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Colombijn JM, Hooft L, Jun M, Webster AC, Bots ML, Verhaar MC, Vernooij RW. Antioxidants for adults with chronic kidney disease. Cochrane Database Syst Rev 2023; 11:CD008176. [PMID: 37916745 PMCID: PMC10621004 DOI: 10.1002/14651858.cd008176.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a significant risk factor for cardiovascular disease (CVD) and death. Increased oxidative stress in people with CKD has been implicated as a potential causative factor. Antioxidant therapy decreases oxidative stress and may consequently reduce cardiovascular morbidity and death in people with CKD. This is an update of a Cochrane review first published in 2012. OBJECTIVES To examine the benefits and harms of antioxidant therapy on death and cardiovascular and kidney endpoints in adults with CKD stages 3 to 5, patients undergoing dialysis, and kidney transplant recipients. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies until 15 November 2022 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included all randomised controlled trials investigating the use of antioxidants, compared with placebo, usual or standard care, no treatment, or other antioxidants, for adults with CKD on cardiovascular and kidney endpoints. DATA COLLECTION AND ANALYSIS Titles and abstracts were screened independently by two authors who also performed data extraction using standardised forms. Results were pooled using random effects models and expressed as risk ratios (RR) or mean difference (MD) with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS We included 95 studies (10,468 randomised patients) that evaluated antioxidant therapy in adults with non-dialysis-dependent CKD (31 studies, 5342 patients), dialysis-dependent CKD (41 studies, 3444 patients) and kidney transplant recipients (21 studies, 1529 patients). Two studies enrolled dialysis and non-dialysis patients (153 patients). Twenty-one studies assessed the effects of vitamin antioxidants, and 74 assessed the effects of non-vitamin antioxidants. Overall, the quality of included studies was moderate to low or very low due to unclear or high risk of bias for randomisation, allocation concealment, blinding, and loss to follow-up. Compared with placebo, usual care, or no treatment, antioxidant therapy may have little or no effect on cardiovascular death (8 studies, 3813 patients: RR 0.94, 95% CI 0.64 to 1.40; I² = 33%; low certainty of evidence) and probably has little to no effect on death (any cause) (45 studies, 7530 patients: RR 0.95, 95% CI 0.82 to 1.11; I² = 0%; moderate certainty of evidence), CVD (16 studies, 4768 patients: RR 0.79, 95% CI 0.63 to 0.99; I² = 23%; moderate certainty of evidence), or loss of kidney transplant (graft loss) (11 studies, 1053 patients: RR 0.88, 95% CI 0.67 to 1.17; I² = 0%; moderate certainty of evidence). Compared with placebo, usual care, or no treatment, antioxidants had little to no effect on the slope of urinary albumin/creatinine ratio (change in UACR) (7 studies, 1286 patients: MD -0.04 mg/mmol, 95% CI -0.55 to 0.47; I² = 37%; very low certainty of evidence) but the evidence is very uncertain. Antioxidants probably reduced the progression to kidney failure (10 studies, 3201 patients: RR 0.65, 95% CI 0.41 to 1.02; I² = 41%; moderate certainty of evidence), may improve the slope of estimated glomerular filtration rate (change in eGFR) (28 studies, 4128 patients: MD 3.65 mL/min/1.73 m², 95% CI 2.81 to 4.50; I² = 99%; low certainty of evidence), but had uncertain effects on the slope of serum creatinine (change in SCr) (16 studies, 3180 patients: MD -13.35 µmol/L, 95% CI -23.49 to -3.23; I² = 98%; very low certainty of evidence). Possible safety concerns are an observed increase in the risk of infection (14 studies, 3697 patients: RR 1.30, 95% CI 1.14 to 1.50; I² = 3%; moderate certainty of evidence) and heart failure (6 studies, 3733 patients: RR 1.40, 95% CI 1.11 to 1.75; I² = 0; moderate certainty of evidence) among antioxidant users. Results of studies with a low risk of bias or longer follow-ups generally were comparable to the main analyses. AUTHORS' CONCLUSIONS We found no evidence that antioxidants reduced death or improved kidney transplant outcomes or proteinuria in patients with CKD. Antioxidants likely reduce cardiovascular events and progression to kidney failure and may improve kidney function. Possible concerns are an increased risk of infections and heart failure among antioxidant users. However, most studies were of suboptimal quality and had limited follow-up, and few included people undergoing dialysis or kidney transplant recipients. Furthermore, the large heterogeneity in interventions hampers drawing conclusions on the efficacy and safety of individual agents.
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Affiliation(s)
- Julia Mt Colombijn
- Department of Nephrology and Hypertension, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Lotty Hooft
- Cochrane Netherlands, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Min Jun
- The George Institute for Global Health, UNSW, Sydney, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Department of Transplant and Renal Medicine, Westmead Hospital, Westmead, Australia
| | - Michiel L Bots
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University of Utrecht, Utrecht, Netherlands
| | - Robin Wm Vernooij
- Department of Nephrology and Hypertension, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
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Yu H, Song YY, Li XH. Early diabetic kidney disease: Focus on the glycocalyx. World J Diabetes 2023; 14:460-480. [PMID: 37273258 PMCID: PMC10236994 DOI: 10.4239/wjd.v14.i5.460] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
The incidence of diabetic kidney disease (DKD) is sharply increasing worldwide. Microalbuminuria is the primary clinical marker used to identify DKD, and its initiating step in diabetes is glomerular endothelial cell dysfunction, particularly glycocalyx impairment. The glycocalyx found on the surface of glomerular endothelial cells, is a dynamic hydrated layer structure composed of pro-teoglycans, glycoproteins, and some adsorbed soluble components. It reinforces the negative charge barrier, transduces the shear stress, and mediates the interaction of blood corpuscles and podocytes with endothelial cells. In the high-glucose environment of diabetes, excessive reactive oxygen species and proinflammatory cytokines can damage the endothelial glycocalyx (EG) both directly and indirectly, which induces the production of microalbuminuria. Further research is required to elucidate the role of the podocyte glycocalyx, which may, together with endothelial cells, form a line of defense against albumin filtration. Interestingly, recent research has confirmed that the negative charge barrier function of the glycocalyx found in the glomerular basement membrane and its repulsion effect on albumin is limited. Therefore, to improve the early diagnosis and treatment of DKD, the potential mechanisms of EG degradation must be analyzed and more responsive and controllable targets must be explored. The content of this review will provide insights for future research.
