MODIFIED FORMULATION OF FEBUXOSTAT: IMPROVED EFFICACY AND SAFETY

Objective: Febuxostat, a xanthine oxidoreductase inhibitor, is a drug of choice for hyperuricemia and Gout. But it also suffers from drawbacks in terms of pharmacokinetic profile and toxicity. It is available as immediate release formulation in the market. The objective is to develop a modified release formulation of febuxostat that can serve the dual purpose of increasing the efficacy and decreasing the toxicity, thereby improving safety.Methods: Pharmacokinetic and pharmacodynamic data, including drug concentration profile, efficacy data and toxicity data have been reviewed thoroughly. Based on available data, target pharmacokinetic profile has been identified as about 50 % reduction in Cmax and improvement in plasma drug concentration above required level during 6-24 hour. Desired in-vitro dissolution profile has been selected, and formulation modification has been sought to achieve the desired profile. The formulation has been prepared with a partial dose in the form of immediate release (IR) and remaining dose as an extended release (ER). IR and ER formulations have been developed separately and combined to form Inlay tablets containing ER inner tablet surrounded by IR.Results: Based on dissolution data and Wagner-Nelson calculations, the plasma concentration profile has been predicted for the developed formulation. It reconfirms that developed formulation will achieve the desired objectives. Formulation stability has been established up to 6 months under accelerated conditions.Conclusion: The developed formulation is a potential candidate for filing to a regulatory agency with the advantage of higher efficacy and less toxicity, which will be beneficial to the patient population and has good commercial viability.Â

The chemistry of gold with unsaturated organics: coordination, activation and catalysis

The aim was to understand gold‟s reactivity with unsaturated organic bonds. We focused on the role of supporting ligands, activating agents and the organic substrates employed in such reactions. Gold tetrafluorophthalimidates have been isolated, with coordination found to be surprisingly strong; no [N(CO)2C6F4]- displacement with ζ- and π-donors were observed. B(C6F5)3 and norbornene addition to [(Ph3P)Au{N(CO)2C6F4}] leads to a [Au(nbe)3]+ cation paired with a new, non-coordinating phthalimido-diborate anion. Aryl-N substituents of [(Ph3P)Au{nacnac}] influences its differing solid state structures; examples of κ1- and (the first example of) asymmetric κ2-coordination was observed. In solution these complexes show intricate fluxional behaviour. Attempts at oxidation to synthesise a gold(III)-oxo complex were unsuccessful. In situ generated Au+ cations can selectively activate benzylic C-H and C-C bonds of methylarenes and dimesitylmethane under mild conditions. Mechanistic and kinetic studies with hexamethylbenzene have identified a C-H activation step of and the formation of a benzyl cation intermediate. Zwitterionic and heterobimetallic gold(I) complexes containing a (o-sulfophenyl)- diphenylphosphine ligand were formed, with the supporting Cl- and R2S ligands on gold(I) found to be non-labile, resulting in the complexes being catalytically inert. The incorporation of anions to [(C6F5)4Au2Ag2]n clusters gave structural and photoluminescent data, which evidently show that the emission colours of these powders are dependent on the extent of aurophilic bonding between cluster units. Dechlorination of [(C6F5)2AuCl]2 in the presence of olefins were prone to reductive elimination to yield „naked‟ gold(I)-(η2)olefin complexes. Repeating the reaction with benzene, toluene and xylenes appeared to give the unstable and unidentified gold(I)-arene analogues. 1H NMR monitoring of gold(III)-catalysed hydroarylation reactions revealed that silver salts do not act as a simple chloride scavengers, but identification of the gold species in solution was unsuccessful. In addition, a family of highly electrophilic fluorosulfonium and fluorobismuthium compounds were synthesised. These complexes decomposed at room temperature by intermolecular fluorination of the aryl substituents. N.B.: CIF files were attached to this thesis at the time of its submission. Please refer to the author for further details

Functional Organization of the Human Brain: How We See, Feel, and Decide.

