Protective effects of a chemically characterized extract from solanum torvum leaves on acetaminophen-induced liver injury.

Distinct parts of Solanum torvum Swartz. (Solanaceae) are popularly used for a variety of therapeutic purposes. This study determined the phytochemical composition of a phenolic fraction of S. torvum leaf aqueous extract and investigated its antioxidant and liver-protective properties. A phenolic compound-enriched fraction, or phenolic fraction (STLAE-PF) of an infusion (STLAE) of S. torvum leaves, was tested in vitro (antagonism of H2O2 in cytotoxicity and DCF assays with HepG2/C3A cells), and in vivo for antioxidant activity and protective effects against acetaminophen (APAP)-induced liver injury in mice. Thirty-eight compounds (flavonoids, esters of hydroxycinnamic acid, and chlorogenic acid isomers) were tentatively identified (high-performance liquid chromatography coupled to high-resolution electrospray mass spectrometry) in the STLAE-PF fraction. In vitro assays in HepG2/C3A cells showed that STLAE-PF and some flavonoids contained in this phenolic fraction, at noncytotoxic levels, antagonized in a concentration-dependent manner the effects of a powerful oxidant agent (H2O2). In C57BL/6 mice, oral administration of STLAE (600 and 1,200 mg/kg bw) or STLAE-PF (300 mg/kg bw) prevented the rise in serum transaminases (ALT and AST), depletion of reduced glutathione (GSH) and elevation of thiobarbituric acid reactive species (TBARs) levels in the liver caused by APAP (600 mg/kg bw, i.p.). The hepatoprotective effects of STLAE-PF (300 mg/kg bw) against APAP-caused liver injury were comparable to those of N-acetyl-cysteine (NAC 300 or 600 mg/kg bw i.p.). These findings indicate that a phenolic fraction of S. torvum leaf extract (STLAE-PF) is a new phytotherapeutic agent potentially useful for preventing/treating liver injury caused by APAP overdosing.

Transplacental Transfer of Primaquine and Neurobehavioral Development of Prenatally Exposed Rats.

Primaquine (PQ) not only eliminates P. falciparum gametocytes but also kills liver dormant forms of P. vivax and P. ovale. Owing to these unique therapeutic properties, it is an essential drug. Although PQ has been used for over 70 years, its toxicological database has gaps such as the absence of studies on its reproductive and developmental toxicity and kinetics in pregnancy. This study investigated the transplacental transfer of PQ and the effects of intrauterine exposure on the postnatal growth, survival, and neurobehavioral development of the offspring. PQ kinetics and transplacental transfer were investigated in rats treated orally (40 mg.kg·bw-1) on gestation day (GD) 21. PQ was analyzed by high-performance liquid chromatography with diode array ultraviolet detection. To evaluate effects of intrauterine exposure on postnatal development, dams were treated orally with PQ (20 mg.kg·bw-1·d-1) or water (controls) on GD 0-21. Postnatal survival, body weight gain, somatic maturation, and reflex acquisition were evaluated. The open field test (OF) was conducted on PND 25. PQ concentration in the fetal plasma was nearly half that in maternal plasma. Except for increase in pregnancy loss, no effects of PQ were noted at term pregnancy and first days of life. Prenatal PQ did not affect postnatal weight gain nor did it impair somatic and neurologic development of the offspring. Pups born to PQ-treated dams showed reduced exploration and enhanced emotionality in the OF. PQ given in pregnancy, at doses greater than those recommended for malaria therapy, may affect pup postnatal survival and emotional behavior.

Malaria-induced Alterations of Drug Kinetics and Metabolism in Rodents and Humans.

BACKGROUND: Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions. OBJECTIVE: In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans. RESULTS: An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals. CONCLUSION: Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.

