The effects of entacapone on cardiorespiratory, autonomic, and clinical responses in L-dopa-treated patients with Parkinson's disease

Rest tremor, rigidity, and slowness of movements-considered to be mainly due to markedly reduced levels of dopamine (DA) in the basal ganglia-are characteristic motor symptoms of Parkinson's disease (PD). Although there is yet no cure for this illness, several drugs can alleviate the motor symptoms. Among these symptomatic therapies, L-dopa is the most effective. As a precursor to DA, it is able to replace the loss of DA in the basal ganglia. In the long run L-dopa has, however, disadvantages. Motor response complications, such as shortening of the duration of drug effect ("wearing-off"), develop in many patients. In addition, extensive peripheral metabolism of L-dopa by aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT) results in its short half-life, low bioavailability, and reduced efficacy. Entacapone, a nitrocatechol-structured compound, is a highly selective, reversible, and orally active inhibitor of COMT. It increases the bioavailability of L-dopa by reducing its peripheral elimination rate. Entacapone extends the duration of clinical response to each L-dopa dose in PD patients with wearing-off fluctuations. COMT is important in the metabolism of catecholamines. Its inhibition could, therefore, theoretically lead to adverse cardiovascular reactions, especially in circumstances of enhanced sympathetic activity (physical exercise). PD patients may be particularly vulnerable to such effects due to high prevalence of cardiovascular autonomic dysfunction, and the common use of monoamine oxidase B inhibitor selegiline, another drug with effects on catecholamine metabolism. Both entacapone and selegiline enhance L-dopa's clinical effect. Their co-administration may therefore lead to pharmacodynamic interactions, either beneficial (improved L-dopa efficacy) or harmful (increased dyskinesia). We investigated the effects of repeated dosing (3-5 daily doses for 1-2 weeks) of entacapone 200 mg administered either with or without selegiline (10 mg once daily), on several safety and efficacy parameters in 39 L-dopa-treated patients with mild to moderate PD in three double-blind placebo-controlled, crossover studies. In the first two, the cardiovascular, clinical, and biochemical responses were assessed repeatedly for 6 hours after drug intake, first with L-dopa only (control), and then after a 2 weeks on study drugs (entacapone vs. entacapone plus selegiline in one; entacapone vs. selegiline vs. entacapone plus selegiline in the other). The third study included cardiovascular reflex and spiroergometric exercise testing, first after overnight L-dopa withdrawal (control), and then after 1 week on entacapone plus selegiline as adjuncts to L-dopa. Ambulatory ECG was recorded in two of the studies. Blood pressure, heart rate, ECG, cardiovascular autonomic function, cardiorespiratory exercise responses, and the resting/exercise levels of circulating catecholamines remained unaffected by entacapone, irrespective of selegiline. Entacapone significantly enhanced both L-dopa bioavailability and its clinical response, the latter being more pronounced with the co-administration of selegiline. Dyskinesias were also increased during simultaneous use of both entacapone and selegiline as L-dopa adjuncts. Entacapone had no effect on either work capacity or work efficiency. The drug was well tolerated, both with and without selegiline. Conclusions: the use of entacapone-either alone or combined with selegiline-seems to be hemodynamically safe in L-dopa-treated PD patients, also during maximal physical effort. This is in line with the safety experience from larger phase III studies. Entacapone had no effect on cardiovascular autonomic function. Concomitant administration of entacapone and selegiline may enhance L-dopa's clinical efficacy but may also lead to increased dyskinesia.

Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC50; 0.62 μM) and E. coli (IC50; 0.26 μM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.

Prospecting for alternate sources of shikimic acid, a precursor of Tamiflu, a bird-flu drug

Shikimic acid, more commonly known by its anionic form, shikimate, is an important intermediate compound of the ‘shikimate pathway’ in plants and microorganisms1. It is the principal precursor for the synthesis of aromatic amino acids, phenylalanine, tryptophan and tyrosine and other compounds such as alkaloids, phenolics and phenyl propanoids2. It is used extensively as a chiral building block for the synthesis of a number of compounds in both pharmaceutical and cosmetic industries3. In the recent past, the focus on shikimic acid has increased since it is the key precursor for the synthesis of Tamiflu, the only drug against avian flu caused by the H5N1 virus4,5. Shikimic acid is converted to a diethyl ketal intermediate, which is then reduced in two steps to an epoxide that is finally transformed to Tamiflu6.

