Poly propyl ether imine (PETIM) dendrimer: A novel non-toxic dendrimer for sustained drug delivery

In the present study, an attempt was made to study the acute and sub-acute toxicity profile of G3-COOH Poly (propyl ether imine) PETIM] dendrimer and its use as a carrier for sustained delivery of model drug ketoprofen. Drug-dendrimer complex was prepared and characterized by FTIR, solubility and in vitro drug release study. PETIM dendrimer was found to have significantly less toxicity in A541 cells compared to Poly amido amine (PAMAM) dendrimer. Further, acute and 28 days sub-acute toxicity measurement in mice showed no mortality, hematological, biochemical or histopathological changes up to 80 mg/kg dose of PETIM dendrimer. The results of study demonstrated that G3-COOH PETIM dendrimer can be used as a safe and efficient vehicle for sustained drug delivery. (C) 2010 Elsevier Masson SAS. All rights reserved.

Electrical Characterization of Airborne Vehicle Exhaust Plume

he induced current and voltage on the skin of an airborne vehicle due to the coupling of external electromagnetic field could be altered in the presence of ionized exhaust plume. So in the present work, a theoretical analysis is done to estimate the electrical parameters such as electrical conductivity and permittivity and their distribution in the axial and radial directions of the exhaust plume of an airborne vehicle. The electrical conductivity depends on the distribution of the major ionic species produced from the propellant combustion. In addition it also depends on temperature and pressure distribution of the exhaust plume as well as the generated shock wave. The chemically reactive rocket exhaust flow is modeled in two stages. The first part is simulated from the combustion chamber to the throat of the supersonic nozzle by using NASA Chemical Equilibrium with Application (CEA) package and the second part is simulated from the nozzle throat to the downstream of the plume by using a commercial Computational Fluid Dynamics (CFD) solver. The contour plots of the exhaust parameters are presented. Eight barrel shocks which influence the distribution of the vehicle exhaust parameters are obtained in this simulation. The computed peak value of the electrical conductivity of the plume is 0.123 S/m and the relative permittivity varies from 0.89 to 0.99. The attenuation of the microwave when it is passing through the conducting exhaust plume has also been presented.

Structural Basis of Drug Resistance by Genetic Variants of HIV Type 1 Clade C Protease from India

Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.

Structure and Conformation of an Antidepressant Drug, Nitroxazepine Hydrochloride Monohydrate

CIsH20N3Oa+.C1-.H2 O, M r = 395, orthorhombic, Pn21a, a = 7.710 (4), b = 11.455 (3), c -- 21.199 (3)/k, Z = 4, V = 1872.4/k 3, D m = 1.38, D C = 1.403 g cm -3, F(000) = 832, g(Cu Kct) = 20.94 cm -l. Intensities for 1641 reflections were measured on a Nonius CAD-4 diffractometer; of these, 1470 were significant. The structure was solved by direct methods and refined to an R index of 0.045 using a blockdiagonal least-squares procedure. The angle between the least-squares planes through the benzene rings is 125.0 (5) ° and the side chain is folded similarly to one of the independent molecules of imipramine hydrochloride.

Structure and conformation of an anti-depressant drug, nitroxazepine hydrochloride monohydrate

CIsH20N3Oa+.C1-.H2 O, M r = 395, orthorhombic, Pn21a, a = 7.710 (4), b = 11.455 (3), c -- 21.199 (3)/k, Z = 4, V = 1872.4/k 3, D m = 1.38, D C = 1.403 g cm -3, F(000) = 832, g(Cu Kct) = 20.94 cm -l. Intensities for 1641 reflections were measured on a Nonius CAD-4 diffractometer; of these, 1470 were significant. The structure was solved by direct methods and refined to an R index of 0.045 using a blockdiagonal least-squares procedure. The angle between the least-squares planes through the benzene rings is 125.0 (5) ° and the side chain is folded similarly to one of the independent molecules of imipramine hydrochloride.

Biochemical effects of the porphyrinogenic drug allylisopropylacetamide. A comparative study with phenobarbital

Successive administrations of allylisopropylacetamide, a potent porphyrinogenic drug, increase liver weight, microsomal protein and phospholipid contents. There is an increase in the rate of microsomal protein synthesis in vivo and in vitro. The drug decreases microsomal ribonuclease activity and increases NADPH–cytochrome c reductase activity. Phenobarbital, which has been reported to exhibit all these changes mentioned, is a weaker inducer of δ-aminolaevulinate synthetase and increases the rate of haem synthesis only after a considerable time-lag in fed female rats, when compared with the effects observed with allylisopropylacetamide. Again, phenobarbital does not share the property of allylisopropylacetamide in causing an initial decrease in cytochrome P-450 content. Haematin does not counteract most of the biochemical effects caused by allylisopropylacetamide, although it is quite effective in the case of phenobarbital. Haematin does not inhibit the uptake of [2-14C]allylisopropylacetamide by any of the liver subcellular fractions.

