poor. PMID:24070102

Maximizing the potential of direct aperture optimization through collimator rotation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milette, Marie-Pierre; Otto, Karl; Medical Physics, BC Cancer Agency-Vancouver Centre, Vancouver, British Columbia

Intensity-modulated radiation therapy (IMRT) treatment plans are conventionally produced by the optimization of fluence maps followed by a leaf sequencing step. An alternative to fluence based inverse planning is to optimize directly the leaf positions and field weights of multileaf collimator (MLC) apertures. This approach is typically referred to as direct aperture optimization (DAO). It has been shown that equivalent dose distributions may be generated that have substantially fewer monitor units (MU) and number of apertures compared to fluence based optimization techniques. Here we introduce a DAO technique with rotated apertures that we call rotating aperture optimization (RAO). The advantagesmore » of collimator rotation in IMRT have been shown previously and include higher fluence spatial resolution, increased flexibility in the generation of aperture shapes and less interleaf effects. We have tested our RAO algorithm on a complex C-shaped target, seven nasopharynx cancer recurrences, and one multitarget nasopharynx carcinoma patient. A study was performed in order to assess the capabilities of RAO as compared to fixed collimator angle DAO. The accuracy of fixed and rotated collimator aperture delivery was also verified. An analysis of the optimized treatment plans indicates that plans generated with RAO are as good as or better than DAO while maintaining a smaller number of apertures and MU than fluence based IMRT. Delivery verification results show that RAO is less sensitive to tongue and groove effects than DAO. Delivery time is currently increased due to the collimator rotation speed although this is a mechanical limitation that can be eliminated in the future.« less

Protein functionalized tramadol-loaded PLGA nanoparticles: preparation, optimization, stability and pharmacodynamic studies.

PubMed

Lalani, Jigar; Rathi, Mohan; Lalan, Manisha; Misra, Ambikanandan

2013-06-01

Poly (d,l-lactide-co-glycolide acid) (PLGA) Nanoparticles (NPs) with sustained drug release and enhanced circulation time presents widely explored non-invasive approach for drug delivery to brain. However, blood-brain barrier (BBB) limits the drug delivery to brain. This can be overcome by anchoring endogenous ligand like Transferrin (Tf) and Lactoferrin (Lf) on the surface of NPs, allowing efficient brain delivery via receptor-mediated endocytosis. The aim of the present investigation was preparation, optimization, characterization and comparative evaluation of targeting efficiency of Tf- vs. Lf-conjugated NPs. Tramadol-loaded PLGA NPs were prepared by nanoprecipitation techniques and optimized using 3(3) factorial design. The effect of polymer concentration, stabilizer concentration and organic:aqueous phase ratio were evaluated on particle size (PS) and entrapment efficiency (EE). The formulation was optimized based on desirability for lower PS (<150 nm) and higher EE (>70%). Optimized PLGA NPs were conjugated with Tf and Lf, characterized and evaluated for stability study. Pharmacodynamic study was performed in rat after intravenous administration. The optimized formulation had 100 mg of PLGA, 1% polyvinyl alcohol (PVA) and 1:2 acetone:water ratio. The Lf and Tf conjugation to PLGA NPs was estimated to 186 Tf and 185 Lf molecules per NPs. Lyophilization was optimized at 1:2 ratio of NPs:trehalose. The NPs were found stable for 6 months at refrigerated condition. Pharmacodynamic study demonstrated enhanced efficacy of ligand-conjugated NPs against unconjugated NPs. Conjugated NPs demonstrated significantly higher pharmacological effect over a period of 24 h. Furthermore Lf functionalized NPs exhibited better antinociceptive effect as compared to Tf functionalized NPs.

Comparison of lasers used in stapedotomy using specialized visualization techniques for mechanical and thermal effects in an inner ear model

NASA Astrophysics Data System (ADS)

Kamalski, Digna M. A.; Verdaasdonk, Rudolf M.; de Boorder, Tjeerd; Grolman, Wilko

2011-03-01

The outcome of stapedotomy depends on several surgical steps. Using laser light, the ossicular chain can be handled and the oval window can be punctured with a non-touch method. Various lasers are being used or considered, however, it is not clear which settings and characteristics will contribute to optimal or adverse effects (vestibule damage and loss hearing frequencies). Using a unique high speed thermal imaging setup based on Schlieren techniques, the mechanical and thermal effects during laser stapedotomy were studied in an inner ear model consisting of human, fresh frozen stapes positioned on a liquid filled cavity in a gel cast. The cw KTP (532 nm), cw CO2 (10.6 μm), cw Thulium (2.0 μm), pulsed Er,Cr;YSGG (2.78 μm) coupled to special fiber delivery systems were applied at typical clinical settings for comparison. The imaging techniques provided a good insight in the extent of heat conduction beneath the footplate and (explosive) vapour formation on both sides. For the pulsed laser modes, explosive vapour expansion can to be controlled with optimized pulse energies while for continuous wave lasers the thermal effects can be controlled with the pulse length and repetition rate. The fluence at the tip of the delivery system and the distance to the footplate has a major impact on the ablation effect. The pulsed IR lasers with fiber delivery show to be promising for a controlled stapedotomy.

Translational research to improve the treatment of severe extremity injuries.

PubMed

Brown, Kate V; Penn-Barwell, J G; Rand, B C; Wenke, J C

2014-06-01

Severe extremity injuries are the most significant injury sustained in combat wounds. Despite optimal clinical management, non-union and infection remain common complications. In a concerted effort to dovetail research efforts, there has been a collaboration between the UK and USA, with British military surgeons conducting translational studies under the auspices of the US Institute of Surgical Research. This paper describes 3 years of work. A variety of studies were conducted using, and developing, a previously validated rat femur critical-sized defect model. Timing of surgical debridement and irrigation, different types of irrigants and different means of delivery of antibiotic and growth factors for infection control and to promote bone healing were investigated. Early debridement and irrigation were independently shown to reduce infection. Normal saline was the most optimal irrigant, superior to disinfectant solutions. A biodegradable gel demonstrated superior antibiotic delivery capabilities than standard polymethylmethacrylate beads. A polyurethane scaffold was shown to have the ability to deliver both antibiotics and growth factors. The importance of early transit times to Role 3 capabilities for definitive surgical care has been underlined. Novel and superior methods of antibiotic and growth factor delivery, compared with current clinical standards of care, have been shown. There is the potential for translation to clinical studies to promote infection control and bone healing in these devastating injuries. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Discrete Optimization Model for Vehicle Routing Problem with Scheduling Side Cosntraints

NASA Astrophysics Data System (ADS)

Juliandri, Dedy; Mawengkang, Herman; Bu'ulolo, F.

2018-01-01

Vehicle Routing Problem (VRP) is an important element of many logistic systems which involve routing and scheduling of vehicles from a depot to a set of customers node. This is a hard combinatorial optimization problem with the objective to find an optimal set of routes used by a fleet of vehicles to serve the demands a set of customers It is required that these vehicles return to the depot after serving customers’ demand. The problem incorporates time windows, fleet and driver scheduling, pick-up and delivery in the planning horizon. The goal is to determine the scheduling of fleet and driver and routing policies of the vehicles. The objective is to minimize the overall costs of all routes over the planning horizon. We model the problem as a linear mixed integer program. We develop a combination of heuristics and exact method for solving the model.

Optimizing light delivery for a photoacoustic surgical system

NASA Astrophysics Data System (ADS)

Eddins, Blackberrie; Lediju Bell, Muyinatu A.

2017-03-01

This work explores light delivery optimization for a photoacoustic surgical system previously proposed to provide real-time, intraoperative visualization of the internal carotid arteries hidden by bone during minimally invasive neurosurgeries. Monte Carlo simulations were employed to study 3D light propagation in tissue. For a 2.4 mm diameter drill shaft and 2.9 mm spherical drill tip, the optimal fiber distance from the drill shaft was 2 mm, determined from the maximum normalized fluence seen by the artery. A single fiber was insufficient to deliver light to arteries separated by a minimum of 8 mm. Using similar drill geometry and the optimal 2 mm fiber-to-drill shaft distance, Zemax ray tracing simulations were employed to propagate a 950 nm wavelength Gaussian beam through one or more 600 μm core diameter optical fibers, and the resulting optical beam profile was detected on the representative bone surface. For equally spaced fibers, a single merged optical profile formed with 7 or more fibers, determined by thresholding the resulting light profile images at 1/e times the maximum intensity. The corresponding spot size was larger than that of a single fiber transmitting the same input energy, thus reducing the fluence delivered to the sphenoid bone and enabling higher energies within safety limits. A prototype was designed and built based on these optimization parameters. The methodology we used to optimize our light delivery system to surround surgical tools is generalizable to multiple interventional photoacoustic applications.

Simultaneous beam sampling and aperture shape optimization for SPORT.

PubMed

Zarepisheh, Masoud; Li, Ruijiang; Ye, Yinyu; Xing, Lei

2015-02-01

Station parameter optimized radiation therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital linear accelerators, in which the station parameters of a delivery system, such as aperture shape and weight, couch position/angle, gantry/collimator angle, can be optimized simultaneously. SPORT promises to deliver remarkable radiation dose distributions in an efficient manner, yet there exists no optimization algorithm for its implementation. The purpose of this work is to develop an algorithm to simultaneously optimize the beam sampling and aperture shapes. The authors build a mathematical model with the fundamental station point parameters as the decision variables. To solve the resulting large-scale optimization problem, the authors devise an effective algorithm by integrating three advanced optimization techniques: column generation, subgradient method, and pattern search. Column generation adds the most beneficial stations sequentially until the plan quality improvement saturates and provides a good starting point for the subsequent optimization. It also adds the new stations during the algorithm if beneficial. For each update resulted from column generation, the subgradient method improves the selected stations locally by reshaping the apertures and updating the beam angles toward a descent subgradient direction. The algorithm continues to improve the selected stations locally and globally by a pattern search algorithm to explore the part of search space not reachable by the subgradient method. By combining these three techniques together, all plausible combinations of station parameters are searched efficiently to yield the optimal solution. A SPORT optimization framework with seamlessly integration of three complementary algorithms, column generation, subgradient method, and pattern search, was established. The proposed technique was applied to two previously treated clinical cases: a head and neck and a prostate case. It significantly improved the target conformality and at the same time critical structure sparing compared with conventional intensity modulated radiation therapy (IMRT). In the head and neck case, for example, the average PTV coverage D99% for two PTVs, cord and brainstem max doses, and right parotid gland mean dose were improved, respectively, by about 7%, 37%, 12%, and 16%. The proposed method automatically determines the number of the stations required to generate a satisfactory plan and optimizes simultaneously the involved station parameters, leading to improved quality of the resultant treatment plans as compared with the conventional IMRT plans.

Gene delivery for periodontal tissue engineering: current knowledge - future possibilities.

PubMed

Chen, Fa-Ming; Ma, Zhi-Wei; Wang, Qin-Tao; Wu, Zhi-Fen

2009-08-01

The cellular and molecular events of periodontal healing are coordinated and regulated by an elaborate system of signaling molecules, pointing to a primary strategy for functional periodontal compartment regeneration to replicate components of the natural cellular microenvironment by providing an artificial extracellular matrix (ECM) and by delivering growth factors. However, even with optimal carriers, the localized delivery of growth factors often requires a large amount of protein to stimulate significant effects in vivo, which increases the risk and unwanted side effects. A simple and relatively new approach to bypassing this dilemma involves converting cells into protein producing factories. This is done by a so-called gene delivery method, where therapeutic agents to be delivered are DNA plasmids that include the gene encoding desired growth factors instead of recombinant proteins. As localized depots of genes, novel gene delivery systems have the potential to release their cargo in a sustained and controlled manner and finally provide time- and space- dependent levels of encoded proteins during all stages of tissue regrowth, offering great versatility in their application and prompting new tissue engineering strategy in periodontal regenerative medicine. However, gene therapy in Periodontology is clearly in its infancy. Significant efforts still need to be made in developing safe and effective delivery platforms and clarifying how gene delivery, in combination with tissue engineering, may mimic the critical aspects of natural biological processes occurring in periodontal development and repair. The aim of this review is to trace an outline of the state-of-the-art in the application of gene delivery and tissue engineering strategies for periodontal healing and regeneration.

Design, development, and optimization of polymeric based-colonic drug delivery system of naproxen.

PubMed

Sharma, Pooja; Chawla, Anuj; Pawar, Pravin

2013-01-01

The aim of present investigation deals with the development of time-dependent and pH sensitive press-coated tablets for colon specific drug delivery of naproxen. The core tablets were prepared by wet granulation method then press coated with hydroxypropyl cellulose (HPC) or Eudragit RSPO : RLPO mixture and further coated with Eudragit S-100 by dip immerse method. The in vitro drug release study was conducted in different dissolution media such as pH 1.2, 6.8, and 7.4 with or without rat caecal content to simulate GIT conditions. Surface morphology and cross-sectional view of the tablets were visualized by scanning electron microscopy (SEM). All prepared batches were in compliance with the pharmacopoeial standards. The tablets which are compression coated with HPC followed by Eudragit S-100 coated showed highest in vitro drug release of 98.10% in presence of rat caecal content. The SEM of tablets suggested that the number of pores got increased in pH 7.4 medium followed by dissolution of coating layer. The tablets coat erosion study suggested that the lag time depends upon the coating concentrations of polymers. A time-dependent hydrophilic polymer and pH sensitive polymer based press-coated tablets of naproxen were promising delivery for colon targeting.

Cellulose nanofiber aerogel as a promising biomaterial for customized oral drug delivery

PubMed Central

Bhandari, Jyoti; Mishra, Harshita; Mishra, Pawan Kumar; Wimmer, Rupert; Ahmad, Farhan J; Talegaonkar, Sushama

2017-01-01

Cellulose nanofiber (CNF) aerogels with favorable floatability and mucoadhesive properties prepared by the freeze-drying method have been introduced as new possible carriers for oral controlled drug delivery system. Bendamustine hydrochloride is considered as the model drug. Drug loading was carried out by the physical adsorption method, and optimization of drug-loaded formulation was done using central composite design. A very lightweight-aerogel-with-matrix system was produced with drug loading of 18.98%±1.57%. The produced aerogel was characterized for morphology, tensile strength, swelling tendency in media with different pH values, floating behavior, mucoadhesive detachment force and drug release profiles under different pH conditions. The results showed that the type of matrix was porous and woven with excellent mechanical properties. The drug release was assessed by dialysis, which was fitted with suitable mathematical models. Approximately 69.205%±2.5% of the drug was released in 24 hours in medium of pH 1.2, whereas ~78%±2.28% of drug was released in medium of pH 7.4, with floating behavior for ~7.5 hours. The results of in vivo study showed a 3.25-fold increase in bioavailability. Thus, we concluded that CNF aerogels offer a great possibility for a gastroretentive drug delivery system with improved bioavailability. PMID:28352172

Design, Development, and Optimization of Polymeric Based-Colonic Drug Delivery System of Naproxen

PubMed Central

Sharma, Pooja; Chawla, Anuj; Pawar, Pravin

2013-01-01

The aim of present investigation deals with the development of time-dependent and pH sensitive press-coated tablets for colon specific drug delivery of naproxen. The core tablets were prepared by wet granulation method then press coated with hydroxypropyl cellulose (HPC) or Eudragit RSPO : RLPO mixture and further coated with Eudragit S-100 by dip immerse method. The in vitro drug release study was conducted in different dissolution media such as pH 1.2, 6.8, and 7.4 with or without rat caecal content to simulate GIT conditions. Surface morphology and cross-sectional view of the tablets were visualized by scanning electron microscopy (SEM). All prepared batches were in compliance with the pharmacopoeial standards. The tablets which are compression coated with HPC followed by Eudragit S-100 coated showed highest in vitro drug release of 98.10% in presence of rat caecal content. The SEM of tablets suggested that the number of pores got increased in pH 7.4 medium followed by dissolution of coating layer. The tablets coat erosion study suggested that the lag time depends upon the coating concentrations of polymers. A time-dependent hydrophilic polymer and pH sensitive polymer based press-coated tablets of naproxen were promising delivery for colon targeting. PMID:24198725

Opportunities and Challenges for Niosomes as Drug Delivery Systems.

PubMed

Thakkar, Miloni; Brijesh, S

2016-01-01

With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy. Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them. Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well. We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

Optimized anion exchange column isolation of zirconium-89 (89Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform.

PubMed

O'Hara, Matthew J; Murray, Nathaniel J; Carter, Jennifer C; Morrison, Samuel S

2018-04-13

Zirconium-89 ( 89 Zr), produced by the (p, n) reaction from naturally monoisotopic yttrium ( nat Y), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89 Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its ability to quantitatively capture Zr from a load solution high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>10 5 ) and has been shown to remove Fe, an abundant contaminant in Y foils, from the 89 Zr elution fraction. Finally, the method was evaluated using cyclotron bombarded Y foil targets; the method was shown to achieve >95% recovery of the 89 Zr present in the foils. The anion exchange column method described here is intended to be the first 89 Zr isolation stage in a dual-column purification process. Copyright © 2018 Elsevier B.V. All rights reserved.

Development and Optimization of Targeted Nanoscale Iron Delivery Methods for Treatment of NAPL Source Zones

DTIC Science & Technology

2011-04-01

27 III.1.2.3. Gum Arabic Emulsion ……………………………………………. 29 III.1.2.4. Reactivity Studies GA...GA Gum Arabic HLB Hydrophobic Lipophilic Balance IFT Interfacial Tension MISER Michigan Soil-Vapor Extraction Remediation model mRNIP Modified...trichloroethylene (TCE) (99.9%) were supplied by Fischer Scientific. Sodium borohydride (NaBH4) (98+%) and Gum Arabic were supplied by Acros Organics. Purified water

Are written information or counseling (WOMAN-PRO II program) able to improve patient satisfaction and the delivery of health care of women with vulvar neoplasms? Secondary outcomes of a multicenter randomized controlled trial

PubMed

Gehrig, Larissa; Kobleder, Andrea; Werner, Birgit; Denhaerynck, Kris; Senn, Beate

2017-01-01

Background: Patients with vulvar neoplasms report a lack of information, missing support in self-management and a gap in delivery of health care. Aim: The aim of the study was to investigate if written information or counseling based on the WOMAN-PRO II program are able to improve patient satisfaction and the delivery of health care from the health professional's perspective of women with vulvar neoplasms. Method: Patient satisfaction and the delivery of health care have been investigated as two secondary outcomes in a multicenter randomized controlled parallel-group phase II study (Clinical Trial ID: NCT01986725). In total, 49 women, from four hospitals (CH, AUT), completed the questionnaire PACIC-S11 after written information (n = 13) and counseling (n = 36). The delivery of health care was evaluated by ten Advanced Practice Nurses (APNs) by using the G-ACIC before and after implementing counseling based on the WOMAN-PRO II program. Results: There were no significant differences between the two groups identified (p = 0.25). Only few aspects were rated highly by all women, such as the overall satisfaction (M = 80.3 %) and satisfaction with organization of care (M = 83.0 %). The evaluation of delivery of health care by APNs in women who received counseling improved significantly (p = 0.031). Conclusions: There are indications, that the practice of both interventions might have improved patient satisfaction and counseling the delivery of health care. The aspects that have been rated low in the PACIC-S11 and G-ACIC indicate possibilities to optimize the delivery of health care.

Knowledge, attitudes and practices of traditional birth attendants in pastoralist communities of Laikipia and Samburu counties, Kenya: a cross-sectional survey

PubMed Central

Reeve, Matthew; Onyo, Pamela; Nyagero, Josephat; Morgan, Alison; Nduba, John; Kermode, Michelle

2016-01-01

Introduction Current efforts to reduce maternal and newborn mortality focus on promoting institutional deliveries with skilled birth attendants (SBAs), and discouraging deliveries at home attended by traditional birth attendants (TBAs). In rural Kenya, semi-nomadic pastoralist communities are underserved by the formal health system, experience high maternal and neonatal mortality, and rely primarily on TBAs for delivery care, despite Government proscription of TBA-assisted births. This study examined the knowledge, attitude and practices of TBAs serving these communities to assess the potential for collaboration between TBAs and SBAs. Methods A cross-sectional, interviewer-administered survey was conducted among 171 TBAs from Maasai and Samburu pastoralist communities in Laikipia and Samburu counties, Kenya, as part of a larger mixed-methods study in partnership with a local service provider. Results BAs were relatively elderly (mean age 59.6 years), and attended an average of 5-6 deliveries per year. A minority (22.2%) had received formal training. They provided antenatal, intra-partum and post-partum care. Most TBA care was non-interventionist, but not necessarily consistent with best practice. Most had encountered birth complications, but knowledge regarding management of complications was sub-optimal. Most had previously referred at least one woman to a health facility (80.1%), were key participants in decision making to refer women (96.5%), and had been present at an institutional delivery (54.4%). Conclusion TBAs continue to be key providers of maternal and neonatal healthcare in regions where the formal health system has poor coverage or acceptability. Strengthening existing TBA/SBA collaborations could improve both community links to the formal health system, and the quality of care provided to pastoralist women, while remaining consistent with current Government policy. PMID:28439337

Why some women fail to give birth at health facilities: a qualitative study of women’s perceptions of perinatal care from rural Southern Malawi

PubMed Central

2013-01-01

Background Despite Malawi government’s policy to support women to deliver in health facilities with the assistance of skilled attendants, some women do not access this care. Objective The study explores the reasons why women delivered at home without skilled attendance despite receiving antenatal care at a health centre and their perceptions of perinatal care. Methods A descriptive study design with qualitative data collection and analysis methods. Data were collected through face-to-face in-depth interviews using a semi- structured interview guide that collected information on women’s perception on perinatal care. A total of 12 in- depth interviews were conducted with women that had delivered at home in the period December 2010 to March 2011. The women were asked how they perceived the care they received from health workers before, during, and after delivery. Data were manually analyzed using thematic analysis. Results Onset of labor at night, rainy season, rapid labor, socio-cultural factors and health workers’ attitudes were related to the women delivering at home. The participants were assisted in the delivery by traditional birth attendants, relatives or neighbors. Two women delivered alone. Most women went to the health facility the same day after delivery. Conclusions This study reveals beliefs about labor and delivery that need to be addressed through provision of appropriate perinatal information to raise community awareness. Even though, it is not easy to change cultural beliefs to convince women to use health facilities for deliveries. There is a need for further exploration of barriers that prevent women from accessing health care for better understanding and subsequently identification of optimal solutions with involvement of the communities themselves. PMID:23394229

How do organisational characteristics influence teamwork and service delivery in lung cancer diagnostic assessment programmes? A mixed-methods study

PubMed Central

Honein-AbouHaidar, Gladys N; Stuart-McEwan, Terri; Waddell, Tom; Salvarrey, Alexandra; Smylie, Jennifer; Dobrow, Mark J; Brouwers, Melissa C; Gagliardi, Anna R

2017-01-01

Objectives Diagnostic assessment programmes (DAPs) can reduce wait times for cancer diagnosis, but optimal DAP design is unknown. This study explored how organisational characteristics influenced multidisciplinary teamwork and diagnostic service delivery in lung cancer DAPs. Design A mixed-methods approach integrated data from descriptive qualitative interviews and medical record abstraction at 4 lung cancer DAPs. Findings were analysed with the Integrated Team Effectiveness Model. Setting 4 DAPs at 2 teaching and 2 community hospitals in Canada. Participants 22 staff were interviewed about organisational characteristics, target service benchmarks, and teamwork processes, determinants and outcomes; 314 medical records were reviewed for actual service benchmarks. Results Formal, informal and asynchronous team processes enabled service delivery and yielded many perceived benefits at the patient, staff and service levels. However, several DAP characteristics challenged teamwork and service delivery: referral volume/workload, time since launch, days per week of operation, rural–remote population, number and type of full-time/part-time human resources, staff colocation, information systems. As a result, all sites failed to meet target benchmarks (from referral to consultation median 4.0 visits, median wait time 35.0 days). Recommendations included improved information systems, more staff in all specialties, staff colocation and expanded roles for patient navigators. Findings were captured in a conceptual framework of lung cancer DAP teamwork determinants and outcomes. Conclusions This study identified several DAP characteristics that could be improved to facilitate teamwork and enhance service delivery, thereby contributing to knowledge of organisational determinants of teamwork and associated outcomes. Findings can be used to update existing DAP guidelines, and by managers to plan or evaluate lung cancer DAPs. Ongoing research is needed to identify ideal roles for navigators, and staffing models tailored to case volumes. PMID:28235969

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery.