Structural Insights into the acyl-intermediates of plasmodium falciparum fatty acid synthesis pathway; the mechanism of expansion of acyl carrier protein core

Acyl carrier protein (ACP) plays a central role in fatty acid biosynthesis. However, the molecular machinery that mediates its function is not yet fully understood. Therefore, structural studies were carried out on the acyl-ACP intermediates of Plasmodium falciparum using NMR as a spectroscopic probe. Chemical shift perturbation studies put forth a new picture of the interaction of ACP molecule with the acyl chain, namely, the hydrophobic core can protect up to 12 carbon units, and additional carbons protrude out from the top of the hydrophobic cavity. The latter hypothesis stems from chemical shift changes observed in C-alpha and C-beta of Ser-37 in tetradecanoyl-ACP. C-13, N-15-Double-filtered nuclear Overhauser effect (NOE) spectroscopy experiments further substantiate the concept; in octanoyl (C-8)- and dodecanoyl (C-12)-ACP, a long range NOE is observed within the phosphopantetheine arm, suggesting an arch-like conformation. This NOE is nearly invisible in tetradecanoyl (C-14)-ACP, indicating a change in conformation of the prosthetic group. Furthermore, the present study provides insights into the molecular mechanism of ACP expansion, as revealed from a unique side chain-to-backbone hydrogen bond between two fairly conserved residues, Ile-55 HN and Glu-48 O. The backbone amide of Ile-55 HN reports a pK(a) value for the carboxylate, similar to 1.9 pH units higher than model compound value, suggesting strong electrostatic repulsion between helix II and helix III. Charge-charge repulsion between the helices in combination with thrust from inside due to acyl chain would energetically favor the separation of the two helices. Helix III has fewer structural restraints and, hence, undergoes major conformational change without altering the overall-fold of P. falciparum ACP.

Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

Antithyroid Drugs and their Analogues Protect Against Peroxynitrite-Mediated Protein Tyrosine Nitration-A Mechanistic Study

In this paper, the effect of some commonly used antithyroid drugs and their analogues on peroxynitrite-mediated nitration of proteins is described. The nitration of tyrosine residues in bovine serum albumin (BSA) and cytochromec was studied by Western blot analysis. These studies reveal that the antithyroid drugs methimazole (MMI), 6-n-propyl-2-thiouracil (PTU), and 6-methyl-2-thiouracil (MTU), which contain thione moieties, significantly reduce the tyrosine nitration of both BSA and cytochrome c. While MMI exhibits good peroxynitrite (PN) scavenging activity, the thiouracil compounds PTU and MTU are slightly less effective than MMI. The S- and Se-methylated compounds show a weak inhibitory effect in the nitration of tyrosine, indicating that the presence of a thione or selone moiety is important for an efficient inhibition. Similarly, the replacement of N-H moiety in MMI by N-methyl or N-m-methoxybenzyl substituents dramatically reduces the antioxidant activity of the parent compound. Theoretical studies indicate that the substitution of N-H moiety by N-Me significantly increases the energy required for the oxidation of sulfur center by PN. However, such substitution in the selenium analogue of MMI increases the activity of parent compound. This is due to the facile oxidation of the selone moiety to the corresponding selenenic and seleninic acids. Unlike N,N'-disubstituted thiones, the corresponding selones efficiently scavenge PN, as they predominantly exist in their zwitterionic forms in which the selenium atom carries a large negative charge.

Reactive Pulsed Laser Deposition of titanium nitride thin film: Optimization of process parameters using Secondary Ion Mass Spectrometry

Reactive Pulsed Laser Deposition is a single step process wherein the ablated elemental metal reacts with a low pressure ambient gas to form a compound. We report here a Secondary Ion Mass Spectrometry based analytical methodology to conduct minimum number of experiments to arrive at optimal process parameters to obtain high quality TiN thin film. Quality of these films was confirmed by electron microscopic analysis. This methodology can be extended for optimization of other process parameters and materials. (C) 2009 Elsevier B.V. All rights reserved.