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Affiliation(s)
- Hui Yu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Yun Song
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Xian-Hua Li
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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Faria J, Gerritsen KGF, Nguyen TQ, Mihaila SM, Masereeuw R. Diabetic proximal tubulopathy: Can we mimic the disease for in vitro screening of SGLT inhibitors? Eur J Pharmacol 2021; 908:174378. [PMID: 34303664 DOI: 10.1016/j.ejphar.2021.174378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 11/27/2022]
Abstract
Diabetic kidney disease (DKD) is the foremost cause of renal failure. While the glomeruli are severely affected in the course of the disease, the main determinant for disease progression is the tubulointerstitial compartment. DKD does not develop in the absence of hyperglycemia. Since the proximal tubule is the major player in glucose reabsorption, it has been widely studied as a therapeutic target for the development of new therapies. Currently, there are several proximal tubule cell lines available, being the human kidney-2 (HK-2) and human kidney clone-8 (HKC-8) cell lines the ones widely used for studying mechanisms of DKD. Studies in these models have pushed forward the understanding on how DKD unravels, however, these cell culture models possess limitations that hamper research, including lack of transporters and dedifferentiation. The sodium-glucose cotransporters (SGLT) are identified as key players in glucose reabsorption and pharmacological inhibitors have shown to be beneficial for the long-term clinical outcome in DKD. However, their mechanism of action has, as of yet, not been fully elucidated. To comprehend the protective effects of SGLT inhibitors, it is essential to understand the complete functional, structural, and molecular features of the disease, which until now have been difficult to recapitulate. This review addresses the molecular events of diabetic proximal tubulopathy. In addition, we evaluate the protective role of SGLT inhibitors in cardiovascular and renal outcomes, and provide an overview of various in vitro models mimicking diabetic proximal tubulopathy used so far. Finally, new insights on advanced in vitro systems to surpass past limitations are postulated.
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Affiliation(s)
- João Faria
- Div. Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
| | - Karin G F Gerritsen
- Dept. Nephrology and Hypertension, University Medical Center Utrecht, the Netherlands
| | - Tri Q Nguyen
- Dept. Pathology, University Medical Center Utrecht, the Netherlands
| | - Silvia M Mihaila
- Div. Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands; Dept. Nephrology and Hypertension, University Medical Center Utrecht, the Netherlands
| | - Rosalinde Masereeuw
- Div. Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands.
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TNF-α inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure. Biochem Pharmacol 2020; 180:114121. [PMID: 32592722 DOI: 10.1016/j.bcp.2020.114121] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
Systemic arterial hypertension is a public health problem associated with an increased risk of cardiovascular disease. Matrix metalloproteinases (MMP) are endopeptidases that participate in hypertension-induced cardiovascular remodeling, which may be activated by oxidative stress. Angiotensin II (Ang II), a potent hypertrophic and vasoconstrictor peptide, increases oxidative stress, MMP-2 activity and tumor necrosis factor (TNF-α) expression. In vitro studies have shown that TNF-α is essential for Ang II-induced MMP-2 expression. Thus, this study evaluated whetherTNF-α inhibition decreases the development of hypertension-induced vascular remodeling via reduction of MMP-2 activity and reactive oxygen species (ROS) formation. Two distinct pharmacological approaches were used in the present study: Pentoxifylline (PTX), a non-selective inhibitor of phosphodiesterases that exerts anti- inflammatory effects via inhibition of TNF-α, and Etanercept (ETN), a selective TNF-α inhibitor. 2-kidney and 1-Clip (2K1C). 2-kidney and 1-Clip (2K1C) and Sham rats were treated with Vehicle, PTX (50 mg/Kg and 100 mg/kg daily) or ETN (0.3 mg/Kg and 1 mg/kg; three times per week). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. Plasma TNF-α and IL-1β levels were evaluated by enzyme-linked immunosorbent assay (ELISA) technique. The vascular hypertrophy was examined in the aorta sections stained with hematoxylin/eosin. ROS in aortas was evaluated by dihydroethidium and chemiluminescence lucigenin assay. Aortic MMP-2 levels and activity were evaluated by gel zymography and in situ zymography, respectively. The 2K1C animals showed a progressive increase in SBP levels and was accompanied by significant vascular hypertrophy (p < 0.05 vs Sham). Treatment with PTX at higher doses decreased SBP and vascular remodeling in 2K1C animals (p < 0.05 vs 2K1C vehicle). Although the highest dose of ETN treatment did not reduce blood pressure, the vascular hypertrophy was significantly attenuated in 2K1C animals treated with ETN1 (p < 0.05). The increased cytokine levels and ROS formation were reversed by the highest doses of both PTX and ETN. The increase in MMP-2 levels and activity in 2K1C animals were reduced by PTX100 and ETN1 treatments (p < 0.05 vs vehicle 2K1C). Lower doses of PTX and ETN did not affect any of the evaluated parameters in this study, except for a small reduction in TNF-α levels. The findings of the present study suggest that PTX and ETN treatment exerts immunomodulatory effects, blunted excessive ROS formation, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement ofvascular remodeling typically found in 2K1C hypertension. Therefore, strategies using anti-hypertensive drugs in combination with TNF alpha inhibitors could be an attractive therapeutic approach to tackle hypertension and its associated vascular remodeling.
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Leehey DJ. Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline? ACTA ACUST UNITED AC 2020; 1:292-299. [DOI: 10.34067/kid.0001252019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.
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Plotnikov MB, Shamanaev AY, Aliev OI, Sidekhmenova AV, Anishchenko AM, Arkhipov AM. Pentoxifylline treatment enhances antihypertensive activity of captopril through hemorheological improvement in spontaneously hypertensive rats during development of arterial hypertension. ACTA ACUST UNITED AC 2017; 11:769-778. [DOI: 10.1016/j.jash.2017.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 09/07/2017] [Accepted: 09/10/2017] [Indexed: 01/23/2023]
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Plotnikov MB, Aliev OI, Shamanaev AY, Sidekhmenova AV, Anfinogenova Y, Anishchenko AM, Fomina TI, Arkhipov AM. Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development. Clin Exp Hypertens 2017; 39:570-578. [PMID: 28722518 DOI: 10.1080/10641963.2017.1291662] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.
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Affiliation(s)
- Mark B Plotnikov
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Oleg I Aliev
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Alexander Y Shamanaev
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Anastasia V Sidekhmenova
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Yana Anfinogenova
- b Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia.,c RASA Center in Tomsk, Tomsk Polytechnic University , Tomsk , Russia
| | - Anna M Anishchenko
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Tatiana I Fomina
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
| | - Alexander M Arkhipov
- a Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences , Tomsk , Russia
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Liu D, Wang LN, Li HX, Huang P, Qu LB, Chen FY. Pentoxifylline plus ACEIs/ARBs for proteinuria and kidney function in chronic kidney disease: a meta-analysis. J Int Med Res 2017; 45:383-398. [PMID: 28415944 PMCID: PMC5536675 DOI: 10.1177/0300060516663094] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Objective This meta-analysis aimed to investigate the efficacy and safety of pentoxifylline (PTF) plus angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) for proteinuria and kidney function in chronic kidney disease (CKD). Methods CENTRAL, EMBASE, Ovid-MEDLINE, PubMed, and CNKI were searched for relevant, randomized, controlled trials (RCTs). A meta-analysis was performed to review the effect of PTF plus ACEIs/ARBs vs. ACEIs/ARBs alone on proteinuria and kidney function in CKD. Results Eleven RCTs including 705 patients were retrieved. PTF plus ACEI/ARB treatment significantly decreased proteinuria in patients with CKD within 6 months (standard mean difference [SMD] −0.52; 95% CI −0.90 to 0.15; I2 = 68%) and significantly attenuated a decrease in estimated glomerular filtration rate (eGFR) in patients with stages 3–5 CKD after 6 months of treatment (standard mean difference [SMD] 0.30; confidence limit [Cl] 95% CI 0.06 to 0.54; I2 = 0%). PTF plus ACEIs/ARBs for 9 to 12 months significantly reduced albuminuria in patients with CKD (SMD−0.30, 95% CI −0.57 to 0.03; I2 = 0%) and alleviated the decline in eGFR in patients with stages 3–5 CKD (SMD 0.51; 95% CI 0.06 to 0.96; I2 = 61%). Conclusion The combination of an ACEI or ARB and PTF has a protective effect in reducing proteinuria by ameliorating the decline in eGFR in patients with stages 3–5 CKD.
