High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function.

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Vitamin E but not 17B-estradiol protect against vascular toxicity induced by B-amyloid wild type and the Dutch amyploid variant

Amyloid β-peptide (Aβ) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in Aβ yielding AβGlu22→Gln. The present study addresses the effect of amyloid fibrils from both wild-type and mutated Aβ on vascular cells, as well as the putative protective role of antioxidants on amyloid angiopathy. For this purpose, we studied the cytotoxicity induced by Aβ1–40 Glu22→Gln and Aβ1–40 wild-type fibrils on human venule endothelial cells and rat aorta smooth muscle cells. We observed that AβGlu22→Gln fibrils are more toxic for vascular cells than the wild-type fibrils. We also evaluated the cytotoxicity of Aβ fibrils bound with acetylcholinesterase (AChE), a common component of amyloid deposits. Aβ1–40 wild-type–AChE fibrillar complexes, similar to neuronal cells, resulted in an increased toxicity on vascular cells. Previous reports showing that antioxidants are able to reduce the toxicity of Aβ fibrils on neuronal cells prompted us to test the effect of vitamin E, vitamin C, and 17β-estradiol on vascular damage induced by Aβwild-type and AβGlu22→Gln. Our data indicate that vitamin E attenuated significantly the Aβ-mediated cytotoxicity on vascular cells, although 17β-estradiol and vitamin C failed to inhibit the cytotoxicity induced by Aβ fibrils.

Lead acetate toxicity in vitro: Dependence on the cell composition of the cultures.

It is well known that exposure to low doses of lead causes long-lasting neurobehavioural deficits, but the cellular changes underlying these behavioural changes remain to be elucidated. A protective role of glial cells on neurons through lead sequestration by astrocytes has been proposed. The possible modulation of lead neurotoxicity by neuron-glia interactions was examined in three-dimensional cultures of foetal rat telencephalon. Mixed-brain cell cultures or cultures enriched in either neurons or glial cells were treated for 10 days with lead acetate (10(-6) m), a concentration below the limit of cytotoxicity. Intracellular lead content and cell type-specific enzyme activities were determined. It was found that in enriched cultures neurons stored more lead than glial cells, and each cell type alone stored more lead than in co-culture. Moreover, glial cells but not neurons were more affected by lead in enriched culture than in co-culture. These results show that neuron-glia interactions attenuate the cellular lead uptake and the glial susceptibility to lead, but they do not support the idea of a protective role of astrocytes.

Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures.

The intravenous, short-acting general anesthetic propofol was applied to three-dimensional (aggregating) cell cultures of fetal rat telencephalon. Both the clinically used formulation (Disoprivan, ICI Pharmaceuticals, Cheshire, England) and the pure form (2,6-diisopropylphenol) were tested at two different periods of brain development: immature brain cell cultures prior to synaptogenesis and at the time of intense synapses and myelin formation. At both time periods and for clinically relevant concentrations and time of exposure (i.e., concentrations > or = 2.0 micrograms/ml for 8 hr), propofol caused a significant decrease of glutamic acid decarboxylase activity. This effect persisted after removal of the drug, suggesting irreversible structural changes in GABAergic neurons. The gamma-aminobutyric acid type A (GABAA) blocking agents bicuculline and picrotoxin partially attenuated the neurotoxic effect of propofol in cultures treated at the more mature phase of development. This protective effect was not observed in the immature brain cells. The present data suggest that propofol may cause irreversible lesions to GABAergic neurons when given at a critical phase of brain development. In contrast, glial cells and myelin appeared resistant even to high doses of propofol.

Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine.