The human brain is responsible for constructing how we perceive, think, and act in the world around us. The organization of these functions is intricately distributed throughout the brain. Here, I discuss how functional magnetic resonance imaging (fMRI) was employed to understand three broad questions: how do we see, feel, and decide? First, high-resolution fMRI was used to measure the polar angle representation of saccadic eye movements in the superior colliculus. We found that eye movements along the superior-inferior visual field are mapped across the medial-lateral anatomy of a subcortical midbrain structure, the superior colliculus (SC). This result is consistent with the topography in monkey SC. Second, we measured the empathic responses of the brain as people watched a hand get painfully stabbed with a needle. We found that if the hand was labeled as belonging to the same religion as the observer, the empathic neural response was heightened, creating a strong ingroup bias that could not be readily manipulated. Third, we measured brain activity in individuals as they made free decisions (i.e., choosing randomly which of two buttons to press) and found the activity within fronto-thalamic networks to be significantly decreased compared to being instructed (forced) to press a particular button. I also summarize findings from several other projects ranging from addiction therapies to decoding visual imagination to how corporations are represented as people. Together, these approaches illustrate how functional neuroimaging can be used to understand the organization of the human brain

Improvement of physicochemical parameters of acyclovir using cocrystallization approach

Acyclovir is an antiviral drug having potent activity against the virus of herpes family and varicella zoster. Unfortunately, drug suffers very poor oral bioavailability (15-30%). The main objective of present study was to develop acyclovir cocrystals with improved solubility which may result in improvement of bioavailability. Hansen solubility approach was used as a tool to predict the cocrystal formation of a drug with selected coformer. Cocrystals of acyclovir with various coformers were screened in order to enhance their water solubility. Cocrystals of the drug were prepared using various methods like solvent evaporation, wet grinding, and antisolvent addition. Formation of cocrystals by solvent evaporation method was found to be better method amongst all. Optimization of cocrystal formation was carried out by employing different solvents as well as the stoichiometric ratio of acyclovir with that of coformer. Synthesis of cocrystals was optimized using water as a solvent system resulted in good agreements. The potential cocrystal formation of acyclovir was characterized by IR, PXRD and DSC techniques. An in-vitro dissolution study was performed to determine the dissolution rate of cocrystals. The results suggest that acyclovir forms cocrystals with tartaric acid and the initial dissolution rate of synthesized cocrystals were considerably faster as compared to pure acyclovir

Empathic Neural Responses Predict Group Allegiance.

Watching another person in pain activates brain areas involved in the sensation of our own pain. Importantly, this neural mirroring is not constant; rather, it is modulated by our beliefs about their intentions, circumstances, and group allegiances. We investigated if the neural empathic response is modulated by minimally-differentiating information (e.g., a simple text label indicating another's religious belief), and if neural activity changes predict ingroups and outgroups across independent paradigms. We found that the empathic response was larger when participants viewed a painful event occurring to a hand labeled with their own religion (ingroup) than to a hand labeled with a different religion (outgroup). Counterintuitively, the magnitude of this bias correlated positively with the magnitude of participants' self-reported empathy. A multivariate classifier, using mean activity in empathy-related brain regions as features, discriminated ingroup from outgroup with 72% accuracy; the classifier's confidence correlated with belief certainty. This classifier generalized successfully to validation experiments in which the ingroup condition was based on an arbitrary group assignment. Empathy networks thus allow for the classification of long-held, newly-modified and arbitrarily-formed ingroups and outgroups. This is the first report of a single machine learning model on neural activation that generalizes to multiple representations of ingroup and outgroup. The current findings may prove useful as an objective diagnostic tool to measure the magnitude of one's group affiliations, and the effectiveness of interventions to reduce ingroup biases

Functional Organization of the Human Brain: How We See, Feel, and Decide.

