Tracking the cognitive pharmacodynamics of psychoactive substances with combinations of behavioral and neurophysiological measures.
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Many common pharmacological treatments have effects on cognitive ability. Psychometric task batteries used to characterize such effects do not provide direct information about treatment-related changes in brain function. Since overt task performance reflects motivation and effort as well as ability, behavioral measures alone may overestimate or underestimate the impact of a pharmacological intervention on brain function. Here we present a method that combines behavioral and neurophysiological measures in an attempt to detect the psychoactive effects of pharmacological treatments with greater sensitivity than that provided by behavioral measures alone. Initial application of the method is made to the data from a double blind, placebo-controlled, crossover study in which caffeine, diphenhydramine, and alcohol were used to alter the mental state of 16 healthy subjects at rest and while they performed low load and high load versions of a working memory task. For each intervention, more sensitive detection of drug or alcohol effects over a four hour period was obtained when EEG variables were included in multivariate analyses than when only behavioral variables were used. These initial results suggest that it can be useful to incorporate neurophysiological measures of brain activity into inferences concerning the acute impact of drugs on mental function, and demonstrate the feasibility of using multivariate combinations of behavioral and neurophysiological measures to sensitively characterize the pharmacodynamics of drug-induced changes in cognition. (+info)
Standard treatment: the role of antihistamines.
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Histamine-1 (H1) antihistamines are the first-line drug for the treatment of urticaria. Major progress has been achieved in recent years both in the understanding of their ligands, the H1-histamine receptors, and therefore in the mechanisms of their pharmacologic effects, as well as in the development of safer antihistamines with low or no sedating effects and no interactions on the level of potassium channels leading to QT-prolongations and interactions on the level of cytochrome P450 isoenzymes. This development has brought antihistamines very close to the ideal antihistamines that are desired by clinicians to treat most types of urticaria in patients who have to take these drugs for a long time. (+info)
Reverse phase thin-layer chromatographic separation of bromodiphenhydramine and diphenhydramine.
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A thin-layer chromatographic system is described for the separation of diphenhydramine and bromodiphenhydramine which is based on a reverse phase paper chromatographic system developed by J. Vecerkova (2,3) in 1962. Chromatographic systems for this separation described in the literature and several systems attempted in this laboratory using normal chromatography have not proven successful. The method using reverse phase thin-layer chromatography involves a stationary phase of mineral oil on silica gel G and a mobile phase of ethanol:water:ammonium hydroxide, 28% NH3, (55:43:2). A 10-cm length of run requires about three hours and provides an excellent separation of the two compounds for identification-differentiation purposes. (+info)
Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol.
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Anti-allergic effects (types I and IV) of the 70% ethanol extract (CM-ext) obtained from Cnidii Monnieri Fructus (dried fruits of Cnidium monnieri) were investigated on 48 h homologous passive cutaneous anaphylaxis (PCA), 2, 4-dinitrofluorobenzene (DNFB)-induced contact dermatitis and picryl chloride (PC)-induced contact dermatitis in experimental animals. CM-ext showed inhibitory effects on these allergic models. Osthol isolated from CM-ext also had the inhibitory effects. These results suggested that Cnidii Monnieri Fructus might be useful as an agent for allergic diseases and that its anti-allergic effect was partially attributable to a coumarin derivative, osthol. (+info)
Transport mechanisms of nicotine across the human intestinal epithelial cell line Caco-2.
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Ulcerative colitis is a disease more commonly seen in nonsmokers. Because nicotine was postulated to be a beneficial component of tobacco smoke for ulcerative colitis, various formulations of nicotine have been developed to improve the local bioavailability within the gastrointestinal tissue. In the present study, to characterize the disposition of nicotine in the intestines, we investigated intestinal nicotine transport using Caco-2 cells. Nicotine was predominantly transported across Caco-2 cell monolayers in a unidirectional mode, corresponding to intestinal secretion, by pH-dependent specific transport systems. The specific uptake systems appear to be distinct from organic cation transporters and the transport system for tertiary amines, in terms of its substrate specificity and the pattern of the interaction. These transport systems could play a role in the intestinal accumulation of nicotine from plasma and could also be responsible for the topical delivery of nicotine for ulcerative colitis therapy. These findings could provide useful information for the design of effective nicotine delivery. (+info)
Inhibition of Na(+) current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker.
