Polymeric nanoparticles - targeted drug delivery systems for treatment of CNS disorders and their possible endocrine disrupting activities.

Drug delivery to the central nervous system (CNS) represents one of the most priority challenges in research and development of pharmaceutical nanotechnology products. Among the various non-invasive approaches for CNS delivery, nanoparticle carriers and particularly polymeric nanoparticles (PNs) seem to be one of the most interesting. This review deals with PNs as CNS drug delivery systems and their potential endocrine disrupting properties. Possible interference with the development of neuroendocrine-reproductive system is considered. Special regard is being paid to potential mechanisms of PNs toxicity. Necessity to investigate the toxicity of nanomaterials and their impact on human health are discussed.

[Liver steatosis and disorders of mitochondrial oxidative phosphorylation after experimental administration of simazine]. / Steatóza pecene a poruchy oxidacnej fosforylácie mitochondrií po aplikácii simazínu v experimente.

BACKGROUND: Triazine herbicides are widely used in extensive agricultural production, however, some ecological and health hazards occur due to water and food contamination. AIM: The aim of this study was to evaluate the effects of long-term simazine feeding on the steatosis development and the changes of liver bioenergetics in experimental animals. METHODS: A population of B6C3F1 mice were fed with simazine (2 g and 4 g/kg/day, respectively) for 35 weeks. The concentration of cholesterol and triacylglycerols were measured in liver tissue. Liver mitochondria were isolated and parameters of oxidative phosphorylation were assessed polarographically using Clark oxygen electrode with NAD glutamate and/or FAD succinate as substrates. RESULTS: Significant changes (p < 0.001) expressed as medians (with confidence intervals) against control animals were found in both experimental groups after simazine feeding. The concentration of triacylglycerols increased from 10.3 (8.8-10.9) to 20.1 (18.0-20.9) and 47.7 (23.8-56.0), respectively. The parameters of oxidative phosphorylation with NAD substrate glutamate decreased as follows: The index of respiratory control from 7.7 (6.4-9.0) to 4.8 (4.0-6.3) resp. 4.4 (3.9-4.6); the rate of oxygen consumption in the state 3 (with ADP) from 84.2 (82.0-92.3) to 65.4 (50.8-70.7) resp. 69.9 (65.0-78.4) nAtO.mg.prot-1.min-1; and phosporylation rate from 215.3 (204.4-232.2) to 166.3 (120.4-193.6) resp. 169.6 (155.3-176.9) nmolATP.mg.prot-1.min-1. Comparable changes were detected in oxidative phosphorylation with FAD succinate as substrate. CONCLUSIONS: Liver steatosis development and mitochondrial energetics inhibition were determined in mice after long-term simazine feeding, nevertheless, liver energy production was sufficient to satisfy the liver function and the needs of the whole organism. (Tab. 4, Fig. 6, Ref. 24.)

Teratological assessment of stobadine after single and repeated administration in mice.

Teratological studies were performed with stobadine, a compound with antiarrhythmic and antihypoxic activity. Single i.v. injections of stobadine in the form of dihydrochloride (DH 1011) to ICR mice on days 3, 6, 9 or 12 of gestation at doses of 1 and 3 mg kg-1 had no teratogenic effect. Slight fetal toxicity was manifested by decreased fetal weight after treatment on days 3 and 6, increased incidence of rudimentary ribs after treatment on days 9 and 12 of gestation and non-significantly increased postimplantation loss after injection on day 6 of gestation. The effect of repeated oral administration in the form of dipalmitate salt (DP 1031) was studied in doses of 12.2, 61.0 and 122.0 mg kg-1 on days 4-16 of gestation. Oral exposure to 61.0 mg kg-1 DP 1031 resulted in significant reduction of implantations, live fetuses and litter weight, and after 122.0 mg kg-1 DP 1031 the fetal weight was significantly decreased. External and skeletal examinations of the fetuses revealed no evidence of teratogenesis. The relevance of the two routes of stobadine administration for risk involvement is discussed.

