Design of quetiapine fumarate loaded polyethylene glycol decorated graphene oxide nanosheets: Invitro-exvivo characterization.

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R2: 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF.

Integrated computational approach towards identification of HSPG and ACE2 mimicking moieties for SARS-CoV-2 inhibition.

A key step to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is to prevent the entry of the virus into the host cells. The receptor-binding domains (RBDs) of spike proteins of SARS-CoV and other human coronaviruses utilize heparan sulfate proteoglycans (HSPGs) as the primary receptors for their accumulation on the cell surface and then scan for binding to the main entry receptor angiotensin-converting enzyme 2 (ACE2). SARS-CoV and SARS-CoV-2 share structurally similar RBDs and therefore, it is possible that SARS-COV-2 primarily binds to HSPGs followed by binding to the ACE2 receptors. A promising strategy to inhibit virus infection is to circulate exogenous bioactive moieties structurally mimicking cellular HSPG and ACE2 which act as decoy receptors binding to SARS-CoV-2 and competitively inhibit virus entry to the host cells mediated by cellular-bound HSPG and ACE2. Using a molecular docking tool, we identified carboxymethyl benzyl amide sulfonate (CMBS) and polyanetholesulfonic acid (PAS) as the suitable HSPG mimicking ligands, and Paenibacillus sp. B38-derived carboxypeptidase (B38-CAP) and Bacillus subtilis-derived carboxypeptidase (BS-CAP) as the potential ACE2-like enzymes having a strong binding affinity to the spike proteins as that of cellular HSPG and ACE2. Further, the binding stability and compactness of these moieties with SARS-CoV-2 were analyzed through molecular dynamics (MD) simulations, and the results indicated that these moieties form well-stable complexes with the RBD of spike proteins. The identified moieties could be conjugated to the surfaces of non-toxic nanoparticles to provide multiple interactions to efficiently shield SARS-CoV-2, and inhibit viral entry to the host cells.

Strongly nonlinear wave dynamics of continuum phononic materials with periodic rough contacts.

We investigate strongly nonlinear wave dynamics of continuum phononic material with discrete nonlinearity. The studied phononic material is a layered medium such that the elastic layers are connected through contact interfaces with rough surfaces. These contacts exhibit nonlinearity by virtue of nonlinear mechanical deformation of roughness under compressive loads and strong nonlinearity stemming from their inability to support tensile loads. We study the evolution of propagating Gaussian tone bursts using time-domain finite element simulations. The elastodynamic effects of nonlinearly coupled layers enable strongly nonlinear energy transfer in the frequency domain by activating acoustic resonances of the layers. Further, the interplay of strong nonlinearity and dispersion in our phononic material forms stegotons, which are solitarylike localized traveling waves. These stegotons satisfy properties of solitary waves, yet exhibit local variations in their spatial profiles and amplitudes due to the presence of layers. We also elucidate the role of rough contact nonlinearity on the interrelationship between the stegoton parameters as well as on the generation of secondary stegotons from the collision of counterpropagating stegotons. The phononic material exhibits strong acoustic attenuation at frequencies close to (and fractional multiples of) layer resonances, whereas it causes energy propagation as stegotons for other frequencies. This study sheds light on the wave phenomena achievable in continuum periodic media with local nonlinearity, and opens opportunities for advanced wave control through discrete and local contact nonlinearity.

Effective property evaluation and analysis of three-dimensional periodic lattices and composites through Bloch-wave homogenization.

Periodic lattices offer enhanced mechanical and dynamic properties per unit mass, and the ability to engineer the material response by optimizing the unit cell. Characterizing the effective properties of these lattice materials through experiments can be a time consuming and costly process, so analytical and numerical methods are crucial. Specifically, the Bloch-wave homogenization approach allows one to characterize the effective static properties of the lattice while simultaneously analyzing wave propagation properties such as band gaps, propagating modes, and wave directionality. While this analysis has been used for some time, a thorough study of this approach on three-dimensional (3D) lattice materials with different symmetries and geometries is presented here. Bloch-wave homogenization is applied to extract the effective stiffness tensor of 3D periodic lattices and confirmed with elastostatic homogenization, both within a finite element framework. Multiple periodic lattices with cubic, transversely isotropic, and tetragonal symmetry, including an auxetic geometry, over a wide range of relative densities are analyzed. Further, this approach is used to analyze 3D periodic composite structures, and a way to tailor their overall anisotropy is demonstrated. This work can serve as the basis for nondestructive evaluation of metamaterials properties using ultrasonic velocity measurements.

