Ru-Catalyzed and Selenium-Directed Selective Formation of ortho- and Dialkenylated Selanes, Mixed Organoselenoethers, and Isoselenochromenes.

Herein, the Ru-catalyzed chemo- and regioselective formation of four novel organoselenium compounds is established. Mono- and dialkenylated selanes were formed by the Se-directed o-C-H activation of benzyl(phenyl)selanes with alkynes. Unprecedented debenzylative/dearylative hydroselenations of alkynes were performed by slightly varying the amount of catalyst and temperature. Catalyst-driven direct formation of novel isoselenochromenes is also recorded. Altogether, 45 new organoseleno compounds were synthesized in good amounts with varieties of alkynes and selanes. This is the first report of its kind to deal with the synthesis of novel, challenging, and unusual organoseleno compounds in one reaction.

A Comprehensive in vitro and in silico Analysis of Nematicidal Action of Essential Oils.

Nematicidal potential of essential oils (EOs) has been widely reported. Terpenoids present in most of the essential oils have been reported responsible for their bioactivity though very less is known about their modes of action. In the present study, an in vitro screening of nine Eos, namely, Citrus sinensis (OEO), Myrtus communis (MTEO), Eucalyptus citriodora (CEO), Melaleuca alternifolia (TEO), Acorus calamus (AEO), Commiphora myrrha (MREO), Cymbopogon nardus (CNEO), Artemisia absinthium (WEO), and Pogostemon cablin (PEO) against Meloidogyne incognita revealed OEO, CNEO, and TEO as most effective with LC50 39.37, 43.22, and 76.28 µg ml-1 respectively. EOs had varying compositions of mono- and sesquiterpenes determined by gas chromatography-mass spectrometry (GC-MS) analysis. The in silico molecular interactions screening of major EO constituents and the seven selected target proteins of the nematode indicated highest binding affinity of geraniol-ODR1 (odorant response gene 1) complex (ΔG = -36.9 kcal mol-1), due to extensive H-bonding, hydrophobic and π-alkyl interactions. The relative binding affinity followed the order: geraniol-ODR1 > ß-terpineol-ODR1 > citronellal-ODR1 > l-limonene-ODR1 > γ-terpinene-ODR1. Taken together, the cumulative in vitro and computational bioefficacy analysis related to the chemoprofiles of EOs provides useful leads on harnessing the potential of EOs as bionematicides. The insight on biochemical ligand-target protein interactions described in the present work will be helpful in logical selection of biomolecules and essential oils for development of practically viable bionematicidal products.

TMJ Arthritis Imaging: Conventional Radiograph vs. CT Scan - Is CT Actually Needed?

OBJECTIVE: The present study was conducted to evaluate the efficacy of conventional TMJ imaging in depicting osseous changes in mandibular condyle and glenoid fossa in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) by comparing the finding against CT and with an objective that if conventional TMJ imaging modality can appreciate the osseous changes in RA and OA then what is the need for CT scan. Thus further reducing the patient's radiation dose. MATERIALS AND METHODS: A total of 70 patients (40 Rheumatoid Arthritis; 30 Osteoarthritis) were taken in the study aged between 40 - 60 years and divided in to age groups. Then according to clinical history they were divided according to being symptomatic and asymptomatic. Further radiographic examination was carried out. First the trans-cranial view was obtained (conventional view left and right TMJ) and subsequently a CT scan was obtained and the interpretation was carried out to note the osseous changes like erosion, flattening, sclerosis and osteophyte formation. RESULTS: After comparison of the two radiographic methods it was observed that both were equally efficacious in evaluating the osseous changes in arthritic patients. CONCLUSION: Thus, it was concluded that when both the radiographic methods (conventional and CT scan) are equally efficacious in evaluating the osseous degenerative changes of TMJ in arthritis. Thus we should prefer the conventional technique so that the patient in not exposed to unnecessary radiation dosage.

Hyaluronated imatinib liposomes with hybrid approach to target CD44 and P-gp overexpressing MDR cancer: an in-vitro, in-vivo and mechanistic investigation.

