Review of the mechanism underlying mefloquine-induced neurotoxicity.

Mefloquine, a potent blood schizontocide, is effective against drug-resistant Plasmodium falciparum. This property, along with its unique pharmacokinetic profile, makes mefloquine a widely prescribed antimalarial drug. However, several epidemiological studies have raised concerns on the safety of mefloquine as prophylaxis for malaria. Well-documented side-effects of mefloquine include abnormal dreams, insomnia, anxiety, and depressed mood, as well as nausea and dizziness (the last two most frequent effects). The mechanisms that underlie the neurological/psychiatric complications of mefloquine are poorly understood. The aim of this study was to review the literature on the neurotoxic mechanisms of action of mefloquine to better understand its potential toxicity in the central nervous system, highlighting the mechanisms that lead to its psychiatric disorders. Experimental studies on the neurotoxic effects of mefloquine discussed herein include brain transporters of mefloquine, alteration in neurotransmitters, disruption on calcium (Ca2+) homeostasis and neuroinflammation, generation of oxidative stress response in neurons (involving glutathione, increased F2-isoprostanes, accumulation of cytosolic lipid globules), and alteration of voltage-dependent channels, as well as gap junction intercellular communications. Although several hypotheses have been proposed for the mechanisms that mediate mefloquine-induced brain damage, they are not fully understood, necessitating additional studies in the future.

Blood cadmium levels and sources of exposure in an adult urban population in southern Brazil.

BACKGROUND: Cadmium (Cd) is a toxic metal that is widely present in the environment due to geologic and anthropogenic sources. Exposures to high Cd levels may cause nephrotoxicity, carcinogenicity, pulmonary and cardiovascular disease, among others. The goal of this study was to investigate in an adult urban population whether an association exists between sources and levels of Cd exposure and blood Cd concentrations. METHODS: Using a census-based design, a total of 959 adults, aged 40 years or older, were randomly selected. Information on socio-demographics, dietary, and lifestyle background was obtained by household interviews. Blood Cd levels were measured by inductively coupled-plasma mass spectrometry. Geometric means (GM) (95% CI) and the 50th percentile were determined, stratified by sex, age, race, education, income class, smoking status, consumption of vegetables, red meat and milk, occupation and blood pressure. To assess the association between Cd exposure and the aforementioned variables, we estimated the geometric mean ratio (GMR) (95%CI) of blood Cd concentrations. RESULTS AND CONCLUSION: The geometric mean (95%CI) of blood Cd levels in the total population was 0.25 (0.22, 0.27) ug/dL. In a univariate analysis, significantly higher blood Cd levels were found in men (p < 0.001), current and former smokers (p < 0.001), alcohol drinkers (p < 0.001), those who never or almost never consumed milk (p < 0.001), and in subjects with higher diastolic blood pressure (p = 0.03). Significant correlations were found between the number of cigarettes consumed daily and blood Cd levels. Multivariate analysis confirmed higher blood Cd concentrations were associated with alcohol consumption (GMR 95%CI = 1.28, 1.04-1.59) and in former and current smokers (GMR 95% IC = 1.33, 1.06-1.67 and 4.23, 3.24-5.52, respectively). Our results shed novel information on variables associated with blood Cd levels in an urban Brazilian population, and should encourage additional research to prevent environmental Cd exposure, both in Brazil and globally.

Amphiphilic poly-N-vinylpyrrolidone nanoparticles as carriers for non-steroidal, anti-inflammatory drugs: In vitro cytotoxicity and in vivo acute toxicity study.

Polymeric nanoparticles were prepared from self-assembled amphiphilic N-vinylpyrrolidone polymers in aqueous media and evaluated as novel carriers of indomethacin, a non-steroidal, anti-inflammatory drug. It was determined that these nanoparticles could be created in spherical morphologies with sizes less than 100nm, narrow size distributions and high indomethacin contents(up to 35%) combined with high drug loading efficiencies(up to 95%). In cytotoxicity tests using the human embryonic stem cell derived fibroblasts (EBF-H9) and hepatocellular carcinoma cells (HepG2), the indomethacin-loaded polymeric nanoparticles showed higher cell viability compared to that of free indomethacin at the same concentration. The median LD50 values, determined by the Litchfield-Wilcoxon method, were 55-70mg/kg body weight depending on the polymer molecular design in both mice and rats. Based on the acquired results, these novel amphiphilic poly-N-vinylpyrrolidone nanoparticles can be considered as potential carriers for new, highly efficient, injectable drug delivery systems for hydrophobic drugs such as indomethacin.

Nanoaggregates of Biphilic Carboxyl-Containing Copolymers as Carriers for Ionically Bound Doxorubicin.

Application of nanocarriers for drug delivery brings numerous advantages, allowing both minimization of side effects common in systemic drug delivery and improvement in targeting, which has made it the focal point of nanoscience for a number of years. While most of the studies are focused on encapsulation of hydrophobic drugs, delivery of hydrophilic compounds is typically performed via covalent attachment, which often requires chemical modification of the drug and limits the release kinetics. In this paper, we report synthesis of biphilic copolymers of various compositions capable of self-assembly in water with the formation of nanoparticles and suitable for ionic binding of the common anticancer drug doxorubicin. The copolymers are synthesized by radical copolymerization of N-vinyl-2-pyrrolidone and acrylic acid using n-octadecyl-mercaptan as a chain transfer agent. With an increase of the carboxyl group's share in the chain, the role of the electrostatic stabilization factor of the nanoparticles increased as well as the ability of doxorubicin as an ion binder. A mathematical description of the kinetics of doxorubicin binding and release is given and thermodynamic functions for the equilibrium ionic binding of doxorubicin are calculated.

Nanosized carriers based on amphiphilic poly-N-vinyl-2-pyrrolidone for intranuclear drug delivery.

AIM: Ability to deliver drugs into the cell nuclei can significantly increase the efficacy of cancer therapies, in particular in the case of multidrug-resistant cancer Results: Polymer nanocarriers based on amphiphilic thiooctadecyl-terminated poly-N-vinyl-2-pyrrolidone were produced and loaded with a model hydrophobic drug, curcumin. Two commonly used loading approaches - emulsification and ultrasonic dispersion - were found to lead to two different size distributions with distinctively different biological effect. While nanocarriers produced via the emulsion method penetrated cells by dynamin-dependent endocytic mechanisms, sub-100 nm dispersion-produced nanocarriers were capable of crossing the membranes via biologically independent mechanisms. CONCLUSION: This finding opens an intriguing possibility of intranuclear delivery by merely tailoring the size of polymeric carriers, thus promising a new approach for cancer therapies.