Prevalence and predictors of ventriculo-atrial conduction in structurally normal hearts.

BACKGROUND: The prevalence of ventriculo-atrial (VA) conduction varies from 20% to 90%, depending on the population studied (Militianu et al., 1997; Inoue et al., 1985; Kazmierczak et al., 1993; Ciemniewski et al., 1990; Hayes and Furman, 1983; Westveer et al., 1984). This wide range is mostly based on studies done in patients with implanted devices or impaired atrioventricular conduction. However, the prevalence of VA conduction in structurally normal heart has not been well documented till date. OBJECTIVE: To study the prevalence and identify predictors of retrograde conduction via the His-Purkinje system and AV node in structurally normal hearts. METHODS: We included 54 consecutive adults without structural heart disease who underwent electrophysiological (EP) study for various tachycardias. The basic parameters including PR, AH and HV intervals, atrioventricular Wenckebach point (AVWP) and anterograde effective refractory period (ERP) of atrioventricular node (AVNERP), were measured after ablation. The VA conduction was assessed basally and if absent, after isoprenaline. The VA Wenckebach point (VAWP) and retrograde ERP(VAERP) were recorded in patients showing VA conduction. RESULTS: The mean age was 37.1±12.6years. Twenty five (46%) of the patients were men. VA conduction was present in 30 (55%) patients at baseline. Of the remaining 24 patients, 18 (34%) showed VA conduction after isoprenaline. Only 6 (11%) patients failed to reveal VA conduction even after adequate response to isoprenaline. Amongst all clinical and EP variables analysed, only the HV interval was shorter (p<0.01) in patients with VA conduction. CONCLUSION: In structurally normal hearts, VA conduction was present at baseline in 55% of patients. Isoprenaline unmasked VA conduction in an additional 34% of the subjects. The HV interval was longer in patients without VA conduction.

Bio-fabrication and statistical optimization of polysorbate 80 coated chitosan nanoparticles of tapentadol hydrochloride for central antinociceptive effect: in vitro-in vivo studies.

Tapentadol hydrochloride (TPD) is a novel analgesic with two mechanisms of actions: agonist activity at the µ-opioid receptor and norepinephrine reuptake inhibition. The conventional delivery of TPD is problematic, owing to its extensive first pass metabolism, low lipophilicity and short half-life that leads to low bioavailability (32%). The intent of the present work was aimed at bio-fabrication of polysorbate 80 coated chitosan nanoparticles (CS-NPs) for CNS targeting of TPD using factorial design approach for enhanced delivery of drug. TPD-CS-NPs were prepared by ionic gelation technique and optimized using 23 factorial design of experiment. The effect of polymer (CS) and cross linker (TPP) concentration was studied on particle size (PS) and entrapment efficiency (EE %). Formulation CNP6 was considered desirable with optimal EE % (87.1 ± 0.4%), PS (329.3 ± 1.0 nm), zeta potential (30.4 ± 0.7 mV) and cumulative drug release of 73.5 ± 2.9% in 24 h. Differential scanning calorimetry revealed the absence of any chemical interaction between TPD, CS, and TPP while SEM study confirmed spherical morphology. In vivo pharmacodynamic studies on rat model verified that pure drug was unable to show considerable antinociceptive activity owing to its hydrophilic nature, conversely polysorbate 80 coated TPD-CS-NPs showed a significant antinociceptive effect over a period of 24 h, which is evidence for brain targeting of TPD-CS-NPs. Accelerated stability studies of optimized batch demonstrated a negligible change in the average PS and EE % after storage at 25 ± 2 °C/60 ± 5% RH (relative humidity) for the period of three months. The ANOVA results for the dependent variables demonstrated that the model was significant (P values < 0.05) for response variables. Above finding suggested practicability of investigated system for effective targeting of many therapeutic agents in the treatment of many life threatening CNS disorders.

Nanostructured lipid carriers as a potential vehicle for Carvedilol delivery: Application of factorial design approach.