The human brain is responsible for constructing how we perceive, think, and act in the world around us. The organization of these functions is intricately distributed throughout the brain. Here, I discuss how functional magnetic resonance imaging (fMRI) was employed to understand three broad questions: how do we see, feel, and decide? First, high-resolution fMRI was used to measure the polar angle representation of saccadic eye movements in the superior colliculus. We found that eye movements along the superior-inferior visual field are mapped across the medial-lateral anatomy of a subcortical midbrain structure, the superior colliculus (SC). This result is consistent with the topography in monkey SC. Second, we measured the empathic responses of the brain as people watched a hand get painfully stabbed with a needle. We found that if the hand was labeled as belonging to the same religion as the observer, the empathic neural response was heightened, creating a strong ingroup bias that could not be readily manipulated. Third, we measured brain activity in individuals as they made free decisions (i.e., choosing randomly which of two buttons to press) and found the activity within fronto-thalamic networks to be significantly decreased compared to being instructed (forced) to press a particular button. I also summarize findings from several other projects ranging from addiction therapies to decoding visual imagination to how corporations are represented as people. Together, these approaches illustrate how functional neuroimaging can be used to understand the organization of the human brain

IN SILICO MOLECULAR DOCKING AND PHARMACOKINETIC PREDICTION OF GALLIC ACID DERIVATIVES AS PPAR-γ AGONISTS

Objective: To perform molecular docking and pharmacokinetic prediction of gallic acid derivatives as Peroxisome proliferator-activated receptors-γ (PPAR-γ) agonist for the treatment of diabetes.Methods: Molecular docking study on gallic acid and different derivatives of gallic acid was performed using GOLD v5.2 software. In addition to this, all the derivatives were analysed for drug likeliness, Lipinski's rule and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties using online tools like admet SAR, Molinspiration and Medchem designer.Results: Molecular docking studies reveals that SSP-12, SSP-13 and SSP-40 demonstrated significant binding to the PPAR-γ receptor with good Gold score fitness (73.11, 69.86 and 75.51 respectively) and relative ligand energy (-8.26,-8.33 and-7.82, respectively) as compared to standard drugs i.e. rosiglitazone and pioglitazone, (64.10 and 66.72) and (-4.30 and-2.47) respectively.Conclusion: The final results of molecular docking along with information gathered from pharmacokinetic parameters of gallic acid derivatives may be utilised further for the development of newer PPAR-γ agonists having anti-diabetic potential with better pharmacokinetic and pharmacodynamic profile

The synthesis and characterization of Cu2ZnSnS4 thin films from melt reactions using xanthate precursors

Kesterite, Cu2ZnSnS4 (CZTS), is a promising absorber layer for use in photovoltaic cells. We report the use of copper, zinc and tin xanthates in melt reactions to produce Cu2ZnSnS4 (CZTS) thin films. The phase of the as-produced CZTS is dependent on decomposition temperature. X-ray diffraction patterns and Raman spectra show that films annealed between 375 and 475 °C are tetragonal, while at temperatures <375 °C hexagonal material was obtained. The electrical parameters of the CZTS films have also been determined. The conduction of all films was p-type, while the other parameters differ for the hexagonal and tetragonal materials: resistivity (27.1 vs 1.23 Ω cm), carrier concentration (2.65 × 10+15 vs 4.55 × 10+17 cm−3) and mobility (87.1 vs 11.1 cm2 V−1 s−1). The Hall coefficients were 2.36 × 103 versus 13.7 cm3 C−1

Production of few-layer phosphorene by liquid exfoliation of black phosphorus

We report the liquid exfoliation of black phosphorus to form few-layer phosphorene nanosheets.</p

Synthesis and Luminescence Modulation of Pyrazine-Based Gold(III) Pincer Complexes

The first examples of pyrazine-based gold(III) pincer complexes have been synthesized; their intense photoemissions can be modified by interactions with the non-coordinating pyrazine-N atom. Luminescence modulation is possible without the need for altering the ligand framework. Emissions shift from red (77 K) to blue (298 K) due to thermally activated delayed fluorescence (TADF