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Affiliation(s)
- Dong Liu
- 1 Department of Nephrology, the Air Force General Hospital, Chinese PLA. Beijing, 100142, China
| | - Li-Na Wang
- 2 Department of Nephrology, Henan Province Hospital of Chinese Medicine, Zhengzhou, 450002, China
| | - Hong-Xia Li
- 1 Department of Nephrology, the Air Force General Hospital, Chinese PLA. Beijing, 100142, China
| | - Ping Huang
- 3 Department of Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Liang-Bo Qu
- 3 Department of Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fei-Yan Chen
- 3 Department of Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Plotnikov MB, Aliev OI, Nosarev AV, Shamanaev AY, Sidekhmenova AV, Anfinogenova Y, Anishchenko AM, Pushkina EV. Relationship between arterial blood pressure and blood viscosity in spontaneously hypertensive rats treated with pentoxifylline. Biorheology 2016; 53:93-107. [DOI: 10.3233/bir-15100] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Mark B. Plotnikov
- E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, Russian Academy of Sciences, Tomsk, Russia
| | - Oleg I. Aliev
- E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, Russian Academy of Sciences, Tomsk, Russia
| | | | - Alexander Y. Shamanaev
- E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, Russian Academy of Sciences, Tomsk, Russia
| | - Anastasia V. Sidekhmenova
- E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, Russian Academy of Sciences, Tomsk, Russia
| | - Yana Anfinogenova
- Federal State Budgetary Scientific Institution “Research Institute for Cardiology”, Tomsk, Russia
- RASA Center in Tomsk, Tomsk Polytechnic University, Tomsk, Russia
| | - Anna M. Anishchenko
- E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, Russian Academy of Sciences, Tomsk, Russia
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Leporini C, Pisano A, Russo E, D⿿Arrigo G, de Sarro G, Coppolino G, Bolignano D. Effect of pentoxifylline on renal outcomes in chronic kidney disease patients: A systematic review and meta-analysis. Pharmacol Res 2016; 107:315-332. [DOI: 10.1016/j.phrs.2016.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/04/2016] [Accepted: 03/02/2016] [Indexed: 12/28/2022]
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Sabounjian L, Graham P, Wu L, Braman V, Cheng C, Liu J, Shipley J, Neutel J, Dao M. A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease. Clin Pharmacol Drug Dev 2016; 5:314-25. [PMID: 27310332 DOI: 10.1002/cpdd.241] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/16/2015] [Accepted: 11/09/2015] [Indexed: 01/10/2023]
Abstract
The prevalence of chronic kidney disease (CKD) related to type 2 diabetes is increasing worldwide. In addition to standard of care, treatment with anti-inflammatory and antifibrotic agents such as CTP-499, a novel oral, multisubtype selective inhibitor of phosphodiesterases, may be important in CKD treatment. A phase 1b randomized, double-blind, placebo-controlled clinical trial of CTP-499 in CKD patients (25 active, 8 placebo) with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) was conducted to assess safety and tolerability. Secondary outcomes included pharmacokinetics and exploratory effects on inflammatory and hematology markers. Patients received 600 mg CTP-499 or matching placebo tablets orally once daily for 2 weeks, then twice daily for 2 additional weeks. CTP-499 was well tolerated with no serious or severe adverse events, or adverse events leading to discontinuation. CTP-499 was rapidly absorbed and produced acceptable interpatient variability. Of the 5 metabolites (M1-M5), M5 was the most abundant in plasma and urine. Exposure to CTP-499 and metabolites was higher in CKD patients than previously reported in healthy volunteers. No statistically significant differences were detected between the CTP-499- and placebo-treated groups for any of the biomarkers tested. This study provides data supporting further evaluation of CTP-499 in CKD patients.
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Affiliation(s)
| | | | - Lijun Wu
- Concert Pharmaceuticals, Inc, Lexington, MA, USA
| | | | | | - Julie Liu
- Concert Pharmaceuticals, Inc, Lexington, MA, USA
| | | | - Joel Neutel
- Orange County Research Center, Tustin, CA, USA
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12
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Wu PC, Wu CJ, Lin CJ, Pan CF, Chen CY, Huang TM, Wu CH, Lin SL, Chen YM, Chen L, Wu VC. Pentoxifylline Decreases Dialysis Risk in Patients With Advanced Chronic Kidney Disease. Clin Pharmacol Ther 2015; 98:442-9. [PMID: 26082272 DOI: 10.1002/cpt.173] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 06/11/2015] [Indexed: 11/08/2022]
Abstract
Few studies evaluated the effects of pentoxifylline on hard endpoints in patients with predialysis stage 5 chronic kidney disease (CKD). Thus, we tried to explore the effects of pentoxifylline and its interaction with renin-angiotensin-aldosterone system (RAAS) blockade on the development of endstage renal disease (ESRD) and mortality. This nationwide cohort study retrospectively included patients who had a serum creatinine level of >6 mg/dL and received erythropoiesis-stimulating agents (ESAs) between 2000 and 2010. We analyzed 7,366 pentoxifylline users and 7,366 propensity score-matched nonusers. Using Cox proportional hazard models, pentoxifylline reduced the risks of ESRD and the composite renal outcome but not that of mortality. In terms of the risks of developing ESRD, pentoxifylline alone exerted a comparable beneficial effect to combined therapy with an RAAS inhibitor and greater renoprotection than RAAS inhibitor monotherapy. This study suggests pentoxifylline is efficacious in slowing progression to ESRD in patients with predialysis stage 5 CKD.