Present invention relates to design of nanostructured lipid carriers (NLC) to augment oral bioavailability of Carvedilol (CAR). In this attempt, formulations of CAR-NLCs were prepared with glyceryl-monostearate (GMS) as a lipid, poloxamer 188 as a surfactant and tween 80 as a co-surfactant using high pressure homogenizer by 2(3) factorial design approach. Formed CAR-NLCs were assessed for various performance parameters. Accelerated stability studies demonstrated negligible change in particle size and entrapment efficiency, after storage at specified time up to 3 months. The promising findings in this investigation suggest the practicability of these systems for enhancement of bioavailability of drugs like CAR.

Incessant fascicular VT presenting as cardiogenic shock with multi-organ dysfunction syndrome.

We report a rare clinical presentation of incessant idiopathic fascicular ventricular tachycardia (FVT), presenting as multi-organ dysfunction (MOD) syndrome with cardiogenic shock. Our patient was a 19-year-old male who presented with slowly progressive dyspnea from New York Heart Association (NYHA) II to NYHA IV at the time of presentation, palpitations, and dilated cardiomyopathy due to drug-refractory FVT. The patient was in cardiogenic shock with raised central venous pressures and required inotropic support for maintaining systolic blood pressure above 90 mmHg. The MOD was seen in the form of deranged liver and kidney parameters. Echocardiography showed a dilated left ventricle (LV, 58 mm at end-diastole, 52 mm at end-systole) and decreased ejection fraction (20%). Electrocardiography showed a wide-QRS tachycardia (QRS 140 ms, cycle length 440 ms), with RsR' in lead V1 and a QRS axis of -60°. After stabilization with ventilation, inotropic support, and cautious use of diuretics, an electrophysiologic study was performed. A Purkinje potential with early local ventricular activation was recorded from the LV inferoseptal region. The tachycardia was ablated at this site with radiofrequency (RF) energy (40 W for 35 sec). Over a 3-month follow-up, the patient remained asymptomatic and the LV size and function returned to normal. .

Sonication-assisted drug encapsulation in layer-by-layer self-assembled gelatin-poly (styrenesulfonate) polyelectrolyte nanocapsules: process optimization.

We report the development of Layer-by-Layer (LbL) polyelectrolyte self-assembled nanocrystalline drug-delivery platform using two experimental factors, namely the number of coatings and temperature during deposition with three varying levels. The optimized formulation (Fopt) was assessed for zeta potential and particle size using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM). Charge reversal along with an increase in particle size confirmed coating of polyelectrolyte on drug nanocrystals. The FT-IR study revealed no signs of incompatibility or change in formulation property during preformulation and stability study. This fact was further supported by DSC results.

Fabrication and statistical optimization of surface engineered PLGA nanoparticles for naso-brain delivery of ropinirole hydrochloride: in-vitro-ex-vivo studies.

Ropinirole hydrochloride (RPN), a nonergot dopamine D2-agonist used in the management of Parkinson's disease, has poor oral bioavailability (52%) due to extensive hepatic metabolism. The intent of present research work was aimed at design and statistical optimization of RPN-loaded poly (lactic-co-glycolic acid) (PLGA)-based biodegradable nanoparticles (NPs) surface modified using natural emulsifier, vitamin E (d-α-tocopheryl polyethylene glycol 1000 succinate [TPGS]) for direct nose-to-brain delivery in order to avoid hepatic first-pass metabolism, and improve therapeutic efficacy with sustained drug release. RPN-NPs were prepared by modified nanoprecipitation technique and optimized using 2(3) factorial design of experiment. The effect of polymer and emulsifier concentration was evaluated on particle size and entrapment efficiency (EE%). Formulation PL6 was considered as desirable with highest EE% (72.3 ± 6.1%), PS (279.4 ± 1.8 nm), zeta potential (-29.4 ± 2.6 mV), and cumulative drug diffusion of 96.43 ± 3.1% in 24 h. The ANOVA results for the dependent variables demonstrated that the model was significant (p value < 0.05) for response variables. Histopathological study of optimized batch (PL6) demonstrated good retention of NPs with no severe signs of damage on the integrity of nasal mucosa. Differential scanning calorimetry revealed the absence of any chemical interaction between RPN, PLGA, and TPGS while SEM study confirmed spherical shape of optimized NPs. Accelerated stability studies of freeze-dried optimized batch demonstrated negligible change in the average PS and EE% after storage at 25 ± 2 °C/60 ± 5% (relative humidity (RH) for the period of three months. The promising results of optimized batch suggested practicability of investigated system for enhancement of bioavailability and brain targeting of CNS acting drugs like RPN.

