Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis.

Angiogenesis has been identified as a crucial process in the development and spread of cancers. There are many regulators of angiogenesis which are not yet fully understood. Methionine aminiopeptidase is a metalloenzyme with two structurally distinct forms in humans, Type-1 (MetAP-1) and Type-2 (MetAP-2). It has been shown that small molecule inhibitors of MetAP-2 suppress endothelial cell proliferation. The initial discovery by Donald Ingber of MetAP-2 inhibition as a potential target in angiogenesis began with a fortuitous observation similar to the discovery of penicillin activity by Sir Alexander Fleming. From a drug design perspective, MetAP-2 is an attractive target. Fumagillin and ovalicin, known natural products, bind with IC50 values in low nanomolar concentrations. Crystal structures of the bound complexes provide 3-dimensional coordinates for advanced computational studies. More recent discoveries have shown other biological activities for MetAP-2 inhibition, which has generated new interests in the design of novel inhibitors. Semisynthetic fumagillin derivatives such as AGM-1470 (TNP-470) have been shown to have better drug properties, but have not been very successful in clinical trials. The rationale and development of novel multicyclic analogs of fumagillin are reviewed.

Regulatory review of acetaminophen clinical pharmacology in young pediatric patients.

The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a child's weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. Acetaminophen is metabolized in the liver mainly through glucuronidation, sulfation, and to a lesser extent oxidation. Because of the difference in the ontogeny of various metabolizing pathways, the relative contribution of each pathway to the overall acetaminophen metabolism in children changes with age. The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age.

Pharmaceutical impurities: regulatory perspective for Abbreviated New Drug Applications.

Impurities in drug substances and drug products have been important regulatory issues in the Office of Generic Drugs by having significant impact on the approvability of Abbreviated New Drug Application (ANDAs). This review begins with a discussion of ANDAs and its similarity/differences with NDAs, highlighting the importance of control of pharmaceutical impurities in generic drug product development and regulatory assessment. An overview of the FDA draft guidance documents "ANDAs: Impurities in Drug Substances" and "ANDAs: Impurities in Drug Products" are provided. This introduces the identification and qualification procedures for ANDAs and approaches to the establishment of acceptance criteria for both drug substance and drug product. Case studies included in this review illustrate the proposed pathway for determination of impurities and their acceptance criteria, based upon the general principles of these guidances.

Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis.

Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Balpha (PKBalpha), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase-activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.