Current Drug Discovery Technologies (v.11, #3)

Microemulsions Based Transdermal Drug Delivery Systems by Harini C. Vadlamudi, Hyndavi Narendran, Tejeswari Nagaswaram, Gowri Yaga, Jyotsna Thanniru, Prasanna R. Yalavarthi (169-180).
Since the discovery of microemulsions by Jack H Schulman, there has been huge progress made in applyingmicroemulsion systems in plethora of research and industrial process. Microemulsions are optically isotropic systems consistingof water, oil and amphiphile. These systems are beneficial due to their thermodynamic stability, optical clarity,ease of preparation, higher diffusion and absorption rates. Moreover, it has been reported that the ingredients of microemulsioncan effectively overcome the diffusion barrier and penetrate through the stratum corneum of the skin. Hence itbecomes promising for both transdermal and dermal drug delivery. However, low viscosity of microemulsion restrains itsapplicability in pharmaceutical industry. To overcome the above drawback, the low viscous microemulsions were addedto viscous gel bases to potentiate its applications as topical drug delivery systems so that various drug related toxic effectsand erratic drug absorption can be avoided. The present review deals with the microemulsions, various techniques involvedin the development of organic nanoparticles. The review emphasized on microemulsion based systems such as hydrogelsand organogels. The physicochemical characteristics, mechanical properties, rheological and stability principlesinvolved in microemulsion based viscous gels were also explored.

Cubosomes as Targeted Drug Delivery Systems - A Biopharmaceutical Approach by Naga M. Lakshmi, Prasanna R. Yalavarthi, Harini C. Vadlamudi, Jyotsna Thanniru, Gowri Yaga, Haritha K (181-188).
Cubosomes are reversed bicontinuous cubic phases and possess unique physicochemical properties. These specialsystems are receiving much attention for the delivery of various hydrophilic, hydrophobic and amphiphilic drugs withenhanced bioavailability and high loading capacity. A wide variety of drugs are applicable for cubosome formulation forvarious routes of delivery. The lipids used in cubosome formulation are more stable and offer stability to the formulationduring shelf-life. The article reviews about the back ground, techniques of cubosome preparation such as high pressurehomogenization, probe ultrasonication and automated cubosome preparation; and also methods of cubosomes preparationsuch as top down, bottom up and other methods with pictorial presentation. This article emphasizes the phase transitionand also targeted approaches of cubosomes. The characterization studies for cubosomes such as cryo transmission electronmicroscopy, differential scanning calorimetry and scanning electron microscopy followed by in-vitro and in-vivo evaluationstudies of cubosomes were explained with appropriate examples. Recent applications of cubosomes were explainedwith reference to flurbiprofen, odorranalectin, diazepam and dexamethasone. The advantages, disadvantages and limitationsof cubosomal technology were emphasized.

Formulation and Pharmacodynamic Evaluation of Glibenclamide Incorporated Niosomal Gel by Harini C. Vadlamudi, Prasanna R. Yalavarthi, Rao P. Satyanarayana, Vandana KR, Jayasri Vulava, Thulasi Chowdary Gutta (189-196).
Objective: The research aims to formulate and develop the controlled release profile of glibenclamide by encapsulatingglibenclamide into niosomes followed by incorporation into an aqueous gel base. Materials and methods:Glibenclamide incorporated niosomes were prepared by a modified ether injection technique using Span 20/Span 80 andcholesterol. The prepared niosomes were evaluated for chemical incompatibility by FT-IR, morphology, vesicle dimension,encapsulation efficiency, in-vitro diffusion and drug release kinetics. Niosomal gels were prepared by incorporatingthe optimized niosomes into a gel base containing Carbopol 934 and evaluated for viscosity, in-vitro diffusion and in-vivopharmacodynamic activity. Results and discussion: The results indicated that relationship between the amount of Spanand niosomal vesicular diameter was inversely proportional. Microscopic images have illustrated the sphere shape vesicles.The cumulative percentage of drug release from niosomal suspension was observed in the order GN-4>GN-2>GN-6>GN-5>GN-3>GN-1. Glibenclamide gel showed highest percentage drug release when compared to niosomal gel. Invivostudy revealed that the glibenclamide incorporated niosomal gel formulation; GNG-1 is more efficient in loweringblood glucose levels in experimental animals. Conclusion: The niosomal gel of glibenclamide had released the drug inwell controlled manner which is supported by pharmacodynamic activity with evidence of consistent lowering of bloodglucose levels.

Transformation of Curcumin from Food Additive to Multifunctional Medicine: Nanotechnology Bridging the Gap by Mohammad Zaki Ahmad, Shabib Akhter, Nehal Mohsin, Basel A. Abdel-Wahab, Javed Ahmad, Musarrat Husain Warsi, Mahfoozur Rahman, Neha Mallick, Farhan Jalees Ahmad (197-213).
Curcumin (CUR) is a yellow-coloured polyphenolic compound obtained from the rhizomes of Curcuma longa.In-depth pharmacological screening of curcumin has given the evidence that CUR persuades shielding and curative effectsagainst various cancers, cardiovascular, wound healing effect and neuro disorders etc owning to anti-oxidant, antiproliferative,anti-inflammatory, anti-angiogenic and antimicrobial activities. However, miserable bioavailability due topoor aqueous solubility limits the application of CUR in various ailments. Different methodologies including the nanoparticletechnology have been reported for the bioavailability enhancement of CUR. Nanoparticles exhibit not only the improvementin the solubility of CUR and alike lipophilic molecules (resulted in improved bioavailability) but also givingthe opportunity for the disease specific cellular and organ targeting. Improved bioavailability and disease based site specificdelivery of CUR is more likely to bring it as a safe multifunctional medicine.

