Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.

Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis.

Oxone-DMSO Triggered Methylene Insertion and C(sp)-C(sp)-H-C(sp) Bond Formation to Access Functional Bis-Heterocycles.

Metal-free insertion of a methylene group was achieved for the construction of a new C(sp)-C(sp)-H-C(sp) bond in order to prepare novel bis-heterocyclic scaffolds. The complete mechanistic investigations included experimental study and DFT calculations, and various symmetric and unsymmetric bis-pyrazoles as well as other pyrazole-based bis-heterocyclic molecules were prepared in moderate to high yields. Further modification of the bridged methylene group in the unsymmetric pyrazoles generated a chiral center to extend the scope of this method.

Direct N-heterocyclization of hydrazines to access styrylated pyrazoles: synthesis of 1,3,5-trisubstituted pyrazoles and dihydropyrazoles.

A microwave-assisted method has been developed for the synthesis of tri-substituted pyrazoles direct N-heterocyclization of hydrazines with metal-acetylacetonate and -dibenzylideneacetonate without using any base or additives. Most importantly, the synthesis of 1-aryl-5-phenyl-3-styryl-1-pyrazoles was achieved in a single step using hydrochloride salt of various phenylhydrazines and this is the first report for direct construction of these molecules. The reaction medium and microwave conditions play a critical role for their selective product formation during the reaction.

4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines as inhibitors of mammalian target of rapamycin.

A series of 4-(N-phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines was designed, synthesized and evaluated for their biological potential as anticancer agents by screening the molecules against panel of five human cancer cell lines viz. HL-60, MiaPaCa-2, HCT116, PC-3 and HEP-G2. The series has shown good mTOR inhibitory activity at 0.

DMSO/I2 mediated C-C bond cleavage of α-ketoaldehydes followed by C-O bond formation: a metal-free approach for one-pot esterification.

A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C-C bond cleavage of aryl-/heteroaryl- or aliphatic α-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol.

A Novel Quinoline Based Second-generation mTOR Inhibitor that Induces Apoptosis and Disrupts PI3K-Akt-mTOR Signaling in Human Leukemia HL-60 Cells.

Deregulation of the PI3K-Akt-mTOR pathway is unanimously pragmatic in a number of tumors. This pathway pedals proliferation, survival, translation, and coupled with tumor-associated endurance. Current efforts focus on the discovery and development of novel inhibitors of this pathway.

C-H oxygenation and N-trifluoroacylation of arylamines under metal-free conditions: a convenient approach to 2-aminophenols and N-trifluoroacyl-ortho-aminophenols.

Direct ortho-hydroxylation through C-H oxygenation and N-trifluoroacylation of anilines was achieved in a single step under metal-free conditions by using a combination of TFA and oxone. The method allowed the formation of functionalised amino phenolic compounds such as ortho-hydroxy-N-trifluoroacetanilides in good yields with broad substrate scope.

Role of cryosurgery in the surgical management of nasoalveolar cyst.

Nasoalveolar cysts are rare developmental, non-odontogenic soft tissue lesions present in the submucosal area of the nasal alar region of the face. The management of nasoalveolar cyst is surgical excision or enucleation by sublabial approach. Most of the times surgeon finds difficult in complete removal of cyst wall especially in the infected cases.

Establishment of in vitro-in vivo equivalence of highly variable drugs - a generic product development perspective.

In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability.

Low dose aspirin estimation: an application to a human pharmacokinetic study.

Low dose to very high dose aspirin is used to prevent heart attack. We have developed and validated a sensitive and robust method that could detect low levels of aspirin and salicylic acid in plasma and also a novel sample collection procedure to carry out sample preparation at room temperature. The total run time was 3.

LC-MS/MS method for simultaneous estimation of candesartan and hydrochlorothiazide in human plasma and its use in clinical pharmacokinetics.

Background: ATACAND HCT(®) (candesartan cilexetil-hydrochlorothiazide [CAN-HCTZ]) combines an angiotensin II receptor (type AT1) antagonist and a diuretic. Quantification of CAN and HCTZ in biological matrices has traditionally been difficult - developing a single method with the desired sensitivity has been the issue.

Results: A high-throughput bioanalytical method for the analysis of CAN and HCTZ in human plasma using liquid-liquid extraction and LC coupled to negative ion mode MS/MS has been developed and validated according to US FDA guidelines.

Development and pharmacological evaluation of a PEG based nanoparticulate camptothecin analog for oral administration.

The aim of this study was to formulate polyethylene glycol (PEG) based nanoparticulate camptothecin analog for oral administration and to evaluate its pharmacological activity. Camptothecin analog (CA) belongs to topoisomerase-I inhibitor class of compounds with proven antitumor activity but exhibits poor solubility. To enhance solubility and oral bioavailability, a PEG based nanoparticulate formulation was developed using a high pressure homogenization technique.

Preparation and characterization of nitrendipine solid lipid nanoparticles.

Nitrendipine, a dihydropyridine calcium channel blocker, has very poor oral bioavailability (10-20%) due to first pass effect. Solid lipid nanoparticle (SLN) delivery systems of nitrendipine have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers stearylamine and dicetyl phosphate. SLNs were prepared by hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperatures above the melting point of lipids.

