Chronic administration of fluoxetine impairs neurogenic and endothelium-dependent relaxation of the rabbit corpus cavernosum smooth muscle

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), cause erectile dysfunction; however, the mechanism by which they cause erectile function is unclear. We investigated the reactivity of the corpus cavernosum after chronic fluoxetine treatment in rabbits. Twelve rabbits were randomly divided into two groups: control (n = 6) or 20 mg/kg/day of fluoxetine delivered i.p. (n = 6). The reactivity of the corpus cavernosum tissue from the fluoxetine-treated and control groups was studied in organ chambers after 21 days of fluoxetine injection. In the fluoxetine-treated group, endothelium-dependent relaxation of the corpus cavernosum in response to acetylcholine was significantly decreased compared to the control group. However, the sensitivity (i.e., pD₂) of the fluoxetine-treated cavernosal tissue strips to acetylcholine was not changed with respect to controls. Electrical field stimulation (EFS)-induced neurogenic relaxation was also significantly reduced in the fluoxetine-treated group. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside was similar between the cavernosal tissues from the two groups. There was also no change in agonist potency between the two groups. Additionally, chronic fluoxetine treatment had no effect on KCl-induced contractile responses. When tissue contraction was produced with phenylephrine to study relaxation in response to various stimuli, the tension induced was similar between the fluoxetine-treated and control groups. This study suggests that chronic fluoxetine treatment causes significant functional changes to the penile erectile tissue of rabbits, and these changes may contribute to the development of impotence.     

前列地尔治疗糖尿病患者勃起功能障碍的临床分析

目的探讨前列地尔治疗糖尿病患者勃起功能障碍的疗效。方法将90例糖尿病合并勃起功能障碍患者按就诊顺序随机分为观察组（45例,伐地那非＋前列地尔）和对照组（45例,伐地那非）,疗程3月,比较两组阴茎的硬度、勃起时间、IIEF-5评分情况。结果观察组与对照组比较,阴茎的硬度满意度（29％VS18％）、勃起时间[（5．6±1．2）分VS（1．2±0．6）分]、IIEF-5评分[（22．1±2．3）分VS（17．5±1．9）分],观察组均有明显升高（P〈0．05,差异具有统计学意义）;观察组有3例发生不良反应,其中面色潮红2例、静脉炎1例。结论在伐地那非基础上加用前列地尔治疗可进一步改善糖尿病合并勃起功能障碍患者的勃起功能,且不良反应少。     

Role of cytochrome P450 metabolites of arachidonic acid in regulation of corporal smooth muscle tone in diabetic and older rats

This study examined the role of cytochrome P450 (CYP) metabolites of arachidonic acid (AA) to rat corporal smooth muscle tone. 11, 12-Epoxyeicosatrienoic acid (EET) (10(-11)-10(-6 )M) produced dose-dependent relaxation of rat (control; 10 weeks old) corpus cavernosum with a pD(2) value of 8.8+/-0.2 and a maximal relaxation of 80+/-9%, whereas 20-hydroxyeicosatetraenoic (20-HETE) did not have an effect. EET-mediated relaxation of corpus cavernosum was attenuated by 71+/-3%, 55+/-2%, 53+/-5% and 84+/-3% in the presence of nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide (NO) synthase, iberiotoxin (5 x 10(-8) M), an inhibitor of calcium-activated potassium (BK) channels, glibenclamide (10(-5) M), an inhibitor of ATP-sensitive K(+) channels or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10(-5) M), an inhibitor of soluble guanylyl cyclase, respectively. EET-mediated relaxation of rat corpus cavernosum was significantly less in the streptozotocin (STZ)-treated (diabetic) and 30 weeks old (older) animals compared to control. Carbachol (10(-9)-10(-4) M)-induced relaxation was significantly reduced whereas phenylephrine (PE) (10(-9)-5 x 10(-3) M)-induced contraction was significantly increased in the cavernosum strips from old and diabetic rats compared to the control. Pre-incubation of the cavernosum strips obtained from control, older or diabetic rats with N-hydroxy-N'-(4-butyl-2-methyl-phenyl)-formamidine (HET0016), a selective inhibitor of 20-HETE synthesis, or 1-cyclohexyl-3-dodecyl urea (CDU), a specific inhibitor of soluble epoxide hydrolase (sEH) resulted in a significant attenuation of PE-induced contraction and improvement in carbachol-induced relaxation. We conclude that 11, 12-EET-induced relaxation of the rat corpus cavernosum involves activation of cGMP/NO pathway as well as activation of ATP-sensitive K(+) channels and BK channels. These results also suggest that inhibition of 20-HETE production or reduction of EET inactivation may have therapeutic potential to prevent erectile dysfunction associated with diabetes and aging.     

