Replacement of the carboxylic acid group of prostaglandin (PG) F 2␣ with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF 2␣ analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC 50 value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [3 H]17-phenyl PGF 2a for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF 2␣ -induced Ca 2ϩ signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [ 3 H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10-to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.Eicosanoids and related fatty acids have long been the subject of extensive investigation. More recently, it has become apparent that the corresponding neutral lipids exist for several fatty acids (Devane et al

The purpose of this study was to determine the mechanisms responsible for intestinal disposition of apigenin in the human Caco-2 cell culture model. The results indicated that most of the absorbed apigenin (10 M) were conjugated and only a small fraction was transported intact. The amounts of conjugates excreted, especially that of the sulfate, were dependent on dayspost-seeding. Apical efflux of apigenin sulfate did not change with concentration of apigenin (4 to 40 M), whereas its basolateral efflux increased (p Ͻ 0.01) with concentration and plateaued at about 25 M. In contrast, sulfate formation rates in cell lysate increased with concentration and plateaued at 25 M and were 4 to 6 times faster than the corresponding excretion rates. Formation and polarized excretion rates of glucuronidated apigenin increased with apigenin concentration but formation rates were usually 2.5 to 6 times faster than the corresponding excretion rates. Inhibitors of multidrug resistance-related proteins (MRPs) such as leukotriene C 4 and MK-571, which inhibited glucuronidation of apigenin at a high concentration (Ն25 M), significantly decreased excretion of both apigenin conjugates, and higher concentrations of MK-571 increased the extent of inhibition. In contrast, an organic anion transporter (OAT) inhibitor estrone sulfate only inhibited excretion of apigenin sulfate. In conclusion, we have shown for the first time that intestinal efflux is the rate-limiting step in the intestinal excretion of phase II conjugates of flavones. Furthermore, MRP and OAT are involved in the intestinal efflux of these hydrophilic phase II conjugates.

Introduction:Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow.Purpose:This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years.Methods:The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered.Results:The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin), Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist.Conclusion:The clinical value of novel compounds for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.

The mouse reelin gene (Rein} encodes a novel protein that, when mutated, results in the characteristic reeler phenotype. A key component of this phenotype is the extensive disruption of the organization of many brain structures. Reelin is believed to be an extracellular protein that controls neural cell positioning during brain development. The reelin gene is conserved in many vertebrate species, including humans. To study the role of the reelin homolog in human brain development, we have isolated and characterized the human gene [RELy. Like its murine counterpart, RELN is large, encoding an mRNA of -12 kb. Overlapping cDNA clones containing the entire open reading frame were isolated and sequenced, revealing that the predicted mouse and human proteins are similar in size (388 kD) and that the amino acid and nucleotide sequences are 94.2% and 87.2% identical, respectively. Northern hybridization analyses revealed that RELN is expressed in fetal and postnatal brain as well as liver. The expression of RELN in postnatal human brain was high in the cerebellum. RELN was mapped to human chromosome 7q22, based on both fluorescence in situ hybridization studies and localization within a well-positioned yeast artificial chromosome [YAC) contig. The YAC contig also contains a number of genetic markers. Together, these studies provide the sequence information and genetic tools for performing more detailed analyses of RELN in an attempt to define its role in human brain development and possibly in human disease.

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