Nephroprotective action of glycosaminoglycans: why the pharmacological properties of sulodexide might be reconsidered

A relatively large body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve biochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic reveals that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Moreover, angiotensin II inhibits heparan sulfate synthesis, while heparins modulate angiotensin II signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in diabetes patients. Sulodexide, a mixture of heparin and dermatan sulfate, appears to be a promising treatment for diabetic proteinuria partially resistant to renin–angiotensin system blocking agents. Sulodexide prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of glomerular basement membrane ionic permselectivity. The antiproteinuric effect appears to be mainly related to the basal proteinuria and consequently to the duration of treatment in a relatively large number of small clinical trials. On the other hand, several sulodexide pharmacodynamic properties could improve the prognosis of chronic kidney disease patients, also independently from its antiproteinuric effect. However, sulodexide development as an antiproteinuric drug needs to be continued, in order to define which kind of patients could better respond to this treatment

Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences?

: Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival

A prospective evaluation of persistence on antihypertensive treatment with different antihypertensive drugs in clinical practice

Persistence on treatment affects the efficacy of antihypertensive treatment. We prospectively investigated the persistence on therapy and the extent of blood pressure (BP) control in 347 hypertensive patients (age 59.4 ± 6 years) randomly allocated to a first-line treatment with: angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers (CCBs), ß-blockers, angiotensin-II receptor blockers (ARBs), or diuretics and followed-up for 24-months. Persistence on treatment was higher in patients treated with ARBs (68.5%) and ACE inhibitors (64.5%) vs CCBs (51.6%; p < 0.05), β-blockers (44.8%, p < 0.05), and diuretics (34.4%, p < 0.01). No ARB, ACE inhibitor, β-blocker, or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class. The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs (59.3% vs 46.6%, p < 0.05). Systolic and diastolic BP was decreased more successfully in patients treated with ARBs (−11.2/−5.8 mmHg), ACE inhibitors (−10.5/−5.1 mmHg), and CCBs (−8.5/−4.6 mmHg) compared with ß-blockers (−4.0/−2.3 mmHg p < 0.05) and diuretics (−2.3/−2.1 mmHg, p < 0.05). No ARB, ACE inhibitor, β-blocker, or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class. A trend toward a better BP control was observed in response to lercanidipine vs other CCBs (p = 0.059). The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice

Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Background: Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings: We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions: Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety

Tinnitus in elderly patients and prognosis of mild-to-moderate congestive heart failure: a cross-sectional study with a long-term extension of the clinical follow-up

<p>Abstract</p> <p>Background</p> <p>The complex mechanism responsible for tinnitus, a symptom highly prevalent in elderly patients, could involve an impaired control of the microcirculation of the inner ear, particularly in patients with poor blood pressure control and impaired left ventricular (LV) function.</p> <p>Methods</p> <p>In order to define the relationship between the presence of tinnitus and the severity and clinical prognosis of mild-to-moderate chronic heart failure (CHF) in a large population of elderly patients (N = 958), a cross-sectional study was conducted with a long-term extension of the clinical follow-up. Blood pressure, echocardiographic parameters, brain natriuretic peptide (BNP), hospitalization, and mortality for CHF were measured. Multivariate logistic regression analysis was used to assess the association between the presence of tinnitus and some of the prognostic determinants of heart failure.</p> <p>Results</p> <p>The presence of tinnitus was ascertained in 233 patients (24.3%; mean age 74.9 ± 6 years) and was associated with reduced systolic and diastolic blood pressure (123.1 ± 16/67.8 ± 9 vs 125.9 ± 15/69.7 ± 9; <it>P </it>= .027/<it>P </it>= .006), reduced LV ejection fraction (LVEF%; 43.6 ± 15 vs 47.9 ± 14%, <it>P </it>= .001), and increased BNP plasma levels (413.1 ± 480 vs 286.2 ± 357, <it>P </it>= .013) in comparison to patients without symptoms. The distribution of CHF functional class was shifted toward a greater severity of the disease in patients with tinnitus. Combined one-year mortality and hospitalization for CHF (events/year) was 1.43 ± 0.2 in patients with tinnitus and 0.83 ± 0.1 in patients without tinnitus, with an adjusted hazard ratio (HR) of 0.61 (95% confidence interval (CI): 0.37 to 0.93, <it>P </it><.002).</p> <p>Conclusions</p> <p>Our preliminary data indirectly support the hypothesis that tinnitus is associated with a worse CHF control in elderly patients and can have some important clinical implications for the early identification of patients who deserve a more aggressive management of CHF.</p

Activity and potential role of licofelone in the management of osteoarthritis

Arrigo FG Cicero, Luca Laghi&ldquo;D. Campanacci&rdquo; Clinical Medicine &amp; Applied Biotechnology Dept. Sant&rsquo;Orsola-Malpighi Hospital &ndash; University of Bologna Via Massarenti, 9, 40138 Bologna, ItalyAbstract: Osteoarthritis is the most common form of arthritis. It is a progressive joint disease associated with aging. It may be found in the knees, hips, or other joints. It is estimated that costs associated with osteoarthritis exceed 2% of the gross national product in developed countries. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide. The main limitation in using NSAIDs consists in their side-effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase (COX), and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). Arachidonic acid can also be converted to leukotrienes (LTs) by the action of 5-lipoxygenase (5-LOX). Licofelone, a LOX/COX competitive inhibitor, decreases the production of proinflammatory leukotrienes and prostaglandins (which are involved in the pathophysiology of osteoarthritis and in gastrointestinal (GI) damage induced by NSAIDs) and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability. Preliminary data with this drug seem promising, but further well-designed clinical trials of this agent in the elderly will be necessary before a final evaluation is possible.Keywords: LOX/COX inhibitor, Licofelone, leukotrienes, osteoarthritis, nonsteroidal anti-inflammatory drug

