Elderly and drugs: risks and necessity of rational use

In recent decades, the world has undergone a demographic transformation with a rapid growth of the elderly population, resulting in an increased demand for funds to maintain their health and drug consumption. Pharmacokinetic and pharmacodynamic changes occurring in the elderly can interfere directly in the adverse effects of drugs and increase the risk of intoxication. In addition, there are external factors interfering with the pharmacotherapy of the elderly, such as inappropriate use and the lack of access to information. Many therapeutic classes of drugs should be used with caution or avoided in the elderly population, such as anti-inflammatory and some anti-hypertensive drugs, diuretics and digitalis. If not managed carefully, these medicines can affect the safety and quality of life in the elderly. Thus, the aim of this review was to identify drugs that should be used with caution in elderly patients in order to avoid intoxication and/or adverse drug events.Durante as últimas décadas, o mundo passou por uma transformação demográfica, com um rápido crescimento da população idosa e, portanto, tanto a demanda para a manutenção da saúde deste grupo populacional, quanto o consumo de medicamentos estão aumentando. Ainda, as mudanças farmacocinéticas e farmacodinâmicas que ocorrem em idosos podem interferir diretamente nos efeitos adversos dos medicamentos e aumentar o risco de intoxicação. Além disso, há fatores externos que interferem na farmacoterapia dos idosos, tais como o uso inadequado e a falta de acesso à informação. Existem várias classes terapêuticas de medicamentos que devem ser utilizados com cautela ou evitados na população idosa, tais como antiinflamatórios, alguns anti-hipertensivos, diuréticos, digitálicos entre outros. Estes medicamentos, se não forem utilizados com cuidado, podem afetar a qualidade de vida e a segurança desta população. Assim, este trabalho visa identificar medicamentos que devem ser utilizados com cuidado em pacientes idosos para evitar intoxicações e/ou eventos adversos aos medicamentos.FAPESPCNPqCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Protective/toxic effects of flavonoids: structure-activity study involving mitochondrial mechanisms, with emphasis on apoptosis.

Realizou-se um estudo estrutura-atividade sobre os efeitos citoprotetor/citotóxico de 5 flavonóides envolvendo processos mitocondriais, com ênfase na apoptose. Nossos resultados mostram que a dupla ligação na posição 2-3 / grupos 3-OH em conjugação com a função 4-oxo no anel C da estrutura dos flavonóides parece favorecer a interação destes compostos com a membrana mitocondrial, diminuindo a sua fluidez, e tanto inibindo a cadeia respiratória das mitocôndrias, quanto causando desacoplamento. Por outro lado, a estrutura o-di-OH no anel B parece favorecer a inibição da cadeia respiratória, sendo que a ausência desta estrutura parece favorecer a atividade desacopladora. Os flavonóides que não afetaram a respiração mitocondrial, induziram a transição de permeabilidade mitocondrial. A capacidade dos flavonóides em liberar o Ca2+ acumulado pelas mitocôndrias correlaciona-se com a sua capacidade de afetar a respiração mitocondrial e sua inabilidade em induzir a transição de permeabilidade mitocondrial. Já os dados referentes aos estudos da atividade protetora contra a formação de radicais livres demonstraram que a quercetina, luteolina e a galangina foram substancialmente mais potentes que a taxifolina e a catequina em conferir proteção contra a lipoperoxidação, embora somente a quercetina tenha sido um efetivo seqüestrador tanto de DPPH?, quanto de O2?-. Esses resultados sugerem que a dupla ligação na posição 2-3 em conjugação com a função 4-oxo na estrutura dos flavonóides são os fatores mais importantes na atividade antioxidante dos flavonóides sobre as mitocôndrias. Ainda, a presença da estrutura o-di-OH no anel B, conforme observado na quercetina, favorece essa atividade via seqüestro de O2?-, enquanto que a ausência dessa característica estrutural na galangina, a favorece via diminuição da fluidez de membrana e/ou desacoplamento mitocondrial. Os ensaios realizados para avaliar o efeito dos flavonóides sobre as células HepG2 mostraram que galangina, luteolina e quercetina são capazes de induzir morte celular. Esse efeito parece estar associado à dissipação do potencial de membrana mitocondrial e à diminuição na capacidade energética celular, mais pronunciada no caso dos dois primeiros; porém, como essa diminuição na concentração de ATP não é drástica, a morte celular pode ocorrer por apoptose. Os experimentos realizados para avaliar essa possibilidade sugerem uma ativação das caspases via mitocôndria, observada pelo aumento das atividades de caspase -9 e -3 e também pela exposição de fosfatidil serina. A taxifolina que não apresentou capacidade de produzir dano celular, apresentou, por outro lado, capacidade de prevenir parcialmente a diminuição de viabilidade das células HepG2 induzida pelo pró-oxidante t-butilhidroperóxido, aparentemente por meio de sua atividade antioxidante que inibiu, também de forma parcial, o acúmulo de espécies reativas de oxigênio.We carried out a structure-activity study addressing the protective/toxic effects of 5 flavonoids (quercetin, taxifolin, luteolin, catechin and galangin) upon mitochondrial aspects with emphasis on the mechanisms potentially involved in cell apoptosis. The major findings were: The 2,3 double bond/3-OH group in conjugation with the 4-oxo function on the C-ring in the flavonoid structure seems favour the interaction of these compounds with the mitochondrial membrane, decreasing its fluidity either inhibiting the respiratory chain of mitochondria or causing uncoupling; while the o-di-OH on the B-ring seems favour the respiratory chain inhibition, the absence of this structure seems favour the uncoupling activity. The flavonoids not affecting the respiration of mitochondria induced MPT. The ability of flavonoids to induce the release of mitochondria-accumulated Ca2+ correlated well with their ability to affect mitochondrial respiration on the one hand, and their inability to induce MPT, on the other. The data concerning the protective activity against the free radical formation showed that quercetin, luteolin and galangin were far more potent than taxifolin and catechin in affording protection against lipid peroxidation, although only quercetin was an effective scavenger of both DPPH? and O2?-. These results suggest that the 2,3-double bound in conjugation with the 4-oxo function in the flavonoid structure are major determinants of the antioxidant activity of flavonoids on mitochondria, the presence of an o-di-OH structure on the B-ring, as occurring in quercetin, favouring this activity via O2?- scavenging, while the absence of this structural feature in galangin, favouring it via decrease in membrane fluidity and/or mitochondrial uncoupling. The assays addressing the flavonoids effects on HepG2 cells showed that galangin, luteolin and quercetin are able to induce cell death. This effect appears to be linked to the mitochondrial membrane potential dissipation and consequent decrease in the cellular energy charge, more pronounced for the galangin or luteolin treatment. However, since this decrease in ATP content is not drastic, the apoptosis process can occur. The set of experiments performed in order to evaluate this possibility demonstrated caspases-9 and -3 activation and also phosphatidylserine exposure on the cell membrane. On the other hand, taxifolin, that did not present ability to induce injury to the cell, was able to partially inhibit a viability decrease of HepG2 cell exposed to the pro-oxidant t-butylhydroperoxide, probably on account of its capacity to partially decrease ROS formation

