Binary and ternary inclusion complexes of finasteride in HP beta CD and polymers: Preparation and characterization

The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HP beta CD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed. (c) 2009 Elsevier Ltd. All rights reserved.

Obtention and Evaluation of Inclusion Complexes of Furosemide with beta-ciclodextrin and hidroxipropil-beta-ciclodextrin: Effects on Drug`s Dissolution Properties

Obtention and Evaluation of Inclusion Complexes of Furosemide with beta-ciclodextrin and hidroxipropil-beta-ciclodextrin: Effects on Drug`s Dissolution Properties. The purpose of this study was to prepare, characterize and evaluate the dissolution behavior of inclusion complexes of furosemide with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Solid complexes of furosemide with P-CD and-HP-beta-CD were prepared by using a freeze-drying method. Physical mixtures were prepared for comparison. The inclusion complexes were characterized by differential scanning calorimetry (DSC), Infrared (IR) and dissolution test. ""In vitro"" dissolutions assays were performed at pH 1,2; pH 4,5 and pH 6,8 media for a 60 min period. Statistical analysis employing ANOVA and Tukey`s Test, for the dissolution efficiency values (ED%), showed that complexation of furosemide with both cyclodextrins improved significantly ED% of the drug in all tested media, suggesting a minor pH influence on dissolution properties of the drug.

pH Influence on the stability of foams with protein-polysaccharide complexes at their interfaces

Food foams such as marshmallow, Chantilly and mousses have behavior and stability directly connected with their microstructure, bubble size distribution and interfacial properties. A high interfacial tension inherent to air/liquid foams interfaces affects its stability, and thus it has a direct impact on processing, storage and product handling. In this work, the interactions of egg albumin with various types of polysaccharides were investigated by drop tensiometry, interfacial rheology and foam stability. The progressive addition of egg albumin and polysaccharide in water induced a drop of the air-water surface tension which was dependent on the pH and polysaccharide type. At pH 4, that is below the isoeletric point of egg albumen (pI = 4.5) the surface tension was decreased from 70 mN/m to 42 mN/m by the presence of the protein, and from 70 mN/m to 43 mN/m, 40 mN/m and 38 mN/m by subsequent addition of xanthan, guar gum and kappa-carrageenan, respectively. At pH 7.5 the surface tension was decreased from 70 mN/m to 43 mN/m by the simultaneous presence of the protein and kappa-carrageenan. However, a higher surface tension of 48 and 50 mN/m was found when xanthan and guar gum were added, respectively, when compared with carrageenan addition. The main role on the stabilization of protein-polysaccharide stabilized interfaces was identified on the elasticity of the interface. Foam stability experiments confirmed that egg-albumin/kappa-carrageenan at pH below the protein isoeletric point are the most efficient systems to stabilize air/water interfaces. These results clearly indicate that protein-polysaccharide coacervation at the air/water interface is an efficient process to increase foam stability. (C) 2009 Elsevier Ltd. All rights reserved.

Direct Zincation of Functionalized Aromatics and Heterocycles by Using a Magnesium Base in the Presence of ZnCl(2)

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)(2)Mg center dot 2LiCl (TMP = 2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl(2). The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine. The zincated arenes and heteroarenes react with various electrophiles providing the expected products in 60-95 % yield.

Structural complexes of human adenine phosphoribosyltransferase reveal novel features of the APRT catalytic mechanism

