Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor.

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine.

Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the ß8-ß9 loop in the extracellular ligand-binding domain. The ß8-ß9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the ß8-ß9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors.

Ants as carriers of antibiotic-resistant bacteria in hospitals

The presence of antimicrobial-resistant bacteria and carried by ants isolated from hospitals was investigated in Campos dos Goytacazes, RJ, Brazil. Three health institutions were visited from 2001 to 2002 and samples were collected within critical areas of medical care based on criteria of greater risk of patient hospital acquired-infection. Four ant species were identified, Tapinoma melanocephalum (Fabricius)(63.1 percent), Paratrechina longicornis (Latreille)(21.1 percent), Monomorium pharaonis (L.)(10.5 percent), and Solenopsis saevissima (S. Smith)(5.3 percent) carrying 21 species of bacteria. The tests for bacteria species identification and antimicrobial-resistance profile were carried out by using standardized kits and evaluated by automated equipment. Among the bacteria isolates, some were considered multiresistant isolates, including genera Acinetobacter, Streptococcus, Gemella, and Klebsiella. For Enterobacter antibacterial analysis the disk diffusion standard method was used. The results suggest that there are risks for patients which seek for health assistance in the hospitals studied, and the presence of emerging bacteria isolates in hospital carried by ants must be considered.

A presença de bactérias resistentes a antimicrobianos e carreadas por formigas isoladas em hospitais foi investigada em Campos dos Goytacazes, RJ. Três instituições de saúde foram visitadas nos períodos de 2001 a 2002 e amostras foram coletadas em áreas de cuidados médicos consideradas críticas baseando-se em critérios de maior risco para a aquisição de infecções por pacientes hospitalizados. Quatro espécies de formigas foram identificadas, Tapinoma melanocephalum (Fabricius)(63,1 por cento), Paratrechina longicornis (Latreille)(21,1 por cento), Monomorium pharaonis (L.)(10,5 por cento) e Solenopsis saevissima (S. Smith)(5,3 por cento) como carreadoras de 21 morfoespécies de bactérias. Os testes de identificação bacteriana e de perfil de resistência antimicrobiana foram realizados por meio de kits padronizados e avaliados por método automatizado. Entre as bactérias isoladas, algumas foram consideradas multirresistentes, incluindo o gênero Acinetobacter, Streptococcus, Gemella, e Klebsiella. Para análise antimicrobiana do gênero Enterobacter foi utilizado o método padrão de difusão em disco. Os resultados sugerem que existem riscos para pacientes que procuram por assistência de saúde nos hospitais estudados e a ocorrência de bactérias emergentes em hospitais carreadas por formigas devem ser consideradas.