Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We developed nanospheres for the intravenous injection that have had sustained release and targeting to the efficiently anti-inflammation effect. These nanospheres formed by poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA), biodegradability and biocompatibility polymer, that were encapsulated betamethasone phosphate and zinc. Result of experimental inflammation models shown that there nanospheres increased effect by targeting to inflammatory sites and also promoted sustained release of betamethasone phosphate from the nanospheres. Moreover, the effect of nanospheres were stronger than clinical pharmaceutical preparation. We propose that these nanospheres are the pharmaceutical preparation to have efficient powerful inflammation action.
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PMID:[Corticosteroid-loading PLA/PLGA-nanospheres]. 1645 89

A plasminogen activator with arginine ester hydrolysis activity (ABUSV-PA) has been identified and purified to homogeneity from Chinese Agkistrodon blomhoffii Ussurensis snake venom. ABUSV-PA, a monomeric protein with molecular mass of 27815.2 Da, was purified 180-fold with 0.02% recovery for protein and 3.6% recovery for esterase activity. ABUSV-PA reacts optimally with its substrate N(alpha)-tosyl-l-arginine-methyl ester (TAME) at approximately pH 7.5 and at 51 degrees C. Measurement from inductively coupled plasma-atomic emission spectroscopy (ICP-AES) reveals that ABUSV-PA is a Zn(2+)-containing protein with a stoichiometry of 1:1 [Zn(2+)]:[ABUSV-PA]. Analyses of esterase hydrolysis and UV absorption and CD spectra indicate that Zn(2+) plays an important role in maintaining the structural integrity rather than the esterase activity of ABUSV-PA. Divalent metal ions, including Ca(2+), Mg(2+), Cu(2+), Ni(2+), Mn(2+), and Co(2+), increase the TAME hydrolysis activity of ABUSV-PA. A red-shift of the emission wavelengths of the synchronous fluorescence of ABUSV-PA, compared to those of free Tyr and Trp, indicates a conformation where the Tyr and Trp residues are in exposed hydrophilic environments. The presence of zinc increases the hydrophobicity of the conformational environments surrounding the Trp residues of ABUSV-PA and affects the secondary structure of ABUSV-PA, as proved by UV absorption and CD spectroscopy.
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PMID:A novel plasminogen activator from Agkistrodon blomhoffii Ussurensis venom (ABUSV-PA): purification and characterization. 1691 41

Alfimeprase is a recombinant, direct-acting fibrinolytic zinc metalloprotease. Alfimeprase has direct proteolytic activity primarily against the fibrin(ogen) Aalpha chain. Alfimeprase is covalently bound and neutralised by serum alpha(2)-macroglobulin, a prevalent mammalian protease inhibitor. Preclinical pharmacology studies have shown that fibrinolysis with alfimeprase is up to sixfold more rapid than with select plasminogen activators, such as tissue-type plasminogen activator and urokinase. Alfimeprase directly delivered to a site of thrombosis has the potential to be a fast and effective fibrinolytic, which does not generate the systemic lytic state seen with plasminogen activators that is associated with major bleeding, including intracerebral haemorrhage. Phase I and II studies in individuals with arterial or venous thrombotic events indicate that alfimeprase is active and generally well tolerated.
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PMID:Alfimeprase: a novel recombinant direct-acting fibrinolytic. 1722 43

Ring-opening polymerization of D,L-lactide was carried out in the presence of monohydroxylated poly(ethylene glycol) (PEG) with Mn of 2000 and 5000, using zinc powder as catalyst. The resulting PEG-b-polylactide (PEG-PLA) diblocks with various ethylene oxide/lactyl (EO/LA) ratios were coupled with adipoyl chloride to yield PEG-PLA-PEG triblock copolymers. N-Dimethylaminopyridine (DMAP) was used as catalyst. The obtained PEG-PLA-PEG triblock copolymers were characterized by various analytical techniques such as IR, 1H NMR, size exclusion chromatography, X-ray diffraction, and differential scanning calorimetry. Data showed that all the copolymers were semicrystalline with the PEG-type crystalline structure, the crystallinity decreasing with increasing PLA block length. Bioresorbable hydrogels were prepared from the water-soluble triblock copolymers. Rheological measurements showed a gel-sol transition with increasing temperature and gelation was found to be thermoreversible. The copolymer solution behaves like a viscoelastic liquid above the gel point and like a viscoelastic solid below the gel point. The critical gelation concentration, the gel-sol transition temperature at a given concentration, and corresponding moduli depend on both the EO/LA ratio and the molecular weight of the copolymers. It is assumed that gelation results from interactions between PEG blocks at low temperatures and that these interactions are disrupted as the temperature is elevated. The shrinking of PEG blocks with increasing temperature seems to be in agreement with the variation of the gel-sol transition temperatures.
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PMID:Synthesis and gelation properties of PEG-PLA-PEG triblock copolymers obtained by coupling monohydroxylated PEG-PLA with adipoyl chloride. 1724 42