Retargeting the management of hypercholesterolemia — Focus on evolocumab

Alessandro Colletti,1 Giuseppe Derosa,2 Arrigo FG Cicero1 1Department of Medical and Surgical Sciences, University of Bologna, Bologna, 2Department of Internal Medicine and Therapeutics, University of Pavia and Policlinico San Matteo Foundation, Pavia, Italy Abstract: Hypercholesterolemia is one of the main risk factors for atherosclerosis and cardiovascular diseases. The treatment is based on the modification of the diet and lifestyle and if necessary on a pharmacological therapy. The most widely used drugs are the inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (statins); nevertheless, many patients do not reach optimal levels of low-density lipoprotein-cholesterol (LDL-C) even with maximal dosage of statins (eventually associated to ezetimibe) or present side effects, which do not allow them to continue the treatment. Inhibitors of PCSK9 represent a new therapeutic approach for lowering LDL-C. Evolocumab and alirocumab are human monoclonal antibodies, which bind to extracellular PCSK9 and thus interfere with the degradation of low-density lipoprotein receptor. Evolocumab use is approved for the treatment of patients with heterozygous familial hypercholesterolemia (FH) and homozygous FH as an adjunct to diet and maximally tolerated statin therapy or for subjects with clinical atherosclerotic cardiovascular disease who require additional lowering of&nbsp;LDL-C. Phase&nbsp;III clinical trials have demonstrated the effectiveness of evolocumab (140&nbsp;mg/every 2&nbsp;weeks or 420&nbsp;mg/month, via subcutaneous injection) in monotherapy and in combination with statins, in the treatment of patients intolerant to statins or with FH. In monotherapy, it reduces LDL-C by 55%, and its association with statins leads to a reduction of LDL-C by up to 63%&ndash;75%. Evolocumab has been demonstrated to be safe and well tolerated. Ongoing clinical trials are assessing the long-term effects of evolocumab on the incidence of cardiovascular risk, safety, and tolerability. This review resumes the available clinical evidence on the efficacy and safety of evolocumab, for which a relatively large amount of clinical data are currently available, and discusses the retargeting of cholesterol-lowering therapy in clinical practice. Keywords: PCSK9, hyperlipidemia, evolocumab, LDL-C, familial hypercholesterolemia&nbsp

Nutraceutical Approach to Peripheral Neuropathies: Evidence from Clinical Trials

Peripheral neuropathies are damages to or disorders of the peripheral nervous system including radiculopathies, plexopathies, mono-, multi- and polyneuropathies. The etiopathogenetic mechanisms include genetic, traumatic, toxic, metabolic, infectious, nutritional, inflammatory and paraneoplastic causes. The treatment of peripheral neuropathies should primarily address their contributing causes. However, symptomatic therapy is also key in these conditions, particularly in pain relief. Several nutraceuticals have been used in the treatment of peripheral neuropathies and seem promising, due to assumed neurotrophic action, low toxicity and favorable metabolic profile. We performed a review of the literature to evaluate safety and effectiveness of nutraceutical compounds in peripheral neuropathies, focusing on the single agents for which randomized controlled trials versus placebo were performed. Vitamin B complex, alpha lipoic acid, L-acetylcarnitine,vitamin E and Coenzyme Q proved effective to different extents in neuropathic pain in polyneuropathies. They all proved less consistently effective on other neuropathic symptoms, neuropathic signs and neurophysiological parameters. All the considered compounds were tolerable even for long periods, however alpha lipoic acid at doses equal or larger than 1200 mg/die was associated with nausea and vomiting in a large number of patients

Effects of early treatment with zofenopril in patients with myocardial infarction and metabolic syndrome: the SMILE Study

Claudio Borghi, Arrigo FG Cicero, Ettore AmbrosioniDepartment of Clinical Medicine, University of Bologna, Bologna, Italy. On behalf of the Survival of Myocardial Infarction Long-term Evaluation (SMILE) StudyObjective: To evaluate the clinical efficacy of the early administration of zofenopril in a group of patients with and without metabolic syndrome (MS+ and MS&ndash;) and anterior myocardial infarction enrolled in the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study.Methods: Patients were randomized double-blind to zofenopril (n = 719) or placebo (n = 699) for 6 weeks. The primary end point was the effect of treatment on the 6-week combined occurrence of death and severe congestive heart failure. The secondary end point was the 1-year mortality rate.Results: Of the 1418 patients included in this post-hoc analysis, 686 (48.3%) had MS. After 6 weeks of treatment zofenopril significantly reduced the incidence of all-cause death and severe congestive failure (risk reduction: 69%, 95% CI: 7&ndash;78; 2p = 0.002) in MS+ patients. This was the case for 1-year mortality, too (29%, 95% CI: 4&ndash;41; 2p = 0.048). Zofenopril was effective also in MS&minus; patients but the amount of relative risk reduction was less than in MS+ for both the primary (&ndash;11%; 2p = 0.61) and secondary endpoint (&ndash;19%; 2p = 0.025).Conclusions: Results of this post-hoc analysis of the SMILE Study demonstrate the striking benefit of early administration of zofenopril in MS+ patients with acute anterior myocardial infarction.Keywords: SMILE Study, angiotensin converting enzyme inhibitor, zofenopril, myocardial infarction, metabolic syndrom