HIV-Protease Inhibitors

Flexner, Charles

doi:10.1056/nejm199804303381808

Cited by 802 publications

(498 citation statements)

References 48 publications

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“…Saquinavir is rapidly metabolized by CYP3A4 via first-pass hepatic metabolism. When coformulated with ritonavir (currently the only available formulation), the bioavailability of saquinavir is much higher [89]. Common adverse effects of saquinavir include nausea, diarrhea, and abdominal discomfort.…”

Section: Saquinavir (Sqv)mentioning

confidence: 99%

“…Ritonavir (Norvir™) is metabolized by CYP3A4 (major) CYP2D6 (minor) and has a serum half-life of 3-5 h. Ritonavir induces its own metabolism [89]. Ritonavir is rarely used at doses with PI activity.…”

Section: Ritonavir (Rtv)mentioning

confidence: 99%

“…The serum half-life is 3.5-5 h [89]. Because nelfinavir induces its own metabolism, trough concentrations at 1 week are about half of those at day 2 [108].…”

Section: Nelfinavir (Nfv)mentioning

confidence: 99%

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A Review of the Toxicity of HIV Medications

et al. 2013

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Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

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Section: Saquinavir (Sqv)mentioning

confidence: 99%

Section: Ritonavir (Rtv)mentioning

confidence: 99%

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A Review of the Toxicity of HIV Medications

et al. 2013

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“…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.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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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The Changing Spectrum of the Cutaneous Manifestations of HIV Disease

Costner¹,

Cockerell²

1998

Arch Dermatol

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HIV-Protease Inhibitors

Cited by 802 publications

References 48 publications

A Review of the Toxicity of HIV Medications

A Review of the Toxicity of HIV Medications

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

The Changing Spectrum of the Cutaneous Manifestations of HIV Disease

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