PubMed

Gonzalez-Mira, E; Egea, M A; Souto, E B; Calpena, A C; García, M L

2011-01-28

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol(®) 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween(®) 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (∼90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery

NASA Astrophysics Data System (ADS)

Gonzalez-Mira, E.; Egea, M. A.; Souto, E. B.; Calpena, A. C.; García, M. L.

2011-01-01

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol® 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween® 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (~90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

PubMed Central

Soni, Shringika; Ruhela, Rakesh Kumar; Medhi, Bikash

2016-01-01

Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder. Method: We reviewed the PubMed databases and extracted several kinds of literature on neuro nanomedicines using keywords, CNS disorders, nanomedicine, and nanotechnology. The inclusion criteria included chemical and green synthesis methods for synthesis of nanoparticles encapsulated drugs and, their in-vivo and in-vitro studies. We excluded nanomedicine gene therapy and nanomaterial in brain imaging. Results: In this review, we tried to identify a highly efficient method for nanomedicine synthesis and their efficacy in neuronal disorders. SLN and PNP encapsulated drugs reported highly efficient by easily crossing BBB. Although, these neuro-nanomedicine play significant role in therapeutics but some metallic nanoparticles reported the adverse effect on developing the brain. Conclusion: Although impressive advancement has made via innovative potential drug development, but their efficacy is still moderate due to limited brain permeability. To overcome this constraint,powerful tool in CNS therapeutic intervention provided by nanotechnology-based drug delivery methods. Due to its small and biofunctionalization characteristics, nanomedicine can easily penetrate and facilitate the drug through the barrier. But still, understanding of their toxicity level, optimization and standardization are a long way to go. PMID:27766216

Investigation on Physicochemical Characteristics of a Nanoliposome-Based System for Dual Drug Delivery

NASA Astrophysics Data System (ADS)

Nam, Jae Hyun; Kim, So-Yeon; Seong, Hasoo

2018-04-01

Synergistic effects of multiple drugs with different modes of action are utilized for combinatorial chemotherapy of intractable cancers. Translation of in vitro synergistic effects into the clinic can be realized using an efficient delivery system of the drugs. Despite a few studies on nano-sized liposomes containing erlotinib (ERL) and doxorubicin (DOX) in a single liposome vesicle, reliable and reproducible preparation methods as well as physicochemical characteristics of a non-PEGylated nanoliposome co-encapsulated with ERL and DOX have not been yet elucidated. In this study, ERL-encapsulated nanoliposomes were prepared using the lipid film-hydration method. By ultrasonication using a probe sonicator, the liposome diameter was reduced to less than 200 nm. DOX was loaded into the ERL-encapsulated nanoliposomes using ammonium sulfate (AS)-gradient or pH-gradient method. Effects of DOX-loading conditions on encapsulation efficiency (EE) of the DOX were investigated to determine an efficient drug-loading method. In the EE of DOX, AS-gradient method was more effective than pH gradient. The dual drug-encapsulated nanoliposomes had more than 90% EE of DOX and 30% EE of ERL, respectively. Transmission electron microscopy and selected area electron diffraction analyses of the dual drug-encapsulated nanoliposomes verified the highly oriented DOX-sulfate crystals inside the liposome as well as the less oriented small crystals of ERL in the outermost region of the nanoliposome. The nanoliposomes were stable at different temperatures without an increase of the nanoliposome diameter. The dual drug-encapsulated nanoliposomes showed a time-differential release of ERL and DOX, implying proper sequential releases for their synergism. The preparation methods and the physicochemical characteristics of the dual drug delivery system contribute to the development of the optimal process and more advanced systems for translational researches.

The Bioactivity of Cartilage Extracellular Matrix in Articular Cartilage Regeneration

PubMed Central

Sutherland, Amanda J.; Converse, Gabriel L.; Hopkins, Richard A.; Detamore, Michael S.

2014-01-01

Cartilage matrix is a particularly promising acellular material for cartilage regeneration given the evidence supporting its chondroinductive character. The ‘raw materials’ of cartilage matrix can serve as building blocks and signals for enhanced tissue regeneration. These matrices can be created by chemical or physical methods: physical methods disrupt cellular membranes and nuclei but may not fully remove all cell components and DNA, whereas chemical methods when combined with physical methods are particularly effective in fully decellularizing such materials. Critical endpoints include no detectable residual DNA or immunogenic antigens. It is important to first delineate between the sources of the cartilage matrix, i.e., derived from matrix produced by cells in vitro or from native tissue, and then to further characterize the cartilage matrix based on the processing method, i.e., decellularization or devitalization. With these distinctions, four types of cartilage matrices exist: decellularized native cartilage (DCC), devitalized native cartilage (DVC), decellularized cell derived matrix (DCCM), and devitalized cell derived matrix (DVCM). Delivery of cartilage matrix may be a straightforward approach without the need for additional cells or growth factors. Without additional biological additives, cartilage matrix may be attractive from a regulatory and commercialization standpoint. Source and delivery method are important considerations for clinical translation. Only one currently marketed cartilage matrix medical device is decellularized, although trends in filed patents suggest additional decellularized products may be available in the future. To choose the most relevant source and processing for cartilage matrix, qualifying testing needs to include targeting the desired application, optimizing delivery of the material, identify relevant FDA regulations, assess availability of raw materials, and immunogenic properties of the product. PMID:25044502

Four-dimensional dose distributions of step-and-shoot IMRT delivered with real-time tumor tracking for patients with irregular breathing: Constant dose rate vs dose rate regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang Xiaocheng; Han-Oh, Sarah; Gui Minzhi

2012-09-15

Purpose: Dose-rate-regulated tracking (DRRT) is a tumor tracking strategy that programs the MLC to track the tumor under regular breathing and adapts to breathing irregularities during delivery using dose rate regulation. Constant-dose-rate tracking (CDRT) is a strategy that dynamically repositions the beam to account for intrafractional 3D target motion according to real-time information of target location obtained from an independent position monitoring system. The purpose of this study is to illustrate the differences in the effectiveness and delivery accuracy between these two tracking methods in the presence of breathing irregularities. Methods: Step-and-shoot IMRT plans optimized at a reference phase weremore » extended to remaining phases to generate 10-phased 4D-IMRT plans using segment aperture morphing (SAM) algorithm, where both tumor displacement and deformation were considered. A SAM-based 4D plan has been demonstrated to provide better plan quality than plans not considering target deformation. However, delivering such a plan requires preprogramming of the MLC aperture sequence. Deliveries of the 4D plans using DRRT and CDRT tracking approaches were simulated assuming the breathing period is either shorter or longer than the planning day, for 4 IMRT cases: two lung and two pancreatic cases with maximum GTV centroid motion greater than 1 cm were selected. In DRRT, dose rate was regulated to speed up or slow down delivery as needed such that each planned segment is delivered at the planned breathing phase. In CDRT, MLC is separately controlled to follow the tumor motion, but dose rate was kept constant. In addition to breathing period change, effect of breathing amplitude variation on target and critical tissue dose distribution is also evaluated. Results: Delivery of preprogrammed 4D plans by the CDRT method resulted in an average of 5% increase in target dose and noticeable increase in organs at risk (OAR) dose when patient breathing is either 10% faster or slower than the planning day. In contrast, DRRT method showed less than 1% reduction in target dose and no noticeable change in OAR dose under the same breathing period irregularities. When {+-}20% variation of target motion amplitude was present as breathing irregularity, the two delivery methods show compatible plan quality if the dose distribution of CDRT delivery is renormalized. Conclusions: Delivery of 4D-IMRT treatment plans, stemmed from 3D step-and-shoot IMRT and preprogrammed using SAM algorithm, is simulated for two dynamic MLC-based real-time tumor tracking strategies: with and without dose-rate regulation. Comparison of cumulative dose distribution indicates that the preprogrammed 4D plan is more accurately and efficiently conformed using the DRRT strategy, as it compensates the interplay between patient breathing irregularity and tracking delivery without compromising the segment-weight modulation.« less

Building a polysaccharide hydrogel capsule delivery system for control release of ibuprofen.

PubMed

Chen, Zhi; Wang, Ting; Yan, Qing

2018-02-01

Development of a delivery system which can effectively carry hydrophobic drugs and have pH response is becoming necessary. Here we demonstrate that through preparation of β-cyclodextrin polymer (β-CDP), a hydrophobic drug molecule of ibuprofen (IBU) was incorporated into our prepared β-CDP inner cavities, aiming to improve the poor water solubility of IBU. A core-shell capsule structure has been designed for achieving the drug pH targeted and sustained release. This delivery system was built with polysaccharide polymer of Sodium alginate (SA), sodium carboxymethylcellulose (CMC) and hydroxyethyl cellulose (HEC) by physical cross-linking. The drug pH-response control release is this hydrogel system's chief merit, which has potential value for synthesizing enteric capsule. Besides, due to our simple preparing strategy, optimal conditions can be readily determined and the synthesis process can be accurately controlled, leading to consistent and reproducible hydrogel capsules. In addition, phase-solubility method was used to investigate the solubilization effect of IBU by β-CDP. SEM was used to prove the forming of core and shell structure. FT-IR and 1 H-NMR were also used to perform structural characteristics. By the technique of UV determination, the pH targeted and sustained release study were also performed. The results have proved that our prepared polysaccharide hydrogel capsule delivery system has potential applications as oral drugs delivery in the field of biomedical materials.

Optimal routes of administration, vehicles and timing of progesterone treatment for inhibition of delivery during pregnancy.

PubMed

Fang, Dajun; Moreno, Mario; Garfield, Robert E; Kuon, Ruben; Xia, Huimin

2017-09-01

Progestins, notably progesterone (P4) and 17 alpha hydroxyprogesterone caproate, are presently used to treat pregnant women at risk of preterm birth. The aim of this study was to assess the optimal treatment options for progesterone (P4) to delay delivery using a sensitive bioassay for progesterone. Pregnant rats, known to be highly sensitive to progestins, were treated with P4, including Prochieve ® (also known as Crinone ® ), in various vehicles from day 13 of gestation and in late gestation, days 19 to 22, and delivery times noted. Various routes of administration of P4 and various treatment periods were studied. Use of micronized P4 by rectal, subcutaneous injection (sc) and topical (transdermal) administration in various oils all significantly (P<0.05-<0.001) delay delivery, but vaginal Prochieve ® did not. Administration of P4 in late gestation also prevented (P<0.001) delivery even when given 8h before delivery. Prochieve ® possesses little biological activity to suppress delivery in a sensitive bioassay system and suggests that this preparation may be of little value in prevention and inhibition of preterm birth. Further, this study shows: 1) Inhibition of delivery is increased with P4 treatments when given subcutaneously or topically. 2) P4 in fish oil provides the best vehicle for topical treatment and may be an effective treatment of preterm birth. 3) P4 in fish oil also delays delivery even when treatment begins just prior to normal delivery. 4) To prevent preterm birth in pregnant women, randomized controlled studies are needed with a potent progestin using better formulations and routes of administration. Copyright © 2017. Published by Elsevier B.V.

Drug delivery.

PubMed

Le Souëf, Peter N

2002-09-16

What we know: In preschool children, small-volume spacers perform better than large-volume spacers. Detergent is the best antistatic agent for spacers, increasing lung delivery two- to threefold, but it must not be rinsed off. A mouthpiece should be used in children aged 2-3 years or older, as lung delivery is two- to threefold higher for oral inhalation than nasal inhalation (ie, by mask). Inhaled drug doses do not generally need to be reduced in infants and young children owing to inefficiencies of delivery in younger patients. Nebulisers are "dinosaurs" and not needed for most children with asthma. What we need to know: What is the best inhalation technique for spacers? How long should children breathe, how many breaths should they take, and at what age should they breath-hold? How should children, parents and doctors be instructed to achieve optimal levels of electrostatic charge reduction for spacers? How much should inhaled steroid dose be reduced when a spacer is used optimally? What dosing instructions should be given for beta(2)-agonists delivered by spacer?

Prodrugs for transdermal drug delivery - trends and challenges.

PubMed

Ita, Kevin B

2016-09-01

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.

In Silico Models of Aerosol Delivery to the Respiratory Tract – Development and Applications

PubMed Central

Longest, P. Worth; Holbrook, Landon T.

2011-01-01

This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract. PMID:21640772

FusionArc optimization: a hybrid volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) planning strategy.

PubMed

Matuszak, Martha M; Steers, Jennifer M; Long, Troy; McShan, Daniel L; Fraass, Benedick A; Romeijn, H Edwin; Ten Haken, Randall K

2013-07-01

To introduce a hybrid volumetric modulated arc therapy/intensity modulated radiation therapy (VMAT/IMRT) optimization strategy called FusionArc that combines the delivery efficiency of single-arc VMAT with the potentially desirable intensity modulation possible with IMRT. A beamlet-based inverse planning system was enhanced to combine the advantages of VMAT and IMRT into one comprehensive technique. In the hybrid strategy, baseline single-arc VMAT plans are optimized and then the current cost function gradients with respect to the beamlets are used to define a metric for predicting which beam angles would benefit from further intensity modulation. Beams with the highest metric values (called the gradient factor) are converted from VMAT apertures to IMRT fluence, and the optimization proceeds with the mixed variable set until convergence or until additional beams are selected for conversion. One phantom and two clinical cases were used to validate the gradient factor and characterize the FusionArc strategy. Comparisons were made between standard IMRT, single-arc VMAT, and FusionArc plans with one to five IMRT∕hybrid beams. The gradient factor was found to be highly predictive of the VMAT angles that would benefit plan quality the most from beam modulation. Over the three cases studied, a FusionArc plan with three converted beams achieved superior dosimetric quality with reductions in final cost ranging from 26.4% to 48.1% compared to single-arc VMAT. Additionally, the three beam FusionArc plans required 22.4%-43.7% fewer MU∕Gy than a seven beam IMRT plan. While the FusionArc plans with five converted beams offer larger reductions in final cost--32.9%-55.2% compared to single-arc VMAT--the decrease in MU∕Gy compared to IMRT was noticeably smaller at 12.2%-18.5%, when compared to IMRT. A hybrid VMAT∕IMRT strategy was implemented to find a high quality compromise between gantry-angle and intensity-based degrees of freedom. This optimization method will allow patients to be simultaneously planned for dosimetric quality and delivery efficiency without switching between delivery techniques. Example phantom and clinical cases suggest that the conversion of only three VMAT segments to modulated beams may result in a good combination of quality and efficiency.

Combined Inter- and Intrafractional Plan Adaptation Using Fraction Partitioning in Magnetic Resonance-guided Radiotherapy Delivery.

PubMed

Lagerwaard, Frank; Bohoudi, Omar; Tetar, Shyama; Admiraal, Marjan A; Rosario, Tezontl S; Bruynzeel, Anna

2018-04-05

Magnetic resonance-guided radiation therapy (MRgRT) not only allows for superior soft-tissue setup and online MR-guidance during delivery but also for inter-fractional plan re-optimization or adaptation. This plan adaptation involves repeat MR imaging, organs at risk (OARs) re-contouring, plan prediction (i.e., recalculating the baseline plan on the anatomy of that moment), plan re-optimization, and plan quality assurance. In contrast, intrafractional plan adaptation cannot be simply performed by pausing delivery at any given moment, adjusting contours, and re-optimization because of the complex and composite nature of deformable dose accumulation. To overcome this limitation, we applied a practical workaround by partitioning treatment fractions, each with half the original fraction dose. In between successive deliveries, the patient remained in the treatment position and all steps of the initial plan adaptation were repeated. Thus, this second re-optimization served as an intrafractional plan adaptation at 50% of the total delivery. The practical feasibility of this partitioning approach was evaluated in a patient treated with MRgRT for locally advanced pancreatic cancer (LAPC). MRgRT was delivered in 40Gy in 10 fractions, with two fractions scheduled successively on each treatment day. The contoured gross tumor volume (GTV) was expanded by 3 mm, excluding parts of the OARs within this expansion to derive the planning target volume for daily re-optimization (PTV OPT ). The baseline GTVV 95%  achieved in this patient was 80.0% to adhere to the high-dose constraints for the duodenum, stomach, and bowel (V 33 Gy <1 cc and V 36 Gy <0.1 cc). Treatment was performed on the MRIdian (ViewRay Inc, Mountain View, USA) using video-assisted breath-hold in shallow inspiration. The dual plan adaptation resulted, for each partitioned fraction, in the generation of Plan PREDICTED1 , Plan RE-OPTIMIZED1  (inter-fractional adaptation), Plan PREDICTED2 , and Plan RE-OPTIMIZED2  (intrafractional adaptation). An offline analysis was performed to evaluate the benefit of inter-fractional versus intrafractional plan adaptation with respect to GTV coverage and high-dose OARs sparing for all five partitioned fractions. Interfractional changes in adjacent OARs were substantially larger than intrafractional changes. Mean GTV V 95% was 76.8 ± 1.8% (Plan PREDICTED1 ), 83.4 ± 5.7% (Plan RE-OPTIMIZED1 ), 82.5 ± 4.3% (Plan PREDICTED2 ),and 84.4 ± 4.4% (Plan RE-OPTIMIZED2 ). Both plan re-optimizations appeared important for correcting the inappropriately high duodenal V 33 Gy values of 3.6 cc (Plan PREDICTED1 ) and 3.9 cc (Plan PREDICTED2 ) to 0.2 cc for both re-optimizations. To a smaller extent, this improvement was also observed for V 25 Gy values. For the stomach, bowel, and all other OARs, high and intermediate doses were well below preset constraints, even without re-optimization. The mean delivery time of each daily treatment was 90 minutes. This study presents the clinical application of combined inter-fractional and intrafractional plan adaptation during MRgRT for LAPC using fraction partitioning with successive re-optimization. Whereas, in this study, interfractional plan adaptation appeared to benefit both GTV coverage and OARs sparing, intrafractional adaptation was particularly useful for high-dose OARs sparing. Although all necessary steps lead to a prolonged treatment duration, this may be applied in selected cases where high doses to adjacent OARs are regarded as critical.

Combined Inter- and Intrafractional Plan Adaptation Using Fraction Partitioning in Magnetic Resonance-guided Radiotherapy Delivery

PubMed Central

Bohoudi, Omar; Tetar, Shyama; Admiraal, Marjan A; Rosario, Tezontl S; Bruynzeel, Anna

2018-01-01

Magnetic resonance-guided radiation therapy (MRgRT) not only allows for superior soft-tissue setup and online MR-guidance during delivery but also for inter-fractional plan re-optimization or adaptation. This plan adaptation involves repeat MR imaging, organs at risk (OARs) re-contouring, plan prediction (i.e., recalculating the baseline plan on the anatomy of that moment), plan re-optimization, and plan quality assurance. In contrast, intrafractional plan adaptation cannot be simply performed by pausing delivery at any given moment, adjusting contours, and re-optimization because of the complex and composite nature of deformable dose accumulation. To overcome this limitation, we applied a practical workaround by partitioning treatment fractions, each with half the original fraction dose. In between successive deliveries, the patient remained in the treatment position and all steps of the initial plan adaptation were repeated. Thus, this second re-optimization served as an intrafractional plan adaptation at 50% of the total delivery. The practical feasibility of this partitioning approach was evaluated in a patient treated with MRgRT for locally advanced pancreatic cancer (LAPC). MRgRT was delivered in 40Gy in 10 fractions, with two fractions scheduled successively on each treatment day. The contoured gross tumor volume (GTV) was expanded by 3 mm, excluding parts of the OARs within this expansion to derive the planning target volume for daily re-optimization (PTVOPT). The baseline GTVV95% achieved in this patient was 80.0% to adhere to the high-dose constraints for the duodenum, stomach, and bowel (V33 Gy <1 cc and V36 Gy <0.1 cc). Treatment was performed on the MRIdian (ViewRay Inc, Mountain View, USA) using video-assisted breath-hold in shallow inspiration. The dual plan adaptation resulted, for each partitioned fraction, in the generation of PlanPREDICTED1, PlanRE-OPTIMIZED1 (inter-fractional adaptation), PlanPREDICTED2, and PlanRE-OPTIMIZED2 (intrafractional adaptation). An offline analysis was performed to evaluate the benefit of inter-fractional versus intrafractional plan adaptation with respect to GTV coverage and high-dose OARs sparing for all five partitioned fractions. Interfractional changes in adjacent OARs were substantially larger than intrafractional changes. Mean GTV V95% was 76.8 ± 1.8% (PlanPREDICTED1), 83.4 ± 5.7% (PlanRE-OPTIMIZED1), 82.5 ± 4.3% (PlanPREDICTED2),and 84.4 ± 4.4% (PlanRE-OPTIMIZED2). Both plan re-optimizations appeared important for correcting the inappropriately high duodenal V33 Gy values of 3.6 cc (PlanPREDICTED1) and 3.9 cc (PlanPREDICTED2) to 0.2 cc for both re-optimizations. To a smaller extent, this improvement was also observed for V25 Gy values. For the stomach, bowel, and all other OARs, high and intermediate doses were well below preset constraints, even without re-optimization. The mean delivery time of each daily treatment was 90 minutes. This study presents the clinical application of combined inter-fractional and intrafractional plan adaptation during MRgRT for LAPC using fraction partitioning with successive re-optimization. Whereas, in this study, interfractional plan adaptation appeared to benefit both GTV coverage and OARs sparing, intrafractional adaptation was particularly useful for high-dose OARs sparing. Although all necessary steps lead to a prolonged treatment duration, this may be applied in selected cases where high doses to adjacent OARs are regarded as critical. PMID:29876156

Systematic Propulsion Optimization Tools (SPOT)

NASA Technical Reports Server (NTRS)

Bower, Mark; Celestian, John

1992-01-01

This paper describes a computer program written by senior-level Mechanical Engineering students at the University of Alabama in Huntsville which is capable of optimizing user-defined delivery systems for carrying payloads into orbit. The custom propulsion system is designed by the user through the input of configuration, payload, and orbital parameters. The primary advantages of the software, called Systematic Propulsion Optimization Tools (SPOT), are a user-friendly interface and a modular FORTRAN 77 code designed for ease of modification. The optimization of variables in an orbital delivery system is of critical concern in the propulsion environment. The mass of the overall system must be minimized within the maximum stress, force, and pressure constraints. SPOT utilizes the Design Optimization Tools (DOT) program for the optimization techniques. The SPOT program is divided into a main program and five modules: aerodynamic losses, orbital parameters, liquid engines, solid engines, and nozzles. The program is designed to be upgraded easily and expanded to meet specific user needs. A user's manual and a programmer's manual are currently being developed to facilitate implementation and modification.