Single Amino Acid Repeats Connect Viruses to Neurodegeneration by Guglielmo Lucchese, Darja Kanduc (214-219).
We report on a high level of octapeptide matching between HCV, HIV-2, MPV, MUV, EBV, HHV-6, and CMV,and human brain antigens that, when altered, have been specifically associated with neuropathologies such as amyotrophiclateral sclerosis, spinocerebellar ataxia, frontotemporal degeneration, Huntington disease, Parkinson disease, cognitiveimpairment, aphasia and oculomotor apraxia. Quantitatively, the extent of the viral octapeptide sharing with neurodegeneration-associated proteins is in excess when analyzed in a stochastic expectation context. Qualitatively, two main featurescharacterize the peptide matching: 1) many common sequences are single amino acid repeats, and 2) mostly, the sharedoctapeptides are part of experimentally validated epitopes, thus suggesting an immune crossreactive potential of the viralpeptides shared with brain antigens involved in neurodegeneration. The present study may have relevance for peptidebasedtherapeutic approaches to block potential autoimmune crossreactions in neurological diseases and dysfunctional behavior.

Effects of Perfluorocarbon Dodecafluoropentane (NVX-108) on Cerebral Microvasculature in the Healthy Rat by Paula F. Moon-Massat, Rania Abutarboush, Georgina Pappas, Ashraful Haque, Chioma Aligbe, Francoise Arnaud, Charles Auker, Richard McCarron, Anke Scultetus (220-226).
NVX-108, a dodecafluoropentane-based perfluorocarbon (PFC) emulsion, has therapeutic potential as an oxygen-carrying fluid for emergency medical treatment for traumatic brain injury (TBI) and hemorrhagic shock. Potentialcerebral vasoactive properties were assessed by directly measuring pial arteriolar vessel diameters before and after a 30minute intravenous (IV) infusion of 1.0 ml/kg (high dose [H]) or 0.25 ml/kg (low dose [L]) NVX-108 compared to 2.0ml/kg Saline (control) in healthy anesthetized rats (N = 6/group). Results showed that post-infusion vessel diameters forsmall (< 50 µm) and medium (50-100 µm)-sized pial arterioles were significantly (p < 0.05) narrower after only the NVX-108 H infusion although this vasoconstriction was not statistically significant when analyzed as a percentage change inthese vessels. Pial arteriolar vessel diameters were not significantly different for mean value or percentage change after eitherNVX-108 L or Saline infusions. There were no significant post-infusion changes from baseline in systolic, mean ordiastolic blood pressures after any of the treatments although post-infusion blood pressure was statistically higher in theNVX-108 L group compared to NVX-108 H and Saline groups. Arterial blood gases, methemoglob in and lactate werenot different from baseline or among groups. No adverse events were observed at either dose of NVX-108. In conclusion,neither 0.25 nor 1.0 ml/kg NVX-108 caused vasoconstriction in cerebral pial arterioles of healthy rats nor resulted inblood pressure changes; the compound should be considered for further investigation for TBI therapy.

Sodium-Assisted Formation of Binding and Traverse Conformations of the Substrate in a Neurotransmitter Sodium Symporter Model by Agnes Simon, Akos Bencsura, Laszlo Heja, Csaba Magyar, Julianna Kardos (227-233).
Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters(NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the criticalelementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet.Here we present modelling of NSS member neuronal GAT1 with the substrate γ-aminobutyric acid (GABA), the majorinhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicitlipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of halfextendedminor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively.The traverse GABA conformation was further stabilized by GAT1-bound Na+(1). We also observed Na+(1) translocationto GAT1-bound Cl- as well as the appearance of water molecules at GABA and GAT1-bound Na+(2), conjecturingcausality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitorswith high efficacy. The potential for this finding is significant with impact not only in pharmacology but whereverunderstanding of the mechanism of neurotransmitter uptake is valuable.

Biofilm Formation by Candida albicans is Inhibited by 4,4-Dichloro Diphenyl Diselenide (pCl-PhSe)2 by Isabela Bueno Rosseti, Paulo Taube Junior, Claudia Barbosa Ladeira de Campos, Joao Batista Teixeira da Rocha, Maricilia Silva Costa (234-238).
Candida species are the fourth most common cause of nosocomial bloodstream infections. An increase in thefrequency of infections which have become refractory to standard antifungal therapyhave been observed. Recently, the effectof different organochalcogenide compounds reducing both growth and germ tube formation by Candida albicans wasdemonstrated. This work studied the effect of the organochalcogenide compound (pCl-PhSe)2 on both growth and biofilmformation by Candida albicans. A decrease in C. albicans growth in the presence of crescent concentrations of (pCl-PhSe)2 was observed, in a cell density dependent manner. The inhibition of Candida growth by 10µM (pCl-PhSe)2 was~60, 57, 47 and 24%, in cell densities of 103, 104, 105 and 106 cells/ml, respectively. The compound (pCl-PhSe)2 was ableto inhibit biofilm formation by Candida albicans, when biofilm was performed using a cell density of 106 cells/ml. In addition,an increase in both ROS production (96%) and cell membrane permeability (1.107-fold) by 10 µM (pCl-PhSe)2was observed in C. albicans.These results demonstrate that the organochalcogenide compound (pCl-PhSe)2 presents agreat potential to inhibit both growth and biofilm formation by C. albicans.