3-Benzyl-6-benzylamino-1-methyl-5-nitro-1,2,3,4-tetrahydropyrimidine

In the title compound, C19H22N4O2, the tetrahydropyrimidine ring adopts an envelope conformation (with the N atom connected to the benzyl group representing the flap). This benzyl group occupies a quasi-axial position. The two benzyl groups lie over the tetrahydropyridimidine ring. The amino group is a hydrogen-bond donor to the nitro group.

Manifestation of geometric frustration on magnetic and thermodynamic properties of the pyrochlores Sm2X2O7 (X=Ti,Zr)

We present here magnetization, specific heat, and Raman studies on single-crystalline specimens of the first pyrochlore member Sm2Ti2O7 of the rare-earth titanate series. Its analogous compound Sm2Zr2O7 in the rare-earth zirconate series is also investigated in the polycrystalline form. The Sm spins in Sm2Ti2O7 remain unordered down to at least T=0.5 K. The absence of magnetic ordering is attributed to very small values of exchange (θcw∼−0.26 K) and dipolar interaction (μeff∼0.15 μB) between the Sm3+ spins in this pyrochlore. In contrast, the pyrochlore Sm2Zr2O7 is characterized by a relatively large value of Sm-Sm spin exchange (θcw∼−10 K); however, long-range ordering of the Sm3+ spins is not established at least down to T=0.67 K due to frustration of the Sm3+ spins on the pyrochlore lattice. The ground state of Sm3+ ions in both pyrochlores is a well-isolated Kramers doublet. The higher-lying crystal field excitations are observed in the low-frequency region of the Raman spectra of the two compounds recorded at T=10 K. At higher temperatures, the magnetic susceptibility of Sm2Ti2O7 shows a broad maximum at T=140 K, while that of Sm2Zr2O7 changes monotonically. Whereas Sm2Ti2O7 is a promising candidate for investigating spin fluctuations on a frustrated lattice, as indicated by our data, the properties of Sm2Zr2O7 seem to conform to a conventional scenario where geometrical frustration of the spin excludes their long-range ordering.

Conditional Probability-Based Significance Tests for Sequential Patterns in Multineuronal Spike Trains

We consider the problem of detecting statistically significant sequential patterns in multineuronal spike trains. These patterns are characterized by ordered sequences of spikes from different neurons with specific delays between spikes. We have previously proposed a data-mining scheme to efficiently discover such patterns, which occur often enough in the data. Here we propose a method to determine the statistical significance of such repeating patterns. The novelty of our approach is that we use a compound null hypothesis that not only includes models of independent neurons but also models where neurons have weak dependencies. The strength of interaction among the neurons is represented in terms of certain pair-wise conditional probabilities. We specify our null hypothesis by putting an upper bound on all such conditional probabilities. We construct a probabilistic model that captures the counting process and use this to derive a test of significance for rejecting such a compound null hypothesis. The structure of our null hypothesis also allows us to rank-order different significant patterns. We illustrate the effectiveness of our approach using spike trains generated with a simulator.

Supramolecular Organization in Tetra Aqua (mu-8-Hydroxyquinoline-5-sulfonate) Barium (II) and Ag center dot center dot center dot I Interactions in a Pseudopolymorphic Form of (7-Iodo-8-hydroxyquinoline-5-sulfonate) Silver (I) Monohydrate

The complexes, Ba (HQS) (H2O)(4) (HQS = 8-hydroxyquinoline-5-sulfonic acid) (1) and Ag (HIQS) (H2O) (Ferron = 7-iodo-8-hydroxyquinoline-5-sulfonic acid) (2) have been synthesized and characterized by X-ray diffraction analysis and spectroscopic studies. In compound 1, Ba2+ ion has a nine-coordinate monocapped antiprismatic geometry. In compound 2, Ag+ has distorted tetrahedral coordination and Ag center dot center dot center dot I interactions generate the supramolecular architectures. The complexes have been characterized by FT-IR and UV-Visible measurements. In both the structures, the inversion-related organic ligands are stacked over one another leading to three-dimensional networks.