Effects of the Rho-kinase inhibitors,Y-27632 and fasudil,on the corpus cavernosum from diabetic mice

Relaxant responses to two Rho-kinase inhibitors, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632) and fasudil, were compared in the corpus cavernosum obtained from diabetic and non-diabetic mice. Streptozotocin (100 mg kg(-1) day(-1), for 2 days) induced diabetes with a blood glucose level of 318+/-55.4 mg dl(-1); whereas it was 85.4+/-4.1 mg dl(-1) in control mice (P<0.05). Electrical field stimulation (40 V, 0.5 ms, 1, 2, 4, 8, 16 Hz for 15 s) and acetylcholine-induced relaxations were markedly attenuated in the corpus cavernosum from streptozotocin-diabetic mice whereas responses to Y-27632 (10(-9)-3 x 10(-5) M) and fasudil (10(-9)-3 x 10(-5) M) were not altered. EC(50) values for Y-27632 were 2.98+/-0.89 and 4.19+/-2.71 microM in the corpus cavernosum from control and diabetic mice, respectively (P>0.05). The values for fasudil were 7.42+/-4.91 and 3.53+/-1.41 microM in the corpus cavernosum from control and diabetic mice, respectively (P>0.05). These results may suggest that, in diabetes, the relaxant effects of the Rho-kinase inhibitors may not be changed and thus, they may have a beneficial therapeutic effect in diabetic erectile dysfunction.     

Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.     

Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes

ABSTRACT

Background: Histamine receptor activation and degranulation of mast cells are the mechanisms by which the ocular itching, hyperemia, chemosis, eyelid swelling, and tearing of seasonal allergic conjunctivitis are induced. Some of the topical solutions available as anti-allergy therapies are intended to interfere with these mechanisms, and the body of research regarding the capabilities of these therapeutic molecules continues to expand.

Objective: To review the currently available literature regarding one topical ophthalmic anti-allergy agent, olopatadine (Patanol), and its anti-histaminic and mast cell stabilizing actions, both in pre-clinical and clinical settings.

Design and methods: Relevant research of laboratory, animal model, and clinical trial studies performed using olopatadine was reviewed. MEDLINE literature searches were conducted and supplemented by additional reports which furthered relevant discussion or were necessary to verify the information resulting from original searches.

Results: Olopatadine demonstrates unique properties both pre-clinically and clinically which differentiate it from other therapeutic molecules in its class of dual action mast cell stabilizer/anti-histamine. Its non-perturbation of cell membranes, human conjunctival mast cell stabilization in vivo and in vitro, and superior efficacy as compared to other topical anti-allergic medications including mast cell stabilizers, anti-histamines, and dual action agents, all contribute to olopatadine's profile.

Conclusions: Peer-reviewed literature suggests that olopatadine is clinically superior to the other anti-allergic molecules because of its strong anti-histaminic qualities and its unique ocular mast cell stabilizing properties.     

The effect of sildenafil on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit

Sildenafil, a type V phosphodiesterase inhibitor, enhances smooth muscle relaxation in normal human and rabbit corpus cavernosum. We investigated the in vitro effects of sildenafil on non-adrenergic, non-cholinergic and nitric oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbits, since alterations in this pathway are recognised in diabetic erectile dysfunction. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan. Cavernosal strips from age-matched control, 3- and 6-month diabetic animals were mounted in organ baths. Relaxation responses to electrical field stimulation (1-20 Hz) or sodium nitroprusside (10(-8)-10(-4) M) were assessed in the absence and presence of sildenafil (10(-8) and 10(-7) M). The effect of sildenafil on cGMP formation by the corpus cavernosum was also assessed following stimulation with sodium nitroprusside, A23187 and acetylcholine. Sodium nitroprusside-stimulated relaxations were significantly (P<0.03) impaired in the corpus cavernosum from both diabetic groups, (IC(50)=4.6 x 10(-6) M following 3 months of diabetes mellitus and 4.0 x 10(-6) M following 6 months of diabetes mellitus; compared to 7.5 x 10(-7) M for pooled age-matched controls). Sildenafil (10(-7) M) significantly enhanced sodium nitroprusside-stimulated relaxation in control (P<0.05) and diabetic groups (P<0.03). Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 6-month diabetes mellitus and enhanced by sildenafil (10(-8) M). cGMP formation by the diabetic corpus cavernosum was impaired significantly, but restored towards normal by sildenafil. We suggest that the impairment of NO-mediated relaxation of the corpus cavernosum reflect, at least in part, a defect in guanylyl cyclase activity. These findings support the use of sildenafil as an effective, orally administered, treatment for diabetic erectile dysfunction.     