A critical appraisal of the harm reduction argument for heat-not-burn tobacco products

[ABSTRACT]. Heat-not-burn products (HNBs) are efficient nicotine delivery devices that heat tobacco instead of burning it, as conventional cigarettes do. Since heating yields less carbon monoxide and other tobacco pyrolysis–derived toxicants, tobacco companies claim that HNBs are less harmful than conventional cigarettes are. Although this hypothesis is plausible, no long-term clinical trials and/or observational studies are available to corroborate it. To overcome barriers to the entry of tobacco products to the market, manufacturers of HNBs argue that they are a new wave of harm reduction alternatives. Nonetheless, even if HNBs were in fact less harmful than conventional cigarettes, they would still have the potential to cause nicotine addiction (a major health hazard) and other harms to smokers’ health. HNBs deliver nicotine, provide users a tobacco aroma and flavor and some rituals of smoking, and are supposedly safer than conventional cigarettes. Owing to these features, HNBs are likely to enhance smoking appeal and initiation among young persons and discourage smokers’ attempts to quit. In other words, if HNBs were freely available on the market, they would increase the prevalence of smoking. However, HNBs may constitute a harm reduction alternative for nicotine-dependent smokers who are unable or unwilling to quit smoking. Given these facts, approval of HNBs for use under medical supervision (prescription only), along with strict restrictions on advertising, is a balanced regulatory option that would reconcile the therapeutic needs of nicotine-addicted patients with the public heath goal of achieving a smoke-free generation in the near future.

[RESUMEN]. Los productos de tabaco calentado (PTC) son dispositivos eficientes para la administración de nicotina que calientan el tabaco en vez de quemarlo (como sucede con los cigarrillos convencionales). Al calentar el tabaco se produce menos monóxido de carbono y se liberan menos sustancias tóxicas derivadas de la pirólisis del tabaco; por tanto, las empresas tabacaleras sostienen que los PTC son menos nocivos que los cigarrillos convencionales. Aunque esta hipótesis es verosímil, no hay ningún ensayo clínico ni estudios de observación a largo plazo que la corroboren. Para superar las barreras a la entrada de los productos de tabaco en el mercado, los fabricantes de PTC sostienen que estos productos son una nueva ola de alternativas menos dañinas. Sin embargo, aunque los PTC fueran realmente menos nocivos que los cigarrillos convencionales, seguirían teniendo el potencial de causar adicción a la nicotina (un riesgo grave para la salud), así como otros perjuicios para la salud de los fumadores. Los PTC administran nicotina y brindan a los consumidores el aroma y el sabor del tabaco, así como algunos de los rituales del acto de fumar, a la vez que son supuestamente más seguros que los cigarrillos convencionales. Precisamente por estas características, los PTC pueden volverse una forma de fumar atractiva que incite a los jóvenes a comenzar a usarlos y disuada a los fumadores de dejar de hacerlo. Es decir, si los PTC estuviesen disponibles sin restricciones en el mercado, aumentaría la prevalencia del consumo de tabaco. Sin embargo, los PTC pueden ser una alternativa menos dañina para los fumadores adictos a la nicotina que no pueden o no quieren dejar de fumar. Por todo ello, aprobar los PTC para su uso bajo supervisión médica (únicamente con prescripción), junto con restricciones estrictas en cuanto a su promoción publicitaria, es una opción regulatoria en la que se equilibrarían las necesidades terapéuticas de los pacientes adictos a la nicotina con el objetivo de salud pública de conseguir una generación sin tabaco en un futuro próximo.

