Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
Add more filters










Publication year range
2.
Eur J Med Chem ; 46(9): 3976-85, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21741133

ABSTRACT

Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.


Subject(s)
Bridged-Ring Compounds/chemical synthesis , Bridged-Ring Compounds/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , Bridged-Ring Compounds/chemistry , Computer Simulation , HIV-1/enzymology , Magnetic Resonance Spectroscopy , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Quantum Theory , Stereoisomerism
3.
Antimicrob Agents Chemother ; 54(11): 4903-6, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20805393

ABSTRACT

Patterns of HIV-1 protease inhibitor (PI) resistance-associated mutations (RAMs) and effects on PI susceptibility associated with the L76V mutation were studied in a large database. Of 20,501 sequences with ≥1 PI RAM, 3.2% contained L76V; L76V was alone in 0.04%. Common partner mutations included M46I, I54V, V82A, I84V, and L90M. L76V was associated with a 2- to 6-fold decrease in susceptibility to lopinavir, darunavir, amprenavir, and indinavir and a 7- to 8-fold increase in susceptibility to atazanavir and saquinavir.


Subject(s)
HIV Protease Inhibitors/pharmacology , HIV Protease/genetics , Antiviral Agents/pharmacology , Carbamates/pharmacology , Darunavir , Furans , HIV Protease Inhibitors/antagonists & inhibitors , Humans , Indinavir/pharmacokinetics , Lopinavir , Mutation , Pyrimidinones/pharmacology , Sulfonamides/pharmacology
5.
J Am Coll Surg ; 200(6): 820-30, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15922191

ABSTRACT

BACKGROUND: HIV protease inhibitor ritonavir (RTV) is associated with many cardiovascular complications and causes vascular dysfunction through oxidative stress. In the present study, we determined the effects of RTV and curcumin (a pigment derived from turmeric) on porcine coronary arteries. STUDY DESIGN: Artery rings were incubated with 15 microM concentration of RTV and curcumin (5 or 10 microM) for 24 hours. Vasomotor function was studied with a myograph tension system. Endothelial nitric oxide synthase (eNOS) mRNA and protein levels were studied using real-time polymerase chain reaction, Western blot, and immunohistochemistry. Nitric oxide was measured using Griess assay. Superoxide anion levels were determined by lucigenin enhanced chemiluminescence. RESULTS: RTV considerably reduced vessel contraction by 71%, endothelium-dependent relaxation by 59%, and endothelium-independent relaxation by 52%, as compared with controls. Curcumin effectively blocked RTV-induced vasomotor dysfunction. RTV-treated arteries showed substantial reductions of eNOS mRNA by 77%, eNOS protein by 72%, and nitric oxide release by 37% as compared with controls. The RTV plus curcumin-treated vessels showed substantial increases of eNOS and nitric oxide levels as compared with the RTV-treated vessels. Finally, there was a 47% increase of superoxide anion production in the RTV-treated vessels as compared with controls. Again, curcumin effectively reversed this effect of RTV. CONCLUSIONS: HIV protease inhibitor RTV impairs vasomotor functions, reduces eNOS expression and nitric oxide release, and increases oxidative stress in porcine coronary arteries. Curcumin effectively blocks these detrimental effects of RTV.


Subject(s)
Coronary Vessels/drug effects , Curcumin/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , Ritonavir/antagonists & inhibitors , Vasomotor System/drug effects , Animals , Blotting, Western , Coronary Vessels/chemistry , HIV Protease Inhibitors/pharmacology , Immunohistochemistry , In Vitro Techniques , Luminescent Measurements , Myography , Nitric Oxide/analysis , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type III , Polymerase Chain Reaction , Proteins/analysis , RNA, Messenger/analysis , Ritonavir/pharmacology , Superoxides/analysis , Swine
6.
Am J Physiol Heart Circ Physiol ; 288(6): H2965-71, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15681703

