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PubMed1987

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin.

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.

Acetone↗
PubMed1989

The interaction of papain with polycations.

An investigation has been made of the interactions of the enzyme papain with the polycations protamine, polybrene, poly(L-lysine), spermine, spermidine and the neutral polymer polyvinylpyrrolidone (PVP). At low concentrations, each behaves as an inhibitor of the enzyme. As their concentrations increased above a certain level, the activity of the systems increased, and their inhibition of the enzyme appeared to be less pronounced. When acting by themselves in the presence of the substrate haemoglobin, each of the polycations was a weak proteolytic catalyst with a ranking of catalytic effectiveness of protamine greater than polybrene greater than poly(L-lysine) greater than polyvinyl-pyrrolidone greater than spermidine greater than spermine. This effect could explain the anomalous inhibition of papain by these polycations. The interaction of papain with dansyl protamine (DNSP) and the extent of complex formation were studied using a fluorescence polarization technique and the results showed that there was a strong interaction occurred. The strength of binding was assessed by determination of the critical electrolyte concentration (0.2 M, NaNO3). The stoichiometry of the DNSP-papain complex was found to be 63 base moles of DNSP to one mole of papain.

Catalysis↗
PubMed1989

Topical application of penetration enhancers to the skin of nude mice: a histopathological study.

Eighteen potential penetration enhancers, some at concentrations that might be used for that purpose, have been examined to evaluate their irritancy potential on nude mouse skin. A biopsy technique was employed followed by histological examination. Up to 50% glycerol, 10% hydroxyethyl lactamide (HELA), 10% oleyl alcohol, 10% Solketal, 10% glycofurol, 100% tetrahydrofurfuryl alcohol (THFA) and 10% urea induced no discernible change in the histological appearance of the skin whereas 100% dimethyl sulphoxide (DMSO), 100% dimethyl formamide (DMF), 100% N-methyl-2-pyrrolidone, 10% Azone, 10% oleic acid, 10% methyl laurate, 10% benzyl alcohol and 10% glycerol formal caused severe skin irritation.

Animals↗
PubMed1990

Evaluation of in-vitro percutaneous absorption across human skin and in animal models.

The in-vitro permeability characteristics of human skin have been examined and compared with results in laboratory animals using various types of penetration enhancers. The study was focused on evaluation of predictable validity of the data obtained in animals mostly used in permeation studies. The results in man using the same penetration enhancers were about 30% of the value in the rat. The least potent enhancer was dimethylsulphoxide and the maximum efficacy was observed with sodium laurylsulphate in the rat experiments while in man the results were approximately equal when using any of the studied enhancers. Comparison of the results of experiments performed with N-methyl-2-pyrrolidone in several laboratory animals and man showed that the skin permeability in man is approximately 4 times lower than with the rat. Man and guinea-pig were not significantly different in these experiments. There were no significant differences in laurocapram penetration enhancing effect in the concentration range 0.1 to 0.5%, but there was an optimum concentration of laurocapram of 1%. The results showed quantitative differences in percutaneous absorption in various animal species in comparison with man. These differences should be considered in selecting a suitable model for preclinical drug evaluation. The guinea-pig skin penetration seems to be most similar to that in man.

Adult↗
PubMed1996

Characteristics of shed snake skin permeability to indomethacin and fatty alcohols.

To investigate the utilities of a shed snake skin as a model membrane for preclinical studies of transdermal drug delivery, the flux of indomethacin was determined under various conditions by using a diffusion cell. The flux of fatty alcohols was determined and compared with that in human skin reported in references. The esterase activity of shed snake skin was also determined. It was found that the flux of indomethacin decreased with an increase of pH and the amount of ethanol in a vehicle. The flux of indomethacin increased by the addition of Azone, N-methyl-2-pyrrolidone and N,N-dimethyl-m-toluamide in the cream. The flux of fatty alcohols in shed snake skin was greater than that reported in human skin, and shed snake skin had similar esterase activity to human skin.

Animals↗
PubMed1969

An analysis of the mechanism of cessation of uptake of macromolecular substances by the intestine of the young rat ('closure').