[RESUMO]. Os cigarros aquecidos são aparelhos eficientes de liberação de nicotina que aquecem o tabaco em vez de queimá-lo como os cigarros convencionais. Como o aquecimento produz menos monóxido de carbono e outros produtos tóxicos derivados da queima do tabaco, as empresas de tabaco alegam que os cigarros aquecidos são menos prejudiciais que os convencionais. Apesar de esta hipótese ser plausível, não existem estudos clínicos e/ou observacionais de longo prazo para corroborá-la. Para vencer os obstáculos à entrada no mercado dos produtos derivados do tabaco, os fabricantes dos cigarros aquecidos argumentam que eles fazem parte de um novo ciclo de alternativas para redução de danos. No entanto, mesmo se os cigarros aquecidos forem de fato menos prejudiciais que os convencionais, eles continuam tendo o potencial de causar dependência da nicotina (um sério risco à saúde) e outros danos à saúde dos fumantes. Os cigarros aquecidos liberam nicotina, dispensando o aroma e o sabor do tabaco e proporcionando ao usuário alguns dos rituais do ato de fumar, e supostamente seriam mais seguros que os cigarros convencionais. Devido a essas características, eles podem tornar o ato de fumar mais atraente e fazer os jovens começarem a fumar e desincentivar os fumantes a parar de fumar. Em outras palavras, se forem comercializados livremente no mercado, aumentariam a prevalência do tabagismo. Porém, os cigarros aquecidos podem ser uma alternativa para a redução de danos em fumantes dependentes da nicotina que não conseguem ou relutam em parar de fumar. Diante destes fatos, a aprovação dos cigarros aquecidos para uso sob supervisão médica (com prescrição), aliada a restrições rigorosas à publicidade do produto, é uma opção regulamentar ponderada que conciliaria as necessidades terapêuticas dos pacientes dependentes de nicotina com a meta de saúde pública de ter uma geração que não fuma em um futuro próximo.

Study on the developmental toxicity of ß-ionone in the rat.

ß-ionone (BIO) is used in fragrances, toiletries and non-cosmetic products, and as a flavor food additive. Notwithstanding the widespread human exposure, there are limited data on the reproductive toxicity of BIO. This study evaluated the developmental toxicity of BIO (0, 125, 250, 500 and 1000 mg/kg body weight/day) given orally to rats on days 6-15 of gestation (GD6-15). C-section was on GD21 and implantations, living and dead fetuses and resorptions were recorded. Fetuses were weighed, and examined for external abnormalities and skeleton and visceral anomalies. The embryotoxicity of a single oral dose of BIO (1000 mg/kg body wt) given on GD11 was evaluated as well. At the highest dose, BIO reduced weight gain and produced chromodacryorrhea and other signs of toxicity. BIO did not increase the frequency of malformations nor did it retard fetal growth. Nonetheless, BIO decreased the pregnancy rate in the group of females exposed on GD6-15, and increased the resorption rate in those treated on GD11 only. In conclusion, except for a higher embryolethality at a maternally toxic dose, BIO caused no embryotoxic effect over the dose range tested and the study NOAEL for maternal and developmental toxicity was 500 mg of BIO/ kg of body weight/day.

A critical appraisal of the harm reduction argument for heat-not-burn tobacco products.

Heat-not-burn products (HNBs) are efficient nicotine delivery devices that heat tobacco instead of burning it, as conventional cigarettes do. Since heating yields less carbon monoxide and other tobacco pyrolysis-derived toxicants, tobacco companies claim that HNBs are less harmful than conventional cigarettes are. Although this hypothesis is plausible, no long-term clinical trials and/or observational studies are available to corroborate it. To overcome barriers to the entry of tobacco products to the market, manufacturers of HNBs argue that they are a new wave of harm reduction alternatives. Nonetheless, even if HNBs were in fact less harmful than conventional cigarettes, they would still have the potential to cause nicotine addiction (a major health hazard) and other harms to smokers' health. HNBs deliver nicotine, provide users a tobacco aroma and flavor and some rituals of smoking, and are supposedly safer than conventional cigarettes. Owing to these features, HNBs are likely to enhance smoking appeal and initiation among young persons and discourage smokers' attempts to quit. In other words, if HNBs were freely available on the market, they would increase the prevalence of smoking. However, HNBs may constitute a harm reduction alternative for nicotine-dependent smokers who are unable or unwilling to quit smoking. Given these facts, approval of HNBs for use under medical supervision (prescription only), along with strict restrictions on advertising, is a balanced regulatory option that would reconcile the therapeutic needs of nicotine-addicted patients with the public heath goal of achieving a smoke-free generation in the near future.

