Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Fluorine in Pharmaceuticals: Looking Beyond Intuition.

It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

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Fluorine in medicinal chemistry.

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

Human exposure to bisphenol A (BPA).

The development and clinical use of 4-aminoquinoline antimalarial agents such as amodiaquine have been limited by toxicity to neutrophils. We have investigated the chemical basis of amodiaquine-induced toxicity and compared the findings with those for established antimalarial drugs proposed for human use. Amodiaquine, like chloroquine, mefloquine and halofantrine, was lysosomotropic and accumulated in human neutrophils. Amodiaquine did not lead to impairment of either cellular function or cell viability at therapeutic levels. In contrast to other antimalarial agents, amodiaquine (because it contains a 4-aminophenol function) depleted glutathione in activated neutrophils, by formation of an electrophilic quinoneimine metabolite. Bioactivation was accompanied by the expression of a drug-related antigen on the cell surface, which was recognized by drug-specific antibodies, suggesting that a type II hypersensitivity reaction is responsible for the observed toxicity. Similar bioactivation and accumulation were observed for the structurally related amopyroquine. The effects of chemical modifications at the 3'- and 5'-positions, which are known to enhance antimalarial activity, were also investigated. The introduction of a lipophilic 5'-chlorophenyl group and 3'-t-butyl group blocked bioactivation but enhanced cellular accumulation, with resultant impairment of function and neutrophil viability, whereas introduction of a second cationic dialkylamino group (bis-mannich compounds) blocked bioactivation and reduced cellular accumulation, without producing noticeable effects on cellular function and viability. These data provide a chemical rationale for the idiosyncratic agranulocytosis observed with amodiaquine, and they suggest that similar toxicity might be anticipated for amopyroquine but is less likely with bis-mannich antimalarial agents such as pyronaridine.

Disposition of Amodiaquine and Related Antimalarial Agents in Human Neutrophils: Implications for Drug Design

The effects of two antimalarial drugs, chloroquine and primaquine on antipyrine kinetics and metabolism have been studied in volunteers Chloroquine (250 mg) given 2 h before antipyrine (600 mg orally) had no effect on salivary kinetics of antipyrine or on the urinary recovery of metabolites Primaquine (45 mg) given 2 h before antipyrine (300 mg orally), increased antipyrine half-life (calculated from 0-24 h) from 127 +/- 32 (mean +/- sd) to 253 +/- 39 h and decreased clearance from 301 +/- 067 to 132 +/- 032 1 h-1 There was no change in the apparent volume of distribution Antipyrine half life changed with time in the presence of primaquine and when calculated between 24 and 48 h had returned to control After primaquine, the metabolic clearance (calculated from 0-24 h) of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine was significantly reduced There was no selective effect on a particular metabolic pathway There was no change in 6 beta-hydroxycortisol excretion (expressed as a ratio of total 17-hydroxy-corticosteroids) in the period 0-48 h following primaquine administration The inhibition of hepatic metabolism by primaquine but not the structurally related chloroquine may be an example of a structure activity phenomenon and could be of clinical significance

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Effect of chloroquine and primaquine on antipyrine metabolism

In vitro metabolism of dexamethasone (DEX) in human liver and kidney : The involvement of CYP3A4 and CYP17 (17,20 LYASE) and molecular modelling studies

Antigen-presenting cells (APC) are thought to play an important role in the pathogenesis of drug-induced immune reactions. Various pathological factors can activate APC and therefore influence the immune equilibrium. It is interesting that several diseases have been associated with an increased rate of drug allergy. The aim of this project was to evaluate the impact of such “danger signals” on sulfamethoxazole (SMX) metabolism in human APC (peripheral blood mononuclear cells, Epstein-Barr virus-modified B lymphocytes, monocyte-derived dendritic cells, and two cell lines). APC were incubated with SMX (100 μM–2 mM; 5 min–24 h), in the presence of pathological factors: bacterial endotoxins (lipopolysaccharide and staphylococcal enterotoxin B), flu viral proteins, cytokines [interleukin (IL)-1β, IL-6, IL-10; tumor necrosis factor-α; interferon-γ; and transforming growth factor-β], inflammatory molecules (prostaglandin E2, human serum complement, and activated protein C), oxidants (buthionine sulfoximine and H2O2), and hyperthermia (37.5–39.5°C). Adduct formation was evaluated by enzyme-linked immunosorbent assay and confocal microscopy. SMX-protein adduct formation was time- and concentration-dependent for each cell type tested, in both physiological and danger conditions. A danger environment significantly increased the formation of SMX-protein adducts and significantly shortened the delay for their detection. An additive effect was observed with a combination of danger signals. Dimedone (chemical selectively binding cysteine sulfenic acid) and antioxidants decreased both baseline and danger-enhanced SMX-adduct formation. Various enzyme inhibitors were associated with a significant decrease in SMX-adduct levels, with a pattern varying depending on the cell type and the culture conditions. These results illustrate that danger signals enhance the formation of intracellular SMX-protein adducts in human APC. These findings might be relevant to the increased frequency of drug allergy in certain disease states.

"Danger" conditions increase sulfamethoxazole-protein adduct formation in human antigen presenting cells

Adverse drug reactions, in particular drug-induced hepatotoxicity, represent a major challenge for clinicians and an impediment to safe drug development. Novel blood or urinary biomarkers of chemically-induced hepatic stress also hold great potential to provide information about pathways leading to cell death within tissues. The earlier pre-clinical identification of potential hepatotoxins and non-invasive diagnosis of susceptible patients, prior to overt liver disease is an important goal. Moreover, the identification, validation and qualification of biomarkers that have in vitro, in vivo and clinical transferability can assist bridging studies and accelerate the pace of drug development. Drug-induced chemical stress is a multi-factorial process, the kinetics of the interaction between the hepatotoxin and the cellular macromolecules are crucially important as different biomarkers will appear over time. The sensitivity of the bioanalytical techniques used to detect biological and chemical biomarkers under...

B.K. Park

Papers

Disposition of Amodiaquine and Related Antimalarial Agents in Human Neutrophils: Implications for Drug Design

Effect of chloroquine and primaquine on antipyrine metabolism

In vitro metabolism of dexamethasone (DEX) in human liver and kidney : The involvement of CYP3A4 and CYP17 (17,20 LYASE) and molecular modelling studies

"Danger" conditions increase sulfamethoxazole-protein adduct formation in human antigen presenting cells

Mechanism-based bioanalysis and biomarkers for hepatic chemical stress