酶消化法分离培养糖尿病大鼠结肠平滑肌细胞

目的探讨糖尿病(DM)大鼠结肠平滑肌细胞(SMC)的培养方法。方法建立DM大鼠模型,分离结肠,用酶消化法体外培养正常及DM大鼠结肠SMC,α-肌动蛋白免疫荧光鉴定。结果造模后大鼠体重(165±16.8)g,较正常组(286±14.5)g明显减轻(P<0.01);血糖(25.4±3.4)mmol/L,明显高于正常组(4.3±0.8)mmol/L(P<0.01)。正常结肠SMC培养7 d左右即可融合成片、相互交叉成多层,进行传代;DM大鼠结肠SMC需12～14 d融合成片,进行传代;传代后正常结肠SMC需3～4 d即可进行下一次传代,而糖尿病结肠SMC则需5 d。α-肌动蛋白免疫组化染色鉴定均为SMC。结论 DM大鼠结肠SMC增殖速度比正常SMC慢,培养条件也较正常SMC更严格,形态学上与正常SMC相似。     

Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: a retrospective analysis of pooled data from placebo-controlled trials*

ABSTRACT

Objective: Cardiovascular (CV) risk factors are associated with an increased risk of erectile dysfunction (ED). In men with diabetes mellitus (DM), pooled from clinical trials of sildenafil treatment for ED, this retrospective analysis determined efficacy and safety, overall and in subgroups with additional CV risk (i.e., hypertension, dyslipidemia, and smoking).

Research design and methods: From the manufacturer's database of worldwide research, 12‐week data from men with DM were pooled from randomized, double-blind, placebo-controlled trials of flexible-dose sildenafil (25, 50, or 100?mg, PRN) for ED.

Main outcome measures: Question 3 (achieving an erection), question 4 (maintaining an erection), and the Erectile Function domain of the International Index of Erectile Function; percentage of successful intercourse attempts according to patient event logs; and response to a global efficacy question (GEQ). Differences between groups were determined using logistic regression (percentage of responders according to GEQ) and analysis of covariance (all other outcomes).

Results: Inclusion criteria were met by 11 trials and by 974 men with DM and ED who were randomized to placebo (n = 482) and sildenafil (n = 492) within the selected trials. For all outcomes, overall and regardless of additional CV risk, the benefit was greater for sildenafil versus placebo (?p ≤ 0.0001), including 3-fold more men responding that sildenafil treatment improved their erections (62% vs. 18%) and a more than doubling of the mean ± standard error percentage of successful sexual intercourse attempts (52.6 ± 5.0 vs. 22.4 ± 5.1). Adverse events were mild to moderate and included (sildenafil vs. placebo) headache (5% vs. 2%), flushing (7% vs. 2%), and dyspepsia (4% vs. 0%), which is consistent with the profile in the general population of men treated with sildenafil for ED.

Conclusion: This retrospective analysis of pooled data showed that sildenafil was well tolerated and improved erectile function and intercourse success in men with ED and DM, regardless of additional CV risk factors.     

Repositioning of molsidomine for its efficacy in diabetes induced erectile dysfunction in rats: In silico,in vitro and in vivo approach

Background

Well known risk factors for diabetic erectile dysfunction include impaired nitric oxide synthesis and endothelial dysfunction. We proposed to evaluate the efficacy of nitric oxide donor, molsidomine in rat model of diabetic erectile dysfunction.

综合医院糖尿病患者及其家属糖尿病相关知识掌握现状调查

目的了解石家庄三甲医院内分泌科糖尿病患者及家属关于糖尿病的知、信、行情况;了解患者接受糖尿病健康教育的现状;为下一步对糖尿病患者开展健康教育,建立有效的糖尿病防治模式提供依据。方法自行设计糖尿病患者及家属糖尿病知信行调查问卷,于石家庄三甲医院中随机抽样492例患者及其418名亲属进行问卷调查。结果糖尿病患者对糖尿病基本常识、控制饮食、运动治疗、并发症等较亲属认识程度要高,糖尿病患者的知识态度得分与其家属知识态度得分成正比,糖尿病患者的糖尿病防治态度较家属更积极,血糖监测、体育锻炼等健康行为形成率比较低。结论多数糖尿病患者及家属对糖尿病基本知识掌握情况不足,态度和行为有待于改进,糖尿病防治工作依然比较严峻。     