Los productos de tabaco calentado (PTC) son dispositivos eficientes para la administración de nicotina que calientan el tabaco en vez de quemarlo (como sucede con los cigarrillos convencionales). Al calentar el tabaco se produce menos monóxido de carbono y se liberan menos sustancias tóxicas derivadas de la pirólisis del tabaco; por tanto, las empresas tabacaleras sostienen que los PTC son menos nocivos que los cigarrillos convencionales. Aunque esta hipótesis es verosímil, no hay ningún ensayo clínico ni estudios de observación a largo plazo que la corroboren. Para superar las barreras a la entrada de los productos de tabaco en el mercado, los fabricantes de PTC sostienen que estos productos son una nueva ola de alternativas menos dañinas. Sin embargo, aunque los PTC fueran realmente menos nocivos que los cigarrillos convencionales, seguirían teniendo el potencial de causar adicción a la nicotina (un riesgo grave para la salud), así como otros perjuicios para la salud de los fumadores. Los PTC administran nicotina y brindan a los consumidores el aroma y el sabor del tabaco, así como algunos de los rituales del acto de fumar, a la vez que son supuestamente más seguros que los cigarrillos convencionales. Precisamente por estas características, los PTC pueden volverse una forma de fumar atractiva que incite a los jóvenes a comenzar a usarlos y disuada a los fumadores de dejar de hacerlo. Es decir, si los PTC estuviesen disponibles sin restricciones en el mercado, aumentaría la prevalencia del consumo de tabaco. Sin embargo, los PTC pueden ser una alternativa menos dañina para los fumadores adictos a la nicotina que no pueden o no quieren dejar de fumar. Por todo ello, aprobar los PTC para su uso bajo supervisión médica (únicamente con prescripción), junto con restricciones estrictas en cuanto a su promoción publicitaria, es una opción regulatoria en la que se equilibrarían las necesidades terapéuticas de los pacientes adictos a la nicotina con el objetivo de salud pública de conseguir una generación sin tabaco en un futuro próximo.

Os cigarros aquecidos são aparelhos eficientes de liberação de nicotina que aquecem o tabaco em vez de queimá-lo como os cigarros convencionais. Como o aquecimento produz menos monóxido de carbono e outros produtos tóxicos derivados da queima do tabaco, as empresas de tabaco alegam que os cigarros aquecidos são menos prejudiciais que os convencionais. Apesar de esta hipótese ser plausível, não existem estudos clínicos e/ou observacionais de longo prazo para corroborá-la. Para vencer os obstáculos à entrada no mercado dos produtos derivados do tabaco, os fabricantes dos cigarros aquecidos argumentam que eles fazem parte de um novo ciclo de alternativas para redução de danos. No entanto, mesmo se os cigarros aquecidos forem de fato menos prejudiciais que os convencionais, eles continuam tendo o potencial de causar dependência da nicotina (um sério risco à saúde) e outros danos à saúde dos fumantes. Os cigarros aquecidos liberam nicotina, dispensando o aroma e o sabor do tabaco e proporcionando ao usuário alguns dos rituais do ato de fumar, e supostamente seriam mais seguros que os cigarros convencionais. Devido a essas características, eles podem tornar o ato de fumar mais atraente e fazer os jovens começarem a fumar e desincentivar os fumantes a parar de fumar. Em outras palavras, se forem comercializados livremente no mercado, aumentariam a prevalência do tabagismo. Porém, os cigarros aquecidos podem ser uma alternativa para a redução de danos em fumantes dependentes da nicotina que não conseguem ou relutam em parar de fumar. Diante destes fatos, a aprovação dos cigarros aquecidos para uso sob supervisão médica (com prescrição), aliada a restrições rigorosas à publicidade do produto, é uma opção regulamentar ponderada que conciliaria as necessidades terapêuticas dos pacientes dependentes de nicotina com a meta de saúde pública de ter uma geração que não fuma em um futuro próximo.