Two- and Three-Dimensional Open-Framework Uranium Arsenates: Synthesis, Structure, and Characterization

Hydrothermal reactions between uranium salts and arsenic pentoxide in the presence of two different amines yielded six new uranium arsenate phases exhibiting open-framework structures, ethylenediamine (en): [C2N2H9]-[(UO2)(ASO(4))] I; [C2N2H10][(UO2)F(HASO(4))]2 center dot 4H(2)O, II; [C2N2H9][U2F5(HASO(4))(2)], III; [C2N2H9][UF2(ASO(4))], IV; diethylenetriamine (DETA), [C4N3H16][U2F3(ASO(4))(2)(HAsO4)] V; and [C4N3H16][U2F6(AsO4)(HAsO4)], VI. The structures were determined using single crystal studies, which revealed two- (I, II, V) and three-dimensional (III, IV, VI) structures for the uranium arsenates. The uranium atom, in these compounds, exhibits considerable variations in the coordination (6 to 9) that appears to have some correlation with the synthetic conditions. The water molecules in [C2N2H10][(UO2)F(HAsO4)](2 center dot)4H(2)O, II, could be reversibly removed, and the dehydrated phase, [C2N2H10][(UO2)F(HAsO4)](2), IIa, was also characterized using single crystal studies. The observation of many mineralogical structures in the present compounds suggests that the hydrothermal method could successfully replicate the geothermal conditions. As part of this study, we have observed autunite, Ca[(UO2)(PO4)](2)(H2O)(11), metavauxite, [Fe(H2O)(6)][Al(OH)(H2O)(PO4)](2), finarite, PbCU(SO4)(OH)(2), and tancoite, LiNa2H[Al(PO4)(2)(OH)], structures. The repeated observation of the secondary building unit, SBU-4, in many of the uranium arsenate structures suggests that these are viable building units. Optical studies on the uranium arsenate compound, [C4N3H16][U2F6(AsO4)(HASO(4))), VI, containing uranium in the +4 oxidation state indicates a blue emission through an upconversion process. The compound also exhibits antiferromagnetic behavior.

Stabilization of an All-Metal Antiaromatic Molecule (Al4Li4) Using BH and C as Caps

It has been reported by Pati et al. (J. Am. Chem. Soc. 2005, 127, 3496) that coordination with a transition metal can stabilize the “antiaromatic”, all-metal compound Al4Li4. Here, we report that it can also be stabilized by capping with a main group element like C and its isoelectronic species BH. Our calculations of binding energy, nuclear independent chemical shift, energy decomposition analysis, and molecular orbital analysis support the capping-induced stability, reduction of bond length alternation, and increase of aromaticity of these BH/C-capped Al4Li4 systems. The interaction between px and py orbitals of BH/C and the HOMO and LUMO of Al4Li4 is responsible for the stabilization. Our calculations suggest that capping can introduce fluxionality at room temperature.

Scanning Tunneling Spectroscopy on Pr0.68Pb0.32MnO3 single crystals

Scanning tunneling microscopy/spectroscopy studies were carried out on single crystals of colossal magnetoresistive manganite Pr0.68Pb0.32MnO3 at different temperatures in order to probe their spatial homogeneity across the metal-insulator transition temperature TM-I(similar to 255 K). A metallic behavior of the local conductance was observed for temperatures T < TM-I. Zero bias conductance (dI/dV)v=(0), which is directly proportional to the local surface density of states at the Fermi level, shows a single distribution at temperatures T < 200 K suggesting a homogeneous electronic phase at low temperatures. In a narrow temperature window of 200 K < T < TM-I, however, an inhomogeneous distribution of (dI/dV)v=(0) has been observed. This result gives evidence for phase separation in the transition region in this compound.

Scanning Tunneling Spectroscopy on Pr0.68Pb0.32MnO3 single crystals

Scanning tunneling microscopy/spectroscopy studies were carried out on single crystals of colossal magnetoresistive manganite Pr0.68Pb0.32MnO3 at different temperatures in order to probe their spatial homogeneity across the metal-insulator transition temperature TM-I(similar to 255 K). A metallic behavior of the local conductance was observed for temperatures T < TM-I. Zero bias conductance (dI/dV)v=(0), which is directly proportional to the local surface density of states at the Fermi level, shows a single distribution at temperatures T < 200 K suggesting a homogeneous electronic phase at low temperatures. In a narrow temperature window of 200 K < T < TM-I, however, an inhomogeneous distribution of (dI/dV)v=(0) has been observed. This result gives evidence for phase separation in the transition region in this compound.