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Affiliation(s)
- P-C Wu
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - C-J Wu
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, Taipei, Taiwan.,Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - C-J Lin
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, Taipei, Taiwan.,Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - C-F Pan
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - C-Y Chen
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - T-M Huang
- Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Yunlin County, Taiwan
| | - C-H Wu
- Division of Nephrology, Taipei Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi University, Taipei, Taiwan
| | - S-L Lin
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Y-M Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - L Chen
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - V-C Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Efficacy and safety of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in diabetic nephropathy: a meta-analysis. Int Urol Nephrol 2015; 47:815-22. [PMID: 25862237 DOI: 10.1007/s11255-015-0968-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 03/29/2015] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Pentoxifylline (PTF) has anti-inflammatory properties, which may be beneficial for diabetic nephropathy (DN). A meta-analysis was conducted to assess the additive effect of pentoxifylline and its safety among patients with type 2 DN under blockade of angiotensin system. DATA SOURCES Relevant studies were searched from PubMed, CBM, EMBASE, CENTRAL and Cochrane renal group specialized register. SELECTION CRITERIA All RCTs that compared the benefits and harms of pentoxifylline and ACEI/ARB with ACEI/ARB alone for DN were included. DATA EXTRACTION AND ANALYSIS Pertinent data were extracted independently by two authors. Meta-analyses were performed when more than one study provided data on a comparable outcome. Standard mean differences (SMDs) for proteinuria and albuminuria, mean differences (MDs) for systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, serum creatinine (Scr), creatinine clearance (CrCl) and urine tumor necrosis factor-alpha (UTNF-α), 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed with the I (2) test. Adverse effects were assessed using descriptive techniques. RESULTS Eight studies including 587 patients with a median duration of 5 months were identified. Compared with ACEI/ARB alone, the combination of PTF and ACEI/ARB significantly reduced proteinuria (SMD 0.76, 95% CI 0.52-0.99), albuminuria (SMD 0.36, 95% CI 0.12-0.59) and UTNF-α (MD 1.56 ng/g, 95% CI 0.09-3.03). However, no statistically significant changes were observed for SBP, DBP, HbA1c, Scr and CrCl. The most frequent adverse effects in patients treated with PTF were gastrointestinal symptoms (28/298) and dizziness (7/298), but in most cases, these symptoms were mild, only six participants withdrew due to intractable nausea and vomiting. CONCLUSIONS Pentoxifylline can significantly provide additive antiproteinuric effect independent from the decrease in BP or improvement in glycemic control in DN patients under blockade of angiotensin system. Further large, multicenter, high-quality studies with long duration are necessary to prove whether it really has renoprotective effects in this patient population.
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Shahidi S, Hoseinbalam M, Iraj B, Akbari M. Effect of pentoxifylline on microalbuminuria in diabetic patients: a randomized controlled trial. Int J Nephrol 2015; 2015:259592. [PMID: 25874129 PMCID: PMC4385644 DOI: 10.1155/2015/259592] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 01/22/2015] [Accepted: 02/08/2015] [Indexed: 01/08/2023] Open
Abstract
Background. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with anti-inflammatory properties. Human studies have proved its antiproteinuric effect in patients with glomerular diseases, but this study was designed to assess the effects of add-on pentoxifylline to available treatment on reduction of microalbuminuria in diabetic patients without glomerular diseases. Methods. In a double-blind placebo-controlled, randomized study we evaluated the influence of pentoxifylline on microalbuminuria in type 2 diabetic patients. 40 diabetic patients with estimated glomerular filtration rate (eGFR) of more than 60 mL/min/1.73 m(2) in eight weeks and microalbuminuria were randomized to two groups which will receive pentoxifylline 1200 mg/day or placebo added to regular medications for 6 months. albuminuria; eGFR was evaluated at three- and six-month follow-up period. Results. Baseline characteristics were similar between the two groups. At six months, the mean estimated GFR and albuminuria were not different between two groups at 3- and 6-month follow-up. Trend of albumin to creatinine ratio, systolic and diastolic blood pressure, and eGFR in both groups were decreased, but no significant differences were noted between two groups (P value > 0.05). Conclusion. Pentoxifylline has not a significant additive antimicroalbuminuric effect compared with placebo in patients with type 2 diabetes with early stage of kidney disease; however, further clinical investigations are necessary to be done.
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Affiliation(s)
- Shahrzad Shahidi
- Isfahan Kidney Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marziyeh Hoseinbalam
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bijan Iraj
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojtaba Akbari
- Department of Epidemiology, School of Health and Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran
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Blumenthal SS. Evolution of Treatment for Diabetic Nephropathy: Historical Progression from RAAS Inhibition and Onward. Postgrad Med 2015; 123:166-79. [DOI: 10.3810/pgm.2011.11.2506] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Gentile G, Mastroluca D, Ruggenenti P, Remuzzi G. Novel effective drugs for diabetic kidney disease? or not? Expert Opin Emerg Drugs 2014; 19:571-601. [PMID: 25376947 DOI: 10.1517/14728214.2014.979151] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Diabetes mellitus is increasingly common worldwide and is expected to affect 592 million people by 2035. The kidney is often involved. A key goal in treating diabetes is to reduce the risk of development of kidney disease and, if kidney disease is already present, to delay the progression to end-stage renal disease (ESRD). This represents a social and ethical issue, as a significant proportion of patients reaching ESRD in developing countries do not have access to renal replacement therapy. AREAS COVERED The present review focuses on novel therapeutic approaches for diabetic nephropathy (DN), implemented on the basis of recent insights on its pathophysiology, which might complement the effects of single inhibition of the renin-angiotensin-aldosterone system (RAAS), the cornerstone of renoprotective interventions in diabetes, along with glycemic and blood pressure control. EXPERT OPINION Although a plethora of new treatment options has arisen from experimental studies, the number of novel renoprotective molecules successfully implemented in clinical practice over the last two decades is disappointingly low. Thus, new investigational strategies and diagnostic tools - including the appropriate choice of relevant renal end points and the study of urinary proteome of patients - will be as important as new therapeutic interventions to fight DN. Finally, in spite of huge financial interests in replacing the less expensive ACE inhibitors and angiotensin II receptor blockers with newer drugs, any future therapeutic approach has to be tested on top of - rather than instead of - optimal RAAS blockade.
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Affiliation(s)
- Giorgio Gentile
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" , Villa Camozzi, Via Giambattista Camozzi 3, 24020, Ranica, Bergamo , Italy +39 03545351 ; +39 0354535371 ;
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Agrawal NK, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014; 5:697-710. [PMID: 25317247 PMCID: PMC4138593 DOI: 10.4239/wjd.v5.i5.697] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 04/24/2014] [Accepted: 05/29/2014] [Indexed: 02/05/2023] Open
Abstract
Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications.
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Mora-Fernández C, Domínguez-Pimentel V, de Fuentes MM, Górriz JL, Martínez-Castelao A, Navarro-González JF. Diabetic kidney disease: from physiology to therapeutics. J Physiol 2014; 592:3997-4012. [PMID: 24907306 DOI: 10.1113/jphysiol.2014.272328] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Diabetic kidney disease (DKD) defines the functional, structural and clinical abnormalities of the kidneys that are caused by diabetes. This complication has become the single most frequent cause of end-stage renal disease. The pathophysiology of DKD comprises the interaction of both genetic and environmental determinants that trigger a complex network of pathophysiological events, which leads to the damage of the glomerular filtration barrier, a highly specialized structure formed by the fenestrated endothelium, the glomerular basement membrane and the epithelial podocytes, that permits a highly selective ultrafiltration of the blood plasma. DKD evolves gradually over years through five progressive stages. Briefly they are: reversible glomerular hyperfiltration, normal glomerular filtration and normoalbuminuria, normal glomerular filtration and microalbuminuria, macroalbuminuria, and renal failure. Approximately 20-40% of diabetic patients develop microalbuminuria within 10-15 years of the diagnosis of diabetes, and about 80-90% of those with microalbuminuria progress to more advanced stages. Thus, after 15-20 years, macroalbuminuria occurs approximately in 20-40% of patients, and around half of them will present renal insufficiency within 5 years. The screening and early diagnosis of DKD is based on the measurement of urinary albumin excretion and the detection of microalbuminuria, the first clinical sign of DKD. The management of DKD is based on the general recommendations in the treatment of patients with diabetes, including optimal glycaemic and blood pressure control, adequate lipid management and abolishing smoking, in addition to the lowering of albuminuria.
