The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart

Reyskens, Kathleen M. S. E.; Essop, M. Faadiel

doi:10.1016/j.ijcard.2013.04.128

Cited by 13 publications

(16 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The drug cocktail composed of AZT (100 mg kg −1 day −1 ), ritonavir (20 mg kg −1 day −1 ), and saquinavir (25 mg kg −1 day −1 ) was administered twice daily for 7 days by continuous intravenous injection. Each drug dose was based on previously published studies in rodents (Shibata et al 2002; Huisman et al 2003; Manda et al 2010; Pistell et al 2010; Waring et al 2010; Yang et al 2010; du Plooy et al 2011; Fontes et al 2011; Lledo-Garcia et al 2011; Wagner et al 2011; Mak et al 2013; Reyskens and Essop 2013a, b; Reyskens et al 2013). The catheters were flushed with 0.3 ml heparin (50 IU/ml) in PBS until the end of treatments.…”

Section: Methodsmentioning

confidence: 99%

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

et al. 2014

View full text Add to dashboard Cite

HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

show abstract

Section: Methodsmentioning

confidence: 99%

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It is therefore likely that other mechanisms may be responsible for such effects, e.g. PI treatment can attenuate adipokine levels (adiponectin, leptin) [40] and subsequently increase overall energy expenditure thereby contributing to weight loss [41,42]. By contrast, previous work from our laboratory found that two months of PI treatment resulted in a significant increase in rat body weight [16].…”

Section: Discussionmentioning

confidence: 99%

“…Thus also raises the point which preclinical model would be most suited to simulate the clinical context. As we have previously employed an osmotic pump mode of delivery that resulted in greater pathology [16,42], we propose that this may be a model better suited to employ for such studies. However, it should be noted that the vehicle (1% ethanol) used to dissolve the PIs may potentially cause problems for longer-term studies and also that this experimental model requires sub-cutaneous implantation of mini-osmotic pumps (to be changed at regular intervals).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration

et al. 2017

Self Cite

View full text Add to dashboard Cite

Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.

show abstract

“…Therapy with ART may exacerbate these abnormalities. 5,10,11 The mechanisms of these metabolic abnormalities are complex and interdependent with the impaired glucose metabolism and dyslipidemia partly due to abnormal fat distribution (especially abdominal fat) and inflammation. 12,13 The role of inflammation in the pathogenesis of atherosclerosis is well known in the general population 14 and is thought to play a significant and unique role in the development of CVD and increased risk in patients infected with HIV.…”

Section: Human Immunodeficiency Virusmentioning

confidence: 99%

Lipid Management in Human Immunodeficiency Virus

Myerson¹

2015

Cardiology Clinics

View full text Add to dashboard Cite

The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart

Cited by 13 publications

References 22 publications

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration

Lipid Management in Human Immunodeficiency Virus

Contact Info

Product

Resources

About