Design and development of novel dual-compartment capsule for improved gastroretention.

The aim of the proposed research work was to develop a novel dual-compartment capsule (NDCC) with polymeric disc for gastroretentive dosage form, which will ultimately result in better solubility and bioavailability of Ofloxacin. Floating ring caps were formulated by using different natural polymers, separating ring band and swellable polymer located at the bottom of capsule. Formulated ring caps were assessed for coating thickness, In vitro buoyancy, In vitro drug release, release kinetics and stability studies. Coating attained by the capsule shell was found to be 0.0643 mm. Depending on nature of natural polymer used, most of the formulations showed buoyancy for more than 9 hrs. Developed formulation demonstrated considerably higher drug release up to 9 hrs. The developed formulation F(E2) depicted the drug release according to Korsmeyer-Peppas model. There was not any significant change in performance characteristics of developed ring caps after subjecting them to stability studies. The present study suggests that the use of NDCC for oral delivery of Ofloxacin could be an alternative to improve its systemic availability which could be regulated by the floating approach. The designed dosage system can have futuristic applications over payloads which require stomach-specific delivery.

Stimuli-sensitive layer-by-layer (LbL) self-assembly systems: targeting and biosensory applications.

Stimuli-sensitive layer-by-layer (LbL) self-assembly systems have generated much interest among researchers worldwide due to the simplicity of the process by which they are produced and their numerous applications in drug delivery. LbL self-assembly systems involve simple alternative adsorption of oppositely charged polyelectrolytes on core materials and are thus considered to be promising tools for drug delivery and biosensing. Here, we discuss the latest findings from research into LbL systems, with special emphasis on drug delivery systems. This review highlights various stimuli-responsive LbL systems and their targeting and biosensory applications. For the convenience of readers, these stimuli-responsive LbL systems are classified as exogenous stimuli-responsive LbL systems and endogenous stimuli-responsive LbL systems.

Design and statistical optimization of osmotically driven capsule based on push-pull technology.

In present investigation attempt was made to develop and statistically optimize osmotically active capsule tailor made from the concept of bilayer (push-pull) osmotic tablet technology. The capsule was comprised of active (drug) and push (osmogen) layer. Active layer was compressed in form of tablet by mixing known amount of drug and formulation excipients. Similarly push layer was made by compressing Mannitol with formulation excipients. Finally, both layers were packed in hard gelatin capsule having small aperture at top and coated with semipermeable membrane to form osmotically active capsule. Formulated and optimized capsules were characterized for Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC), scanning electron microscopy, In-vitro drug release study and Release models and kinetics. Statistically optimized formulation showed good correlation between predicted and experimented results, which further confirms the practicability and validity of the model.

First total synthesis of prasinic acid and its anticancer activity.

The first total synthesis of prasinic acid is being reported along with its biological evaluation. The ten step synthesis involved readily available and cheap starting materials and can easily be transposed to large scale manufacturing. The crucial steps of the synthesis included the formation of two different aromatic units (7 and 9) and their coupling reaction. The synthetic prasinic acid exhibited moderate antitumor activity (IC(50) 4.3-9.1 µM) in different lines of cancer cells.

Solid lipid based nanocarriers: an overview.

In the era of nanoparticulate controlled and site specific drug delivery systems, use of solid lipids to produce first generation lipid nanoparticles, solid lipid nanoparticles (SLN), became a revolutionary approach in the early nineties. The present review is designed to provide an insight into how SLN are finding a niche as promising nanovectors and forms a sound basis to troubleshoot the existing problems associated with traditional systems. Herein, authors had tried to highlight the frontline aspects prominent to SLN. An updated list of lipids, advanced forms of SLN, methods of preparation, characterization parameters, and various routes of administration of SLN are explored in-depth. Stability, toxicity, stealthing, targeting efficiency and other prospectives of SLN are also discussed in detail. The present discussion embodies the potential of SLN, now being looked up by various research groups around the world for their utility in the core areas of pharmaceutical sciences, thereby urging pharmaceutical industries to foster their scale-up.

Ionic liquids as refolding additives: variation of the anion.