A critical appraisal of the harm reduction argument for heat-not-burn tobacco products / Evaluación crítica del argumento de que los productos que calientan el tabaco en vez de quemarlo son menos nocivos / Uma análise crítica do argumento de redução de danos dos cigarros aquecidos

ABSTRACT Heat-not-burn products (HNBs) are efficient nicotine delivery devices that heat tobacco instead of burning it, as conventional cigarettes do. Since heating yields less carbon monoxide and other tobacco pyrolysis-derived toxicants, tobacco companies claim that HNBs are less harmful than conventional cigarettes are. Although this hypothesis is plausible, no long-term clinical trials and/or observational studies are available to corroborate it. To overcome barriers to the entry of tobacco products to the market, manufacturers of HNBs argue that they are a new wave of harm reduction alternatives. Nonetheless, even if HNBs were in fact less harmful than conventional cigarettes, they would still have the potential to cause nicotine addiction (a major health hazard) and other harms to smokers' health. HNBs deliver nicotine, provide users a tobacco aroma and flavor and some rituals of smoking, and are supposedly safer than conventional cigarettes. Owing to these features, HNBs are likely to enhance smoking appeal and initiation among young persons and discourage smokers' attempts to quit. In other words, if HNBs were freely available on the market, they would increase the prevalence of smoking. However, HNBs may constitute a harm reduction alternative for nicotine-dependent smokers who are unable or unwilling to quit smoking. Given these facts, approval of HNBs for use under medical supervision (prescription only), along with strict restrictions on advertising, is a balanced regulatory option that would reconcile the therapeutic needs of nicotine-addicted patients with the public heath goal of achieving a smoke-free generation in the near future.

RESUMEN Los productos de tabaco calentado (PTC) son dispositivos eficientes para la administración de nicotina que calientan el tabaco en vez de quemarlo (como sucede con los cigarrillos convencionales). Al calentar el tabaco se produce menos monóxido de carbono y se liberan menos sustancias tóxicas derivadas de la pirólisis del tabaco; por tanto, las empresas tabacaleras sostienen que los PTC son menos nocivos que los cigarrillos convencionales. Aunque esta hipótesis es verosímil, no hay ningún ensayo clínico ni estudios de observación a largo plazo que la corroboren. Para superar las barreras a la entrada de los productos de tabaco en el mercado, los fabricantes de PTC sostienen que estos productos son una nueva ola de alternativas menos dañinas. Sin embargo, aunque los PTC fueran realmente menos nocivos que los cigarrillos convencionales, seguirían teniendo el potencial de causar adicción a la nicotina (un riesgo grave para la salud), así como otros perjuicios para la salud de los fumadores. Los PTC administran nicotina y brindan a los consumidores el aroma y el sabor del tabaco, así como algunos de los rituales del acto de fumar, a la vez que son supuestamente más seguros que los cigarrillos convencionales. Precisamente por estas características, los PTC pueden volverse una forma de fumar atractiva que incite a los jóvenes a comenzar a usarlos y disuada a los fumadores de dejar de hacerlo. Es decir, si los PTC estuviesen disponibles sin restricciones en el mercado, aumentaría la prevalencia del consumo de tabaco. Sin embargo, los PTC pueden ser una alternativa menos dañina para los fumadores adictos a la nicotina que no pueden o no quieren dejar de fumar. Por todo ello, aprobar los PTC para su uso bajo supervisión médica (únicamente con prescripción), junto con restricciones estrictas en cuanto a su promoción publicitaria, es una opción regulatoria en la que se equilibrarían las necesidades terapéuticas de los pacientes adictos a la nicotina con el objetivo de salud pública de conseguir una generación sin tabaco en un futuro próximo.