Multi Drug Resistance (MDR) of cancer cells is a constant threat to the clinically used drugs as well as new drug development. In present work, we aimed to assess in-vitro as well as in-vivo efficacy of the developed Imatinib loaded liposomes in MDR cancer. An array of tests was also carried out to comprehensively understand the bio-mechanism that enable these nanocarriers to modulate P-gp activity. Hyaluronic acid coated, Imatinib mesylate containing lipsomes (HA-LIPO-IM) were analysed through in-vitro and in-vivo studies in MDR cancer cells and tumour models. Effect of developed hyaluronated liposomes on various biomolecular mechanisms was also evaluated. Around 3.5 times lower IC50 for HA-LIPO-IM in comparison to drug solution in HT-29 and Colo-320 cells proved the enhanced action of the drug in MDR cells. HA-LIPO formulations were demonstrated to have inhibitory effect on ATPase enzyme. Molecular masking of Imatinib mesylate and CD-44 mediated endocytosis were also found responsible for anti-MDR effect. In-vivo studies revealed the prolonged tumour accumulation and 4-fold increase in tumour regression efficacy of HA-LIPO-IM in comparison to free drug solution. The work demonstrated the target specific accumulation of HA-LIPO-IM in CD-44 overexpressing cancer cells through P-gp modulation.

Novel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro, ex vivo and in vivo investigations.

A receptor level interaction of etoposide with P-glycoprotein (P-gp) and subsequent intestinal efflux has an adverse effect on its oral absorption. The present work is aimed to enhance the bioavailability of etoposide by co-administering it with quercetin (a P-gp inhibitor) in dual-loaded polymeric nanoparticle formulation. Poly-lactic-co-glycolic acid (PLGA) nanoparticles were optimized for various parameters like o/w phase volume ratio, poly-vinyl alcohol concentration, PLGA concentration and sonication time. The cytotoxicity studies (MTT assay) revealed a 9- and 11-fold decrease in the IC 50 values for etoposide-loaded nanoparticles (ENP) and etoposide + quercetin dual-loaded nanoparticles (EQNP) when compared to that of free etoposide, respectively, and the results were further supported by florescent-activated cell sorter studies. The confocal imaging of the intestinal sections treated with ENP and EQNP containing fluorescent probe (rhodamine) showed the superiority of the EQNP to permeate deeper. Furthermore, pharmacokinetic studies on rats revealed that EQNP exhibited a 2.4-fold increase in bioavailability of etoposide than ENP with no quercetin. The developed loaded nanoparticles have the high potential to enhance the bioavailability of the etoposide and sensitize the resistant cells.

Determination of normal range for fasting salivary glucose in Type 1 diabetics.

BACKGROUND: The most commonly employed investigative procedure for monitoring glucose levels is blood investigation, which is invasive and gives discomfort to the patient. The purpose of the study was to validate a noninvasive, easy, and reliable method for predicting glucose levels in Type 1 diabetics and to validate a regression equation for converting the known values of salivary glucose to blood glucose. MATERIALS AND METHODS: 200 volunteers consisting of 100 Type 1 diabetics and 100 healthy controls were included, and their fasting blood and salivary glucose levels were assessed, using a semi-auto analyzer. RESULTS: On analysis of the data, statistically significant positive results were obtained (P < 0.05) when the blood and salivary glucose levels were considered among the study group participants, control group participants, and both study and control group participants. A cut-off value for salivary glucose (11.60 mg%) was defined, above which a person may be considered as diabetic. Also, the regression equation was obtained which could be used for the conversion of known value of salivary glucose to blood glucose and vice versa. CONCLUSION: The present study successfully demonstrated the role of saliva as a noninvasive and reliable marker for the prediction of glucose levels in Type 1 diabetics who show elevated blood glucose levels.

Hyaluronic acid decorated lipid nanocarrier for MDR modulation and CD-44 targeting in colon adenocarcinoma.

