Reverse Phase High-Performance Liquid Chromatography Method for the Analysis of Amprenavir, Efavirenz, Indinavir, Lopinavir, Nelfinavir and Its Active Metabolite (M8), Ritonavir, and Saquinavir in Heparinized Human Plasma

Keil, Kim M.; Frerichs, Valerie; DiFrancesco, Robin; Morse, Gene D.

doi:10.1097/00007691-200306000-00015

Cited by 56 publications

(43 citation statements)

References 14 publications

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“…Our present results indicate that both Lopinavir and Ritonavir at concentrations reached in treated patients [32] are able to modulate the cytokine production by PBMCs and macrophages of healthy individuals. We have also shown that the NO-hybridization significantly alters the immunopharmacological profile of Lopinavir but not that of Ritonavir.…”

Section: Resultssupporting

confidence: 50%

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Fagone

Mangano

Quattrocchi

et al. 2015

Basic Clin Pharmacol Toxicol

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HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non-steroidal, anti-inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect, acquires antitumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO-hybridization on two other PIs, Lopinavir and Ritonavir. The two NO-derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir-NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir-NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir-NO effects overlapped those of Ritonavir. These data demonstrate that NO-hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T-cell secretory capacity. Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis. Antiretroviral protease inhibitors (PIs) in combination with nucleoside or non-nucleoside reverse transcriptase inhibitors are the basis for the highly active antiretroviral therapy (HA-ART) that is efficient in suppression of HIV replication and reduction of clinical manifestations of the disease [1].In addition to their primary pharmacological indication, these drugs have also been described to possess antineoplastic and immunomodulatory properties both in in vitro and in vivo pre-clinical settings [2][3][4].However, serious side effects including dyslipidaemia, insulin resistance, lipodystrophy, hepatotoxicity and atherosclerotic cardiovascular complications [5][6][7][8][9] have dampened the possible extension of these drugs to therapeutic areas different than HIV infection.It has been previously demonstrated that nitric oxide (NO)-hybridization may reduce toxicity of parental compounds while enhancing the pharmacological potency of the drugs [10]. Along this line of research, several derivatives of PIs have been synthesized at OncoNOx (Copenhagen, Denmark) by covalent attachment of NO moiety to the parental molecules.Previous work carried out by ourselves and others has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretro...

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Section: Resultssupporting

confidence: 50%

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Fagone

Mangano

Quattrocchi

et al. 2015

Basic Clin Pharmacol Toxicol

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“…Efavirenz and lopinavir concentrations in plasma were measured by high-performance liquid chromatography in the Pharmacology Support Laboratory at the University at Buffalo with methods validated within the Adult AIDS Clinical Trials Group Quality Assurance Proficiency Testing program (18). The lower limits of quantitation were Ͻ100 and Ͻ200 ng/ml for efavirenz and lopinavir, respectively.…”

Section: Methodsmentioning

confidence: 99%

Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

DiCenzo

Peterson

Cruttenden

et al. 2004

Antimicrob Agents Chemother

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Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavirritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0 ) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC 0-24 s) of EFV (n ‫؍‬ 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC 0-8 s of LPV (n ‫؍‬ 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n ‫؍‬ 11) were ؊1.0 (؊9.4, 7.4) g/ml and ؊2.1 (؊11.1, 6.9) g/ml for EFV (n ‫؍‬ 10) and ؊5.0 (؊13.2, 3.3) g/ml and ؊6.7 (؊17.6, 4.2) g/ml for LPV/r (n ‫؍‬ 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA.

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“…2.6.2 Atazanavir and ritonavir assays-RTV was quantified using a previously published simultaneous high-performance liquid chromatography (HPLC) assay with slight modification (Keil et al, 2003;Keil et al, in press). ATV was added to this method at a later date following approval.…”

Section: Biochemical Assaysmentioning

confidence: 99%

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

McCance‐Katz

Moody

Morse

et al. 2007

Drug and Alcohol Dependence

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Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxonemaintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxonemaintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

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Reverse Phase High-Performance Liquid Chromatography Method for the Analysis of Amprenavir, Efavirenz, Indinavir, Lopinavir, Nelfinavir and Its Active Metabolite (M8), Ritonavir, and Saquinavir in Heparinized Human Plasma

Cited by 56 publications

References 14 publications

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

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