In vitro release of acyclovir from semisolid dosage forms: effect of cyclodextrin and polyethylene glycol

Presynaptic depolarization of trigemino-thalamic (TGT) terminals may contribute to modulation of ascending oro-facial somatosensory information during active (or rapid eye movement) sleep. The relative excitability of TGT terminals was inferred from changes in the current required to maintain an antidromic firing probability of 50% (EC50) during quiet wakefulness as compared to active sleep. Depolarization or hyperpolarization of TGT terminals was defined as a decrease or increase, respectively, in the EC50. Overall, the EC50 of 8 TGT terminals was reduced by a mean 8.8+/-3.6 microA during active sleep relative to quiet wakefulness. This result suggests that depolarization of TGT terminals, which may act to suppress the transfer of sensory information from the trigeminal nucleus to the thalamus, occurs during active sleep.     

Ondansetron absorption in adults: effect of dosage form, food, and antacids

Ondansetron is a competitive serotonin 5-HT3 receptor blocker that has proved useful in the prevention of emesis due to cisplatin and other cancer chemotherapeutic agents. In a randomized, open-label, crossover study in 24 healthy male subjects, the relative bioavailability of a single 8-mg tablet was compared with that of an 8-mg solution using the two one-sided t-tests. The tablet and solution formulations were bioequivalent, as confirmed by similarities in mean Cmax (26.3 vs 27.7 ng/mL), Tmax (1.79 vs 1.70 h), and AUC (166.0 vs 167.3 ng.h/mL) values. In another randomized, open-label, crossover study in 12 healthy male subjects, the bioavailability of an 8-mg ondansetron tablet administered 5 min after a standard meal was slightly but significantly greater than in fasted subjects, as indicated by comparative mean AUC values [201.4 ng.h/mL (fed) vs 172.5 ng.h/mL (fasted)]. Coadministration of a magnesium hydroxide/aluminum hydroxide antacid did not affect the bioavailability of the ondansetron tablet.     

High-performance liquid chromatographic method for the determination of norfloxacin glutamate and glucuronate in solid and liquid dosage forms and its application to stability testing

A simple, precise, stability-indicating reversed-phase high-performance liquid chromatographic method for norfloxacin glutamate and norfloxacin glucuronate in liquid and solid dosage forms is described. Chloronitrodiazepine was used as the internal standard. The eluent used with a C18 bonded phase column was methanol-water-diethylamine (50:50:0.4, v/v/v) (pH* 5.5). The effects of the eluent pH*, the ratio of methanol to water, and the quantity of diethylamine on the retention times of the sample and internal standard were investigated. The method showed good linearity in the range 1-45 micrograms ml-1 for norfloxacin. Solid samples were ground, dissolved in the eluent, filtered, and then determined by this method. Liquid samples were dissolved in the same solvent. The average recoveries of norfloxacin glutamate and norfloxacin glucuronate in their simulated preparations were 99.5% for solid products and 99.8% for liquid products. The method was applied to the study of the thermal stability of the drugs by following the degradation of norfloxacin glutamate and glucuronate in the four products in accelerated tests at 37-80 degrees C for up to 3 months. Shelf-lives at 25 degrees C of the four products were predicted from the results assuming zero- and first-order kinetics of decomposition, and were at least 1.5 years for liquid products and 2 years for solid products.     

Histamine levels in the blood of humans experimental animals under normal conditions and following vaccination]

The authors present the results of study of the blood histamine content in intact rabbits and in the animals to which commercial vaccines with a different degree of reactogenic property for man were administered. The blood histamine level was also studied in practically healthy individuals and in those vaccinated with inactivated tick-borne encephalitis vaccine. The blood histamine content varied in intact rabbits from 4 to 10 microgram/ml, averaging 6.4 +/- 0.09 microgram/ml. Animal immunization caused elevation of the blood histamine content correlating with the reactogenic properties of the preparations for man: vaccines with low reactogenic properties--inactivated encephalitis and live measles vaccine produced no significant changes in the index under study; as to the typhoid vaccine with sextatoxoid, and smallpox vaccine with marked reactogenic properties--they stimulated significant histaminemia in rabbits. Revaccination of man against tick-borne encephalitis with the inactivated cultural vaccine caused an increase in the blood histamine content.     