In present investigation, we developed a novel hyaluronated cationic nanostructured lipid carrier (CNLCs) which contains CPT-11/irinotecan to target CD44 biomarker which commonly overexpresses on colon cancer. The cationic core NLCs was developed by using capmule MCM and compritol as mix lipid phase with 150 ± 2.5 nm particles size and 93.98 ± 2.5% entrapment efficiency. The cationic core NLCs were coated with hyaluronic acid by ionic conjugation. The particle size of hyaluronated CNLCs was enhanced to 255 ± 4.2 nm. In-vitro drug release studies revealed a slow and sustain release of the drug and a practically no leaching of coumarin-6. The confocal laser microscopy studies were performed with developed CNLCs in two CD44 overexpressing cell lines (HT-29 and Colo-320). The studies revealed marked uptake of the CNLCs by both the cell lines in just two hours. The results were comparable to the FITC conjugated CD44 antibodies. Therefore, the developed dual purpose CNLCs were found to be highly specific for CD44 biomarker. The developed formulations were found to be compatible with blood components. The MTT assay revealed that the developed particles had enhanced cytotoxicity against non-MDR as well MDR cancer cells.

Hyaluronan coated liposomes as the intravenous platform for delivery of imatinib mesylate in MDR colon cancer.

Imatinib mesylate has been evaluated for possible potential in treatment of colon cancer in recent times. However, due to significant reporting of P-gp expression in colon cancer, it can come across set back due to MDR. Therefore, in present work the liposomal formulation containing imatinib-bile salt conjugate was developed and investigated for its comparative performance in MDR colon cancer cells and surface modified with hyaluronic acid for achieving low hemotoxicity with stealth characteristics. Imatinib was successfully conjugated with sodium-deoxycholate by charged conjugation and evaluated through FTIR, DSC and PXRD. The developed conjugate (IM-SD) was encapsulated in liposomes and the conditions were optimized by Box-Behnken statistical design to achieve a size of 56.56±1.23 nm along with 99.11±0.89% entrapment efficiency (LIPO). The liposomes were surface modified with hyaluronic acid and the size was enhanced to 159.14±3.2 nm (HA-LIPO). Flow cytometric studies demonstrated the enhanced uptake of P-gp substrate rhodamine dye in P-gp positive colo 320 colon cancer cells. In addition, an enhanced cellular internalization of HA-LIPO in CD-44 positive HT-29 and colo 320 cells indicates the targeting attributes of the hyaluronan coated liposomes. Finally, the hyaluronan coated liposomes were also found to have low opsonization activity.

Sterically stabilized polymeric nanoparticles with a combinatorial approach for multi drug resistant cancer: in vitro and in vivo investigations.

The present work describes the preparation of sterically stabilize polymeric nanoparticles of mitoxantrone dihydrochloride (MTO) along with an efflux transporter (Pgp/BCRP) inhibitor that enhance the circulation time of nanoparticles and simultaneously surmount the problem of multidrug resistance (MDR). Mitoxantrone dihydrochloride being hydrophilic in nature had very low entrapment efficiency (%E.E.), thus in order to further enhance the lipophilicity and the %E.E., it was complexed with sodium deoxycholate (SDC) and this MTO-SDC-complex was used to formulate nanoparticles with/without Pgp/BCRP inhibitor by nanoprecipitation technique and was characterized for various in vitro and in vivo attributes. In vitro cell line studies were conducted on MCF7, A2780(p) and A2780(adr) cells. Furthermore, the targeting potential of hyaluronic acid (HA) coated nanoparticles for CD44 receptors was investigated using the MCF7 cell line. A reduction in the IC50 value observed with the inhibitor loaded nanoparticles in different cell lines indicated the BCRP/Pgp inhibiting ability of the formulated nanoparticles. The reduced macrophage uptake and the increased residence time in blood demonstrated the long circulating behaviour of the nanoparticles. The enhanced cellular uptake of HA coated nanoparticles in MCF7 cells revealed their targeting potential. The HA coated nanoparticles along with efflux transporter inhibitor exhibits a great potential for targeted chemotherapy in CD44 overexpressing MDR breast cancer.