The role of ascorbic acid on the redox status and the concentration of malondialdehyde in streptozotocin-lnduced diabetic Rats

We investigated the role of ascorbic acid on the redox status in streptozotocin-induced diabetic rats. In the plasma of diabetic rats, the ratio of reduced/total ascorbic acid was significantly decreased as compared with normal control. Ascorbic acid supplementation increased the reduced and total ascorbic acid contents as compared with diabetic control. In the rutin-treatment group, reduced and total contents of ascorbic acid were significantly decreased, however, the ratio of reduced/total contents of ascorbic acid had no difference as compared with diabetic rats. In the insulin-treatment group, this ratio is not significantly different as compared with diabetic control. However, in the insulin plus ascorbic acid treatment group, reduced form and the ratio of reduced/total ascorbic acid were significantly increased as compared with diabetic control. In addition, we measured the contents of malondialdehyde (MDA) in the plasma of diabetic rats. The contents of MDA was increased as compared with normal control, however, in insulin-treatment group, the contents of MDA was decreased as compared with diabetic rats. Ascorbic acid had no effects on the increases of MDA in diabetic rats. In conclusion, plasma ascorbic acid level and its reduced/total ratio reflects the status of the oxidative stress in the diabetic rats. Supplement of ascorbic acid did not correct the ratio of the reduced/ total ascorbic acid. However, supplement of insulin and ascorbic acid corrected the ratio of reduced/total ascorbic acid.     

糖化白蛋白在糖尿病及糖尿病肾病诊断中的临床意义

目的探讨血清糖化白蛋白(GA)水平及其他代谢产物与糖尿病(DM)及糖尿病肾病(DN)的相关性及其临床意义。方法 50例糖尿病患者作为糖尿病组, 50例糖尿病肾病患者作为糖尿病肾病组,50例健康人作为健康对照组,将100例糖尿病组和糖尿病肾病组患者根据尿微量白蛋白水平不同分为尿微正常组(58例)及尿微增高组(42例)。检测并比较各组间的空腹血糖(GLU)、血尿素氮(BUN)、肌酐(Cr)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、糖化血红蛋白(HbA1c)、GA水平。结果健康对照组、糖尿病组和糖尿病肾病组的TC、LDL-C水平两两比较,差异均无统计学意义(P>0.05)。健康对照组的HDL-C(1.52±0.47)mmol/L高于糖尿病组的(1.17±0.54)mmol/L及糖尿病肾病组的(1.09±0.52)mmol/L,差异均具有统计学意义(P<0.05);糖尿病组及糖尿病肾病组的HDL-C水平比较,差异无统计学意义(P>0.05)。糖尿病组和糖尿病肾病组的GLU、BUN、Cr、TG、HbA1c、GA水平均高于健康对照组,糖尿病肾病组的GLU、BUN、Cr、TG、HbA1c、GA水平均高于糖尿病组,差异均具有统计学意义(P<0.05)。尿微正常组和尿微增高组的TC、LDL-C水平比较,差异均无统计学意义(P>0.05)。尿微增高组的GLU、BUN、Cr、TG、HbA1c、GA水平均高于尿微正常组, HDL-C水平低于尿微正常组,差异均具有统计学意义(P<0.05)。结论 GA可为糖尿病及糖尿病肾病的诊断及治疗提供重要的临床依据。     

The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus

Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.     

Comparison of tricyclic antidepressants in rabbits: Antinociception and potentiation of the noradrenaline pressor responses

The antinociceptive effect on the rabbit's dental pain of 10 tricyclic antidepressants (2–5 mg/kg i.v.) was compared with their potentiation of the noradrenaline (NA) pressor responses in conscious rabbits. The receptor desensitization by tricyclic antidepressants was tested on the rabbit's isolated aortic spiral.Tertiary amines imipramine, amitriptyline, doxepine, and trimipramine were most antinociceptive but inferior to 5 mg/kg of morphine. They were also most potent in enchancing the morphine analgesia, amitriptyline and doxepine in particular. The secondary amines desipramine and nortriptyline were less antinociceptive than their tertiary analogues imipramine and amitriptyline. The effects of opipramol and imipramine N-oxide were inconsistent. Dibenzepine and iprindole were inactive. Lithium abolished the antinociceptive action of protriptyline without modifying that of the combination of protriptyline and morphine.The secondary amines, protriptyline and nortriptyline, proved most effective in enhancing the NA pressor response, followed by dibenzepine, desipramine, and imipramine. Opipramol, amitriptyline and iprindole were least active. Trimipramine reduced the NA pressor responses and the effect of doxepine was variable. Lithium did not modify the NA potentiation by protriptyline.It is concluded that antinociception by tricyclic antidepressants is more likely related to their central tryptaminergic mechanisms or to local anaesthetic properties than to their adrenergic or adrenolytic activity.     

