Nano titanium exposure induces dose- and size-dependent cytotoxicity on human epithelial lung and colon cells.

The productions as well as use of Titanium dioxide nanoparticles (TNPs) were rapidly increasing in the present nano-world. The TNP becomes an inevitable part our daily life in the form of cosmeceutical, bio-medical, and nano-pharmaceutical applications. The TNPs are either inhaled or ingested into the human body through common routes of exposure like the lungs and the oral-gastrointestinal tract (GIT). Human lung and colon were exposed to test particles, TNP 18 nm (TNP 18), TNP 30 nm (TNP 30), and TNP 87 nm (TNP 87) with a dose range 0.1-100 µg/ml. The effect of exposure was determined using MTT, LDH, and DCFH-DA methods. The TNP 18, TNP 30, and TNP 87 significantly (p < 0.001) reduced cell viability in a dose- and a size-dependent manner in 60 and 100 µg/ml. The lowest IC50 values 21.80 and 24.83 µg/ml were observed in A549 and Caco-2 for the smallest size, TNP 18. Further, for TNP 30, IC50 values were 23.30 and 28.59 µg/ml compared to Nano QTZ 43.82 and 45.86 µg/ml. The EC25 values of LDH leakage were 5.83 and 9.50 µg/ml for TNP 18 in lung and colon cells. Besides, ROS levels increased significantly at doses 60 (p < 0.01) and 100 (p < 0.001) µg/ml in two cells. The smaller size particle, TNP 18 has produced a significant (p < 0.05) toxic effect at the lowest dose i.e., 10 µg/ml. Therefore, we conclude that TNP 18, TNP 30, and TNP 87 induced a dose- and size-dependent cytotoxicity via decreased cell viability, increased LDH and ROS levels by in vitro methods.

Assessment of oxidative stress induced by gold nanorods following intra-tracheal instillation in rats.

Gold nanorods (GNRs) are used for their wide variety of applications in various industries. There is a little availability of data related to toxicity and ecological implications of these GNRs. The study evaluated the oxidative stress induction following intra-tracheal instillation of 1 and 5 mg/kg b.w. doses of 10 and 25 nm GNRs by estimating various oxidative stress markers including lipid peroxidation (malondialdehyde; MDA), glutathione (GSH), superoxide dismutase (SOD), catalase and total antioxidant capacity (TAC) after 1 day, 1 week, 1 month, and 3 months post exposure periods. The results have shown increased MDA levels and decreased GSH levels following 1 day and 1 week post exposure periods, indicating induction of oxidative stress. Also, the SOD, catalase and TAC levels were significantly decreased following exposure of both 10 and 25 nm GNRs after 1 day and 1 week after exposures, indicating the inhibition of antioxidant defense mechanisms. Moreover, the 10 nm GNRs at 5 mg/kg dose displayed greater changes in all the estimated parameters, representing dose and size based induction of oxidative stress by GNRs. In contrast, a little change was observed during 1 month and 3 months post exposure periods, may be due to recovery. Finally, the GNRs induced dose-size-dependent oxidative stress induction by various oxidative stress markers following intra-tracheal instillation in rats.

Extra Pulmonary Toxicity Assessment of Gold and Silver Nanorods Following Intra Tracheal Instillation in Rats.

The gold nanorods (GNRs) and silver nanorods (SNRs) are utilized in various types of industrial and commercial applications. But, there is limited availability of extra pulmonary toxicity data regarding these nanorods. The present investigation evaluated the extra pulmonary toxicity induced by 10 and 25 nm GNRs and SNRs in rats following intra tracheal instillation. The serum biochemical analysis results have shown elevated levels of serum alanine transaminase (ALT) and serum creatinine following 1 day and 1 week post instillation. GNRs have shown greatly increased serum ALT levels at 1 day, 1 week and 1 month post exposure periods compared to SNRs and quartz (QTZ) treated rats. In case of serum creatinine levels, both GNRs and SNRs have shown similar elevated levels. Histopathology studies of rat liver tissues following exposure of GNRs and SNRs displayed that congestion of central vein, shrinkage and ballooning of hepatocytes and lymphocytic infiltration leading to degeneration after 1 week and 1 month post instillation periods. The histopathology of rat kidney tissue was showed tubular dilation, degeneration and necrosis with 10 nm SNRs and 10 nm GNRs after 1 month post instillation period. The 10 nm GNRs and SNRs have shown great changes in serum biochemical analysis and histopathological studies compared to 25 nm test nanorods. These observations suggest the size and dose dependent translocation and extra pulmonary toxicity of both GNRs and SNRs.

Assessment of pulmonary toxicity of gold nanorods following intra-tracheal instillation in rats.