Atypical CT Findings in Plexiform Ameloblastoma.

Ameloblastoma is an uncommon epithelial odontogenic neoplasm that is nonmineralized, locally aggressive, and, in most cases, benign. Most ameloblastomas develop in the molar-ramus region of the mandible with 70% of them arising in the molar-ramus area. Radiologically they are unilocular or multilocular radiolucency with a honeycomb or soap bubble appearance. The radiographic appearance of ameloblastoma can vary according to the type of tumor. CT is usually helpful in determining the contours of the lesion, its contents, and its extension into soft and hard tissues. Through this case we would bring to light some of the unusual CT findings which include the destruction of the surrounding structures by the lesion which appeared to be normal routine lesion when viewed clinically.

Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part II. In vivo biodistribution, pharmacodynamic and hematological toxicity studies.

Irinotecan loaded nanostructured lipid carrier (NLC-Ir) was surface decorated with hyaluronic acid graft polymer. Hyaluronic acid is a biocompatible, non-antigenic and hydrophilic, CD-44 ligand that can impart many useful features to the nanocarrier for anticancer drug delivery. The present investigation demonstrated that hyaluronic acid coated HA-NLC had significantly lower haemolytic potential as compared to uncoated NLC. Further, HA-NLC had a reduced plasma protein interaction and low macrophage uptake. The in vivo tumor targeting and pharmacodynamics efficacy of HA-NLC was studied in Ehrlich's Ascites Tumor (EAT) allograft model. Radio scintigraphic biodistribution studies revealed that HA-NLC carrier got accumulated in the tumor tissues in good proportion. Additionally, the content of radioactivity associated with tumor tissues remained constant at 2, 4 and 24 h (2.41, 2.48 and 2.47%, respectively), while it got reduced in other organs. Furthermore, tumor to muscle ratio of radioactivity suggested a better accumulation of HA-NLC in tumor tissues that was significantly enhanced (P<0.05) with time. In vivo antitumor activity of hyaluronan coated HA-NLC-Ir was 5.8 and 2.6 times higher as compared to control and free drug solution respectively. Furthermore, encapsulation of irinotecan in HA-NLC-Ir nanocarrier was found to have reduced the thrombocytopenia and neutropenia associated with free irinotecan. Thus, it can be inferred that the hyaluronic acid decorated nanocarrier can provide a haemo-compatible, non-toxic and target based delivery system for the effective management of cancer.

Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part I. Synthesis, characterization and in vitro investigation.

Over expression of P-glycoprotein (P-gp) in cancer cells often results in highly aggressive, multi-drug resistant (MDR) phenotype. Such tumors are very difficult to treat with conventional therapy and often lead to failure of the treatment. In this work, we fabricated surface engineered hybrid lipid nanoparticles grafted with novel AL-HA polymer by mineralization technique. AL-HA graft polymer was prepared by covalent conjugation of alendronate sodium and hyaluronic acid. Compritol ATO 888 and capmule MCM C8 hybrid lipid mix was employed to prepare irinotecan containing nanostructured lipid carrier (NLC) by using functional excipients with P-gp inhibition activity. AL-HA was successfully grafted over NLC-Ir (uncoated irinotecan loaded NLC) by calcium-assisted mineralization. HA-NLC-Ir (hyaluronic acid coated irinotecan loaded NLC) particles have a nanoscale size of 386±2.2 nm along with a zeta potential value of 19.7±1.2 mV. NLC-Ir as well as HA-NLC-Ir showed a slow and sustained drug release. In vitro cell line studies performed on HT-29 and Colo-320 colon cancer cells revealed a reduced IC50 even in MDR cells. Flowcytometry studies demonstrated the capability of the developed nanocarriers to deliver the P-gp substrate moieties in MDR cancer cells. Furthermore, the targeting potential of HA-NLC was confirmed by CLSM studies. The cell line studies also revealed that NLC formulation had a potential of inhibiting P-gp by affecting ATPase activity and MDR1 gene expression.