Chronic prostatitis (CP) is a common disease among adult men. It can result in male infertility mainly by alternating the semen quality, volume, pH, component, viscosity and liquefaction. There seems to be a strong association between CP and semen delayed liquefaction. Researches on the mechanism of semen delayed liquefaction resulting from CP mainly focus on the proteolytic ferment, plasminogen activator, prostate acid phosphatase, tissue factor, lack of zinc, and pH. This article briefly reviews the progress in these aspects.
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PMID:[Progress in the studies of semen delayed liquefaction from chronic prostatitis]. 1730 37

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in the remodelling of connective tissues during the development and wound healing. Moreover, two MMPs, Gelatinase A (MMP-2) and Gelatinase B (MMP-9), are also present in body fluids such as blood and urine and, therefore, they can be in contact with implanted biomaterials and can be adsorbed onto their surface. In order to test this hypothesis disks of different polymers (polystyrene (PS), polyvinyl chloride (PVC), poly(D,L-lactide) (PLA), polymethyl methacrylate (PMMA) and poly(2-hydroxyethyl methacrylate) (PHEMA)) have been exposed to human plasma and adsorbed proteins have been eluted and analyzed. Using Western blot and substrate zymography analysis, we observed that both MMP-2 and MMP-9 adsorbed onto the surfaces of all the polymers, especially hydrophilic ones (PMMA and PHEMA) and PLA, in both the active and inactive forms. Furthermore, we observed that adhesion of human granulocyte neutophils to PMMA, the polymer that adsorbed the higher quantity of MMP-2 and MMP-9 compared to the others, was reduced by more that 50% by the presence of a gelatinase inhibitor. This data suggest a surprising role of these absorbed enzymes in the adhesion of neutrophil onto some polymeric biomaterials surface and, therefore, in the setting of inflammation.
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PMID:Adsorption of matrix metalloproteinases onto biomedical polymers: a new aspect in biological acceptance. 1817 51

