Mukesh Doble

Background Pioglitazone is an effective drug for the treatment of type 2 diabetes. The drug was suspended from Indian market in June 2013 due to the risk of bladder cancer but was reintroduced in July 2013 because its benefits outweighed the risks. The risks associated with pioglitazone can be minimized if its dose is reduced. Hypothesis Ellagic acid, a polyphenolic antioxidant, is reported to reduce blood sugar in diabetic rats. The mechanism of anti-diabetic action of ellagic acid is not known. Drugs with same pharmacological action but different mechanism may act in synergistic way when combined together. The combination of ellagic acid with pioglitazone could enhance its activity and hence reduce its dose. Study design and methods Diabetes was induced in Wistar rats by intraperitoneal administration of 175 mg of nicotinamide/kg body weight in combination with 65 mg of streptozotocin/kg body weight and then fed with high fat diet for 4 weeks (Group II-VII). Non-diabetic rats were fed with normal chow diet (Group I). Group I and II received vehicle only whereas group III to VII received ellagic acid, pioglitazone or their combination. The treatment was given orally once a day for 21 days. Results The induction of type 2 diabetes in rats caused increase in blood glucose, LDL, triglyceride, and cholesterol and decrease in HDL. The diabetic rats showed improvement in hyperglycemia, dyslipidemia, liver and kidney function markers after treatment with ellagic acid, pioglitazone or their combinations. A combination of 10 mg of ellagic acid/kg BW with 10 mg of pioglitazone/kg BW resulted in significant improvement in all the biochemical parameters when compared to any of the individual treatment. The treatment of diabetic rats with the same combination significantly increased the expression levels of GLUT4, PPAR-γ and adiponectin in skeletal muscle. Conclusion The present study indicates that the dose of pioglitazone, required to achieve normoglycemia in diabetic rats, can be reduced by two folds by combining it with ellagic acid. The combinations reported here can be superior, since dose associated side effects and toxicity of the pioglitazone can be reduced.

The methanol extract of pomegranate peels was re-extracted with ethyl acetate. It was then evaporated to dryness. It was found to have a profound effect on the glucose uptake in L6 myotubes. The major constituents of this extract were ellagic acid and its glycosides and so further studies were carried out with pure commercial ellagic acid. Its effect on glucose uptake and expression of genes involved in the insulin signalling were investigated individually and in combination with a commercial drug, pioglitazone. They interact synergistically to increase insulin stimulated glucose uptake. Ellagic acid increases the expression of glucose transporter type 4 (GLUT4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of the latter by pioglitazone upregulates adiponectin, but when combined with pure ellagic acid, this upregulation is achieved at lower concentrations of the drug. The current study proves that insulin sensitising activity of pioglitazone can be enhanced at low doses by combining it with ellagic acid.

Diabetes mellitus is a chronic disorder characterized by increased blood glucose level. The available commercial oral antidiabetic drugs have some serious side effects; hence there is a need for new hypoglycemic agents which will have therapeutic efficacy as well as less side effects. Ferulic acid, a phytochemical, might be a good supplement to manage diabetes. We investigated the antidiabetic and antilipidemic effect of ferulic acid alone and in combination with oral antidiabetic drugs (metformin and Thiazolidinedione (THZ)). Blood glucose, plasma lipid profiles levels, liver function and kidney function markers were measured in control and streptozotocin induced diabetic rats three weeks after administrating ferulic acid and OHDs (oral hypoglycemic drugs) alone and in combinations. The histopathological analysis of the pancreas was also carried out. Ferulic acid and OHDs significantly reduced the blood glucose, lipid profile, urea, creatinine, serum glutamic pyruvic transaminases (SGPT) and serum glutamic oxaloacetate transaminases (SGOT) in diabetic rats. Same level of reduction in blood glucose levels was achieved when ferulic acid was used in combination with even reduced amounts of OHDs. It decreased most of the side effects when used in combination with THZ. Histopathological analysis showed that combinations increased the number of islets. Ferulic acid interacts synergistically with both the drugs. It might be a good supplement with the OHDs to manage diabetic complications as well as reduces the use of the later. © 2013 Elsevier GmbH. All rights reserved.

Background and purpose Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. Methods Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. Results Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. Conclusion The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side effects of metformin therapy can be reduced.

Antibiotics have been effective in treating infectious diseases, but resistance to these drugs has led to the emergence of new and the reemergence of old infectious diseases. One strategy employed to overcome these resistance mechanisms is the use of combination of drugs, such as β-lactams together with β-lactamase inhibitors. Several plant extracts have exhibited synergistic activity against microorganisms. This review describes in detail, the observed synergy and mechanism of action between natural products including flavonoids and essential oils and synthetic drugs in effectively combating bacterial, fungal and mycobacterial infections. The mode of action of combination differs significantly than that of the same drugs acting individually; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries. © 2008 Elsevier GmbH. All rights reserved.

Eugenol, the principal chemical component of clove oil from Eugenia aromatica has been long known for its analgesic, local anesthetic, anti-inflammatory, and antibacterial effects. The interaction of the eugenol with ten different hydrophobic and hydrophilic antibiotics was studied against five different Gram negative bacteria. The MIC of the combination was found to decrease by a factor of 5-1000 with respect to their individual MIC. This synergy is because of the membrane damaging nature of eugenol, where 1 mM of its concentration is able to damage nearly 50% of the bacterial membrane. Eugenol was also able to enhance the activities of lysozyme, Triton X-100 and SDS in damaging the bacterial cell membrane. The hydrophilic antibiotics such as vancomycin and β-lactam antibiotics which have a marginal activity on these gram negative bacteria exhibit an enhanced antibacterial activity when pretreated with eugenol. Reduced usage of antibiotics could be employed as a treatment strategy to slow down the onset of antibiotic resistance as well as decrease its toxicity. Experiments performed with human blood cells indicated that the concentration of eugenol used for the combination studies were below its cytotoxic values. Pharmacodynamic studies of the combinations need to be performed to decide on the effective dosage. © 2009 Elsevier GmbH. All rights reserved.