Adenine phosphoribosyltransferase (APRT) is an important enzyme component of the purine recycling pathway. Parasitic protozoa of the order Kinetoplastida are unable to synthesize purines de novo and use the salvage pathway for the synthesis of purine bases rendering this biosynthetic pathway an attractive target for antiparasitic drug design. The recombinant human adenine phosphoribosyltransferase (hAPRT) structure was resolved in the presence of AMP in the active site to 1.76 angstrom resolution and with the substrates PRPP and adenine simultaneously bound to the catalytic site to 1.83 angstrom resolution. An additional structure was solved containing one subunit of the dimer in the apo-form to 2.10 angstrom resolution. Comparisons of these three hAPRT structures with other `type I` PRTases revealed several important features of this class of enzymes. Our data indicate that the flexible loop structure adopts an open conformation before and after binding of both substrates adenine and PRPR Comparative analyses presented here provide structural evidence to propose the role of Glu 104 as the residue that abstracts the proton of adenine N9 atom before its nucleophilic attack on the PRPP anomeric carbon. This work leads to new insights to the understanding of the APRT catalytic mechanism.

A new approach to the granulation of beta-cyclodextrin inclusion complexes

Cyclodextrins (CDs) are annular oligosaccharides containing 6-12 glucose unities joined together by alpha-1,4 bonds. They have a conical-truncated shape with a lipophilic cavity in which different molecules can be included resulting in a stable inclusion complex. The cyclodextrins have been widely applied in pharmaceutical technology with the objective of increasing the solubility, stability and bioavailability of drugs in different pharmaceutical dosage forms, such as tablets. In order to obtain beta-CD tablets, liquid dispersions of drug/beta-CD are usually submitted to different drying processes, like spray-drying, freeze-drying or slow evaporation, being this dry material added to a number of excipients. However, such drying processes can generate particulate materials showing problems of flow and compressibility, needing their conversion into granulates by means of wetting with granulation liquid followed by additional drying. In this work, the main objective was to evaluate the preparation of tablets without the need of this additional drying step. For this purpose an aqueous dispersion containing acetaminophen/beta-CD complex and cornstarch was dried using a spouted bed and the obtained granules were compressed in tablets. Acetaminophen was used as model drug due to its low water solubility and the inexpensive and widely available cornstarch was chosen as excipient. Acetaminophen powder was added into a beta-cyclodextrin solution prepared in distilled water at 70 degrees C. Stirring was kept until this dispersion cooled to room temperature. Then cornstarch was added and the resulting dispersion was dried in spouted bed equipment. This material was compressed into tablets using an Erweka Korsh EKO tablet machine. This innovative approach allowed the tablets preparation process to be carried out with fewer steps and represents a technological reliable strategy to produce beta-cyclodextrin inclusion complexes tablets. (C) 2010 Elsevier By. All rights reserved.

The use of electrospray ionization tandem mass spectrometry on the structural characterization of novel asymmetric metallo-organic supermolecules, based on pentafluorophenylporphyrins and ruthenium complexes

The novel asymmetric metallo-organic triads cis- and trans-[B(4-py)BPFPH(2){Ru(3)O(Ac)(6)(py)(2)}(Ru(bpy)(2)Cl}](PF(6))(2) (5a,b) for which cis- and trans-B(4-py)BPFPH(2)=5,10-bis(pentafluorophenyl)-15,20-bis(4-pyridyl)porphyrin and 5,15-bis(pentafluorophenyl)-10,20-bis(4-pyridyl)porphyrin, respectively; Ac = acetate; py = pyridine and bpy = 2,2`-bipyridine, as well as their corresponding monosubstituted dyads cis- and trans-[B(4-py)BPFPH(2){Ru(3)O(Ac)(6)(py)(2)}]PF(6) (4a,b) have been structurally characterized via electrospray ionization mass spectrometry (ESI-MS and ESI-MS/MS). The ESI-MS of dyads 4a,b display two characteristic Ru-multicomponent clusters of isotopologue ions corresponding to singly charged ions 4a,b(+) of m/z 1629 and doubly charged ions [4a,b+H](2+) of m/z 815 and the triads 5a,b are detected by ESI-MS as the intact doubly charged cluster of isotopologue ions of m/z 1039 [5a,b](2+). The ESI-MS/MS of 4a,b(+), [4a,b+H](2+) and [5a,b](2+) reveal characteristic dissociation pathways, which confirm the structural assignments providing additional information on the intrinsic binding strengths of the gaseous ions. Although the gas-phase behavior of each pair of isomers was rather similar, the less symmetric dyads 4a,b are distinguished via the (1)H NMR spectral profile of the pyrrolic signals. Exploratory photophysical assays have shown that both modifying motifs alter the porphyrinic core emission profile, opening the possibility to use these asymmetric systems as photophysical devices. (C) 2008 Elsevier Ltd. All rights reserved.