1. The longitudinal distribution of cells capable of absorbing macro-molecular material has been determined in the small intestine of the young rat by measurements of the uptake of [(125)I]polyvinyl pyrrolidone (PVP).2. PVP uptake was never seen in the duodenum and became restricted to the distal half of the small intestine by the 18th day of life. The subsequent decline to zero in PVP uptake was due to an almost uniform decrease in PVP uptake by the distal half of the small intestine.3. Histological studies indicate that this rapid decline in PVP uptake did not reflect a decrease in uptake by individual cells, but rather their replacement by new cells incapable of taking up PVP.4. Autoradiographic estimates of turnover time in the intestinal epithelium using tritiated thymidine reveal good agreement between the time needed to replace completely the epithelium of the ileum (62 hr) and the duration of the rapid decline in PVP uptake (approximately 3 days).5. It is concluded that on or about the 18th post-natal day there is an abrupt change in the functional characteristics of the apical plasma membrane of cells produced by the crypts of Lieberkühn in the distal half of the small intestine. The stimulus for this change is unknown, but cells produced subsequently cannot take up PVP.

Age Factors↗
PubMed1969

The influence of specific chemical factors in the solvent on the absorption of macromolecular substances from the small intestine of the new-born calf.

1. The absorption, without change, of [(131)I] and [(125)I]solutes of high molecular weight after duodenal infusion has been measured in anaesthetized calves less than 20 hr old by analysis of lymph collected from the thoracic or intestinal duct.2. Factors present in boiled bovine colostrum whey known to be necessary for the rapid absorption of [(131)I]bovine serum gamma-globulin have now been shown to accelerate the passage of [(131)I]polyvinyl pyrrolidone (PVP) of mean mol. wt. 160,000 (K.60) into the lymph in a comparable manner.3. [(131)I]PVP K.30 (mean mol. wt. 40,000) and [(131)I]human serum albumin could be absorbed to some degree in the absence of solvent factors necessary for the absorption of solutes of higher mol. wt. and a large proportion of the solute thus absorbed passed directly into the portal capillaries.4. Lactate and pyruvate and salts of certain lower volatile fatty acids resemble factors in colostrum whey in their facilitation of the absorption of both gamma-globulin and PVP K.60: these active compounds were not however found in colostrum in significant quantities.5. Potassium isobutyrate was the most effective of the compounds tested and at concentrations of 56.7 m-mole/l. generally accelerated absorption to a greater degree than did colostrum whey itself.6. Absorption of both gamma-globulin and PVP K.60 from colostrum whey was characterized by a profuse flow of lymph containing relatively low concentrations of labelled solute. In contrast, when these solutes were fed in solutions containing simple compounds such as potassium isobutyrate they appeared in very high concentrations in the lymph, the flow of which remained relatively scant.7. When [(125)I]PVP was administered in water, little was absorbed. If, however, such an infusion was followed 3 hr later by a duodenal infusion of colostrum, [(125)I]PVP passed into the lymph almost immediately. This response was too rapid for the colostrum to have reached the absorbing cells in the terminal ileum.8. Intravenous infusions of L+lactate have been found to facilitate the absorption of [(125)I]PVP K.60 introduced into the duodenum in water. This indicates that some of the solvent factors which accelerate absorption may reach the terminal ileum via the blood vascular system after they themselves have been absorbed from the upper small intestine.

Animals↗
PubMed1973

The influence of exogenous steroids on macromolecule uptake by the small intestine of the new-born rat.

1. Plasma concentrations of cortisol and corticosterone measured by competitive protein binding in rats between 5 and 28 days after birth have been related to the intestinal uptake of [(125)I]polyvinyl pyrrolidone (PVP).2. Plasma cortisol concentration was consistently low throughout the period studied, but there was an increase in plasma corticosterone concentration at the time (18-21 days) when PVP uptake declined to zero (closure).3. Injection of a large dose of cortisone acetate 5 days after birth resulted in precocious closure; PVP uptake declined progressively to zero during the 6 days following the injection. Injection of this steroid at 12 days of age caused closure within 4 days.4. Precocious closure induced by cortisone acetate was closely comparable histologically with natural closure; the decline in PVP uptake was associated with the progressive displacement of vacuolated cells from the villi of the terminal intestine.5. Injection of corticosterone at either 5 or 12 days after birth also reduced PVP uptake. However, the reduction was transient and uptake returned to control levels some days after the injection.6. The temporary reduction in PVP uptake following corticosterone injection was not associated with any change in the histological appearance of the small intestine at the light microscope level.7. The injection of either cortisone acetate or corticosterone was followed by a period of impaired body growth and also a reduction of adrenal weight in animals injected at 12 days but not in animals injected at 5 days.

