In Vitro and In Vivo Anticandidal Activity of Human Immunodeficiency Virus Protease Inhibitors

1999 ◽  
Vol 180 (2) ◽  
pp. 448-453 ◽  
Author(s):  
Antonio Cassone ◽  
Flavia De Bernardis ◽  
Antonella Torosantucci ◽  
Evelina Tacconelli ◽  
Mario Tumbarello ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Anticandidal Activity

scholarly journals Synergy of Human Immunodeficiency Virus Protease Inhibitors with Chloroquine against Plasmodium falciparum In Vitro and Plasmodium chabaudi In Vivo

2008 ◽  
Vol 52 (7) ◽  
pp. 2653-2656 ◽  
Author(s):  
Zhengxiang He ◽  
Li Qin ◽  
Lili Chen ◽  
Nanzheng Peng ◽  
Jianlan You ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Plasmodium Chabaudi ◽  
Malaria Parasites ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Antimalarial Action

ABSTRACT The synergy of the activities between chloroquine and various human immunodeficiency virus protease inhibitors was investigated in chloroquine-resistant and -sensitive malaria parasites. In both in vitro and in vivo assay systems, ritonavir was found to be the most potent in potentiating the antimalarial action of chloroquine.

scholarly journals Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro

2007 ◽  
Vol 51 (10) ◽  
pp. 3498-3504 ◽  
Author(s):  
Leah Tong ◽  
Truc K. Phan ◽  
Kelly L. Robinson ◽  
Darius Babusis ◽  
Robert Strab ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Interactions ◽  
Intestinal Absorption ◽  
Protease Inhibitors ◽  
Plasma Levels ◽  
Human Immunodeficiency Virus Protease ◽  
Mdckii Cells ◽  
Immunodeficiency Virus ◽  
Secretory Transport

ABSTRACT Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; −15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 μM (lopinavir) to >100 μM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.

scholarly journals In Vitro Activity of Human Immunodeficiency Virus Protease Inhibitors againstPneumocystis carinii

2000 ◽  
Vol 181 (5) ◽  
pp. 1629-1634 ◽  
Author(s):  
Chiara Atzori ◽  
Elena Angeli ◽  
Annalisa Mainini ◽  
Fiorenza Agostoni ◽  
Valeria Micheli ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus

scholarly journals Ex Vivo and In Vitro Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Apoptosis

2000 ◽  
Vol 182 (5) ◽  
pp. 1536-1539 ◽  
Author(s):  
Claudio M. Mastroianni ◽  
Fabio Mengoni ◽  
Miriam Lichtner ◽  
Claudia D'Agostino ◽  
Gabriella d'Ettorre ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Ex Vivo ◽  
Neutrophil Apoptosis ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Vitro Effect

scholarly journals Estimation of Serum-Free 50-Percent Inhibitory Concentrations for Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

2004 ◽  
Vol 48 (8) ◽  
pp. 2911-2917 ◽  
Author(s):  
Dean Hickman ◽  
Sudthida Vasavanonda ◽  
George Nequist ◽  
Lynn Colletti ◽  
Warren M. Kati ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Culture Media ◽  
Free Fraction ◽  
Specific Patient ◽  
Serum Free ◽  
Human Immunodeficiency Virus Protease ◽  
Tissue Culture Media ◽  
Immunodeficiency Virus

ABSTRACT Using measured free fraction and 50% inhibitory concentration (IC50) values for the human immunodeficiency virus protease inhibitors lopinavir (LPV) and ritonavir (RTV) in tissue culture media with various protein concentrations ranging from 5 to 50%, we estimated serum-free IC50 values for each drug. The range of serum-free IC50 values (0.64 to 0.77 ng/ml for LPV and 3.0 to 5.0 ng/ml for RTV) did not exhibit a trend with increasing protein concentrations, despite a 10-fold difference in the free fraction value (0.006 to 0.063) for LPV and a 5-fold difference in the free fraction value (0.013 to 0.057) for RTV. The mean serum-free IC50 by the MTT-MT4 assay (0.69 ng/ml for LPV and 4.0 ng/ml for RTV) may be the most accurate parameter for the estimation of the inhibitory quotient (IQ), a relative measure of in vivo potency defined as the ratio of the minimal free drug concentration in plasma (C trough,free) for a specific patient population and the serum-free IC50. Using this approach, we calculated the average IQs for protease inhibitor-naïve patients for LPV and RTV to be 67 and 5.6, respectively.

scholarly journals Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro

2006 ◽  
Vol 51 (2) ◽  
pp. 759-762 ◽  
Author(s):  
T. S. Skinner-Adams ◽  
K. T. Andrews ◽  
L. Melville ◽  
J. McCarthy ◽  
D. L. Gardiner
Keyword(s):  
Human Immunodeficiency Virus ◽  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Antimalarial Activity ◽  
Digestive Vacuole ◽  
Synergistic Interactions ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Pepstatin A

ABSTRACT The antimalarial activity of several antiretroviral protease inhibitor combinations was investigated. Data demonstrate that ritonavir and saquinavir behave synergistically with chloroquine and mefloquine. These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins.

scholarly journals Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria

2006 ◽  
Vol 50 (2) ◽  
pp. 639-648 ◽  
Author(s):  
Katherine T. Andrews ◽  
David P. Fairlie ◽  
Praveen K. Madala ◽  
John Ray ◽  
David M. Wyatt ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Antimalarial Activity ◽  
Ligand Docking ◽  
Oral Drug ◽  
Geographical Regions ◽  
Immunodeficiency Virus

ABSTRACT Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

scholarly journals Antimalarial Effects of Human Immunodeficiency Virus Protease Inhibitors in Rhesus Macaques

2011 ◽  
Vol 55 (6) ◽  
pp. 3039-3042 ◽  
Author(s):  
Youjia Li ◽  
Li Qin ◽  
Nanzheng Peng ◽  
Guangjie Liu ◽  
Siting Zhao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Plasmodium Knowlesi ◽  
Antimalarial Activity ◽  
Rhesus Macaques ◽  
Day Treatment ◽  
Content Type ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus

ABSTRACTThe antimalarial activity of the human immunodeficiency virus protease inhibitors indinavir and saquinavir was evaluated in rhesus macaques for the first time. Indinavir effectively suppressed the growth ofPlasmodium cynomolgiandPlasmodium knowlesi in vivoafter a 7- or 3-day treatment, respectively, with clinically relevant doses, whereas saquinavir showed only weak activity againstP. cynomolgi.

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