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PubMedDate not supplied

Polymeric pseudolatices bearing pilocarpine for controlled ocular delivery.

The pseudolatex-based ocular formulations of pilocarpine were prepared using different combinations of Eudragit RS 100 and polyvinyl pyrrolidone for prolonged and controlled release of the drug. The designed system was essentially based on polymeric pseudolatex dispersion. The process variables that effect the latex particle size, drug loading and release profiles of drug were studied. Preparations were evaluated for their in vitro performance with regard to release profile and diffusion co-efficient. The designed system exhibited linear relationship between cumulative drug release (Q) and square root of time (t0.5). The products selected on the basis of in vitro characterization were studied for in vivo performance evaluation. It was observed that the preparations exhibited in vivo prolonged therapeutic efficacy. Thus polymer based pseudolatices hold promise for controlled pilocarpine ocular delivery.

Absorption↗
PubMed1989

Comparative effects of pilocarpine in different vehicles on pupil diameter in albino rabbits and squirrel monkeys.

Several commercial pilocarpine preparations have been compared for their efficacy of drug delivery as evaluated by changes in pupil diameter, and return to base-line pupil size, in rabbits and squirrel monkeys. Adsorbocarpine, Isoptocarpine, Pilocar, all at 2%, and Pilopine HS gel, 4%, were used. In albino rabbits the order of efficacy, as judged by area under the curve, or maximal pupil diameter change, was Pilopine greater than Isoptocarpine = Adsorbocarpine greater than Pilocar = saline (prepared in this laboratory). In general, greater areas under the curve were associated with greater changes in pupil diameter. Pupil diameter had returned to normal by a maximum of 5 hours after drop instillation. In squirrel monkeys, the maximum pupillary change was statistically (P greater than 0.05) the same for all preparations, as was the percentage change in pupil diameter at 6 hours since pupils were still somewhat constricted at this time after drop instillation. The differences in area under the curve were minor. The greater response in primates compared to rabbits may be due to differences in pigment, intraocular kinetics and a far more active ciliary muscle in primates. Also studied were newly developed, non-surfactant containing, preservative-free polymer- and microparticle-based vehicles. Some of the vehicles, based on cyanoacrylate, modified hyaluronate, anionic copolymers, polyvinyl-pyrrolidone, cross-linked gelatin and microparticles showed greater pupillary changes and areas under the curve in rabbits compared to saline vehicle. When compared to commercial preparations in the monkey eye cyanoacrylate block copolymer and modified hyaluronate showed an increase in efficacy. Polyvinylpyrrolidone, anionic copolymer and cross-linked gelatin were equal to the commercial preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Improved dissolution rate of indomethacin by adsorbents.

Samples of indomethacin and kaolin or microcrystalline cellulose (Avicel) were prepared by solvent deposition or simple blending methods. Dissolution rates of these samples were studied. The surface adsorption of indomethacin on the studied adsorbents was shown to improve the dissolution rate of the drug in water. The solvent-deposited samples of indomethacin on kaolin or Avicel in the ratio 1:4 released 25% of the drug at 34 or 60 min, respectively (t25%), while 25% of the pure drug was released at 140 min. Meanwhile, the t25% of the corresponding drug-adsorbent simple blends were 108 and 110 min, respectively. The effect of addition of polyvinyl pyrrolidone (PVP) as a third component to indomethacin-adsorbent was studied and showed further improvement in in vitro availability of the drug-kaolin adsorbents.

Adsorption↗
PubMed1998

Preliminary evaluation of Leucaena leucocephala seed gum as a tablet binder.

The seed galactomannan of Leucaena leucocephala Lam. de Wit var.K-8 (family Leguminosae), a natural polysaccharide, with properties comparable to guar gum, was evaluated as a pharmaceutical binder. Characterization was done using studies of compressibility, micromeritic, and mechanical properties of granules prepared by wet granulation and subsequent studies on compacts, both containing 5% w/w of binder. The seed gum was subsequently used as a binder with a badly compressible material, paracetamol, and studied likewise. The seed gum compared will with standard pharmaceutical binders (starch and polyvinyl pyrrolidone [PVP] K30), at least for properties studied herein.

Chemical Phenomena↗
PubMed1984

Evidence that L-glutamic acid mediates baroreceptor function in the cat.