ABSTRACT

Human immunodeficiency virus (HIV) protease inhibitor ritonavir (RTV) may induce vascular dysfunction through oxidative stress. Ginsenosides have been shown to have potential benefits on the cardiovascular system through diverse mechanisms, including antioxidative property. The objective of this study was to determine whether ginsenosides could prevent coronary arteries from RTV-induced dysfunction. Porcine coronary artery rings were incubated with RTV and ginsenosides Rb1, Rc, and Re for 24 h. Vasomotor function was recorded by a myograph tension system. In response to the thromboxane A(2) analog U-46619, the contraction of the vessel rings was significantly reduced. When cocultured with Rb1, Rc, and Re, the contractility significantly increased. In response to bradykinin at 10(-5) M, the endothelium-dependent relaxation of vessel rings was significantly reduced by 59% for RTV compared with controls (P < 0.05). When cocultured with Rb1, Rc, and Re, the relaxation significantly increased 100%, 90%, and 134%, respectively, compared with the RTV-alone groups (P > 0.05). In response to sodium nitroprusside, RTV significantly reduced vasorelaxation. In addition, the endothelial nitric oxide synthase (eNOS) mRNA levels were significantly reduced by 78% for RTV group (P < 0.05) by real-time PCR analysis. The eNOS protein levels measured by Western blot analysis and nitrite concentrations measured by Griess assay were also decreased, whereas O(2)(-) production by lucigenin-enhanced chemiluminescence was significantly increased in the RTV-treated group. These effects of RTV were effectively blocked by ginsenosides. Thus HIV protease inhibitor RTV significantly impaired the vasomotor function of porcine coronary arteries. This effect may be mediated by the downregulation of eNOS and overproduction of O(2)(-). These results suggest that ginsenosides can effectively block RTV-induced vascular dysfunction.


Subject(s)
Coronary Vessels/physiology , Ginsenosides/pharmacology , HIV Protease Inhibitors/pharmacology , Ritonavir/pharmacology , Vasoconstriction/drug effects , Vasodilation/drug effects , Animals , Base Sequence , Bradykinin/pharmacology , Coronary Vessels/drug effects , Coronary Vessels/physiopathology , DNA Primers , HIV Protease Inhibitors/antagonists & inhibitors , In Vitro Techniques , Models, Animal , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Polymerase Chain Reaction , Ritonavir/antagonists & inhibitors , Swine
7.
Biochem Biophys Res Commun ; 327(2): 571-4, 2005 Feb 11.
Article in English | MEDLINE | ID: mdl-15629151

ABSTRACT

Nelfinavir and other HIV protease inhibitors effectively suppress morbidity and mortality in HIV-infected patients. However, therapeutic use of HIV protease inhibitors has been temporally associated with the development of a lipodystrophy/insulin resistance syndrome and some evidence suggests that HIV protease inhibitors may be the causative agent. We report here that nelfinavir promotes loss of cytoplasmic triglyceride from fully differentiated adipocytes and inhibits preadipocyte differentiation at biologically relevant concentrations. Forced expression of the adipogenic transcription factor C/EBPalpha rescues some of the anti-adipogenic effects of nelfinavir. These results suggest that nelfinavir may mediate an anti-adipogenic effect by antagonizing expression of C/EBPalpha.


Subject(s)
Adipocytes/drug effects , Adipocytes/metabolism , CCAAT-Enhancer-Binding Protein-alpha/metabolism , HIV Protease Inhibitors/pharmacology , Nelfinavir/pharmacology , 3T3-L1 Cells , Adipocytes/pathology , Animals , CCAAT-Enhancer-Binding Protein-alpha/antagonists & inhibitors , CCAAT-Enhancer-Binding Protein-alpha/genetics , Gene Expression , HIV Protease Inhibitors/antagonists & inhibitors , Humans , Mice , Nelfinavir/antagonists & inhibitors , Triglycerides/metabolism
9.
Br J Clin Pharmacol ; 56(5): 526-36, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14651727

ABSTRACT

AIMS: To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4. METHODS: Human liver microsomes and cDNA-expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively. RESULTS: Carbamazepine biotransformation to its 10,11-epoxide by human liver microsomes (Vmax = 10.3 nmol min(-1) nmol(-1) P450, apparent Km = 362 microm), cDNA-expressed CYP3A4 (Vmax = 1.17 nmol min(-1) nmol(-1) P450, apparent Km = 119 microm) and CYP2C8 (Vmax = 0.669 nmol min(-1) nmol(-1) P450, apparent Km = 757 microm) was inhibited by stiripentol (IC50 14, 5.1, 37 microM and apparent Ki 3.7, 2.5, 35 microm, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (Vmax = 5.7 nmol min(-1) nmol(-1) P450, apparent Km = 0.79 microm) was inhibited by stiripentol (IC50 163 microM, apparent Ki 86 microm). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 microm. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for Cmax and AUC of saquinavir between the placebo and stiripentol phase were (-39.8, 39.8) and (-33.2, 112), respectively. CONCLUSIONS: These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11-epoxide formation in vitro and in vivo in epileptic patients.