Comparison of linear and nonlinear programming approaches for "worst case dose" and "minmax" robust optimization of intensity-modulated proton therapy dose distributions.

PubMed

Zaghian, Maryam; Cao, Wenhua; Liu, Wei; Kardar, Laleh; Randeniya, Sharmalee; Mohan, Radhe; Lim, Gino

2017-03-01

Robust optimization of intensity-modulated proton therapy (IMPT) takes uncertainties into account during spot weight optimization and leads to dose distributions that are resilient to uncertainties. Previous studies demonstrated benefits of linear programming (LP) for IMPT in terms of delivery efficiency by considerably reducing the number of spots required for the same quality of plans. However, a reduction in the number of spots may lead to loss of robustness. The purpose of this study was to evaluate and compare the performance in terms of plan quality and robustness of two robust optimization approaches using LP and nonlinear programming (NLP) models. The so-called "worst case dose" and "minmax" robust optimization approaches and conventional planning target volume (PTV)-based optimization approach were applied to designing IMPT plans for five patients: two with prostate cancer, one with skull-based cancer, and two with head and neck cancer. For each approach, both LP and NLP models were used. Thus, for each case, six sets of IMPT plans were generated and assessed: LP-PTV-based, NLP-PTV-based, LP-worst case dose, NLP-worst case dose, LP-minmax, and NLP-minmax. The four robust optimization methods behaved differently from patient to patient, and no method emerged as superior to the others in terms of nominal plan quality and robustness against uncertainties. The plans generated using LP-based robust optimization were more robust regarding patient setup and range uncertainties than were those generated using NLP-based robust optimization for the prostate cancer patients. However, the robustness of plans generated using NLP-based methods was superior for the skull-based and head and neck cancer patients. Overall, LP-based methods were suitable for the less challenging cancer cases in which all uncertainty scenarios were able to satisfy tight dose constraints, while NLP performed better in more difficult cases in which most uncertainty scenarios were hard to meet tight dose limits. For robust optimization, the worst case dose approach was less sensitive to uncertainties than was the minmax approach for the prostate and skull-based cancer patients, whereas the minmax approach was superior for the head and neck cancer patients. The robustness of the IMPT plans was remarkably better after robust optimization than after PTV-based optimization, and the NLP-PTV-based optimization outperformed the LP-PTV-based optimization regarding robustness of clinical target volume coverage. In addition, plans generated using LP-based methods had notably fewer scanning spots than did those generated using NLP-based methods. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Determining optimal gestational weight gain in a multiethnic Asian population.

PubMed

Ee, Tat Xin; Allen, John Carson; Malhotra, Rahul; Koh, Huishan; Østbye, Truls; Tan, Thiam Chye

2014-04-01

To define the optimal gestational weight gain (GWG) for the multiethnic Singaporean population. Data from 1529 live singleton deliveries was analyzed. A multinomial logistic regression analysis, with GWG as the predictor, was conducted to determine the lowest aggregated risk of a composite perinatal outcome, stratified by Asia-specific body mass index (BMI) categories. The composite perinatal outcome, based on a combination of delivery type (cesarean section [CS], vaginal delivery [VD]) and size for gestational age (small [SGA], appropriate [AGA], large [LGA]), had six categories: (i) VD with LGA; (ii) VD with SGA; (iii) CS with AGA; (iv) CS with SGA; (v) CS with LGA; (vi) and VD with AGA. The last was considered as the 'normal' reference category. In each BMI category, the GWG value corresponding to the lowest aggregated risk was defined as the optimal GWG, and the GWG values at which the aggregated risk did not exceed a 5% increase from the lowest aggregated risk were defined as the margins of the optimal GWG range. The optimal GWG by pre-pregnancy BMI category, was 19.5 kg (range, 12.9 to 23.9) for underweight, 13.7 kg (7.7 to 18.8) for normal weight, 7.9 kg (2.6 to 14.0) for overweight and 1.8 kg (-5.0 to 7.0) for obese. The results of this study, the first to determine optimal GWG in the multiethnic Singaporean population, concur with the Institute of Medicine (IOM) guidelines in that GWG among Asian women who are heavier prior to pregnancy, especially those who are obese, should be lower. However, the optimal GWG for underweight and obese women was outside the IOM recommended range. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

Design and evaluation of bilayered buccal film preparations for local administration of lidocaine hydrochloride.

PubMed

Preis, Maren; Woertz, Christina; Schneider, Katharina; Kukawka, Jennifer; Broscheit, Jens; Roewer, Norbert; Breitkreutz, Jörg

2014-04-01

Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug administration via the oral cavity. Adding a non-soluble or slowly eroding/dissolving backing layer to a mucoadhesive drug-loaded layer enables unidirectional drug delivery. The aim of this study was to investigate different approaches to the manufacture of bilayered films and to examine their properties by applying different characterization methods including an optimized experimental setup for the study of drug release from bilayered films. A solvent suitability study was performed screening over 15 polymers with respect to their feasibility for viscous film formation for film preparation by solvent casting method. Two methods (double-casting and pasting) were found as suitable methods for bilayered film manufacturing. Results from drug release experiments indicated that slowly eroding hypromellose backing layer films revealed the best shielding of the drug-loaded layer to enable unidirectional drug release. In summary, manufacturing of bilayered films using the described methods was feasible. Furthermore, the use of an optimized experimental setup for drug dissolution studies enabled monitoring of drug release without delays in sampling. Copyright © 2014 Elsevier B.V. All rights reserved.

A novel needleless liquid jet injection methodology for improving direct cardiac gene delivery: An optimization of parameters, AAV mediated therapy and investigation of host responses in ischemic heart failure

NASA Astrophysics Data System (ADS)

Fargnoli, Anthony Samuel

Heart disease remains the leading cause of mortality and morbidity worldwide, with 22 million new patients diagnosed annually. Essentially, all present therapies have significant cost burden to the healthcare system, yet fail to increase survival rates. One key employed strategy is the genetic reprogramming of cells to increase contractility via gene therapy, which has advanced to Phase IIb Clinical Trials for advanced heart failure patients. It has been argued that the most significant barrier preventing FDA approval are resolving problems with safe, efficient myocardial delivery, whereby direct injection in the infarct and remote tissue areas is not clinically feasible. Here, we aim to: (1) Improve direct cardiac gene delivery through the development of a novel liquid jet device approach (2) Compare the new method against traditional IM injection with two different vector constructions and evaluate outcome (3) Evaluate the host response resulting from both modes of direct cardiac injection, then advance a drug/gene combination with controlled release nanoparticle formulations.

Interprofessional Clinical Rounding: Effects on Processes and Outcomes of Care.

PubMed

Ashcraft, Susan; Bordelon, Curry; Fells, Sheila; George, Vera; Thombley, Karen; Shirey, Maria R

Communication breakdown is viewed as a significant contributor to preventable patient harm. Interprofessional rounding (IPR) is one method of communication supporting the evidenced-based care delivery. The purpose of this paper is to explore the benefits of IPR for patients, clinicians, and the healthcare system. Interprofessional rounding supports collaboration, discussion, and timely intervention to prevent miscommunication leading to adverse patient events. Adherence to evidence-based care suggests a positive impact on patient, process, and financial outcomes. Statistically significant IPR-related improvements are seen in reducing mortality, lengths of stay, medication errors, and hospitalization costs as well as improved staff and patient satisfaction. One IPR-related gap in the literature is integrative care delivery, a strategy that provides a unified plan to meet the complex needs of patients and produce optimal outcomes. Activation and standardization with active participation in IPR support a collaborative integration of care. Embracing IPR and advocating for collaboration across the care continuum is a crucial process in preventing adverse events. Integrated care delivery through IPR provides a unified plan to meet the complex needs of patients, prevent harm, and produce best possible outcomes.

Fundamentals of pulmonary drug delivery.

PubMed

Groneberg, D A; Witt, C; Wagner, U; Chung, K F; Fischer, A

2003-04-01

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Based on the growing knowledge on pulmonary cell biology and pathophysiology due to modern methods of molecular biology, the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.

A laser syringe aimed at delivering drug into the outer layer of human skin

NASA Astrophysics Data System (ADS)

Yoh, Jack J.; Jang, Hun-jae; Park, Mi-ae; Han, Tae-hee; Hah, Jung-moo

2012-07-01

A desire to eliminate hypodermic needle in transdermal drug delivery may now be realized. Imaging of the skin after injection of fluorescent probe and biotin via the bio-ballistic technique revealed the epidermal and dermal layers which were stained well below 60 μm underneath the abdominal skin of the guinea-pig. An extensive network of cells are shown in the deeper layer of the stained dermis as the distributed fluorescein isothiocyanate (FITC) dose is administered by repeated injection via the laser-based microjet. Here, we show our method of laser-based microjet drug delivery is capable of breaching guinea-pig's skin tissue and then delivering controlled dose of drug to the targeted region between 10 to 400 μm underneath the outermost layer of the skin. While minimizing pain and tissue damage by reducing the injection volume to ˜100 nl per pulse and the microjet diameter of half the conventional syringe needle in 100 μm, the optimally controlled delivery of liquid drug by the irradiated laser pulse is shown possible.

Self-nanoemulsifying performance of two grades of Lauroglycol (Lauroglycol-90 and Lauroglycol-FCC) in the presence of mixed nonionic surfactants.

PubMed

Shakeel, Faiyaz; Haq, Nazrul; Alanazi, Fars K; Alsarra, Ibrahim A

2014-11-01

The present study was undertaken to evaluate the impact of various combinations of nonionic surfactants on self-nanoemulsifying performance of two grades of Lauroglycol (Lauroglycol-90 and Lauroglycol-FCC) in glibenclamide (GBN) nanoemulsion. Formulations (L1-L30) were prepared by spontaneous emulsification method. Prepared formulations were subjected to thermodynamic stability and self-nanoemulsification test. Results of thermodynamic stability and self-nanoemulsification tests were confirmed by further characterization of these formulations in terms of droplet size, viscosity, refractive index and % transmittance. Formulations prepared with Labrasol, HCO-60 and Gelucire-44/14 were found to be suitable for self-emulsifying drug delivery system only whereas those prepared with Tween-80 and Cremophor-EL were found to be suitable for self-nanoemulsifying or self-microemulsifying drug delivery system of GBN with respect to Lauroglycol-90 or Lauroglycol-FCC. Formulation L24 (Lauroglycol-FCC/Tween-80/ethanol/water) was optimized as best formulation for self-nanoemulsifying drug delivery system of GBN. These results indicated that Tween-80 could be the best surfactant in terms of self-nanoemulsification.

Bespoke program design for school-aged therapy disability service delivery.

PubMed

Weatherill, Pamela; Bahn, Susanne; Cooper, Trudi

2012-01-01

This article uses the evaluation of a school-aged therapy service for children with disabilities in Western Australia to investigate models of service delivery. The current literature on family-centered practice, multidisciplinary and transdisciplinary approaches, and 4 models of service are reviewed. The models include the life needs model, the relational goal-orientated model of optimal service delivery to children and families, the quality of life model, and the collaborative model of service delivery. Analysis of the data is presented together with a bespoke model of service delivery for children with disabilities, arguing that local contexts benefit from custom-made service design.

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment.

PubMed

Yang, Yinxian; Gao, Hailing; Zhou, Shuang; Kuang, Xiao; Wang, Zhenjie; Liu, Hongzhuo; Sun, Jin

2018-05-10

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that C max of artemether and lumefantrine for the optimized lipid emulsions were significantly increased than the injectable solution, which was critical for rapid antimalarial activity. Furthermore, the AUC 0-t of artemether and lumefantrine in the lipid emulsion group were 5.01- and 1.39-fold of those from the solution, respectively, suggesting enhanced bioavailability. With these findings, the developed lipid emulsion is a promising alternative parenteral therapy for the malaria treatment, especially for severe or complicated malaria.

Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning

PubMed Central

Liu, Shi; Wu, Yu; Wooten, H. Omar; Green, Olga; Archer, Brent; Li, Harold

2016-01-01

A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image‐guided radiation therapy (MR‐IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam‐on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam‐on time can be calculated using both the planned beam‐on time and the decay‐corrected dose rate. To predict the remain‐ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22 min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of the proposed prediction algorithm is sufficient to support patient treatment appointment scheduling. This developed software tool is currently applied in use on a daily basis in our clinic, and could also be used as an important indicator for treatment plan complexity. PACS number(s): 87.55.N PMID:27074472

Plan averaging for multicriteria navigation of sliding window IMRT and VMAT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craft, David, E-mail: dcraft@partners.org; Papp, Dávid; Unkelbach, Jan

2014-02-15

Purpose: To describe a method for combining sliding window plans [intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT)] for use in treatment plan averaging, which is needed for Pareto surface navigation based multicriteria treatment planning. Methods: The authors show that by taking an appropriately defined average of leaf trajectories of sliding window plans, the authors obtain a sliding window plan whose fluence map is the exact average of the fluence maps corresponding to the initial plans. In the case of static-beam IMRT, this also implies that the dose distribution of the averaged plan is the exact dosimetricmore » average of the initial plans. In VMAT delivery, the dose distribution of the averaged plan is a close approximation of the dosimetric average of the initial plans. Results: The authors demonstrate the method on three Pareto optimal VMAT plans created for a demanding paraspinal case, where the tumor surrounds the spinal cord. The results show that the leaf averaged plans yield dose distributions that approximate the dosimetric averages of the precomputed Pareto optimal plans well. Conclusions: The proposed method enables the navigation of deliverable Pareto optimal plans directly, i.e., interactive multicriteria exploration of deliverable sliding window IMRT and VMAT plans, eliminating the need for a sequencing step after navigation and hence the dose degradation that is caused by such a sequencing step.« less

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design.

PubMed

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X(1)), surfactant (X(2)), and drug/lipid ratio (X(3)) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was -8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas-Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release.

NHF-McMaster Guideline on Care Models for Haemophilia Management.

PubMed

Pai, M; Key, N S; Skinner, M; Curtis, R; Feinstein, M; Kessler, C; Lane, S J; Makris, M; Riker, E; Santesso, N; Soucie, J M; Yeung, C H T; Iorio, A; Schünemann, H J

2016-07-01

This guideline was developed to identify evidence-based best practices in haemophilia care delivery, and discuss the range of care providers and services that are most important to optimize outcomes for persons with haemophilia (PWH) across the United States. The guideline was developed following specific methods described in detail in this supplement and based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation approach). Direct evidence from published literature and the haemophilia community, as well as indirect evidence from other chronic diseases, were reviewed, synthesized and applied to create evidence-based recommendations. The Guideline panel suggests that the integrated care model be used over non-integrated care models for PWH (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence. The panel suggests that a haematologist, a specialized haemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over an integrated care team that does not include all of these components (conditional recommendation, very low certainty in the evidence). Based on available evidence, the integrated model of care in its current structure, is suggested for optimal care of PWH. There is a need for further appropriately designed studies that address unanswered questions about specific outcomes and the optimal structure of the integrated care delivery model in haemophilia. © 2016 John Wiley & Sons Ltd.

"Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route* ".

PubMed

Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

2016-08-01

The objective of the present investigation was to optimize and develop quetiapine fumarate (QF) loaded chitosan nanoparticles (QF-NP) by ionic gelation method using Box-Behnken design. Three independent variables viz., X1-Concentration of chitosan, X2-Concentration of sodium tripolyphosphate and X3-Volume of sodium tripolyphosphate were taken to investigate their effect on dependent variables (Y1-Size, Y2-PDI and Y3-%EE). Optimized formula of QF-NP was selected from the design space which was further evaluated for physicochemical, morphological, solid state characterization, nasal diffusion and in-vivo distribution for brain targeting following non-invasive intranasal administration. The average particle size, PDI, %EE and nasal diffusion were found to be 131.08±7.45nm, 0.252±0.064, 89.93±3.85% and 65.24±5.26% respectively. Neither toxicity nor structural damage on nasal mucosa was observed upon histopathological examination. Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in brain with QF-NP in comparison to drug solution following intranasal administration revealed preferential nose to brain transport bypassing blood-brain barrier and prolonged retention of QF at site of action suggesting superiority of chitosan as permeability enhancer. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design

PubMed Central

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X1), surfactant (X2), and drug/lipid ratio (X3) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was −8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas–Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release. PMID:21556343

From Data to Improved Decisions: Operations Research in Healthcare Delivery.

PubMed

Capan, Muge; Khojandi, Anahita; Denton, Brian T; Williams, Kimberly D; Ayer, Turgay; Chhatwal, Jagpreet; Kurt, Murat; Lobo, Jennifer Mason; Roberts, Mark S; Zaric, Greg; Zhang, Shengfan; Schwartz, J Sanford

2017-11-01

The Operations Research Interest Group (ORIG) within the Society of Medical Decision Making (SMDM) is a multidisciplinary interest group of professionals that specializes in taking an analytical approach to medical decision making and healthcare delivery. ORIG is interested in leveraging mathematical methods associated with the field of Operations Research (OR) to obtain data-driven solutions to complex healthcare problems and encourage collaborations across disciplines. This paper introduces OR for the non-expert and draws attention to opportunities where OR can be utilized to facilitate solutions to healthcare problems. Decision making is the process of choosing between possible solutions to a problem with respect to certain metrics. OR concepts can help systematically improve decision making through efficient modeling techniques while accounting for relevant constraints. Depending on the problem, methods that are part of OR (e.g., linear programming, Markov Decision Processes) or methods that are derived from related fields (e.g., regression from statistics) can be incorporated into the solution approach. This paper highlights the characteristics of different OR methods that have been applied to healthcare decision making and provides examples of emerging research opportunities. We illustrate OR applications in healthcare using previous studies, including diagnosis and treatment of diseases, organ transplants, and patient flow decisions. Further, we provide a selection of emerging areas for utilizing OR. There is a timely need to inform practitioners and policy makers of the benefits of using OR techniques in solving healthcare problems. OR methods can support the development of sustainable long-term solutions across disease management, service delivery, and health policies by optimizing the performance of system elements and analyzing their interaction while considering relevant constraints.

Comparative evaluation of gene delivery devices in primary cultures of rat hepatic stellate cells and rat myofibroblasts

PubMed Central

Weiskirchen, Ralf; Kneifel, Jens; Weiskirchen, Sabine; van de Leur, Eddy; Kunz, Dagmar; Gressner, Axel M

2000-01-01

Background The hepatic stellate cell is the primary cell type responsible for the excessive formation and deposition of connective tissue elements during the development of hepatic fibrosis in chronically injured liver. Culturing quiescent hepatic stellate cells on plastic causes spontaneous activation leading to a myofibroblastic phenotype similar to that seen in vivo. This provides a simple model system for studying activation and transdifferentiation of these cells. The introduction of exogenous DNA into these cells is discussed controversially mainly due to the lack of systematic analysis. Therefore, we examined comparatively five nonviral, lipid-mediated gene transfer methods and adenoviral based infection, as potential tools for efficient delivery of DNA to rat hepatic stellate cells and their transdifferentiated counterpart, i.e. myofibroblasts. Transfection conditions were determined using enhanced green fluorescent protein as a reporter expressed under the transcriptional control of the human cytomegalovirus immediate early gene 1 promoter/enhancer. Results With the use of chemically enhanced transfection methods, the highest relative efficiency was obtained with FuGENE™6 gene mediated DNA transfer. Quantitative evaluation of representative transfection experiments by flow cytometry revealed that approximately 6% of the rat hepatic stellate cells were transfected. None of the transfection methods tested was able to mediate gene delivery to rat myofibroblasts. To analyze if rat hepatic stellate cells and myofibroblasts are susceptible to adenoviral infection, we have inserted the transgenic expression cassette into a recombinant adenoviral type 5 genome as replacement for the E1 region. Viral particles of this replication-deficient Ad5-based reporter are able to infect 100% of rat hepatic stellate cells and myofibroblasts, respectively. Conclusions Our results indicate that FuGENE™6-based methods may be optimized sufficiently to offer a feasible approach for gene transfer into rat hepatic stellate cells. The data further demonstrate that adenoviral mediated transfer is a promising approach for gene delivery to these hepatic cells. PMID:11178102

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

PubMed Central

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID:23635256

SU-E-T-586: Optimal Determination of Tolerance Level for Radiation Dose Delivery Verification in An in Vivo Dosimetry System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Y; Souri, S; Gill, G

Purpose: To statistically determine the optimal tolerance level in the verification of delivery dose compared to the planned dose in an in vivo dosimetry system in radiotherapy. Methods: The LANDAUER MicroSTARii dosimetry system with screened nanoDots (optically stimulated luminescence dosimeters) was used for in vivo dose measurements. Ideally, the measured dose should match with the planned dose and falls within a normal distribution. Any deviation from the normal distribution may be redeemed as a mismatch, therefore a potential sign of the dose misadministration. Randomly mis-positioned nanoDots can yield a continuum background distribution. A percentage difference of the measured dose tomore » its corresponding planned dose (ΔD) can be used to analyze combined data sets for different patients. A model of a Gaussian plus a flat function was used to fit the ΔD distribution. Results: Total 434 nanoDot measurements for breast cancer patients were collected across a period of three months. The fit yields a Gaussian mean of 2.9% and a standard deviation (SD) of 5.3%. The observed shift of the mean from zero is attributed to the machine output bias and calibration of the dosimetry system. A pass interval of −2SD to +2SD was applied and a mismatch background was estimated to be 4.8%. With such a tolerance level, one can expect that 99.99% of patients should pass the verification and at most 0.011% might have a potential dose misadministration that may not be detected after 3 times of repeated measurements. After implementation, a number of new start breast cancer patients were monitored and the measured pass rate is consistent with the model prediction. Conclusion: It is feasible to implement an optimal tolerance level in order to maintain a low limit of potential dose misadministration while still to keep a relatively high pass rate in radiotherapy delivery verification.« less

Design Expert® supported optimization and predictive analysis of selegiline nanoemulsion via the olfactory region with enhanced behavioural performance in Parkinson’s disease

NASA Astrophysics Data System (ADS)

Kumar, Shobhit; Ali, Javed; Baboota, Sanjula

2016-10-01

Selegiline is a monoamine oxidase B (MAO-B) inhibitor and is used in the treatment of Parkinson’s disease. The main problem associated with its oral administration is its low oral bioavailability (10%) due to its poor aqueous solubility and extensive first pass metabolism. The aim of the present research work was to develop a nanoemulsion loaded with selegiline for direct nose-to-brain delivery for the better management of Parkinson’s disease. A quality by design (QbD) approach was used in a statistical multivariate method for the preparation and optimization of nanoemulsion. In this study, four independent variables were chosen, in which two were compositions and two were process variables, while droplet size, transmittance, zeta potential and drug release were selected as response variables. The optimized formulation was assessed for efficacy in Parkinson’s disease using behavioural studies, namely forced swimming, locomotor, catalepsy, muscle coordination, akinesia and bradykinesia or pole test in Wistar rats. The observed droplet size, polydispersity index (PDI), refractive index, transmittance, zeta potential and viscosity of selegiline nanoemulsion were found to be 61.43 ± 4.10 nm, 0.203 ± 0.005, 1.30 ± 0.01, 99.80 ± 0.04%, -34 mV and 31.85 ± 0.24 mPas respectively. Surface characterization studies demonstrated a spherical shape of nanoemulsion which showed 3.7 times enhancement in drug permeation as compared to drug suspension. The results of behaviour studies showed that treatment of haloperidol induced Parkinson’s disease in rats with selegiline nanoemulsion (administered intranasally) showed significant improvement in behavioural activities in comparison to orally administered drug. These findings demonstrate that nanoemulsion could be a promising new drug delivery carrier for intranasal delivery of selegiline in the treatment of Parkinson’s disease.