Addressing the potential toxicities of the non-specific P-glycoprotein modulation by amalgamation with targeted approach in MDR tumors.

Multidrug resistance (MDR) is an area of concern for the drug developers as well as clinical practitioners. This phenomenon is putting an emance pressure on treatment modalities of many diseases as well as posing a grave danger over clinically accepted drugs as well as molecules under clinical development. P-glycoprotein (P-gp) mediated efflux of xenobiotics is one of the major mechanisms involved in MDR. Hence, an effective modulation of P-gp may restore the potential of many substrate drugs. However, the non-specific P-gp modulation may be associated with many unwanted toxic effects. Therefore, an approach involving simultaneous exploitation of P-gp modulation as well as targeted delivery in a particulate carrier system may result in a more effective MDR reversal, accompanying a safer drug profile.

Development of protocol for screening the formulation components and the assessment of common quality problems of nano-structured lipid carriers.

The present study investigates the screening of the formulation components as well as evaluates the quality issues of the nanostructured lipid carriers (NLCs) for the anticancer agent, CPT-11. The stepwise screening of the components for the preparation of NLCs requires the selection of liquid lipid or oil, based on the relative solubility of CPT-11 in different oils. Maximum solubility of the CPT-11 was found in capmul MCM-C8 (81±0.5 mg/ml). Hence, it was selected as the liquid lipid for the development of NLCs. Solid lipids gelucire 39/1, glyceryl mono stearate (GSM) and compritol ATO 888 were observed to have good affinity for the drug on systematic screening of different solid lipids. However, gelucire 39/1 and GSM were found to have lower physical compatibility (miscibility) with capmul MCM C-8. Hence, compritol ATO 888 was selected as the solid lipid phase for the preparation of NLCs. Ratio of liquid lipid (oil) to solid lipid was optimized with the intention of maximizing the oil concentration (as oil was found to have higher solubility of drug) as well as producing a lipid mix with sufficient melting point to maintain solid state. The liquid-solid lipid mixture in the ratio up to 30:70 was observed to have sufficient melting point (52.48±1.2 °C). Pluronic F-68 was selected as the main surfactant for the preparation of NLCs because of its good emulsification efficacy for the solid lipid liquid mix. The optimized formulation was also evaluated for the different quality issues. PXRD data revealed that the characteristic peaks of the compritol were present in the NLC samples and there was no appreciable polymorphic change when the formulation was stored for 6 months. Electron microscopic and DLS studies proved the absence of different colloidal species. Thermal analysis by DSC revealed that the lipid particles maintained sufficiently good melting point even after nanosizing. Absence of gelation on multiple syringing and resilience for the stress provided by autoclaving further established the quality of the developed NLCs.

Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-Glycoprotein modulation.

Irinotecan is a camptothecin derivative with low oral bioavailability due to active efflux by intestinal P-glycoprotein receptors. Hence, no oral formulation is marketed for Irinotecan till date. However, an optimized Self micro emulsifying drug delivery system (SMEDDS), formulated to produce nano range oil droplets by using P-gp modulator excipients can tackle the issue and elevate the systemic availability of Irinotecan. The present work focuses on the development of SMEDDS for Irinotecan and evaluation of its in vitro, ex vivo and in vivo potentials. The SMEDDS were developed using Capmul MCM-C8, Cremophor EL and Pluronic L-121 as oil, surfactant and co-surfactant respectively and has good oil carrying capacity (30%) with competence to produce nano-scale oil droplets (130 ± 2.13 nm) on spontaneous emulsification. A much deeper penetration to the intestine was observed with SMEDDS by using confocal laser scanning microscopy (CLSM). Flow-cytometric studies also revealed the greater uptake of fluorescent probe in Caco-2 cell-lines with the use of SMEDDS. Biochemical estimation of LDH from the intestinal tissues treated with SMEDDS and free drug suspension confirmed that the developed formulation is safe for use. Furthermore, the AUC0 → t of Irinotecan from the optimized SMEDDS formulation was found to be 4 folds higher than that from Irinotecan suspension on oral administration. The optimized SMEDDS formulation was found to be capable of maintaining the sustained plasma drug level of Irinotecan with better bioavailability.

