Association between major dietary patterns and Parkinson's disease risk: a case-control study.

Background: There has been emerging attention to investigate the possible role of some dietary factors in the pathogenesis of Parkinson's disease (PD); however, evidence about the relationship between dietary components and the risk of PD is limited. The aim of this study was to determine the association between major dietary patterns and the risk of PD.

Methods: This case-control study was performed on 105 patients with newly diagnosed PD and 215 healthy controls.

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NO-mediated cGMP signaling.

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of praliciguat, a clinical-stage soluble guanylate cyclase stimulator in rats.

The pharmacokinetics (PK), metabolism, excretion, mass balance, and tissue distribution of [ C]praliciguat were evaluated following oral administration of a 3-mg/kg dose in Sprague-Dawley rats and in a quantitative whole-body autoradiography (QWBA) study conducted in male Long-Evans rats. Plasma T was 1 hour and the t of total plasma radioactivity was 23.7 hours.

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease.

Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5'-triphosphate to cGMP upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes and have been associated with other disease states and aging. Soluble guanylate cyclase (sGC) stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling.

Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys.

MM-433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase-1 (FAAH-1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM-433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM-433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8-11 mL/min/kg.

The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model.

The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-Delta8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects.

A mechanism for the formation of bis-glutathione conjugates of propargyl alcohol.

Our earlier research clearly revealed glutathione (GSH) conjugation as a major pathway for the metabolism of propargyl alcohol (2-propyn-1-ol) in rats and in mice. The identification of the metabolite 3,3-bis[(2-acetylamino-2-carboxyethyl)thio]-1-propanol (I) and its congeners represented the first example of multi-glutathione addition to a triple bond, and invoked further research to determine the mechanism for bis-conjugation. To determine whether GSH conjugated directly with propargyl alcohol or after oxidation of the latter to 2-propynal, urinary metabolites from rats administered deuterium-labeled propargyl alcohol were characterized.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in mouse urine by (13)C NMR and mass spectrometry and comparison to rat.

Species differences in the metabolism of acetylenic compounds commonly used in the formulation of pharmaceuticals and pesticides have not been investigated. To better understand the in vivo reactivity of this bond, the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, was examined in rats and mice. An earlier study (Banijamali, A.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in rat urine by (13)C NMR and mass spectrometry.

Little is known about the metabolism of acetylenic (C&tbd1;C) compounds commonly used in the formulation of pesticides. To better understand the in vivo reactivity of this bond, we examined the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, used extensively in the chemical industry. [1,2,3-(13)C, 2,3-(14)C]PA was administered orally to male Sprague-Dawley rats.

Solid state 2H-NMR as a method for determining the orientation of cannabinoid analogs in membranes.

In order to investigate the correlation between the pharmacological activities of cannabinoids and the geometric features of their interactions with membranes, we have calculated the molecular orientations of five analogs in model membrane bilayers. The studies involved the stereospecific 2H-labeling of each analog in different positions and the use of solid state 2H-NMR. The cannabinoids included in our study are (-)-delta 9-tetrahydrocannabinol (THC), (-)-delta 8-THC and its methylated ether analog (-)-O-methyl-delta 8-THC, as well as two hexahydrocannabinols (HHC) having an additional hydroxyl in the 11-position, (-)-11-OH-9 alpha-HHC and (-)-11-OH-9 beta-HHC.

Pharmacological evaluation of halogenated delta 8-THC analogs.

-(-)-5'-Bromo-delta 8-THC, (-)-5'-trifluoromethyl-delta 8-THC, (-)-5'-iodo-delta 8-THC, (-)-5'-fluoro-delta 8-THC, (-)-11-fluoro-delta 8-THC and (-)-2-iodo-delta 8-THC were synthesized and evaluated in male ICR mice for their effects on sedation, temperature, catalepsy and antinociception following intravenous injection. The analogs were also tested for relative affinities for cannabinoid binding sites derived from rat cortex membranes, using [3H] CP-55,940 as the tritiated ligand. The results showed that the 5'-bromo, 5'-iodo and 5'-trifluoromethyl analogs were 2-40 times more potent than (-)-delta 8-THC in all biological tests, while the 5'-fluoro and 11-fluoro derivatives were less active.

Inhibition of bovine dihydrofolate reductase and enhancement of methotrexate sensitivity by N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone.

N4-(2-Acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC) belongs to a series of molecules known to have broad antimicrobial inhibitory activity. These molecules contain the 2-acetoxyethoxy moiety which could conceivably take up a conformation analogous to that of the ribosyl group. Moreover, the thiosemicarbazone moiety, when in the presence of a suitable enzymatic site, could mimic the triazine group, which is found in a number of antifolate drugs.

The orientation of (-)-delta 9-tetrahydrocannabinol in DPPC bilayers as determined from solid-state 2H-NMR.

The orientation of the motional axis of (-)-delta 9-tetrahydrocannabinol in dipalmitoylphosphatidylcholine model membrane was calculated from the 2H quadrupolar splittings (delta nu Q) of individual deuterons strategically located on the cannabinoid tricyclic component. The molecule assumes an orientation in which its long axis is nearly perpendicular to the phospholipid chains and its most ordered axis is almost in the plane of the aromatic ring. This 'awkward' cannabinoid orientation in the membrane presumably occurs in order to allow the phenolic hydroxyl group to direct itself towards the polar bilayer interface.

Synthesis and antimicrobial activities of N4-(2-acetoxyethoxymethyl)thiosemicarbazones and N3-(2-acetoxyethoxymethyl)thioureas.

A series of thiosemicarbazones and thioureas having an open-chain analogue of the ribosyl group, the 2-acetoxyethoxymethyl moiety, has been synthesized. Significant growth inhibitory activity versus gram-positive and gram-negative organisms, a yeast, and a mold has been found with the 2-acetoxyethoxymethyl derivatives of N-alkyl-, aryl-, and heteroaryl-thiosemicarbazones and thioureas. The molecules may function as inhibitors of ribonucleotide reductase or in utilization of the carbamyl group in pyrimidine biosynthesis.

Relationship between azo dye structure and rat hepatic azoreductase activity.

The rate of reduction was determined for a variety of azo dyes using the rat hepatic azoreductase enzyme system. In decreasing order, the rates of reduction for the azo dyes expressed as nmol of arylamine product formed/min/0.25 g of liver were amaranth (33.