Acoustically-Responsive Scaffolds: Control of Growth Factor Release for Tissue Regeneration Using Ultrasound

NASA Astrophysics Data System (ADS)

Moncion, Alexander

Administration of exogenous growth factors (GFs) is a proposed method of stimulating tissue regeneration. Conventional administration routes, such as at-site or systemic injections, have yielded problems with efficacy and/or safety, thus hindering the translation of GF-based regenerative techniques. Hydrogel scaffolds are commonly used as biocompatible delivery vehicles for GFs. Yet hydrogels do not afford spatial or temporal control of GF release - two critical parameters for tissue regeneration. Controlled delivery of GFs is critical for angiogenesis, which is a crucial process in tissue engineering that provides oxygen and nutrients to cells within an implanted hydrogel scaffold. Angiogenesis requires multiple GFs that are presented with distinct spatial and temporal profiles. Thus, controlled release of GFs with spatiotemporal modulation would significantly improve tissue regeneration by recapitulating endogenous GF presentation. In order to achieve this goal, we have developed acoustically-responsive scaffolds (ARSs), which are fibrin hydrogels doped with sonosensitive perfluorocarbon (PFC) emulsions capable of encapsulating various payloads. Focused, mega-Hertz range, ultrasound (US) can modulate the release of a payload non-invasively and in an on-demand manner from ARSs via physical mechanisms termed acoustic droplet vaporization (ADV) and inertial cavitation (IC). This work presents the relationship between the ADV/IC thresholds and various US and hydrogel parameters. These physical mechanisms were used for the controlled release of fluorescent dextran in vitro and in vivo to determine the ARS and US parameters that yielded optimal payload release. The optimal ARS and US parameters were used to demonstrate the controlled release of basic fibroblast growth factor from an in vivo subcutaneous implant model - leading to enhanced angiogenesis and perfusion. Additionally, different acoustic parameters and PFCs were tested and optimized to demonstrate the controlled release of two encapsulated payloads within an ARS. Overall, ARSs are a promising platform for GF delivery in tissue regeneration applications.

Optimization of Time Controlled 6-mercaptopurine Delivery for Site- Specific Targeting to Colon Diseases.

PubMed

Hude, Rahul U; Jagdale, Swati C

2016-01-01

6-MP has short elimination time (<2 h) and low bioavailability (~ 50%). Present study was aimed to develop time controlled and site targeted delivery of 6-Mercaptopurine (6-MP) for treatment of colon diseases. Compression coating technique was used. 32 full factorial design was designed for optimization of the outer coat for the core tablet. For outer coat amount of Eudragit RS 100 and hydroxypropyl methylcellulose (HPMC K100) were employed as independent variables each at three levels while responses evaluated were swelling index and bursting time. Direct compression method was used for tablets formulation. 80% w/w of microcrystalline cellulose and 20% w/w of croscarmellose sodium were found to be optimum concentration for the core tablet. The outer coat of optimized batch (ED) contains 21.05% w/w Eudragit RS 100 and 78.95% w/w HPMC K100 of total polymer weight. In-vitro dissolution study indicated that combination of polymer retards the drug release in gastric region and releases ≥95% of drug in colonic region after ≥7 h. Whereas in case of in-vivo placebo x-ray imaging study had shown that the tablet reaches colonic part after 5±0.5 h providing the proof of arrival in the colon. Stability study indicated that the optimized formulation were physically and chemically stable. Present research work concluded that compression coating by Eudragit RS 100 and HPMC K100 to 6-MP core provides potential colon targeted system with advantages of reduced gastric exposure and enhanced bioavailability. Formulation can be considered as potential and promising candidate for the treatment of colon diseases.

Optimization of multi-epitopic HIV-1 recombinant protein expression in prokaryote system and conjugation to mouse DEC-205 monoclonal antibody: implication for in-vivo targeted delivery of dendritic cells

PubMed Central

Rahimi, Roghayeh; Ebtekar, Massoumeh; Moazzeni, Seyed Mohammad; Mostafaie, Ali; Mahdavi, Mehdi

2015-01-01

Objective(s): Multi-epitopic protein vaccines and direction of vaccine delivery to dendritic cells (DCs) are promising approaches for enhancing immune responses against mutable pathogens. Escherichia coli is current host for expression of recombinant proteins, and it is important to optimize expression condition. The aim of this study was the optimization of multi-epitopic HIV-1 tat/pol/gag/env recombinant protein (HIVtop4) expression by E. coli and conjugation of purified protein to anti DEC-205 monoclonal antibody as candidate vaccine. Materials and Methods: In this study, expression was induced in BL21 (DE3) E. coli cells by optimization of induction condition, post induction incubation time, temperature and culture medium formula. Some culture mediums were used for cell culture, and isopropyl-beta-D-thiogalactopyranoside was used for induction of expression. Protein was purified by Ni-NTA column chromatography and confirmed against anti-His antibody in western-blotting. To exploit DCs properties for immunization purposes, recombinant protein chemically coupled to αDEC-205 monoclonal antibody and confirmed against anti-His antibody in western-blotting. Results: The optimum condition for expression was 1 mM IPTG during 4 hr cultures in 2XYT medium, and final protein produced in soluble form. Conjugation of purified protein to αDEC-205 antibody resulted in smears of protein: antibodies conjugate in different molecular weights. Conclusion: The best cultivation condition for production of HIVtop4 protein is induction by 1 mM IPTG during 4 hr in 2XYT medium. The final concentration of purified protein was 500 µg/ml. PMID:25810888

High throughput RNAi assay optimization using adherent cell cytometry.

PubMed

Nabzdyk, Christoph S; Chun, Maggie; Pradhan, Leena; Logerfo, Frank W

2011-04-25

siRNA technology is a promising tool for gene therapy of vascular disease. Due to the multitude of reagents and cell types, RNAi experiment optimization can be time-consuming. In this study adherent cell cytometry was used to rapidly optimize siRNA transfection in human aortic vascular smooth muscle cells (AoSMC). AoSMC were seeded at a density of 3000-8000 cells/well of a 96 well plate. 24 hours later AoSMC were transfected with either non-targeting unlabeled siRNA (50 nM), or non-targeting labeled siRNA, siGLO Red (5 or 50 nM) using no transfection reagent, HiPerfect or Lipofectamine RNAiMax. For counting cells, Hoechst nuclei stain or Cell Tracker green were used. For data analysis an adherent cell cytometer, Celigo® was used. Data was normalized to the transfection reagent alone group and expressed as red pixel count/cell. After 24 hours, none of the transfection conditions led to cell loss. Red fluorescence counts were normalized to the AoSMC count. RNAiMax was more potent compared to HiPerfect or no transfection reagent at 5 nM siGLO Red (4.12 +/-1.04 vs. 0.70 +/-0.26 vs. 0.15 +/-0.13 red pixel/cell) and 50 nM siGLO Red (6.49 +/-1.81 vs. 2.52 +/-0.67 vs. 0.34 +/-0.19). Fluorescence expression results supported gene knockdown achieved by using MARCKS targeting siRNA in AoSMCs. This study underscores that RNAi delivery depends heavily on the choice of delivery method. Adherent cell cytometry can be used as a high throughput-screening tool for the optimization of RNAi assays. This technology can accelerate in vitro cell assays and thus save costs.

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies

PubMed Central

Wang, Zheng; Mu, Hong-Jie; Zhang, Xue-Mei; Ma, Peng-Kai; Lian, Sheng-Nan; Zhang, Feng-Pu; Chu, Sheng-Ying; Zhang, Wen-Wen; Wang, Ai-Ping; Wang, Wen-Yan; Sun, Kao-Xiang

2015-01-01

Background Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). Purpose The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. Methods Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. Results The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil®, 13.44% Cremophor® RH40, 6.72% Labrasol®, and 5.04% Transcutol® HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro®). The microemulsion gel irritated the skin less than Neupro. Conclusion A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability. PMID:25609965

[Clinical analysis of prenatal diagnosis and intervention for primary pleural effusion of 13 cases].

PubMed

Wang, X Q; Li, W J; Yan, R L; Xiang, J W; Liu, M Y

2018-02-25

Objective: To optimize the clinical managements of primary fetal hydrothorax (PFHT) fetus by comparing the perinatal survival rate of different prenatal treatments. Methods: Totally 13 fetuses diagnosed with PFHT from July 2009 to December 2015 in the First Affiliated Hospital of Jinan University were collected and received prenatal expectant treatment, thoracocentesis (TC), and thoraco-amniotic shunting (TAS), respectively. The perinatal survival rate was compared among the three treatments. Results: Among 13 fetuses of PFHT, pleural effusion was absorbed or remained stable in 2(2/13) cases, and progressed in 11(11/13) cases. Six cases received expectant treatment (2 cases had termination of pregnancy due to progressing effusion, 2 cases had term delivery, and 2 cases had intrauterine death); the perinatal survival rate was 2/6. Six cases received TC (2 cases had term delivery, 2 cases had preterm delivery, and 2 cases had termination of pregnancy due to progressing effusion), the perinatal survival rate was 4/6. One case received TC+TAS (term delivery), the perinatal survival rate was 1/1. The overall perinatal survival rate of prenatal intrauterine intervention was 5/7. Conclusions: The clinical process of PFHT is changeable, and the pleural effusion will progress with gestational age. Intrauterine interventions could improve the perinatal survival rate.

Application of modelling and nanotechnology-based approaches: The emergence of breakthroughs in theranostics of central nervous system disorders.

PubMed

Hassanzadeh, Parichehr; Atyabi, Fatemeh; Dinarvand, Rassoul

2017-08-01

The limited efficiency of the current treatment options against the central nervous system (CNS) disorders has created increasing demands towards the development of novel theranostic strategies. The enormous research efforts in nanotechnology have led to the production of highly-advanced nanodevices and biomaterials in a variety of geometries and configurations for targeted delivery of genes, drugs, or growth factors across the blood-brain barrier. Meanwhile, the richness or reliability of data, drug delivery methods, therapeutic effects or potential toxicity of nanoparticles, occurrence of the unexpected phenomena due to the polydisperse or polymorphic nature of nanomaterials, and personalized theranostics have remained as challenging issues. In this respect, computational modelling has emerged as a powerful tool for rational design of nanoparticles with optimized characteristics including the selectivity, improved bioactivity, and reduced toxicity that might lead to the effective delivery of therapeutic agents. High-performance simulation techniques by shedding more light on the dynamical behaviour of neural networks and pathomechanisms of CNS disorders may provide imminent breakthroughs in nanomedicine. In the present review, the importance of integration of nanotechnology-based approaches with computational techniques for targeted delivery of theranostics to the CNS has been highlighted. Copyright © 2017. Published by Elsevier Inc.

Delivering the Goods for Genome Engineering and Editing.

PubMed

Skipper, Kristian Alsbjerg; Mikkelsen, Jacob Giehm

2015-08-01

A basic understanding of genome evolution and the life and impact of microorganisms, like viruses and bacteria, has been fundamental in the quest for efficient genetic therapies. The expanding tool box for genetic engineering now contains transposases, recombinases, and nucleases, all created from naturally occurring genome-modifying proteins. Whereas conventional gene therapies have sought to establish sustained expression of therapeutic genes, genomic tools are needed only in a short time window and should be delivered to cells ideally in a balanced "hit-and-run" fashion. Current state-of-the-art delivery strategies are based on intracellular production of protein from transfected plasmid DNA or in vitro-transcribed RNA, or from transduced viral templates. Here, we discuss advantages and challenges of intracellular production strategies and describe emerging approaches based on the direct delivery of protein either by transfer of recombinant protein or by lentiviral protein transduction. With focus on adapting viruses for protein delivery, we describe the concept of "all-in-one" lentiviral particles engineered to codeliver effector proteins and donor sequences for DNA transposition or homologous recombination. With optimized delivery methods-based on transferring DNA, RNA, or protein-it is no longer far-fetched that researchers in the field will indeed deliver the goods for somatic gene therapies.

Amiloride-enhanced gene transfection of octa-arginine functionalized calcium phosphate nanoparticles.

PubMed

Vanegas Sáenz, Juan Ramón; Tenkumo, Taichi; Kamano, Yuya; Egusa, Hiroshi; Sasaki, Keiichi

2017-01-01

Nanoparticles represent promising gene delivery systems in biomedicine to facilitate prolonged gene expression with low toxicity compared to viral vectors. Specifically, nanoparticles of calcium phosphate (nCaP), the main inorganic component of human bone, exhibit high biocompatibility and good biodegradability and have been reported to have high affinity for protein or DNA, having thus been used as gene transfer vectors. On the other hand, Octa-arginine (R8), which has a high permeability to cell membrane, has been reported to improve intracellular delivery systems. Here, we present an optimized method for nCaP-mediated gene delivery using an octa-arginine (R8)-functionalized nCaP vector containing a marker or functional gene construct. nCaP particle size was between 220-580 nm in diameter and all R8-functionalized nCaPs carried a positive charge. R8 concentration significantly improved nCaP transfection efficiency with high cell compatibility in human mesenchymal stem cells (hMSC) and human osteoblasts (hOB) in particular, suggesting nCaPs as a good option for non-viral vector gene delivery. Furthermore, pre-treatment with different endocytosis inhibitors identified that the endocytic pathway differed among cell lines and functionalized nanoparticles, with amiloride increasing transfection efficiency of R8-functionalized nCaPs in hMSC and hOB.

SU-F-T-391: Comparative Study of Treatment Planning Between IMRT and IMAT for Malignant Pleural Mesothelioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, J

Purpose: The purpose of this study was to compare the dosimetric differences between intensitymodulated radiation therapy (IMRT) and intensity modulated arc therapy (IMAT) for malignant pleural mesothelioma (MPM) patients with regard to the sparing effect on organs at risk (OARs), plan quality, and delivery efficiency. Methods: Ten MPM patients were recruited in this study. To avoid the inter-operator variability, IMRT and IMAT plans for each patient were performed by one experienced dosimetrist. The treatment planning optimization process was carried out using the Eclipse 13.0 software. For a fair comparison, the planning target volume (PTV) coverage of the two plans wasmore » normalized to the same level. The treatment plans were evaluated on the following dosimetric variables: conformity index (CI) and homogeneity index (HI) for PTV, OARs dose, and the delivery efficiency for each plan. Results: All plans satisfied clinical requirements. The IMAT plans gained better CI and HI. The IMRT plans performed better sparing for heart and lung. Less MUs and control points were found in the IMAT plans. IMAT shortened delivery time compared with IMRT. Conclusion: For MPM, IMAT gains better conformity and homogeneity for PTV with IMRT, but increases the irradiation dose for OARs. IMAT shows an advantage in delivery efficiency.« less

Synthesis and characterization of pH-responsive nanoscale hydrogels for oral delivery of hydrophobic therapeutics.

PubMed

Puranik, Amey S; Pao, Ludovic P; White, Vanessa M; Peppas, Nicholas A

2016-11-01

pH-responsive, polyanionic nanoscale hydrogels were developed for the oral delivery of hydrophobic therapeutics, such as common chemotherapeutic agents. Nanoscale hydrogels were designed to overcome physicochemical and biological barriers associated with oral delivery of hydrophobic therapeutics such as low solubility and poor permeability due to P-glycoprotein related drug efflux. Synthesis of these nanoscale materials was achieved by a robust photoemulsion polymerization method. By varying hydrophobic monomer components, four formulations were synthesized and screened for optimal physicochemical properties and in vitro biocompatibility. All of the responsive nanoscale hydrogels were capable of undergoing a pH-dependent transition in size. Depending on the selection of the hydrophobic monomer, the sizes of the nanoparticles vary widely from 120nm to about 500nm at pH 7.4. Polymer composition was verified using Fourier transform infrared spectroscopy and 1 H-nuclear magnetic resonance spectroscopy. Polymer biocompatibility was assessed in vitro with an intestinal epithelial cell model. All formulations were found to have no appreciable cytotoxicity, defined as greater than 80% viability after polymer incubation. We demonstrate that these nanoscale hydrogels possess desirable physicochemical properties and exhibit agreeable in vitro biocompatibility for oral delivery applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Noninvasive imaging of cationic lipid-mediated delivery of optical and PET reporter genes in living mice.

PubMed

Iyer, Meera; Berenji, Manijeh; Templeton, Nancy S; Gambhir, Sanjiv S

2002-10-01

Gene therapy involves the safe and effective delivery of one or more genes of interest to target cells in vivo. The advantages of using nonviral delivery systems include ease of preparation, low toxicity, and weak immunogenicity. Nonviral delivery methods, when combined with a noninvasive, clinically applicable imaging assay, will greatly aid in the optimization of gene therapy approaches for cancer. We demonstrate cationic lipid-mediated noninvasive monitoring of reporter gene expression of firefly (Photinus pyralis) luciferase (fl) and a mutant herpes simplex virus type I thymidine kinase (HSV1-sr39tk, tk) in living mice using a cooled charge coupled device (CCD) camera and positron emission tomography (PET), respectively. We observe a high level of fl and tk reporter gene expression predominantly in the lungs after a single injection of the extruded DOTAP:cholesterol DNA liposome complexes by way of the tail vein, seen to be time- and dose-dependent. We observe a good correlation between the in vivo bioluminescent signal and the ex vivo firefly luciferase enzyme (FL) activity in different organs. We further demonstrate the feasibility of noninvasively imaging both optical and PET reporter gene expression in the same animal using the CCD camera and microPET, respectively.

Design of a nanoplatform for treating pancreatic cancer

NASA Astrophysics Data System (ADS)

Manawadu, Harshi Chathurangi

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. Asymptomatic early cancer stages and late diagnosis leads to very low survival rates of pancreatic cancers, compared to other cancers. Treatment options for advanced pancreatic cancer are limited to chemotherapy and/or radiation therapy, as surgical removal of the cancerous tissue becomes impossible at later stages. Therefore, there's a critical need for innovative and improved chemotherapeutic treatment of (late) pancreatic cancers. It is mandatory for successful treatment strategies to overcome the drug resistance associated with pancreatic cancers. Nanotechnology based drug formulations have been providing promising alternatives in cancer treatment due to their selective targeting and accumulation in tumor vasculature, which can be used for efficient delivery of chemotherapeutic agents to tumors and metastases. The research of my thesis is following the principle approach to high therapeutic efficacy that has been first described by Dr. Helmut Ringsdorf in 1975. However, I have extended the use of the Ringsdorf model from polymeric to nanoparticle-based drug carriers by exploring an iron / iron oxide nanoparticle based drug delivery system. A series of drug delivery systems have been synthesized by varying the total numbers and the ratio of the tumor homing peptide sequence CGKRK and the chemotherapeutic drug doxorubicin at the surfaces of Fe/Fe3O 4-nanoparticles. The cytotoxicity of these nanoformulations was tested against murine pancreatic cancer cell lines (Pan02) to assess their therapeutic capabilities for effective treatments of pancreatic cancers. Healthy mouse fibroblast cells (STO) were also tested for comparison, because an effective chemotherapeutic drug has to be selective towards cancer cells. Optimal Experimental Design methodology was applied to identify the nanoformulation with the highest therapeutic activity. A statistical analysis method known as response surface methodology was carried out to evaluate the in-vitro cytotoxicity data, and to determine whether the chosen experimental parameters truly express the optimized conditions of the nanoparticle based drug delivery system. The overall goal was to optimize the therapeutic efficacy in nanoparticle-based pancreatic cancer treatment. Based on the statistical data, the most effective iron/iron oxide nanoparticle-based drug delivery system has been identified. Its Fe/Fe3O4 core has a diameter of 20 nm. The surface of this nanoparticle is loaded with the homing sequence CGKRK (139-142 peptide molecules per nanoparticle surface) and the chemotherapeutic agent doxorubicin (156-159 molecules per surface), This nanoplatform is a promising candidate for the nanoparticle-based chemotherapy of pancreatic cancer.

SU-G-BRC-16: Theory and Clinical Implications of the Constant Dosimetric Leaf Gap (DLG) Approximation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumaraswamy, L; Xu, Z; Podgorsak, M

Purpose: Commercial dose calculation algorithms incorporate a single DLG value for a given beam energy that is applied across an entire treatment field. However, the physical processes associated with beam generation and dose delivery suggest that the DLG is not constant. The aim of this study is to evaluate the variation of DLG among all leaf pairs, to quantify how this variation impacts delivered dose, and to establish a novel method to correct dose distributions calculated using the approximation of constant DLG. Methods: A 2D diode array was used to measure the DLG for all 60 leaf pairs at severalmore » points along each leaf pair travel direction. This approach was validated by comparison to DLG values measured at select points using a 0.6 cc ion chamber with the standard formalism. In-house software was developed to enable incorporation of position dependent DLG values into dose distribution optimization and calculation. The accuracy of beam delivery of both the corrected and uncorrected treatment plans was studied through gamma pass rate evaluation. A comparison of DVH statistics in corrected and uncorrected treatment plans was made. Results: The outer 20 MLC leaf pairs (1.0 cm width) have DLG values that are 0.32 mm (mean) to 0.65 mm (maximum) lower than the central leaf-pair. VMAT plans using a large number of 1 cm wide leaves were more accurately delivered (gamma pass rate increased by 5%) and dose coverage was higher (D100 increased by 3%) when the 2D DLG was modeled. Conclusion: Using a constant DLG value for a given beam energy will result in dose optimization, dose calculation and treatment delivery inaccuracies that become significant for treatment plans with high modulation complexity scores delivered with 1 cm wide leaves.« less

TU-C-BRE-11: 3D EPID-Based in Vivo Dosimetry: A Major Step Forward Towards Optimal Quality and Safety in Radiation Oncology Practice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mijnheer, B; Mans, A; Olaciregui-Ruiz, I

Purpose: To develop a 3D in vivo dosimetry method that is able to substitute pre-treatment verification in an efficient way, and to terminate treatment delivery if the online measured 3D dose distribution deviates too much from the predicted dose distribution. Methods: A back-projection algorithm has been further developed and implemented to enable automatic 3D in vivo dose verification of IMRT/VMAT treatments using a-Si EPIDs. New software tools were clinically introduced to allow automated image acquisition, to periodically inspect the record-and-verify database, and to automatically run the EPID dosimetry software. The comparison of the EPID-reconstructed and planned dose distribution is donemore » offline to raise automatically alerts and to schedule actions when deviations are detected. Furthermore, a software package for online dose reconstruction was also developed. The RMS of the difference between the cumulative planned and reconstructed 3D dose distributions was used for triggering a halt of a linac. Results: The implementation of fully automated 3D EPID-based in vivo dosimetry was able to replace pre-treatment verification for more than 90% of the patient treatments. The process has been fully automated and integrated in our clinical workflow where over 3,500 IMRT/VMAT treatments are verified each year. By optimizing the dose reconstruction algorithm and the I/O performance, the delivered 3D dose distribution is verified in less than 200 ms per portal image, which includes the comparison between the reconstructed and planned dose distribution. In this way it was possible to generate a trigger that can stop the irradiation at less than 20 cGy after introducing large delivery errors. Conclusion: The automatic offline solution facilitated the large scale clinical implementation of 3D EPID-based in vivo dose verification of IMRT/VMAT treatments; the online approach has been successfully tested for various severe delivery errors.« less

Children’s Oxygen Administration Strategies Trial (COAST):  A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia

PubMed Central

Maitland, Kathryn; Kiguli, Sarah; Opoka, Robert O.; Olupot-Olupot, Peter; Engoru, Charles; Njuguna, Patricia; Bandika, Victor; Mpoya, Ayub; Bush, Andrew; Williams, Thomas N.; Grieve, Richard; Sadique, Zia; Fraser, John; Harrison, David; Rowan, Kathy

2018-01-01

Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO 2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO 2 TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%. Clinical trial registration: ISRCTN15622505 Trial status: Recruiting PMID:29383331

Second trimester maternal urine for the diagnosis of trisomy 21 and prediction of poor pregnancy outcomes.