Flame Retardants: New And Old Environmental Contaminants

Flame retardants are a group of compounds used in a variety of consumer goods to inhibit or retard the spread of flames. Several classes of chemical compounds have such capabilities, however, the persistence of these compounds in the environment and their toxicity are crucial points for a risk assessment. Classes such as polybrominated diphenyl ethers (PBDEs) have already been banned in some parts of the world while they are still permitted and extensively used in other parts of the globe. In the need for substitutes for the toxic compounds used, new structures have been synthesized and suggested by the industry as an alternative and substitutives flame retardants. The objective of this review is to address the classes of compounds used as flame retardants in terms of their toxicity to human or non-human organisms and their persistence in the environment

Comparative Assessment of the Toxicity of Brominated and Halogen-Free Flame Retardants to Zebrafish in Terms of Tail Coiling Activity, Biomarkers, and Locomotor Activity

BDE-47, a flame retardant that is frequently detected in environmental compartments and human tissues, has been associated with various toxic effects. In turn, information about the effects of aluminum diethyl-phosphinate (ALPI), a halogen-free flame retardant from a newer generation, is limited. This study aims to assess and compare the toxicity of BDE-47 and ALPI to zebrafish by analyzing the tail coiling, locomotor, acetylcholinesterase activities, and oxidative stress biomarkers. At 3000 µg/L BDE-47, the coiling frequency increased at 26–27 h post-fertilization (hpf), but the burst activity (%) and mean burst duration (s) did not change significantly. Here, we considered that the increased coiling frequency is a slight neurotoxic effect because locomotor activity was impaired at 144 hpf and 300 µg/L BDE-47. Moreover, we hypothesized that oxidative stress could be involved in the BDE-47 toxicity mechanisms. In contrast, only at 30,000 µg/L did ALPI increase the catalase activity, while the motor behavior during different developmental stages remained unaffected. On the basis of these findings, BDE-47 is more toxic than ALPI

Characterization of Rubus fruticosus mitochondria and salicylic acid inhibition of reactive oxygen species generation at Complex III/Q cycle: potential implications for hypersensitive response in plants