Dual Drug Delivery Microcapsules via Layer-by-Layer Self-Assembly

The integration of hydrophobic and hydrophilic drugs in the polymer microcapsule offers the possibility of developing a new drug delivery system that combines the best features of these two distinct classes of material. Recently, we have reported the encapsulation of an uncharged water-insoluble drug in the polymer membrane. The hydrophobic drug is deposited using a layer-by-layer (LbL) technique, which is based on the sequential adsorption of oppositely charged polyelectrolytes onto a charged substrate. In this paper, we report the encapsulation of two different drugs, which are invariably different in structure and in their solubility in water. We have characterized these dual drug vehicular capsules by confocal laser scanning microscopy, atomic force microscopy, visible microscopy, and transmission electron microscopy. The growth of a thin film on a flat substrate by LbL was monitored by UV−vis spectra. The desorption kinetics of two drugs from the thin film was modeled by a second-order rate model.

A Modified Dubins Method for Optimal Path Planning of a Miniature Air Vehicle Converging to a Straight Line Path

This paper presents a Dubins model based strategy to determine the optimal path of a Miniature Air Vehicle (MAV), constrained by a bounded turning rate, that would enable it to fly along a given straight line, starting from an arbitrary initial position and orientation. The method is then extended to meet the same objective in the presence of wind which has a magnitude comparable to the speed of the MAV. We use a modification of the Dubins' path method to obtain the complete optimal solution to this problem in all its generality.

Modified ILMI algorithm for practical PID/PD implementation on a Micro Air Vehicle

This paper extends the iterative linear matrix inequality algorithm (ILMI) for systems having non-ideal PI, PD and PID implementations. The new algorithm uses the practical implementation of the feedback blocksto form the equivalent static output feedback plant. The LMI based synthesis techniques are used in the algorithm to design a multi-loop, multi-objective fixed structure control. The benefits of such a control design technique are brought out by applying it to the lateral stabilizing and tracking feedback control problem of a 30cm wingspan micro air vehicle.

Determination of optimal trajectory under design constraints for a satellite launch vehicle

An optimal pitch steering programme of a solid-fuel satellite launch vehicle to maximize either (1) the injection velocity at a given altitude, or (2) the size of circular orbit, for a given payload is presented. The two-dimensional model includes the rotation of atmosphere with the Earth, the vehicle's lift and drag, variation of thrust with time and altitude, inverse-square gravitational field, and the specified initial vertical take-off. The inequality constraints on the aerodynamic load, control force, and turning rates are also imposed. Using the properties of the central force motion the terminal constraint conditions at coast apogee are transferred to the penultimate stage burnout. Such a transformation converts a time-free problem into a time-fixed one, reduces the number of terminal constraints, improves accuracy, besides demanding less computer memory and time. The adjoint equations are developed in a compact matrix form. The problem is solved on an IBM 360/44 computer using a steepest ascent algorithm. An illustrative analysis of a typical launch vehicle establishes the speed of convergence, and accuracy and applicability of the algorithm.

Computer-Aided Drug Design of Pyranopyrazoles and Related Compounds for Checkpoint Kinase-1

Checkpoint-1 kinase plays an important role in the G(2)M cell cycle control, therefore its inhibition by small molecules is of great therapeutic interest in oncology. In this paper, we have reported the virtual screening of an in-house library of 2499 pyranopyrazole derivatives against the ATP-binding site of Chk1 kinase using Glide 5.0 program, which resulted in six hits. All these ligands were docked into the site forming most crucial interactions with Cys87, Glu91 and Leu15 residues. From the observed results these ligands are suggested to be potent inhibitors of Chk1 kinase with sufficient scope for further elaboration.