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Affiliation(s)
- Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain Sociedad Española de Nefrología & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain
| | | | - Mercedes Muros de Fuentes
- Sociedad Española de Nefrología & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain Clinical Analysis Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - José L Górriz
- Sociedad Española de Nefrología & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain University Hospital Dr. Peset, Valencia, Spain
| | - Alberto Martínez-Castelao
- Sociedad Española de Nefrología & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain University Hospital of Bellvitge, Barcelona, Spain
| | - Juan F Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain Sociedad Española de Nefrología & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
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Tang X, Bridson G, Ke J, Wu L, Erol H, Graham P, Lin CH, Braman V, Zhao H, Liu JF, Lin ZJ, Cheng C. Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 963:1-9. [PMID: 24927417 DOI: 10.1016/j.jchromb.2014.05.043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/15/2014] [Accepted: 05/20/2014] [Indexed: 10/25/2022]
Abstract
CTP-499 is a novel oral multi-subtype selective inhibitor of PDEs that is currently in clinical testing, in combination with angiotensin modulators, as a potentially first-in-class treatment for diabetic kidney disease. The compound was discovered and developed by using Concert's proprietary DCE Platform(®) in which deuterium was incorporated at select positions of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX). CTP-499 metabolizes to five major metabolites: C-21256, D-M2, D-M3, D-M4 and M5, of which all contains deuterium except M5. During in vivo metabolism, however, H/D exchange takes place. As a result, each analyte, except M5, has multiple molecular masses. To accurately quantify the analytes, we developed an LC-MS/MS method focusing on the core structures of the molecules, termed "core-structure analyses". The core-structure analyses method was then validated under GLP guidance in dog, rat and rabbit plasma, with a sample volume of 50 μL. Results demonstrated that this approach accurately quantifies each of the six analytes despite partial exchange of deuterium with hydrogen atoms in the in vivo samples. The validation parameters included accuracy, precision, sensitivity, stability, dilution integrity, hemolysis, matrix effect, selectivity, and recovery. Acceptable intra-run and inter-run assay precision (%CV ≤ 5.5%) and accuracy (90.1-106.7%) were achieved over a linear range of 10-5,000 ng/mL of each analyte. Various stability tests, including bench-top, freeze/thaw, stock solution, and long-term storage, were also performed. All stability results met acceptance criteria. The robustness of the methods was demonstrated by the incurred sample reproducibility (ISR) tests. After validation, the method was successfully used in support of multiple toxicological studies of CTP-499.
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Affiliation(s)
- Xiaonan Tang
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Gary Bridson
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States
| | - Jing Ke
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Lijun Wu
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States
| | - Halil Erol
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Phillip Graham
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States
| | - Chih Hsien Lin
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Virginia Braman
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States
| | - Harry Zhao
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Julie F Liu
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States
| | - Zhongping John Lin
- Frontage Laboratories, Inc., 700 Pennsylvania Drive, Exton, PA 19341, United States
| | - Changfu Cheng
- Concert Pharmaceuticals, Inc., 99 Hayden Ave, Suite 500, Lexington, MA 02421, United States.
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Chen PM, Lai TS, Chen PY, Lai CF, Wu V, Chiang WC, Chen YM, Wu KD, Tsai TJ. Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in advanced chronic kidney disease. J Formos Med Assoc 2014; 113:219-26. [PMID: 24512756 DOI: 10.1016/j.jfma.2014.01.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 12/19/2013] [Accepted: 01/08/2014] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND/PURPOSE Several studies have shown the renoprotective effects of pentoxifylline in the treatment of chronic kidney disease (CKD). This study was conducted to examine whether there was an increased benefit of including pentoxifylline with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the treatment of CKD. METHODS A single-center retrospective analysis was conducted. A total of 661 Stage 3B-5 CKD patients who received ACEI or ARB treatment were recruited. The patients were divided into the pentoxifylline use group and the no pentoxifylline group. Renal survival analysis of the two groups was compared. Subgroup analysis was performed by dividing the patients into lower [urine protein to creatinine ratio (UPCR)<1 g/g] and higher (UPCR ≥ 1 g/g) proteinuria subgroups. RESULTS There was no between-groups difference regarding mortality and cardiovascular events. Addition of pentoxifylline showed a better renal outcome (p = 0.03). The protective effect of add-on pentoxifylline was demonstrated in the higher proteinuria subgroup (p = 0.005). In the multivariate Cox regression model, pentoxifylline use also showed a better renal outcome [hazard ratio (HR): 0.705; 95% confidence interval (CI): 0.498-0.997; p = 0.048]. This effect was more prominent in the higher proteinuria subgroup (HR: 0.602; 95% CI: 0.413-0.877; p = 0.008). CONCLUSION In the advanced stages of CKD, patients treated with a combination of pentoxifylline and ACEI or ARB had a better renal outcome than those treated with ACEI or ARB alone. This effect was more prominent in the higher proteinuria subgroup. More large randomized control trials are needed to provide concrete evidence of the add-on effect of pentoxifylline.
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Affiliation(s)
- Ping-Min Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Shuan Lai
- Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Ping-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, Chi Mei Medical Center, Chiali Campus, Tainan, Taiwan
| | - Chun-Fu Lai
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Vincent Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chih Chiang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yung-Ming Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kwan-Dun Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tun-Jun Tsai
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Hamed AT, Taha MM, Nasser LM. Renoprotective effect of aliskiren monotherapy and aliskiren−pentoxifylline combination in hypertensive-diabetic type 2 patients with diabetic nephropathy. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.bfopcu.2013.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Mima A, Qi W, King GL. Implications of treatment that target protective mechanisms against diabetic nephropathy. Semin Nephrol 2013; 32:471-8. [PMID: 23062988 DOI: 10.1016/j.semnephrol.2012.07.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.
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Affiliation(s)
- Akira Mima
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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Braman V, Graham P, Cheng C, Turnquist D, Harnett M, Sabounjian L, Shipley J. A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy. Clin Pharmacol Drug Dev 2013; 2:53-66. [DOI: 10.1002/cpdd.3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 10/10/2012] [Indexed: 11/06/2022]
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Mima A. Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J Diabetes Res 2013; 2013:248563. [PMID: 23862164 PMCID: PMC3686081 DOI: 10.1155/2013/248563] [Citation(s) in RCA: 140] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/15/2013] [Indexed: 12/16/2022] Open
Abstract
Diabetes and insulin resistance can greatly increase microvascular complications of diabetes including diabetic nephropathy (DN). Hyperglycemic control in diabetes is key to preventing the development and progression of DN. However, it is clinically very difficult to achieve normal glucose control in individual diabetic patients. Many factors are known to contribute to the development of DN. These include diet, age, lifestyle, or obesity. Further, inflammatory- or oxidative-stress-induced basis for DN has been gaining interest. Although anti-inflammatory or antioxidant drugs can show benefits in rodent models of DN, negative evidence from large clinical studies indicates that more effective anti-inflammatory and antioxidant drugs need to be studied to clear this question. In addition, our recent report showed that potential endogenous protective factors could decrease inflammation and oxidative stress, showing great promise for the treatment of DN.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Graduate School of Medicine, Institute of Health Biosciences, University of Tokushima, Tokushima 770-8503, Japan.
