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The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-β-cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (260 nm), drug loading (17.8 and 16.9 μg/mg, respectively) and yield (75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrins-poly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.

Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

Hybrid abinitio calculations (GIAO/B3LYP/6-31G*) together with new DNMR experiments (1H and 13C) have been used to clarify the problem of the conformation of 5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene. The carbon-13 chemical shifts have been assigned unambiguously to the chair C and twist-boat TB conformations. Lineshape analysis of the 1H NMR spectra has been carried out at several temperatures using an estimated set of Karplus-type vicinal coupling constants.

A reduction of the tetracyclic skeleton of sordarins and sordaricins to a cyclopentane ring bearing the pharmacophore functional groups led to new derivatives retaining part of their in vitro and whole-cell activity.

En: Bioorganic and Medicinal Chemistry Letters. ISSN 0960-894x. n. 9, 1999, págs 103-108 A reduction of the tetracyclic skeleton of sordarins and sordaricins to a cyclopentane ring bearing the pharmacophore functional groups led to new derivatives retaining part of their in vitro and whole-cell activity.

Hybrid ab initio calculations (GIAO/B3LYP/6-31G*) together with new DNMR experiments (1H and 13C) have been used to clarify the problem of the conformation of 5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene. The carbon-13 chemical shifts have been assigned unambiguously to the chair C and twist-boat TB conformations. Lineshape analysis of the 1H NMR spectra has been carried out at several temperatures using an estimated set of Karplus-type vicinal coupling constants., Financial support from the Spanish DGICYT (Project No. PB96-0001-C03) is gratefully acknowledged.

BackgroundBone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.MethodsSeveral proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice,Igf+/+, n = 10), heterozygousIgf+/-group with partial IGF-I deficiency (Hz, n = 10), and heterozygousIgf+/-mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10).ResultsData in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity.ConclusionsLow doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

A series of eighteen substituted pyrazoles, bis- and tris-azolyl-methanes or ethanes was investigated for their interaction with the zinc enzyme carbonic anhydrase (CA). Several types of activities were detected, generally as CA activators, but CA inhibitory properties were also discovered for the very sterically-demanding derivatives of these series. Kinetic determinations by a stopped-flow technique for carbon dioxide hydration reaction allowed the determination of Michaelis-Menten constants, which are identical in the absence or in the presence of these modulators, proving a noncompetitive mechanism of activation-inhibition. MNDO calculations were used with moderate success to explain the biological results.

A correlation was found between the carbonic anhydrase II activating power and the pKa values for a series of azoles, bisazolylmethanes and bisazolylethanes. Strong activations were found for compounds with pKa's in the interval 6.5-8.0. The mechanism of action for such activators is discussed.

Gantrez AN nanoparticles can be obtained by desolvation of the poly(anhydride) with an aqueous medium, followed by a purification step and freeze-drying. In order to simplify this method, a spray-drying procedure was evaluated here. For this purpose, suspensions of nanoparticles were mixed with carbohydrates before their drying. Lactose, in a saccharide/polymer ratio of 2, was found to be the most suitable excipient regarding the physicochemical characteristics and stability of the resulting nanoparticles. These conditions can be successfully applied to the preparation of conventional, combined cyclodextrin/polyanhydride or pegylated nanoparticles. The capabilities of the new procedure were also studied by the characterization of nanoparticles loaded with either an antigenic extract (HS from Brucella ovis) or atovaquone. In all cases, the new formulations displayed similar physico-chemical characteristics to those of nanoparticles obtained by lyophilization. In summary, the spray-drying procedure can be an adequate alternative to lyophilization in the preparative process of poly(anhydride) nanoparticles.