Synthesis and In Vitro Evaluation of N‐Aryl Pyrido‐Quinazolines Derivatives as Potent Epidermal Growth Factor Receptor Inhibitors

A series of pyrido‐quinazolines have been synthesised, characterized, and tested for their in vitro epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. The compounds were prepared from Alkylideno/arylideno‐bis‐ureas. Their final structure of the compounds was elucidated on the basis of spectral studies (IR, ¹H NMR, FT‐IR, and EI‐MS). The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Most of the synthesized compounds displayed potent EGFR‐TK inhibitory activity and structurally halogenated derivatives had a pronounced effect in inhibiting EGFR internalization.     

Assessment of human health risk for heavy metals in fish and shrimp collected from Subarnarekha river,India

Five fish species and one shrimp species from the Subarnarekha river were analyzed for heavy metals using inductively coupled plasma-mass spectrometry. The geometric mean concentration of As, Cd, Cu, Fe, Pb, Ni, Zn, Cr, Co, and Sr for all the samples was found to be 0.248, 0.031, 5.16, 104.9, 0.121, 4.68, 52.2, 0.784, 0.207, and 42.86 mg kg^?1_fresh, respectively. The concentrations of metals in the fish and shrimp exceed the limits of Indian and FAO standards for food for As, Cu, Ni, Cd, and Zn in many samples. The mean target hazard quotient (THQ) values for the 10 metals were below one for all the samples; however, the maximum THQ was more than one for shrimp in case of As, Cu, and Cr. The results indicate that the concentration of metals in some species, especially shrimp, at some locations is alarming and do present an appreciable hazard risk on human health.     

Falling Plasmodium knowlesi Malaria Death Rate among Adults despite Rising Incidence,Sabah, Malaysia, 2010–2014

Deaths from Plasmodium knowlesi malaria have been linked to delayed parenteral treatment. In Malaysia, early intravenous artesunate is now recommended for all severe malaria cases. We describe P. knowlesi fatalities in Sabah, Malaysia, during 2012–2014 and report species-specific fatality rates based on 2010–2014 case notifications. Sixteen malaria-associated deaths (caused by PCR-confirmed P. knowlesi [7], P. falciparum [7], and P. vivax [1] and microscopy-diagnosed “P. malariae” [1]) were reported during 2012–2014. Six patients with severe P. knowlesi malaria received intravenous artesunate at hospital admission. For persons >15 years of age, overall fatality rates during 2010–2014 were 3.4, 4.2, and 1.0 deaths/1,000 P. knowlesi, P. falciparum, and P. vivax notifications, respectively; P. knowlesi–associated fatality rates fell from 9.2 to1.6 deaths/1,000 notifications. No P. knowlesi–associated deaths occurred among children, despite 373 notified cases. Although P. knowlesi malaria incidence is rising, the notification-fatality rate has decreased, likely due to improved use of intravenous artesunate.     

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

Abstract

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.     

Chemopreventive potential of Apium leptophyllum (Pers.) against DMBA induced skin carcinogenesis model by modulatory influence on biochemical and antioxidant biomarkers in Swiss mice

Aim:

The study was designed to investigate the chemopreventive potential of flavonoidal fractions of Apium leptophyllum fruits (FFALF) on Swiss mice.

Materials and Methods:

Skin tumor or papilloma was developed by topical application of DMBA (25 μg in 0.1 ml acetone) on intrascapular region of mice, twice weekly for 8 weeks. The animals were divided into six groups: Group I (vehicle control); group II (FFALF control, 5 mg/kg); group III (carcinogenic control, DMBA treated initially for 8 weeks); and group IV, V and VI as pre-treated group (FFALF 5, 10 and 20 mg/kg respectively for 16 weeks along with DMBA treatment). After the 16^th week of treatment; the tumor morphology, skin histopathology, and biochemical and antioxidant biomarkers were measured and compared with carcinogenic control as well as vehicle control.

Results:

The co-administration of FFALF with DMBA-treated groups showed significant (P ≤ 0.001) prevention against skin papilloma and normalized the status of lipid peroxidation with antioxidant biomarkers in a dose-dependent manner as compared to carcinogenic control.

Conclusions:

Thus, the present study suggests that the FFALF is non-carcinogenic and has chemopreventive potential on DMBA-induced carcinogenesis in mouse, which may be due to the modulation of cutaneous lipid peroxidation or enhancement of total antioxidant capacity.KEY WORDS: Apium leptophyllum, antioxidant biomarker, chemoprevention, DMBA, skin papilloma     

Effect of Morphine on the Neuropathogenesis of SIVmac Infection in Indian Rhesus Macaques

Morphine is known to prevent the development of cell-mediated immune (CMI) responses and enhance expression of the CCR5 receptor in monocyte macrophages. We undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis of simian immunodeficiency virus (SIV) infection in Indian Rhesus Macaques. Hypothetically, the effect of morphine would be to prevent the development of CMI responses to SIV and to enhance the infection in macrophages. Sixteen Rhesus Macaques were divided into three experimental groups: M (morphine only, n = 5), VM (morphine + SIV, n = 6), and V (SIV only, n = 5). Animals in groups M and VM were given 2.5 mg/kg of morphine sulfate, four times daily, for up to 59 weeks. Groups VM and V were inoculated with SIVmacR71/17E 26 weeks after the beginning of morphine administration. Morphine prevented the development of enzyme-linked immunosorbent spot-forming cell CMI responses in contrast to virus control animals, all of which developed CMI. Whereas morphine treatment had no effect on viremia, cerebrospinal fluid viral titers or survival over the time course of the study, the drug was associated with a tendency for greater build-up of virus in the brains of infected animals. Histopathological changes in the brains of animals that developed disease were of a demyelinating type in the VM animals compared to an encephalitic type in the V animals. This difference may have been associated with the immunosuppressive effect of the drug in inhibiting CMI responses.     

Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro

Tumor necrosis factor-alpha (TNF-alpha) is a vital component of the inflammatory process and its aberrant over-expression has been linked to numerous disease states. New treatment strategies have sought to reduce circulating TNF-alpha, either with neutralizing anti-TNF-alpha binding proteins such as etanercept or via drugs that inhibit de novo TNF-alpha synthesis like pirfenidone. In the present study, we examined the effects of both classes of drugs on secreted and cell-associated TNF-alpha produced by THP-1 cells. All of the tested drugs significantly reduced secreted levels of bioactive TNF-alpha following stimulation with LPS as measured by bioassay. However, etanercept-treated cells had approximately six-fold higher levels of cell-associated TNF-alpha compared with that of the LPS-alone treatment group. Surprisingly, LPS+infliximab treated cells did not increase cell-associated TNF-alpha relative to the LPS-alone treatment. Pirfenidone significantly reduced both secreted and cell-associated TNF-alpha levels. These drug-related differences in cell-associated TNF-alpha may have broad implications in the future for the therapeutic uses of anti-TNF-alpha drugs in the management of TNF-alpha diseases.     

Small-molecule inhibitors of Bcl-2 family proteins as therapeutic agents in cancer

This review focuses on the recent patents and use of small-molecule inhibitors (SMIs) of Bcl-2 family proteins as therapeutic agents against cancer. Bcl-2 members are crucial regulators of apoptotic cell death. Apoptosis is an evolutionarily conserved process of programmed cell death that plays an essential role in organism development and tissue homeostasis. Several mechanisms exist allowing cells to escape programmed cell death among them is the overexpression of the antiapoptotic proteins. Cancer cells are often found to overexpress many of these members such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w and A1/Bfl1 and are usually resistant to a wide range of anti-cancer drugs and treatments. Many groups have been working to develop anti-cancer drugs that block the function of anti-apoptotic Bcl-2 members, thus favoring cell death. Methods include the downregulation of Bcl-2 expression or the use of peptides or small organic molecules to the Bcl-2 binding pocket, preventing its sequestration of proapoptotic proteins such as Bid and Bim. One of the most promising aspects of SMIs in treating cancer is that their targets and mechanisms of action are different from those of cytotoxic drugs and radiation. This makes it feasible to combine SMIs with other treatments, creating a synergistic therapy, without likely development of cross-resistance or increased toxicity. A broad-spectrum or "pan" SMI which targets multiple Bcl-2 family proteins is the goal.     

The Effects of Paraquat and Superoxide Dismutase on Pulmonary Vascular Permeability and Edema in Mice

Intraperitoneal administration of 50 mg/kg paraquat dichloride to mice significantly increased pulmonary vascular permeability at 24 and 48 hr, as measured by ¹²⁵I-albumin content of alveolar lavage. Lung edema, measured by lung weight as percent body weight, was significantly increased 48 hr after paraquat treatment. Intravenous administration of four doses of superoxidase dismutase at 12-hr intervals (i.e., one before and three after paraquat treatment) failed to inhibit paraquat-induced increased pulmonary vascular permeability and pulmonary edema. Superoxide dismutase treatment also failed to reduce mortality and had no significant effect on the death time course in animals challenged with paraquat. The results of this study suggest that acute toxic effects of paraquat, such as increased pulmonary vascular permeability and pulmonary edema, may not be mediated through the generation of superoxide anion.     

Diabetes and Hypertension in Urban Bhutanese Men and Women

Background:

Bhutan is a mountainous country with 31% urban population. There is no information on prevalence of diabetes and hypertension in Bhutan yet. This was the first study of its kind conducted in the capital city.

Objective:

To determine prevalence of diabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and hypertension in urban Bhutanese population aged 25 to 74 years.

Materials and Methods:

Stratified two-stage sampling was adopted to include 2474 respondents (Males: 1132, Females: 1342) equally distributed among different age and sex groups. A questionnaire containing demographic, educational and social details and history of diabetes and hypertension was administered on the sampled population the previous evening and blood pressure measured the next morning in nearby camp where fasting blood samples were collected and an oral glucose tolerance test done.

Results:

Age and sex standardized prevalence of diabetes, IGT and IFG were 8.2.0, 21.6 and 4%, respectively. Only 66.5% of the population had normal blood sugar. Prevalence of diabetes and IGT increased progressively with increasing age. Prevalence of hypertension was 26% (Males: 28.3%, Females: 23.2%). It was observed that 54.1% of diabetes population had hypertension.

Conclusion:

The study shows that not only is prevalence of diabetes and hypertension high in the urban Bhutanese but also there is a high diagnosis and treatment gap in these disorders.