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

The biodegradable polymers poly(lactic/glycolic acid) (PLGA) and poly(lactic acid) (PLA) were used as wall materials in the preparation of microspheres (msp) containing the LH-RH superagonist leuprorelin (leuprolide) acetate. A novel W/O/W emulsion-solvent evaporation method was devised for the preparation of msp containing this water-soluble peptide. This method achieved high entrapment efficiency and sustained drug release over a long period predominantly due to polymer bioerosion. The msp are fine microcapsules with polycores containing the peptide at a high concentration and are easily injectable through a conventional fine needle. Leuprorelin msp made with PLGA(75/25)-14,000 or PLA-15,000 released the drug in a zero-order fashion, maintained constant serum drug levels and attained persistent objective suppression of the pituitary-gonadal system ('chemical castration') over 1 or 3 months after i.m. or s.c. injection into animals. These results indicate that depot formulations may be potentially useful in the therapy of endocrine diseases in humans. In this paper, studies on the formulation, drug release and pharmacological effects in animals for these leuprorelin depot formulations are reviewed.
 ...
PMID:One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. 1083 64

A 120-day poly(D,L-lactide) (PLA) microsphere delivery system for a luteinizing hormone-releasing hormone (LHRH) analogue, leuprolide, was prepared and evaluated. Leuprolide microspheres were prepared with PLA (m.w. 11000 Da) by a dispersion/solvent extraction-evaporation method and characterized for drug load by HPLC, particle size by laser diffractometry and surface morphology by scanning electron microscopy. In vitro peptide release and polymer degradation were studied using a modified dialysis method. Serum peptide and testosterone levels were analyzed after subcutaneous administration using a rat model. Spherical microspheres with a mean diameter of 52 microm containing 13.4% peptide released 10% of the peptide within 24 h, followed by a linear release for 150 days. Serum leuprolide levels increased immediately after administration of the microspheres to 45.6 ng/ml, but then fell to 4.3 ng/ml at 15 days and approximately 2.0 ng/ml at 30 days where they remained for 120 days. The testosterone levels increased initially to 15 ng/ml and then decreased to below 0.5 ng/ml by day 4 where they remained for 120 days. In conclusion, a 120-day microsphere formulation of leuprolide was developed with excellent controlled peptide release characteristics and in vivo efficacy.
 ...
PMID:Preparation, characterization and in vivo evaluation of 120-day poly(D,L-lactide) leuprolide microspheres. 1148 18

Reversible hetero-stereoselective complexes were obtained by mixing acetonitrile solutions of enantiomeric D-poly(lactic acid) (d-PLA) and leuprolide, an L-configured nonapeptide LHRH analogue. The complex spontaneously aggregated and precipitated in high yields (95%) from acetonitrile solutions, forming uniform, porous microparticles with a mean unweighed particle size of 1.7 microm. The complexation of L-configured peptide occurred only with D-PLA, and not with L-PLA or racemic D,L-PLA. Various factors affecting the release pattern of leuprolide from the hetero-stereocomplexes were investigated. Complexes with D-PLA of low molecular weight (< 10,000 Da) displayed lower release rates of leuprolide than high molecular weight D-PLA (> 50,000 Da). Changing the leuprolide: D-PLA ratio from 1:50 to 1:10 (w/w) in the stereocomplex, resulted in a faster release of leuprolide. Similarly, the release rate of leuprolide was twice as fast when adding poly(ethylene glycol) to the acetonitrile complexation solution. Leuprolide was released from most of the formulations in a first order pattern, with only a small burst release during the first 24 h. Addition of water to the complexation solution significantly increased the initial release of the peptide. Low testosterone levels for over 25 days were observed in an in vivo release study of leuprolide from a hetero-stereocomplex formulation, monitoring testosterone levels in the blood of rats after sub cutaneous injection.
 ...
PMID:Hetero-stereocomplexes of D-poly(lactic acid) and the LHRH analogue leuprolide. Application in controlled release. 1545 19

Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.
 ...
PMID:GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. 1639 60