Browsing by Subject "Quinolines"

Now showing 1 - 7 of 7
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    Diabetes Risk Factors in People With HIV Receiving Pitavastatin Versus Placebo for Cardiovascular Disease Prevention : A Randomized Trial
    (American College of Physicians, 2024) Fitch, Kathleen V.; Zanni, Markella V.; Manne-Goehler, Jennifer; Diggs, Marissa R.; Gattu, Arijeet K.; Currier, Judith S.; Bloomfield, Gerald S.; Hsiao, Chiu-Bin; Gupta, Samir K.; Aberg, Judith A.; Malvestutto, Carlos D.; Fichtenbaum, Carl J.; Lu, Michael T.; Douglas, Pamela S.; Ribaudo, Heather J.; Grinspoon, Steven K.; Medicine, School of Medicine
    Background: REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) led to new guidelines for statin use among people with HIV (PWH) with low to moderate risk for atherosclerotic cardiovascular disease (ASCVD). Little is known about the natural history of diabetes mellitus (DM) or mechanisms contributing to statin effects on DM among this population. Objective: To determine the contribution of known DM risk factors to excess risk for DM with pitavastatin in REPRIEVE. Design: Phase 3, primary ASCVD prevention trial over a median of 5.6 years of follow-up. (ClinicalTrials.gov: NCT02344290). Setting: Global, multicenter trial. Participants: 7731 PWH aged 40 to 75 years with low to moderate ASCVD risk (by the pooled cohort equations from the American College of Cardiology and American Heart Association) without DM at study entry. Intervention: Random 1:1 assignment to pitavastatin, 4 mg daily, or placebo. Measurements: New-onset DM was determined at each visit by clinical diagnosis requiring initiation of medication treatment for DM. The incidence of new-onset DM was assessed in relation to predefined demographic and metabolic risk factors, stratified by treatment group. Treatment effects of pitavastatin on progression to new DM in key subgroups were determined. Results: Participants with at least 3 DM risk factors (vs. no risk factors) had increased risk for DM in each treatment group (incidence rate, 3.24 per 100 person-years [PY] vs. 0.34 per 100 PY [pitavastatin] and 2.66 per 100 PY vs. 0.27 per 100 PY [placebo]). The incidence of DM was highest in South Asia. In adjusted analyses, high body mass index, prediabetes, and metabolic syndrome components were strongly associated with new-onset DM (all P < 0.005). Limitation: Pitavastatin was the only statin assessed; DM was assessed clinically. Conclusion: Metabolic risk factors, including prediabetes and obesity, contributed to new-onset DM in statin- and placebo-treated participants. A clinically significant effect of pitavastatin on DM was seen primarily among those with multiple risk factors for DM at entry. Strategies targeting key metabolic risk factors, like obesity and prediabetes, may help protect against DM among PWH.
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    Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy
    (Springer Nature, 2022-05-19) Daeschler, Simeon C.; Zhang, Jennifer; Gordon, Tessa; Borschel, Gregory H.; Feinberg, Konstantin; Surgery, School of Medicine
    Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.
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    Impact of the expanded label for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with no F508del variant in the USA
    (European Respiratory Society, 2024-11-14) Cromwell, Elizabeth A.; Ostrenga, Josh S.; Sanders, Don B.; Morgan, Wayne; Castellani, Carlo; Szczesniak, Rhonda; Burgel, Pierre-Regis; Pediatrics, School of Medicine
    Background: Elexacaftor/tezacaftor/ivacaftor (ETI), which is approved for people with cystic fibrosis (pwCF) with a F508del variant, was further approved based on in vitro data in the USA for those carrying at least one of 177 rare CFTR (cystic fibrosis transmembrane conductance regulator) variants. Methods: PwCF, aged ≥6 years, carrying no F508del variant but with at least one of these 177 rare variants, were identified within the US Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2020 and 2022. The evolution of forced expiratory volume in 1 s (FEV1) percentage predicted and rates of pulmonary exacerbations were analysed over the first year following ETI initiation, using a linear regression with generalised estimating equations and a negative binomial model, respectively. Results: A total of 1791 individuals aged ≥6 years with rare CFTR variants were eligible for ETI, corresponding to 5.2% of CFFPR participants. 815 individuals (45.5%), of which 57.9% were already treated with another CFTR modulator, initiated ETI within the first 2 years following approval. Individuals with more severe respiratory disease were more likely to initiate ETI, whereas those previously treated with another CFTR modulator or those with no private insurance coverage had less ETI initiation. ETI initiation was associated with an increase in mean FEV1 % pred by +3.39 (95% CI 2.14-4.64) and a decrease in the rates of pulmonary exacerbations (adjusted rate ratio 0.55, 95% CI 0.38-0.79). These effects were greater in individuals naïve of previous CFTR modulators. Conclusions: Extension of the ETI label to rare CFTR variants is associated with meaningful improvements in lung function and a marked reduction in pulmonary exacerbations.