Influence of surface chemistry of mesoporous alumina with wide pore distribution on controlled drug release

The crucial role of the drug carrier surface chemical moeities on the uptake and in vitro release of drug is discussed here in a systematic manner. Mesoporous alumina with a wide pore size distribution (2-7 nm) functionalized with various hydrophilic and hydrophobic surface chemical groups was employed as the carrier for delivery of the model drug ibuprofen. Surface functionalization with hydrophobic groups resulted in low degree of drug loading (approximately 20%) and fast rate of release (85% over a period of 5 h) whereas hydrophilic groups resulted in a significantly higher drug payloads (21%-45%) and slower rate of release (12%-40% over a period of 5 h). Depending on the chemical moiety, the diffusion controlled (proportional to time(-0.5)) drug release was additionally observed to be dependent on the mode of arrangement of the functional groups on the alumina surface as well as on the pore characteristics of the matrix. For all mesoporous alumina systems the drug dosages were far lower than the maximum recommended therapeutic dosages (MRTD) for oral delivery. We envisage that the present study would aid in the design of delivery systems capable of sustained release of multiple drugs.

Computational systems approach for drug target discovery

Importance of the field: The shift in focus from ligand based design approaches to target based discovery over the last two to three decades has been a major milestone in drug discovery research. Currently, it is witnessing another major paradigm shift by leaning towards the holistic systems based approaches rather the reductionist single molecule based methods. The effect of this new trend is likely to be felt strongly in terms of new strategies for therapeutic intervention, new targets individually and in combinations, and design of specific and safer drugs. Computational modeling and simulation form important constituents of new-age biology because they are essential to comprehend the large-scale data generated by high-throughput experiments and to generate hypotheses, which are typically iterated with experimental validation. Areas covered in this review: This review focuses on the repertoire of systems-level computational approaches currently available for target identification. The review starts with a discussion on levels of abstraction of biological systems and describes different modeling methodologies that are available for this purpose. The review then focuses on how such modeling and simulations can be applied for drug target discovery. Finally, it discusses methods for studying other important issues such as understanding targetability, identifying target combinations and predicting drug resistance, and considering them during the target identification stage itself. What the reader will gain: The reader will get an account of the various approaches for target discovery and the need for systems approaches, followed by an overview of the different modeling and simulation approaches that have been developed. An idea of the promise and limitations of the various approaches and perspectives for future development will also be obtained. Take home message: Systems thinking has now come of age enabling a `bird's eye view' of the biological systems under study, at the same time allowing us to `zoom in', where necessary, for a detailed description of individual components. A number of different methods available for computational modeling and simulation of biological systems can be used effectively for drug target discovery.

An adaptive drug delivery design using neural networks for effective treatment of infectious diseases: A simulation study

An adaptive drug delivery design is presented in this paper using neural networks for effective treatment of infectious diseases. The generic mathematical model used describes the coupled evolution of concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of a damaged organ due to the disease under the influence of external drugs. From a system theoretic point of view, the external drugs can be interpreted as control inputs, which can be designed based on control theoretic concepts. In this study, assuming a set of nominal parameters in the mathematical model, first a nonlinear controller (drug administration) is designed based on the principle of dynamic inversion. This nominal drug administration plan was found to be effective in curing "nominal model patients" (patients whose immunological dynamics conform to the mathematical model used for the control design exactly. However, it was found to be ineffective in curing "realistic model patients" (patients whose immunological dynamics may have off-nominal parameter values and possibly unwanted inputs) in general. Hence, to make the drug delivery dosage design more effective for realistic model patients, a model-following adaptive control design is carried out next by taking the help of neural networks, that are trained online. Simulation studies indicate that the adaptive controller proposed in this paper holds promise in killing the invading pathogens and healing the damaged organ even in the presence of parameter uncertainties and continued pathogen attack. Note that the computational requirements for computing the control are very minimal and all associated computations (including the training of neural networks) can be carried out online. However it assumes that the required diagnosis process can be carried out at a sufficient faster rate so that all the states are available for control computation.

Prospecting for alternate sources of shikimic acid, a precursor of Tamiflu, a bird-flu drug

Shikimic acid, more commonly known by its anionic form, shikimate, is an important intermediate compound of the ‘shikimate pathway’ in plants and microorganisms1. It is the principal precursor for the synthesis of aromatic amino acids, phenylalanine, tryptophan and tyrosine and other compounds such as alkaloids, phenolics and phenyl propanoids2. It is used extensively as a chiral building block for the synthesis of a number of compounds in both pharmaceutical and cosmetic industries3. In the recent past, the focus on shikimic acid has increased since it is the key precursor for the synthesis of Tamiflu, the only drug against avian flu caused by the H5N1 virus4,5. Shikimic acid is converted to a diethyl ketal intermediate, which is then reduced in two steps to an epoxide that is finally transformed to Tamiflu6.