Mucosal tenofovir 1% gel stimulates cell proliferation and type I/III interferon pathways.

The pyrophosphate (PPi) analogue phosphonoformic acid (PFA or foscarnet) inhibits the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1); however, the mechanisms of drug action and resistance remain elusive. Here we studied the effects of the translocational status of HIV-1 RT on drug binding and inhibition of DNA synthesis. We identified "hot spots" for inhibition during active elongation. Site-specific footprinting analyses revealed that the corresponding complexes exist predominantly in the pre-translocational state. The sensitivity to PFA is significantly reduced with sequences that show a bias toward the post-translocational state. Binding studies showed that PFA stabilizes selectively the complex in the pre-translocated configuration. These findings are consistent with a Brownian ratchet model of polymerase translocation. The enzyme can rapidly shuttle between pre- and post-translocated states. The bound inhibitor acts like a pawl of a ratchet and prevents the forward motion of HIV-1 RT, whereas the bound nucleotide binds to the post-translocated complex and prevents the reverse motion. The proposed mechanisms of RT translocation and drug action are consistent with the PFA-resistant phenotypes. We show that certain sequences and the PFA-resistant E89K mutant diminishes the stability of the pre-translocated complex. In these cases, the enzyme is seen at multiple positions around the 3' end of the primer, which provides a novel mechanism for resistance. These findings validate the pre-translocated complex as a target for the development of novel, perhaps less toxic and more potent inhibitors that block HIV-1 RT translocation.

Characterized by impaired mucociliary clearance with subsequent compromised microbial elimination, chronic rhinosinusitis (CRS) is known as a multifactorial disease process in which bacterial infection or colonization could play a role in the initiation or propagation of the inflammatory response. Various non-systemic, topical therapies have recently emerged as an alternative to conventional oral regimens in managing CRS. A topical sinonasal drug delivery system using a bioabsorbable stent represents one of the most attractive methods among multiple topical delivery options. This review discusses the commercially available topical drug delivery platform (sinus stents) for CRS and its shortcomings. Based on the current drawbacks of sinus stents, this article has also highlighted the future developmental perspectives to create the next generation of a sinus stent, thereby harnessing the full potential of the sinus stent as efficient topical drug delivery for recalcitrant CRS.

5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.

Over the last decades the treatment of disease has been accomplished by administering drug to human body via various routes namely oral, sublingual, rectal and parental etc. The topical drug delivery system generally used when the systems of drug administration fails or in local infection like fungal infection. The topical application of the drug offer the potential advantages for delivering the drug directly to the site of action and delivering the drug for extended period of time at the affected site that mainly acts at the related region. Topical drug delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorder e.g. acne or the cetaceous disorder. The various groups of semisolid preparations, the use of gels has expanded both in cosmetics and in pharmaceutical preparations. Despite of several advantages of gels there is a major limitation in delivery of hydrophobic drug moiety. This limitation can be overcome by the use of novel topical drug delivery i.e. Emulgel. Emulgel is one of the recent technologies in NDDS used topically having characteristics of dual control release i.e. emulsion as well as gel. Emulgel are having major advantages on novel vesicular systems as well as on conventional systems in various aspects. Emulgel for dermatological use have several favorable properties such as being thixotropic, greaseless, easily spreadable, emollient, non-staining; water soluble, longer shelf life, bio-friendly, transparent and pleasing appearance.

A novel reverse transcriptase (RT) assay based on the combined use of macrobead-bound template and125I-iododeoxyuridine-triphosphate (IUTP) was used to determine the IC50values of various RT inhibitors. The results showed that this assay and the conventional assay gave similar IC50values. The introduction of carrier bound template-primer, template, or primer also made it possible to design assays revealing the mechanism of action of various RT inhibitors. Unlabelled inhibitor substance could be incubated with carrier bound template-primer in the presence of excess enzyme, after which the inhibitor was removed and the residual template-primer function was analysed by RT assay. By this procedure it was found that chain elongation terminators like 2′,3′-dideoxy-TTP and 3′-azido-TTP destroyed the template-primer at low concentrations which corresponded to the amount of primer. In contrast, 20–200 times higher concentrations were needed for template-primer destruction when using substances continuously incorporated into the DNA, such as IUTP or TTP. Further, an inhibitor such as phosphonoformic acid (PFA) did not affect the template-primer at all. By excluding the excess RT in the first incubation, it was possible to determine whether or not the template-primer destruction of a given substance was enzyme dependent. Another feature of the macrobead bound template-primer, template, or primer useful for elucidation of the mechanism of action of RT inhibitors is that it can be used to study the interference between an inhibitor and the RTs binding to the template-primer, template, or primer. Briefly, the bead carrying the substrate is incubated with RT in the absence or presence of various inhibitor concentrations, followed by thorough wash. After this the bound RT activity is determined. Such analyses showed that, in contrast to different nucleic acids and oligonucleotides, the classic RT inhibitors either did not interfere or only interfered weakly with the binding of RT to the carrier bound template-primer, template, or primer. Due to the technical simplicity of this novel RT assay it is a far better tool to rapidly screen RT inhibitors than conventional procedures used to date. Further, the use of carrier bound template-primer, template, or primer offers a unique and simple technology for analysis of the mechanisms of action of different RT inhibitors and for analysis of the characteristics of different RT isozymes and mutated RT.

Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

Researchers have been inventing new drugs since time immemorial. Of late it is established that the development of new drugs alone is not sufficient to ensure progress in drug therapy. The missing link is a potential strategy. It involves the apt selection of drug carrier systems. Lipid particles based on triglycerides, waxes or fatty acids as matrix lipids are being intensively investigated as potential carrier systems, in particular for lipophilic substances. The lipospheres system is a newly introduced lipid-based carrier system developed for parenteral and topical delivery of drugs. Lipospheres consist of water-dispersible solid microparticles of particle size between 0.2–500 μm in diameter and composed of a solid hydrophobic fat core stabilized by one monolayer of phospholipid molecules embedded in their surface. A new dimension in this area is delivery of peptides and oral delivery of drugs. The liposphere carrier system has several advantages over other delivery systems, including emulsions, liposomes and microspheres, such as: better physical stability, low cost of ingredients, ease of preparation and scale-up, high dispersibility in an aqueous medium, high entrapment of hydrophobic drugs, controlled particle size and extended release of entrapped drug.

Human immunodeficiency virus type 1 (HIV-1)-specific pyridinone reverse transcriptase (RT) inhibitors prevent HIV-1 replication in cell culture (M. E. Goldman, J. H. Nunberg, J. A. O'Brien, J.C. Quintero, W. A. Schleif, K. F. Freund, S. L. Gaul, W. S. Saari, J. S. Wai, J. M. Hoffman, P. S. Anderson, D. J. Hupe, E. A. Emini, and A. M. Stern, Proc. Natl. Acad. Sci. USA 88:6863-6867, 1991). In contrast to nucleoside analog inhibitors, such as AZT, which need to be converted to triphosphates by host cells, these compounds act directly to inhibit RT via a mechanism which is noncompetitive with respect to deoxynucleoside triphosphates. As one approach to define the mechanism of action of pyridinone inhibitors, we isolated resistant mutants of HIV-1 in cell culture. Serial passage in the presence of inhibitor yielded virus which was 1,000-fold resistant to compounds of this class. Bacterially expressed RTs molecularly cloned from resistant viruses were also resistant. The resistant RT genes encoded two amino acid changes, K-103 to N and Y-181 to C, each of which contributed partial resistance. The mutation at amino acid 181 lies adjacent to the conserved YG/MDD motif found in most DNA and RNA polymerases. The mutation at amino acid 103 lies within a region of RT which may be involved in PPi binding. The resistant viruses, although sensitive to nucleoside analogs, were cross-resistant to the structurally unrelated RT inhibitors TIBO R82150 (R. Pauwels, K. Andries, J. Desmyter, D. Schols, M. J. Kukla, H. J. Breslin, A. Raeymaeckers, J. Van Gelder, R. Woestenborghs, J. Heykanti, K. Schellekens, M. A. C. Janssen, E. De Clercq, and P. A. J. Janssen, Nature [London] 343:470-474, 1990) and BI-RG-587 (V. J. Merluzzi, K. D. Hargrave, M. Labadia, K. Grozinger, M. Skoog, J. C. Wu, C.-K. Shih, K. Eckner, S. Hattox, J. Adams, A. S. Rosenthal, R. Faanes, R. J. Eckner, R. A. Koup, and J. L. Sullivan, Science 250:1411-1413, 1990). Thus, these nonnucleoside analog inhibitors may share a common binding site on RT and may all make up a single pharmacologic class of RT inhibitor. This observation may have important implications for the clinical development of these compounds.

Background: Nanostructured lipid carriers (NLCs) of fluconazole were prepared to improve permeability and thereby effective topical drugdelivery. Materials and methods: NLCs were prepared andevaluated, and then the optimized NLC suspension was incorporated into a gel that was further evaluated for topical drug delivery. Results and discussion: F-2 NLC formulation was optimized based on results of particle size (161.3±1.385nm), polydispersity index (0.401), zeta potential (-33±0.46), entrapment efficiency (82.26±0.91%) and in vitro drug release (76.40±0.21%). Ex vivo skin permeation studies showed flux of F-2 gel and the comparisonmarketed gel as 0.21and 0.18mg/cm2/h, respectively. The in vitro antifungal study revealed significantly better activity compared with the marketed gel. Conclusion: Fluconazole NLCs increase drugpermeability and proved to be effective in topical drug delivery.