Subject(s)
Anticonvulsants/pharmacology , Carbamazepine/analogs & derivatives , Carbamazepine/antagonists & inhibitors , Dioxolanes/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , Saquinavir/antagonists & inhibitors , Adolescent , Child , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Time Factors
10.
Xenobiotica ; 33(6): 643-54, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12851040

ABSTRACT

1. The use of a beneficial interaction between indinavir and compound A, a potent investigational HIV protease inhibitor to enhance systemic exposure of compound A, was investigated. 2. When administrated alone, compound A underwent extensive hepatic first-pass metabolism in rats and monkeys, resulting in low oral bioavailability. 3. In vitro studies with liver microsomes revealed that compound A metabolism was mediated exclusively by CYP3A enzymes in rats, dogs and monkeys. Indinavir, which also was metabolized predominantly by CYP3A enzymes, extensively inhibited compound A metabolism in microsomes, whereas compound A showed weak inhibitory potency on indinavir metabolism. 4. Consistent with in vitro observations, co-administration of the two compounds resulted in a 17-fold increase in oral AUC of compound A in rats owing to the inhibition of metabolism of compound A by indinavir, whereas compound A did not affect indinavir metabolism as indicated by the unchanged indinavir AUC. Similarly, the systemic exposure of compound A in dogs and monkeys was increased substantially following oral co-administration with indinavir by 7- and > 50-fold, respectively. 5. Enhancement in compound A systemic exposure by indinavir in humans, as predicted based on the in vivo animal and in vitro human liver microsomal data, was confirmed in subsequent clinical studies.


Subject(s)
Benzofurans/pharmacology , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/pharmacokinetics , Indinavir/analogs & derivatives , Indinavir/pharmacology , Piperazines/pharmacology , Animals , Antibodies, Blocking/pharmacology , Area Under Curve , Benzofurans/antagonists & inhibitors , Benzofurans/pharmacokinetics , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System , Dogs , Drug Synergism , Enzyme Inhibitors/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , Indinavir/antagonists & inhibitors , Indinavir/pharmacokinetics , Injections, Intravenous , Macaca mulatta , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Piperazines/antagonists & inhibitors , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Species Specificity , Spectrophotometry, Ultraviolet
11.
Antimicrob Agents Chemother ; 47(2): 759-69, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12543689

ABSTRACT

Protease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances the virus develops resistance to the inhibitor, thereby negating the benefits of this therapy. We have carried out selections for high-level resistance to each of three protease inhibitors (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over most of the course of the increasing selective pressure. There was significant overlap in the identity of the mutations selected with the different inhibitors, and this gave rise to high levels of cross-resistance. Virus particles from the resistant variants all showed defects in processing at the NC/p1 protease cleavage site in Gag. Selections with pairs of inhibitors yielded similar patterns of resistance mutations. A virus that could replicate at near-toxic levels of the three protease inhibitors combined was selected. The pro sequence of this virus was similar to that of the viruses that had been selected for high-level resistance to each of the drugs singly. Finally, a molecular clone carrying the eight most common resistance mutations seen in these selections was characterized. The sequence of this virus was relatively stable during selection for revertants in spite of displaying poor processing at the NC/p1 site and having significantly reduced fitness. These results reveal patterns of drug resistance that extend to near the limits of attainable selective pressure with these inhibitors and confirm the patterns of cross-resistance for these three inhibitors and the attenuation of virion protein processing and fitness that accompanies high-level resistance.


