Gene/Protein Disease Symptom Drug Enzyme Compound
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We applied the finite element method (FEM) to calculate release profiles from computer simulated slabs, one with a limited number of exit holes on the exterior surface, and the other with uniform structure. The former slab showed a first order release rate, and a nearly uniform drug concentration distribution within the device during the release process. It was concluded that circulation of the drug molecules within the slab resulted in the uniform concentration and consequently first order release rate. This theoretical work was used to explain the first order release rate of an active ingredient (flourescin-4-isothiocyanate-dextran, M(W)=71000 Da) from porous PLA (poly(D,L)-lactic acid) microspheres, which by canning electron microscopy (SEM) examination showed only a few exit holes on their exterior surface. Calculations indicated that the internal surface adsorption of the active ingredient, or the pore size distribution of the microspheres, could not influence the mechanism for the first order release rate, and the small number of exit holes on the exterior surface was likely to be the rate-determining factor. The exit holes could be observed by SEM and their size and number is consistent with our interpretations.
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PMID:First order release rate from porous PLA microspheres with limited exit holes on the exterior surface. 1070 76

Membrane components, such as phospholipids, play an important role in the regulation of prostatic 5alpha-reductase activity. To describe in more detail the impact of such regulation on 5alpha-reductase activity, epithelial and stromal cell homogenates of human BPH were treated with phospholipases to specifically alter the structure of cellular phospholipid components. Phospholipase A(2) (PLA(2)) was used to alter the structure of the nonpolar, hydrophobic region of the membrane bilayer. Various types of phospholipase C (PLC) affect the polar, hydrophilic region of phospholipids. In epithelium and stroma, 5alpha-reductase activity was dose-dependently inhibited by PLA(2) and PLC type III. In epithelium and stroma, the mean IC(50) values of PLA(2) were 9.4 +/- 1.1 and 13.9 +/- 2.6 [U/mg protein +/- SEM], respectively. The mean IC(50) values of PLC type III in epithelium and stroma were 4.5 +/- 1.2 and 1.7 +/- 0.2 [U/mg protein +/- SEM], respectively. In epithelium as well as in stroma, 5alpha-reductase activity was more greatly inhibited by PLC type III than by PLA(2). Both in epithelium and stroma, PLA(2) significantly decreased the V(max) of 5alpha-reductase whereas its K(m) remained unaffected. A similar decrease in V(max) was found with PLC type III in epithelium and stroma. Furthermore, the K(m) of epithelial 5alpha-reductase increased significantly following the addition of PLC type III. The two phospholipases, with their specific substrate affinities and sites of hydrolysis, exhibited significantly different effects on 5alpha-reductase, indicating that 5alpha-reductase activity is not unspecifically affected by modification of the hydrophilic milieu. Rather, 5alpha-reductase activity is specifically modulated by various phospholipids and/or phospholipolysis mediated degradation products. These findings suggest that the structural composition of the lipid environment plays a fundamental role in the post-translational regulation of 5alpha-reductase activity in the epithelium and stroma of human BPH. Thus, changes in membrane phospholipid content seem to be instrumental in the expression of DHT-dependent processes.
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PMID:In vitro modulation of steroid 5alpha-reductase activity by phospholipases in epithelium and stroma of human benign prostatic hyperplasia. 1118 41

To prepare spray-dried powders of poly(D,L-lactic acid) (PLA) or poly-epsilon-caprolactone (P epsilonC) from colloidal suspensions containing indomethacin (IND) using benzyl benzoate (BnB), nanocapsules (NC) were prepared by nanoprecipitation. To select the best NC formulations, increasing drug concentrations were tested (1.0, 1.5, or 2.0 mg/mL). The particle size was measured by Nanosizer. Spray-dried powders (SDP) were prepared by addition of Aerosil 200 into suspensions of NC. IND was assayed by HPLC. Free IND was determined using an Ultrafree. NC-SPD were examined under SEM. The particle sizes of all formulations are in the sub-300 nm range and are IND-associated, with drug recovery close to 100%. After 1 month, the formulations with highest drug content (2.0 mg/mL) showed a decline of total quantity of IND. After spray-drying, IND recovery for SDP presented values above 100%, indicating that the drug was concentrated from loss of mass during the process. To verify the relationship of oil phase with this loss of mass, similar NC (IND 1.5 mg/mL) prepared with Miglyol 810 (MI) were spray-dried, and SEM analysis showed nanostructures adsorbed onto SiO2. Similar nano-structures were not visualized for NC samples prepared with BnB. A swelling experiment showed the complete dissolution of both polymer by the BnB, whereas for MI the polymer masses remained unchanged. In conclusion, BnB is a solvent for PLA and P epsilonC and this ester is entrained during spray-drying. Despite the use of BnB in formulations of NC, PLA, or P epsilonC, colloidal suspensions prepared with BnB could be micelles instead of nanocapsules.
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PMID:Influence of benzyl benzoate as oil core on the physicochemical properties of spray-dried powders from polymeric nanocapsules containing indomethacin. 1119 25

