Nebivolol – a place in the therapy of hypertension in various clinical situations

Nebivolol is a long-acting, most cardioselective β1-blocker. It stimulates endothelial production of nitric oxide, demonstrating vasodilatory and pleiotropic effects. It has better tolerance compared to classic β-blockers. It lowers the central pressure, reducing the risk of cardiovascular events. It is the preferred β-blocker in the treatment of hypertension in various clinical situations.

The role of diuretics in the treatment of hypertension: a focus on chlorthalidone (lecture)

The lecture discusses the role of thiazide and thiazide-like diuretics, in particular chlorthalidone, in the modern treatment of arterial hypertension. The modern concepts about the mechanism of action of thiazide diuretics and chlorthalidone are presented. Differences in the degree of antihypertensive effect of hydrochlorothiazide and chlorthalidone are discussed. The results of large randomized trials SHEP, MRFIT, ALLHAT were analyzed, in which chlorthalidone therapy significantly reduced the risk of developing cardiovascular and cerebrovascular complications of hypertension. The effect of thiazide diuretics on glucose metabolism and the impact of carbohydrate metabolism disorders during treatment with chlorthalidone on the risk of cardiovascular complications was considered. The lecture also discusses the effect of chlorthalidone therapy on kidney function, the possibility of its use in chronic kidney disease. The data are presented on the prevention of resistant hypertension and chro-nic heart failure during long-term therapy of hypertension with chlorthalidone. The frequency and terms of the development of side effects of hypertension therapy with thiazide-like diuretics were also analyzed.

The value of assessing cerebrovascular reactivity in hypertension and comorbid pathology

The review presents the rationale for the importance of studies on the reactivity of cerebral vessels, the classification of cerebrovascular reactivity (CVR) and the threshold values of quantitative indicators of the reserve phase and autoregulation of cerebral blood flow in healthy volunteers. Features of CVR in hypertension are described depending on the clinical course, daily blood pressure profile, the presence of comorbid pathology, the treatment approaches in treatment CVR disorders. We discuss the evidence-based data on the role of CVR assessment in diagnosing latent cerebral circulation insufficiency, prediction of cerebrovascular complications, monitoring the effectiveness and safety of drug and devise-based therapy of hypertension associated with abnormal CVR.

STEM-04. NICARDIPINE SENSITIZES APOPTOSIS OF GLIOMA STEM CELLS INDUCED BY TEMOZOLOMIDE THROUGH INHIBITING AUTOPHAGY

BACKGROUND Glioma stem cells (GSCs) play an important role in tumor progression and recurrence. Currently, treatments of glioma are limited mainly due to strong tolerance of GSCs against conventional chemotherapeutic drugs such as temozolomide. Nicardipine, a calcium antagonist, is commonly used in the therapy of hypertension, which is recently repurposed in the comprehensive strategies against gliomas in our previous studies. Here, we explored the cytotoxic sensitization effect of nicardipine combining temozolomide and the underlying mechanisms. METHODS Two human glioma stem cell lines were applied and treated with nicardipine, temozolomide, and combination of both, respectively. Cell viability was detected by CCK-8, cell apoptosis was analyzed by flow cytometry, and immunoblot was used to detect autophagic-releated proteins including p62, LC3 and mTOR. The mTOR agonists and inhibitors were applied to further evaluate whether nicardipine inhibits autophagy via mTOR pathway. RESULTS GSCs had strong tolerance against temozolomide while nicardipine could significantly inhibit the viaibility of GSCs and promote cell apoptosis when acting together with temozolomide, indicating that nicardipine could sensitize the toxicity of temozolomide. Furthermore, both temozolomide and nicardipine could inhibit autophagy, and the effects of nicardipine was more prominent, suggesting that nicardipine might enhance GSCs apoptosis induced by temozolomide through inhibiting autophagy. Further molecular studies showed that the cytotoxic sensitization effects of nicardipine was induced through activation of the phosphorylation level of mTOR, which was abolished with the treatment of rapamycin, a mTOR inhibitor. CONCLUSION Our results suggested that nicardipine could sensitize apoptosis of glioma stem cells induced by temozolomide through inhibiting autophagy, which was mediated by activation of mTOR activity.

Chronopharmacology of high blood pressure—a critical review of clinical evidence

Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment.

Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy

Hypertension is usually associated with deficient nitric oxide (NO) bioavailability, and therefore stimulating NO activity is an important antihypertensive strategy. Recently, many studies have shown that both nitrite and nitrate anions are not simple products of NO metabolism and indeed may be reduced back to NO. While enzymes with nitrite-reductase activity capable of generating NO from nitrite may contribute to antihypertensive effects of nitrite, another mechanism involving the generation of NO-related species in the stomach from nitrite has been validated. Under the acidic conditions of the stomach, nitrite generates NO-related species that form S-nitrosothiols. Conversely, drugs that increase gastric pH may impair the gastric formation of S-nitrosothiols, which may mediate antihypertensive effects of oral nitrite or nitrate. Therefore, it is now becoming clear that promoting gastric formation of S-nitrosothiols may result in effective antihypertensive responses, and this mechanism opens a window of opportunity in the therapy of hypertension. In this review, we discuss the recent studies supporting the gastric generation of S-nitrosothiols as a potential antihypertensive mechanism of oral nitrite. We also highlight some drugs that increase S-nitrosothiols bioavailability, which may also improve the responses to nitrite/nitrate therapy. This new approach may result in increased nitrosation of critical pharmacological receptors and enzymes involved in the pathogenesis of hypertension, which tend to respond less to their activators resulting in lower blood pressure.

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.