On the role of myosin-II in cytokinesis: division of Dictyostelium cells under adhesive and nonadhesive conditions

We have investigated the role of myosin in cytokinesis in Dictyostelium cells by examining cells under both adhesive and nonadhesive conditions. On an adhesive surface, both wild-type and myosin-null cells undergo the normal processes of mitotic rounding, cell elongation, polar ruffling, furrow ingression, and separation of daughter cells. When cells are denied adhesion through culturing in suspension or on a hydrophobic surface, wild-type cells undergo these same processes. However, cells lacking myosin round up and polar ruffle, but fail to elongate, furrow, or divide. These differences show that cell division can be driven by two mechanisms that we term Cytokinesis A, which requires myosin, and Cytokinesis B, which is cell adhesion dependent. We have used these approaches to examine cells expressing a myosin whose two light chain-binding sites were deleted (DeltaBLCBS-myosin). Although this myosin is a slower motor than wild-type myosin and has constitutively high activity due to the abolition of regulation by light-chain phosphorylation, cells expressing DeltaBLCBS-myosin were previously shown to divide in suspension (Uyeda et al., 1996). However, we suspected their behavior during cytokinesis to be different from wild-type cells given the large alteration in their myosin. Surprisingly, DeltaBLCBS-myosin undergoes relatively normal spatial and temporal changes in localization during mitosis. Furthermore, the rate of furrow progression in cells expressing a DeltaBLCBS-myosin is similar to that in wild-type cells.     

Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line

PURPOSE: To determine and compare the relationship between in vivo oral absorption in humans and the apparent permeability coefficients (Papp) obtained in vitro on two human intestinal epithelial cell lines, the parental Caco-2 and the TC-7 clone. METHODS: Both cell lines were grown for 5-35 days on tissue culture-treated inserts. Cell monolayers were analysed for their morphology by transmission electron micrography, and for their integrity with respect to transepithelial electrical resistance, mannitol and PEG-4000 transport, and cyclosporin efflux. Papp were determined for 20 compounds exhibiting large differences in chemical structure, molecular weight, transport mechanisms, and percentage of absorption in humans. RESULTS: The TC-7 clone exhibits morphological characteristics similar to those of the parental Caco-2 cell line, concerning apical brush border, microvilli, tight junctions and polarisation of the cell line. The TC-7 clone however appeared more homogenous in terms of cell size. Both cell lines achieved a similar monolayer integrity towards mannitol and PEG-4000. Monolayer integrity was achieved earlier for the TC-7 clone, mainly due to its shorter doubling time, i.e. 26 versus 30 hours for parental Caco-2 cells. When using cyclosporin A as a P-glycoprotein substrate, active efflux was lower in the TC-7 clone than in the parental Caco-2 cells. The Papp and mechanisms of transport (paracellular or transcellular routes, passive diffusion and active transport) were determined for 20 drugs. A relationship was established between the in vivo oral absorption in humans and Papp values, allowing to determine a threshold value for Papp of 2 10(-6) cm/sec, above for which a 100% oral absorption could be expected in humans. Both correlation curves obtained with the two cell types, were almost completely superimposable. These studies also confirmed that the dipeptide transporter is underexpressed in both cell lines. CONCLUSIONS: On the basis of morphological parameters, biochemical activity and drug transport characteristics, the TC-7 clone appeared to be a valuable alternative to the use of parental Caco-2 cells for drug absorption studies.     

Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice

In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients who do not become seizure-free while receiving established anticonvulsants. Up to now, no single drug has been shown to be more effective at controlling seizures of a particular type than another, so other factors such as mechanism of action, pharmacokinetics, dosage regimens or the spectrum of adverse drug reactions and interactions are used when making a choice between one agent and another. The mechanism of action of tiagabine and vigabatrin is very specific; both agents increase gamma-aminobutyric acid (GABA) levels through inhibition of reuptake and catabolism respectively. However, the mechanism of action of gabapentin is unknown and those of felbamate, lamotrigine and topiramate are not sufficiently clarified as yet, and may be multiple. Great advances have been made in improving the pharmacokinetic characteristics of these newer anticonvulsants. Gabapentin and vigabatrin exhibit relatively ideal pharmacokinetic properties as they are not bound to proteins, are excreted mostly unchanged in the urine and show linear pharmacokinetics. Lamotrigine possesses a highly variable elimination half-life depending on the co-medication. Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised. Problematic drug interactions between newer anticonvulsants and other drugs in general occur rarely when these agents are given concomitantly. However, in common with most new drugs, there are very few data on the use of the newer anticonvulsants in women of childbearing age. Studies done so far on interactions with oral contraceptives used low anticonvulsant dosages for a very short time. The newer anticonvulsants elicit adverse reactions that, while not being unique, are particularly associated with that drug. For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia. Topiramate and zonisamide cause kidney stones, and vigabatrin may induce psychiatric syndromes. Although highly diverse in structure and activity, these newer drugs offer new possibilities for treating refractory epilepsy. However, since no single factor can dictate the choice of drug nor predict the success of treatment, prescribing of these rather expensive drugs has to depend upon careful consideration of the aims of treatment, the characteristics of the drug and the needs of the individual patient.     

Biodegradable polyesters for controlled release of trypanocidal drugs: in vitro and in vivo studies

Copolymers of epsilon-caprolactone and L-lactide P(CL-LLA), epsilon-caprolactone and D,L-lactide P(CL-DLLA) and epsilon-caprolactone and trimethylene carbonate P(CL-TMC) were synthesized. The composition of comonomers and their sequence lengths were determined by means of 1H and 13C NMR measurements. The effect of the comonomer on the thermal properties was investigated by differential scanning calorimetry (DSC) analysis. The in vitro degradation of the rods obtained by melt extrusion of the synthesized copolymers and the commercial homopolymers poly(epsilon-caprolactone) P(CL) and poly(D,L-lactide) P(DLLA) was carried out in phosphate buffer (PB) pH 7.4 at 37 degrees C. The rate of degradation depends on comonomers and polymer composition. The in vitro release of the selected drugs, isometamidium chloride (IMM) and ethidium bromide (EtBr), from such devices was carried out under the same conditions as used for the in vitro degradation. The release experiments show that the release of IMM is faster than for EtBr. During the first stage, for IMM the release is governed by osmotic pressure whereas for EtBr the release is mainly diffusion-controlled. The in vitro release of these drugs is governed by polymer matrix degradation at the later stage of the release process. Comparative in vitro release study from the different polymers showed that the release depends mainly on the physical properties of the polymer. The in vivo experiments carried out in the field on cattle and in the laboratory on rabbits using the classical treatment (intramuscular injection) and the sustained release devices (SRD) subcutaneously implanted, showed that the prophylactic period is significantly enhanced in the case of SRD as compared to intramuscular injection. The comparative efficacy of SRD containing IMM and EtBr evaluated in the case of rabbits showed that, the SRD (IMM) prophylactic period is much longer than for SRD (EtBr).     

Sustained-release dosage form of phenylpropanolamine hydrochloride. Part II: Formulation and in vitro release kinetics from tableted microcapsules

This work was planned to prepare sustained-action preparations of phenylpropanolamine hydrochloride by microencapsulation and by tableted microcapsules. Dissolution from both suspended microcapsules and the tablets was studied using the USP XXII basket method in simulated gastric and intestinal fluid without enzyme. The results were applied to zero-order, first-order, Hixson Crowell, RRSBW, Q/square root of t, (Bt)a and Higuchi kinetic models. Dissolution of PPA.HCl was found to be governed by the core:wall ratio, drug particle size, media pH and type of disintegrating agent. Dissolution kinetics were studied and evaluated.     

