Cell-based in vitro models for predicting drug permeability

INTRODUCTION: In vitro cell models have been used to predict drug permeation in early stages of drug development, since they represent an easy and reproducible method, allowing the tracking of drug absorption rate and mechanism, with an advantageous cost-benefit ratio. Such cell-based models are mainly composed of immortalized cells with an intrinsic ability to grow in a monolayer when seeded in permeable supports, maintaining their physiologic characteristics regarding epithelium cell physiology and functionality. AREAS COVERED: This review summarizes the most important intestinal, pulmonary, nasal, vaginal, rectal, ocular and skin cell-based in vitro models for predicting the permeability of drugs. Moreover, the similitude between in vitro cell models and in vivo conditions are discussed, providing evidence that each model may provisionally resemble different drug absorption route. EXPERT OPINION: Despite the widespread use of in vitro cell models for drug permeability and absorption evaluation purposes, a detailed study on the properties of these models and their in vitro-in vivo correlation compared with human data are required to further use in order to consider a future drug discovery optimization and clinical development.     

Influence of spike lavender (Lavandula latifolia Med.) essential oil in the quality,stability and composition of soybean oil during microwave heating

Lipids oxidation is one of the main factors leading to quality losses in foods. Its prevention or delay could be obtained by the addition of antioxidants. In this sense the present work intend to monitor the protective effects of Lavandula latifolia essential oil during soybean oil microwave heating. To achieve the proposed goal quality parameters (free acidity, peroxide value, specific coefficients of extinction and ΔK), fatty acids profile, tocopherols and tocotrienols composition, antioxidant activity and oxidative stability were evaluated in soybean oil with and without spike lavender essential oils (EO) submitted to different microwave heating exposure times (1, 3, 5, 10 and 15 min; 1000 Watt) with a standard domestic microwave equipment. Microwave heating induced severe quality and composition losses, mainly above 3 min of microwave heating, regardless the sample tested. However, spike lavender EO addition counteracts the oxidation comparatively to control oils, by presenting enhanced values in quality parameters. A higher protection in unsaturated fatty acids loss was also observed as well as a higher antioxidant activity and oxidative stability. The microwave heating effects were clearly different in the samples with essential oils addition, allowing discrimination from plain soybean oils by a principal component analysis, being also capable to discriminate the different heating times tested within each sample.     

The role of 5-HT₁A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism

Epidemiological and dietary studies show that nutritional deficit of omega-3 polyunsaturated fatty acids (ω-3 PUFA) is directly related to the prevalence and severity of depression. Supplementation with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) during critical periods of development (pregnancy and lactation) is essential for cortical maturation, synaptogenesis and myelination, and may also mitigate the risk for cognitive deficits and psychopathologies in young adults. The present study was performed to evaluate the involvement of serotonin (5-HT) receptors, particularly of 5-HT(1A), and hippocampal brain-derived neurotrophic factor (BDNF) expression in the antidepressant effect of ω-3 PUFA supplementation. In Experiment 1, the antidepressant effects of fish oil were assessed by the modified forced swim test in adult rats. The data indicated a robust antidepressant effect produced by this supplementation and that treatment of the rats with WAY 100135 reversed this effect. In Experiment 2, cortical and hippocampal contents of BDNF, 5-HT, dopamine (DA) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC), were determined in animals subjected to the same protocol. Increased BDNF expression in the cortex and hippocampus of both age groups was detected. In 90 day-old rats, 5-HT content in the hippocampus was increased, whereas 5-HIAA formation was diminished in the fish oil group. We suggest the occurrence of a reciprocal involvement of 5-HT(1A) receptors activation and the hippocampal BDNF-increased expression mediated by fish oil supplementation. These data corroborate and expand the notion that supplementation with ω-3 PUFA produces antidepressant effects mediated by an increase in serotonergic neurotransmission, particularly in the hippocampus. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Brazilian plants with possible action on the central nervous system: a study of historical sources from the 16th to 19th century