PubMed

Diaz, Sílvia O; Barros, António S; Goodfellow, Brian J; Duarte, Iola F; Galhano, Eulália; Pita, Cristina; Almeida, Maria do Céu; Carreira, Isabel M; Gil, Ana M

2013-06-07

Given the recognized lack of prenatal clinical methods for the early diagnosis of preterm delivery, intrauterine growth restriction, preeclampsia and gestational diabetes mellitus, and the continuing need for optimized diagnosis methods for specific chromosomal disorders (e.g., trisomy 21) and fetal malformations, this work sought specific metabolic signatures of these conditions in second trimester maternal urine, using (1)H Nuclear Magnetic Resonance ((1)H NMR) metabolomics. Several variable importance to the projection (VIP)- and b-coefficient-based variable selection methods were tested, both individually and through their intersection, and the resulting data sets were analyzed by partial least-squares discriminant analysis (PLS-DA) and submitted to Monte Carlo cross validation (MCCV) and permutation tests to evaluate model predictive power. The NMR data subsets produced significantly improved PLS-DA models for all conditions except for pre-premature rupture of membranes. Specific urinary metabolic signatures were unveiled for central nervous system malformations, trisomy 21, preterm delivery, gestational diabetes, intrauterine growth restriction and preeclampsia, and biochemical interpretations were proposed. This work demonstrated, for the first time, the value of maternal urine profiling as a complementary means of prenatal diagnostics and early prediction of several poor pregnancy outcomes.

One-Step Method to Prepare PLLA Porous Microspheres in a High-Voltage Electrostatic Anti-Solvent Process

PubMed Central

Wang, Ying; Zhu, Li-Hui; Chen, Ai-Zheng; Xu, Qiao; Hong, Yu-Juan; Wang, Shi-Bin

2016-01-01

A one-step method using a high-voltage electrostatic anti-solvent process was employed to fabricate poly-l-lactide (PLLA) porous microspheres (PMs). To address the simplification and control of the preparation process, a 24 full factorial experiment was performed to optimize the operating process and analyze the effect of the factors on the morphology and aerodynamic properties of the PLLA PMs, and various characterization tests were also performed. The resulting PLLA PMs exhibited an even and porous morphology with a density less than 0.4 g/cm3, a geometric mean diameter (Dg) of 10–30 μm, an aerodynamic diameter (Da) of 1–5 μm, a fine particle fraction (FPF) of 56.3%, and a porosity of 76.2%, meeting the requirements for pulmonary drug delivery. The physicochemical characterizations reveal that no significant chemical change occurred in the PLLA during the process. An investigation of its in vitro cytotoxicity and pulmonary toxicity shows no obvious toxic response, indicating good biosafety. This study indicates that the one-step method using a high-voltage electrostatic anti-solvent process has great potential in developing an inhalable drug carrier for pulmonary drug delivery. PMID:28773489

Severe asphyxia due to delivery-related malpractice in Sweden 1990–2005

PubMed Central

Berglund, S; Grunewald, C; Pettersson, H; Cnattingius, S

2008-01-01

Objective To describe possible causes of delivery-related severe asphyxia due to malpractice. Design and setting A nationwide descriptive study in Sweden. Population All women asking for financial compensation because of suspected medical malpractice in connection with childbirth during 1990–2005. Method We included infants with a gestational age of ≥33 completed gestational weeks, a planned vaginal onset of delivery, reactive cardiotocography at admission for labour and severe asphyxia-related outcomes presumably due to malpractice. As asphyxia-related outcomes, we included cases of neonatal death and infants with diagnosed encephalopathy before the age of 28 days. Main outcome measure Severe asphyxia due to malpractice during labour. Results A total of 472 case records were scrutinised. One hundred and seventy-seven infants were considered to suffer from severe asphyxia due to malpractice around labour. The most common events of malpractice in connection with delivery were neglecting to supervise fetal wellbeing in 173 cases (98%), neglecting signs of fetal asphyxia in 126 cases (71%), including incautious use of oxytocin in 126 cases (71%) and choosing a nonoptimal mode of delivery in 92 cases (52%). Conclusion There is a great need and a challenge to improve cooperation and to create security barriers within our labour units. The most common cause of malpractice is that stated guidelines for fetal surveillance are not followed. Midwives and obstetricians need to improve their shared understanding of how to act in cases of imminent fetal asphyxia and how to choose a timely and optimal mode of delivery. Please cite this paper as:Berglund S, Grunewald C, Pettersson H, Cnattingius S. Severe asphyxia due to delivery-related malpractice in Sweden 1990–2005. BJOG 2008;115:316–323. PMID:18190367

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study

NASA Astrophysics Data System (ADS)

Bowen, S. R.; Nyflot, M. J.; Herrmann, C.; Groh, C. M.; Meyer, J.; Wollenweber, S. D.; Stearns, C. W.; Kinahan, P. E.; Sandison, G. A.

2015-05-01

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [18F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study.

PubMed

Bowen, S R; Nyflot, M J; Herrmann, C; Groh, C M; Meyer, J; Wollenweber, S D; Stearns, C W; Kinahan, P E; Sandison, G A

2015-05-07

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [(18)F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study

PubMed Central

Bowen, S R; Nyflot, M J; Hermann, C; Groh, C; Meyer, J; Wollenweber, S D; Stearns, C W; Kinahan, P E; Sandison, G A

2015-01-01

Effective positron emission tomography/computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [18F]FDG. The lung lesion insert was driven by 6 different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy (VMAT) were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses (EUD), and 2%-2mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10–20%, treatment planning errors were 5–10%, and treatment delivery errors were 5–30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5–10% in PET/CT imaging, < 5% in treatment planning, and < 2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery. PMID:25884892

Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol

PubMed Central

Li, Jian-Chun; Zhu, Na; Zhu, Jin-Xiu; Zhang, Wen-Jing; Zhang, Hong-Min; Wang, Qing-Qing; Wu, Xiao-Xiang; Wang, Xiu; Zhang, Jin; Hao, Ji-Fu

2015-01-01

Background The aim of this study was to optimize the preparation method for self-assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. Material/Methods In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high-pressure homogenization. We evaluated the Zeta potential of these promising skin-targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. Results Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. Conclusions The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application. PMID:26517086

Effective Parenting Interventions to Reduce Youth Substance Use: A Systematic Review

PubMed Central

Garcia-Huidobro, Diego; Porta, Carolyn; Curran, Dorothy; Patel, Roma; Miller, Jonathan; Borowsky, Iris

2016-01-01

CONTEXT: Parenting interventions may prevent adolescent substance use; however, questions remain regarding the effectiveness of interventions across substances and delivery qualities contributing to successful intervention outcomes. OBJECTIVE: To describe the effectiveness of parent-focused interventions in reducing or preventing adolescent tobacco, alcohol, and illicit substance use and to identify optimal intervention targeted participants, dosage, settings, and delivery methods. DATA SOURCES: PubMed, PsycINFO, ERIC, and CINAHL. STUDY SELECTION: Randomized controlled trials reporting adolescent substance use outcomes, focusing on imparting parenting knowledge, skills, practices, or behaviors. DATA EXTRACTION: Trained researchers extracted data from each article using a standardized, prepiloted form. Because of study heterogeneity, a qualitative technique known as harvest plots was used to summarize findings. RESULTS: A total of 42 studies represented by 66 articles met inclusion criteria. Results indicate that parenting interventions are effective at preventing and decreasing adolescent tobacco, alcohol, and illicit substance use over the short and long term. The majority of effective interventions required ≤12 contact hours and were implemented through in-person sessions including parents and youth. Evidence for computer-based delivery was strong only for alcohol use prevention. Few interventions were delivered outside of school or home settings. LIMITATIONS: Overall risk of bias is high. CONCLUSIONS: This review suggests that relatively low-intensity group parenting interventions are effective at reducing or preventing adolescent substance use and that protection may persist for multiple years. There is a need for additional evidence in clinical and other community settings using an expanded set of delivery methods. PMID:27443357

[Pharmaceutical logistic in turnover of pharmaceutical products of Azerbaijan].

PubMed

Dzhalilova, K I

2009-11-01

Development of pharmaceutical logistic system model promotes optimal strategy for pharmaceutical functioning. The goal of such systems is organization of pharmaceutical product's turnover in required quantity and assortment, at preset time and place, at a highest possible degree of consumption readiness with minimal expenses and qualitative service. Organization of the optimal turnover chain in the region is offered to start from approximate classification of medicaments by logistic characteristics. Supplier selection was performed by evaluation of timeliness of delivery, quality of delivered products (according to the minimum acceptable level of quality) and time-keeping of time spending for orders delivery.

MO-FG-BRA-08: Swarm Intelligence-Based Personalized Respiratory Gating in Lung SAbR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modiri, A; Sabouri, P; Sawant, A

Purpose: Respiratory gating is widely deployed as a clinical motion-management strategy in lung radiotherapy. In conventional gating, the beam is turned on during a pre-determined phase window; typically, around end-exhalation. In this work, we challenge the notion that end-exhalation is always the optimal gating phase. Specifically, we use a swarm-intelligence-based, inverse planning approach to determine the optimal respiratory phase and MU for each beam with respect to (i) the state of the anatomy at each phase and (ii) the time spent in that state, estimated from long-term monitoring of the patient’s breathing motion. Methods: In a retrospective study of fivemore » lung cancer patients, we compared the dosimetric performance of our proposed personalized gating (PG) with that of conventional end-of-exhale gating (CEG) and a previously-developed, fully 4D-optimized plan (combined with MLC tracking delivery). For each patient, respiratory phase probabilities (indicative of the time duration of the phase) were estimated over 2 minutes from lung tumor motion traces recorded previously using the Synchrony system (Accuray Inc.). Based on this information, inverse planning optimization was performed to calculate the optimal respiratory gating phase and MU for each beam. To ensure practical deliverability, each PG beam was constrained to deliver the assigned MU over a time duration comparable to that of CEG delivery. Results: Maximum OAR sparing for the five patients achieved by the PG and the 4D plans compared to CEG plans was: Esophagus Dmax [PG:57%, 4D:37%], Heart Dmax [PG:71%, 4D:87%], Spinal cord Dmax [PG:18%, 4D:68%] and Lung V13 [PG:16%, 4D:31%]. While patients spent the most time in exhalation, the PG-optimization chose end-exhale only for 28% of beams. Conclusion: Our novel gating strategy achieved significant dosimetric improvements over conventional gating, and approached the upper limit represented by fully 4D optimized planning while being significantly simpler and more clinically translatable. This work was partially supported through research funding from National Institutes of Health (R01CA169102) and Varian Medical Systems, Palo Alto, CA, USA.« less

Preparation, optimization, and evaluation of Zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery.

PubMed

Mishra, Ratnesh; Prabhavalkar, Kedar S; Bhatt, Lokesh Kumar

2016-12-01

Zaltoprofen, a non-steroidal anti-inflammatory drug, has potent inhibitory action against nociceptive responses. However, gastrointestinal ulcer accompanied with anemia due to the bleeding are most cited side effects associated with it. Due to this, administration of Zaltoprofen is not suitable for individuals with gastric ulcer. Thus, there is unmet need to develop an alternative delivery system that will be easy to administer and can avoid ulcerogenic side effects associated with it. Present study was aimed to prepare and evaluate microemulsion (ME) and microemulsion-based gel formulation of Zaltoprofen for transdermal delivery. Pseudo-ternary phase diagrams were utilized to prepare ME formulations. Effect of surfactant and co-surfactant mass ratio on the ME formation and permeation of ME were evaluated and formulation was optimized. Permeation studies were performed using excised pigskin was studied. Efficacy of optimized formulations was evaluated in rat model of inflammation and pain. Composition of optimized formulation was 1% (w/w) Zaltoprofen, 20% (w/w) Capryol 90, 50% (w/w) Smix (2:1, Cremophor RH 40 and Transcutol P). Optimized formulation showed globule size of 22.11 nm, polydispersity index of 0.251 and zeta potential of -11.4 mV. ME gel was found safe in skin irritation study. Significant analgesic activity and anti-inflammatory activity of ME gel was observed in hot plate test and rat paw edema test, respectively. In conclusion, results of present study suggest that ME could be a promising formulation for transdermal administration of Zaltoprofen.

Performance Analysis of Cyber Security Awareness Delivery Methods

NASA Astrophysics Data System (ADS)

Abawajy, Jemal; Kim, Tai-Hoon

In order to decrease information security threats caused by human-related vulnerabilities, an increased concentration on information security awareness and training is necessary. There are numerous information security awareness training delivery methods. The purpose of this study was to determine what delivery method is most successful in providing security awareness training. We conducted security awareness training using various delivery methods such as text based, game based and a short video presentation with the aim of determining user preference delivery methods. Our study suggests that a combined delvery methods are better than individual secrity awareness delivery method.

4D dose calculation and delivery with interplay effects between respiratory motion and uniform scanning proton beam

NASA Astrophysics Data System (ADS)

Zhao, Qingya

2011-12-01

Proton radiotherapy has advantages to deliver accurate high conformal radiation dose to the tumor while sparing the surrounding healthy tissue and critical structures. However, the treatment effectiveness is degraded greatly due to patient free breathing during treatment delivery. Motion compensation for proton radiotherapy is especially challenging as proton beam is more sensitive to the density change along the beam path. Tumor respiratory motion during treatment delivery will affect the proton dose distribution and the selection of optimized parameters for treatment planning, which has not been fully addressed yet in the existing approaches for proton dose calculation. The purpose of this dissertation is to develop an approach for more accurate dose delivery to a moving tumor in proton radiotherapy, i.e., 4D proton dose calculation and delivery, for the uniform scanning proton beam. A three-step approach has been carried out to achieve this goal. First, a solution for the proton output factor calculation which will convert the prescribed dose to machine deliverable monitor unit for proton dose delivery has been proposed and implemented. The novel sector integration method is accurate and time saving, which considers the various beam scanning patterns and treatment field parameters, such as aperture shape, aperture size, measuring position, beam range, and beam modulation. Second, tumor respiratory motion behavior has been statistically characterized and the results have been applied to advanced image guided radiation treatment. Different statistical analysis and correlation discovery approaches have been investigated. The internal / external motion correlation patterns have been simulated, analyzed, and applied in a new hybrid gated treatment to improve the target coverage. Third, a dose calculation method has been developed for 4D proton treatment planning which integrates the interplay effects of tumor respiratory motion patterns and proton beam delivery mechanism. These three steps provide an innovative integrated framework for accurate 4D proton dose calculation and treatment planning for a moving tumor, which extends the functionalities of existing 3D planning systems. In short, this dissertation work addresses a few important problems for effective proton radiotherapy to a moving target. The outcomes of the dissertation are very useful for motion compensation with advanced image guided proton treatment.

Design and evaluation of liposomal formulation of pilocarpine nitrate.

PubMed

Rathod, S; Deshpande, S G

2010-03-01

Prolonged release drug delivery system of pilocarpine nitrate was made by optimizing thin layer film hydration method. Egg phosphatidylcholine and cholesterol were used to make multilamellar vesicles. Effects of charges over the vesicles were studied by incorporating dicetylphosphate and stearylamine. Various factors, which may affect the size, shape, encapsulation efficiency and release rate, were studied. Liposomes in the size range 0.2 to 1 µm were obtained by optimizing the process. Encapsulation efficiency of neutral, positive and negatively charged liposomes were found to be 32.5, 35.4 and 34.2 percent, respectively. In vitro drug release rate was studied on specially designed model. Biological response in terms of reduction in intraocular pressure was observed on rabbit eyes. Pilocarpine nitrate liposomes were lyophilized and stability studies were conducted.

Optimization of input parameters of acoustic-transfection for the intracellular delivery of macromolecules using FRET-based biosensors

NASA Astrophysics Data System (ADS)

Yoon, Sangpil; Wang, Yingxiao; Shung, K. K.

2016-03-01

Acoustic-transfection technique has been developed for the first time. We have developed acoustic-transfection by integrating a high frequency ultrasonic transducer and a fluorescence microscope. High frequency ultrasound with the center frequency over 150 MHz can focus acoustic sound field into a confined area with the diameter of 10 μm or less. This focusing capability was used to perturb lipid bilayer of cell membrane to induce intracellular delivery of macromolecules. Single cell level imaging was performed to investigate the behavior of a targeted single-cell after acoustic-transfection. FRET-based Ca2+ biosensor was used to monitor intracellular concentration of Ca2+ after acoustic-transfection and the fluorescence intensity of propidium iodide (PI) was used to observe influx of PI molecules. We changed peak-to-peak voltages and pulse duration to optimize the input parameters of an acoustic pulse. Input parameters that can induce strong perturbations on cell membrane were found and size dependent intracellular delivery of macromolecules was explored. To increase the amount of delivered molecules by acoustic-transfection, we applied several acoustic pulses and the intensity of PI fluorescence increased step wise. Finally, optimized input parameters of acoustic-transfection system were used to deliver pMax-E2F1 plasmid and GFP expression 24 hours after the intracellular delivery was confirmed using HeLa cells.

Co-delivery of chemotherapeutics and proteins for synergistic therapy.

PubMed

He, Chaoliang; Tang, Zhaohui; Tian, Huayu; Chen, Xuesi

2016-03-01

Combination therapy with chemotherapeutics and protein therapeutics, typically cytokines and antibodies, has been a type of crucial approaches for synergistic cancer treatment. However, conventional approaches by simultaneous administration of free chemotherapeutic drugs and proteins lead to limitations for further optimizing the synergistic effects, due to the distinct in vivo pharmacokinetics and distribution of small drugs and proteins, insufficient tumor selectivity and tumor accumulation, unpredictable drug/protein ratios at tumor sites, short half-lives, and serious systemic adverse effects. Consequently, to obtain optimal synergistic anti-tumor efficacy, considerable efforts have been devoted to develop the co-delivery systems for co-incorporating chemotherapeutics and proteins into a single carrier system and subsequently releasing the dual or multiple payloads at desired target sites in a more controllable manner. The co-delivery systems result in markedly enhanced blood stability and in vivo half-lives of the small drugs and proteins, elevated tumor accumulation, as well as the capability of delivering the multiple agents to the same target sites with rational drug/protein ratios, which may facilitate maximizing the synergistic effects and therefore lead to optimal antitumor efficacy. This review emphasizes the recent advances in the co-delivery systems for chemotherapeutics and proteins, typically cytokines and antibodies, for systemic or localized synergistic cancer treatment. Moreover, the proposed mechanisms responsible for the synergy of chemotherapeutic drugs and proteins are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimization of a Multi-Product Intra-Supply Chain System with Failure in Rework.

PubMed

Chiu, Singa Wang; Chen, Shin-Wei; Chang, Chih-Kai; Chiu, Yuan-Shyi Peter

2016-01-01

Globalization has created tremendous opportunities, but also made business environment highly competitive and turbulent. To gain competitive advantage, management of present-day transnational firms always seeks options to trim down various transaction and coordination costs, especially in the area of controllable intra-supply chain system. This study investigates a multi-product intra-supply chain system with failure in rework. To achieve maximum machine utilization, multiple products are fabricated in succession on a single machine. During the process, production of some defective items is inevitable. Reworking of nonconforming items is used to reduce the quality cost in production and achieving the goal of lower overall production cost. Because reworks are sometimes unsuccessful, failures in rework are also considered in this study. Finished goods for each product are transported to the sales offices when the entire production lot is quality assured after rework. A multi-delivery policy is used, wherein fixed quantity n installments of the finished lot are transported at fixed intervals during delivery time. The objective is to jointly determine the common production cycle time and the number of deliveries needed to minimize the long-term expected production-inventory-delivery costs for the problem. With the help of a mathematical model along with optimization technique, the optimal production-shipment policy is obtained. We have used a numerical example to demonstrate applicability of the result of our research.

Optimization of a Multi–Product Intra-Supply Chain System with Failure in Rework

PubMed Central

2016-01-01

Globalization has created tremendous opportunities, but also made business environment highly competitive and turbulent. To gain competitive advantage, management of present-day transnational firms always seeks options to trim down various transaction and coordination costs, especially in the area of controllable intra-supply chain system. This study investigates a multi–product intra-supply chain system with failure in rework. To achieve maximum machine utilization, multiple products are fabricated in succession on a single machine. During the process, production of some defective items is inevitable. Reworking of nonconforming items is used to reduce the quality cost in production and achieving the goal of lower overall production cost. Because reworks are sometimes unsuccessful, failures in rework are also considered in this study. Finished goods for each product are transported to the sales offices when the entire production lot is quality assured after rework. A multi-delivery policy is used, wherein fixed quantity n installments of the finished lot are transported at fixed intervals during delivery time. The objective is to jointly determine the common production cycle time and the number of deliveries needed to minimize the long–term expected production–inventory–delivery costs for the problem. With the help of a mathematical model along with optimization technique, the optimal production–shipment policy is obtained. We have used a numerical example to demonstrate applicability of the result of our research. PMID:27918588

Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer.

PubMed

Tangutoori, Shifalika; Spring, Bryan Q; Mai, Zhiming; Palanisami, Akilan; Mensah, Lawrence B; Hasan, Tayyaba

2016-01-01

A lack of intracellular delivery systems has limited the use of biologics such as monoclonal antibodies (mAb) that abrogate molecular signaling pathways activated to promote escape from cancer treatment. We hypothesized that intracellular co-delivery of the photocytotoxic chromophore benzoporphyrin derivative monoacid A (BPD) and the anti-VEGF mAb bevacizumab in a nanophotoactivatable liposome (nanoPAL) might enhance the efficacy of photodynamic therapy (PDT) combined with suppression of VEGF-mediated signaling pathways. As a proof-of-concept we found that nanoPAL-PDT induced enhanced extra- and intracellular bevacizumab delivery and enhanced acute cytotoxicity in vitro. In an in vivo subcutaneous mouse model of pancreatic ductal adenocarcinoma, nanoPAL-PDT achieved significantly enhanced tumor reduction. We attribute this to the optimal incorporation of insoluble BPD into the lipid bilayer, enhancing photocytotoxicity, and the simultaneous spatiotemporal delivery of bevacizumab, ensuring efficient neutralization of the rapid but transient burst of VEGF following PDT. From the Clinical Editor: Most patients with pancreatic ductal adenocarcinoma (PDAC) by the time present the disease it is very advanced, which unavoidably translates to poor survival. For these patients, use of traditional chemotherapy often becomes ineffective due to tumor resistance to drugs. Photodynamic therapy (PDT) can be an effective modality against chemo-resistant cancers. In this article, the authors investigated the co-delivery of a photocytotoxic agent and anti-VEGF mAb using liposomes. This combination was shown to results in enhanced tumor killing. This method should be applicable to other combination of treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Improving IMRT delivery efficiency using intensity limits during inverse planning.