Thrombin promotes platelet-mediated melanoma cell adhesion to endothelial cells under flow conditions: role of platelet glycoproteins P-selectin and GPIIb-IIIA

We investigated the role of platelets in human melanoma cell (line 397) interaction with vascular endothelial cells (ECs) under flow conditions. The ability of the tumour cells to adhere to the EC monolayer was significantly reduced by application of flow at a shear rate of 250 s(-1). A 2.2-fold increase in tumour cell adhesion to ECs under flow was observed upon addition of thrombin receptor agonist peptide (TRAP)-activated platelets but not resting platelets. A similar increase (2.5-fold) in tumour cell adhesion to ECs under flow was observed when the tumour cells were incubated with resting platelets on thrombin-treated ECs. However, thrombin treatment of the ECs alone had no effect on tumour cell adhesion in the absence of platelets. The enhancement of tumour cell adhesion to ECs by TRAP-activated platelets was virtually abolished by blockade of the platelet glycoproteins P-selectin and GPIIb-IIIa by monoclonal antibodies. Blockade of P-selectin also inhibited the direct adhesion of TRAP-activated platelets to ECs, but did not affect the interaction of the tumour cells with platelets immobilized on subendothelial extracellular matrix (ECM). Blockade of GPIIb-IIIa inhibited both platelet-EC and platelet-tumor cell interactions. Our results indicate that tumour cell adhesion to the endothelium under flow is enhanced by platelets under conditions that allow platelet adhesion to ECs. Inhibition studies suggest that activated platelet adhesion to ECs is mediated by P-selectin and GPIIb-IIIA, and tumour cell adhesion to EC-bound platelets--mainly by GPIIb-IIIa.     

Oral bioavailability of CHF1194, an inclusion complex of piroxicam and beta-cyclodextrin, in healthy subjects under single dose and steady-state conditions

CHF1194 is an inclusion complex of beta-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, beta-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-beta-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of beta-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5'-hydroxypiroxicam and beta-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80-125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5'-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with beta-cyclodextrin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effectiveness and toxicity screening of various absorption enhancers in the large intestine: intestinal absorption of phenol red and protein and phospholipid release from the intestinal membrane

The effectiveness and local toxicity of absorption enhancers on the absorption of phenol red (PR) from the large intestine of rats were examined using an in situ loop method. The absorption enhancers used in this study were sodium glycocholate (GC-Na), sodium taurocholate (TC-Na), sodium deoxycholate (DC-Na), EDTA, sodium salicylate (Sal-Na), sodium caprate (Cap-Na), diethyl maleate (DM), N-lauryl-beta-D-maltopyranoside (LM) and mixed micelles (MM), all used at a concentration of 20 mM. Local toxicity was also investigated by assessing protein and phospholipid release as biological markers. DC-Na and MM were the most effective absorption enhancers, but they caused considerable release of proteins and phospholipids. GC-Na, TC-Na and LM, which caused little or only slight membrane damage, promoted PR absorption. Sal-Na, DM and EDTA did not enhance PR absorption. Overall, a correlation exists between the area under the curve of PR and protein and phospholipid release in the presence of absorption enhancers. However, GC-Na, TC-Na and LM promoted the absorption of PR with low toxicity. From these results, we concluded that GC-Na, TC-Na and LM are effective absorption enhancers which have low levels of toxicity at a concentration of 20 mM.     

Prejudice and perception: The role of automatic and controlled processes in misperceiving a weapon.