Reproductive toxicity studies with cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate in rats.

cis-(-)-2,3,4,4a,5,9b-Hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate (stobadin dipalmitate; in the following briefly called STB) a new prospective cardioprotective drug, was evaluated for effects on fertility, general reproductive performance, prenatal and peri-postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/d were administered orally in aqueous suspension to rats in all studies. Daily treatment of male rats for 70 days before mating and female rats for 14 days before mating and during gestation and lactation had no adverse effects on fertility, survival rate and weight gains of parental animals or on prenatal and postnatal development of pups. There was only evidence of slight adult toxicity late in the experiment, significant increase of anomalous foetuses in both the 15 and 50 mg/kg/d doses and decreased body weight of the young at 50 mg/kg/d on day 21 post partum. Daily oral treatment of pregnant rats with STB throughout organogenesis (day 4 to 16) had no overt effects on dams or on embryo-foetal development, except of increased incidence of some skeletal variations in all treated groups. In the peri-postnatal toxicity study treatment of pregnant dams with STB continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/d, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. The results of these studies did not reveal serious developmental hazard potentials of STB administered to rats in doses up to 50 mg/kg/d.

[Characteristics of new approaches for evaluation of embryotoxic effects of chemical substances]. / Charakteristika nových prístupov k hodnoteniu embryotoxických úcinkov chemických látok.

New approaches to the evaluation of embryotoxic effects of xenobiotics are characterized in the light of mother--fetus interrelationship. The first part of the paper analyzes problems of evaluating maternal and embryofetal toxicity and substantiates the necessity of sensitive selection and precise evaluation of individual parameters of toxicity. The second part presents a survey of classical testing procedures and of alternative methods used in assessing the safety of new drugs. The third part characterizes methods of quantitative determination of risks inherent to chemical substances. A detailed description of the principles of the new method is presented which is based on the interrelationship of maternal and embryofetal toxicity (adult/developmental--A/D). The acceptability of the new method has been verified experimentally on evaluating some new prospective drugs according to standard teratological studies.

Teratological study of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate in Swiss mice.

Teratological studies of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate were carried out in mice. Pregnant mice were given etofylline clofibrate and fenofibrate in doses 11.7, 117.1, and 585.5 mg/kg orally from day 7 to 16 of gestation. Terminal maternal body weight was significantly decreased after all doses of etofylline clofibrate in a non-dose-related fashion compared to the control group. The foetuses were examined on day 19 of gestation. They were weighed and inspected for external, skeletal and visceral abnormalities. The low and middle doses of etofylline clofibrate and fenofibrate had no adverse effects on embryofoetal development. The highest etofylline clofibrate dose induced a significant decrease of foetal weight at term, likewise postimplantation loss was significantly increased after the highest dose of fenofibrate. The incidence of external, skeletal and visceral anomalies was not dose-dependent. In this study no teratogenic effects were detected, yet with the highest etofylline clofibrate and fenofibrate doses some foetotoxic effects were observed.

Teratological and cytogenetical evaluation of two antihistamines (pipethiadene and pizotifen maleate) in mice.

The teratogenic and cytogenetic effects of two drugs with antihistamine properties, Pipethiadene and Pizotifen maleate, were investigated. Three groups of pregnant mice were treated daily with oral doses (0.24, 0.6 and 1.2 mg/kg) of these drugs from day 4 to day 16 of gestation. The following parameters were investigated: reproductive health of the dams, external, skeletal and visceral malformations of fetuses and frequencies of micronuclei and chromosome aberrations in bone marrow cells of dams. Oral administration of Pipethiadene or Pizotifen maleate produced no teratogenic effects. No elevation was observed in the frequencies of micronuclei and chromosome aberrations. However, the significant reduction of fetal weight after all doses of Pipethiadene or Pizotifen maleate was found to correlate well with the decreased values of the mitotic indices of bone marrow cells of mice, suggesting a potential embryotoxic effect of the tested substances.

Effect of pyridoindole derivative (DH 1011) on late chick embryo-genesis.

The pyridoindole derivative (DH 1011), a new antiarrhythmic agent, and quinidine were examined for teratogenic and embryotoxic activity in chick embryos. The tested substance was injected into egg albumen on incubation days 5, 6 or 7 in doses of 0.4, 0.8 or 1.6 mg per egg. All embryos were examined on day 19. A significantly decreased survival rate of embryos was recorded only after the dose of 1.6 mg DH 1011 per egg administered on incubation day 5. Correlation between body and heart weight was found in all surviving embryos after administration of each agent on incubation days 5 and 6. Chondrodystrophy was the major deformity in chick embryos treated on incubation day 5. The results of this investigation suggest that neither quinidine nor DH 1011 have adverse effects on the late embryonal development of chickens.