Alfimeprase, a fibrolase derivative with thrombolytic activity produced by recombinant DNA technology, was discovered by Amgen and was in development with Nuvelo for the treatment of stroke and catheter occlusion. However, development has been discontinued. Fibrolase is a zinc-containing metalloendopeptidase that was first isolated from the venom of the Southern copperhead snake, Agkistrodon contortrix contortrix. Alfimeprase directly degrades fibrin to break down clots. Alfimeprase is infused directly into the thrombus (side-hole catheter pushed through the entire clot) via multiple manual pulsed infusions. Alfimeprase degrades fibrin directly and entrapped blood cells are freed. Excess alfimeprase is rapidly inactivated by alpha-2 macroglobulin through an irreversible, covalent interaction. Phase III development of alfimeprase for peripheral arterial occlusion was discontinued based on poor results from the NAPA-2 and SONOMA-2 trials; however, Nuvelo resumed development of alfimeprase in 2007 for stroke and catheter occlusion.Alfimeprase's thrombolytic activity appears to be localized to the site of delivery because it is rapidly inactivated by alpha-2 macroglobulin, a naturally occurring protein in the blood, as it moves away from the site of delivery and into general blood circulation. In January 2002, Amgen and Hyseq Pharmaceuticals (now Nuvelo) entered into a collaboration to develop and commercialize alfimeprase. Nuvelo is to develop the product through clinical trials and Amgen was to be responsible for its manufacture. Both companies were to participate in commercial activities; Amgen was to have the option to lead these. Full financial terms were not disclosed. Further to this agreement, in November 2004 Amgen granted Nuvelo worldwide rights to develop and commercialize alfimeprase in exchange for milestone and royalty payments. In August 2007, Nuvelo decided to focus on core development programmes that it believed would produce the nearest-term proof-of-concept data. As a result of this realignment of organizational expenses, Nuvelo decided to continue to pursue the development of alfimeprase. In February 2003, Hyseq Pharmaceuticals merged with Variagenics Inc. to form Nuvelo Inc. In January 2006, Nuvelo and Bayer HealthCare entered a collaboration to develop and commercialize alfimeprase. Bayer was to commercialize the drug in all territories outside the US, whilst Nuvelo retains full US rights. Nuvelo was to receive other territory royalties and milestone payments to a total of $US385 million. A $US50 million upfront payment will be made to Nuvelo, while Bayer was to be responsible for 40% of the commercialization cost for global development. This partnership was to also develop stroke and deep vein thrombosis therapies. Data from the SONOMA-3 trial fell short of the company's expectations and so Nuvelo has decided to discontinue further development of alfimeprase. Nuvelo previously had decided to resume development of alfimeprase for the treatment of multiple coagulation-related disorders, including acute ischaemic stroke, catheter occlusion (CO) and acute peripheral arterial occlusion.Previously, results from the NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) trial and SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase) phase III trial of alfimeprase in patients with acute peripheral arterial occlusion and catheter occlusion did not meet their primary endpoints. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment with alfimeprase, whilst the SONOMA-2 trial's endpoint was the restoration of function at 15 minutes after dosing. In addition, these trials did not meet their secondary endpoints. As a result, Nuvelo and Bayer suspended enrolment in the NAPA-3 and SONOMA-3 phase III trials until additional analysis was complete; the SONOMA-3 trial was re-initiated. Nuvelo concluded that the delivery method for alfimeprase in the treatment of peripheral arterial occlusive disorders was suboptimal. The company closed the suspended NAPA-3 trial and planned to initiate preclinical studies focused on identifying optimized delivery methods in acute PAO in the second half of 2007. Data from the NAPA-2 trial suggested that efficacy could potentially be enhanced by maintaining alfimeprase longer at the site of the thrombus. Nuvelo's multinational phase III programme for peripheral arterial occlusion consisted of the NAPA-2 and NAPA-3 trials. Both trials were randomized, double-blind studies comparing 0.3 mg/kg of alfimeprase with placebo in a total of 600 patients in 100 centres. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment; secondary endpoints included safety and pharmacoeconomics such as length of hospital and intensive care unit stay. Results from both trials have been presented. The phase II trial (NAPA-1) was completed in June 2004. This open-label, dose-escalation trial assessed the safety and efficacy of alfimeprase in 115 patients with acute peripheral arterial occlusion and was conducted in centres across the US, Europe and South Africa. Full data from the trial have been presented, which indicated that the 0.3 mg/kg dose appeared to be the optimal dose for investigation in phase III trials. In March 2003, Nuvelo announced the positive results of a phase I trial initiated in the US in July 2002; an IND was transferred from Amgen to Nuvelo in January 2002. In the SONOMA-2 trial, alfimeprase restored catheter function in patients with occluded catheters within 15 minutes with a p-value of 0.022. However, it did not meet the company's target product profile for commercial success with a p-value < 0.00125. Data from a phase II trial were presented at the 46th Annual Meeting of the American Society of Hematology held in December 2004. The study was closed in July 2004 with 55 patients enrolled. Initially the phase II study was to compare three doses of alfimeprase with the approved dose of alteplase in over 90 patients in the US. Nuvelo initiated the phase II CARNEROS-1 (Catheter Directed Alfimeprase for Restoration of Neurologic Function and Rapid Opening of Arteries in Stroke) study of alfimeprase in the treatment of acute ischaemic stroke in June 2007. CARNEROS-1 was a multicentre, open-label, dose-escalation study beginning with doses of 1, 5 and 10 mg of alfimeprase in 100 patients within 3-9 hours of stroke onset. The primary endpoints were recanalization (unblocking) of the occlusive lesion within 120 minutes of treatment, and symptomatic intracerebral haemorrhage. The first patient was dosed in December 2007; enrolment was taking place in the US and Canada. In the US, three patents have been issued relating to alfimeprase; US Patent Nos 6 261 820 (alfimeprase protein sequence), 6 440 414 (formulation of alfimeprase with a zinc stabilizer) and 6 455 269 (methods for localized administration of alfimeprase).
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PMID:Alfimeprase. 1845 71