The possible role of L-glutamic acid (L-glu) as a neurotransmitter of baroreceptor afferent neurons was investigated in the cat by monitoring the changes in three indices of baroreceptor function seen with the L-glu antagonists L-glutamic acid diethyl ester (GDEE) and 1-hydroxy-3-amino-pyrrolidone-2-(HA-966). Baroreceptor function was determined from a) the computer summed inhibition of sympathetic nerve discharge (SND) evoked by electrical stimulation of vagal baroreceptor afferent pathways, b) the locking of SND to the cardiac cycle, and c) the sympathoinhibitory response to i.v. pressor doses of phenylephrine. Direct bilateral microinjections of GDEE (20 micrograms) and HA-966 (4 micrograms) into the region of the nucleus tractus solitarii (NTS) resulted in immediate, marked reductions in the SND inhibitory response to vagal stimulation, a loss in SND locking to the cardiac cycle, a shift in the arterial pulse/SND phase relation, and a diminished sympathoinhibitory response to phenylephrine. Control microinjections of isotonic saline (1 mu 1/NTS) were devoid of these effects. The vagal induced sympathoinhibitory response was restored after NTS microinjections of GDEE by increasing the intensity of the vagal stimulus, or by directly stimulating the NTS injection site, suggesting that the impairment in baroreceptor function seen with this L-glu antagonist was independent of mechanical or local anesthetic effects. These data strongly suggest that L-glu may act as a neurotransmitter of baroreceptor afferent neurons in the NTS of the cat.

Afferent Pathways↗
PubMedDate not supplied

[3H]5,7-dichlorokynurenic acid recognizes two binding sites in rat cerebral cortex membranes.

Binding of [3H]5,7-dichlorokynurenic acid ([3H]DCKA), a competitive antagonist of the strychnine-insensitive glycine site of the N-methyl-D-aspartate (NMDA) receptor channel complex, was characterized in synaptic plasma membranes from rat cerebral cortex. Non linear curve fitting of [3H]DCKA saturation and homologous displacement isotherms indicated the existence of two binding sites: a specific, saturable, high affinity site, with a pKD value of 7.24 (KD = 57.5 nmol/l) and a maximum binding value (Bmax) of 6.9 pmol/mg of protein and a second site, with micromolar affinity. The pharmacological profile of both binding components was determined by studying the effect on [3H]DCKA and [3H]glycine binding of a series of compounds known to interact with different excitatory and inhibitory amino acid receptors. These studies confirmed the identity of the high affinity site of [3H]DCKA binding with the strychnine-insensitive glycine site of the NMDA receptor channel complex. 3-[2-(Phenylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carb oxylic acid sodium salt (GV 150526A), a new, high affinity, selective glycine site antagonist (1), was the most potent inhibitor of this component of binding (pKi = 8.24, Ki = 5.6 nmol/l). The low affinity component of [3H]DCKA binding was insensitive to the agonists glycine and D-serine and the partial agonist (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA 966), though recognised by glycine site antagonists. The precise nature of this second, low affinity [3H]DCKA binding site remains to be elucidated.

Animals↗
PubMed1991

Alteration of macrophage activity in experimental septic shock in the rabbit.

We studied alteration in macrophage activity during experimental septic shock and the effect of the protease inhibitor Trasylol on these alterations. Studies were carried out on three groups of 6 rabbits of each. One group (A) served as a control and in the other two groups (B,C) septic shock was induced using the cecal ligation technique. Group B received i.v. Trasylol prior to and following cecal ligation. The clearance and reticuloendothelial system (R.E.S.) distribution of 125I labelled polyvinyl pyrrolidone (PVP) was used to study macrophage function. PVP was injected into all animals 18 h prior to cecal ligation. For 48 h following the operation, PVP blood levels were repeatedly measured and clearance calculated. The animals were then sacrificed, and total radioactivity of the various organs was measured. In the early stages after cecal ligation a significantly higher PVP clearance rate was noted in groups B and C (P less than 0.01); In the later stages of the experiment, however, group C demonstrated the slowest clearance rate with intermediate values in group B. The highest PVP concentrations were found in the liver and spleen. A significantly higher PVP concentration was noted in the spleen of the animals in group A and B as compared to group C (P less than 0.01) while the difference between group A and B was not significant. Our results indicate that septic shock reduces macrophage function as measured by the changes in PVP clearance and distribution. Injections of Trasylol seem to ameliorate these changes. The model of 125I PVP clearance seems to offer a convenient, valid and informative model for measurement of macrophage activity in pathological conditions.

