Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocin-induced diabetic model

Wahba

Zagazig Journal of Pharmaceutical Sciences

et al. 2016

Diabetic nephropathy (DN) is the main cause of end stage renal disease. Complex mechanisms are implicated in the pathogenesis of DN including the accumulation of advanced glycation end products (AGEs), oxidative stress, and inflammation mediated through the upregulation of toll-like receptor 4 (TLR4). Hibiscus sabdariffa is widely used in food products possessing anti-oxidative, anti-inflammatory, anti-diabetic, and anti-hypertensive effects. The present study aimed to investigate the role of hibiscus extract against streptozotocin(STZ)induced DN compared to lisinopril, and to evaluate the effects of their combined administration. Rats were treated with hibiscus extract (100, 200, or 400 mg/kg), lisinopril (5 mg/kg), or lisinopril plus hibiscus extract (2.5/100 mg/kg) for 8 weeks. Hibiscus extract caused a dosedependent improvement of nephropathy, and suppressed oxidative stress, inflammation, and the upregulation of TLR4 induced by STZ. The effects of hibiscus extract (400 mg/kg) were comparable to lisinopril (5 mg/kg). Interestingly, the combined administration of lisinopril plus hibiscus extract (2.5/100 mg/kg) significantly improved the manifestations of nephropathy better than lisinopril or hibiscus extract alone. These results might support the application of hibiscus extract as an alternative to the conventional angiotensin-converting enzyme inhibitors (ACEIs) or at least as an adjunctive to augment their effects in DN.

Section: Discussionsupporting

confidence: 91%

Hibiscus sabdariffa extract augments the renoprotective effect of lisinopril against streptozotocin-induced diabetic nephropathy in rats

Wahba

Zagazig Journal of Pharmaceutical Sciences

et al. 2016

“…Although sildenafil is reported to exert endothelial effects in various diabetic rat models, [81][82][83][84][85] using sublingual nitro-glycerine administration (due to its contraindication with sildenafil). However, in none of the treatment groups was blood pressure or BAD (prehyperaemia) altered compared to placebo; findings consistent with an absence of blood pressure effect with SAR247799 in healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Although sildenafil is reported to exert endothelial effects in various diabetic rat models, [81][82][83][84][85] a direct comparison to SAR247799 was not performed in ZDF rats as the objective of our preclinical studies was simply to aid in selecting doses of SAR247799 for human testing.…”

Section: Concurrent Therapy Nmentioning

confidence: 99%

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Bergougnan

Andersen

Plum‐Mörschel

et al. 2020

Brit J Clinical Pharma

agonist designed to activate endothelial S1P 1 and provide endothelial-protective properties, while limiting S1P 1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P 1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flowmediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. Results: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. The authors confirm that the Principal Investigators for the clinical study were Grit Anderson and Leona Plum-Mörschel and that they had direct clinical responsibility for patients at the Neuss and Mainz sites, respectively. In addition, Grit Andersen was coordinating principal investigator.

Fundamemntal Clinical Pharma

“…Sildenafil (3 mg/kg/day for 8 weeks) augmented the protective role of telmisartan (10 mg/kg/day for 8 weeks) against diabetic nephropathy in a streptozotocin‐induced diabetic model and saved renal microarchitecture [150]. Sildenafil citrate (50 mg/day for one month) reduced HbA1c and microalbuminuria in male patients with type 2 diabetes [151].…”

Section: The Promising Effects Of Sildenafil In Liver and Kidneymentioning

confidence: 99%

Sildenafil beyond erectile dysfunction and pulmonary arterial hypertension: Thinking about new indications

Ala

Jafari

Dehpour

2020

Sildenafil, approved two decades ago, is the inhibitor of phosphodiesterase 5 (PDE5). First of all, it was designated for angina pectoris, but soon it showed a wonderful efficacy in erectile dysfunction (ED) and then pulmonary arterial hypertension (PAH). Due to the distribution of phosphodiesterase (PDE) in almost all organs, maybe it effects other diseases. Hence, a great number of investigations began to understand the role of PDEi in different organs. Preliminary research on sildenafil in cell culture and animal models has yielded promising results. Soon, a greater number of animal researches and clinical trials joined them. The results disclosed sildenafil can have beneficial effects in each organ such as heart, liver, kidney, brain, and intestines. Furthermore, it has significantly improved the prognosis of organ ischemia in various animal models. Clinical trials in several diseases, such as recurrent spontaneous miscarriage, fatty liver disease, bronchopulmonary dysplasia (BPD), heart failure, and premature ejaculation (PE) brought promising results. Although some clinical trials are available on the effects of sildenafil on various diseases, further studies on humans are needed to consolidate the ultimate effects of sildenafil. The aim of this review was to describe the effects of sildenafil on each organ and explain its mechanisms of action. Further, other PDE inhibitors such as tadalafil and vardenafil have been briefly discussed in parts of this review.