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)

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
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PMID:Monocrotaline pneumotoxicity in mice. 257 Apr 81

The solvent evaporation process has been used to form hydrocortisone-loaded microspheres from poly((+/-)-lactide) (PLA) and a lactide-glycolide copolymer (65/35). Methylene chloride was the casting solvent. Partially hydrolysed (88%) poly(vinyl alcohol) and methylcellulose were used as aqueous phase emulsifiers. Methylcellulose was preferred, because it gave stable emulsions as the amount of hydrocortisone being encapsulated increased whereas poly(vinyl alcohol) did not. With methylcellulose as the emulsifier, a broad size range of spherical microspheres containing up to 50% (w/w) hydrocortisone could be prepared. Thermal and X-ray analyses established that poly((+/-)-lactide) microspheres containing hydrocortisone retained thermal events characteristic of both materials. This is evidence that such microspheres contain, to some extent, crystalline hydrocortisone domains dispersed in a PLA matrix. But most of the encapsulated drug was molecularly dispersed in the PLA glass. The stability of hydrocortisone in microspheres was evaluated in different storage conditions: no degradation of drug was found. The release of hydrocortisone from 250-350 microns diameter microspheres into agitated 37 degrees C water (nitrogen atmosphere) was determined by HPLC analysis. The microspheres evaluated had initial hydrocortisone payloads of 12 to 47% (w/w). The rate of drug release increased as the initial drug payload carried by the microspheres increased. The release data are not adequately described by zero order, first order, or square-root-of-time release kinetics. Drug release from microspheres that contain 12% (w/w) hydrocortisone approached a plateau value well below the amount of drug actually carried by the microspheres. This is particularly true for hydrocortisone encapsulated in lactide-glycolide polymer.
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PMID:The formation and characterization of hydrocortisone-loaded poly((+/-)-lactide) microspheres. 287 87

Since streptokinase and urokinase became available for clinical use, numerous attempts have been made to improve these useful thrombolytic agents. To decrease its antigenicity, streptokinase has been fragmented or coupled to human plasminogen or polyethylene glycols. With a plasmin B chain-streptokinase complex a more potent agent was obtained. To prolong their half-life, streptokinase and urokinase were immobilized with water-soluble carriers. Coupling urokinase with fibrin-specific antibodies increases its thrombolytic efficacy, at least in vitro. The only thrombolytic agents with a relative fibrin specificity available for clinical purposes are tissue-type plasminogen activator and single chain urokinase-type plasminogen activator. Mutants and hybrids of these molecules are being constructed and may further improve their fibrin specificity and therapeutic potential.
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PMID:The search for the ideal thrombolytic agent. 295 14

The pyrrolizidine alkaloid monocrotaline produces pulmonary inflammation, hemorrhage, fibrosis, and hypertension. In rats, monocrotaline pneumotoxicity can be ameliorated by cotreatment with inhibitors of angiotensin converting enzyme (ACE), such as CL242817. In the present study, serum and urine copper (Cu) concentrations were evaluated as indices of cardiopulmonary injury in rats sacrificed after six weeks of continuous administration of monocrotaline (0 to 3.6 mg per kg per day, in the drinking water) or CL242817 (60 mg per kg per day, in the feed), or both. Monocrotaline-treated rats exhibited dose-dependent increases in (1) pulmonary histopathology, (2) pulmonary endothelial dysfunction (decreased lung plasminogen activator activity, and increased prostacyclin and thromboxane production), (3) pulmonary hydroxyproline (collagen) content, and (4) cardiac right ventricular hypertrophy (an anatomic correlate of pulmonary hypertension). The severity of cardiopulmonary damage was accompanied by a dose-dependent elevation in serum Cu concentration. Serum iron concentration, in contrast, did not change. Urinary Cu concentration correlated roughly with that of serum, but the variability within groups was high. Cotreatment with the ACE inhibitor CL242817 not only ameliorated monocrotaline-induced right heart enlargement and lung hydroxyproline accumulation but also reduced the hypercupremia in monocrotaline-treated rats. Thus, serum copper concentration appears to be an accurate and minimally invasive index of monocrotaline pneumotoxicity in this model of pulmonary hypertension.
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PMID:Serum copper concentration as an index of cardiopulmonary injury in monocrotaline-treated rats. 314 70

Poly(dl-lactide) (PLA) microspheres containing quinidine or quinidine sulphate were prepared by the emulsification-solvent evaporation technique. The in vitro release profile of quinidine or quinidine sulphate from the microspheres was characterized by three phases: a lag time, a rapid release phase (burst), and a slow release phase. Drug release was studied as a function of the ionic strength of the dissolution medium, to demonstrate the importance of the water imbition into the microspheres which induced the drug release. The lag time increased with increasing ionic strength. The microspheres stayed intact during the dissolution study as shown by scanning electron microscopy (SEM). Disintegration of microspheres which was initially observed was an artifact introduced during the SEM procedure. The high vacuum applied either during the coating of the microspheres with gold-palladium or during the actual observation in the scanning electron microscope caused the microspheres to collapse or rupture.
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PMID:Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation method. III. Morphology of the microspheres during dissolution studies. 323 52

Since streptokinase and urokinase became available for clinical use, numerous attempts have been made to improve these useful thrombolytic agents. In order to decrease its antigenicity, streptokinase has been fragmented or coupled to human plasminogen or polyethylene glycols. With a plasmin B-chain-streptokinase complex a more potent agent was obtained. To prolong their half-life, streptokinase and urokinase were immobilized with water-soluble carriers. Coupling urokinase or tissue-type plasminogen activator with fibrin-specific antibodies increases its thrombolytic efficiency, at least in vitro. The only thrombolytic agents with a relative fibrin-selectivity presently available for clinical purposes are tissue-type plasminogen activator and single chain urokinase-type plasminogen activator. Structural manipulation allows to design and produce mutant proteins with specific deletions, additions or substitutions of non-protease domains. Also chimaeric molecules combining fragments of tissue-type plasminogen activator and single chain urokinase-type plasminogen activator have already been constructed. These modifications of natural molecules may further improve their fibrin-specificity and therapeutic potential.
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PMID:[Recent developments in fibrinolysis]. 327 56

