Stability Studies of Gabapentin in Aqueous Solutions

Gabapentin is a -aminobutyric acid analogue, which has been shown to be an effective antiepileptic. The solution stability of gabapentin in buffered systems was studied in order to facilitate the formulation of a liquid product. The degradation of the drug was followed as a function of pH, buffer concentration, ionic strength, and temperature. The results indicated that the rate of degradation was proportional to the buffer concentration and temperature. The pH–rate profile of gabapentin degradation showed that the rate of degradation was minimum at an approximate pH of 6.0. Further, the data suggested a slower solvent-catalyzed degradation rate for the zwitterionic species compared to the cationic or anionic species in the pH range of 4.5 to 7.0. There was no influence of ionic strength on the rate of degradation. Arrhenius plots of the data indicated that a shelf life of 2 years or more at room temperature may be obtained in an aqueous solution at a pH value of 6.0.     

Direct interaction of serotonin type 3 receptor ligands with recombinant and native alpha 9 alpha 10-containing nicotinic cholinergic receptors

In the present work, we characterized the effects of serotonin type 3 receptor ligands on recombinant and native alpha 9 alpha 10-containing nicotinic acetylcholine receptors (nAChRs). Our results indicate that the recombinant alpha 9 alpha 10 nAChR shares striking pharmacological properties with 5-HT(3) ligand-gated ion channels. Thus, 5-HT(3) receptor antagonists block ACh-evoked currents in alpha 9 alpha 10-injected Xenopus laevis oocytes with a rank order of potency of tropisetron (IC(50), 70.1 +/- 0.9 nM) > ondansetron (IC(50), 0.6 +/- 0.1 microM) = MDL 72222 (IC(50), 0.7 +/- 0.1 microM). Although serotonin does not elicit responses in alpha 9 alpha 10-injected oocytes, it blocks recombinant alpha 9 alpha 10 receptors in a noncompetitive and voltage-dependent manner (IC(50), 5.4 +/- 0.6 microM). On the other hand, we demonstrate an in vivo correlate of these properties of the recombinant receptor, with those of the alpha 9 alpha 10-containing nAChR of frog saccular hair cells. The possibility that the biogenic amine serotonin might act as a neuromodulator of the cholinergic efferent transmission in the vestibular apparatus and in the organ of Corti is discussed.     

The development and stability assessment of extemporaneous pediatric formulations of Accupril

Quinapril, the active ingredient in Accupril tablets, is an ACE inhibitor used to treat hypertension. Quinapril is unstable in aqueous solution and therefore the development of a liquid formulation is a significant challenge. Previous studies show the rate of degradation of quinapril into its two major degradants to be pH dependent, indicating the parent compound to be most stable in the narrow pH range of 5.5-6.5. Accupril (20 mg) and readily available pharmaceutical components were combined to generate three formulations that are stable for at least 28 days, possess acceptable appearance, and are palatable to pediatric patients. To combat the presence of magnesium carbonate in the Accupril tablets, which increase the pH of the solution above 6.5, several pharmaceutically available buffers were incorporated. Nine prototypes were developed and their characteristics evaluated after 1 week under stressed conditions. The three that most closely matched the stability criteria were chosen for a definitive stability study. A stability-indicating method was developed and validated for these studies. All three formulations met the following specifications when stored at 5 degrees C for 6 weeks; Quinapril remained >or=90% intact and the two known degradants did not reach values >or=3.0% individually or >or=5.0% combined.     

Complementary function and integrated wiring of the evolutionarily distinct Drosophila olfactory subsystems

To sense myriad environmental odors, animals have evolved multiple, large families of divergent olfactory receptors. How and why distinct receptor repertoires and their associated circuits are functionally and anatomically integrated is essentially unknown. We have addressed these questions through comprehensive comparative analysis of the Drosophila olfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs). We identify ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols. IR and OR sensory neurons exhibit glomerular convergence in segregated, although interconnected, zones of the primary olfactory center, but these circuits are extensively interdigitated in higher brain regions. Consistently, behavioral responses to odors arise from an interplay between IR- and OR-dependent pathways. We integrate knowledge on the different phylogenetic and developmental properties of these receptors and circuits to propose models for the functional contributions and evolution of these distinct olfactory subsystems.