The biodegradable hollow fibers of DL-PLA were prepared by a dry-wet phase inversion spinning process. By using four different spinning systems, DL-PLA hollow fibers with varying asymmetric membrane structure were obtained. The structure of hollow fiber wall was examined by SEM. In vitro release of norethisterone from the DL-PLA hollow fibers was also investigated. The hollow fibers were filled with a 50 wt% NET in castor oil. The DL-PLA hollow fibers NET release was found to be dependent on the membrane structure of the hollow fiber wall. Possible release mechanisms were discussed.
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PMID:[The preparation of poly (DL-lactide) hollow fiber and the release of drug in vitro]. 1132 42

A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses. Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared. Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions. Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC. SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37 degrees C for up to 5 weeks. NMR showed a decrease in the CH2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded. In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for approximately 2 months in a static system. It was observed that release was according to Higuchi kinetics (Q vs. t(1/2)), and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.
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PMID:Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks. 1181 62

Composite microspheres with two different fillers were developed using a solid-in-oil-in-water (s/o/w) emulsion solvent removal method. Two types of bioactive ceramic powders, specifically calcium hydroxyapatite (HA) and modified bioactive glass (MBG), were incorporated into degradable poly(lactic acid) (PLA) polymer matrix to form composite microspheres. For each filler material, microspheres with three different weight ratios of filler material to polymer, namely, 1: 1, 1: 3, and 1: 9, were synthesized. In vitro immersion using simulated physiological fluid (SPF) was employed to evaluate the surface reactivity of the microspheres. SEM analysis revealed that after a 14-day immersion the surface of the microspheres containing 50% MBG was fully transformed into a bone-like apatite. In contrast, a limited number of mineral nodules were present on the surface of microspheres containing HA. The solution chemical analyses performed to determine changes of Ca, P, and Si concentrations as a function of the immersion time showed that the ion concentration profiles were similar for all microspheres, except the [Si] profile. A higher Si concentration was detected in the SPF immersed with MBG-containing microspheres. These data show that the MBG filler significantly enhances the surface reactivity of the composite microspheres. This observation enables us to conclude that the composite MBG-containing microspheres are the preferable microspheres for three-dimensional bone tissue engineering.
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PMID:Bioactive, degradable composite microspheres: effect of filler material on surface reactivity. 1244 47

Physostigmine is an anti-cholinesterase used for the pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins. The aim of this study is to design a polymeric microparticle system for sustained release of physostigmine. In this paper, we have attempted to encapsulate physostigmine in microparticles made from poly(D,L-lactide-co-glycolide) (PLGA) with various contents of glycolide and poly(D,L-lactide) (PLA) using spray-drying and single emulsion techniques. It was found that during the single emulsion process, most of the physostigmine molecules were lost in the external aqueous phase. However, more than 90% encapsulation efficiency of physostigmine was obtained using the spray-drying technique. SEM micrographs revealed that spherical microparticles containing physostigmine with a smooth surface were yielded with PLA, PLGA 50:50, RG 502 (PLGA 50:50 with a lower molecular weight) and PLGA 65:35 but PLGA 85:15, PLGA 75:25 and PLGA 50:50 with a high concentration produced microparticles with irregular shapes. An increased inlet temperature yielded a higher physostigmine release rate from the PLA microparticles. Physostigmine release from the microparticles showed a biphasic pattern, characterized by an initial burst release followed by a sustained release for PLGA 65:35, PLGA 50:50 and RG 502 or a non-detectable release for PLGA 85:15, PLGA 75:25 and PLA. A sustained-release of physostigmine with a low initial burst over 1 week was achieved from RG 502 microparticles, which would be used as an injectable dosage form in our further animal studies.
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PMID:Design of physostigmine-loaded polymeric microparticles for pretreatment against exposure to organophosphate agents. 1252 68

