Authors(s): Harjeet Singh, Pooja Arora, Ramdayal Gupta, H. S. Lamba
Authors(s): Pooja Arora, Harjeet Singh, Ramdayal Gupta, H. S. Lamba
Curcumin as potential therapeutic natural product: a nanobiotechnological perspective
Objectives: Nanotechnology-based drug delivery systems can resolve the poor bioavailability issue allied with curcumin. The therapeutic potential of curcumin can be enhanced by making nanocomposite preparation of curcumin with metal oxide nanoparticles, poly lactic-co-glycolic acid (PLGA) nanoparticles and solid lipid nanoparticles that increases its bioavailability in the tissue.
Key findings: Curcumin has manifold therapeutic effects which include antidiabetic, antihypertensive, anticancer, anti-inflammatory and antimicrobial properties. Curcumin can inhibit diabetes, heavy metal and stress-induced hypertension with its antioxidant, chelating and inhibitory effects on the pathways that lead to hypertension. Curcumin is an anticancer agent that can prevent abnormal cell proliferation. Nanocurcumin is an improved form of curcumin with enhanced therapeutic properties due to improved delivery to the diseased tissue, better internalization and reduced systemic elimination.
Summary: Curcumin has multiple pharmacologic effects, but its poor bioavailability reduces its therapeutic effects. By conjugating curcumin to metal oxide nanoparticles or encapsulation in lipid nanoparticles, dendrimers, nanogels and polymeric nanoparticles, the water solubility and bioavailability of curcumin can be improved and thus increase its pharmacological effectiveness.
Forecasting oral absorption across biopharmaceutics classification system classes with physiologically based pharmacokinetic models
Objectives: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success.
Methods: Simcyp Simulator, GastroPlus™ and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters. Simulation success was evaluated with the average fold error (AFE) and absolute average fold error (AAFE). Parameter sensitivity analysis (PSA) to selected parameters was performed.
Key findings: Plasma concentration–time profiles after intravenous administration were forecast within an AAFE < 3. The addition of absorption processes resulted in more variability in the prediction of the plasma profiles, irrespective of biopharmaceutics classification system (BCS) class. The reliability of literature permeability data was identified as a key issue in the accuracy of predicting oral drug absorption.
Conclusion: For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs.
A comparative study of the hypolipidaemic effects of a new polysaccharide, mannan Candida albicans serotype A, and atorvastatin in mice with poloxamer 407-induced hyperlipidaemia
Objectives: We evaluated the hypolipidaemic effect of mannan Candida albicans serotype A, relative to atorvastatin, in a mouse model of hyperlipidaemia.
Methods: Mannan serotype A was investigated in vitro and in vivo to determine its effects on macrophage proliferation, nitric oxide (NO) production by cultured macrophages, serum and liver lipids, changes in liver morphology and serum chitotriosidase activity and its expression in the liver.
Key findings: Mannan serotype A stimulates the macrophage proliferation and NO production in murine peritoneal macrophages in vitro. The activity of serum chitotriosidase (an enzyme released from the activated macrophages) was found to be significantly increased in P-407-induced hyperlipidaemic mice pretreated with low-dose mannan compared with mice administered P-407 only. Mannan treatment in mice was shown to significantly increase the chitotriosidase expression in the liver of both non-hyperlipidaemic and P-407-induced hyperlipidaemic mice. Lastly, mice pretreated with mannan before the induction of hyperlipidaemia with P-407 showed a significant reduction in the serum concentration of atherogenic LDL cholesterol, total cholesterol, triglycerides and liver triglycerides.
Conclusions: It is suggested that mannan serotype A, like β-glucan, may represent another hypolipidaemic agent, which could potentially be used as an adjunctive therapy with conventional antihyperlipidaemic drugs (statins and fibrates) in humans.
Development of hemiacetal esterified levofloxacin to prevent chelation with metal-containing drugs
Objectives: To avoid the chelate formation between levofloxacin (LVFX) and aluminium hydroxide in gastrointestinal tract, an ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) was synthesised as a prodrug.
Methods: The effects of aluminium hydroxide on the bioavailability of LVFX following oral administration of LVFX-EHE were investigated in rats. Furthermore, the effects of aluminium hydroxide on small intestinal absorption of LVFX and LVFX-EHE when subjected to a hydrolysis experiment using in situ everted gut sac were investigated, and the minimal inhibitory concentrations (MICs) of LVFX and LVFX-EHE for various intestinal bacteria were measured.
Key findings: When LVFX-EHE was co-administered with and without aluminium hydroxide, the AUC0–4 h values of LVFX hydrolysed from LVFX-EHE were similar to that of LVFX alone. In everted gut sac experiments, LVFX-EHE was efficiently absorbed even in the presence of aluminium ions after 1 h of incubation, whereas the absorption of LVFX decreased significantly in the presence of aluminium ions. MIC values of LVFX-EHE were far higher than LVFX.
Conclusions: This study suggests the benefit of ethoxycarbonyl 1-ethyl hemiacetal esterification of the carboxyl group of new quinolone as a prodrug which is able to avoid chelate formation.
Alpha-lipoic acid–stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study
Objectives: This study was designed to demonstrate the potential of novel α-lipoic acid–stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX).
Methods: α-lipoic acid–stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification–diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats.
Key findings: Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues.
Conclusions: α-lipoic acid–stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects.
Immunomodulatory/inflammatory effects of geopropolis produced by Melipona fasciculata Smith in combination with doxorubicin on THP-1 cells
Objectives: Geopropolis (GEO) in combination with doxorubicin (DOX) reduced HEp-2 cells viability compared to GEO and DOX alone. A possible effect of this combination on the innate immunity could take place, and its effects were analysed on THP-1 cell – a human leukaemia monocytic cell line used as a model to study monocyte activity and macrophage activity, assessing cell viability, expression of cell markers and cytokine production.
Methods: THP-1 cells were incubated with GEO, DOX and their combination. Cell viability was assessed by MTT assay, cell markers expression by flow cytometry and cytokine production by ELISA.
Key findings: GEO + DOX did not affect cell viability. GEO alone or in combination increased TLR-4 and CD80 but not HLA-DR and TLR-2 expression. GEO stimulated TNF-α production while DOX alone or in combination did not affect it. GEO alone or in combination inhibited IL-6 production.
Conclusions: GEO exerted a pro-inflammatory profile by increasing TLR-4 and CD80 expression and TNF-α production, favouring the activation of the immune/inflammatory response. GEO + DOX did not affect cell viability and presented an immunomodulatory action. Lower concentrations of DOX combined to GEO could be used in cancer patients, avoiding side effects and benefiting from the biological properties of GEO.