Acidity and photolability of ruthenium salen nitrosyl and aquo complexes in aqueous solutions

The photochemical behavior of nitrosyl complexes Ru(salen)(NO)(OH(2))(+) and Ru(salen)(NO) Cl (salen = N, N`-ethylenebis-(salicylideneiminato) dianion) in aqueous solution is described. Irradiation with light in the 350-450 nm range resulted in nitric oxide (NO) release from both. For Ru(salen)(NO) Cl secondary photoreactions also resulted in chloride aquation. Thus, in both cases the final photoproduct is the diaquo cation Ru(III) (salen) (OH(2))(2)(+), for which pK(a)`s of 5.9 and 9.1 were determined for the coordinated waters. The pK(a) of the Ru(salen)(NO)(OH(2))+ cation was also determined as 4.5 +/- 0.1, and the relative acidities of these ruthenium aquo units are discussed in the context of the bonding interactions between Ru(III) and NO. (C) 2007 Elsevier B.V. All rights reserved.

Efficient Phosphodiester Hydrolysis by Luminescent Terbium(III) and Europium(III) Complexes

The synthesis and structures of two new isostructural mononuclear [Ln(L)(NO(3))(H(2)O)(3)](NO(3))(2) complexes, with Ln = Tb (complex 1) and Eu (complex 2), which display high activity in the hydrolysis of the substrate 2,4-bis(dinitrophenyl)phosphate, are reported. These complexes displayed catalytic behavior similar to the mononuclear gadolinium complex [Gd(L)(NO(3))(H(2)O)(3)](NO(3))(2) previously reported by us (lnorg. Chem. 2008, 47, 2919-2921); one hydrolysis reaction in two stages where the diesterase and monoesterase activities could be monitored separately, with the first stage dependent on and the second independent of the complex concentration. Through potentiometric studies, electrospray ionization mass spectrometry (ESI-MS) analysis, and determination of the kinetic behaviors of 1 and 2 in acetonitrile/water solution, the species present in solution could be identified and suggested a dinuclear species, with one hydroxo group, as the most prominent catalyst under mild conditions. The complexes show high activity (k(1)= 7 and 18 s(-1) for 1 and 2, respectively) and catalytic efficiency. Complexes 1 and 2 were found to be active toward the cleavage of plasmid DNA, and complete kinetic studies were carried out. Studies with a radical scavenger (dimethylsulfoxide) confirmed the hydrolytic action of 1 and 2 in the cleavage of DNA. Studies on the incubation of distamycin with plasmid DNA suggested that 1 and 2 are regio-specific, interacting with the minor groove of DNA. These complexes displayed luminescent properties. Complex 1 showed higher emission intensity than 2 due to a more efficient energy transfer between triplet and emission levels of terbium (T -> (5)D(4)), along with nonradiative deactivation mechanisms of the excited states of europium via multiphonon decays and the ligand-to-metal charge transfer state. Lifetime measurements of the (5)D(4) and (5)D(0) excited levels for 1 and 2, respectively, indicated the numbers of coordinated water molecules for the complexes.

