Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few data exist about the incidence of drug-induced pancreatitis in the general population. 20 cases of drug-related pancreatitis were reported in Switzerland over a period of 12 years. The proportion of cases of pancreatitis caused by drugs is estimated to be around 2% in the general population, with much higher proportions in specific subpopulations, such as children and patients who are HIV positive. The literature about drug-induced pancreatitis consists mainly of anecdotal case reports. Clear evidence of a definite association with pancreatitis, by means of rechallenge tests, or consistent case reports, supported by animal experiments or data on the incidence of acute pancreatitis in drug trials exists for didanosine, valproic acid (sodium valproate), aminosalicylates, estrogen, calcium, anticholinesterases and sodium stibogluconate. An association with drug-induced pancreatitis is likely but not definitely proven for thiazide diuretics, pentamidine, ACE inhibitors, asparaginase, vinca alkaloids, some nonsteroidal anti-inflammatory drugs and clozapine. Pancreatitis is possibly caused by azathioprine, furosemide (frusemide), tetracycline, metronidazole, isoniazid, rifampicin (rifampin), sulphonamides, cyclosporin and some antineoplastic drugs. Many drugs have been reported to be associated with acute pancreatitis. However, lack of rechallenge evidence, consistent statistical data, or evidence from experimental studies on a possible mechanism prohibit definitive conclusions about most of them. The high incidence of concurrent illnesses known to induce acute pancreatitis, makes a trigger role or co-factor role for the drug seem most likely.
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PMID:Drug-induced pancreatitis. 882 18

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.
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PMID:Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma. 1128 17

Erythrocytes are potential biocompatible vectors for different bioactive substances, including drugs. These can be used successfully as biological carriers of drugs, enzymes and peptides. There are currently diverse methods that permit drug encapsulation in erythrocytes with an appropriate yield. The methods most commonly employed are based on a high-haematocrit dialysis procedure, mainly hypo-osmotic dialysis. Erythrocytes loaded with drugs and other substances allow for different release rates to be obtained. Encapsulation in erythrocytes significantly changes the pharmacokinetic properties of drugs in both animals and humans, enhancing liver and spleen uptake and targeting the reticulo-endothelial system (RES). Amongst other applications, erythrocytes have been used for drug-targeting the RES with aminoglycoside antibiotics; the selective transport to certain organs and tissues of certain antineoplastic drugs, such as methotrexate, doxorubicine, etoposide, carboplatin, etc.; the encapsulation of angiotensin-converting enzyme (ACE) inhibitors, systemic corticosteroids, the encapsulation of new prodrugs with increased duration of action, etc. Erythrocytes are also attractive systems in the sense of their potential ability to deliver proteins and therapeutic peptides. Thus, erythrocytes have been used for the transport of enzymes destined for the correction of metabolic alterations as l-asparaginase, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AlDH) among others. Erythrocytes have been used successfully as carriers of anti-HIV peptides, such as AZT, nucleoside analogues, antisense oligonucleotides, antineoplastic peptides, erythropoietin, interleukin 3, etc. Amongst other applications, mention may be made of paramagnetic erythrocytes, encapsulation of MRI contrast agents or the study of the metabolism of the red cell. Although erythrocytes have been applied with different uses in human medicine, their deployment is still very limited due to difficulties involving storage, its exposure to contamination and the absence of a validated industrial procedure for its preparation.
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PMID:Drug, enzyme and peptide delivery using erythrocytes as carriers. 1501 30

Macromolecular drugs such as proteins and gene products are presumably the most desirable therapeutic agents due to their unmatched substrate specificity and reaction efficiency. Yet, clinical use of these drugs has met with limited success, primarily due to the impermeable nature of the cell membrane that restricts cellular drug uptake to only small (<600 Da) and hydrophobic molecules. The recent discovery of the protein transduction domain (PTD) membrane-penetrating peptides, such as HIV-TAT, has finally offered the possibility of resolving this cell-membrane barrier for macromolecular drug delivery. Via covalent linkages, these PTD peptides have been shown to ferry the attached macromolecular species across membranes of all cell types, both in vitro and in vivo. Nevertheless, the lack of selectivity for PTD-mediated internalization restricts the application of this cell uptake method in clinical practice, due to concerns of inducing systemic toxicity caused by the carried drugs. Presented herein is a modified version of our previously established "ATTEMPTS" approach in delivery of macromolecular drugs, which integrates the cell-penetrating PTDs into a heparin/protamine-regulated delivery system. In vitro findings using asparaginase (ASNase) as a model macromolecular anti-tumor agent were able to validate the feasibility of this delivery system. The chemically constructed TAT-ASNase conjugates not only were able to translocate into the MOLT-4 cells and elicit the cytotoxic effects, but also this PTD-mediated intracellular drug uptake could be regulated (with on/off control) by the addition of heparin and protamine. This modified ATTEMPTS system therefore presents a new avenue of treatment of various types of cancers and other diseases with macromolecular drugs. In vitro characterization and a preliminary proof-of-concept animal investigation that demonstrates the feasibility of this PTD-mediated ASNase therapeutic system is subsequently described.
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PMID:PTD-modified ATTEMPTS system for enhanced asparaginase therapy: a proof-of-concept investigation. 1865 56

Cell systems have recently emerged as biological drug carriers, as an interesting alternative to other systems such as micro- and nano-particles. Different cells, such as carrier erythrocytes, bacterial ghosts and genetically engineered stem and dendritic cells have been used. They provide sustained release and specific delivery of drugs, enzymatic systems and genetic material to certain organs and tissues. Cell systems have potential applications for the treatment of cancer, HIV, intracellular infections, cardiovascular diseases, Parkinson's disease or in gene therapy. Carrier erythrocytes containing enzymes such us L-asparaginase, or drugs such as corticosteroids have been successfully used in humans. Bacterial ghosts have been widely used in the field of vaccines and also with drugs such as doxorubicin. Genetically engineered stem cells have been tested for cancer treatment and dendritic cells for immunotherapeutic vaccines. Although further research and more clinical trials are necessary, cell-based platforms are a promising strategy for drug delivery.
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PMID:Cell-based drug-delivery platforms. 2283 31