RESUMO Os cigarros aquecidos são aparelhos eficientes de liberação de nicotina que aquecem o tabaco em vez de queimá-lo como os cigarros convencionais. Como o aquecimento produz menos monóxido de carbono e outros produtos tóxicos derivados da queima do tabaco, as empresas de tabaco alegam que os cigarros aquecidos são menos prejudiciais que os convencionais. Apesar de esta hipótese ser plausível, não existem estudos clínicos e/ou observacionais de longo prazo para corroborá-la. Para vencer os obstáculos à entrada no mercado dos produtos derivados do tabaco, os fabricantes dos cigarros aquecidos argumentam que eles fazem parte de um novo ciclo de alternativas para redução de danos. No entanto, mesmo se os cigarros aquecidos forem de fato menos prejudiciais que os convencionais, eles continuam tendo o potencial de causar dependência da nicotina (um sério risco à saúde) e outros danos à saúde dos fumantes. Os cigarros aquecidos liberam nicotina, dispensando o aroma e o sabor do tabaco e proporcionando ao usuário alguns dos rituais do ato de fumar, e supostamente seriam mais seguros que os cigarros convencionais. Devido a essas características, eles podem tornar o ato de fumar mais atraente e fazer os jovens começarem a fumar e desincentivar os fumantes a parar de fumar. Em outras palavras, se forem comercializados livremente no mercado, aumentariam a prevalência do tabagismo. Porém, os cigarros aquecidos podem ser uma alternativa para a redução de danos em fumantes dependentes da nicotina que não conseguem ou relutam em parar de fumar. Diante destes fatos, a aprovação dos cigarros aquecidos para uso sob supervisão médica (com prescrição), aliada a restrições rigorosas à publicidade do produto, é uma opção regulamentar ponderada que conciliaria as necessidades terapêuticas dos pacientes dependentes de nicotina com a meta de saúde pública de ter uma geração que não fuma em um futuro próximo.

Interstrain differences in the expression and activity of Cyp2a5 in the mouse liver.

BACKGROUND: Cytochrome P450 2A5 (Cyp2a5), a mouse enzyme orthologous of human CYP2A6, catalyzes a number of toxicologically important reactions, including the metabolism of nicotine, aflatoxin B1, and several other xeno- and endobiotics. Cyp2a5 expression is complex and not yet fully understood. We investigated inter-strain differences in the activity and mRNA expression of hepatic Cyp2a5. Cyp1a1/2 and Cyp2b9/10 activities were evaluated for comparative purposes. Data on the interstrain differences in the expression and activity of Cyp2a5 are important to select a suitable mouse model for studying CYP2A6-mediated metabolism. RESULTS: Activity of Cyp2a5 (coumarin 7-hydroxylase) was highest in DBA-2 and DBA-1, intermediate in B6D2F1 (hybrid) and low in the remaining strains (C57BL/6, C57BL/10, CBA, BALB/cAn, SW). Contrasting with the activity, background levels of Cyp2a4/5 mRNA did not differ between high- and low-activity murine strains. Phenobarbital (PB, 80 mg/kg body weight/day × 3 days, i.p.) increased Cyp2a5, Cyp1a1/2 (ethoxyresorufin-O-deethylase) and Cyp2b9/10 (bezyloxyresorufin-O-debenzylase) activities while only Cyp2a5 was enhanced by pyrazole (PYR, 100 mg/kg body weight/day × 3 days, i.p.). Inductions of Cyp2a5 activity by PYR and PB were accompanied by increases of Cyp2a4/5 mRNA. PYR and PB did not upregulate heme oxygenase-1 (hmox-1) mRNA expression in any strain, a finding that is apparently at odds with the notion that Cyp2a5 and hmox-1 inductions are coordinated events. CONCLUSIONS: Since background levels of Cyp2a4/5 gene transcripts of high-activity strains did not differ from those of low-activity mice, distinct constitutive activities did not result from different transcription rates and/or mRNA half-lives. Results therefore suggested that interstrain differences in constitutive activity of Cyp2a5 possibly arise from distinct translation efficiencies, protein half-lives and/or enzyme kinetics toward the substrate. Data from this study indicated that all tested strains are suitable models for studying toxicants that are substrates for human CYP2A6; DBA-2, DBA-1 and the hybrid B62DF1, however, have the advantage of presenting high constitutive activities of Cyp2a5.

Glyphosate and adverse pregnancy outcomes, a systematic review of observational studies.

