ritonavir and Hypertension--Pulmonary

Apoptosis resistance is a recognized pathogenetic mechanism in pulmonary hypertension. However, the link between apoptosis signal-regulating kinase-1 (ASK-1) and pulmonary hypertension (PH) is unclear. This study was conducted to elucidate ASK-1 as a potential biomarker in PH. The study aimed to identify the role of ASK-1 in the mechanism of monocrotaline-induced PH in rats.. Forty adult male Sprague-Dawley rats (body weight: 200-250 g) were randomly divided into five groups (n=8 per group). The four treatment groups received a single intraperitoneal injection of monocrotaline (MCT) at a dose of 60 mg. kg-1 while the control group received an equivalent volume of intraperitoneal saline injection. Zidovudine (100mg. kg-1), ritonavir (30mg. kg-1), or combination of both drugs (zidovudine 100mg. kg-1 and ritonavir 30mg. kg-1) were administrated daily for the study period of 28 days to the rats in three of the four treatment groups with MCT for 28 days. On the twenty-eighth day of the study, rats were sacrificed, and organ harvested with the heart analyzed using RT-PCR for ASK-1. Antioxidant enzyme activities were determined using the colorimetric method.. Animal survival rate was one hundred percent in the treated and control groups while the untreated group recorded 62% survival rate. There was significantly lower mRNA gene expression of ASK-1 in the heart tissues of the treated rats with zidovudine (2.67 ± 0.09, p < 0.0001), ritonavir (2.57 ±0.11, p < 0.0001) and a combination of both (2.75 ± 0.06, p < 0.0001) when compared to rats in the untreated group. An overexpressed mRNA gene of ASK-1 in the untreated rats was observed (12.0 ± 0.90, p < 0.0001) when compared to the controls.. ASK-1 is a veritable biomarker for anti-apoptotic characteristics of PH. Our findings will spur new investigations on the role of ASK-1 in PH and the potential therapeutic benefits of antiretroviral medications in the prevention of PH.. La résistance à l’apoptose est une pathogénétique reconnue mécanisme dans l’hypertension pulmonaire. Cependant, le lien entrekinase-1 régulatrice du signal d’apoptose (ASK-1) et pulmonaire l’hypertension (HTP) n’est pas claire. La présente étude a été menée pour :élucider ASK-1 comme biomarqueur potentiel de l’HTP. L’étude visait à :identifier le rôle de l’ASK-1 dans le mécanisme induit par la monocrotalinePH chez le rat.. Quarante rats Sprague-Dawley mâles adultes (poids corporel:200 à 250 g) ont été divisés au hasard en cinq groupes (n = 8 par groupe).Les quatre groupes de traitement ont reçu une seule injection intrapéritonéalede monocrotaline (TCM) à une dose de 60 mg. kg–1 pendant que le témoina reçu un volume équivalent d’injection intrapéritonéale de solution saline.Zidovudine (100 mg kg–1), ritonavir (30 mg kg–1) ou combinaison deles deux médicaments (zidovudine 100 mg. Kg–1 et ritonavir 30 mg. kg–1) étaient administré quotidiennement pendant la période d’étude de 28 jours aux rats dans trois des quatre groupes de traitement avec MCT pendant 28 jours. Sur levingt-huitième jour de l’étude, des rats ont été sacrifiés et des organesrécolté avec le cœur analysé à l’aide de rt-PCR pour ASK-1. Les activités enzymatiques antioxydantes ont été déterminées à l’aide de la colorimétrieméthode.. Le taux de survie des animaux était de cent pour cent dans les groupes traités et témoins tandis que le groupe non traité a enregistré 62 %taux de survie. L’expression des gènes de l’ARNm était significativement plus faible d’ASK-1 dans les tissus cardiaques des rats traités par la zidovudine (2.67 ± 0.09, p < 0.0001), ritonavir (2.57 ±0.11, p < 0.0001) et acombinaison des deux (2.75 ± 0.06, p < 0.0001) par rapport aux rats dans le groupe non traité. Un gène d’ARNm surexprimé d’ASK-1 dans les rats non traités ont été observés (12.0 ± 0.90, p < 0.0001) lorsque par rapport aux contrôles.. ASK-1 est un véritable biomarqueur antiapoptotique caractéristiques du pH. Nos conclusions donneront lieu à de nouvelles enquêtes sur le rôle de l’ASK-1 dans l’HTP et les avantages thérapeutiques potentiels demédicaments antirétroviraux dans la prévention de l’HTP.. Hypertension pulmonaire, régulation du signal d’apoptosekinase 1 (ASK-1), zidovudine, ritonavir, VIH/SIDA.