PubMed

Coselmon, Martha M; Moran, Jean M; Radawski, Jeffrey D; Fraass, Benedick A

2005-05-01

Inverse planned intensity modulated radiotherapy (IMRT) fields can be highly modulated due to the large number of degrees of freedom involved in the inverse planning process. Additional modulation typically results in a more optimal plan, although the clinical rewards may be small or offset by additional delivery complexity and/or increased dose from transmission and leakage. Increasing modulation decreases delivery efficiency, and may lead to plans that are more sensitive to geometrical uncertainties. The purpose of this work is to assess the use of maximum intensity limits in inverse IMRT planning as a simple way to increase delivery efficiency without significantly affecting plan quality. Nine clinical cases (three each for brain, prostate, and head/neck) were used to evaluate advantages and disadvantages of limiting maximum intensity to increase delivery efficiency. IMRT plans were generated using in-house protocol-based constraints and objectives for the brain and head/neck, and RTOG 9406 dose volume objectives in the prostate. Each case was optimized at a series of maximum intensity ratios (the product of the maximum intensity and the number of beams divided by the prescribed dose to the target volume), and evaluated in terms of clinical metrics, dose-volume histograms, monitor units (MU) required per fraction (SMLC and DMLC delivery), and intensity map variation (a measure of the beam modulation). In each site tested, it was possible to reduce total monitor units by constraining the maximum allowed intensity without compromising the clinical acceptability of the plan. Monitor unit reductions up to 38% were observed for SMLC delivery, while reductions up to 29% were achieved for DMLC delivery. In general, complicated geometries saw a smaller reduction in monitor units for both delivery types, although DMLC delivery required significantly more monitor units in all cases. Constraining the maximum intensity in an inverse IMRT plan is a simple way to improve delivery efficiency without compromising plan objectives.

Optimized anion exchange column isolation of zirconium-89 ( 89 Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Hara, Matthew J.; Murray, Nathaniel J.; Carter, Jennifer C.

Zirconium-89 (89Zr), produced by the (p,n) reaction from naturally monoisotopic yttrium (natY), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its ability to quantitatively capturemore » Zr from a load solution that is high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>105) and has been shown to separate Fe, an abundant contaminant in Y foils, from the 89Zr elution fraction. Finally, the performance of the method was evaluated using cyclotron bombarded Y foil targets. The separation method was shown to achieve >95% recovery of the 89Zr present in the foils. The 89Zr eluent, however, was in a chemical matrix not immediately conducive to labeling onto proteins. The main intent of this study was to develop a tandem column 89Zr purification process, wherein the anion exchange column method described here is the first separation in a dual-column purification process.« less

Spatial optimization of cropping pattern for sustainable food and biofuel production with minimal downstream pollution.

PubMed

Femeena, P V; Sudheer, K P; Cibin, R; Chaubey, I

2018-04-15

Biofuel has emerged as a substantial source of energy in many countries. In order to avoid the 'food versus fuel competition', arising from grain-based ethanol production, the United States has passed regulations that require second generation or cellulosic biofeedstocks to be used for majority of the biofuel production by 2022. Agricultural residue, such as corn stover, is currently the largest source of cellulosic feedstock. However, increased harvesting of crops residue may lead to increased application of fertilizers in order to recover the soil nutrients lost from the residue removal. Alternatively, introduction of less-fertilizer intensive perennial grasses such as switchgrass (Panicum virgatum L.) and Miscanthus (Miscanthus x giganteus Greef et Deu.) can be a viable source for biofuel production. Even though these grasses are shown to reduce nutrient loads to a great extent, high production cost have constrained their wide adoptability to be used as a viable feedstock. Nonetheless, there is an opportunity to optimize feedstock production to meet bioenergy demand while improving water quality. This study presents a multi-objective simulation optimization framework using Soil and Water Assessment Tool (SWAT) and Multi Algorithm Genetically Adaptive Method (AMALGAM) to develop optimal cropping pattern with minimum nutrient delivery and minimum biomass production cost. Computational time required for optimization was significantly reduced by loose coupling SWAT with an external in-stream solute transport model. Optimization was constrained by food security and biofuel production targets that ensured not more than 10% reduction in grain yield and at least 100 million gallons of ethanol production. A case study was carried out in St. Joseph River Watershed that covers 280,000 ha area in the Midwest U.S. Results of the study indicated that introduction of corn stover removal and perennial grass production reduce nitrate and total phosphorus loads without compromising on food and biofuel production. Optimization runs yielded an optimal cropping pattern with 32% of watershed area in stover removal, 15% in switchgrass and 2% in Miscanthus. The optimal scenario resulted in 14% reduction in nitrate and 22% reduction in total phosphorus from the baseline. This framework can be used as an effective tool to take decisions regarding environmentally and economically sustainable strategies to minimize the nutrient delivery at minimal biomass production cost, while simultaneously meeting food and biofuel production targets. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis and characterization of insulin/zirconium phosphate@TiO2 hybrid composites for enhanced oral insulin delivery applications.

PubMed

Safari, Mostafa; Kamari, Younes; Ghiaci, Mehran; Sadeghi-Aliabadi, Hojjat; Mirian, Mina

2017-05-01

In this work, a series of composites of insulin (Ins)/zirconium phosphate (ZrP) were synthesized by intercalation method, then, these composites were coated with TiO 2 by sol-gel method to prepare Ins/ZrP@TiO 2 hybrid composites and the drug release of the composites was investigated by using UV-Vis spectroscopy. Ins/ZrP (10, 30, 60 wt%) composites were prepared by intercalation of insulin into the ZrP layers in water. Then Ins/ZrP composites were coated with different amounts of TiO 2 (30, 50, 100 wt %) by using titanium tetra n-butoxide, as precursor. Formation of intercalated Ins/ZrP and Ins/ZrP@TiO 2 hybrid composites was characterized by FT-IR, FE-SEM, BET and XRD analysis. Zeta potential of the optimized Ins/ZrP@TiO 2 hybrid composite was determined -27.2 mV. Cytotoxic effects of the optimized Ins/ZrP@TiO 2 hybrid composite against HeLa and Hek293T cell lines were evaluated using MTT assay and the results showed that designed drug delivery system was not toxic in biological environment. Compared to the Ins/ZrP composites, incorporation of TiO 2 coating enhanced the drug entrapment considerably, and reduced the drug release. The Ins/ZrP composites without TiO 2 coating released the whole drug after 30 min in pH 7.4 (phosphate buffer solution) while the TiO 2 -coated composites released the entrapped drug after 20 h. In addition to increasing the shelf life of hormone, this nanoencapsulation and nanocoating method can convert the insulin utilization from injection to oral and present a painless and more comfortable treatment for diabetics.

Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue.

PubMed

Sakadzić, Sava; Roussakis, Emmanuel; Yaseen, Mohammad A; Mandeville, Emiri T; Srinivasan, Vivek J; Arai, Ken; Ruvinskaya, Svetlana; Devor, Anna; Lo, Eng H; Vinogradov, Sergei A; Boas, David A

2010-09-01

Measurements of oxygen partial pressure (pO(2)) with high temporal and spatial resolution in three dimensions is crucial for understanding oxygen delivery and consumption in normal and diseased brain. Among existing pO(2) measurement methods, phosphorescence quenching is optimally suited for the task. However, previous attempts to couple phosphorescence with two-photon laser scanning microscopy have faced substantial difficulties because of extremely low two-photon absorption cross-sections of conventional phosphorescent probes. Here we report to our knowledge the first practical in vivo two-photon high-resolution pO(2) measurements in small rodents' cortical microvasculature and tissue, made possible by combining an optimized imaging system with a two-photon-enhanced phosphorescent nanoprobe. The method features a measurement depth of up to 250 microm, sub-second temporal resolution and requires low probe concentration. The properties of the probe allowed for direct high-resolution measurement of cortical extravascular (tissue) pO(2), opening many possibilities for functional metabolic brain studies.

Preparation and characteristics of biosilica derived from marine diatom biomass of Nitzschia closterium and Thalassiosira

NASA Astrophysics Data System (ADS)

Qi, Yarong; Wang, Xin; Cheng, Jay Jiayang

2017-05-01

In this study, biosilica of high purity was successfully prepared from marine diatom ( Nitzschia closterium and Thalassiosira) biomass using an optimized novel method with acid washing treatment followed by thermal treatment of the biomass. The optimal condition of the method was 2% diluted HCl washing and baking at 600°C. The SiO2 contents of N. closterium biosilica and Thalassiosira biosilica were 92.23% and 91.52%, respectively, which were both higher than that of diatomite biosilica. The SiO2 morphologies of both biosilica are typical amorphous silica. Besides, N. closterium biosilica possessed micropores and fibers with a surface area of 59.81m2/g. And Thalassiosira biosilica possessed a mesoporous hierarchical skeleton with a surface area of 9.91m2/g. The results suggest that the biosilica samples obtained in this study present highly porous structures. The prepared porous biosilica material possesses great potential to be used as drug delivery carrier, biosensor, biocatalyst as well as adsorbent in the future.

Biophase equilibration times.

PubMed

Veng-Pedersen, P; Mandema, J W; Danhof, M

1991-09-01

Various methods for describing how quickly a drug equilibrates at the biophase are proposed. The biophase equilibration time (BET) is the time it takes the biophase drug level to reach a given percentage (p) of its predicted steady state in a drug administration that leads to a steady-state condition. The time to reach biophase equilibrium may be defined as the BET value for p = 95, and the 50% biophase equilibration time is obtained when p = 50. Biophase equilibration profiles (BEPs), obtained by plotting p versus BET, give a dynamic representation of the approach to equilibrium and may serve as an indicator of the rate of drug delivery to the biophase. A pharmacodynamic system analysis method is proposed to determine BETs and BEPs from the biophase conduction function. The approach is demonstrated using pharmacodynamic data from the CNS effect of amobarbital evaluated by an aperiodic analysis of EEG recordings. The relevance of the BET and/or BEP principles in optimal computer-controlled drug infusion, drug design, and evaluation of targeted drug delivery is discussed. Both vascular and extravascular drug administrations are considered in the analysis.

Use of urea and creatinine levels in vaginal fluid for the diagnosis of preterm premature rupture of membranes and delivery interval after membrane rupture.

PubMed

Gezer, Cenk; Ekin, Atalay; Golbasi, Ceren; Kocahakimoglu, Ceysu; Bozkurt, Umit; Dogan, Askin; Solmaz, Ulaş; Golbasi, Hakan; Taner, Cuneyt Eftal

2017-04-01

To determine whether urea and creatinine measurements in vaginal fluid could be used to diagnose preterm premature rupture of membranes (PPROM) and predict delivery interval after PPROM. A prospective study conducted with 100 pregnant women with PPROM and 100 healthy pregnant women between 24 + 0 and 36 + 6 gestational weeks. All patients underwent sampling for urea and creatinine concentrations in vaginal fluid at the time of admission. Receiver operator curve analysis was used to determine the cutoff values for the presence of PPROM and delivery within 48 h after PPROM. In multivariate logistic regression analysis, vaginal fluid urea and creatinine levels were found to be significant predictors of PPROM (p < 0.001 and p < 0.001, respectively) and delivery within 48 h after PPROM (p = 0.012 and p = 0.017, respectively). The optimal cutoff values for the diagnosis of PPROM were >6.7 mg/dl for urea and >0.12 mg/dl for creatinine. The optimal cutoff values for the detection of delivery within 48 h were >19.4 mg/dl for urea and >0.23 mg/dl for creatinine. Measurement of urea and creatinine levels in vaginal fluid is a rapid and reliable test for diagnosing and also for predicting delivery interval after PPROM.

Administration of Substances to Laboratory Animals: Equipment Considerations, Vehicle Selection, and Solute Preparation

PubMed Central

Turner, Patricia V; Pekow, Cynthia; Vasbinder, Mary Ann; Brabb, Thea

2011-01-01

Administration of substances to laboratory animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. The equipment selected to deliver substances to animals depends on the length of the study and the nature of the material being administered. This selection provides a significant opportunity for refining animal treatment. Similarly, when substances are administered as solutions or suspensions, attention should be given to selection of vehicles and methods used for preparing the solutions and suspensions. The research team, veterinarian, technical personnel, and IACUC members should be aware of reasons underlying selection of equipment for substance delivery and should consider carefully how substances will be prepared and stored prior to administration to animals. Failure to consider these factors during experimental planning may result in unintentional adverse effects on experimental animals and confounded results. PMID:22330706

Computer and Internet Interventions to Optimize Listening and Learning for People With Hearing Loss: Accessibility, Use, and Adherence.

PubMed

Ferguson, Melanie; Henshaw, Helen

2015-09-01

The aim of this research forum article was to examine accessibility, use, and adherence to computerized and online interventions for people with hearing loss. Four intervention studies of people with hearing loss were examined: 2 auditory training studies, 1 working memory training study, and 1 study of multimedia educational support. A small proportion (approximately 15%) of participants had never used a computer, which may be a barrier to the accessibility of computer and Internet-based interventions. Computer competence was not a factor in intervention use or adherence. Computer skills and Internet access influenced participant preference for the delivery method of the multimedia educational support program. It is important to be aware of current barriers to computer and Internet-delivered interventions for people with hearing loss. However, there is a clear need to develop and future-proof hearing-related applications for online delivery.

Spatial service delivery system for smart licensing & enforcement management

NASA Astrophysics Data System (ADS)

Wahap, N. A.; Ismail, N. M.; Nor, N. M.; Ahmad, N.; Omar, M. F.; Termizi, A. A. A.; Zainal, D.; Noordin, N. M.; Mansor, S.

2016-06-01

Spatial information has introduced a new sense of urgency for a better understanding of the public needs in term of what, when and where they need services and through which devices, platform or physical locations they need them. The objective of this project is to value- add existing license management process for business premises which comes under the responsibility of Local Authority (PBT). Manipulation of geospatial and tracing technology via mobile platform allows enforcement officers to work in real-time, use a standardized system, improve service delivery, and optimize operation management. This paper will augment the scope and capabilities of proposed concept namely, Smart Licensing/Enforcement Management (SLEm). It will review the current licensing and enforcement practice of selected PBT in comparison to the enhanced method. As a result, the new enhanced system is expected to offer a total solution for licensing/enforcement management whilst increasing efficiency and transparency for smart city management and governance.

Surface chemistry governs cellular tropism of nanoparticles in the brain

NASA Astrophysics Data System (ADS)

Song, Eric; Gaudin, Alice; King, Amanda R.; Seo, Young-Eun; Suh, Hee-Won; Deng, Yang; Cui, Jiajia; Tietjen, Gregory T.; Huttner, Anita; Saltzman, W. Mark

2017-05-01

Nanoparticles are of long-standing interest for the treatment of neurological diseases such as glioblastoma. Most past work focused on methods to introduce nanoparticles into the brain, suggesting that reaching the brain interstitium will be sufficient to ensure therapeutic efficacy. However, optimized nanoparticle design for drug delivery to the central nervous system is limited by our understanding of their cellular deposition in the brain. Here, we investigated the cellular fate of poly(lactic acid) nanoparticles presenting different surface chemistries, after administration by convection-enhanced delivery. We demonstrate that nanoparticles with `stealth' properties mostly avoid internalization by all cell types, but internalization can be enhanced by functionalization with bio-adhesive end-groups. We also show that association rates measured in cultured cells predict the extent of internalization of nanoparticles in cell populations. Finally, evaluating therapeutic efficacy in an orthotopic model of glioblastoma highlights the need to balance significant uptake without inducing adverse toxicity.

An Overview of Insulin Pumps and Glucose Sensors for the Generalist

PubMed Central

McAdams, Brooke H.; Rizvi, Ali A.

2016-01-01

Continuous subcutaneous insulin, or the insulin pump, has gained popularity and sophistication as a near-physiologic programmable method of insulin delivery that is flexible and lifestyle-friendly. The introduction of continuous monitoring with glucose sensors provides unprecedented access to, and prediction of, a patient’s blood glucose levels. Efforts are underway to integrate the two technologies, from “sensor-augmented” and “sensor-driven” pumps to a fully-automated and independent sensing-and-delivery system. Implantable pumps and an early-phase “bionic pancreas” are also in active development. Fine-tuned “pancreas replacement” promises to be one of the many avenues that offers hope for individuals suffering from diabetes. Although endocrinologists and diabetes specialists will continue to maintain expertise in this field, it behooves the primary care physician to have a working knowledge of insulin pumps and sensors to ensure optimal clinical care and decision-making for their patients. PMID:26742082

Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability.

PubMed

Ramos Yacasi, Gladys Rosario; Calpena Campmany, Ana Cristina; Egea Gras, María Antonia; Espina García, Marta; García López, María Luisa

2017-04-01

The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development. Optimization of the FD to improve long-term stability of ocular administration's FB-PɛCL-NPs. FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components. Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at -50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, -16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD. An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.

Topical Delivery of Erythromycin Through Cubosomes for Acne.

PubMed

Khan, Sana; Jain, Poorva; Jain, Sourabh; Jain, Richa; Bhargava, Saurabh; Jain, Aakanchha

2018-01-01

Topical delivery is an attractive route for local and systemic treatment. The novel topical application has many advantages like averting the GI-irritation, preventing the metabolism of drugs in the liver and increasing the bioavailability of the drug over the conventional dosage forms. The aim of present work was to prepare and characterized erythromycin encapsulated cubosomes using different concentrations of glyceryl monooleate and poloxamer 407 by the emulsification method. The prepared dispersion of cubosomes was characterized for surface morphology, particle size, entrapment efficiency and in vitro release. Further, optimized formulation was converted to cubosomal gel by incorporating carbopol 934 at different concentrations. The prepared gel was characterized for homogeneity, pH, viscosity, spreadibility, drug content and in vitro drug release study. The result of optimized cubosomes showed average particle size of 264.5±2.84nm and entrapment efficiency about 95.29±1.32 % and the pH of optimized cubosomal was found to be 6.5, viscosity 2475-8901(cp), drug content 95.29% and the spreadability was found to be 11.74 gm.cm/sec. The in vitro drug release kinetics of optimized formulation was found to follow Korsmeyer peppas model having highest R2 value 0.835 and in vitro drug release of optimized erythromycin loaded cubosomal gel and plain drug gel in 24 hr was found to be 89.91±0.73 and 88.64±2.16, while in 36 hr plain drug gel and cubosomal gel showed drug release about 87.64±0.97 and 91.55±1.09, and sustained release was obtained after 24 hr in case of cubosomal gel. Thus, as a whole it can be concluded that erythromycin loaded cubosomes are effective in topically delivering drug in sustained and non-invasive manner for treatment and prevention of acne. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Site Targeted Press Coated Delivery of Methylprednisolone Using Eudragit RS 100 and Chitosan for Treatment of Colitis.

PubMed

Jagdale, Swati; Chandekar, Apoorva

2016-01-01

Inflammatory bowel disease (IBD) is one of the five most prevalent gastrointestinal disease burdens which commonly require lifetime care. Worldwide incidence rate of ulcerative colitis and Crohn's disease is about 16.8% and 13.4% respectively. Colitis is an inflammation of the colon. Colon targeted drug delivery will direct the drug to the colon. The drug will reach at the site of action and hence its side effects as well as dose can be reduced. Recent patent describes treatment of ulcerative colitis using anti CD3 antibodies, with nicotine and anti-depressant drugs, budesonide foam etc. Present study deals with optimization of site targeted methylprednisolone delivery for treatment of colitis. Chitosan and Eudragit RS 100 were used as coating polymers. Tablets were prepared by press coated technology. The core tablets contain drug, avicel as binder, croscarmellose sodium as super disintegrant and dicalcium phosphate as diluent. Drug excipient compatibility was carried out using FTIR, UV and DSC. Design of experiment was used to optimize the formulation. Tablets were evaluated for thickness, weight variation, hardness, swelling index, in-vitro drug release and release of drug in simulated media. Optimized batch (B2) contained chitosan 40% and eudragit RS 100 17.5%. B2 showed in-vitro drug release 85.65 ± 7.6% in 6.8 pH phosphate buffer and 96.7 ±9.1% in simulated media after 7.5 hours. In-vivo x-ray placebo study for formulation B2 had shown that the tablet reached to the ascending colon after 5 hours. This indicated a potential site targeted delivery of optimized batch B2.

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

PubMed

Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

2018-01-01

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.

SU-F-BRB-07: A Plan Comparison Tool to Ensure Robustness and Deliverability in Online-Adaptive Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hill, P; Labby, Z; Bayliss, R A

Purpose: To develop a plan comparison tool that will ensure robustness and deliverability through analysis of baseline and online-adaptive radiotherapy plans using similarity metrics. Methods: The ViewRay MRIdian treatment planning system allows export of a plan file that contains plan and delivery information. A software tool was developed to read and compare two plans, providing information and metrics to assess their similarity. In addition to performing direct comparisons (e.g. demographics, ROI volumes, number of segments, total beam-on time), the tool computes and presents histograms of derived metrics (e.g. step-and-shoot segment field sizes, segment average leaf gaps). Such metrics were investigatedmore » for their ability to predict that an online-adapted plan reasonably similar to a baseline plan where deliverability has already been established. Results: In the realm of online-adaptive planning, comparing ROI volumes offers a sanity check to verify observations found during contouring. Beyond ROI analysis, it has been found that simply editing contours and re-optimizing to adapt treatment can produce a delivery that is substantially different than the baseline plan (e.g. number of segments increased by 31%), with no changes in optimization parameters and only minor changes in anatomy. Currently the tool can quickly identify large omissions or deviations from baseline expectations. As our online-adaptive patient population increases, we will continue to develop and refine quantitative acceptance criteria for adapted plans and relate them historical delivery QA measurements. Conclusion: The plan comparison tool is in clinical use and reports a wide range of comparison metrics, illustrating key differences between two plans. This independent check is accomplished in seconds and can be performed in parallel to other tasks in the online-adaptive workflow. Current use prevents large planning or delivery errors from occurring, and ongoing refinements will lead to increased assurance of plan quality.« less

TH-AB-BRB-04: Quality Assurance for Advanced Digital Linac Implementations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V.

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

TH-AB-BRB-00: Research Opportunities with Digital Linear Accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

Diffusing, side-firing, and radial delivery laser balloon catheters for creating subsurface thermal lesions in tissue

NASA Astrophysics Data System (ADS)

Chang, Chun-Hung; Fried, Nathaniel M.