Brazil is a country rich in biodiversity, endemism, and cultural diversity, inhabited by different types of population. European expeditions and the migratory processes that began in the 16th century greatly contributed both to cultural diversity and to Brazilian popular therapeutics, and produced the first records on medicinal plants in Brazil. This study comprises a bibliographical survey of historic books found in Sao Paulo libraries (16th through 19th centuries) on medicinal plants exerting effects on the central nervous system (CNS). Thirty-four plants native to Brazil were selected from the reading of the books. Of these 34 plants, 13 were also recorded in ethnopharmacological studies among modern Brazilian communities and 16 have been studied phytochemically. Only eight have been the object of pharmacological studies, six of these, recently, with a request for a patent. Results showed that most of the species recorded in this study have been reported as medicinal for centuries, but have never been the object of pharmacological investigation down to the present time. Such results provide ideas for a selection of these species as potentially bioactive to be included in future pharmacological studies.     

Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice

This work studied the central behavioural effects of hydroalcoholic extracts from the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus maze, open field, and rota rod tests in mice. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. Single doses of the extracts were administered orally (200, 400 or 800 mg kg(-1)) or intraperitoneally (200 or 400 mg kg(-1)) to female mice. A reduction of the locomotor activity was observed in the open field test with both hydroalcoholic extracts after intraperitoneal treatment with all doses, but only with the highest dose after oral administration. In addition, oral and intraperitoneal administration of the extracts decreased the incidence of rearing and grooming. Decreases in the number of entries in the open (NEOA) and closed (NECA) arms of the elevated plus maze were observed after the administration of the highest dose (800 mg kg(-1), p.o.) of both hydroalcoholic extracts, and this effect may be due to the decrease in locomotor activity. These hydroalcoholic extracts failed to affect the motor coordination in the rota rod test. In conclusion, we showed that the hydroalcoholic extracts of E. velutina and E. mulungu have depressant effects on the central nervous system, which, at least partially, corroborates the popular use of these species as tranquilizers in Brazilian popular medicine.     

Hippocampal antioxidant system in neonates from methylmercury-intoxicated rats

Methylmercury (MeHg) is a well-known environmental pollutant toxic to the nervous tissue, particularly during development. We recently described transitory hippocampal changes in neonate rats prenatally exposed to MeHg. In this study, we evaluate oxidative stress in the hippocampus on the 1st and 30th postnatal days. Motor behavior (open-field, foot-fault and strength tests) of these animals also was studied after the 30th postnatal day. Female Wistar rats were injected with MeHg (5 mg/Hg/day) on the 12th, 13th and 14th gestational days. Biochemical parameters measured for oxidative stress were levels of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). Total antioxidant reactivity (TAR) and protein oxidation (contents of tryptophan and tyrosine) were also recorded. Our results showed low activities of antioxidant enzymes in the MeHg group at birth. SOD activity remained reduced on the 30th postnatal day. Moreover, a decrease of TAR and protein oxidation was observed only at 30 days of age. No changes were observed in the motor behavior of these animals. Although mercury content in hippocampus is present at undetectable levels at 30 days of age, we observed more persistent changes in oxidative balance. Our data confirm that mercury induces oxidative stress in hippocampus and that this alteration, particularly SOD activity, remained altered even when mercury was no longer present.     

Ring-testing and Field-validation of a Terrestrial Model Ecosystem(TME) – An Instrument for Testing Potentially Harmful Substances: Effects of Carbendazim on Organic Matter Breakdown and Soil Fauna Feeding Activity

