New Potential Antimalarial Agents: Therapeutic-Index Evaluation of Pyrroloquinazolinediamine and Its Prodrugs in a Rat Model of Severe Malaria
| Autor: | Ai J. Lin, Jing Zhang, Lisa H. Xie, Donald S. Skillman, Qigui Li, Kirsten S. Smith |
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| Rok vydání: | 2006 |
| Předmět: |
Drug
Maximum Tolerated Dose Plasmodium berghei media_common.quotation_subject Drug Evaluation Preclinical Artesunate Parasitemia Pharmacology Rats Sprague-Dawley Antimalarials Random Allocation chemistry.chemical_compound Therapeutic index medicine Animals Experimental Therapeutics Prodrugs Pyrroles Pharmacology (medical) Antimalarial Agent Dosing media_common Dose-Response Relationship Drug biology business.industry Prodrug medicine.disease biology.organism_classification Artemisinins Malaria Rats Disease Models Animal Infectious Diseases Therapeutic Equivalency chemistry Quinazolines business Sesquiterpenes |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 50:1649-1655 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.50.5.1649-1655.2006 |
| Popis: | Tetra-acetamide pyrroloquinazolinediamine (PQD-A4) and bis-ethylcarbamyl pyrroloquinazolinediamine (PQD-BE) are new derivatives of pyrroloquinazolinediamine (PQD) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. Comparative studies to assess the therapeutic indices of PQD-A4, PQD-BE, and PQD were conducted in Plasmodium berghei -infected rats following daily intragastric dosing for three consecutive days. Artesunate (AS), a standard drug for treatment of severe malaria, was used as a comparator. The minimum doses required to clear malaria parasitemia were 156 μmol/kg of body weight for AS and 2.4 μmol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 μmol/kg, and its therapeutic index was calculated to be 4. The MTDs of PQD-A4, PQD-BE, and PQD were found to be 190, 77, and 24 μmol/kg, respectively, yielding therapeutic indices of 80, 32, and 10, respectively. Although PQD-A4 and PQD-BE are only half as potent as PQD based on their curative effects, the two new derivatives, PQD-4A and PQD-BE, are 8.0-fold and 3.2-fold safer, respectively, than their parent compound when they are dosed for three consecutive days. Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous AS. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20.0, 8.0, and 2.5 times safer than AS given intravenously. The results indicate that PQD-4A is a promising candidate for antimalarial treatment. |
| Databáze: | OpenAIRE |
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