Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice

Singh, Shubhra; Dwivedi, Richa; Chaturvedi, Vinita

doi:10.1128/aac.01702-12

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…Sodium carboxymethyl cellulose (CMC) and polysorbate-80, known as GRAS (generally recommended as safe) agents approved by FDA, are most commonly used suspending agents. They are widely used in pediatric oral formulations, in eye lubricants, in food products; and to test the efficacy of investigational molecules and drugs by oral route in animal models . Therefore, Tam and LCA-Tam-PC (as per 10 mg/kg equivalent of Tam) were suspended in 0.2 mL (for each mice) of suspending vehicle (0.5% CMC and 0.1% polysorbate-80 in distilled water) for oral delivery.…”

Section: Results and Discussionmentioning

confidence: 99%

“…They are widely used in pediatric oral formulations, 38 in eye lubricants, in food products; 39 and to test the efficacy of investigational molecules and drugs by oral route in animal models. 40 Therefore, Tam and LCA-Tam-PC (as per 10 mg/kg equivalent of Tam) were suspended in 0.2 mL (for each mice) of suspending vehicle (0.5% CMC and 0.1% polysorbate-80 in distilled water) for oral delivery. Tumor bearing mice were randomized into four groups of ten animals each.…”

Section: Bioconjugate Chemistrymentioning

confidence: 99%

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Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

et al. 2017

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Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Bioconjugate Chemistrymentioning

confidence: 99%

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

et al. 2017

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“…Compound was dissolved/solubilized in 0.1% carboxymethylcellulose (CMC): 0.1% of Tween-80 using a mortar-pestle. The usability of these vehicles for oral administration of a test compound was shown by (48). The mixture was then transferred to a tube, vortexed and sonicated in a water bath sonicator.…”

Section: Dgat1 Inhibitor (T863) Administrationmentioning

confidence: 99%

Inhibition of Granuloma Triglyceride Synthesis Imparts Control of Mycobacterium tuberculosis Through Curtailed Inflammatory Responses

et al. 2021

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Lipid metabolism plays a complex and dynamic role in host-pathogen interaction during Mycobacterium tuberculosis infection. While bacterial lipid metabolism is key to the success of the pathogen, the host also offers a lipid rich environment in the form of necrotic caseous granulomas, making this association beneficial for the pathogen. Accumulation of the neutral lipid triglyceride, as lipid droplets within the cellular cuff of necrotic granulomas, is a peculiar feature of pulmonary tuberculosis. The role of triglyceride synthesis in the TB granuloma and its impact on the disease outcome has not been studied in detail. Here, we identified diacylglycerol O-acyltransferase 1 (DGAT1) to be essential for accumulation of triglyceride in necrotic TB granulomas using the C3HeB/FeJ murine model of infection. Treatment of infected mice with a pharmacological inhibitor of DGAT1 (T863) led to reduction in granuloma triglyceride levels and bacterial burden. A decrease in bacterial burden was associated with reduced neutrophil infiltration and degranulation, and a reduction in several pro-inflammatory cytokines including IL1β, TNFα, IL6, and IFNβ. Triglyceride lowering impacted eicosanoid production through both metabolic re-routing and via transcriptional control. Our data suggests that manipulation of lipid droplet homeostasis may offer a means for host directed therapy in Tuberculosis.

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“…Rats in a control group received drinking water while rats in hypertensive groups received L-NAME (40 mg/kg BW/day) in their drinking water. Genistein and lisinopril were dissolved in 10% dimethyl sulfoxide (DMSO) and propylene glycol [48]. The treatment was orally administered using a gavage feeding tube for 5 weeks.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Genistein Prevents Nitric Oxide Deficiency-Induced Cardiac Dysfunction and Remodeling in Rats

et al. 2021

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Genistein is an isoflavone found in soybeans. This study evaluates the protective effects of genistein on Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension, cardiac remodeling, and dysfunction in rats. Male Wistar rats were treated with L-NAME 40 mg/kg/day together for 5 weeks, with or without genistein at a dose of 40 or 80 mg/kg/day or lisinopril 5 mg/kg/day (n = 8 per group). Genistein prevented L-NAME-induced hypertension in rats. Increases in the left ventricular weight, metalloproteinase-2, metalloproteinase-9, and collagen type I intensity were observed in L-NAME rats, and these changes were attenuated in the genistein-treated group. Genistein reduced circulating angiotensin-converting enzyme activity and angiotensin II concentrations in L-NAME rats. L-NAME increased plasma and cardiac malondialdehyde and vascular superoxide generations, as well as reductions of serum and cardiac catalase activities in rats. Plasma nitrate/nitrite were protected in the genistein-treated group. Genistein prevented the L-NAME-induced overexpression of angiotensin II receptor type I (AT1R), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 2 (gp91phox), and transforming growth factor beta I (TGF-β1) in hypertensive rats. In conclusion, genistein exhibited a cardioprotective effect in hypertensive rats in this study. The molecular mechanisms might be mediated by suppression of oxidative stress through the Ang II/AT1R/NADPH oxidase/TGF-β1 signaling pathway.

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Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice

Cited by 7 publications

References 28 publications

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

Inhibition of Granuloma Triglyceride Synthesis Imparts Control of Mycobacterium tuberculosis Through Curtailed Inflammatory Responses

Genistein Prevents Nitric Oxide Deficiency-Induced Cardiac Dysfunction and Remodeling in Rats

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