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    In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases
    (ASPET, 2015-12) Cardoso, Josiane de Oliveira; Oliveira, Regina Vincenzi; Lu, Jessica Bo Li; Desta, Zeruesenay; Department of Medicine, IU School of Medicine
    Montelukast has been recommended as a selective in vitro and in vivo probe of cytochrome P450 (P450) CYP2C8 activity, but its selectivity toward this enzyme remains unclear. We performed detailed characterization of montelukast metabolism in vitro using human liver microsomes (HLMs), expressed P450s, and uridine 5′-diphospho-glucuronosyltransferases (UGTs). Kinetic and inhibition experiments performed at therapeutically relevant concentrations reveal that CYP2C8 and CYP2C9 are the principal enzymes responsible for montelukast 36-hydroxylation to 1,2-diol. CYP3A4 was the main catalyst of montelukast sulfoxidation and stereoselective 21-hydroxylation, and multiple P450s participated in montelukast 25-hydroxylation. We confirmed direct glucuronidation of montelukast to an acyl-glucuronide. We also identified a novel peak that appears consistent with an ether-glucuronide. Kinetic analysis in HLMs and experiments in expressed UGTs indicate that both metabolites were exclusively formed by UGT1A3. Comparison of in vitro intrinsic clearance in HLMs suggest that direct glucuronidation may play a greater role in the overall metabolism of montelukast than does P450-mediated oxidation, but the in vivo contribution of UGT1A3 needs further testing. In conclusion, our in vitro findings provide new insight toward montelukast metabolism. The utility of montelukast as a probe of CYP2C8 activity may be compromised owing to involvement of multiple P450s and UGT1A3 in its metabolism.
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    Management of hypertension in advanced kidney disease
    (Wolters Kluwer, 2022) Georgianos, Panagiotis I.; Agarwal, Rajiv; Medicine, School of Medicine
    Purpose of review: The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD). Recent findings: In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension. Summary: Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.
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    Quinoline Derivative MC1626, a Putative GCN5 Histone Acetyltransferase (HAT) Inhibitor, Exhibits HAT-Independent Activity against Toxoplasma gondii
    (American Society for Microbiology, 2007) Smith, Aaron T.; Livingston, Meredith R.; Mai, Antonello; Filetici, Patrizia; Queener, Sherry F.; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of Medicine
    We report that quinoline derivative MC1626, first described as an inhibitor of the histone acetyltransferase (HAT) GCN5, is active against the protozoan parasite Toxoplasma gondii in vitro. However, MC1626 does not inhibit Toxoplasma GCN5 HATs or reduce HAT-mediated activity; rather, this quinoline may target the plastid organelle called the apicoplast.
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    Weekly dihydroartemisinin–piperaquine versus monthly sulfadoxine–pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial
    (Elsevier, 2025) Idro, Richard; Nkosi-Gondwe, Thandile; Opoka, Robert; Ssenkusu, John M.; Dennis, Kalibbala; Tsirizani, Lufina; Akun, Pamela; Rujumba, Joseph; Nambatya, Winnie; Kamya, Carol; Phiri, Nomsa; Joanita, Kirikumwino; Komata, Ronald; Innussa, Mailosi; Tenywa, Emmanuel; John, Chandy C.; Tarning, Joel; Denti, Paolo; Wasmann, Roeland E.; ter Kuile, Feiko O.; Robberstad, Bjarne; Phiri, Kamija S.; Pediatrics, School of Medicine
    Background: In many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine-pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin-piperaquine and monthly sulfadoxine-pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine-pyrimethamine resistance of P falciparum in Uganda and Malawi. Methods: We did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin-piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine-pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099. Findings: Between April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin-piperaquine group and 357 participants in the sulfadoxine-pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2-18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin-piperaquine group and 43.7 events per 100 person-years in the sulfadoxine-pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14-0·30], p<0·0001). The incidence of hospitalisation with any malaria was lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (10·4 vs 37·0 events per 100 person-years; IRR 0·29 [0·20-0·42], p<0·0001) and the number of blood transfusions was also lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (52·1 vs 72·5 events per 100 person-years; IRR 0·70 [0·54-0·90], p=0·006). The incidence of all-cause unscheduled clinic visits and all-cause hospitalisations were similar between the two groups, however, participants in the dihydroartemisinin-piperaquine group had more clinic visits unrelated to malaria (IRR 1·12 [1·00-1·24], p=0·042) and more hospitalisations with lower respiratory tract events (16·5 vs 8·5 events per 100 person-years; IRR 1·99 [1·25-3·16], p=0·0036) than participants in the sulfadoxine-pyrimethamine group. The number of serious adverse events in the dihydroartemisinin-piperaquine group was similar to that in the sulfadoxine-pyrimethamine group (vaso-occlusive crisis [154 of 367 participants dihydroartemisinin-piperaquine group vs 132 of 357 participants in the sulfadoxine-pyrimethamine group] and suspected sepsis [115 participants vs 92 participants]), with the exception of acute chest syndrome or pneumonia (51 participants vs 32 participants). The number of deaths were similar between groups (six [2%] of 367 participants in the dihydroartemisinin-piperaquine group and eight (2%) of 357 participants in the sulfadoxine-pyrimethamine group). Interpretation: Malaria chemoprophylaxis with weekly dihydroartemisinin-piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine-pyrimethamine. However, monthly sulfadoxine-pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin-piperaquine should be considered as an alternative to sulfadoxine-pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years.