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.

/pdf/fluorine-in-medicinal-chemistry-4kwoqx8yba.pdf

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).

1. IgG, IgM and IgE anti-benzylpenicilloyl (BPO) antibody activities were determined by enzyme-linked immunosorbent assay (ELISA) in sera from 100 patients who claimed to be allergic to penicillin, and from 50 healthy volunteers. Continuous frequency distributions for all three classes of anti-BPO antibody, defined as differential binding (delta OD) to BPO-human serum albumin (HSA) and HSA, were obtained for both groups. 2. For IgM and IgE classes the anti-BPO activities were slightly but statistically significantly higher in the patient group compared with the volunteer group. 3. Hapten inhibition ELISAs were performed to confirm specificity for the BPO determinant. On the basis of antibody activities (delta OD values) greater than or equal to 0.3 and 50% inhibition of binding in the presence of 100 micrograms ml-1 BPO-caproate, BPO-specific IgG antibody was identified in 4/100 of the patients' sera and in 1/50 of the volunteers' sera; BPO-specific IgM was identified in 7/100 patients' sera and 1/50 volunteers' sera; and BPO-specific IgE in 5/100 patients' sera and 1/50 volunteers' sera. 4. Not all sera with differential antibody binding to BPO-HSA/HSA were inhibited by the BPO hapten. Hence, hapten inhibition assays are essential for the unambiguous demonstration of drug specific antibodies.

A survey of the prevalence of penicillin-specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition, in patients with suspected penicillin allergy and in healthy volunteers

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug-induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

https://journals.sagepub.com/doi/pdf/10.1177/0960327115606529

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury:

The mechanism of salicylate-induced hypothrombinaemia has been investigated in the rabbit. Administration of methyl salicylate produced a significant decrease in prothrombin complex activity, in the activity of clotting factors II, VII and X but no significant change in factor V activity. Metabolic studies with [3H]vitamin K1 showed that salicylate increased the plasma concentration ratio of [3H]vitamin K1-epoxide: [3H]vitamin K1. The results are consistent with the concept that salicylate produces its anticoagulant effect, like the coumarin anticoagulants, by interruption of the physiologically important vitamin K1-epoxide cycle at the epoxide reductase.

On the mechanism of salicylate-induced hypothrombinaemia.

The disposition of, and pharmacological response to, a single intravenous dose of vitamin K1 (10 mg) was studied in eleven patients on daily warfarin therapy. The pharmacokinetics of vitamin K1 in patients were similar to those reported previously in healthy volunteers, terminal half-life 1.7 h. All patients had been taking warfarin for at least 3 months. Steady state warfarin plasma concentrations ranged from 0.5 to 1.4 micrograms ml-1. Prothrombin complex activity ranged from 15 to 28.5%. There was considerable inter-individual variation in pharmacodynamic response as expressed by prothrombin complex activity (PCA) and Factor VII. The maximum values for PCA and Factor VII were reached at 24-96 h and 24-48 h, respectively, after the administration of vitamin K1. Vitamin K1 (10 mg) has a long duration of action (greater than 168 h) in terms of clotting factor synthesis in patients on steady state warfarin. All the patients on warfarin had measurable levels (CPmax 0.3-1.2 micrograms ml-1) of vitamin K1 2, 3-epoxide. There was a significant correlation between the pharmacodynamic response as expressed by change in % PCA and the AUC for vitamin K1 2,3-epoxide (P less than 0.05).

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1985.tb05123.x

Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients.

Aminoquinoline resistance correlates with lipid solubility at pH 7.2. Consequently, the in vivo dealkylation of amodiaquine, to the less lipid-soluble desethylamodiaquine, is a likely contributor to therapeutic failure in vivo. Therefore, 4-aminoquinoline drugs with lipid solubilities similar to that of amodiaquine, but which are not subject to side chain modification in vivo, should be superior antimalarial agents. In this study, we have identified amopyroquine and N-tertbutylamodiaquine as two such compounds. The values for the logarithms of the partition coefficients for amopyroquine and N-tertbutylamodiaquine are between those for amodiaquine and its dealkylated metabolite, desethylamodiaquine. Both amopyroquine and N-tertbutylamodiaquine possess levels of antimalarial activity greater than that of desethylamodiaquine and significantly reduced cross-resistance patterns; i.e., the former two compounds are not subject to the verapamil-sensitive resistance mechanism. Simple in vitro markers of direct toxicity and potential reactive metabolite formation suggest that these two compounds are no more toxic than amodiaquine and desethylamodiaquine.

B.K. Park

Papers

A survey of the prevalence of penicillin-specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition, in patients with suspected penicillin allergy and in healthy volunteers

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury:

On the mechanism of salicylate-induced hypothrombinaemia.

Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients.

Manipulation of the N-alkyl substituent in amodiaquine to overcome the verapamil-sensitive chloroquine resistance component.