Hyperammonemia can provoke irreversible damage to the developing brain, with the formation of cortical atrophy, ventricular enlargement, demyelination or gray and white matter hypodensities. Among the various pathogenic mechanisms involved, alterations in cerebral energy have been demonstrated. In particular, we could show that ammonia exposure generates a secondary deficiency in creatine in brain cells, by altering the brain expression and activity of the genes allowing creatine synthesis (AGAT and GAMT) and transport (SLC6A8). On the other hand, it is known that creatine administration can exert protective effects in various neurodegenerative processes. We could also show that creatine co-treatment under ammonia exposure can protect developing brain cells from some of the deleterious effects of ammonia, in particular axonal growth impairment. This article focuses on the effects of ammonia exposure on creatine metabolism and transport in developing brain cells, and on the potential neuroprotective properties of creatine in the brain exposed to ammonium.

Ammonia toxicity to the brain.

Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches.

In vitro assessment of the pulmonary toxicity and gastric availability of lead-rich particles from a lead recycling plant

Epidemiological studies in urban areas have linked increasing respiratory and cardiovascular pathologies with atmospheric particulate matter (PM) from anthropic activities. However, the biological fate of metal-rich PM industrial emissions in urban areas of developed countries remains understudied. Lead toxicity and bioaccessibility assessments were therefore performed on emissions from a lead recycling plant, using complementary chemical acellular tests and toxicological assays, as a function of PM size (PM(10-2.5), PM(2.5-1) and PM(1)) and origin (furnace, refining and channeled emissions). Process PM displayed differences in metal content, granulometry, and percentage of inhalable fraction as a function of their origin. Lead gastric bioaccessibility was relatively low (maximum 25%) versus previous studies; although, because of high total lead concentrations, significant metal quantities were solubilized in simulated gastrointestinal fluids. Regardless of origin, the finest PM(1) particles induced the most significant pro-inflammatory response in human bronchial epithelial cells. Moreover, this biological response correlated with pro-oxidant potential assay results, suggesting some biological predictive value for acellular tests. Pulmonary effects from lead-rich PM could be driven by thiol complexation with either lead ions or directly on the particulate surface. Finally, health concern of PM was discussed on the basis of pro-inflammatory effects, accellular test results, and PM size distribution.

Causes développementales dans la variabilité de l'efficacité et de la toxicité des antalgiques en pédiatrie [Developmental causes in variability of efficacy and toxicity of analgesics in pediatrics]

The intensity of pain perception and its sensibility to analgesic drugs is highly variable and unpredictable between individuals. Drug disposition varies during development due to the physiological maturation of enzymatic systems and physiological processes responsible for the absorption, distribution, elimination and effect at the site of action. Many of those developmental variables are not yet clearly defined, but their consideration is important for avoiding potential risks of ineffective or toxic treatment. Implications of those developmental changes for day-to-day clinical practice depend on the age of the child, on the type of drug, on the underlying disease and on the potential co-administration of other chemicals.

Low malathion concentrations influence metabolism in Chironomus sancticaroli (Diptera, Chironomidae) in acute and chronic toxicity tests

Low malathion concentrations influence metabolism in Chironomus sancticaroli (Diptera, Chironomidae) in acute and chronic toxicity tests. Organophosphate compounds are used in agro-systems, and in programs to control pathogen vectors. Because they are continuously applied, organophosphates often reach water sources and may have an impact on aquatic life. The effects of acute and chronic exposure to the organophosphate insecticide malathion on the midge Chironomus sancticaroli are evaluated. To that end, three biochemical biomarkers, acetylcholinesterase (AChE), alpha (EST-α) and beta (EST-β) esterase were used. Acute bioassays with five concentrations of malathion, and chronic bioassays with two concentrations of malathion were carried out. In the acute exposure test, AChE, EST-α and EST-β activities declined by 66, 40 and 37%, respectively, at 0.251 µg L-1 and more than 80% at 1.37, 1.96 and 2.51 µg L-1. In chronic exposure tests, AChE and EST-α activities declined by 28 and 15% at 0.251 µg L-1. Results of the present study show that low concentrations of malathion can influence larval metabolism, indicating high toxicity for Chironomus sancticaroli and environmental risk associated with the use of organophosphates.