BACKGROUND: A study in frog and chicken embryos, and reports of a high incidence of birth defects in regions of intensive GM-soy planting have raised concerns on the teratogenic potential of glyphosate-based herbicides. These public concerns prompted us to conduct a systematic review of the epidemiological studies testing hypotheses of associations between glyphosate exposure and adverse pregnancy outcomes including birth defects. METHODS: A systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Bireme-BVS and SCOPUS databases using different combinations of exposure and outcome terms. A case-control study on the association between pesticides and congenital malformations in areas of extensive GM soy crops in South America, and reports on the occurrence of birth defects in these regions were reviewed as well. RESULTS: The search found ten studies testing associations between glyphosate and birth defects, abortions, pre-term deliveries, small for gestational date births, childhood diseases or altered sex ratios. Two additional studies examined changes of time-to-pregnancy in glyphosate-exposed populations. Except for an excess of Attention Deficit Hyperactivity Disorder - ADHD (OR = 3.6, 1.3-9.6) among children born to glyphosate appliers, no significant associations between this herbicide and adverse pregnancy outcomes were described. Evidence that in South American regions of intensive GM-soy planting incidence of birth defects is high remains elusive. CONCLUSIONS: Current epidemiological evidence, albeit limited to a few studies using non-quantitative and indirect estimates and dichotomous analysis of exposures, does not lend support to public concerns that glyphosate-based pesticides might pose developmental risks to the unborn child. Nonetheless, owing to methodological limitations of existing analytical observational studies, and particularly to a lack of a direct measurement (urine and/or blood levels), or an indirect estimation of exposure that has proven valid, these negative findings cannot be taken as definitive evidence that GLY, at current levels of occupational and environmental exposures, brings no risk for human development and reproduction.

Thyroid hormone disruption and cognitive impairment in rats exposed to PBDE during postnatal development.

Polybrominated diphenyl ether flame-retardants (PBDEs) are thyroid-disrupting environmental chemicals. We investigated the effects of postnatal exposure to DE-71 (a mixture of tetra- and penta-brominated congeners), n-propylthiouracil (PTU) and thyroxine (T4) replacement on open-field (OF) and radial maze (RAM) tests. Wistar rats (5 males/5 females per litter, 32 litters) were treated orally (PND 5-22) with PTU (4mg/kg bw/d), DE-71 (30mg/kg bw/d), with and without co-administration of T4 (15µg/kg bw/d, sc). PTU depressed T4 serum levels and body weight gain and enlarged thyroid gland. Although decreasing T4 levels, DE-71 did not change thyroid and body weights. PTU-treated rats showed hyperactivity (PND 42 and 70), and working and reference memory learning deficits (RAM, PND 100). Although not altering motor activity and working memory, DE-71 caused a reference memory deficit (females only). T4 co-administration averted hypothyroxinemia and long-term cognitive deficits caused by PTU and DE-71.

Modulation of cytochrome P450 2A5 activity by lipopolysaccharide: low-dose effects and non-monotonic dose-response relationship.

Mouse cytochrome P450 (CYP) 2A5 is induced by inflammatory conditions and infectious diseases that down-regulate the expression and activity of most other CYP isoforms. Enhanced oxidative stress and nuclear factor (erythroid 2-related factor) 2 (Nrf2) transcription factor activation have been hypothesised to mediate up-regulation of CYP2A5 expression in the murine liver. The unique and complex regulation of CYP2A5, however, is far from being thoroughly elucidated. Sepsis and high doses of bacterial lipopolysaccharide (LPS) elicit oxidative stress in the liver, but depression, not induction, of CYP2A5 has been observed in studies of mice treated with LPS. The foregoing facts prompted us to evaluate the response of CYP2A5 liver activity in female DBA-2 mice over a broad range of LPS doses (0, 0.025, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, and 20 mg/kg). Cytokine levels (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17A, interferon gamma, tumour necrosis factor alpha) and nitric oxide (NO) were measured in the blood serum. Activities of CYP1A (EROD) and CYP2B (BROD) in the liver were also determined for comparative purposes. LPS depressed CYP2A5 at low doses (0.025-2.0 mg/kg) but not at doses (>2 mg/kg) that increased pro-inflammatory cytokines and NO serum levels, and depressed CYP1A and CYP2B activities. Blockade of pro-inflammatory cytokines and the overproduction of NO induced by co-treatment with pentoxifylline and LPS and iNOS inhibition with aminoguanidine both extended down-regulation of CYP2A5 to the high dose range while not affecting LPS-induced depression of CYP1A and CYP2B. Overall, the results suggested that NO plays a role in the reversal of the low-dose LPS-induced depression of CYP2A5 observed when mice were challenged with higher doses of LPS.

