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 case histories of two patients exposed to the novel anticoagulants brodifacoum and difenacoum are reported. Abnormal vitamin K1 metabolism, as indicated by elevated vitamin K1 2,3-epoxide plasma concentrations after i.v. administration of vitamin K1, could be detected for more than 18 months after exposure to the anticoagulants. There was a marked prolongation of prothrombin time (greater than 50 s) in both cases, at the time of exposure. However, subsequent haematological investigations (prothrombin time and vitamin K-dependent clotting factor activity) have been shown to be normal in both cases for at least 18 months. These cases confirm the long-acting nature of brodifacoum and difenacoum and present an apparent dissociation between the effect of coumarin anticoagulants on vitamin K1 metabolism and clotting factor activity.

Abnormal vitamin K metabolism in the presence of normal clotting factor activity in factory workers exposed to 4-hydroxycoumarins.

Autoxidative formation of a chemically reactive intermediate from amodiaquine, a myelotoxin and hepatotoxin in man.

1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) which is used in Alzheimer's disease, causes elevation of liver transaminases ('tacrine transaminitis') in 40-50% of patients. This may be related to the formation of a chemically reactive metabolite from tacrine, which can be detoxified in vitro by glutathione. 2. Glutathione-S-transferase mu (GSTM1), a detoxication enzyme, is polymorphically expressed being absent in about 50% of patients. Its role in the detoxication of the reactive metabolite of tacrine is not known. 3. The frequency of the enzyme deficiency (GSTM1*0) has been investigated in patients with tacrine transaminitis using polymerase chain reaction (PCR) to determine whether the GSTM1 status can be used as an absolute predictive factor for susceptibility to tacrine transaminitis. 4. The frequency of the GSTM1*0 genotype in patients with tacrine transaminitis (n = 33; 45.5%) was not significantly different from that in patients treated with tacrine without liver dysfunction (n = 37; 43%), and when compared with all the controls used in the study (n = 167; 56%). 5. The frequency of the GSTM1*0 genotype in patients with Alzheimer's disease (n = 79; 46%) was not significantly different from that in healthy volunteers (n = 121; 59.5%). 6. Our results indicate that the GSTM1 status cannot be used clinically to predict individual susceptibility to tacrine transaminitis, and that patients with the GSTM1*0 genotype are unlikely to have an increased risk of tacrine-induced liver damage. Furthermore, the GSTM1 status was not associated with Alzheimer's disease.

Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.

Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.

Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.

The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme-inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. CMT alone had no significant effect on antipyrine kinetics, urinary 6 beta-hydroxycortisol excretion or leucocyte delta-aminolaevulinic acid synthase (ALA.S) activity. CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P less than 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. Antipyrine clearance and urinary 6 beta-hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P less than 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 beta-hydroxycortisol excretion was unaffected. Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P less than 0.05). CBZ half-life fell by 36% and clearance rose by 29% (both P less than 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. CMT inhibits CBZ auto- and hetero-induction in man. Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.

B.K. Park

Papers

Abnormal vitamin K metabolism in the presence of normal clotting factor activity in factory workers exposed to 4-hydroxycoumarins.

Autoxidative formation of a chemically reactive intermediate from amodiaquine, a myelotoxin and hepatotoxin in man.

Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.

Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.

Effects of cimetidine on carbamazepine auto- and hetero-induction in man.