Organic matter (OM) decomposition and soil fauna feeding activity were integrated as functional endpoints into ecotoxicological tests with intact-soil-core Terrestrial Model Ecosystems (TMEs). Cellulose filter paper served as standardized OM and was either inserted into the top soil or placed on the soil surface for a period of up to 16 weeks. Faunal feeding activity was assessed by the bait-lamina method. The fungicide carbendazim, applied at six dosages ranging from 0.36 kg/ha to 87.5 kg a.i./ha, served as a model chemical. To validate the results from the TME test, a field study was run in parallel. In TMEs the cellulose paper inserted into the soil was decomposed faster than under field conditions. The carbendazim-induced effects on OM decomposition in TMEs and in the field were comparable and followed a clear dose-response relationship. The calculated EC50 values after 8 weeks of incubation were 9.5, 7.1 and 2.1 kg carbendazim/ha for grassland TMEs, grassland field and arable TMEs, respectively. The feeding activity of the soil fauna showed a large variability. The EC50 values for the effect of carbendazim on bait-lamina consumption ranged between 2.0 and 56 kg a.i./ha. Effects on decomposition were correlated with effects on enchytraeids and earthworms but not with effects on bait-lamina consumption.     

Intra-urban differences in vulnerability among the elderly population

This study examined the adequacy of a health vulnerability index (HVI) for identifying intra-urban differences in vulnerability in the elderly population. Study participants (n = 1,055) were selected by probabilistic sampling of residents in the city of Belo Horizonte, Minas Gerais State, Brazil, aged 60 years or older (mean = 70.1 years). The HVI was constructed with indicators of socioeconomic conditions and premature mortality at the census tract level. Based on its location and HVI value, each participant's household was classified as low, medium, or high-risk. Results of multivariate ordinal logistic regression models showed graded and statistically significant associations between the household's risk level and the social and physical environment, health conditions and behaviors, and health service needs (adjusted prevalence ratios ranging from 1.17; 95% CI: 1.02-1.34 to 1.65; 95% CI: 1.45-1.88). The HVI appears to be a useful instrument for identifying health and social service needs among the elderly.     

Biodistribution and Pharmacokinetics of Dapivirine-Loaded Nanoparticles after Vaginal Delivery in Mice

Purpose

To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery.

Methods

Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages.

Results

PEO-PCL NPs (180–200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days.

Conclusions

Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.     

Oleanolic Acid Improves Gut Atrophy Induced by Parenteral Nutrition

Background: Nutrition support with parenteral nutrition (PN) is associated with gut atrophy. Prior studies have shown improvement with enteral chenodeoxycholic acid, a dual agonist for the farnesoid X receptor (FXR) and bile acid receptor TGR5. We hypothesized that gut growth is induced by TGR5 activation, and gut atrophy during PN administration could be prevented with the TGR5‐specific agonist oleanolic acid (OA). Methods: Neonatal pigs were implanted with duodenal and jugular vein catheters. Animals were provided equi‐nutritious PN or enteral swine milk. A PN subgroup received enteral OA at 50 mg/kg/d. Results: PN caused marked gut atrophy compared with enterally fed (EN) control animals. OA treatment led to preservation of gut mass demonstrated grossly and histologically. The mean ± SD gut weight as a percentage of body weight was 4.30 ± 0.26 for EN, 1.92 ± 0.06 for PN (P < .05, EN vs PN), and 3.39 ± 0.79 for PN+OA (P < .05, PN+OA vs PN). Mean ± SD gut density (g/cm) was 0.31 ± 0.03 for EN, 0.18 ± 0.03 for PN (P < .05 EN vs PN), and 0.27 ± 0.01 for PN+OA (P < .05 PN+OA vs PN). Histologically, a markedly decreased villous to crypt ratio was noted with PN, and OA significantly prevented this decrease. The mean ± SD v/c ratio was 3.51 ± 0.59 for EN, 1.69 ± 0.10 for PN (P < .05, EN vs PN), and 2.90 ± 0.23 for PN+OA (P < .05, PN+OA vs PN). Gut TGR5 messenger RNA expression was significantly elevated with OA treatment compared with both PN and EN. Conclusion: The bile acid–activated G protein–coupled receptor TGR5 agonist OA prevented gut atrophy associated with PN.