Subject(s)
HIV Protease Inhibitors/antagonists & inhibitors , HIV Protease/physiology , HIV-1/drug effects , Cells, Cultured , Drug Resistance, Viral/genetics , HIV Protease/genetics , HIV Protease Inhibitors/pharmacology , HIV-1/genetics , Indinavir/antagonists & inhibitors , Indinavir/pharmacology , Mutation , Ritonavir/antagonists & inhibitors , Ritonavir/pharmacology , Saquinavir/antagonists & inhibitors , Saquinavir/pharmacology
12.
Ther Drug Monit ; 24(4): 487-91, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12142631

ABSTRACT

The authors investigated the steady-state plasma pharmacokinetics of nelfinavir in HIV-1-infected children in a dosage of 30 mg/kg every 8 hours and 45 mg/kg every 12 hours in 12 HIV-1-infected children (aged 2.1 to 10.8 years) participating in an open-label study of nelfinavir in combination with stavudine and lamivudine. Median values of the primary pharmacokinetic parameters of nelfinavir 30 mg/kg every-8-hours (n = 8) and 45 mg/kg every 12 hours (n = 10) were, respectively, for the area under the plasma concentration-time curve over 24 hours, 90.5 and 71.9 h x microg/mL, for the trough concentration 1.9 and 1.0 microg/mL, and for the maximal concentration 6.3 and 5.2 microg/mL. Overall, a 7-fold interpatient variability was observed for the exposure to nelfinavir. Nelfinavir 30 mg/kg every-8-hours or 45 mg/kg every 12 hours in HIV-1-infected children generally resulted in plasma concentrations higher than those obtained in adults. However, due to a large interpatient variability in the exposure, individual dosage adjustments based on plasma concentrations may be necessary for both dosing regimens to ensure optimal treatment.


Subject(s)
Anti-HIV Agents/pharmacokinetics , HIV Infections/metabolism , Nelfinavir/pharmacokinetics , Administration, Oral , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Area Under Curve , Child , Child, Preschool , Chromatography, High Pressure Liquid , Cross-Over Studies , Drug Therapy, Combination , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/antagonists & inhibitors , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/therapeutic use , Humans , Lamivudine/therapeutic use , Male , Nelfinavir/administration & dosage , Nelfinavir/therapeutic use , Powders , Stavudine/therapeutic use , Tablets
15.
Lancet ; 355(9203): 547-8, 2000 Feb 12.
Article in English | MEDLINE | ID: mdl-10683007

ABSTRACT

St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.


Subject(s)
HIV Protease Inhibitors/pharmacokinetics , Hypericum/adverse effects , Indinavir/pharmacokinetics , Plants, Medicinal , Administration, Oral , Adult , Area Under Curve , Chromatography, High Pressure Liquid , Drug Resistance , Female , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/antagonists & inhibitors , Humans , Indinavir/administration & dosage , Indinavir/antagonists & inhibitors , Male , Middle Aged , Treatment Failure
16.
Article in Russian | MEDLINE | ID: mdl-10096217

ABSTRACT

The problems of the effectiveness of the treatment of HIV-infected patients with 11 medicinal preparations and their combinations are discussed. 5 preparations (AZT, zalcitabine, videx, stavudine and lamivudine) are the nucleoside inhibitors of the synthesis of provirus DNA, catalyzed by inverse transcriptases; 2 preparations (nevirapine and rescriptor) are the inhibitors of this enzyme, having nonnucleoside nature, and 4 preparations (saquinarin, ritonavir, indinavir and nelfinavir) are the inhibitors of the processing of virus RNA, catalyzed by HIV protease. The modern concepts of the mechanism of action of the above-mentioned preparations are presented and the problem of the search of new effective medicinal preparations is discussed.


Subject(s)
HIV Infections/drug therapy , HIV-1 , Anti-HIV Agents/antagonists & inhibitors , Anti-HIV Agents/therapeutic use , Drug Resistance, Microbial , Drug Therapy, Combination , HIV Protease Inhibitors/antagonists & inhibitors , HIV Protease Inhibitors/therapeutic use , Humans , Remission Induction , Treatment Failure
17.
Biochemistry ; 37(43): 15042-9, 1998 Oct 27.
Article in English | MEDLINE | ID: mdl-9790666

