Nitrolipids in kidney physiology and disease

Jobbagy, Soma; Tan, Roderick J.

doi:10.1016/j.niox.2018.03.021

Cited by 7 publications

(3 citation statements)

References 90 publications

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“…The lead compound for development in acute and chronic settings is CXA-10 (10-NO 2 -OA, a specific positional isomer of NO 2 -OA). Although initially focused on acute kidney injury with particular interest in contrast-induced nephropathy, the primary pharmacological targets were later changed to focal segmental glomerulosclerosis and pulmonary arterial hypertension based on promising preclinical studies (72,73). …”

Section: Development Of Nitrated Fatty Acid As Drugsmentioning

confidence: 99%

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

Schöpfer

Vitturi

Jorkasky³

et al. 2018

Nitric Oxide

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Nitrated oleic acid (NO2-OA) was first identified in 2003, and after the characterization of its formation and thiol reactivity, it was used as a prototypical molecule to investigate the physiological actions of endogenous nitrated fatty acids (NO2-FA). Based on in vitro observations showing significant activation of cytoprotective and anti-inflammatory signaling responses by NO2-FA, experiments were designed to determine their pharmacological potential. Supported by strong intellectual protection and favorable pharmacokinetic and pharmacodynamic data, 10-NO2-OA (CXA-10) underwent pharmaceutical development as a drug to treat fibrotic and inflammatory diseases. NO2-FA are at the intersection of three unconventional drug candidate classes that include 1) fatty acids, 2) metabolic intermediates and 3) electrophilic molecules. These three groups use different scaffolds for drug development, are characterized by broad activities and are individually gaining traction as alternatives to mono-target drug therapies. In particular, NO2-FA share key characteristics with currently approved pharmacological agents regarding reactivity, distribution, and mechanism of action. This review first presents the characteristics, liabilities, and opportunities that these different drug candidate classes display, and then discusses these issues in the context of current progress in the preclinical and clinical development of NO2-FA as drugs. Lessons learned from the novel approaches presented herein were considered early on during development to structurally define and improve NO2-FA and their disease targets.

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Section: Development Of Nitrated Fatty Acid As Drugsmentioning

confidence: 99%

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

Schöpfer

Vitturi

Jorkasky³

et al. 2018

Nitric Oxide

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“…10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10) is a specific regioisomer of OA‐NO 2 , characterized by a nitro group on carbon 10 with effects similar to the mixed isomer. NFAs, in general, and CXA‐10, in particular, demonstrate potential as effective therapeutic agents in multiple disease indications in which metabolic and oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles …”

mentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Garner¹,

Mould

Chieffo³

et al. 2019

Clinical Translational Sci

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10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA‐10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA‐10. After single and multiple ascending doses, CXA‐10 demonstrated dose‐proportional increases in plasma exposure. CXA‐10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA‐10‐202, a consistent decrease from baseline was observed with CXA‐10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP‐1, and IL‐6. In CXA‐10‐203, after coadministration with CXA‐10, geometric mean peak plasma concentration (Cmax) and area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval (AUC0−t) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA‐10. Adverse events (AEs) were dose‐related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA‐10 was safe and well‐tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA‐10 75–300 mg once daily.

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“…Chronic kidney disease involves the bilateral, progressive, chronic deterioration of nephrons and becomes apparent when 50 -75% of approximately two million nephrons have ceased their physiological function. In such cases, death is inevitable unless renal replacement therapies are undertaken (1,2). This disease poses a significant health problem due to its substantial financial burden, and the absence of early and appropriate management can lead to end-stage renal disease (3).…”

Section: Introductionmentioning

confidence: 99%

Survival Rate of Hemodialysis Patients and Its Predictors: A Multicentric Retrospective Cohort Study

Ahmadi Valiabadi,

Hosseinigolafshani,

Ranjbaran

2024

Jundishapur J Chronic Dis Care

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Background: Despite advancements in medical and nursing care, the mortality rate among hemodialysis patients remains unexpectedly high. Objectives: This study aimed to evaluate the survival rates and identify mortality predictors among hemodialysis patients in Qazvin Province, Iran, over a five-year period from March 2015 to March 2020. Methods: This historical cohort study involved 378 hemodialysis patients from seven hospitals in Qazvin province, including Bu Ali Sina, Velayat, Razi, Alvand, Valiasr, Bueen Zahra, and Avaj, covering the period from March 21, 2015, to March 20, 2020. The study was based on data extracted from the patient's medical records, offering a detailed overview of their medical history and treatments during this timeframe. Results: The study revealed a median survival time of 38.5 months, with survival rates at 1, 2, 3, 4, and 5 years being 84.3%, 68.1%, 53.2%, 39.8%, and 18.0%, respectively. Cox regression analysis identified several key predictors of mortality. Mortality rates increased with age, higher levels of blood urea nitrogen, and when hemoglobin levels fell below 10 g/dL or calcium levels exceeded 9.5 mg/dL. Conversely, patients who underwent hemodialysis three times a week had higher levels of education, used fistula access, and experienced significantly lower mortality rates. Conclusions: The study highlighted the need for targeted interventions to improve both the survival rates and quality of life for hemodialysis patients in Qazvin Province. It emphasized the importance of careful monitoring and effective management of factors such as age, blood urea nitrogen, hemoglobin, and calcium levels, as well as the patients' educational background, frequency of dialysis sessions, and type of vascular access. By focusing on these aspects, healthcare professionals in the region could significantly enhance patient outcomes and prognoses in hemodialysis care.

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Nitrolipids in kidney physiology and disease

Cited by 7 publications

References 90 publications

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Survival Rate of Hemodialysis Patients and Its Predictors: A Multicentric Retrospective Cohort Study

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