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Shan D, Wu HM, Yuan QY, Li J, Zhou RL, Liu GJ, Cochrane Kidney and Transplant Group. Pentoxifylline for diabetic kidney disease. Cochrane Database Syst Rev 2012; 2012:CD006800. [PMID: 22336824 PMCID: PMC11831249 DOI: 10.1002/14651858.cd006800.pub2] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is associated with increased morbidity and mortality, mostly relating to cardiovascular complications. The relevance of inflammation in the pathogenesis of DKD has been investigated in recent years, and it has been shown that inflammatory markers are higher in people with DKD compared with the wider population. Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favourable anti-inflammatory effects and immunoregulatory properties. The anti-inflammatory effects conferred by pentoxifylline may be beneficial in the management of DKD. OBJECTIVES To assess the benefits and harms of pentoxifylline for treating people with DKD. SEARCH METHODS We searched the Cochrane Renal Group's specialised register (January 2012), CENTRAL (Issue 12, 2011), MEDLINE, EMBASE and four Chinese biomedical literature databases (CBM-disc, 1979 to July 2009), Chinese Science and Technique Journals Database (VIP, until July 2009), China National Knowledge Infrastructure (CNKI, until July 2009) and WanFang database (until July 2009). SELECTION CRITERIA All randomised controlled trials (RCTs) and quasi-RCTs studying the benefits and harms of pentoxifylline for DKD. DATA COLLECTION AND ANALYSIS Data were extracted independently by two authors. Meta-analyses were performed when more than one study provided data on a comparable outcome in sufficiently similar patients. Results of dichotomous outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CI). Mean differences (MD) were calculated to assess the effects of treatment where outcomes were expressed on continuous scales, and standardised mean differences (SMD) calculated where different scales were used. Data was pooled using the random effects model. Adverse effects were assessed using descriptive techniques and where possible, risk differences (RD) with 95% CI. MAIN RESULTS We identified 17 studies that included a total of 991 participants with DKD which met our inclusion criteria. Overall, the methodological quality of included studies was low: 4/17 reported the method of randomisation, 13/17 did not; no study described the method of random allocation; 4/17 studies were considered to be at high risk of bias and 13/17 were considered to have unclear risk for incomplete outcome data reporting; 9/17 studies were at low risk bias and in 8/17 the risk of bias was unclear for selective outcome reporting.Compared with placebo, pentoxifylline significantly reduced serum creatinine (SCr) (MD -0.10 mg/dL, 95% CI -0.17 to -0.03), albuminuria (SMD -2.28, 95% CI -3.85 to -0.70) and overt proteinuria (MD -428.58 µg/min, 95% CI -661.65 to -195.50), but there was no difference in creatinine clearance (CrCl) (MD -5.18 mL/min, 95% CI -15.55 to 5.19). When compared with routine treatment alone, pentoxifylline did not significantly reduce SCr (MD 0.00 mg/dL, 95% CI -0.06 to 0.07) or blood pressure (systolic (SBP): MD -0.28 mm Hg, 95% CI -2.20 to 1.63; diastolic (DBP): MD -0.15 mm Hg, 95% CI -1.44 to 1.14), but did significantly reduce albuminuria (SMD 0.62, 95% CI 0.18 to 1.07) and proteinuria (MD 0.46 g/24 h, 95% CI 0.17 to 0.74). There was no significant difference in SCr (MD 0.00 mg/dL, 95% CI -0.08 to 0.07), albuminuria (MD -8.79 µg/min, 95% CI -27.18 to 9.59), proteinuria (MD -0.01 g/24 h, 95% CI -0.03 to 0.01) or blood pressure (SBP: MD 1.46 mm Hg, 95% CI -0.57 to 3.50; DBP: MD 1.37 mm Hg, 95% CI -0.23 to 2.98) between pentoxifylline and the active comparator (captopril or clonidine/methyldopa) for patients with type 1 and type 2 DKD. CrCl was significantly increased when pentoxifylline was compared to clonidine/methyldopa (MD 10.90 mL/min, 95% CI -1.40 to 20.40) but not with captopril (MD 3.26 mL/min, 95% CI -1.05 to 7.59). No data were available on the incidence of end-stage kidney disease (ESKD), time to ESKD, quality of life, or all-cause mortality. The adverse events of pentoxifylline were mild; no serious adverse events were reported in any of the included studies. AUTHORS' CONCLUSIONS From the available evidence, pentoxifylline seems to offer some beneficial effects in renal function improvement and reduction in albuminuria and proteinuria, with no obvious serious adverse effects for patients with DKD. However, most studies were poorly reported, small, and methodologically flawed. Evidence to support the use of pentoxifylline for DKD was insufficient to develop recommendations for its use in this patient population. Rigorously designed, randomised, multicentre, large scale studies of pentoxifylline for DKD are needed to further assess its therapeutic effects.
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Affiliation(s)
- Dan Shan
- West China Hospital, Sichuan UniversityDepartment of GeriatricsNo. 37 Guo Xue Xiang StreetChengduSichuanChina610041
| | - Hong Mei Wu
- West China Hospital, Sichuan UniversityDepartment of GeriatricsNo. 37 Guo Xue Xiang StreetChengduSichuanChina610041
| | - Qi Yuan Yuan
- No.5 People's Hospital of ChengduIntensive Care DepartmentChengduSichuanChina610041
| | - Jun Li
- West China Hospital, Sichuan UniversityDepartment of GeriatricsNo. 37 Guo Xue Xiang StreetChengduSichuanChina610041
| | - Rong Le Zhou
- Xi'an No.4 Hospital, Xi'an JiaoTong UniversityDepartment of OphthalmologyNo.21, Jie Fang RoadXi'anShaanxiChina710004
| | - Guan J Liu
- West China Hospital, Sichuan UniversityChinese Cochrane Centre, Chinese Evidence‐Based Medicine CentreNo. 37, Guo Xue XiangChengduSichuanChina610041
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Luis-Rodríguez D, Martínez-Castelao A, Górriz JL, De-Álvaro F, Navarro-González JF. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. World J Diabetes 2012; 3:7-18. [PMID: 22253941 PMCID: PMC3258536 DOI: 10.4239/wjd.v3.i1.7] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 12/09/2011] [Accepted: 01/09/2012] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication.
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Affiliation(s)
- Desirée Luis-Rodríguez
- Desirée Luis-Rodríguez, Alberto Martínez-Castelao, José Luis Górriz, Fernando de Álvaro, Juan F Navarro-González, Grupo Español para el Estudio de la Nefropatía Diabética (GEENDIAB), Spain
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Abstract
Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.