Animals↗
PubMed1975

Effects of vitamin E deficiency on GSH-induced swelling of rat liver mitochondria.

Liver mitochondria from alphatocopherol deficient rats swell more rapidly, both spontaneously and in the presence of GSH, than those from control animals. The increased swelling of deficient mitochondria induced by GSH was completely eliminated when mitochondria were left longer than two hours at 0 degrees in the suspending medium. GSH-induced swelling of liver mitochondria from alpha-tocopherol deficient rats is reversed by ATP, polyvinyl pyrrolidone (PVP) and by oral administration alpha-tocopherol (2 mg/day per rat). Swelling of mitochondria in the above system was completely inhibited by the respiratory chain inhibitor, cyanide (.001 M), and partially by azide (0.001 M). We suggest that the swelling tendency of liver mitochondria from alpha-tocopherol deficient rats might be associated with an altered respiratory mechanism and/or an alteration in membrane permeability.

Adenosine Triphosphate↗
PubMed1984

Integrity of arterial endothelium following acute exposure to high shear stress.

Shear-induced injury or denudation of arterial endothelium has been implicated in atherogenesis. This study reports on an in vitro technique for imposing high, controlled shear stresses on endothelium. Samples of dog aorta were mounted in a chamber so that the endothelium was 1 mm +/- 0.03 mm from a rotating disc. The chamber was filled with a high viscosity solution (10% polyvinyl pyrrolidone in Tyrode's solution, viscosity = 1.97 +/- .07 Poise) which was sheared over the endothelium by the disc. A servo amplifier drove the motor that rotated the disc, so that motor RPM (therefore shear stress) could be made to follow either steady or pulsatile signals played into the amplifier. Acute (10 min-1 hr) exposure to steady shear stresses of up to 2000 dyne/cm2 did not cause gross endothelial injury or denudation. Exposure of endothelium to pulsatile shear stresses that followed a tape recording of physiological flow waveforms (electromagnetic flowmeter) did not cause gross injury or denudation even when peak shear exceeded 1500 dyne/cm2. Furthermore exposure to high shear stress did not degrade the nonthrombogenic nature of the endothelium because subsequent platelet adhesion was poorly and negatively correlated with shear stress.

Animals↗
PubMed1976

Arginine-lysine relationship in rapeseed meal.

A series of experiments was conducted using White Leghorn male chicks to study the arginine-lysine relationship in rapeseed meal (RSM). Semi-purified diets containing 15% protein either from RSM or soybean meal (SBM) were fed. Arginine supplementation completely reversed the growth depression caused by the addition of lysine to RSM diets. Potassium acetate was only partially effective in alleviating the growth depression caused by supplemental lysine, while polyvinyl pyrrolidone significantly reduced chick performance. Tannic acid addition (1.5%) to SBM diets resulted in a severe growth depression which was partially corrected by the supplementation of arginine in the presence of methionine. Supplementation of these amino acids to RSM had a less drastic effect. It is suggested that a portion of the arginine in rapeseed meal may be required for metabolic processes involved in tannic acid excretion.

Acetates↗
PubMed2005

A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells.

Incubation of purified C57BL/6 murine CD4(+) T lymphocytes with anti-CD3 mAb serves as a model of TCR-mediated activation and results in increased IFN-gamma production and cell surface expression of CD25 and CD69. We demonstrate here that signaling through the TCR causes a rapid (4-h) 5-fold increase in A(2A) adenosine receptor (AR) mRNA, which is correlated with a significant increase in the efficacy of A(2A)AR-mediated cAMP accumulation in these cells. A(2A)AR activation reduces TCR-mediated production of IFN-gamma by 98% with a potency order of 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}cyclohexanecarboxylic acid methyl ester (ATL146e; EC(50) = 0.19 +/- 0.03 nM) > 4-{3-[6-amino-9-(5-cyclopropyl-carbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}piperidine-1-carboxylic acid methyl ester (ATL313; 0.43 +/- 0.06 nM) > 5'-N-ethylcarboxamidoadenosine (3.5 +/- 0.77 nM) > 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680; 7.2 +/- 1.4 nM) >> N(6)-cyclohexyladenosine (110 +/- 33 nM) > 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamide (390 +/- 160 nM), similar to the potency order to compete for radioligand binding to the recombinant murine A(2A)AR but not the A(3)AR. The selective A(2A)AR antagonist, 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385), inhibits the effect of ATL146e with a pA(2) of 0.34 nM and also inhibits the effects of N(6)-cyclohexyl-adenosine and 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamide. In CD4(+) T cells derived from A(2A)AR(-/-) and A(2A)AR(+/-) mice, the IFN-gamma release response to ATL146e is reduced by 100 and 50%, respectively, indicative of a gene dose effect. The response of T cells to the phosphodiesterase inhibitor, 4-(3'-cyclopentyloxy-4'-methoxyphenyl)-2-pyrrolidone (rolipram), is not affected by A(2A)AR deletion. We conclude that the rapid induction of the A(2A)AR mRNA in T cells provides a mechanism for limiting T cell activation and secondary macrophage activation in inflamed tissues.