Effects of magnesium intake deficiency on bone metabolism and bone tissue around osseointegrated implants

Objectives: This study evaluated the effect of magnesium dietary deficiency on bone metabolism and bone tissue around implants with established osseointegration. Materials and methods: For this, 30 rats received an implant in the right tibial metaphysis. After 60 days for healing of the implants, the animals were divided into groups according to the diet received Control group (CTL) received a standard diet with adequate magnesium content, while test group (Mg) received the same diet except for a 90% reduction of magnesium. The animals were sacrificed after 90 days for evaluation of calcium, magnesium, osteocalcin and parathyroid hormone (PTH) serum levels and the deoxypyridinoline (DPD) level in the urine. The effect of magnesium deficiency on skeletal bone tissue was evaluated by densitometry of the lumbar vertebrae, while the effect of bone tissue around titanium implants was evaluated by radiographic measurement of cortical bone thickness and bone density. The effect on biomechanical characteristics was verified by implant removal torque testing. Results: Magnesium dietary deficiency resulted in a decrease of the magnesium serum level and an increase of PTH and DPD levels (P <= 0.05). The Mg group also presented a loss of systemic bone mass decreased cortical bone thickness and lower values of removal torque of the implants (P <= 0.01). Conclusions: The present study concluded that magnesium-deficient diet had a negative influence on bone metabolism as well as on the bone tissue around the implants.

Effect of Severe Dietary Magnesium Deficiency on Systemic Bone Density and Removal Torque of Osseointegrated Implants

Purpose This study evaluated the effect of severe magnesium (Mg) dietary deficiency on systemic bone density and biomechanical resistance of bone tissue to the removal torque of osseointegrated implants Materials and Methods The sample consisted of 45 rats, each received a titanium implant in their tibial metaphysis After 60 days, the animals were divided into three groups (n = 15) according to their dietary Mg the control group received the recommended content of Mg, group Mg1 received a 75% reduction in dietary Mg content, and group Mg2 was fed a diet with a 90% reduction in Mg con tent Animals were sacrificed 150 days after implant placement Serum concentrations of Mg were measured and the effect of Mg deficiency on systemic bone density was evaluated by densitometry of the lumbar vertebrae and femur Biomechanical characteristics were measured by resistance of the bone tissue to removal of the implants Results Lower Mg serum concentrations were found for the Mg1 and Mg2 groups, however, densitometric analysis and torque evaluations showed a statistically significant difference only in the Mg2 group (P < 05) There was a statistically significant difference in removal torque between the Mg2 group and the control group Conclusions This study showed that a severe deficiency of Mg decreased the systemic bone density and removal torque of osseointegrated implants INT J ORAL MAXILLOFAC IMPLANTS 2010 25 1125-1130

Cationic technetium and rhenium complexes with pendant carbohydrates

Three carbohydrate conjugated dipicolylamine chelators, 2-bis(2-pyridinylmethyl)amino)ethyl 1-deoxy-1-thio-beta-D-glucopyranoside (L(1)), 2-bis(2-pyridinylmethyl)amino)ethyl-beta-D-glucopyranoside (L(2)), and 2-bis(2-pyridinylmethyl)amino)carboxamide-N-(2-amino-2-deoxy-D-glucopyranose) (L(3)) were complexed to the [M(Co)(3)](+) core (M=Tc, Re) and the properties of the resulting complexes were investigated. Synthesis and characterization of the chelator 2-bis(2-pyridinylmethyl)amino)ethyl 1-deoxy-1-thio-beta-D-glucopyranoside (L(1)) and the corresponding Re complex are reported. All chelators were radiolabeled in high yield with [(99)mTc(CO)(3)(H(2)O)(3)](+) ( > 98%) and [(186)Re(CO)(3)(H(2)O)(3)](+) ( > 80%). The chelators and Re-complexes were determined to not be substrates for the glucose metabolism enzyme hexokinase. However, the biodistribution of each of the (99m)Tc complexes demonstrated fast clearance from most background tissue, including >75% clearance of the activity in the kidneys and the liver within 2 h post-injection. (C) 2010 Elsevier Ltd. All rights reserved.