Targeting enteral endocrinal L-cells with dietary carbohydrates, by increasing the availability of miglitol in the intestinal lumen, leads to multi-fold enhancement of plasma glucagon-like peptide-1 levels in non-diabetic canines.

The principle aim of this study was to design a controlled release (CR), bioadhesive formulation of miglitol (in form of pellets) which would regulate the post-prandial glucose levels via reversible inhibition of α-glucosidase enzyme as well as by modulating the glucagon-like peptide-1 (GLP-1) pathway in non-diabetic canines. A multilayered pellet formulation which was both bioadhesive (because of hydroxy propyl methyl cellulose polymer) and CR (because of the ethyl cellulose layer) was formulated. We report a novel finding that the CR formulation of miglitol (S3) induced a 2.

Core-in-cup tablet design of metoprolol succinate and its evaluation for controlled release.

The core-in-cup matrix tablets of Metoprolol succinate were prepared by wet granulation technique. Of all the investigated formulations, the optimized formulation of MS-09 followed zero-order kinetics of drug release. Trail on MS-09 was formulated using 7.

Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal alpha-glucosidases and enhancement of plasma glucagon like peptide-1 levels.

Alpha-glucosidase enzyme is present ubiquitously throughout the lumen of the small intestine. It is responsible for the breakdown of complex into simple carbohydrates. alpha-Glucosidase inhibitors such as miglitol, are drugs that have greater affinity towards this enzyme in comparison to carbohydrates.

Ketorolac tromethamine transdermal gel: development, in vitro and in vivo evaluation.

The authors developed and evaluated a transdermal gel formulation of ketorolac tromethamine (ketorolac) for the treatment of nociceptive somatic pain. The formulation was optimized for skin permeation enhancers, pH of the system, and dosage strength using in vitro and in vivo techniques. Of the various permeation enhancers evaluated, dimethyl sulfoxide (DMSO) and oleic acid were found to significantly increase skin permeation flux of ketorolac.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies.

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles--flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification.

Design and evaluation of a novel matrix type multiple units as biphasic gastroretentive drug delivery systems.

A biphasic gastroretentive floating drug delivery system with multiple-unit mini-tablets based on gas formation technique was developed to maintain constant plasma level of a drug concentration within the therapeutic window. The system consists of loading dose as uncoated core units, and prolonged-release core units are prepared by direct compression process; the latter were coated with three successive layers, one of which is seal coat, an effervescent (sodium bicarbonate) layer, and an outer polymeric layer of polymethacrylates. The formulations were evaluated for quality control tests, and all the parameters evaluated were within the acceptable limits.

Development of SLN and NLC enriched hydrogels for transdermal delivery of nitrendipine: in vitro and in vivo characteristics.

The purpose of this research was to investigate novel particulate carrier systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carrier (NLC) for transdermal delivery of nitrendipine (NDP). For this investigation, four different gel-forming agents were selected for hydrogel preparation. Aqueous dispersions of lipid nanoparticles made from trimyristin (TM) were prepared by hot homogenization technique followed by sonication and then incorporated into the freshly prepared hydrogels.

Development of nitrendipine controlled release formulations based on SLN and NLC for topical delivery: in vitro and ex vivo characterization.

The aim of the investigation is to develop solid lipid nanoparticles (SLN) and nano-structured lipid carrier (NLC) as carriers for topical delivery of nitrendipine (NDP). NDP-loaded SLN and NLC were prepared by hot homogenization technique followed by sonication, and they were characterized for particle size, zeta potential, entrapment efficiency, stability, and in vitro release profiles. Also the percutaneous permeation of NDPSLN A, NDPSLN B, and NDPNLC were investigated in abdominal rat skin using modified Franz diffusion cells.

Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles.

The purpose of this research was to study whether the bioavailability of lovastatin could be improved by administering lovastatin solid lipid nanoparticles (SLN) duodenally to rats. Lovastatin SLN were developed using triglycerides by hot homogenization followed by ultrasonication. Particle size and zeta potential were measured by photon correlation spectroscopy.

Pharmacokinetics, tissue distribution and bioavailability of nitrendipine solid lipid nanoparticles after intravenous and intraduodenal administration.

Purpose: The aim of this research was to study whether the bioavailability of nitrendipine (NDP) could be improved by administering nitrendipine solid lipid nanoparticles (SLN) duodenally to rats.

Methods: Nitrendipine was incorporated into SLN prepared by hot homogenization followed by ultrasonication method. SLN were produced using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers (dicetyl phosphate, DCP and stearylamine, SA).

Radioprotective effect of transferrin targeted citicoline liposomes.

The high level of expression of transferrin receptors (Tf-R) on the surface of endothelial cells of the blood-brain-barrier (BBB) had been widely utilized to deliver drugs to the brain. The primary aim of this study was to use transferrin receptor mediated endocytosis as a pathway for the rational development of holo-transferrin coupled liposomes for drug targeting to the brain. Citicoline is a neuroprotective agent used clinically to treat for instance Parkinson disease, stroke, Alzheimer's disease and brain ischemia.