Adrenal Glands↗
PubMed1973

The effect of adrenalectomy or pharmacological inhibition of adrenocortical function on macromolecule uptake by the new-born rat intestine.

1. Bilateral adrenalectomy in 18-day-old rats resulted in an extension by approximately 4 days of the period during which the villous epithelial cells of the small intestine took up polyvinyl pyrrolidone (PVP) of mean mol. wt. 160,000.2. The eventual termination of PVP uptake (;closure') closely resembled normal closure in control animals: the time course of the decline in uptake and the histological changes indicated that more mature ;PVP-impermeable' cells progressively ascended the villi.3. Injection of Metopirone was ineffective in animals 10 days after birth, but when injected after day 13 caused closure within 3 days.4. Metopirone injection significantly reduced the plasma concentration of corticosterone and caused a marked rise in the plasma concentration of deoxycorticosterone.5. Aminoglutethimide injection also produced precocious closure and had an effect similar to Metopirone on the plasma concentrations of corticosterone and deoxycorticosterone.6. Injection of Metopirone or aminoglutethimide increased the relative adrenal weight compared with control animals. Aminoglutethimide was more effective and caused approximately a 100% increase in adrenal weight.

Adrenal Glands↗
PubMed1974

The absorption of 125I-labelled immunoglobulin G by different regions of the gut in young rats.

1. (125)I-labelled homologous IgG was injected into different regions of the small intestine of rats aged 12, 16, 18, 20 and 22 days. At 12 days the proximal and middle regions of the intestine readily absorbed globulin and transmitted it to the circulation. The distal region of the intestine transmitted little to the circulation at all ages tested.2. The intestine loses its ability to transmit globulin to the circulation in a distal-proximal direction. At 16 and 18 days the ability of the middle region had declined significantly, and this decline continued so that little globulin was transmitted from this region at 20 and 22 days.3. The proximal intestine retained the ability to transmit globulin to the circulation in significant amounts up to 20 days.4. There is a close negative correlation between body weight and total radioactivity of the sera of rats which had received doses of labelled globulin into the proximal and middle regions of the intestine. There was no such correlation after injection into the distal intestine - suggesting a restricted throughput of radioactive material by the absorptive cells of this region.5. These results are discussed in the context of the termination of antibody absorption, and in relation to the results obtained using polyvinyl pyrrolidone.

Age Factors↗
PubMed1976

Blockade by amino acid antagonists of neuronal excitation mediated by the pyramidal tract.

1. The responses to glutamate and amino acid antagonists of cells in the cuneate nucleus of anaesthetized rats have been examined.2. 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) and glutamic acid diethylester applied by micro-iontophoresis reduced glutamate excitation of the neurons. HA-966 WAS EFFECTIVE ON MORE CELLS THAN GLUTAMIC ACID DIETHYLESTER AND WAS MORE POTENT. HA-966 DID NOT AFFECT EXCITATORY RESPONSES TO ACETYLCHOLINE.3. Spike activity of cuneate cells was evoked by stimulating the cerebral cortex. Spikeswhich could be attributed to monosynaptic activation of the cells were studied. The pyramidal tract is the only corticofugal pathway known to be capable of short latency activation of dorsal column nucleus neurones.4. HA-966 reversibly blocked the evoked activity in twenty-eight (70%) of forty units in which monosynaptically evoked spikes were induced.5. The results raise the possibility that the neurotransmitter released by neurones of the pyramidal tract may be an excitatory amino acid.

Action Potentials↗
PubMed1982

The nature of the excitatory transmitter mediating X and Y cell inputs to the cat dorsal lateral geniculate nucleus.