A logical approach to optimize the nanostructured lipid carrier system of irinotecan: efficient hybrid design methodology.

Development of an effective formulation involves careful optimization of a number of excipient and process variables. Sometimes the number of variables is so large that even the most efficient optimization designs require a very large number of trials which put stress on costs as well as time. A creative combination of a number of design methods leads to a smaller number of trials. This study was aimed at the development of nanostructured lipid carriers (NLCs) by using a combination of different optimization methods. A total of 11 variables were first screened using the Plackett-Burman design for their effects on formulation characteristics like size and entrapment efficiency. Four out of 11 variables were found to have insignificant effects on the formulation parameters and hence were screened out. Out of the remaining seven variables, four (concentration of tween-80, lecithin, sodium taurocholate, and total lipid) were found to have significant effects on the size of the particles while the other three (phase ratio, drug to lipid ratio, and sonication time) had a higher influence on the entrapment efficiency. The first four variables were optimized for their effect on size using the Taguchi L9 orthogonal array. The optimized values of the surfactants and lipids were kept constant for the next stage, where the sonication time, phase ratio, and drug:lipid ratio were varied using the Box-Behnken design response surface method to optimize the entrapment efficiency. Finally, by performing only 38 trials, we have optimized 11 variables for the development of NLCs with a size of 143.52 ± 1.2 nm, zeta potential of -32.6 ± 0.54 mV, and 98.22 ± 2.06% entrapment efficiency.

Role of CD44 in tumour progression and strategies for targeting.

CD44 or hyaluronan receptor is a transmembrane receptor associated with aggressive tumour growth, proliferation, and metastasis. In normal physiology, this receptor has a crucial role in cell adhesion, inflammation, and repair processes. However, many tumour cells over-express this receptor and abuse it to become progressive and perpetual units. The article comments from common functioning of the CD44 receptor, to its diabolic multi-dimensional effects in promotion of malignant cells. It also illuminates the relations of CD44 endorsed processes with other biomolecular events in cancer progression. In an end, the review focuses comprehensively at ongoing researches to exploit the CD44 over-expression as a probable target in treatment, management, and diagnosis of malignancy.

Oil based nanocarrier system for transdermal delivery of ropinirole: a mechanistic, pharmacokinetic and biochemical investigation.

Ropinirole, a recent introduction in the clinical treatment of Parkinson's disease, suffers with the problems of low oral bioavailability and frequent dosing. An effective transdermal nano-emulsion drug delivery system can however resolve these issues effectively with greater therapeutic benefits and clinical significance. Therefore, the present work focuses precisely on pharmacokinetic, biochemical and mechanistic assessment of transdermal nanoemulsion gel in rats induced with Parkinson lesioned brain by 6-OHDA. DSC and FT-IR studies showed that NEG affects the normal lipid packing of stratum corneum to enhance the drug permeation. Study of pharmacokinetic parameters (AUC, C(max), and T(max)) revealed a greater and more extended release of ropinirole from nanoemulsion gel compared to that from a conventional gel (RPG) and oral marketed tablet (Ropitor). The AUC(0→∞) for RPCNG and RPTNG was found to be 928.07 ± 206.5 and 1055.99 ± 251.7 ngh/mL, respectively in comparison to 137.25 ± 31.3 and 467.15 ± 106.1 ngh/mL for RPG and oral tablet, respectively. The relative bioavailability of ropinirole has been enhanced more than two fold by RPTNG. Furthermore, antiparkinson activity was evaluated in terms of estimating the level of thiobarbituric acid reactive substances, glutathione antioxidant enzymes and catalase in lesioned brain of rats. Formulations were also found to be non-toxic and non-irritant by histological investigations.