Statistical and econometric analysis of the treatment of HIV/AIDS

Topical Drug Delivery System Drug: The application of a medication containing formulation for the skin in order to treat the cutaneous condition directly is known as topical drug delivery. Factors Affecting Topical Drug Delivery System: Physiological factors are Skin condition, Lipid content, Blood flow, Skin hydration, Skin temperature and Physiochemical factors are partition coefficient, Molecular weight, Drug concentration, Effect on vehicles. Physiology of Skin: Skin consists of Epidermis Dermis Subcutaneous Tissue. Epidermis is composed basically of: Keratinocytes, Melanocytes, Langerhans cells. Introduction: Emulgels are emulsions oil-in-water or water-in-oil that are combined with an emulsifying agent to form gels. Emulgel is made up of two components: Emulsion: An emulsion is a biphasic system made up of two immiscible liquids, which is one of finely and consistently propagated as globules throughout the other to form an emulsion. Gel: According to the U.S.P., gels are semisolid systems made up of a dispersion whether large organic molecules or small inorganic particles that are encased and penetrated by liquid. Characterization and Evaluation of Herbal Emulgel: Physical Appearance, pH, Viscosity study, Spreadability, Total Ash Value, Loss on drying, In-vitro Diffusion Study. Conclusion: The dosage forms are enhancing topical drug delivery of natural drugs for various topical problem.

Topical drug delivery has been used for centuries for the treatment of local skin disorders. Emulgel have emerged as one of the most interesting topical delivery system as it has dual control release system i.e. gel and emulsion. One side the topical applications of the drug offers the potential advantages of delivering the drug directly to the site of action and secondly delivering the drug for extended period of time at the effected site. Topical non-steroidal anti-inflammatory drug (NSIAD) formulations are designed to deliver therapeutic levels of the active ingredients to the inflamed tissue without elevating serum levels after application on the skin. This route is an attractive alternative to the oral administration of NSAIDS which is associated with high incidence of gastrointestinal tract (GIT) complications and other systemic toxic effects. Flurbiprofen is a potent non-steroidal anti-inflammatory agent usually well tolerated as compared to other NSAIDS product. It has analgesic and antipyretic properties. It is used in the treatment of rheumatic disorders such as ankylosing spondilities, oesteoarthritis and intraoperative miosis. It suffers from major GIT disturbances. The aim of the present study was to develop an emulgel formulation of flurbiprofen using water soluble polymer of hydroxy propyl methyl cellulose (HPMC K100M), carbopol 940, carbopol 941 and xanthan gum. Oleic acid and propylene glycol were used as permeation enhancers. The influence of the type of the gelling agent on the drug release from the prepared emulgel was investigated. The prepared emulgels were evaluated for their physical appearance, pH determination, viscosity, spreadability, extrudability, in-vitro drug release, ex-vivo drug release and stability. All the prepared emulgels showed acceptable physical properties, homogeneity, consistency, spreadability, viscosity and pH value. The emulgels were found to be stable with respect to physical appearance, pH, and rheological properties and drug content at all temperature and conditions for one month. Keywords: Emulgel, Topical drug delivery, Flurbiprofen, Carbopol, Hydroxy propyl methyl cellulose

Background: Topical drug delivery is a painless route of drug administration. Skin is one of the most easily accessible parts of human body for topical administration and also is a main route of topical drug delivery system. There are different skin diseases and infections caused by fungus. An antifungal compound is a pharmaceutical fungicide used to treat mycoses such as dermatophytes which have the ability to attack keratinized tissues and used keratin cause dermatophytosis, the most common human contagious fungal disease. Because of drug resistance, side effects and cytotoxicity associated with long-term treatment with antifungal drugs, finding new useful drugs to treat fungal infections is necessary. Objectives: The purpose of the present study was to formulate topical gel containing stabilized extract of Lactobacillus as an antidermatophytic preparation and evaluate its physicochemical properties. Materials and Methods: Lactobacillus casei was cultured in MRS anaerobically and then its extract was collected by separating the bacterial cells with centrifugation. Firstly, antifungal activity of the extract against four dermatophyte species (Tricophyton rubrum, Tricophyton verocosum, Microsporum canis, and Microsporum gypseum) was done using the well-plate method. The macrodilution method was used to determine the minimum inhibitory concentration (MIC) of the probiotic extract in the range of 0.0625 mg/mL to 1 mg/mL. To select the best gel formulation, one general formula was considered and then corrected by changing the polymer ratio. Gel formulations were characterized for monotonousness, probiotic extract content, pH determination, viscosity measurement, grittiness and antifungal activity in comparison to topical cream of clotrimazole 1%. Results: The results showed the same effect of the probiotic extract against 4 pathogens; however, the greatest average zone of inhibition was measured 34 mm against T. rubrum. The MIC test showed that stabilized probiotic extract had more antidermatophyte effect compared to supernatant (P < 0.01). Formulation containing 5% probiotic extract (F5) was chosen as the best antidermatophyte topical gel because of its more stability. Also, all formulations were studied for antifungal activity compared to clotrimazole, and F5 was found to be significantly more effective than clotrimazole (P < 0.01). Conclusions: The results of this study show that the beneficial effect of Lactobacillus casei is related to its metabolites. A formulated gel shows a significant antidermatophytosis activity compared to clotrimazole.

Discovery of synergistic permeation enhancers for oral drug delivery

Exosome-biomimetic nanocarriers for oral drug delivery