The present investigation was aimed to evaluate the pulmonary toxicity of 10 and 25nm gold nanorods (GNRs) following intra-tracheal instillation in rats using bronchoalveolar lavage (BAL) fluid and lung histopathological analysis. The GNRs displayed that the dose-dependent toxicity via elevated lactate dehydrogenase leakage, alkaline phosphatase, lipid peroxidation and total microprotein levels in BAL fluids after 1day, 1 week and 1 month post exposure periods. All the parameters were returned to normal values after 3 months post exposure period may be due to recovery. The rat lung histopathology displayed that accumulation of macrophages, inflammatory response and tissue thickening for both sizes of GNRs. 10nm GNRs increased all BAL fluid parameters significantly following 1day, 1 week and 1 month post exposure periods whereas 25nm GNRs have shown similar effects but less extent. These investigations proposed that the dose and size dependent pulmonary toxicity of GNRs.

Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions.

BACKGROUND: Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. OBJECTIVE: The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. METHODS: A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). RESULTS: The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054Lh-1 and 4.419L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. CONCLUSION: The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions.

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension.

BACKGROUND: Olmesartan medoxomil is an orally given angiotensin II receptor antagonist indicated for the treatment of hypertension. OBJECTIVE: The aim of the study was to establish a population pharmacokinetic model for olmesartan, the active metabolite of olmesartan medoxomil, in Indian hypertensive patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of olmesartan. METHODS: The population pharmacokinetic model for olmesartan was developed using Phoenix NLME 1.3 with a non-linear mixed-effect model. Bootstrap and visual predictive check were used simultaneously to validate the final population pharmacokinetic models. The covariates included age, sex, body surface area (BSA), bodyweight, height, creatinine clearance (CLCR) as an index of renal function and liver parameters as indices of hepatic function. RESULTS: A total of 205 olmesartan plasma sample concentrations from 69 patients with hypertension were collected in this study. The pharmacokinetic data of olmesartan was well described by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and V/F of olmesartan in the patients were 0.31565 L/h and 44.5162 L, respectively. Analysis of covariates showed that age and CLCR were factors influencing the clearance of olmesartan and the volume of distribution of olmesartan was dependent on age and BSA. CONCLUSION: The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of olmesartan in Indian patients with hypertension.

Evaluation of oxidative stress induction in rats following exposure to silver nanorods.

The study investigated the oxidative stress induction by the 10 and 25 nm silver nanorods (SNRs) following intra-tracheal instillation in rats after 1 day, 1 week, 1 month and 3 months post instillation periods at 1 and 5 mg/kg b.w. doses. The blood was withdrawn by retro orbital plexus method after exposure periods and different oxidative stress markers were estimated. The results showed that the both sizes of SNRs induced increased levels of malondialdehyde (MDA) and depleted glutathione (GSH) levels after 1 day and 1 week post exposure periods. The 10 and 25 nm SNRs at both doses displayed that significantly reduced levels of superoxide dismutase (SOD) and catalase following 1 day and 1 week post exposure periods. Also, the results have shown that decrease in total antioxidant capacity (TAC) of both sizes of SNRs significantly following 1 day and 1 week post exposure periods, indicating the oxidative stress induction by SNRs. In spite, there were no significant changes in oxidative stress markers following 1 month and 3 months post exposure periods may be due to recovery. The increased levels of MDA and decreased levels of GSH, SOD, catalase and TAC activity are strongly associated to ROS production and lipid peroxidation, suggesting the induction of oxidative stress in rats. The 10 nm SNRs at 5 mg/kg b.w. dose exposures in rats have shown greater changes in all oxidative stress parameters, indicating the greater induction of oxidative stress when compared with the 25 nm SNRs, representing the size-dose-dependent induction of oxidative stress of SNRs.

Cytotoxicity, oxidative stress, and inflammation in human Hep G2 liver epithelial cells following exposure to gold nanorods.

The gold nanorods (GNRs) are great potentials in imaging, therapy, biosensing, and many other commercial applications. However, GNRs interactions with human cells and potential health risks remain not well known. The present investigation aimed to evaluate the in vitro toxicity of 10 and 25 nm GNRs (10-50 µg/mL) following exposure for 48 h in human Hep G2 liver epithelial cells using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, glutathione (GSH) estimation, lipid peroxidation (TBARS), caspase-3 levels, and interleukin-8 (IL-8) release assays. Exposure of GNRs to cells results in decrease in cell viability and causes cell membrane damage through LDH leakage results in cytotoxicity. The IC50 (concentration required to inhibit 50% of cells) values of 10 nm GNRs, 25 nm GNRs, and quartz (toxic control)-treated cells were found to be 19.9, 26.8, and 36.35 µg/mL, suggesting the higher cytotoxicity of GNRs. The GNRs exposure to liver cells found in depleted GSH levels, increased lipid peroxidation, and increased caspase-3 levels leads to induction of oxidative stress. In addition, enhanced levels of IL-8 were found, a sign of inflammation. The 10 nm GNRs have shown significant toxicity against all biochemical assays when compare to 25 nm GNRs and quartz-treated cells. Finally, the data indicate that the concentration size-dependent in vitro toxicity of GNRs toward liver Hep G2 cells. The toxicity of GNRs may be due to cell membrane damage, induction of oxidative stress, and inflammatory mediator release. Further investigations are necessitated to elucidate the in vivo toxicity of GNRs.