Central venous catheter (CVC) occlusion occurs frequently and remains a significant clinical problem in patients with cancer receiving infusional or intravenous chemotherapy. Thrombotic occlusions frequently limit the benefits of potentially curable cytotoxic agents by interrupting the delivery of infusion of chemotherapy, intravenous medication, nutritional support, and blood products, as well as the frequent acquisition of venous blood samples for laboratory testing. Urokinase has been used as a thrombolytic agent for dysfunctional occluded CVCs, but the alterations in manufacturing practice prompted the Food and Drug Administration to suspend further production of urokinase in 1999. Although streptokinase had a potential as a thrombolytic agent in place of urokinase, the risk of life-threatening anaphylaxis associated with this agent prompted researchers to look for newer agents to dissolve CVC occlusions. Several novel thrombolytic agents are currently being evaluated as a potential treatment for patients with CVC occlusions and acute or chronic peripheral arterial occlusions. Alfimeprase, a recombinant fibrinolytic zinc metalloprotease, has shown promising clinical utility in blood clot lysis in patients with CVC occlusions and peripheral arterial occlusions. Based on the encouraging data, alfimeprase has received orphan drug designation from the Food and Drug Administration and the Committee for Orphan Medicinal Products of the European Medicines Agency for the evaluation of acute peripheral arterial occlusions as a potential indication. Other novel thrombolytic agents such as alteplase and reteplase are undergoing clinical evaluation for their utility in restoring the function of occluded CVCs. The clinical potency of these novel agents and their ongoing clinical trials are discussed briefly herein.
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PMID:Clinical utility of novel agents in the treatment of central venous catheter occlusion. 1863 86

The venom proteomes of the snakes Bothrops caribbaeus and Bothrops lanceolatus, endemic to the Lesser Antillean islands of Saint Lucia and Martinique, respectively, were characterized by reverse-phase HPLC fractionation, followed by analysis of each chromatographic fraction by SDS-PAGE, N-terminal sequencing, MALDI-TOF mass fingerprinting, and collision-induced dissociation tandem mass spectrometry of tryptic peptides. The venoms contain proteins belonging to seven ( B. caribbaeus) and five ( B. lanceolatus) types of toxins. B. caribbaeus and B. lanceolatus venoms contain phospholipases A 2, serine proteinases, l-amino acid oxidases and zinc-dependent metalloproteinases, whereas a long disintegrin, DC-fragments and a CRISP molecule were present only in the venom of B. caribbaeus, and a C-type lectin-like molecule was characterized in the venom of B. lanceolatus. Compositional differences between venoms among closely related species from different geographic regions may be due to evolutionary environmental pressure acting on isolated populations. The venoms of these two species differed in the composition and the relative abundance of their component toxins, but they exhibited similar toxicological and enzymatic profiles in mice, characterized by lethal, hemorrhagic, edema-forming, phospholipase A 2 and proteolytic activities. The venoms of B. caribbaeus and B. lanceolatus are devoid of coagulant and defibrinogenating effects and induce only mild local myotoxicity in mice. The characteristic thrombotic effect described in human envenomings by these species was not reproduced in the mouse model. The toxicological profile observed is consistent with the abundance of metalloproteinases, PLA 2s and serine proteinases in the venoms. A polyvalent (Crotalinae) antivenom produced in Costa Rica was able to immunodeplete approximately 80% of the proteins from both B. caribbaeus and B. lanceolatus venoms, and was effective in neutralizing the lethal, hemorrhagic, phospholipase A 2 and proteolytic activities of these venoms.
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PMID:Snake venomics of the Lesser Antillean pit vipers Bothrops caribbaeus and Bothrops lanceolatus: correlation with toxicological activities and immunoreactivity of a heterologous antivenom. 1878 68

Solid nanoparticles consisting of biodegradable polymers have emerged as a promising carrier for various drugs, but unfortunately the encapsulation of drugs remains challenging. In this study, a technique for encapsulation of water-soluble drugs in solid nanoparticles was developed. Nanoparticles were prepared from a blend of biodegradable polymers, including poly(lactic acid) (PLA) and poly(lactic/glycolic acid) (PLGA), and monomethoxypolyethyleneglycol-polylactide block copolymer by an oil-in-water solvent diffusion method. Betamethasone sodium phosphate (BP) was not encapsulated by the nanoparticles due to its hydrophilicity, but it was effectively encapsulated in the presence of appropriate amounts of zinc and diethanolamine. It was found that BP formed an ionic complex with zinc at a certain pH range obtained by addition of diethanolamine. Furthermore, a carboxyl group located at the end of PLA/PLGA was shown to be essential for encapsulation of BP in nanoparticles, and the molar ratio among BP, zinc, and carboxyl groups in various nanoparticles was almost constant. These results strongly suggested that the encapsulation was promoted by zinc creating an ionic bridge between a carboxyl group on PLA/PLGA and a phosphate group on BP. This technique for entrapment of water-soluble drugs in solid biodegradable nanoparticles may expand the use of nanoparticles for various therapeutic applications.
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PMID:Efficient encapsulation of a water-soluble corticosteroid in biodegradable nanoparticles. 1880 57


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