Peletização do lodo de esgoto e adição de CaCO3 na produção de matéria seca e absorção de Zn, Cu e Ni pelo milho em três latossolos

Em experimento de casa de vegetação, realizado em Campinas (SP), no período de janeiro a maio de 1980, estudaram-se os efeitos da peletização do lodo de esgoto, nas doses 0, 1 e 5% (v/v) do material seco, na produção de matéria seca e na absorção de Zn, Cu e Ni pela parte aérea do milho (Zea mays L.), em latossolo roxo (LR), latossolo vermelho-escuro (LE) e latossolo vermelho-amarelo (LV), que receberam ou não adição de CaCO3 suficiente para elevação do pH em água para 6,0. O experimento foi realizado em vasos com dois litros de capacidade, delineados em blocos ao acaso, com três repetições, e os tratamentos arranjados num esquema fatorial. Após 200 dias de incubação dos solos com o lodo e CaCO3, cultivaram-se quatro plantas de milho em cada vaso. A parte aérea foi quantificada 56 dias após a germinação, sendo cortada, seca, pesada e analisada para os elementos Zn, Cu e Ni. Amostras de terra de cada tratamento foram retiradas e tiveram os metais extraídos pelo DTPA. A peletização do lodo de esgoto resultou em diminuição significativa na produção de matéria seca pela parte aérea do milho, nos três solos estudados, em comparação com o lodo não peletizado. A adição de CaCO3 proporcionou aumento significativo na produção de matéria seca do milho apenas nos dois solos mais ácidos (LE e LV) e diminuiu o acúmulo de Zn na parte aérea desse vegetal cultivado no LE, sem distinção quanto ao tipo de lodo aplicado, não se observando diferenças significativas na absorção de Ni, em todos os solos analisados. A incorporação do lodo peletizado , que continha 19% menos Zn e Ni que o não peletizado, resultou em menor absorção de Zn, Cu e Ni nos três solos, exceto para o Ni no LR. Para todos os solos investigados, o método do DTPA mostrou-se mais adequado em prognosticar as quantidades disponíveis de Zn e de Cu para o milho, independentemente do tipo de lodo de esgoto aplicado e da elevação ou não do pH do solo pela adição de CaCO3.

Increase of grain and green matter of corn by liming

Despite the fact that aluminum toxicity to crops is eliminated near soil water pH of 5.5, lime recommendation in many regions aims to increase soil pH up to 6.0 or even higher. For highly buffered soils, high rates of limestone are required to raise the pH from 5.5 to 6.0, resulting in additional, sometimes unnecessary, costs. The objective of this study was to evaluate the effect of soil pH on corn yield in a very acid Hapludox. The experiment was carried out in Lages, Southern Brazil, from 1992 to 1996. The soil had water pH of 4.7, Al3+ of 33 mmol c kg-1, O.M. of 45 g kg-1 and lime requirement to pH 6.0 of 9.0 t ha-1. Dolomitic limestone at rates of 0, 4.5, 9.0, 13.5 and 18.0 t ha-1 (equivalent to pure CaCO3) was incorporated into the soil down to 17 cm depth, in 1992. Liming increased linearly the values of soil pH (from 4.7 to 6.6) and Ca and Mg, eliminated Al3+ with rates of 9.0 t ha-1 or higher, decreased slightly Al-CuCl2, Fe and Cu, and did not affect Zn and Mn. Maximum average corn yield for grain (7.9 t ha-1) and for green matter for silage (GM) (59 t ha-1) was obtained, respectively, at soil pH of 6.0 (12 t ha-1 of limestone) and of 6.1 (14 t ha-1 of limestone); maximum economic efficiency for grain was obtained at pH 5.6 (7.5 t ha-1 of limestone). Maximum yield increments due to liming were 17% for grain and 20% for GM.

