It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand 11C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.
Sulindac is an analgesic and anti-inflammatory agent. It has the general side-effects of non-steroidal anti-inflammatory drugs, owing to presence of a free carboxylic acid group. The aim of the study was to retard the adverse gastrointestinal effects of the drug. Various conjugates of sulindac were synthesized by amidation with methyl esters of 10 amino acids. The synthesized conjugates were characterized by melting-point, thin-layer chromatography and Fourier transform infrared, nuclear magnetic resonance and mass spectroscopy. The synthesized conjugates were evaluated pharmacologically for analgesic, anti-inflammatory and ulcerogenic activity. Amide conjugation had a synergistic potentiating effect, with less disruption of mucosal surfaces. This conjugate approach can therefore be used successfully to minimize gastrointestinal toxicity with no loss of the desired anti-inflammatory and analgesic activities of the drug. Methyl 2-(2-((7Z)-1-(4-(methylsulfinyl)benzlidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamido)-3-phenylpropanoate and methyl 2-(2((6Z)-1-(4-(methylsulfinyl)benzlidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamido)-3-methylbutanoate showed excellent pharmacological responses and encouraging hydrolysis rates in simulated gastric fluid, simulated intestinal fluid and 80% human plasma. Conjugates with longer aliphatic side chains or aromatic substituents had higher partition coefficients but lower dissolution and hydrolysis rates. These conjugates could be considered for sustained release preparations.
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