Several ionic liquids have been shown to act as suppressors of protein aggregation and to effectively promote the in vitro refolding of denatured proteins. In this work, the influence of the anion of these organic salts on their performance as refolding enhancers was tested, using a series of N-ethyl-N'-methyl imidazolium (EMIM) salts. Variation of the anion had a profound effect on the renaturation of the recombinant plasminogen activator rPA, which served as a model protein. The effect was roughly correlated with the stability of proteins in the tested aqueous ionic liquid solutions. Strongly destabilizing anions with higher alkyl substitutions like, e.g., hexyl sulfate were unable to promote protein refolding. However, the dimethyl and diethyl phosphate salts, which are known to be quite compatible with protein stability, also effectively suppressed renaturation, while alkylated sulfate anions with the same influence on protein stability did promote in vitro refolding. Only ionic liquid co-solvent systems with an intermediate capacity for solubilizing the proteinogenic amino acid tryptophan were found to permit effective renaturation of the model protein rPA. The most effective refolding enhancer among the tested ionic liquids was EMIM chloride.

Adhesive force assisted imprinting of soft solid polymer films by flexible foils.

We report a simple, rapid, room temperature, pressure-less and large area (approximately cm2) imprinting technique for high fidelity patterning of soft solid polymer films and surfaces like cross-linked polydimethylsiloxane (PDMS) and polyacrylamide (PAA) based hydrogels, both on planar and curved surfaces. The key element of the method is the use of patterned thin flexible foils that readily and rapidly attain a conformal contact with soft (shear modulus < 0.1 MPa) solid surfaces because of adhesive interfacial interactions. The conformal contact is established at all length scales by bending of the foil at scales larger than the feature size, in conjunction with the spontaneous elastic deformations of the surface on the scale of the features. For example, we used the protective aluminum foils of commercial data storage discs, both with or without data stored, for micron and sub-micron pattern transfer. The patterns are made permanent by UV-ozone treatment (for PDMS) or by controlled drying (for hydrogels). Interestingly, elastic contact imprinting of very thin (< 300 nm) films results in about 50% miniaturization of the original foil feature sizes. Complex two dimensional patterns could also be formed even by using a simple one dimensional master by multiple imprinting. The technique can be particularly useful for the bulk nano applications requiring routine fabrication of templates, for example, in the study of confined chemistry phenomena, nanofluidics, bio-MEMS, micro-imprinting, optical coatings and controlled dewetting.

In vitro-refolding of a single-chain Fv fragment in the presence of heteroaromatic thiols.

The aim of the present work was to explore the use of heteroaromatic thiol compounds, namely derivatives of pyridine and pyrimidine, as redox reagents for the in vitro-refolding of a recombinantly expressed single-chain Fv fragment (scFvOx). The mixed disulfide of scFvOx with glutathione was used as a starting material, while reduced glutathione, 4-mercaptopyridine, 2-mercaptopyrimidine, 2-mercaptopyridine N-oxide, and the mercaptobenzene derivative thiosalicylic acid, respectively, served as catalysts for the formation of native disulfide bonds during renaturation. In contrast to thiosalicylic acid, and despite their significantly lower thiol pKa values, none of the heteroaromatic thiol compounds accelerated the apparent kinetics of in vitro-refolding compared to the naturally occurring peptide glutathione. However, significantly improved renaturation yields were observed in the presence of 4-mercaptopyridine and 2-mercaptopyrimidine, demonstrating the usefulness of aromatic thiol compounds as reagents for the in vitro-refolding of antibody fragments.

Ionic liquids as refolding additives: N'-alkyl and N'-(omega-hydroxyalkyl) N-methylimidazolium chlorides.

The purpose of this work was to investigate the influence of a series of N'-alkyl and N'-(omega-hydroxy-alkyl)-N-methylimidazolium chlorides on the renaturation of two model proteins, namely hen egg white lysozyme and the single-chain antibody fragment ScFvOx. All tested ionic liquids acted as refolding enhancers, with varying efficacies and efficiencies. The results of the refolding screening could be interpreted by taking into account the effect of the studied ionic liquids on protein aggregation, together with the systematic variations of their influence on the stability of native proteins in solution. More hydrophobic imidazolium cations carrying longer alkyl chains were increasingly destabilizing, while terminal hydroxylation of the alkyl chain made the salts more compatible with protein stability. The studied ionic liquids can be classified as preferentially bound, slightly to moderately chaotropic cosolvents for proteins.