1. In experiments examining the possibility that an excitatory amino acid may be an optic nerve transmitter in mammals, excitatory amino acid antagonists have been ionophoretically applied to cells in layers A and A(1) of the cat dorsal lateral geniculate nucleus and their effect on the excitatory response to visual stimulation of the receptive field centre has been assessed.2. The antagonists used were D-alpha-aminoadipate (D-alpha-AA), DL-alpha-epsilon-diaminopimelic acid (DAP), 1-hydroxy-3-amino-2-pyrrolidone (HA-966) and L-glutamate diethyl ester (GDEE). The antagonist effects on the visual response were compared with their effect on similar magnitude responses evoked by ionophoretic pulses of selected agonists and a control excitant, generally acetylcholine.3. Both D-alpha-AA and HA-966 would selectively block or depress the visual response with respect to the response to the control excitant. At the stage the visual input was blocked, responses to the agonists N-methyl-D-aspartate (NMDA), DL-homocysteic acid (DLH) and glutamate were also greatly reduced or blocked. At dose levels below those causing a significant reduction in the visual response, D-alpha-AA and HA-966 would selectively depress responses to NMDA and DLH with respect to the response to glutamate.4. GDEE was relatively ineffective in blocking either agonist responses or the visual response and only produced a significant reduction in either at dose levels that caused a similar depression in the response to acetylcholine. DAP would block responses to DLH but produced no significant effect on the visual response or the responses to glutamate and acetylcholine.5. The cholinergic antagonists atropine and dihydro-beta-erythroidine (DHbetaE) blocked responses to acetylcholine without significantly reducing either visual driving or the response to DLH.6. The effects were the same for X and Y cells in the dorsal lateral geniculate nucleus (dLGN). There was also no distinctions between ;on' and ;off' centre types of each of the two groups.7. The significance of these results is discussed. It is argued that they reintroduce the possibility that either L-aspartate, L-glutamate or a similar substance may be the transmitter mediating the optic nerve input to the cat dLGN.

2-Aminoadipic Acid↗
PubMed1986

The stiffness of frog skinned muscle fibres at altered lateral filament spacing.

When the surface membrane is removed from a frog muscle fibre the myofibrils swell, so that the spacing between the filaments increases by 10-30%. In this study, the stiffness of skinned fibres was measured when the lateral spacing of the filament lattice was reduced osmotically using polyvinyl pyrrolidone (PVP), a synthetic linear polymer. In the absence of PVP, the apparent stiffness of relaxed skinned fibres measured during ramp stretches was about 0.05-0.1 of the stiffness of intact fibres. The stiffness increased when the lattice spacing was decreased. The mechanical characteristics of resting stiffness in the presence of PVP (or bovine serum albumin) were similar to those of the short-range elastic component of resting intact fibres. However, when the spacing of skinned fibres was reduced osmotically to that of the intact lattice, the stiffness of skinned fibres was about 1.6 times higher. In the absence of PVP, Ca2+-activated skinned fibres were less stiff than are fully active intact fibres during isometric tetani. The skinned fibre force-extension relation was markedly curved. As the filament spacing was reduced, the stiffness of the Ca2+-activated skinned fibres increased, with little change in isometric tension, and the force-extension curve became more linear. Experiments at varied filament overlap and during feed-back control of sarcomere length, monitored by laser diffraction, showed that PVP increased the stiffness of the sarcomeres. The increase of active stiffness in the presence of PVP could be partially dissociated from the increase of resting stiffness by inclusion of Mg tripolyphosphate in the bathing solutions. It is concluded that the low stiffness and the non-linearity of the force-extension curve observed in fully activated skinned fibres are due primarily to the increase of filament separation that occurs when a fibre is skinned. The mechanism may be related to an increased angle between the subfragment-2 part of the cross-bridge and the backbone of the thick filament, perhaps leading to buckling of cross-bridges under compression.

Actin Cytoskeleton↗
PubMed2003

Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons.

Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. N-Methyl-D-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bell-shaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 microM. Glycine at 3 microM potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 microM prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor.

Animals↗
PubMed2001

Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons.

Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechanism of action of nefiracetam and aniracetam on neuronal nicotinic acetylcholine receptors (nnAChRs). Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell, patch-clamp technique. Two types of currents were evoked by acetylcholine (ACh): alpha-bungarotoxin-sensitive, alpha 7-type currents and alpha-bungarotoxin-insensitive, alpha 4 beta 2-type currents. Although nefiracetam and aniracetam inhibited alpha 7-type currents only weakly, these nootropic agents potentiated alpha 4 beta 2-type currents in a very potent and efficacious manner. Nefiracetam at 1 nM and aniracetam at 0.1 nM reversibly potentiated alpha 4 beta 2-type currents to 200 to 300% of control. Nefiracetam at very high concentrations (approximately 10 microM) also potentiated alpha 4 beta 2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship. Nefiracetam markedly increased the saturating responses induced by high concentrations of ACh. However, human alpha 4 beta 2 subunits expressed in human embryonic kidney cells were inhibited rather than potentiated by nefiracetam. The specific protein kinase A inhibitors (H-89, KT5720, and peptide 5-24) and protein kinase C inhibitors (chelerythrine, calphostin C, and peptide 19--63) did not prevent nefiracetam from potentiating alpha 4 beta 2-type currents, indicating that these protein kinases are not involved in nefiracetam action. The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin. Therefore, G(s) proteins, but not G(i)/G(o) proteins, are involved in nefiracetam potentiation. These results indicate that nnAChRs are an important site of action of nefiracetam and G(s) proteins may be its crucial target.