Effects of acute magnesium loading on pulmonary function of stable COPD patients

Background: Magnesium (Mg) use has the potential to promote bronchodilatation and to improve lung function in obstructive diseases. IV administration of Mg during exacerbations of chronic obstructive pulmonary disease (COPD) has led to improved peak flow. This study aimed to investigate the effects of acute IV Mg loading on respiratory parameters of stable COPD patients. Material/Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-two male COPD patients (64 +/- 6 years old, FEV1: 49 +/- 20%) received an IV infusion of 2 g of magnesium sulfate or placebo on two distinct occasions. Spirometry and mouth maximal respiratory pressures were obtained before and 45 minutes after the infusions. Results: Mg use led to significant changes in functional respiratory capacity (-0.48 1,95% CI: -0.96, -0.01), inspiratory capacity (0.21 1,95% CI: 0.04, 0.37). The treatment was also associated with a marginally significant decrease in residual volume (-0.47 1,95% CI: -0.96, 0.02, p=0.06). Conclusions: Acute IV Mg loading in stable COPD patients was associated with a reduction in lung hyperinflation and improvement of respiratory muscle strength. The clinical potential for chronic magnesium supplementation in COPD deserves further investigation.

Vascular biology of magnesium and its transporters in hypertension

Magnesium may influence blood pressure by modulating vascular tone and structure through its effects on myriad biochemical reactions that control vascular contraction/dilation, growth/apoptosis, differentiation and inflammation. Magnesium acts as a calcium channel antagonist, it stimulates production of vasodilator prostacyclins and nitric oxide and it alters vascular responses to vasoconstrictor agents. Mammalian cells regulate Mg(2+) concentration through special transport systems that have only recently been characterized. Magnesium efflux occurs via Na(2+)-dependent and Na(2+)-independent pathways. Mg(2+) influx is controlled by recently cloned transporters including Mrs2p, SLC41A1, SLC41A2, ACDP2, MagT1, TRPM6 and TRPM7. Alterations in some of these systems may contribute to hypomagnesemia and intracellular Mg(2+) deficiency in hypertension and other cardiovascular pathologies. In particular, increased Mg(2+) efflux through dysregulation of the vascular Na(+)/Mg(2+) exchanger and decreased Mg(2+) influx due to defective vascular and renal TRPM6/7 expression/activity may be important in altered vasomotor tone and consequently in blood pressure regulation. The present review discusses the role of Mg(2+) in vascular biology and implications in hypertension and focuses on the putative transport systems that control magnesium homeostasis in the vascular system. Much research is still needed to clarify the exact mechanisms of cardiovascular Mg(2+) regulation and the implications of aberrant cellular Mg(2+) transport and altered cation status in the pathogenesis of hypertension and other cardiovascular diseases.

Antileishmanial activity of ruthenium(II)tetraammine nitrosyl complexes

The complexes trans-[Ru(NO)(NH(3))(4)L](X)(3) (X = BF(4)(-), PF(6)(-) or Cl(-) and L = N-heterocyclic ligands, P (OEt)(3), SO(3)(-2)), and [Ru(NO)Hedta)] were shown to exhibit IC(50pro) in the range of 36 (L = imN) to 5000 mu M (L = imC). The inhibitory effects of trans-[Ru(NO)(NH(3))(4)imN](BF(4))(3) and of the Angeli`s salt on the growth of the intramacrophage amastigote form studied were found to be similar while the trans-[Ru(NH(3))(4)imN(H(2)O)](2+) complex was found not to exhibit any substantial antiamastigote effect. The trans-[Ru(NO)(NH(3))(4)imN](BF(4))(3) compound, administered (500 nmol kg(-1) day(-1)) in BALB/c mice infected with Leishmania major, was found to exhibit a 98% inhibition on the parasite growth. Furthermore, this complex proved to be at least 66 times more efficient than glucantime in in vivo experiments. (C) 2010 Elsevier Masson SAS. All rights reserved.