Adenosine↗
PubMed1978

A32390A, a new biologically active metabolite. III. In vitro and in vivo antifungal activity.

A32390A, an isonitrile-containing derivative of mannitol, represents a new class of antifungal antibiotics. In vitro antifungal activity of A32390A was found against Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum. In vivo antifungal activity of A32390A was demonstrated in mice infected with C. albicans. Accumulative doses of 37.5 approximately 600 mg/kg, administered subcutaneously over a 24-hour period, showed significant activity without demonstrating toxicity. A32390A was effective, but not as effective as amphotericin B, in reducing the number of Candida cells isolated from the kidney of infected mice. Urinary excretion of A32390A accounted for only 10% of the administered dose. Improved bioavailability of A32390A was accomplished when the antibiotic was combined with polyvinyl pyrrolidone (PVP) in a solid dispersion. Administration of A32390A as a 10% dispersion in PVP resulted in increased urinary excretion of the drug and reduced the amount of drug required for in vivo activity.

Animals↗
PubMed1976

The participation of the renal tubules to the metabolism of insulin.

The role of renal tubules was explored by two kinds of experiments: (1) inhibition of the tubular reabsorption of insulin by induced polyuria; (2) suppression of insulin filtration by ureter clamping; 1. Anaesthetized dogs maintained in normoglycaemia by glucose compensation were infused with crystalline and 125I-insulins. Polyuria was induced by: (1) saline-bicarbonate infusion; (2) furosemide with saline-bicarbonate infusion to replace urine losses; (3) massive infusion of mannitol. Inulin and paraminohippuric acid were used to estimate the glomerular filtration rate and the renal plasma flow. The permeability of the glomerular wall (pore radius and total area of the pores per unit of path length) was determined by measuring the sieving curve of 131I-polyvinyl-pyrrolidone fractions during basal and treatment periods. Mannitol infusion was able to bring the insulin/inulin clearance ratio up the values of the sieving coefficient of insulin (insulin filtration rate) without modifying the permeability of the glomerular wall; saline infusion displayed a similar effect; furosemide, only a minute one although it induced a more marked polyuria. 2. Clamping of the left ureter was performed on dogs with catheters inserted into the artery, the left renal vein, the pelvis and a renal lymphatic vessel. Almost complete suppression of the glomerular filtration was achieved. It slightly increased the high insulinic concentration of the renal lymph, entailed a 1/3 decrease in the extraction ratio of insulin and reduced by half its renal clearance. In conclusion, the tubules participate to the catabolism of insulin by two different mechanisms: (1) an uptake from the tubular fluid which can be inhibited by diuretics exerting their main action on the proximal tubules; (2) a direct catabolism from the interstitial fluid resulting from the large permeability of the peritubular capillaries to insulin.

Animals↗
PubMed1976

[Quantitative Coombs' test in autoimmune hemolytic anemia].

The detection of iso- and autoantibodies to red cells and complement on the surface of erythrocytes has been studied in a continuous flow system using a single channel autoanalyzer. A macromolecule, polyvinyl pyrrolidone, is added to the washed cells in order to increase their aggregability. With this system it is possible to establish a direct relationship between the quantity of antibodies present on the surface of the cells and the red cells agglutinated by an antiglobulin serum. By this method it is possible to evaluate the degree of autoantibody coating of erythrocytes in autoimmune hemolytic anemia, and to adjust therapy accordingly.

Anemia, Hemolytic, Autoimmune↗
PubMedDate not supplied

Statistical optimization of transdermal drug delivery system of terbutaline sulfate by factorial analysis.