Caracterització de les metal·lotioneïnes CnMT1 i CnMT2 del fong Cryptococcus neoformans. Estudi de la capacitat coordinant davant dels ions Zn(II), Cd(II) i Cu(I)

En aquest treball de recerca, s’han estudiat les dues isoformes de metal·lotioneïna CnMT1 i CnMT2 presents en el fong patogen Cryptococcus neoformans. Recentment s’ha descobert que aquest fong té com a factor de virulència, els nivells de coure del medi on es troba. Les dues isoformes produïdes en medis rics en Zn(II) s’han utilitzat per a fer valoracions amb Cu(I) i Cd(II), i s’ha seguit l’evolució dels experiments mitjançant les tècniques DC, UV-vis, i ESI-MS. S’ha pogut observar que les dues isoformes tenen preferència per enllaçar Cu(I). Per altra banda també s’ha establert una gran homologia entre les dues seqüències.

Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics.

Introduction: Besides therapeutic effectiveness, drug tolerability is a key issue for treatments that must be taken indefinitely. Given the high prevalence of toxicity in HIV therapy, the factors implicated in drug-induced morbidities should be identified in order to improve the safety, tolerability and adherence to the treatments. Current approaches have focused almost exclusively on parent drug concentrations; whereas recent evidence suggests that drug metabolites resulting from complex genetic and environmental influences can also contribute to treatment outcome. Pharmacogenetic variations have shown to play a relevant role in the variability observed in antiretroviral drug exposure, clinical response and sometimes toxicity. The integration of pharmacokinetic, pharmacogenetic and metabolic determinants will more probably address current therapeutic needs in patients. Areas covered: This review offers a concise description of three classes of antiretroviral drugs. The review looks at the metabolic profile of these drugs and gives a comprehensive summary of the existing literature on the influence of pharmacogenetics on their pharmacokinetics and metabolic pathways, and the associated drug or metabolite toxicity. Expert opinion: Due to the high prevalence of toxicity and the related risk of low adherence to the treatments, association of kinetic, genetic and metabolic markers predictive of therapeutic or toxicity outcomes could represent a more complete approach for optimizing antiretroviral therapy.

Efeito de ZN, Cd e Cu no comportamento de fungos ectomicorrízicos em meio de cultura

Os fungos ectomicorrízicos são capazes de tolerar concentrações de metais pesados tóxicas às plantas hospedeiras, apesar de serem adversamente influenciados pelo excesso de alguns metais. Avaliou-se o crescimento de um isolado de Pisolithus tinctorius e outro de Suillus bovinus em meio de cultura líquido com doses crescentes de sais de Zn, Cu ou Cd adicionados individualmente em frascos de 125 mL que continham 50 mL de meio Mellin-Norkrans modificado (MNM), em pH 4,8. Os fungos cresceram por 20 dias em câmara de crescimento a 28ºC. O crescimento dos fungos foi inibido com a elevação das concentrações dos metais, porém de forma diferenciada. As concentrações suficientes para inibir 50% do crescimento foram de 2,71 x 10-3 mol L-1 de Zn, 1,18 x 10-3 mol L-1 de Cu e 12,2 x 10-6 mol L-1 de Cd, para o P. tinctorius, e de 2,15 x 10-3 mol L-1 de Zn, 0,12 x 10-3 mol L-1 de Cu e 7,2 x 10-6 mol L-1 de Cd, para o S. bovinus. O efeito inibitório dos metais sobre o crescimento dos fungos seguiu a seguinte ordem decrescente: Cd > Cu > Zn. O isolado de S. bovinus apresentou tolerância ao Zn similar à observada para o P. tinctorius, mas foi menos tolerante que este em relação aos outros dois metais. O crescimento de P. tinctorius foi favorecido por pequena dose de Cu. A produção de pigmentos extracelulares nestes isolados foi estimulada por todos os metais estudados. O P. tinctorius, o mais tolerante, produziu mais pigmentos extracelulares por grama de micélio, o que sugere a relação positiva entre a capacidade de produção de pigmentos e a tolerância aos metais.