Twelve patients with intractable nonunions of the femoral diaphyseal or metaphyseal-diaphyseal shaft were successfully treated by a combination of internal fixation and implants of human bone morphogenetic protein (h-BMP). There was an average of 4.3 surgical procedures per patient attempting union prior to h-BMP implantation. Union was obtained in 11 of 12 patients and in one patient with a repeat stabilization and implantation of h-BMP. Four patients received autogeneic cancellous bone graft and four patients received allogeneic bone grafts. The BMP implant was prepared in the form of an aggregate of h-BMP and bone matrix water-insoluble noncollagenous proteins (h-BMP/iNCP). Fifty to 100 mg of h-BMP/iNCP was either implanted in the fracture gap in ultra thin gelatin capsules, or incorporated in a strip of polylactic/polyglycolic acid copolymer (PLA/PGA) and placed as an onlay across the fracture gap. The average time to union was 4.7 months. Further clinical investigations are planned as a series of matched cases with and without BMP augmentation in order to distinguish h-BMP effects from new or improved methods of fracture fixation combined with autogeneic cancellous bone grafts.
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PMID:Bone morphogenetic protein augmentation grafting of resistant femoral nonunions. A preliminary report. 328 78

Several compounds such as caffeine, diazepam, hydrocortisone, progesterone, quinidine, quinidine hydrochloride, quinidine sulfate, and theophylline were evaluated for incorporation into poly(dl-lactide) (PLA) microspheres using the solvent evaporation technique. The process is generally limited to the entrapment of water-insoluble drugs. Adjustment of the pH of the aqueous phase to minimize drug solubility resulted in increased drug contents within the microspheres in the case of ionizable drugs. The release profile of quinidine from the microspheres was characterized by three different release phases, a lag time with no drug release, a burst effect of rapid drug release within a short period of time, and a slow release phase, respectively. The structure of the microsphere surface layer, which was a function of the pH of the aqueous phase at preparation, strongly influenced the rate and amount of drug released. Thermal analysis of quinidine-loaded microspheres revealed three thermal events, corresponding to the glass transition temperature of the polymer and to the recrystallization and melting of quinidine.
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PMID:The preparation and evaluation of drug-containing poly(dl-lactide) microspheres formed by the solvent evaporation method. 350 58

Pulmonary microemboli can create an ARDS-like state in dogs (high pulmonary vascular resistance, pulmonary oedema and arterial hypoxemia). CPPV can correct the hypoxemia of pulmonary microemboli but reduces cardiac output (Q) and tissue oxygenation. This paper compares the effect of improving Q by infusing volume, reducing afterload, or increasing myocardial contractility. Four groups of seven dogs were studied. All had 0.125 g . kg-1 of starch microemboli (63-74 microns) infused and then CPPV at 15 cm H2O applied. The control group had no further treatment applied. In three other groups volume (dextran) or dobutamine or nitroprusside (NTP) was infused to return Q to the level before CPPV was applied. All treatments (volume, dobutamine and NTP) improved Q and O2 transport. Only the volume group had a significant increase in pulmonary microvascular pressure, Pmv = PLA + 0.4 (PPA - PLA) from 2.53 +/- 0.27 to 3.35 +/- 0.13 kPa, p less than 0.05. Only the volume group demonstrated a significant increase in lung water above (double) the control group as measured by a double indicator dilution technique (ETVL) and post mortem lung weights. We conclude volume infusions to improve a CPPV depressed Q may increase lung water and that better treatment would be to infuse NTP or dobutamine, thus maintaining a lower Pmv and therefore lung water. As a corollary the least CPPV should be applied to maintain adequate oxygenation and create the least need for interventions to improve Q.
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PMID:The effects of dobutamine, nitroprusside, or volume expansion on cardiac output and lung water after CPPV. 351 43

Changes in the flexural and/or tensile strength of plates and rods made of PGA/PLA copolymer submerged in water for a period of 4 wk were investigated. During this time, the effects of PGA/PLA fibre self-reinforcement, carbon fibre reinforcement and gold plating on tensile and/or flexural strength were examined. The results were used for evaluation of the surgical applications of PGA/PLA copolymer and its composites. The initial tensile strength of non-reinforced material was 45 Mpa and its flexural strength was 150 MPa: the flexural strength of self-reinforced material was 265 MPa. The tensile strength of carbon fibre reinforced material was 90 MPa and its flexural strength 190 MPa. The initial strengths of plated and unplated samples were the same but plating delayed the loss of the mechanical strength of carbon fibre reinforced samples. After 4 wk the flexural strength of self-reinforced and carbon fibre reinforced samples was decreased to the level of cancellous bone (10-20 MPa) while the flexural strength of non-reinforced samples was below that level (less than or equal to 5 MPa). The results suggested that self-reinforced PGA/PLA composites may be used for the treatment of fractures in cancellous bone. Positive animal experiments led to clinical studies in vivo. These studies showed that there was no difference in outcome between 2 groups of patients with displaced fractures of the ankle treated with metallic implants or PGA/PLA fibre self-reinforced implants, respectively. Self-reinforced biodegradable implants are now used routinely in Helsinki University Central Hospital.
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PMID:The effects of fibre reinforcement and gold plating on the flexural and tensile strength of PGA/PLA copolymer materials in vitro. 382 44


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