A matrix type of transdermal drug delivery system of terbutaline sulfate was designed and developed by full 3(2) factorial method using polyvinyl alcohol (PVA) of medium molecular weight and polyvinyl pyrrolidone (PVP K-30) as matrix forming polymer and propylene glycol as plasticizer. Patches were designed to deliver 62 micrograms/cm2/hr of the drug into the systemic circulation. These were evaluated for in vitro skin permeation study through excised guinea pig skin. The permeation followed Higuchi kinetics, as its coefficients of correlation (r = 0.965-0.978) predominates over other permeation kinetics. Various physico-chemical parameters of the patches were investigated. Statistical optimization of in vitro permeation rate of the drug from the films were evaluated using two way analysis of variance (ANOVA), regression analysis.

Administration, Cutaneous↗
PubMed2000

Hydrogel lens monomer constituents modulate protein sorption.

PURPOSE: To examine the effect of hydrogel lens monomer constituents on protein sorption. METHODS: A series of hydroxyethylmethacrylate (HEMA)-based hydrogels with various amounts of methacrylic acid (MAA) or N-vinyl pyrrolidone (NVP) were synthesized. A radiolabel tracer technique was used to measure the amount of protein adsorbed on or penetrating into the hydrogels. Penetration of fluorescence-labeled proteins in the hydrogels was studied by laser scanning confocal microscopy. Single-protein solutions of human serum albumin (HSA) and hen egg lysozyme were studied. RESULTS: Inclusion of the comonomers MAA or NVP in hydrogels resulted in an increase in water content and also had a strong impact on protein sorption. An increase in the amount of MAA in the poly(HEMA-co-MAA) hydrogels increased lysozyme adsorption and penetration but reduced HSA adsorption. However, the amount of protein adsorbed for both HSA and lysozyme increased with the amount of NVP in the poly(HEMA-co-NVP) hydrogels. In contrast to the marked effect of MAA on protein sorption, in particular, on lysozyme sorption, NVP had little influence on protein sorption. When a hydrogel contains both MAA and NVP, MAA has the dominant effect on protein sorption-in particular, on lysozyme sorption. Furthermore, a large difference was observed in the amount of lysozyme adsorbed on the hydrogels that had similar water contents but little variation in adsorption of HSA. CONCLUSIONS: Negatively charged carboxyl groups of the MAA constituent may influence lysozyme sorption in two ways: by electrostatic attraction and by increasing the possibility for the small lysozyme molecule to penetrate the hydrogels. Interactions of the surface lactam groups of NVP with proteins may be attributable to the attraction of proteins to NVP. Water content is not a primary factor in determining protein adsorption. It appears that the monomer constituents, such as MAA or NVP, control protein adsorption.

Adsorption↗
PubMed1976

Thymic function in NZB mice. II. Regulatory influence of a circulating thymic factor on antibody production against polyvinylpyrrolidone in NZB mice.

Administration of a circulating thymic factor isolated from normal pig blood prevented the development of the exaggerated production of anti-polyvinyl pyrrolidone (PVP) antibody in young NZB mice. However, treatment was ineffective if initiated after the 4th week of life at a time when endogenous serum thymic factor (TF) normally disappears in these mice. These data suggest that circulating TF is necessary for the survival of short-lived suppressor T cells normally implicated in the regulation of the production of antibodies against PVP, a thymus-independent antigen. In older NZB mice, TF treatment increased paradoxically anti-PVP antibody production, which suggests that "amplifier" T cell activity could also be under TF influence.

Age Factors↗
PubMed2000

Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles.

Piracetam (PIR) and levetiracetam (LEV), an S-enantiomer, are pyrrolidone derivatives that share similar chemical structures but have distinct pharmacological profiles and consequently different clinical uses. Although the mode of action of neither drug has been fully elucidated, they do not interact with inhibitory or excitatory neurotransmission or alter membrane excitability. A brain-specific stereoselective binding site has been identified for which LEV and other S-enantiomers, but not PIR, have high affinity. In preclinical studies, PIR significantly improves learning and memory; in contrast, LEV has less effect but is much more active in preventing seizures. Both drugs have a high therapeutic index and are well tolerated. PIR, a nootropic drug, is used in the therapy of age-related cognitive disturbances and poststroke aphasia. Clinical experience has also shown that at high doses it is effective against cortical myoclonus. LEV is an antiepileptic drug. Clinical trials have confirmed its efficacy in partial seizures and preliminary findings suggest that it is also effective in generalized seizures and myoclonus.

Animals↗