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Roozbeh J, Banihashemi MA, Ghezlou M, Afshariani R, Salari S, Moini M, Sagheb MM. Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. Ren Fail 2010; 32:172-8. [PMID: 20199178 DOI: 10.3109/08860221003602645] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Chronic kidney disease is a worldwide health problem. Type II diabetes mellitus is now a major cause of end stage renal disease. The effect of diabetes mellitus through the dysregulation of the innate immunity results in increased tumor necrosis factor-alpha. This can lead to an increasing protein trafficking through the glomerular capillary, which can have an intrinsic renal toxicity. Seventy-four patients with type II diabetes mellitus with overt proteinuria were included in the study. They were randomly assigned to two groups of 37 patients (group 1: captopril 25 mg three times a day, group 2: captopril 25 mg and pentoxifylline 400 mg each three times per day). In the course of the study, two patients were excluded from each group. Daily urinary protein excretion was assessed at baseline and at two and six months. The reduction of urinary protein to creatinine clearance ratio in group 2 was 15.16 points more than in group 1 from baseline to the end of the study (p = 0.001). The difference in reduction only started after two months of pentoxifylline use. The differences in HbA1c and duration of diabetes mellitus at baseline in the two groups had not adversely affected the outcome of the study. There was a modest decrease in systolic blood pressure in group 2 as well (p = 0.041). Combining an angiotensin-converting enzyme inhibitor and pentoxifylline can lead to a greater reduction in proteinuria.
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Affiliation(s)
- Jamshid Roozbeh
- Division of Nephrology, Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Fars, Iran
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Turgut F, Bolton WK. Potential new therapeutic agents for diabetic kidney disease. Am J Kidney Dis 2010; 55:928-40. [PMID: 20138415 DOI: 10.1053/j.ajkd.2009.11.021] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 11/12/2009] [Indexed: 01/05/2023]
Abstract
Diabetic nephropathy is the leading cause of end-stage renal disease, and both the incidence and prevalence of diabetic nephropathy continue to increase. Currently, various treatment regimens and combinations of therapies provide only partial renoprotection. It is obvious that new approaches are desperately needed to retard the progression of diabetic nephropathy. Recently, a number of new agents have been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of end-stage renal disease. These include inhibitors and breakers of advanced glycation end products, receptor antagonists for advanced glycation end products, protein kinase C inhibitors, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitors, glycosaminoglycans, endothelin receptor antagonists, antifibrotic agents, and growth factor inhibitors. This review addresses these promising new therapeutic agents for delaying the progression of diabetic kidney disease.
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Affiliation(s)
- Faruk Turgut
- Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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Dávila-Esqueda ME, Vertiz-Hernández AA, Martínez-Morales F. Comparative Analysis of the Renoprotective Effects of Pentoxifylline and Vitamin E on Streptozotocin-Induced Diabetes Mellitus. Ren Fail 2009. [DOI: 10.1081/jdi-42728] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Laczy B, Cseh J, Mohás M, Markó L, Tamaskó M, Koszegi T, Molnár GA, Wagner Z, Wagner L, Wittmann I. Effects of pentoxifylline and pentosan polysulphate combination therapy on diabetic neuropathy in type 2 diabetes mellitus. Acta Diabetol 2009; 46:105-11. [PMID: 18839054 DOI: 10.1007/s00592-008-0064-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Accepted: 09/12/2008] [Indexed: 01/14/2023]
Abstract
Vascular dysfunction, including impaired perfusion has a pivotal role in the pathogenesis of microvascular complications in diabetes mellitus. Both pentoxifylline (PF) and pentosan polysulphate (PPS) are known to improve microcirculation. Antioxidant and antiproteinuric effects of PF are also known. In a placebo-controlled study, we determined the possible efficacy of PF-PPS combination therapy on diabetic neuropathy and nephropathy in type 2 diabetic patients. Patients in Verum group (n = 77) received PF-PPS infusions (100-100 mg/day) for 5 days. Control diabetics (Placebo group; n = 12) were given only saline infusions. Specialized cardiovascular autonomic reflex tests, vibration threshold values and urinary albumin excretion were assessed before and after therapy. In Verum group, autonomic score, indicating the severity of cardiac autonomic dysfunction, decreased after therapy (p < or = 0.001). Of the reflexes, deep breath and handgrip tests also improved after therapy (p < or = 0.001). Vibration threshold values, an indicator of the loss of sensory nerve function, were increased after therapy (p < or = 0.001). Results of cardiac autonomic tests and vibration threshold values remained unaltered in Placebo group. Majority of patients had normalbuminuria, which was not affected by PF-PPS. In conclusion, short-term PF-PPS therapy was effective on cardiovascular autonomic function and vibration perception, whereas it failed to reduce albuminuria within normal range in type 2 diabetic patients.
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Affiliation(s)
- Boglárka Laczy
- Second Department of Medicine and Nephrological Center, Faculty of Medicine, University of Pecs, Pacsirta u. 1., 7624, Pecs, Hungary
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Abstract
Diabetes and its complications have become a public health problem. One of the most important complications is diabetic nephropathy, which is nowadays the main cause of chronic renal failure. In spite of our greater understanding of this complication, the intimate mechanisms leading to the development and progression of renal injury are not well understood. New perspectives in activated innate immunity and inflammation appear to be relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including adipokines, Toll-like receptors, chemokines, adhesion molecules and pro-inflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.
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Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM. Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis 2009; 53:606-16. [PMID: 19216016 DOI: 10.1053/j.ajkd.2008.11.026] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2008] [Accepted: 11/12/2008] [Indexed: 12/25/2022]
Abstract
BACKGROUND Pentoxifylline is a nonspecific phosphodiesterase inhibitor with anti-inflammatory properties. It reduces proteinuria in patients with glomerular disease, although its impact on glomerular filtration rate (GFR) is unknown. We hypothesized that pentoxifylline would slow the estimated GFR decrease in patients with chronic kidney disease at high risk of progression. STUDY DESIGN Pilot randomized double-blind placebo-controlled trial. SETTING & PARTICIPANTS 40 outpatients with decreased GFR, hypertension, and proteinuria greater than 1 g/24 h currently treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or the combination and followed up in a nephrology clinic at a tertiary medical care facility. INTERVENTION Pentoxifylline, 400 mg twice daily, or matching placebo. OUTCOMES Difference in rates of estimated GFR change during the 1-year study period between the 2 groups. MEASUREMENTS Estimated GFR (4-variable Modification of Diet in Renal Disease Study equation) and proteinuria by 24-hour urine collection were assessed at baseline and 6 and 12 months after enrollment. RESULTS Baseline characteristics were similar between the 2 groups. At 1 year, the mean estimated GFR decrease was significantly less in the pentoxifylline group than the placebo group (-1.2 +/- 7.0 versus -7.2 +/- 8.2 mL/min/1.73 m2/y; mean difference, -6.0 mL/min/1.73 m2/y; 95% confidence interval, -11.4 to -0.6; P = 0.03). For pentoxifylline-treated participants, the mean estimated GFR decrease during treatment was slower compared with the year before study enrollment (-9.6 +/- 11.9 mL/min/1.73 m2/y; mean difference, -8.4 mL/min/1.73 m2/y; 95% confidence interval, -14.8 to -2.1; P = 0.01). Proteinuria was not different between the pentoxifylline and placebo groups at baseline, 6 months, or 1 year. LIMITATIONS Small sample size and incomplete follow-up. CONCLUSIONS Pentoxifylline may slow the estimated GFR decrease in high-risk patients. This may be independent of its antiproteinuric properties and warrants further investigation.