Two experiments used a priming paradigm to investigate the influence of racial cues on the perceptual identification of weapons. In Experiment 1, participants identified guns faster when primed with Black faces compared with White faces. In Experiment 2, participants were required to respond quickly, causing the racial bias to shift from reaction time to accuracy. Participants misidentified tools as guns more often when primed with a Black face than with a White face. L. L. Jacoby's (1991) process dissociation procedure was applied to demonstrate that racial primes influenced automatic (A) processing, but not controlled (C) processing. The response deadline reduced the C estimate but not the A estimate. The motivation to control prejudice moderated the relationship between explicit prejudice and automatic bias. Implications are discussed on applied and theoretical levels. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Automatic and controlled processing in Stroop negative priming: The role of attentional set.

The distinction between automatic and controlled attentional influences on priming effects was examined in a series of Stroop color-naming experiments. As expected, priming effects depended on the proportion of repeated trials-those in which a color word prime matched a following ink-color probe. However, responses were slower for repeated trials than for unrepeated trials when the proportion of repeated trials was no greater than chance (.25 with 4 colors). This effect was shown not to depend on slow-to-develop expectancies but did depend on the selective-attention requirements of the probe task. This dependence on probe task selection parallels an often reported result in the negative-priming literature (e.g., D. G. Lowe, 1979; S. P. Tipper & M. Cranston, 1985). Implications of these results for the distractor inhibition and episodic retrieval accounts of negative priming are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

N-methyl-D-aspartic acid stimulation of vasopressin release: role in osmotic regulation and modulation by gonadal steroids

Previous experiments demonstrated that excitatory amino acids participate in the osmotic regulation of vasopressin secretion, but the specific involvement of N-methyl-D-aspartic acid (NMDA) receptors was not evaluated. This was demonstrated in the present studies. NMDA stimulated vasopressin release from perifused explants of the hypothalamo-neurohypophyseal system (HNS), and osmotic stimulation of vasopressin release was inhibited by MK-801 (10 microM) and AP5 (100 microM) NMDA receptor antagonists. The effective concentration of NMDA was dependent upon the Mg2+ concentration of the perifusate with stimulation observed at 1 microM NMDA in Mg2+-replete compared with 5 microM in low-Mg2+ medium. Previous experiments also demonstrated that estradiol and dihydrotestosterone (DHT) inhibited osmotically stimulated vasopressin secretion, and a nongenomic mechanism of action was suggested by the ability of steroids conjugated to bovine serum albumin to replicate the effect. Experiments were performed to explore the potential role of NMDA receptors in this mechanism. Estradiol (50 pg/ml) and DHT (3 ng/ml) inhibited NMDA stimulated vasopressin release in perifused HNS explants. These results suggest a role of NMDA receptors in the mediation of vasopressin secretion in osmotically stimulated release. Furthermore, estradiol and DHT may exert their inhibitory effect on osmotically stimulated vasopressin release via the NMDA receptor.     

Age differences in the likelihood of destructive anger responses under different relationship contexts: A comparison of mainland and Hong Kong Chinese.

This brief report examined how the likelihood of destructive anger responses varied with age across relationship contexts. Seventy-six older adults and 100 younger adults from Hong Kong and Mainland China reported their responses to anger-eliciting scenarios elicited by a kin, a close or a casual friend. Results indicated that compared with their younger counterparts, older Hong Kong Chinese were less likely to report direct aggression toward kin, but older Mainland Chinese were more likely to do so. Older Hong Kong Chinese were less likely to report malevolent and fractious motives than were younger Chinese across all relationships; Older Mainland Chinese were less likely to do so only in friendship. Findings have implications for conceptualizing age-related emotion regulation across relationships and cultures. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

A hydrogel based on a polyaspartamide: characterization and evaluation of in-vivo biocompatibility and drug release in the rat

This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of alpha, beta-poly[N-(2-hydroxyethyl)-DL-aspartamide] (PHEA). When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and alpha-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHEA microparticles significantly improved the gastric tolerance and oral bioavailability of the drug in comparison with free diflunisal. These results suggest the potential application of PHEA hydrogel as a new delivery system for the oral administration of anti-inflammatory drugs.