Drugs online research references
J Pharm Sci. 1998 Jan;87(1):31-9.
Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.
Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenbeck DK, Gregg SM.
Lilly Research Laboratories, Eli Lilly and Company, Lafayette, Indiana 47905, USA.
Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose-fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4 H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9452965&dopt=Abstract
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Horm Behav. 1997 Dec;32(3):184-91.
Effects of the selective serotonin reuptake inhibitor fluoxetine on social behaviors in male and female prairie voles (Microtus ochrogaster).
Villalba C, Boyle PA, Caliguri EJ, De Vries GJ.
Department of Psychology, University of Massachusetts, Amherst 01003-7710, USA.
The selective serotonin reuptake inhibitor fluoxetine modifies social behavior in a number of species, including humans. Because the neural substrates for social behavior in prairie voles are sexually dimorphic, we tested whether the effects of fluoxetine on these behaviors differ by sex. Parental and pair-bonded voles were chronically treated with fluoxetine or saline and subsequently tested for parental responsiveness. Fluoxetine-treated animals displayed a longer latency to exhibit parental responsiveness than did saline-treated controls (p < 0.02), but they did not differ in other aspects of parental care. There were no sex differences in the effects of fluoxetine on parental behavior. After completion of the tests for parental behavior, the subjects were tested for aggressive behavior using the resident-intruder paradigm. Fluoxetine-treated males displayed less aggressive behavior than their saline-treated counterparts (p < 0.02). Although we did not find any effects of fluoxetine on aggressive behavior in females, no significant interaction was found between sex and treatment. Fluoxetine did not alter nonsocial behaviors. The findings suggest that serotonin influences social behavior in prairie voles.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9454669&dopt=Abstract
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J Pharmacol Exp Ther. 1998 Feb;284(2):736-43.
Norepinephrine transporters in rat placenta labeled with [3H]nisoxetine.
Shearman LP, Meyer JS.
Department of Psychology, Neuroscience and Behavior Program, University of Massachusetts, Amherst, Massachusetts 01003-7710, USA.
Previous research has identified a norepinephrine (NE) transporter in brush-border membranes from human placental syncytiotrophoblastic cells. In the present study, we used the selective ligand [3H]nisoxetine to demonstrate the presence of an NE transporter in rat placental membranes, determine the binding characteristics of the transporter and ascertain its localization by means of in vitro film and dry-emulsion autoradiography. Additional membrane binding studies were performed with [3H]GBR 12935 to determine whether a dopamine transporter also was present in rat placenta. Saturation analyses carried out on washed membrane fractions from whole rat placentas at gestational day 20 showed saturable [3H]nisoxetine binding (mean Kd = 1.00 nM, Bmax = 1.24 pmol/mg of protein) but no saturable binding of [3H]GBR 12935. When various monoamine uptake inhibitors were tested for their potency to inhibit placental [3H]nisoxetine binding, the results supported the conclusion that the radioligand was labeling an NE transporter. Autoradiographic studies showed the presence of [3H]nisoxetine binding in all three cellular zones of the rat placenta: the decidua, junctional zone and labyrinth. Binding was greatest in the junctional zone, particularly in the giant trophoblastic cells. These findings indicate the presence of a high density of NE transporters in the late-gestation rat placenta. Catecholamine uptake probably has a multifunctional role in placental physiology, and blockade of the NE transporter by certain drugs such as cocaine may therefore contribute to the adverse effects of such compounds on pregnancy outcome and offspring development.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9454822&dopt=Abstract
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