In addition to adenosine triphosphate (ATP) production, mitochondria have been implicated in the regulation of several physiological responses in plants, such as programmed cell death (PCD) activation. Salicylic acid (SA) and reactive oxygen species (ROS) are essential signaling molecules involved in such physiological responses; however, the mechanisms by which they act remain unknown. In non-photosynthesizing tissues, mitochondria appear to serve as the main source of ROS generation. Evidence suggests that SA and ROS could regulate plant PCD through a synergistic mechanism that involves mitochondria. Herein, we isolate and characterize the mitochondria from non-photosynthesizing cell suspension cultures of Rubus fruticosus. Furthermore, we assess the primary site of ROS generation and the effects of SA on isolated organelles. Mitochondrial Complex III was found to be the major source of ROS generation in this model. In addition, we discovered that SA inhibits the electron transport chain by inactivating the semiquinone radical during the Q cycle. Computational analyses confirmed the experimental data, and a mechanism for this action is proposed.CAPESCNPqFAPES

Evaluation of the mutagenic activity of chrysin, a flavonoid inhibitor of the aromatization process

Chrysin is one of the natural flavonoids present in plants, and large amounts are present in honey and propolis. In addition to anticancer, antioxidation, and anti-inflammatory activities, chrysin has also been reported to be an inhibitor of aromatase, an enzyme converting testosterone into estrogen. The present study evaluated the mutagenicity of this flavonoid using micronucleus (MN) with HepG2 cells and Salmonella. Cell survival after exposure to different concentrations of chrysin was also determined using sulforhodamine B (SRB) colorimetric assay in HepG2 cells and the influence of this flavonoid on growth of cells in relation to the cell cycle and apoptosis. TheMN test showed that from 1 to 15 mu M of this flavonoid mutagenic activity was noted in HepG2 cells. The Salmonella assay demonstrated a positive response to the TA100 Salmonella strain in the presence or absence of S9, suggesting that this compound acted on DNA, inducing base pair substitution before or after metabolism via cytochrome P-450. The SRB assay illustrated that chrysin promoted growth inhibition of HepG2 cells in both periods studied (24 and 48 h). After 24 h of exposure it was noted that the most significant results were obtained with a concentration of 50 mu M, resulting in 83% inhibition and SubG0 percentage of 12%. After 48 h of incubation cell proliferation inhibition rates (97% at 50 mu M) were significantly higher. Our results showed that chrysin is a mutagenic and cytotoxic compound in cultured human HepG2 cells and Salmonella typhimurium. Although it is widely accepted that flavonoids are substances beneficial to health, one must evaluate the risk versus benefit relationship and concentrations of these substances to which an individual may be exposed.Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao PauloFaculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao PauloFaculdade de Filosofia, Ciencias e Letras de Ribeirao Preto, Universidade de Sao PauloFaculdade de Filosofia, Ciencias e Letras de Ribeirao Preto, Universidade de Sao PauloFAPESPFAPESPCAPESCAPE

Skin Sensitization Tests: The LLNA and the RhE IL-18 Potency Assay

Contact allergy is of considerable importance to the toxicologist, and regulatory authorities worldwide require testing for skin sensitization potential and appropriate hazard labeling to enable management of the risk to human health. Although traditionally the identification of skin-sensitizing chemicals has been carried out using animal models, in Europe legislative changes have promoted, and now require, the use of non-animal methods (i.e., Cosmetic Directive, REACH). Several in vitro alternatives for hazard identification have now been validated, but do not provide information on the potency of a skin sensitizer. Here, we describe an animal model, the local lymph node assay (LLNA), and an in vitro model, the RhE IL-18 potency assay, in the context of the identification and potency classification of skin sensitizers. These two assays have been chosen among the different available tests as representative of an alternative in vivo model (the LLNA) and a promising in vitro method with the potential of both hazard identification and potency classification

A Dangerous Couple: Sequential Effect of Phosphorus Flame-Retardant and Polyurethane Decrease Locomotor Activity in Planarian <i>Girardia tigrina</i>

Understanding the interplay among organophosphorus flame retardants (OPFRs), microplastics, and freshwater organisms is crucial for unravelling the dynamics within freshwater environments and foreseeing the potential impacts of organic pollutants and plastic contamination. For that purpose, the present research assessed the exposure impact of 10 mg L−1 flame-retardant aluminium diethylphosphinate (ALPI), 10 μg mg−1liver microplastics polyurethane (PU), and the combination of ALPI and PU on the freshwater planarian Girardia tigrina. The exposure to both ALPI and PU revealed a sequential effect, i.e., a decrease in locomotor activity, while oxidative stress biomarkers (total glutathione, catalase, glutathione S-transferase, lipid peroxidation) and metabolic responses (cholinesterase activity, electron transport system, and lactate dehydrogenase) remained unaffected. Despite this fact, it was possible to observe that the range of physiological responses in exposed organisms varied, in particular in the cases of the electron transport system, cholinesterase activity, glutathione S-transferase, catalase, and levels of total glutathione and proteins, showing that the energetic costs for detoxification and antioxidant capacity might be causing a lesser amount of energy allocated for the planarian activity. By examining the physiological, behavioural, and ecological responses of planarians to these pollutants, insights can be gained into broader ecosystem-level effects and inform strategies for mitigating environmental risks associated with OPFRs and microplastic pollution in freshwater environments