Sexual maturation and fertility of mice exposed to triphenyltin during prepubertal and pubertal periods.

This study investigated the effects of pre- and peripubertal exposure (PND 15-45) to triphenyltin hydroxide (TPT: 0, 1.875, 3.75, 7.5 and 15 mg/kg bw/d po) on mouse sexual maturation and fertility. Half of the mice were euthanized on PND 46 and the remaining mice were submitted to fertility tests on PND 65-75. TPT caused a transient decrease of weight gain at 3.75 mg/kg bw/d, and deaths and body weight deficits at higher doses. Delays of testes descent (TD), vaginal opening (VO) and first estrus (FE) occurred at doses ≥3.75 (TD) and ≥7.5 mg/kg bw/d (VO, FE), respectively. Body weight on the days of TD, VO and FE did not differ among groups. TPT at doses ≥3.75 mg/kg decreased sperm and spermatid counts at the end of treatment (PND 46) but no alteration was noted later on PND 75. Testicular histopathology (PND 46) showed a dose-dependent reduction of seminiferous tubules diameter, a greater degree of vacuolation in Sertoli cells and germ cell degeneration and necrosis in TPT-treated mice. TPT did not affect the outcome of fertility tests. Study-derived NOAEL was 1.875 mg TPT/kg bw/d for males and 3.75 mg TPT/kg bw/d for females. The detrimental effects of TPT on spermatogenesis were reversed after treatment discontinuation.

Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility.

Meglumine antimoniate (MA) is a pentavalent antimony drug used to treat leishmaniases. We investigated the neurobehavioral development, sexual maturation and fertility of the offspring of MA-treated rats. Dams were administered MA (0, 75, 150, 300 mg Sb(V)/kg body wt/d, sc) from gestation day 0, throughout parturition and lactation, until weaning. At the highest dose, MA reduced the birth weight and the number of viable newborns. In the male offspring, MA did not impair development (somatic, reflex maturation, weight gain, puberty onset, open field test), sperm count, or reproductive performance. Except for a minor effect on body weight gain and vertical exploration in the open field, MA also did not affect the development of female offspring. Measurements of the Sb levels (ICP-MS) in the blood of MA-treated female rats and their offspring demonstrated that Sb is transferred to the fetuses via the placenta and to the suckling pups via milk.

Traditional use and safety of herbal medicines

In the European Union, traditional herbal medicines that are regarded as "acceptably safe, albeit not having a recognized level of efficacy" fit into a special category of drugs ("traditional herbal medicine products") for which requirements of non-clinical and clinical studies are less rigorous. A regulation proposal published by the Brazilian National Health Surveillance (Anvisa) defines a similar drug category ("traditional phytotherapeutic products") for registration purposes. Regarding herbal medicines, both agencies seem to be lenient regarding proof of efficacy, and consider long-standing folk use as evidence of safety and a waiver of a thorough toxicological evaluation. Nonetheless, several herbal products and constituents with a long history of folk usage are suspected carcinogenic and/or hepatotoxic. Herbal products have also been shown to inhibit and/or induce drug-metabolizing enzymes. Since herbal medicines are often used in conjunction with conventional drugs, kinetic and clinical interactions are a cause for concern. A demonstration of the safety of herbal medicines for registration purposes should include at least in vitro and in vivo genotoxicity assays, long-term rodent carcinogenicity tests (for drugs intended to be continuously used for > 3 months or intermittently for > 6 months), reproductive and developmental toxicity studies (for drugs used by women of childbearing age), and investigation of the effects on drug-metabolizing enzymes.