Topics: Animals; Anti-Retroviral Agents; Apoptosis; Biomarkers; Hypertension, Pulmonary; Male; Monocrotaline; Rats; Rats, Sprague-Dawley; Ritonavir; Zidovudine

Sildenafil is increasingly used for the therapy of pulmonary arterial hypertension (PAH) in HIV infected patients. However, concerns exist about pharmacokinetic interactions between sildenafil and protease inhibitors (PI); in particular, ritonavir has been shown to increase sildenafil AUC and Cmax by several folds. The aim of our study was to determine the plasma levels of sildenafil and PI in two HIV patients with PAH treated with antiretroviral therapy including ritonavir-boosted PI. Our patients both experienced sildenafil Cmax above 500 ng/mL; however, they did not report any significant adverse reactions to sildenafil during the follow-up period. Therapeutic drug monitoring of sildenafil should be taken in consideration during treatment in order to avoid overdosage.

Topics: Adult; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Ritonavir; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension (PH) is among the complications of HIV infection. Combination antiretroviral therapy may influence the progression of HIV-related PH. Because Akt signaling is a potential molecular target of HIV protease inhibitors (HPIs), we hypothesized that these drugs altered monocrotaline- and hypoxia-induced PH in rats by downregulating the Akt pathway, thereby inhibiting pulmonary artery smooth muscle cell proliferation.. Daily treatment with each of 3 first-generation HPIs (ritonavir 30 mg/kg, amprenavir 100 mg/kg, and nelfinavir 500 mg/kg) started 3 weeks after a subcutaneous monocrotaline injection (60 mg/kg) substantially diminished pulmonary artery pressure, right ventricular hypertrophy, number of muscularized pulmonary vessels, pulmonary arterial wall thickness, and proliferating pulmonary vascular Ki67-labeled cells without affecting vessel caspase 3 staining. HPI treatment partially prevented the development of hypoxia- and monocrotaline-induced PH. Monocrotaline-induced PH was associated with marked activation of Akt signaling in the lungs and proximal pulmonary arteries, with increases in phosphorylated Akt, phosphorylated glycogen-synthase-kinase-3β (GSK3), and phosphorylated endothelial nitric oxide synthase, all of which decreased markedly after treatment with each HPI. In contrast, PH-associated increases in phosphorylated extracellular signal-related kinase 1/2 and myosin light-chain phosphatase were unaltered by the HPIs. The 3 HPIs and the phosphatidylinositol 3-kinase inhibitor LY294002 inhibited platelet-derived growth factor-induced phosphorylation of Akt and GSK3 in cultured pulmonary artery smooth muscle cells and blocked cell proliferation; this last effect was abolished by the GSK3 inhibitor SB216763.. These results support an effect of HPIs on pulmonary vascular remodeling mediated by inhibition of Akt phosphorylation and consequently of pulmonary artery smooth muscle cell proliferation.

Topics: Animals; Animals, Newborn; Antiretroviral Therapy, Highly Active; Antiviral Agents; Blood Pressure; Carbamates; Cell Division; Furans; Hemodynamics; HIV Protease Inhibitors; Hypertension, Pulmonary; Hypoxia; Male; Monocrotaline; Nelfinavir; Pulmonary Artery; Rats; Rats, Wistar; Ritonavir; Sulfonamides