2016-02-01

Infrared lasers have been used in combination with applied cooling methods to preserve superficial skin layers during cosmetic surgery. Similarly, combined laser irradiation and tissue cooling may also allow development of minimally invasive laser therapies beyond dermatology. This study compares diffusing, side-firing, and radial delivery laser balloon catheter designs for creation of subsurface lesions in tissue, ex vivo, using a near-IR laser and applied contact cooling. An Ytterbium fiber laser with 1075 nm wavelength delivered energy through custom built 18 Fr (6-mm-OD) balloon catheters incorporating either 10-mm-long diffusing fiber tip, 90 degree side-firing fiber, or radial delivery cone mirror, through a central lumen. A chilled solution was flowed through a separate lumen into 9-mm-diameter balloon to keep probe cooled at 7°C. Porcine liver tissue samples were used as preliminary tissue model for immediate observation of thermal lesion creation. The diffusing fiber produced subsurface thermal lesions measuring 49.3 +/- 10.0 mm2 and preserved 0.8 +/- 0.1 mm of surface tissue. The side-firing fiber produced subsurface thermal lesions of 2.4 +/- 0.9 mm2 diameter and preserved 0.5 +/- 0.1 mm of surface tissue. The radial delivery probe assembly failed to produce subsurface thermal lesions, presumably due to the small effective spot diameter at the tissue surface, which limited optical penetration depth. Optimal laser power and irradiation time measured 15 W and 100 s for diffusing fiber and 1.4 W and 20 s, for side-firing fiber, respectively. Diffusing and side-firing laser balloon catheter designs provided subsurface thermal lesions in tissue. However, the divergent laser beam in both designs limited the ability to preserve a thicker layer of tissue surface. Further optimization of laser and cooling parameters may be necessary to preserve thicker surface tissue layers.

Improving Rural Cancer Patients' Outcomes: A Group-Randomized Trial

ERIC Educational Resources Information Center

Elliott, Thomas E.; Elliott, Barbara A.; Regal, Ronald R.; Renier, Colleen M.; Haller, Irina V.; Crouse, Byron J.; Witrak, Martha T.; Jensen, Patricia B.

2004-01-01

Significant barriers exist in the delivery of state-of-the-art cancer care to rural populations. Rural providers' knowledge and practices, their rural health care delivery systems, and linkages to cancer specialists are not optimal; therefore, rural cancer patient outcomes are less than achievable. Purpose: To test the effects of a strategy…

Optimal method for collection of umbilical cord blood: an Egyptian trial for a public cord blood bank.

PubMed

Bassiouny, M R; El-Chennawi, F; Mansour, A K; Yahia, S; Darwish, A

2015-06-01

Umbilical cord blood (UCB) contains stem cells and can be used as an alternative to bone marrow transplantation. Engraftment is dependent on the total nucleated cell (TNC) and CD34+ cell counts of the cord blood units. This study was designed to evaluate the effect of the method of collection of the UCB on the yield of the cord blood units. Informed consent was obtained from 100 eligible mothers for donation of cord blood. Both in utero and ex utero methods were used for collection. The cord blood volume was measured. The TNC and the CD34+ cell counts were enumerated. We have found that in utero collection gave significantly larger volumes of cord blood and higher TNC counts than ex utero collection. There was no significant difference between both methods regarding the CD34+ cell counts. This study revealed a significant correlation between the volume of the collected cord blood and both TNC and CD34+ cell counts. It is better to collect cord blood in utero before placental delivery to optimize the quality of the cord blood unit. © 2015 AABB.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Kham, E-mail: khamdiep@gmail.com; UT MD Anderson Cancer Center, School of Health Professions—Unit 2, Houston, TX; Cummings, David

The purpose of this study was to evaluate the differences between volumetric modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) in the treatment of nasal cavity carcinomas. The treatment of 10 patients, who had completed IMRT treatment for resected tumors of the nasal cavity, was replanned with the Philips Pinnacle{sup 3} Version 9 treatment-planning system. The IMRT plans used a 9-beam technique whereas the VMAT (known as SmartArc) plans used a 3-arc technique. Both types of plans were optimized using Philips Pinnacle{sup 3} Direct Machine Parameter Optimization algorithm. IMRT and VMAT plans' quality was compared by evaluating the maximum,more » minimum, and mean doses to the target volumes and organs at risk, monitor units (MUs), and the treatment delivery time. Our results indicate that VMAT is capable of greatly reducing treatment delivery time and MUs compared with IMRT. The reduction of treatment delivery time and MUs can decrease the effects of intrafractional uncertainties that can occur because of patient movement during treatment delivery. VMAT's plans further reduce doses to critical structures that are in close proximity to the target volume.« less

Integrated beam orientation and scanning-spot optimization in intensity-modulated proton therapy for brain and unilateral head and neck tumors.

PubMed

Gu, Wenbo; O'Connor, Daniel; Nguyen, Dan; Yu, Victoria Y; Ruan, Dan; Dong, Lei; Sheng, Ke

2018-04-01

Intensity-Modulated Proton Therapy (IMPT) is the state-of-the-art method of delivering proton radiotherapy. Previous research has been mainly focused on optimization of scanning spots with manually selected beam angles. Due to the computational complexity, the potential benefit of simultaneously optimizing beam orientations and spot pattern could not be realized. In this study, we developed a novel integrated beam orientation optimization (BOO) and scanning-spot optimization algorithm for intensity-modulated proton therapy (IMPT). A brain chordoma and three unilateral head-and-neck patients with a maximal target size of 112.49 cm 3 were included in this study. A total number of 1162 noncoplanar candidate beams evenly distributed across 4π steradians were included in the optimization. For each candidate beam, the pencil-beam doses of all scanning spots covering the PTV and a margin were calculated. The beam angle selection and spot intensity optimization problem was formulated to include three terms: a dose fidelity term to penalize the deviation of PTV and OAR doses from ideal dose distribution; an L1-norm sparsity term to reduce the number of active spots and improve delivery efficiency; a group sparsity term to control the number of active beams between 2 and 4. For the group sparsity term, convex L2,1-norm and nonconvex L2,1/2-norm were tested. For the dose fidelity term, both quadratic function and linearized equivalent uniform dose (LEUD) cost function were implemented. The optimization problem was solved using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA). The IMPT BOO method was tested on three head-and-neck patients and one skull base chordoma patient. The results were compared with IMPT plans created using column generation selected beams or manually selected beams. The L2,1-norm plan selected spatially aggregated beams, indicating potential degeneracy using this norm. L2,1/2-norm was able to select spatially separated beams and achieve smaller deviation from the ideal dose. In the L2,1/2-norm plans, the [mean dose, maximum dose] of OAR were reduced by an average of [2.38%, 4.24%] and[2.32%, 3.76%] of the prescription dose for the quadratic and LEUD cost function, respectively, compared with the IMPT plan using manual beam selection while maintaining the same PTV coverage. The L2,1/2 group sparsity plans were dosimetrically superior to the column generation plans as well. Besides beam orientation selection, spot sparsification was observed. Generally, with the quadratic cost function, 30%~60% spots in the selected beams remained active. With the LEUD cost function, the percentages of active spots were in the range of 35%~85%.The BOO-IMPT run time was approximately 20 min. This work shows the first IMPT approach integrating noncoplanar BOO and scanning-spot optimization in a single mathematical framework. This method is computationally efficient, dosimetrically superior and produces delivery-friendly IMPT plans. © 2018 American Association of Physicists in Medicine.

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery.

PubMed

Abd-Elsalam, Wessam H; El-Zahaby, Sally A; Al-Mahallawi, Abdulaziz M

2018-11-01

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 2 3 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Nonviral Vectors for Gene Delivery

NASA Astrophysics Data System (ADS)

Baoum, Abdulgader Ahmed

2011-12-01

The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,L-lactide- co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (˜200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. On the other hand, a more simple method to synthesize 50-200 nm complexes capable of high transfection efficiency or high gene knockdown was also explored. Positively charged CPPs were complexed with pDNA or siRNA, which resulted in 'loose' (˜1 micron) particles. These were then condensed into small nanoparticles by using calcium, which formed "soft" crosslinks by interacting with both phosphates on nucleic acids and amines on CPPs. An optimal amount of CaCl2 produced stable, ˜100 nm complexes that exhibited higher transfection efficiency and gene silencing than PEI polyplexes. CPPs also displayed negligible cytotoxicity up to 5 mg/mL. Biophysical studies of the pDNA structure within complexes suggested that pDNA within CPP complexes (condensed with calcium) had similar structure, but enhanced thermal stability compared to PEI complexes. Thus, CPP complexes emerged as simple, attractive candidates for future studies on nonviral gene delivery in vivo.

Development and in vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer

PubMed Central

Jin, Bao-Zhong; Dong, Xiao-Qi; Xu, Xin; Zhang, Feng-He

2018-01-01

The present study focused on the development of a mucoadhesive patch of methotrexate (MTX) for targeted delivery in oral cancer. Initially, MTX-loaded liposomes were prepared using the thin film hydration method, and had a mean diameter of 105.7–137.4 nm and percentage entrapment efficiency of 54.6±3.5. These liposomes were cast in optimized mucoadhesive film. The film was characterized by its release pattern, thickness, weight and percentage swelling index and the sustained release profile of the optimized film was evaluated. The developed liposomes and liposomes cast in the film formulation were evaluated for cytotoxicity in HSC-3 cells using an MTT assay, and a significant decrease in the half maximal inhibitory concentration of MTX was identified with the MTX-entrapped liposomal film, M-LP-F7. The results of the mitochondria-dependent intrinsic pathway demonstrated that there was significant mitochondrial membrane potential disruption with M-LP-F7 compared with the plain drug. M-LP-F7 increased the rate of apoptosis in HSC-3 cells by almost 3-fold. Elevated levels of reactive oxygen species provided evidence that M-LP-F7 exerts a pro-oxidant effect in HSC-3 cells. PMID:29434971

Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors.

PubMed

Akter, Shanjida; Clem, Brian F; Lee, Hyun Jin; Chesney, Jason; Bae, Younsoo

2012-03-01

To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Particulate characterization showed that the PEG-p(HYD) block copolymers conjugated with 3PO (2.08∼2.21 wt.%) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38 nm and 259 nm when 5 kDa and 12 kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. A novel micelle formulation for controlled delivery of 3PO was successfully prepared.

Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol

PubMed Central

Kaur, Amanpreet; Kaur, Gurpreet

2011-01-01

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route. PMID:23960773

Mucoadhesive buccal patches based on interpolymer complexes of chitosan-pectin for delivery of carvedilol.

PubMed

Kaur, Amanpreet; Kaur, Gurpreet

2012-01-01

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.

Self nanoemulsifying drug delivery system of stabilized ellagic acid-phospholipid complex with improved dissolution and permeability.

PubMed

Avachat, Amelia M; Patel, Vijay G

2015-07-01

Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid-phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid-phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid-phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83-85 °C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA.

Numerical modeling of the agricultural-hydrologic system in Punjab, India

NASA Astrophysics Data System (ADS)

Nyblade, M.; Russo, T. A.; Zikatanov, L.; Zipp, K.

2017-12-01

The goal of food security for India's growing population is threatened by the decline in freshwater resources due to unsustainable water use for irrigation. The issue is acute in parts of Punjab, India, where small landholders produce a major quantity of India's food with declining groundwater resources. To further complicate this problem, other regions of the state are experiencing groundwater logging and salinization, and are reliant on canal systems for fresh water delivery. Due to the lack of water use records, groundwater consumption for this study is estimated with available data on crop yields, climate, and total canal water delivery. The hydrologic and agricultural systems are modeled using appropriate numerical methods and software. This is a state-wide hydrologic numerical model of Punjab that accounts for multiple aquifer layers, agricultural water demands, and interactions between the surface canal system and groundwater. To more accurately represent the drivers of agricultural production and therefore water use, we couple an economic crop optimization model with the hydrologic model. These tools will be used to assess and optimize crop choice scenarios based on farmer income, food production, and hydrologic system constraints. The results of these combined models can be used to further understand the hydrologic system response to government crop procurement policies and climate change, and to assess the effectiveness of possible water conservation solutions.

Optimized Preparation of Levofloxacin-loaded Chitosan Nanoparticles by Ionotropic Gelation

NASA Astrophysics Data System (ADS)

Guan, J.; Cheng, P.; Huang, S. J.; Wu, J. M.; Li, Z. H.; You, X. D.; Hao, L. M.; Guo, Y.; Li, R. X.; Zhang, H.

The present work investigates the feasibility of fabricating chitosan (CS)-levofloxacin (LOF) nanoparticles by ionotropic gelation technology. An orthogonal experiment was designed to optimize its preparing parameters and multi-index comprehensive weighed score analysis method was used to study the effects of various factors including concentration of CS, concentration of tripolyphosphate (TPP), mass ratio of CS to TPP, and mass ratio of CS to LOF on the properties of nanoparticles. The particles prepared under optimal condition of 2 mg/ml CS concentration, 2 mg/ml TPP concentration, 0.5:1 mass ratio of oil to water and 4:1 mass ratio of CS to TPP had 140 nm diameter, 0.95 span, 6.13% loading capacity (LC) and 24.91% encapsulation efficiency (EE). In vitro release profile showed that LOF released fast initially and then slowly with T90 occurring at 76.5 h. Future studies should focus on antibacterial and biocompatible properties in order to evaluate its potential as sustainable delivery system.

PREPARATION AND PROPERTIES OF COMPOUND ARNEBIAE RADIX MICROEMULSION GEL

PubMed Central

Chen, Jing; He, Yanping; Gao, Ting; Zhang, Licheng; Zhao, Yuna

2017-01-01

Background: Compound Arnebiae radix oil has been clinically applied to treat burns and scalds for a long time. However, it is unstable and inconvenient to use. The aim of this study was to prepare a compound Arnebiae radix microemulsion gel for transdermal delivery system and evaluate its characteristics. Materials and Methods: Based on the solubility of Shikonin, the active component of Arnebiae radix and the results of phase studies, adequate ratio of each component in microemulsion was determined. The optimized microemulsion gel was prepared using Carbomer 940. The gels were characterized in terms of appearance, preliminary stability test and the content of Shikonin in the compound Arnebiae radix microemulsion gel with HPLC analysis. Results: The optimized conditions for preparing microemulsion were Tween-80, glycerin, isopropyl myristate (IPM) with the ratio of 6:3:2. The optimal microemulsion gel was obtained with Carbomer 940 (1.0%). Conclusion: The prepared compound Arnebiae radix microemulsion gel showed good stability over time. It is more convenience in application than the previous used formulations. PMID:28480438

Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets.

PubMed

Yan, Hong-Xiang; Zhang, Shuang-Shuang; He, Jian-Hua; Liu, Jian-Ping

2016-09-05

The present study aimed to develop and optimize the wax based floating sustained-release dispersion pellets for a weakly acidic hydrophilic drug protocatechuic acid to achieve prolonged gastric residence time and improved bioavailability. This low-density drug delivery system consisted of octadecanol/microcrystalline cellulose mixture matrix pellet cores prepared by extrusion-spheronization technique, coated with drug/ethyl cellulose 100cp solid dispersion using single-step fluid-bed coating method. The formulation-optimized pellets could maintain excellent floating state without lag time and sustain the drug release efficiently for 12h based on non-Fickian transport mechanism. Observed by SEM, the optimized pellet was the dispersion-layered spherical structure containing a compact inner core. DSC, XRD and FTIR analysis revealed drug was uniformly dispersed in the amorphous molecule form and had no significant physicochemical interactions with the polymer dispersion carrier. The stability study of the resultant pellets further proved the rationality and integrity of the developed formulation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Researching Seeds: Films, Sanitation Methods, Microbiological Growth, Viability, and Selection for New Crops

NASA Technical Reports Server (NTRS)

Padgett, Niki; Smith, Trent

2018-01-01

A major factor in long-term human exploration of the solar system is crop growth in microgravity. Space crops can provide fresh, nutritious food to supplement diets for astronauts. Important factors impacting space plant growth and consumption are water delivery to root zone in microgravity, sanitation methods for microbiological safety, plant responses to light quality/spectrum, and identifying optimal edible plants suitable for growth on the International Space Station (ISS). Astronauts growing their own food on the ISS provides necessary data for crop production for long duration deep space missions. The seed film project can be used in Advanced Plant Habitat and Veggies that are currently being utilized on the ISS.

SU-E-T-452: Impact of Respiratory Motion On Robustly-Optimized Intensity-Modulated Proton Therapy to Treat Lung Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, W; Schild, S; Bues, M

Purpose: We compared conventionally optimized intensity-modulated proton therapy (IMPT) treatment plans against the worst-case robustly optimized treatment plans for lung cancer. The comparison of the two IMPT optimization strategies focused on the resulting plans' ability to retain dose objectives under the influence of patient set-up, inherent proton range uncertainty, and dose perturbation caused by respiratory motion. Methods: For each of the 9 lung cancer cases two treatment plans were created accounting for treatment uncertainties in two different ways: the first used the conventional Method: delivery of prescribed dose to the planning target volume (PTV) that is geometrically expanded from themore » internal target volume (ITV). The second employed the worst-case robust optimization scheme that addressed set-up and range uncertainties through beamlet optimization. The plan optimality and plan robustness were calculated and compared. Furthermore, the effects on dose distributions of the changes in patient anatomy due to respiratory motion was investigated for both strategies by comparing the corresponding plan evaluation metrics at the end-inspiration and end-expiration phase and absolute differences between these phases. The mean plan evaluation metrics of the two groups were compared using two-sided paired t-tests. Results: Without respiratory motion considered, we affirmed that worst-case robust optimization is superior to PTV-based conventional optimization in terms of plan robustness and optimality. With respiratory motion considered, robust optimization still leads to more robust dose distributions to respiratory motion for targets and comparable or even better plan optimality [D95% ITV: 96.6% versus 96.1% (p=0.26), D5% - D95% ITV: 10.0% versus 12.3% (p=0.082), D1% spinal cord: 31.8% versus 36.5% (p =0.035)]. Conclusion: Worst-case robust optimization led to superior solutions for lung IMPT. Despite of the fact that robust optimization did not explicitly account for respiratory motion it produced motion-resistant treatment plans. However, further research is needed to incorporate respiratory motion into IMPT robust optimization.« less

Core-shell alginate-ghatti gum modified montmorillonite composite matrices for stomach-specific flurbiprofen delivery.

PubMed

Bera, Hriday; Ippagunta, Sohitha Reddy; Kumar, Sanoj; Vangala, Pavani

2017-07-01

Novel alginate-arabic gum (AG) gel membrane coated alginate-ghatti gum (GG) modified montmorillonite (MMT) composite matrices were developed for intragastric flurbiprofen (FLU) delivery by combining floating and mucoadhesion mechanisms. The clay-biopolymer composite matrices containing FLU as core were accomplished by ionic-gelation technique. Effects of polymer-blend (alginate:GG) ratios and crosslinker (CaCl 2 ) concentrations on drug entrapment efficiency (DEE, %) and cumulative drug release after 8h (Q 8h , %) were studied to optimize the core matrices by a 3 2 factorial design. The optimized matrices (F-O) demonstrated DEE of 91.69±1.43% and Q 8h of 74.96±1.56% with minimum errors in prediction. The alginate-AG gel membrane enveloped optimized matrices (F-O, coated) exhibited superior buoyancy, better ex vivo mucoadhesion and slower drug release rate. The drug release profile of FLU-loaded uncoated and coated optimized matrices was best fitted in Korsmeyer-Peppas model with anomalous diffusion and case-II transport driven mechanism, respectively. The uncoated and coated matrices containing FLU were also characterized for drug-excipients compatibility, drug crystallinity, thermal behaviour and surface morphology. Thus, the newly developed alginate-AG gel membrane coated alginate-GG modified MMT composite matrices are appropriate for intragastric delivery of FLU over an extended period of time with improved therapeutic benefits. Copyright © 2017 Elsevier B.V. All rights reserved.

Histone-Targeted Nucleic Acid Delivery for Tissue Regenerative Applications

NASA Astrophysics Data System (ADS)

Munsell, Erik V.

Nucleic acid delivery has garnered significant attention as an innovative therapeutic approach for treating a wide variety of diseases. However, the design of non-viral delivery systems that negotiate efficient intracellular trafficking and nuclear entry represents a significant challenge. Overcoming these hurdles requires a combination of well-controlled materials approaches with techniques to understand and direct cellular delivery. Recent investigations have highlighted the roles histone tail sequences play in directing nuclear delivery and retention, as well as activating DNA transcription. We established the ability to recapitulate these natural histone tail activities within non-viral gene nanocarriers, driving gene transfer/expression by enabling effective navigation to the nucleus via retrograde vesicular trafficking. A unique finding of this histone-targeted approach was that nanocarriers gained enhanced access to the nucleus during mitosis. The work described in this dissertation builds off of these fundamental insights to facilitate the translation of this histone-targeted delivery approach toward regenerative medicine applications. During native tissue repair, actively proliferating mesenchymal stem cells (MSCs) respond to a complex series of growth factor signals that direct their differentiation. Accordingly, the investigations in this work focused on utilizing the histone-targeted nanocarriers to enhance osteogenic growth factor gene transfer in dividing MSCs leading to augmented MSC chondrogenic differentiation, an essential first step in skeletal tissue repair. Concurrently, additional studies focused on optimizing the histone-targeted nanocarrier design strategy to enable improved plasmid DNA (pDNA) binding stability and tunable harnessing of native cellular processing pathways for enhanced gene transfer. Overall, the work presented herein demonstrated substantial increases in growth factor expression following histone-targeted gene transfer. This enhanced expression enabled more robust levels of chondrogenesis in MSCs than treatments with equivalent amounts of recombinant growth factor protein. Additionally, nanocarrier design optimization provided effective pDNA condensation and controllable interactions with native histone effectors. Importantly, these optimized nanocarriers conferred stable nanoplex formation and maintained transfection efficiency under physiologically relevant conditions. Taken together, these advances may help drive the clinical translation of histone-targeted nucleic acid delivery strategies for the regeneration of damaged tissue following traumatic injury.

Metal powder production by gas atomization

NASA Technical Reports Server (NTRS)

Ting, E. Y.; Grant, N. J.

1986-01-01

The confined liquid, gas-atomization process was investigated. Results from a two-dimensional water model showed the importance of atomization pressure, as well as delivery tube and atomizer design. The atomization process at the tip of the delivery tube was photographed. Results from the atomization of a modified 7075 aluminum alloy yielded up to 60 wt pct. powders that were finer than 45 microns in diameter. Two different atomizer designs were evaluated. The amount of fine powders produced was correlated to a calculated gas-power term. An optimal gas-power value existed for maximized fine powder production. Atomization at gas-power greater than or less than this optimal value produced coarser powders.

Risk factors for technical failure of endoscopic double self-expandable metallic stent placement by partial stent-in-stent method.