The neuromuscular and skeletal muscle actions of Naja naja kaouthia snake venom were studied in mammalian (rat left hemidiaphragm) and avian (chick biventer cervicis) nerve-muscle preparations. The venom (5 and 10 micro g/ml) produced neuromuscular blockade (85% in 36.8+/-2.0min, mean+/-SEM, n=5, and 18+/-0.6min, n=3, p<0.01, respectively) in the rat preparation. That the phospholipase A(2) (PLA(2)) activity of the venom is involved in this effect was evaluated by inhibiting this enzyme with p-bromophenacyl bromide. This resulted in significantly (p<0.01) increasing the time required for 85% blockade with 5 and 10 micro g/ml to 54+/-4.6min (n=3) and 29+/-0.6min (n=3), respectively. In chick preparations, the venom (5 micro g/ml) produced neuromuscular blockade in 14.0+/-1.8min (n=5). The contractures to exogenous acetylcholine were completely inhibited by the venom, whereas those to 134 micro M KCl were partially blocked in chick preparations (n=4, n=3, respectively). The venom (5 micro g/ml) produced a progressive decrease in the amplitude of miniature end-plate potentials (m.e.p.ps) in the rat hemidiaphragm, but did not alter the resting membrane potential at 5 micro g/ml. Neostigmine (5.8 micro M) immediate and partially reversed the 85% blockade produced by venom (61%, n=3) in rat preparations, as did 4-aminopyridine (53 micro M) ( approximately 59%, n=3). The 4-aminopyridine and neostigmine also restored the m.e.p.ps to pre-venom (control) values. In rat preparations, the venom damaged 47%+/-11% and 62.7+/-3.6% of the muscle fibers at concentrations of 5 and 10 micro g/ml, respectively. For venom in which PLA(2) activity was inhibited, the corresponding values were 38+/-11.8% (5 micro g/ml) and 67+/-9.6% (10 micro g/ml). These findings suggest a post-synaptic neurotoxic action for N. n. kaouthia venom, and that inhibiting phospholipase activity of the venom reduces significantly the neuromuscular block but not the direct myotoxicity.
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PMID:Neurotoxic and myotoxic actions of Naja naja kaouthia venom on skeletal muscle in vitro. 1272 70

Temperature-sensitive diblock copolymers, poly(N-isopropylacrylamide)-b-poly(D,L-lactide) (PNIPAAm-b-PLA) with different PNIPAAm contents were synthesized and utilized to fabricate microspheres containing bovine serum albumin (BSA, as a model protein) by a water-in-oil-in-water double emulsion solvent evaporation process. XPS analysis showed that PNIPAAm was a dominant component of the microspheres surface. BSA was well entrapped within the microspheres, and more than 90% encapsulation efficiency was achieved. The in vitro degradation behavior of microspheres was investigated using SEM, NMR, FTIR, and GPC. It was found that the microspheres were erodible, and polymer degradation occurred in the PLA block. Degradation of PLA was completed after 5 months incubation in PBS (pH 7.4) at 37 degrees C. A PVA concentration of 0.2% (w/v) in the internal aqueous phase yielded the microspheres with an interconnected porous structure, resulting in fast matrix erosion and sustained BSA release. However, 0.05% PVA produced the microspheres with a multivesicular internal structure wrapped with a dense skin layer, resulting in lower erosion rate and a biphasic release pattern of BSA that was characterized with an initial burst followed by a nonrelease phase. The microspheres made from PNIPAAm-b-PLA with a higher portion of PNIPAAm provided faster BSA release. In addition, BSA release from the microspheres responded to the external temperature changes. BSA release was slower at 37 degrees C (above the LCST) than at a temperature below the LCST. The microspheres fabricated with PNIPAAm-b-PLA having a 1:5 molar ratio of PNIPAAm to PLA and 0.2% (w/v) PVA in the internal aqueous phase provided a sustained release of BSA over 3 weeks in PBS (pH 7.4) at 37 degrees C.
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PMID:Preparation and characterization of temperature-sensitive poly(N-isopropylacrylamide)-b-poly(D,L-lactide) microspheres for protein delivery. 1460 9

The aim of this study was to develop a bioactive membrane for inducing bone regeneration. The membrane was composed of polylactic acid, collagen, recombinant human bone morphogenetic protein-2 (rhBMP-2). The PLA + collagen + rhBMP-2 membrane was fabricated by solvent-casting and cool-drying. The mechanic properties of this compound membrane were tested. The two surfaces of membrane were observed by SEM. Degradability of PLA was evaluated by SEM observation and molecular weight measure in vitro and in vivo. The compound membranes were implanted in rabbit muscles. The samples were obtained when animals were sacrificed at different periods: 2 weeks, 1, 2, 3, 6 months after surgery. The biodegradability and biocompatibility of the membrane were evaluated. The heterotopic bone inducing activity of BMP was identified. The results indicated that the strength at extension to failure of the compound membrane was 36.4MPa at 2.3% strain. The compound membrane was found bearing active factor on its coarse side, which can induce bone regeneration. After implantation in vivo, the membrane maintained the structure for three months and degraded in 6 months. Based on histological analysis, there was no obvious inflammation. Heterotopic bone was induced. We could conclude that the PLA + collagen + rhBMP-2 membrane is an absorbable compound membrane that possesses good biocompatibility, adequate mechanic properties and excellent property of bone induction. It could be applied as an ideal membrane for inducing bone regeneration.
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PMID:[Experimental study on the fabrication of bioactive membrane for inducing bone regeneration]. 1555 72


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