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).

We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon chambers are separated by a semi-permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/- NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0-1000 microM) and NADPH prior to the addition of dapsone (100 microM) and NADPH (1 mM) resulted in a concentration-dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/- 47 to 40 +/- 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration-dependent reduction in methaemoglobin measured (from 7.1 +/- 0.7 to 3.5 +/- 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone-dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.

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The effect of preincubation with cimetidine on the N-hydroxylation of dapsone by human liver microsomes.

The antimalarial agent amodiaquine is effective against both chloroquine-resistant and -sensitive strains of Plasmodium falciparum (24). However, its use has been curtailed due to the development of adverse reactions to the drug during prophylactic administration (7, 11). These drug-induced reactions have been attributed to the ability of amodiaquine to undergo oxidative metabolism to a chemically reactive quinoneimine species, detected in vivo as the excretion of glutathione conjugates in experimental animals (6, 10, 19).

Formation of this metabolite requires the presence of a 4-aminophenol group allowing formation of an electrophilic quinoneimine. To date, amodiaquine is unique among antimalarial agents in its ability to form this type of chemically reactive metabolite and to produce idiosyncratic drug reactions in humans. Most toxicities associated with the use of antimalarial agents are related to the dose (9) and have been ascribed to the ability of these compounds to accumulate in acidic cellular lysosomes. However, this mechanism of accumulation has also been proposed as a requirement for the pharmacological activities of some antimalarial agents (4, 8, 30). It has been shown that both the basicity and the lipophilicity have a great influence on the ability of compounds to accumulate (8) and on the site of accumulation (3). The extent of tissue storage is, in turn, known to influence the pharmacokinetics, and tissue distribution plays a major part in the pharmacological profile of a compound with respect to its duration of action, its potency in vivo, and its toxicology. A review of novel and therapeutically used compounds revealed that many antimalarial agents contain a 4-aminophenol group, which may influence their toxicological profiles. These compounds, analogs of amodiaquine, can be classed as Mannich antimalarial agents due to the incorporation of an amine group in their side chains.

The introduction of a C-5′-chlorophenyl group (5′-ClPAQ and tebuquine; Fig. ​Fig.1)1) increased the in vivo activity of amodiaquine 20-fold against Plasmodium berghei in the mouse (26). However, neither of these compounds has been used in the clinic. In the case of tebuquine, this was due to chronic toxicity seen during tests with animals, including the appearance of foamy macrophages (25a), a histological finding also seen following the chronic administration of chloroquine to humans (29). Tissue accumulation has been implicated in chloroquine toxicity (9), and the mechanism of tebuquine toxicity may also be a consequence of accumulation. 



FIG. 1

Chemical structures of amodiaquine and its analogs.



Previous studies have shown that bis-Mannich analogs of amodiaquine (cycloquine and bis-pyroquine; Fig. ​Fig.1)1) have higher levels of activity than their mono-Mannich derivatives against both chloroquine-resistant and -sensitive strains of the malarial parasite in vitro (17). In vivo, the activities of bis-Mannich and mono-Mannich compounds are comparable against Plasmodium vinckei vinckei after intraperitoneal (i.p.) administration (1). However, the inclusion of the extra group at the C-5′ position of amodiaquine increases the duration of action for bis-Mannich antimalarial agents. Pyronaridine (Fig. ​(Fig.1),1), a bis-Mannich antimalarial substituted at the C-5′ with a pyrrolidine group and an acridine rather than a quinoline nucleus is currently undergoing clinical trials in China and has already been used effectively in the treatment of resistant strains of P. falciparum both in vitro (17) and in the clinic (20, 27).

The aim of this study was to investigate the influence of pharmacokinetics on pharmacodynamics with reference to three types of Mannich antimalarial compounds: the mono-Mannich compound amodiaquine, which has two sites of protonation; 5′-ClPAQ, which contains a chlorophenyl group at C-5′ of amodiaquine and which has a higher level of lipophilicity than amodiaquine; and the bis-Mannich cycloquine, which has three sites of protonation and which has a greater basicity than amodiaquine. These results have been extrapolated to related compounds to see whether physiochemical properties can explain the observed duration of antimalarial activity through changes in the disposition of the compound in vivo.

Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

— The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigated. Fluorine substitution adjacent to the hydroxyl group increased lipophilicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the amide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into the amide group of paracetamol increased the lipophilicity 4-fold and also increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluorine reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correlation of the analgesic activity with the physicochemical properties indicated that conjugation (and planarity) of the amide group with the aromatic ring is essential for activity and that ease of oxidation may also be an important factor.

B.K. Park

Papers

The effect of preincubation with cimetidine on the N-hydroxylation of dapsone by human liver microsomes.

Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

The Effect of Fluorine Substitution on the Physicochemical Properties and the Analgesic Activity of Paracetamol

Drug-protein conjugates--V. Sex-linked differences in the metabolism and irreversible binding of 17 alpha-ethinylestradiol in the rat.

Activation of mianserin and its metabolites by human liver microsomes.