ABSTRACT

The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , HIV Protease/genetics , HIV-1/enzymology , Urea/analogs & derivatives , Amino Acid Substitution/genetics , Azepines , Binding Sites/drug effects , Binding Sites/genetics , Drug Resistance, Microbial/genetics , HIV Protease/pharmacology , HIV Protease Inhibitors/antagonists & inhibitors , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , Humans , Macromolecular Substances , Models, Molecular , Mutagenesis, Site-Directed , Substrate Specificity , Urea/antagonists & inhibitors , Urea/chemistry , Urea/pharmacology
18.
Biochemistry ; 37(11): 3594-601, 1998 Mar 17.
Article in English | MEDLINE | ID: mdl-9530286

ABSTRACT

The FDA approved HIV-1 protease inhibitors, ritonavir, saquinavir, and indinavir, are very effective in inhibiting HIV-1 replication, but their long-term efficacy is unknown. Since in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether these protease inhibitors are recognized by the MDR1 multidrug transporter (P-glycoprotein, or P-gp), thereby reducing their intracellular accumulation. In vitro studies in isolated membrane preparations from insect cells infected with MDR1-expressing recombinant baculovirus showed that these inhibitors significantly stimulated P-gp-specific ATPase activity and that this stimulation was inhibited by SDZ PSC 833, a potent inhibitor of P-gp. Furthermore, photoaffinity labeling of P-gp with the substrate analogue [125I]iodoarylazidoprazosin (IAAP) was inhibited by all three inhibitors. Cell-based approaches to evaluate the ability of these protease inhibitors to compete for transport of known P-gp substrates showed that all three HIV-1 protease inhibitors were capable of inhibiting the transport of some of the known P-gp substrates but their effects were generally weaker than other documented P-gp modulators such as verapamil or cyclosporin A. Inhibition of HIV-1 replication by all three protease inhibitors was reduced but could be restored by MDR1 inhibitors in cells expressing MDR1. These results indicate that the HIV-1 protease inhibitors are substrates of the human multidrug transporter, suggesting that cells in patients that express the MDR1 transporter will be relatively resistant to the anti-viral effects of the HIV-1 protease inhibitors, and that absorption, excretion, and distribution of these inhibitors in the body may be affected by the multidrug transporter.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Drug Resistance, Multiple , Genes, MDR , HIV Protease Inhibitors/metabolism , HIV-1/enzymology , 3T3 Cells , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Adenosine Triphosphatases/metabolism , Affinity Labels , Animals , Azides/metabolism , Binding, Competitive , Biological Transport/drug effects , Carcinoma, Squamous Cell , Enzyme Activation/drug effects , HIV Protease Inhibitors/antagonists & inhibitors , HIV Protease Inhibitors/pharmacology , Humans , Iodine Radioisotopes , Mice , Prazosin/analogs & derivatives , Prazosin/metabolism , Spodoptera/genetics , Substrate Specificity , Tumor Cells, Cultured , Vinblastine/pharmacology
19.
J Infect Dis ; 171(3): 546-51, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7876599

ABSTRACT

Since plasma protein binding of antiinfectives can adversely affect drug activity, the effect of serum proteins on the in vitro antiviral activity of A77003, a human immunodeficiency virus type 1 (HIV) protease inhibitor, was investigated. In vitro, A77003 is effective in both acute and chronic infection in 10% fetal bovine or human serum. As the concentration of human serum was increased to 50%, antiviral efficacy decreased 3- to 6-fold. Purified human alpha 1 acid glycoprotein (alpha 1-AGP) at physiologic concentrations (0.5-2 mg/mL) dose-dependently reduced the antiviral activity of A77003. alpha 1-AGP at 1 mg/mL also antagonized the anti-HIV activity of A77003-zidovudine combinations. Therefore, higher concentrations of HIV protease inhibitors than would be predicted, on the basis of in vitro activity in the absence of physiologic concentrations of binding protein, may be required to effectively limit viral replication in vivo.


Subject(s)
Antiviral Agents/antagonists & inhibitors , HIV Protease Inhibitors/antagonists & inhibitors , HIV-1/drug effects , Methylurea Compounds , Orosomucoid/pharmacology , Pyridines , Dose-Response Relationship, Drug , HIV Protease Inhibitors/metabolism , Humans , Orosomucoid/metabolism , Protein Binding , Valine/analogs & derivatives , Zidovudine/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...