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Affiliation(s)
- Robert M Perkins
- Nephrology Service, Madigan Army Medical Center, Fort Lewis, WA 98431, USA.
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Basic J, Golubovic E, Miljkovic P, Bjelakovic G, Cvetkovic T, Milosevic V. Microalbuminuria in children with vesicoureteral reflux. Ren Fail 2008; 30:639-43. [PMID: 18661415 DOI: 10.1080/08860220802134805] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Vesicoureteral reflux (VUR) is a common congenital anomaly of the urinary tract that may be inherited. Reflux of infected urine may cause scarring in susceptible kidneys with the potential to compromise renal function. The aim of the study was to evaluate the possible influence of different grades of VUR on glomerular damage using microalbuminuria as a parameter. Children with VUR detected by voiding cystourethrography (VCUG) were investigated. According to the grade of VUR, patients were separated into three groups. The first group included 12 children with VUR grade I-II. The second group consisted of 12 children with grade III of VUR. Patients with VUR grade IV-V (n = 11) were members of the third group. The control group consisted of 17 healthy children. Microalbuminuria was examined in samples of morning urine specimens using a microalbumin/creatinine reagent kit. Serum urea, creatinine levels and creatinine clearance (CCR) were measured as markers of renal function. The mean value of microalbumin excretion in the third group showed a statistically significant increase (p < 0.001) compared to all other groups. CCR in the third group was statistically significantly decreased (p < 0.05) in comparison to the group of healthy children. There were no statistically significant changes of microalbumin excretion and CCR in the first and second group compared to control values. We discussed the presence of microalbuminuria and decrease of CCR in children with high grade of VUR as a possible consequence of retrograde urine flow (intrarenal reflux), glomerulosclerosis, and consecutive hyperfiltration.
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Affiliation(s)
- J Basic
- Institute of Biochemistry, Medical Faculty, University of Nis, Nis, Serbia.
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McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am J Kidney Dis 2008; 52:454-63. [PMID: 18433957 DOI: 10.1053/j.ajkd.2008.01.025] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2007] [Accepted: 01/02/2008] [Indexed: 01/12/2023]
Abstract
BACKGROUND Pentoxifylline is a potential therapeutic agent for diabetic kidney disease because it has anti-inflammatory, antifibrotic, and hemorheological properties. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials. SETTING, POPULATION, & INTERVENTION Adult patients with diabetic kidney disease who received oral pentoxifylline. SELECTION CRITERIA FOR STUDIES We searched bibliographic databases for trials involving pentoxifylline that reported proteinuria, glomerular filtration rate, or blood pressure. OUTCOMES The primary outcome measure was the effect of pentoxifylline on proteinuria stratified by whether pentoxifylline was compared with renin-angiotensin system blockade. RESULTS 10 studies including a total of 476 participants with a median duration of 6 months were identified. Pentoxifylline significantly decreased proteinuria (weighted mean difference, -278 mg/d of protein; 95% confidence interval [CI], -398 to -159; P < 0.001) compared with placebo or usual care. Compared with captopril, the decrease in proteinuria with pentoxifylline was similar (weighted mean difference, 0 mg/d of protein; 95% CI, -17 to 18; P = 0.9). Secondary analysis showed that patients with microalbuminuria had a nonsignificant decrease in protein excretion (weighted mean difference, -87 mg/d; 95% CI, -201 to 27; P = 0.1), whereas those with overt proteinuria (protein > 300 mg/d) had a significant decrease (weighted mean difference, -502 mg/d; 95% CI, -805 to -198; P = 0.001). No significant changes in systolic or diastolic blood pressure or glomerular filtration rate were found. LIMITATIONS Quality scores of studies were low, and there was significant heterogeneity. CONCLUSIONS Available evidence suggests that pentoxifylline may decrease proteinuria in patients with diabetic nephropathy. To confirm these findings, large high-quality studies are required.
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Affiliation(s)
- Brendan B McCormick
- Division of Nephrology, Kidney Research Center, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
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Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19:433-42. [PMID: 18256353 DOI: 10.1681/asn.2007091048] [Citation(s) in RCA: 658] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Juan F Navarro-González
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010 Santa Cruz de Tenerife, Spain.
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Abstract
Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.
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38
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Chen YM, Lin SL, Chiang WC, Wu KD, Tsai TJ. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int 2006; 69:1410-5. [PMID: 16541021 DOI: 10.1038/sj.ki.5000302] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m(2) were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-alpha, interleukin-1beta and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-alpha and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion.
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Affiliation(s)
- Y-M Chen
- Renal Division, Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Mora C, Navarro JF. The role of inflammation as a pathogenic factor in the development of renal disease in diabetes. Curr Diab Rep 2005; 5:399-401. [PMID: 16316588 DOI: 10.1007/s11892-005-0044-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Carmen Mora
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Spain
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Radfar M, Larijani B, Hadjibabaie M, Rajabipour B, Mojtahedi A, Abdollahi M. Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients; a randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother 2005; 59:302-6. [PMID: 15932791 DOI: 10.1016/j.biopha.2005.05.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2005] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND As oxidative stress contributes to both progression and pathologic complications of diabetes and effective therapeutic strategies to prevent or delay the damage remain limited, the aim of the present study was to assess the efficacy of pentoxifylline in reducing of oxidative stress. Since there is a relationship between nitric oxide (NO), epidermal growth factor (EGF) and oxidative stress, we measured the effect of this drug on these parameters in comparison to placebo. METHODS Thirty-nine patients with type-2 diabetes mellitus were randomized in a double blind, placebo-controlled clinical trial to receive either pentoxifylline 400 mg four times a day or placebo for 14 days. Blood samples were obtained at baseline and at the end of the study. Samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), EGF and NO levels. RESULTS Pentoxifylline in comparison to placebo was effective (P < 0.05) in reduction of lipid peroxidation in plasma of the patients without significant effects on TAP, levels of EGF and NO in plasma. CONCLUSION Adding of pentoxifylline to drug regimen of diabetic type-2 patients can be helpful. Exact mechanism of action of pentoxifylline in reduction of blood lipid peroxidation remains to be elucidated.
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Affiliation(s)
- M Radfar
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, PO Box 14155-6451, Tehran, Iran
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Navarro JF, Mora C, Muros M, García J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol 2005; 16:2119-26. [PMID: 15917336 DOI: 10.1681/asn.2005010001] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n = 30) or to a control group (n = 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-alpha (R = 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was -16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-alpha also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-alpha in patients who were treated with PTF (R = 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-alpha excretion.
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Affiliation(s)
- Juan F Navarro
- Servicio de Nefrología, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Tenerife 38010, Spain.
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