PubMed

Kawakubo, Kazumichi; Kawakami, Hiroshi; Toyokawa, Yoshihide; Otani, Koichi; Kuwatani, Masaki; Abe, Yoko; Kawahata, Shuhei; Kubo, Kimitoshi; Kubota, Yoshimasa; Sakamoto, Naoya

2015-01-01

Endoscopic double self-expandable metallic stent (SEMS) placement by the partial stent-in-stent (PSIS) method has been reported to be useful for the management of unresectable hilar malignant biliary obstruction. However, it is technically challenging, and the optimal SEMS for the procedure remains unknown. The aim of this study was to identify the risk factors for technical failure of endoscopic double SEMS placement for unresectable malignant hilar biliary obstruction (MHBO). Between December 2009 and May 2013, 50 consecutive patients with MHBO underwent endoscopic double SEMS placement by the PSIS method. We retrospectively evaluated the rate of successful double SEMS placement and identified the risk factors for technical failure. The technical success rate for double SEMS placement was 82.0% (95% confidence interval [CI]: 69.2-90.2). On univariate analysis, the rate of technical failure was high in patients with metastatic disease and unilateral placement. Multivariate analysis revealed that metastatic disease was a significant risk factor for technical failure (odds ratio: 9.63, 95% CI: 1.11-105.5). The subgroup analysis after double guidewire insertion showed that the rate of technical success was higher in the laser-cut type SEMS with a large mesh and thick delivery system than in the braided type SEMS with a small mesh and thick delivery system. Metastatic disease was a significant risk factor for technical failure of double SEMS placement for unresectable MHBO. The laser-cut type SEMS with a large mesh and thin delivery system might be preferable for the PSIS procedure. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting

PubMed Central

Clementino, Adryana; Buttini, Francesca; Colombo, Gaia; Pescina, Silvia; Stanisçuaski Guterres, Silvia; Nicoli, Sara

2018-01-01

In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery. PMID:29543755

Effectiveness of a tailor-made intervention for pregnancy-related pelvic girdle and/or low back pain after delivery: Short-term results of a randomized clinical trial [ISRCTN08477490

PubMed Central

Bastiaenen, Caroline HG; de Bie, Rob A; Wolters, Pieter MJC; Vlaeyen, Johan WS; Leffers, Pieter; Stelma, Foekje; Bastiaanssen, Janneke M; Essed, Gerard GM; van den Brandt, Piet A

2006-01-01

Background For the moment, scientific evaluation of programs on treatment of pregnancy-related pelvic girdle and/or low back pain after delivery is hardly available with only one study with a positive result, suggesting uncertainty about the optimal approach. Investigators draw particular attention to biomedical factors but there is growing evidence that biopsychosocial factors appear to be even more important as a basis of an intervention program. Methods We studied the effectiveness of a tailor-made program with respect to biopsychosocial factors (intervention group) in women with pregnancy-related pelvic girdle and/ or low back pain versus usual care based on a pain contingent basis (control group) shortly after delivery in a randomized controlled trial. Women with severe complaints shortly after delivery were selected from a longitudinal prospective cohort study (n = 7526), aimed at pregnancy-related pelvic girdle and/or low back pain in the Netherlands. A concealed block randomization was performed after collecting baseline data. Researchers were blinded to treatment assignment. Outcomes were evaluated within the domains of the biopsychosocial approach. Primary outcome concerned limitations in activities (RDQ). Follow-up measurements were performed 12 weeks after delivery. Results Since May 2001 until July 2003, 869 women out of the cohort made a request for treatment by a physiotherapist, 10 days after delivery. Because of a quick recovery in two weeks time, we included only 126 women three weeks after delivery. There was a statistically significant and clinically relevant difference in improvement on the primary outcome (RDQ) between the two groups in favor of the experimental intervention. Conclusion The results favored the hypotheses. Women's worries about their condition were major targets in the experimental intervention. The prognosis after delivery, especially in de first weeks, turned out to be favorable. PMID:16504165

Advances in genetic modification of pluripotent stem cells.

PubMed

Fontes, Andrew; Lakshmipathy, Uma

2013-11-15

Genetically engineered stem cells aid in dissecting basic cell function and are valuable tools for drug discovery, in vivo cell tracking, and gene therapy. Gene transfer into pluripotent stem cells has been a challenge due to their intrinsic feature of growing in clusters and hence not amenable to common gene delivery methods. Several advances have been made in the rapid assembly of DNA elements, optimization of culture conditions, and DNA delivery methods. This has lead to the development of viral and non-viral methods for transient or stable modification of cells, albeit with varying efficiencies. Most methods require selection and clonal expansion that demand prolonged culture and are not suited for cells with limited proliferative potential. Choosing the right platform based on preferred length, strength, and context of transgene expression is a critical step. Random integration of the transgene into the genome can be complicated due to silencing or altered regulation of expression due to genomic effects. An alternative to this are site-specific methods that target transgenes followed by screening to identify the genomic loci that support long-term expression with stem cell proliferation and differentiation. A highly precise and accurate editing of the genome driven by homology can be achieved using traditional methods as well as the newer technologies such as zinc finger nuclease, TAL effector nucleases and CRISPR. In this review, we summarize the different genetic engineering methods that have been successfully used to create modified embryonic and induced pluripotent stem cells. © 2013. Published by Elsevier Inc. All rights reserved.

SU-F-T-592: A Delivery QA-Free Approach for Adaptive Therapy of Prostate Cancer with Static Intensity Modulated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roth, T; Dooley, J; Zhu, T

2016-06-15

Purpose: Clinical implementations of adaptive radiotherapy (ART) are limited mainly by the requirement of delivery QA (DQA) prior to the treatment. Small segment size and small segment MU are two dominant factors causing failures of DQA. The aim of this project is to explore the feasibility of ART treatment without DQA by using a partial optimization approach. Methods: A retrospective simulation study was performed on two prostate cancer patients treated with SMLC-IMRT. The prescription was 180cGx25 fractions with daily CT-on-rail imaging for target alignment. For each patient, seven daily CTs were selected randomly across treatment course. The contours were deformablelymore » transferred from the simulation CT onto the daily CTs and modified appropriately. For each selected treatment, dose distributions from original beams were calculated on the daily treatment CTs (DCT plan). An ART plan was also created by optimizing the segmental MU only, while the segment shapes were preserved and the minimum MU constraint was respected. The overlaps, between PTV and the rectum, between PTV and the bladder, were normalized by the PTV volume. This ratio was used to characterize the difficulty of organs-at-risk (OAR) sparing. Results: Comparing to the original plan, PTV coverage was compromised significantly in DCT plans (82% ± 7%) while all ART plans preserved PTV coverage. ART plans showed similar OAR sparing as the original plan, such as V40Gy=11.2cc (ART) vs 11.4cc (original) for the rectum and D10cc=4580cGy vs 4605cGy for the bladder. The sparing of the rectum/bladder depends on overlap ratios. The sparing in ART was either similar or improved when overlap ratios in treatment CTs were smaller than those in original plan. Conclusion: A partial optimization method is developed that may make the real-time ART feasible on selected patients. Future research is warranted to quantify the applicability of the proposed method.« less

Designing and developing suppository formulations for anti-HIV drug delivery.

PubMed

Ham, Anthony S; Buckheit, Robert W

2017-08-01

Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

A difference-matrix metaheuristic for intensity map segmentation in step-and-shoot IMRT delivery.

PubMed

Gunawardena, Athula D A; D'Souza, Warren D; Goadrich, Laura D; Meyer, Robert R; Sorensen, Kelly J; Naqvi, Shahid A; Shi, Leyuan

2006-05-21

At an intermediate stage of radiation treatment planning for IMRT, most commercial treatment planning systems for IMRT generate intensity maps that describe the grid of beamlet intensities for each beam angle. Intensity map segmentation of the matrix of individual beamlet intensities into a set of MLC apertures and corresponding intensities is then required in order to produce an actual radiation delivery plan for clinical use. Mathematically, this is a very difficult combinatorial optimization problem, especially when mechanical limitations of the MLC lead to many constraints on aperture shape, and setup times for apertures make the number of apertures an important factor in overall treatment time. We have developed, implemented and tested on clinical cases a metaheuristic (that is, a method that provides a framework to guide the repeated application of another heuristic) that efficiently generates very high-quality (low aperture number) segmentations. Our computational results demonstrate that the number of beam apertures and monitor units in the treatment plans resulting from our approach is significantly smaller than the corresponding values for treatment plans generated by the heuristics embedded in a widely use commercial system. We also contrast the excellent results of our fast and robust metaheuristic with results from an 'exact' method, branch-and-cut, which attempts to construct optimal solutions, but, within clinically acceptable time limits, generally fails to produce good solutions, especially for intensity maps with more than five intensity levels. Finally, we show that in no instance is there a clinically significant change of quality associated with our more efficient plans.

Examining the Potential for Response to Intervention (RTI) Delivery Models in Secondary Education: Emerging Research and Opportunities

ERIC Educational Resources Information Center

Epler, Pam

2017-01-01

To provide the highest quality of education to students, school administrators must adopt new frameworks to meet learners' needs. This allows teaching practices to be optimized to create a meaningful learning environment. "Examining the Potential for Response to Intervention (RTI) Delivery Models in Secondary Education: Emerging Research and…

The Delivery of Professional Development in the Middle School: Exploring Optimal Settings, Times, and Participants

ERIC Educational Resources Information Center

Mohr, Carrie A.

2017-01-01

The purpose of this study was to describe and understand the experiences of teachers and instructional leaders related to the delivery of professional development at the middle school level. This qualitative study examines four professional development experiences and provides a summary of emerging themes related to those experiences for both…

Assessing feedback in a mobile videogame

USDA-ARS?s Scientific Manuscript database

Player feedback is an important part of serious games, although there is no consensus regarding its delivery or optimal content. "Mommio" is a serious game designed to help mothers motivate their preschoolers to eat vegetables. The purpose of this study was to assess optimal format and content of pl...

Mixture experiment methods in the development and optimization of microemulsion formulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furlanetto, Sandra; Cirri, Marzia; Piepel, Gregory F.

2011-06-25

Microemulsion formulations represent an interesting delivery vehicle for lipophilic drugs, allowing for improving their solubility and dissolution properties. This work developed effective microemulsion formulations using glyburide (a very poorly-water-soluble hypoglycaemic agent) as a model drug. First, the area of stable microemulsion (ME) formations was identified using a new approach based on mixture experiment methods. A 13-run mixture design was carried out in an experimental region defined by constraints on three components: aqueous, oil, and surfactant/cosurfactant. The transmittance percentage (at 550 nm) of ME formulations (indicative of their transparency and thus of their stability) was chosen as the response variable. Themore » results obtained using the mixture experiment approach corresponded well with those obtained using the traditional approach based on pseudo-ternary phase diagrams. However, the mixture experiment approach required far less experimental effort than the traditional approach. A subsequent 13-run mixture experiment, in the region of stable MEs, was then performed to identify the optimal formulation (i.e., having the best glyburide dissolution properties). Percent drug dissolved and dissolution efficiency were selected as the responses to be maximized. The ME formulation optimized via the mixture experiment approach consisted of 78% surfactant/cosurfacant (a mixture of Tween 20 and Transcutol, 1:1 v/v), 5% oil (Labrafac Hydro) and 17% aqueous (water). The stable region of MEs was identified using mixture experiment methods for the first time.« less

Optimization of rotational arc station parameter optimized radiation therapy

PubMed Central

Dong, P.; Ungun, B.; Boyd, S.; Xing, L.

2016-01-01

Purpose: To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of matching VMAT in both plan quality and delivery efficiency by using three clinical cases of different disease sites. Methods: The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based proximal operator graph solver. To avoid being trapped in a local minimum in beamlet-based aperture selection using the gradient descent algorithm, a stochastic gradient descent was employed here. Apertures with zero or low weight were thrown out. To find out whether there was room to further improve the plan by adding more apertures or SPs, the authors repeated the above procedure with consideration of the existing dose distribution from the last iteration. At the end of the second iteration, the weights of all the apertures were reoptimized, including those of the first iteration. The above procedure was repeated until the plan could not be improved any further. The optimization technique was assessed by using three clinical cases (prostate, head and neck, and brain) with the results compared to that obtained using conventional VMAT in terms of dosimetric properties, treatment time, and total MU. Results: Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. For the prostate case, the volume of the 50% prescription dose was decreased by 22% for the rectum and 6% for the bladder. For the head and neck case, SPORT improved the mean dose for the left and right parotids by 15% each. The maximum dose was lowered from 72.7 to 71.7 Gy for the mandible, and from 30.7 to 27.3 Gy for the spinal cord. The mean dose for the pharynx and larynx was reduced by 8% and 6%, respectively. For the brain case, the doses to the eyes, chiasm, and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the head and neck case. Conclusions: The dosimetric quality and delivery efficiency presented here indicate that SPORT is an intriguing alternative treatment modality. With the widespread adoption of digital linac, SPORT should lead to improved patient care in the future. PMID:27587028

Optimization of rotational arc station parameter optimized radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, P.; Ungun, B.

Purpose: To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of matching VMAT in both plan quality and delivery efficiency by using three clinical cases of different disease sites. Methods: The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based proximal operator graph solver. To avoid being trappedmore » in a local minimum in beamlet-based aperture selection using the gradient descent algorithm, a stochastic gradient descent was employed here. Apertures with zero or low weight were thrown out. To find out whether there was room to further improve the plan by adding more apertures or SPs, the authors repeated the above procedure with consideration of the existing dose distribution from the last iteration. At the end of the second iteration, the weights of all the apertures were reoptimized, including those of the first iteration. The above procedure was repeated until the plan could not be improved any further. The optimization technique was assessed by using three clinical cases (prostate, head and neck, and brain) with the results compared to that obtained using conventional VMAT in terms of dosimetric properties, treatment time, and total MU. Results: Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. For the prostate case, the volume of the 50% prescription dose was decreased by 22% for the rectum and 6% for the bladder. For the head and neck case, SPORT improved the mean dose for the left and right parotids by 15% each. The maximum dose was lowered from 72.7 to 71.7 Gy for the mandible, and from 30.7 to 27.3 Gy for the spinal cord. The mean dose for the pharynx and larynx was reduced by 8% and 6%, respectively. For the brain case, the doses to the eyes, chiasm, and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the head and neck case. Conclusions: The dosimetric quality and delivery efficiency presented here indicate that SPORT is an intriguing alternative treatment modality. With the widespread adoption of digital linac, SPORT should lead to improved patient care in the future.« less

SU-E-T-562: Motion Tracking Optimization for Conformal Arc Radiotherapy Plans: A QUASAR Phantom Based Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Z; Wang, I; Yao, R

Purpose: This study is to use plan parameters optimization (Dose rate, collimator angle, couch angle, initial starting phase) to improve the performance of conformal arc radiotherapy plans with motion tracking by increasing the plan performance score (PPS). Methods: Two types of 3D conformal arc plans were created based on QUASAR respiratory motion phantom with spherical and cylindrical targets. Sinusoidal model was applied to the MLC leaves to generate motion tracking plans. A MATLAB program was developed to calculate PPS of each plan (ranges from 0–1) and optimize plan parameters. We first selected the dose rate for motion tracking plans andmore » then used simulated annealing algorithm to search for the combination of the other parameters that resulted in the plan of the maximal PPS. The optimized motion tracking plan was delivered by Varian Truebeam Linac. In-room cameras and stopwatch were used for starting phase selection and synchronization between phantom motion and plan delivery. Gaf-EBT2 dosimetry films were used to measure the dose delivered to the target in QUASAR phantom. Dose profiles and Truebeam trajectory log files were used for plan delivery performance evaluation. Results: For spherical target, the maximal PPS (PPSsph) of the optimized plan was 0.79: (Dose rate: 500MU/min, Collimator: 90°, Couch: +10°, starting phase: 0.83π). For cylindrical target, the maximal PPScyl was 0.75 (Dose rate: 300MU/min, Collimator: 87°, starting phase: 0.97π) with couch at 0°. Differences of dose profiles between motion tracking plans (with the maximal and the minimal PPS) and 3D conformal plans were as follows: PPSsph=0.79: %ΔFWHM: 8.9%, %Dmax: 3.1%; PPSsph=0.52: %ΔFWHM: 10.4%, %Dmax: 6.1%. PPScyl=0.75: %ΔFWHM: 4.7%, %Dmax: 3.6%; PPScyl=0.42: %ΔFWHM: 12.5%, %Dmax: 9.6%. Conclusion: By achieving high plan performance score through parameters optimization, we can improve target dose conformity of motion tracking plan by decreasing total MLC leaf travel distance and leaf speed.« less

Sci-Thur PM - Colourful Interactions: Highlights 08: ARC TBI using Single-Step Optimized VMAT Fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudson, Alana; Gordon, Deborah; Moore, Roseanne

Purpose: This work outlines a new TBI delivery technique to replace a lateral POP full bolus technique. The new technique is done with VMAT arc delivery, without bolus, treating the patient prone and supine. The benefits of the arc technique include: increased patient experience and safety, better dose conformity, better organ at risk sparing, decreased therapist time and reduction of therapist injuries. Methods: In this work we build on a technique developed by Jahnke et al. We use standard arc fields with gantry speeds corrected for varying distance to the patient followed by a single step VMAT optimization on amore » patient CT to increase dose inhomogeneity and to reduce dose to the lungs (vs. blocks). To compare the arc TBI technique to our full bolus technique, we produced plans on patient CTs for both techniques and evaluated several dosimetric parameters using an ANOVA test. Results and Conclusions: The arc technique is able reduce both the hot areas to the body (D2% reduced from 122.2% to 111.8% p<0.01) and the lungs (mean lung dose reduced from 107.5% to 99.1%, p<0.01), both statistically significant, while maintaining coverage (D98% = 97.8% vs. 94.6%, p=0.313, not statistically significant). We developed a more patient and therapist-friendly TBI treatment technique that utilizes single-step optimized VMAT plans. It was found that this technique was dosimetrically equivalent to our previous lateral technique in terms of coverage and statistically superior in terms of reduced lung dose.« less

Genetic transformation protocols using zygotic embryos as explants: an overview.

PubMed

Tahir, Muhammad; Waraich, Ejaz A; Stasolla, Claudio

2011-01-01

Genetic transformation of plants is an innovative research tool which has practical significance for the development of new and improved genotypes or cultivars. However, stable introduction of genes of interest into nuclear genomes depends on several factors such as the choice of target tissue, the method of DNA delivery in the target tissue, and the appropriate method to select the transformed plants. Mature or immature zygotic embryos have been a popular choice as explant or target tissue for genetic transformation in both angiosperms and gymnosperms. As a result, considerable protocols have emerged in the literature which have been optimized for various plant species in terms of transformation methods and selection procedures for transformed plants. This article summarizes the recent advances in plant transformation using zygotic embryos as explants.

Assessing Feedback in a Mobile Videogame

PubMed Central

Brand, Leah; Beltran, Alicia; Hughes, Sheryl; O'Connor, Teresia; Baranowski, Janice; Nicklas, Theresa; Chen, Tzu-An; Dadabhoy, Hafza R.; Diep, Cassandra S.; Buday, Richard

2016-01-01

Abstract Background: Player feedback is an important part of serious games, although there is no consensus regarding its delivery or optimal content. “Mommio” is a serious game designed to help mothers motivate their preschoolers to eat vegetables. The purpose of this study was to assess optimal format and content of player feedback for use in “Mommio.” Materials and Methods: The current study posed 36 potential “Mommio” gameplay feedback statements to 20 mothers using a Web survey and interview. Mothers were asked about the meaning and helpfulness of each feedback statement. Results: Several themes emerged upon thematic analysis, including identifying an effective alternative in the case of corrective feedback, avoiding vague wording, using succinct and correct grammar, avoiding provocation of guilt, and clearly identifying why players' game choice was correct or incorrect. Conclusions: Guidelines are proposed for future feedback statements. PMID:27058403

[Training and challenges for the health care system in Brazil: an analysis of investments to expand health care service delivery].

PubMed

Soares, Adilson

2007-07-01

The goal of this study is to discuss the investments made by the Brazilian government to expand health care service delivery in the Unified National Health System (SUS) from 1995 to 2001. The data indicate a mismatch between investments to increase service delivery and maintenance and optimization of the health service network's capacity. The paper concludes that there is a need to guarantee financial maintenance of the system and conduct new investments based on an analysis of the installed capacity and the financial possibilities to guarantee resources for continuous delivery of this additional services supply.

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers.

PubMed

Raghavan, Raghu; Howell, Roger W; Zalutsky, Michael R

2017-06-01

Radionuclides conjugated to molecules that bind specifically to cancer cells are of great interest as a means to increase the specificity of radiotherapy. Currently, the methods to disseminate these targeted radiotherapeutics have been either systemic delivery or by bolus injection into the tumor or tumor resection cavity. Herein we model a potentially more efficient method of delivery, namely pressure-driven fluid flow, called convection-enhanced delivery (CED), where a device infuses the molecules in solution (or suspension) directly into the tissue of interest. In particular, we focus on the setting of primary brain cancer after debulking surgery, where the tissue margins surrounding the surgical resection cavity are infiltrated with tumor cells and the most frequent sites of tumor recurrence. We develop the combination of fluid flow, chemical kinetics, and radiation dose models needed to examine such protocols. We focus on Auger electron-emitting radionuclides (e.g. 67 Ga, 77 Br, 111 In, 125 I, 123 I, 193m Pt, 195m Pt) whose short range makes them ideal for targeted therapy in this setting of small foci of tumor spread within normal tissue. By solving these model equations, we confirm that a CED protocol is promising in allowing sufficient absorbed dose to destroy cancer cells with minimal absorbed dose to normal cells at clinically feasible activity levels. We also show that Auger emitters are ideal for this purpose while the longer range alpha particle emitters fail to meet criteria for effective therapy (as neither would energetic beta particle emitters). The model is used with simplified assumptions on the geometry and homogeneity of brain tissue to allow semi-analytic solutions to be displayed, and with the purpose of a first examination of this new delivery protocol proposed for radionuclide therapy. However, we emphasize that it is immediately extensible to personalized therapy treatment planning as we have previously shown for conventional CED, at the price of requiring a fully numerical computerized approach.

How do organisational characteristics influence teamwork and service delivery in lung cancer diagnostic assessment programmes? A mixed-methods study.

PubMed

Honein-AbouHaidar, Gladys N; Stuart-McEwan, Terri; Waddell, Tom; Salvarrey, Alexandra; Smylie, Jennifer; Dobrow, Mark J; Brouwers, Melissa C; Gagliardi, Anna R

2017-02-23

Diagnostic assessment programmes (DAPs) can reduce wait times for cancer diagnosis, but optimal DAP design is unknown. This study explored how organisational characteristics influenced multidisciplinary teamwork and diagnostic service delivery in lung cancer DAPs. A mixed-methods approach integrated data from descriptive qualitative interviews and medical record abstraction at 4 lung cancer DAPs. Findings were analysed with the Integrated Team Effectiveness Model. 4 DAPs at 2 teaching and 2 community hospitals in Canada. 22 staff were interviewed about organisational characteristics, target service benchmarks, and teamwork processes, determinants and outcomes; 314 medical records were reviewed for actual service benchmarks. Formal, informal and asynchronous team processes enabled service delivery and yielded many perceived benefits at the patient, staff and service levels. However, several DAP characteristics challenged teamwork and service delivery: referral volume/workload, time since launch, days per week of operation, rural-remote population, number and type of full-time/part-time human resources, staff colocation, information systems. As a result, all sites failed to meet target benchmarks (from referral to consultation median 4.0 visits, median wait time 35.0 days). Recommendations included improved information systems, more staff in all specialties, staff colocation and expanded roles for patient navigators. Findings were captured in a conceptual framework of lung cancer DAP teamwork determinants and outcomes. This study identified several DAP characteristics that could be improved to facilitate teamwork and enhance service delivery, thereby contributing to knowledge of organisational determinants of teamwork and associated outcomes. Findings can be used to update existing DAP guidelines, and by managers to plan or evaluate lung cancer DAPs. Ongoing research is needed to identify ideal roles for navigators, and staffing models tailored to case volumes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.