Clinical Extrapolation of the Effects of Dolutegravir and Other HIV Integrase Inhibitors on Folate Transport Pathways.

Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to dolutegravir at the time of conception. Folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of folate transport pathways: proton-coupled folate transporter (PCFT), reduced folate carrier (RFC), and folate receptor α (FRα)-mediated endocytosis. Inhibition of folate transport was extrapolated to the clinic by using established approaches for transporters in intestine, distribution tissues, and basolateral and apical membranes of renal proximal tubules (2017 FDA Guidance). The positive controls, methotrexate and pemetrexed, demonstrated clinically relevant inhibition of PCFT, RFC, and FRα in folate absorption, distribution, and renal sparing. Valproic acid was used as a negative control that elicits folate-independent NTDs; valproic acid did not inhibit PCFT, RFC, or FRα At clinical doses and exposures, the observed in vitro inhibition of FRα by dolutegravir and cabotegravir was not flagged as clinically relevant; PCFT and RFC inhibition was not observed in vitro. Bictegravir inhibited both PCFT and FRα, but the observed inhibition did not reach the criteria for clinical relevance. Elvitegravir and raltegravir inhibited PCFT, but only raltegravir inhibition of intestinal PCFT was flagged as potentially clinically relevant at the highest 1.2-g dose (not the 400-mg dose). These studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed. SIGNIFICANCE STATEMENT: Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to the HIV integrase inhibitor dolutegravir at the time of conception; folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of the major folate transport pathways: proton-coupled folate transporter, reduced folate carrier, and folate receptor α-mediated endocytosis. The present studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Furthermore, clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed.

[Acute lung injury and changes of myocardial ATP enzymes induced by lipopolysaccharide in aging rats].

OBJECTIVE: To investigate whether acute lung injury (ALI) and changes of myocardial ATP enzymes were induced by intravenous or intraventricle of left heart injection of lipopolysaccharide (LPS) in aging rats. METHODS: 40 male Wistar rats were used for reproducing aging animal model. Aging rats were randomly divided into aging control group (n = 8), ALI group (LPS, 5 mg/kg body weight intravenous injection, n = 16), and LPS group (same dosage LPS, intraventricle of left heart injection, n = 16). The samples (blood, lung and heart) were collected at 2, 6 hours after LPS or saline administration. RESULTS: Compared with aging control, protein content in bronchial alveolar lavage fluid (BALF), ratio of lung wet/dry weight and the LA, NO2-/NO3- and MDA contents in blood were increased markedly (P < 0.01) at 2, 6 hours in ALI group. The GSH-Px, Na(+)-K(+)-ATPase activities in lung tissue were decreased significantly (P < 0.01), but NO2-/NO3- content in lung tissue was increased obviously (P < 0.01) at 2 hours in ALI group. These changes were maintained until at 6 hours after LPS administration. The above parameters were no obviously changes in myocardium at 2 hours after LPS administration in ALI group. But at 6 hours, MDA content was increased obviously (P < 0.01); Na(+)-K(+)-ATPase, Ca(2+)-Mg(2+)-ATPase and GSH-Px activities in myocardium were decreased markedly (P < 0.01). While in LPS group, only NO2-/NO3- contents were increased (P < 0.05) in blood and lung tissue as well as Na(+)-K(+)-ATPase activity in lung tissue were decreased (P < 0.05), another parameters had no obvious changes. CONCLUSIONS: ALI was obviously formed by intravenous injection LPS after 2, 6 hours in aging rats. Myocardial enzyme etc decreased only at 6 hours in ALI group. But above parameters were no obviously changes in LPS group. It was suggested that there was probable myocardial damage in rats of ALI group, and it was mainly induced by ALI.

[Hepatic injury induced by acute lung injury in aging rats].

OBJECTIVE: To investigate the induction of hepatic function damage by acute lung injury (ALI) in aging rats and the effect of Ginkgo Biloba extract (GBE) on this process. METHODS: Thirty male Wistar rats were used to produce the aging animal model. Aging rats were randomly divided into three groups: the control group, the lipopolysaccharide (LPS, intravenous injection) group, and the GBE + LPS group (GBE given 7 days before experiment, once a day, via the esophagus). Samples from the blood, the lung and the liver were collected 2 and 6 h after LPS or saline administration. RESULTS: ALI was induced by intravenous injection of LPS in aging rats. Compared with the aging control, the total bilirubin content and the glutamic pyruvic transaminase (GPT) activity in serum did not change at 2 h after LPS administration. But at 6 h, they were increased, respectively from (10.9 +/- 0.6) mg/L and (26 +/- 3) U in the control group to (30.1 +/- 2.1) mg/L and (88 +/- 12) U in the LPS group (P < 0.001). MDA content increased in the blood and the lung tissue at 2 has compared to the control group, from (15.9 +/- 1.8) micro mol/L and (18.8 +/- 2.1) nmol/mg protein to (22.1 +/- 1.9) micro mol/L and (28.8 +/- 3.1) nmol/mg protein (all P < 0.001), respectively. SOD activity in the lung tissue was decreased significantly, from (25.5 +/- 2.6) mU/L and (36.1 +/- 2.4) U/mg protein to (20.6 +/- 1.9) mU/L and (32.0 +/- 2.7) U/mg protein, respectively (P < 0.05, P < 0.001). The GSH-P(X) activity and the Na(+)-K(+)-ATPase activity in the lung tissue at 2 hours after LPS administration were decreased markedly, from (28.2 +/- 2.8) U/mg protein and (4.9 +/- 0.5) micromol Pi x mg(-1) protein x h(-1). to (21.1 +/- 2.7) U/mg protein and (3.1 +/- 0.3) micromol Pi x mg(-1) protein x h(-1). These changes lasted 6 h after LPS administration. These parameters did not change significantly in the hepatic tissue at 2 h after LPS administration. But after 6 h, MDA content was increased from (7.9 +/- 0.9) nmol/mg protein to (10.9 +/- 0.7) nmol/mg protein; while the GSH-P(X) and the Na(+)-K(+)-ATPase activities were decreased markedly, from (59.0 +/- 3.9) U/mg protein and (0.87 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) to (49.2 +/- 3.0) U/mg protein and (0.77 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) (P < 0.001, P < 0.01). There was no obvious change in the SOD activity. All the changes were significantly attenuated in the GBE + LPS group (P < 0.05, P < 0.01). CONCLUSION: Hepatic function damage could be induced by ALI in aging rats. GBE showed a protective effect on ALI and hepatic function damage in this animal model.