Acetylcholine↗
PubMed2002

Shape-controlled synthesis of gold and silver nanoparticles.

Monodisperse samples of silver nanocubes were synthesized in large quantities by reducing silver nitrate with ethylene glycol in the presence of poly(vinyl pyrrolidone) (PVP). These cubes were single crystals and were characterized by a slightly truncated shape bounded by [100], [110], and [111] facets. The presence of PVP and its molar ratio (in terms of repeating unit) relative to silver nitrate both played important roles in determining the geometric shape and size of the product. The silver cubes could serve as sacrificial templates to generate single-crystalline nanoboxes of gold: hollow polyhedra bounded by six [100] and eight [111] facets. Controlling the size, shape, and structure of metal nanoparticles is technologically important because of the strong correlation between these parameters and optical, electrical, and catalytic properties.

Journal Article↗
PubMed1996

In vitro modulation of hippocampal pyramidal cell response by quinolones: effects of HA 966 and gamma-hydroxybutyric acid.

The influence of quinolones on electrically evoked pyramidal cell activity in the rat hippocampus in vitro was studied by using the slice technique. We hoped to learn more about the possible mechanisms for the development of side effects of different quinolones and to find a possible treatment. As reported earlier (W. Dimpfel, M. Spüler, A. Dalhoff, W. Hofmann, and G. Schlüter, Antimicrob. Agents Chemother. 35:1142-1146, 1991), the amplitude of the population spike increased in the presence of ciprofloxacin, lomefloxacin, or ofloxacin about twofold in comparison with reference values. This increase could be prevented in a concentration-dependent manner by the concomitant presence of 3-amino-1-hydroxy-2-pyrrolidone (HA 966), a compound acting at the so-called glycine site of the N-methyl-D-aspartate (NMDA) receptor, but not in the presence of aminophosphonovaleric acid (APV), which acts at a different recognition site of the NMDA receptor. Another tool, 6,7-dinitroquinoxaline-2,3-dione, an antagonist of the so-called AMPA receptor (named after the binding of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] to this site), could not antagonize the effect induced by the quinolones. Activation of the glycine site of the NMDA receptor induced by the presence of D-serine in the superfusion medium also resulted in a concentration-dependent increase in the population spike amplitude. This response remained unchanged in the presence of ciprofloxacin, whereas lomefloxacin and ofloxacin led to further increases in the amplitude, especially in the presence of higher concentrations of D-serine. These results also point to an involvement of the glycine site of the central NMDA receptor in the development of side effects by different quinolones. A complete attenuation of the quinolone-induced effects was obtained in the presence of 2.5 microM gamma-hydroxybutyric acid (GHB), a physiological neuromodulator which is marketed in some countries of Europe as a sedative. It is therefore concluded that the excitatory adverse effects of quinolones might be treated by the administration of GHB.

4-Quinolones↗
PubMed1976

Virus inactivation by grapes and wines.

Infusions and extracts of different grapes inactivated poliovirus; agents responsible for this property resided in the skin of the grape. Commercial grape juice at both natural and neutral pH inactivate various enteric viruses and herpes simplex virus; a 1,000-fold reduction in poliovirus infectivity occurred after incubation with grape juice, pH 7.0, for 24 h at 4 degrees C. A variety of wines were antiviral but to a lesser extent than grape juice; red wines were more antiviral than white. Antiviral activity was demonstrable in fractions of grape juice varying in molecular weight from less than 1,000 to greater than 30,000 as determined by membrane filtration. Some restoration of poliovirus infectivity from virus-grape juice complexes was achieved with 1% gelatin, 0.1% Tween 80, 0.5% polyvinyl pyrrolidone, and 0.5% polyethylene glycol.

Antiviral Agents↗