Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma.

OBJECTIVE: The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs. SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations. METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier), which was developed and characterized. RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss). CONCLUSION: The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.

Synthesis and characterization of citric acid crosslinked carboxymethyl tamarind gum-polyvinyl alcohol hydrogel films.

The aim of present work was to synthesize and characterize carboxymethyl tamarind gum-polyvinyl alcohol (CMTG-PVA) hydrogel films using citric acid (CA) as a crosslinker. Hydrogel films were prepared by solvent casting technique. The films were evaluated for total carboxyl content (TCC), tensile strength, protein adsorption, permeability properties, hemocompatibility, swellability, moxifloxacin (MFX) loading and release, in-vivo wound healing activity and characterized using instrumental techniques. An optimal increase in amount of PVA and CA increased the TCC and tensile strength of the hydrogel films. Hydrogel films exhibited low protein adsorption and microbial permeation, good permeability to water vapour and oxygen, and sufficient hemocompatibility. The films prepared using high concentration of PVA and low concentration of CA showed good swellability in phosphate buffer and simulated wound fluids. MFX loading in the hydrogel films was found in the range of 384-440 mg/g. The hydrogel films sustained the release of MFX up to 24 h. The release followed Non-Fickian mechanism. ATR-FTIR, solid state 13C NMR and TGA analysis indicated formation of ester crosslinks. In-vivo study revealed good wound healing activity for hydrogel films. From the overall study, it can be concluded that the citric acid crosslinked CMTG-PVA hydrogel films can be effectively used for wound treatment.

Amelioration of diabetes and its complications by Manilkara zapota (L) P. Royen fruit peel extract and its fractions in alloxan and STZ-NA induced diabetes in Wistar rats.

Purpose: This study aims to evaluate the effects of Manilkara zapota (L) P. Royen fruit peel extract (EMZFP) and its fractions in ameliorating diabetes and its complications in alloxan and STZ-NA induced diabetes in Wistar rats. Methods: Antidiabetic effects of EMZFP were assessed in alloxan (150 mg kg-1) induced diabetes in differently grouped rats (n=6). Diabetic rats were treated with EMZFP 150, 300, and 600 mg kg-1 while, glimepiride (0.09 mg kg-1) was used as a reference standard. Treated animals were assessed for various biological parameters i.e. blood glucose, serum lipids, nephroprotective markers, cardiovascular risk indices, liver glycogen, neuropathy, body weight, and histopathology of kidneys. However, for evaluating antidiabetic effects of fractions (chloroform, acetone, ethyl acetate, and remaining ethanol fraction) of EMZFP, diabetes was induced by streptozotocin (60 mg kg-1)-nicotinamide (120 mg kg-1/ml) in differently grouped male rats (n=6). Diabetic rats were treated with EMZFP fractions 200 mg kg-1 however; glibenclamide (10 mg kg-1) was a reference standard and evaluated for blood glucose, serum lipids, cardiovascular risk indices, and diabetic neuropathy. Results: EMZFP 300 and 600 mg kg-1/day demonstrated significant antihyperglycemic effects with augmentation in glycogen content, perfection in serum lipid profile, cardiovascular risk indices, body weight enhancement, nephroprotective effects, beneficial in peripheral neuropathy, and histopathological evidence of reversal of glomerulosclerosis. EMZFP-Et and EMZFP-EA fractions depicted a significant improvement in blood glucose, serum lipid profile, cardiovascular risk indices, and peripheral neuropathy. Conclusion: EMZFP and its Et and EA fractions ameliorated diabetes and its complications by improving glycemic control and associated biochemical alteration. Highlights: • Manilkara Zapota (L.) P. Royen fruit peel 70% ethanolic extract exert antidiabetic effects• EMZFP significantly ameliorated diabetic biochemical parameters and its complications.• EMZFP-Et and EMZFP-EA fractions exert potential antihyperglycemic, hypolipidemic effects and significantly improved cardiovascular risk indices, and peripheral neuropathy.• Studied MZFP can be used as promising natural herbal source of antidiabetic principles.

Synthesis and characterization of hydrogel films of carboxymethyl tamarind gum using citric acid.

The objective of this study was to synthesize and characterize citric acid crosslinked carboxymethyl tamarind gum (CMTG) hydrogels films. The hydrogel films were characterized by Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, solid state 13C-nuclear magnetic resonance (13C NMR) spectroscopy and differential scanning calorimeter (DSC). The prepared hydrogel films were evaluated for the carboxyl content and swelling ratio. The model drug moxifloxacin hydrochloride was loaded into hydrogels films and drug release was studied at pH 7.4. The hemolysis assay was used to study the biocompatibility of hydrogel films. The results of ATR-FTIR, solid state 13C NMR and DSC confirmed the formation of ester crosslinks between citric acid and CMTG. The total carboxyl content of hydrogel film was found to be decreased when amount of CMTG was increased. The swelling of hydrogel film was found to be decreased with increase in curing temperature and time. CMTG hydrogel films showed high drug loading with non-Fickian release mechanism suggesting controlled release of drug. The hydrogel films were found to be biocompatible. It can be concluded that the citric acid can be used for the preparation of CMTG hydrogel films. Further, CMTG hydrogel film can be used potentially for controlled release of drug.

Alternatives to animal testing: A review.

The number of animals used in research has increased with the advancement of research and development in medical technology. Every year, millions of experimental animals are used all over the world. The pain, distress and death experienced by the animals during scientific experiments have been a debating issue for a long time. Besides the major concern of ethics, there are few more disadvantages of animal experimentation like requirement of skilled manpower, time consuming protocols and high cost. Various alternatives to animal testing were proposed to overcome the drawbacks associated with animal experiments and avoid the unethical procedures. A strategy of 3 Rs (i.e. reduction, refinement and replacement) is being applied for laboratory use of animals. Different methods and alternative organisms are applied to implement this strategy. These methods provide an alternative means for the drug and chemical testing, up to some levels. A brief account of these alternatives and advantages associated is discussed in this review with examples. An integrated application of these approaches would give an insight into minimum use of animals in scientific experiments.

Therapeutic approaches to drug targets in atherosclerosis.

Non-communicable diseases such as cancer, atherosclerosis and diabetes are responsible for major social and health burden as millions of people are dying every year. Out of which, atherosclerosis is the leading cause of deaths worldwide. The lipid abnormality is one of the major modifiable risk factors for atherosclerosis. Both genetic and environmental components are associated with the development of atherosclerotic plaques. Immune and inflammatory mediators have a complex role in the initiation and progression of atherosclerosis. Understanding of all these processes will help to invent a range of new biomarkers and novel treatment modalities targeting various cellular events in acute and chronic inflammation that are accountable for atherosclerosis. Several biochemical pathways, receptors and enzymes are involved in the development of atherosclerosis that would be possible targets for improving strategies for disease diagnosis and management. Earlier anti-inflammatory or lipid-lowering treatments could be useful for alleviating morbidity and mortality of atherosclerotic cardiovascular diseases. However, novel drug targets like endoglin receptor, PPARα, squalene synthase, thyroid hormone analogues, scavenger receptor and thyroid hormone analogues are more powerful to control the process of atherosclerosis. Therefore, the review briefly focuses on different novel targets that act at the starting stage of the plaque form to the thrombus formation in the atherosclerosis.