Combination therapy is the most effective treatment strategy in cancer to overcome drug toxicity and drug induced resistance. The effect of eight phenylpropanoids in combination with 5-fluorouracil against the cervical cancer cells (HeLa) is reported here. The cytotoxic activity of these phenylpropanoids against HeLa cells is in the order of eugenol > ferulic > cinnamic > caffeic > chlorogenic > p-coumaric > 3,4-dimethoxycinnamic > 2,4,5-trimethoxycinnamic acids. Eugenol, ferulic and caffeic acids interacted synergistically with the drug, in bringing about a reduction in the amount of the latter. Flow cytometry results indicated that the combination of eugenol and 5-fluorouracil increased the number of cells in the S and G2/M phases when compared to treatment with the individual compounds alone. This indicates that they possess different cell cycle targets and induce apoptosis in the cancer cells. In vitro hemolytic activity of phenylpropanoids on human erythrocytes showed that the compounds possessed minimum amount of hemolytic activity, indicating that they can be used as drugs without causing adverse toxicity. 3D-quantitative structure activity relationship studies indicate the importance of electrostatic region near the substitutions present in the benzene ring and near the double bond of the compounds for anticancer and hemolytic activities, respectively. The models derived had good statistical predictive capability. © 2012 Elsevier GmbH. All rights reserved.

The present study analyses the effect of eugenol, arecoline and vanillic acid alone and in combination with two oral hypoglycemic drugs (OHD), namely, metformin and 2,4-thiazolodinedione (THZ), on 2-deoxyglucose (2DG) uptake in L6 myotubes. 2DG uptake in L6 myotubes was determined using an enzymatic assay developed by Yamamoto et al. (2006). Lipid content inside the cells has been estimated with oil red O assay. The absorption, distribution, metabolism, and excretion (ADME) and drug likeness properties of these phytochemicals are estimated using software QikProp ®. All the three phytochemicals enhance 2DG uptake both in time- and dose-dependent manner. Eugenol and arecoline enhances 2DG uptake synergistically with both the OHD; whereas vanillic acid showing partly synergy with THZ and antagonistic activity with metformin on 2DG uptake. Eugenol and arecoline significantly increase the expressions of the glucose transporter type 4 (GLUT4) and phosphoinositide 3-kinase (PI3K) genes, but not the peroxisome proliferator-activated receptor (PPAR) gamma. Whereas vanillic acid does not has any significant effect on the expressions of these genes, the ADME results indicate that these phytochemicals are satisfying all the conditions to have a good oral bioavailability. These findings suggest that these phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects caused by the later as well as reduce the secondary complications. © 2010 Elsevier GmbH. All rights reserved.

The present study analyses the effect of two plant phenolic compounds, namely chlorogenic acid and ferulic acid, and a plant alkaloid, berberine, alone and also in combination with two commercial oral hypoglycemic drugs (OHD), namely metformin and 2,4-thiazolodinedione (THZ), on the uptake of 2-deoxyglucose (2DG) by L6 myotubes. 2-DG uptake is determined using an enzymatic assay. All the three natural products enhance the uptake of 2DG in time- and dose-dependent manner. A combination of different concentrations of chlorogenic acid and metformin or THZ, has a synergistic effect in the uptake of 2DG with a maximum of 5.0- and 5.3-times respectively, with reference to the base value (without the drugs or the natural products). Ferulic acid in combination with metformin or THZ has also shown a synergistic effect and the 2DG uptake increases by 4.98- and 5.11-fold when compared to the control respectively. Whereas, berberine, in combination with either metformin or THZ, has shown an additive effect with maximum 2DG uptake of 4.1- and 4.7-times from the base value, respectively. The synergistic interaction has been explained with the use of combination index and isobologram. Expression of GLUT4 and PPAR-γ gene were elevated in chlorogenic acid and berberine treated cells, whereas expression of GLUT4 and PI3K transcripts were significantly enhanced in ferulic acid treated cells. The studies indicate that chlorogenic acid enhances glucose uptake by increasing GLUT4 expression via PI3K independent pathway whereas ferulic acid increases glucose uptake by PI3K dependent pathway. The current findings suggest that the phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects of the later. © 2009 Elsevier GmbH. All rights reserved.

Diabetes mellitus is the most common metabolic disorder. The major cause of mortality and morbidity here is due to the complications caused by increased glucose concentrations. All the available commercial antidiabetic drugs are associated with side effects. The combination therapy could be a new and highly effective therapeutic strategy to manage hyperglycemia. Combination of commercial drugs with phytochemicals may reduce the side effects caused by these synthetic drugs. Herbal products have been thought to be inherently safe, because of their natural origin and traditional use rather than based on systemic studies. New formulation and cocrystallisation strategies need to be adopted to match the bioavailability of the drug and the phytochemical. This review describes in detail, the observed synergy and mechanism of action between phytochemicals and synthetic drugs in effectively combating. The mode of action of combination differs significantly than that of the drugs alone; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries. © 2013 Elsevier GmbH.