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Use-dependent block of Na(+) channels plays an important role in the action of many medications, including the anticonvulsants phenytoin, carbamazepine, and lamotrigine. These anticonvulsants all slowly yet selectively bind to a common receptor site in inactivated but not resting Na(+) channels, constituting the molecular basis of the use-dependent block. However, it remains unclear what channel gating process "makes" the receptor, where the receptor is located, and how the slow drug binding rate (to the inactivated channels) is contrived. Imipramine has a diphenyl structural motif almost identical to that in carbamazepine (a dibenzazepine tricyclic compound), as well as a tertiary amine chain similar to that in many prototypical local anesthetics, and has also been reported to inhibit Na(+) channels in a use-dependent fashion. We found that imipramine selectively binds to the inactivated (dissociation constant approximately 1.3 microM) rather than the resting Na(+) channels (dissociation constant >130 microM). Moreover, imipramine rapidly blocks open Na(+) channels, with a binding rate approximately 70-fold faster than its binding to the inactivated channels. Similarly, carbamazepine and diphenhydramine are open Na(+) channel blockers with faster binding rates to the open than to the inactivated channels. These findings indicate that the anticonvulsant receptor responsible for the use-dependent block of Na(+) channels is located in or near the pore (most likely in the pore mouth) and is made suitable for drug binding during channel activation. The receptor, however, continually changes its conformation in the subsequent gating process, causing the slower drug binding rates to the inactivated Na(+) channels. (+info)
Hypersensitivity and idiosyncratic reactions to oxaliplatin.
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BACKGROUND: Oxaliplatin is a third-generation platinum analog that is used to treat a variety of solid tumors, particularly colorectal carcinoma. Patients may develop hypersensitivity reactions, although this complication occurs infrequently. METHODS: Three patients developed hypersensitivity reactions to oxaliplatin while undergoing treatment on a Phase I trial of oxaliplatin and capecitabine. An Entrez PUBMED search was performed to identify other cases. RESULTS: Two patients experienced the abrupt onset of erythema alone or with pruritus during the 9th and 11th infusions of oxaliplatin, whereas the other patient developed fever and mild dyspnea a few hours after the 9th oxaliplatin infusion. All 3 patients were rechallenged successfully for at least 1 additional oxaliplatin infusion by using oral dexamethasone, 20 mg orally, 6 and 12 hours before the administration of oxaliplatin and by administering intravenously 125 mg of solumedrol, 50 mg of diphenhydramine, and 50 mg of cimetidine 30 minutes before oxaliplatin. The literature review suggests two distinct patterns of reactions: classic hypersensitivity (as experienced by the first two patients) and idiosyncratic reactions (as experienced by the third patient). CONCLUSIONS: Patients who develop mild to moderate hypersensitivity to oxaliplatin may be pretreated with steroids and antagonists of Type 1 and 2 histamine receptors, whereas patients who develop severe reactions are unlikely to tolerate further therapy. (+info)
Drug release from Kollicoat SR 30D-coated nonpareil beads: evaluation of coating level, plasticizer type, and curing condition.
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A newly available polyvinylacetate aqueous dispersion, Kollicoat SR 30D, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound (diphenhydramine hydrochloride) from nonpareil-based systems. Kollicoat SR 30D premixed with a selected plasticizer (10% wt/wt propylene glycol, 2.5% triethyl citrate, or 2.5% dibutyl sebacate), talc, and red #30 lake dye was coated onto the drug beads in an Aeromatic Strea I fluid-bed drier with a Wurster insert using bottom spray. With propylene glycol as the plasticizer, increases in polymer coating level retarded drug release from beads in a stepwise fashion along with apparent permeability, indicating a consistent release mechanism. Stability studies at 40 degrees C/75% RH revealed gradual decreases in dissolution rate, and additional curing studies further confirmed the dependence of release kinetics on curing condition. Furthermore, the type of plasticizer was found to play a key role. Unplasticized formulations exhibited the fastest dissolution, followed by formulations plasticized with triethyl citrate, propylene glycol, and dibutyl sebacate. All 4 formulations (unplasticized and plasticized), nevertheless, revealed a marked difference between uncured and cured dissolution profiles. Kollicoat SR 30D has, thereby, been demonstrated to effectively retard drug release from nonpareil-based systems. However, selected plasticizer type and subsequent curing condition play important roles in controlling drug release from such a system. (+info)