Exenatide BID Observational Study (ExOS): results for primary and secondary endpoints of a prospective research study to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes in a real-world setting

Abstract

Objective:

The Exenatide BID Observational Study (ExOS) was designed to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes (T2D) in a real-world clinical practice setting in the United States.     

糖尿病大鼠海马区胶质细胞源性神经营养因子和胆碱乙酰转氨酶mRNA表达及其与认知功能的关系

目的 观察糖尿病大鼠不同血糖水平下海马区胶质细胞源性神经营养因子（GDNF）和胆碱乙酰转氨酶（CHAT） mRNA表达的变化,探讨其在糖尿病中枢神经病变中的作用.方法 将40只雄性Wistar大鼠随机分为糖尿病血糖未控制组（DM1组）、糖尿病血糖控制组（DM2组）和对照组（NC组）.每4周测血糖和体质量.满12周时测体质量与HbA1c,取海马CA区进行RT-PCR,检测GDNF和ChAT mRNA表达.结果 海马区GDNF和ChAT mRNA的表达与HbA1c水平之间均呈负相关（r=-0.962,-0.974,均P＜0.001）;海马区GDNF与ChAT mRNA表达亦呈正相关（r=0.974,P＜0.001）.结论 长期慢性高血糖可导致海马区GDNF表达降调节,从而引起以ChAT表达下降为标志的中枢胆碱能功能障碍,以致学习记忆功能损害.     

The safety and efficacy of the use of oral anticoagulant medications in patients with diabetes mellitus: A systematic review

AimsDiabetes mellitus (DM) and atrial fibrillation (AF) commonly co-exist. Oral anticoagulants (OACs) are widely used in patients with DM. This review aims to summarise the available literature on the safety (hypoglycaemia or bleeding) and efficacy (stroke or systemic embolism) of the use of OACs in patients with DM.MethodsWe searched the Medline, the Excerpta Medica dataBASE (Embase) and Cochrane databases up to the 10th of December 2020. The search strategy was conducted using both keywords and MeSH terms. We included randomised controlled trials (RCTs) and observational studies that reported on the safety and efficacy of the use of OACs in patients with diabetes from all age groups. Study selection, data extraction and quality assessment were conducted independently by two reviewers.ResultsA total of 3,976 articles were identified through the search process, of which seven studies met the inclusion criteria of the systematic review: four observational studies and three studies that were randomised controlled trials, with a total of 703,855 patients. Two observational studies reported that the use of warfarin was associated with a higher risk of hypoglycaemic events, specifically with sulfonylurea. One observational study and three randomised controlled trials reported that the use of warfarin compared to other oral anticoagulants was associated with a higher risk of bleeding. In addition, three randomised controlled trials reported that the use of warfarin compared to other oral anticoagulants was associated with a lower risk of stroke or systemic embolism.ConclusionsThis systematic review found that DOACs had a better efficacy outcome and safer clinical outcomes in comparison to warfarin in patients with diabetes.     

Synergistic effect of quercetin and quinic acid by alleviating structural degeneration in the liver,kidney and pancreas tissues of STZ-induced diabetic rats: A mechanistic study

The aim of this study was to investigate the synergistic effects of quercetin (QE) and quinic acid (QA) on a STZ-induced diabetic rat model to determine their potential role in alleviating diabetes and its associated complications. In our study design, diabetic rats were treated with single and combined doses of QE and QA for 45 days to analyse their effects on liver, kidney and pancreas tissues. The study result showed that QE and QA treated groups down-regulated hyperglycaemia and oxidative stress by up-regulating insulin and C-peptide levels. Moreover, histological observations of the liver, kidney and pancreas of diabetic rats treated with single and combined doses of QE and QA showed a significant improvement in the structural degeneration. Interestingly, the combination dose of QE and QA (50 mg/kg) exhibited maximum inhibition of the pro-apoptotic protein Bax expression and demonstrate enhancement of the anti-apoptotic protein Bcl-2 expression in the kidney tissues, suggesting a protective role in the kidneys of diabetic rats. Taken together, these results indicates the synergistic effects of QE and QA in ameliorating hyperglycaemia, hyperlipidemia and insulin resistance in diabetic rats and therefore, open a new window of research on the combinatorial therapy of flavonoids.