Current Pharmaceutical Design - Volume 29, Issue 7, 2023

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively novel drug class that most cardiologists are becoming familiar with. By contrasting glucose reabsorption in the proximal convoluted tubule of the nephron, SGLT2 inhibition results in glycosuria with improved glycemic control. Although originally introduced as anti-diabetic medications, the cardiovascular effects of SGLT2i have progressively emerged, leading them to become one of the four pillars for the treatment of heart failure with reduced ejection fraction (HFrEF) according to the 2021 guidelines from the European Society of Cardiology. Also, two recent randomized trials have demonstrated SGLT2i as the first compounds with proven prognostic impact in heart failure with preserved ejection fraction (HFpEF), setting a milestone in the treatment for this condition. While the exact pathogenic mechanisms mediating the substantial reduction in cardiovascular death and heart failure (HF) hospitalizations are still controversial, there is growing clinical evidence on the efficacy and safety of SGLT2i in various subsets of patients with HF. As known, heart failure is a complex and heterogeneous clinical syndrome with a magnitude of phenotypes and a variety of underlying hemodynamic and physiological aspects which cannot be fully incorporated into the traditional left ventricular ejection fraction based classification adopted in clinical trials. The aim of this review is to provide an overview of the cardiovascular benefits and indications of SGLT2i across different HF patterns and to highlight current gaps in knowledge that should be addressed by future research.

Exercise-based cardiac rehabilitation (EBCR) is a treatment modality for patients with heart failure (HF) that has withstood the test of time. It has continued to show benefits even in the current era of pharmacotherapeutics for HF. Participation in a multidisciplinary comprehensive EBCR programme reduces mortality and morbidity, has a multitude of physiological benefits, and improves cardiovascular risk factor control and quality of life. Despite this, historical barriers to enrolment and uptake remain. Strategies to overcome these, as well as alternative delivery methods of EBCR in HF patients, are emerging and include telerehabilitation, focus on special groups and emphasis on behavioural change. This review provides oversight on the modalities of exercise training in HF as well as their benefits and gives an overview of barriers to the utilisation of EBCR along with future progress in the field.

Background: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients. Objective: The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF. Methods: Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy). Results: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HFpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a “positive” randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials. Conclusion: Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patients with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

Heart failure with reduced ejection fraction (HFrEF) has been associated with poor prognosis, reduced quality of life, and increased healthcare expenditure. Despite tremendous advances in HFrEF management, reduced survival and a high rate of hospitalization remain unsolved issues. Furthermore, HFrEF morbidity and economic burden are estimated to increase in the following years; hence, new therapies are constantly emerging. In the last few years, a series of landmark clinical trials have expanded our therapeutic armamentarium with a ground-breaking change in HFrEF-related outcomes. Sodium-glucose co-transporter 2 inhibitors (mainly dapagliflozin and empagliflozin) have already revolutionized the management of HFrEF patients via a significant reduction in cardiovascular mortality and heart failure hospitalizations. Furthermore, vericiguat and omecamtiv mecarbil have emerged as promising and novel disease-modifying therapies. The former restores the impaired cyclic guanosine monophosphate pathway, and the latter stimulates cardiac myosin without marked arrhythmogenesis. Both vericiguat and omecamtiv mecarbil have been shown to reduce heart failure admissions. Sacubitril/valsartan is an established and effective therapy in HFrEF patients and should be considered as a replacement for angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs). Lastly, inflammasome activity is implicated in HFrEF pathophysiology, and the role of anti-inflammatory agents in HFrEF trajectories is readily scrutinized, yet available therapies are ineffective. This mini-review summarizes the major and most recent studies in this field, thus covering the current advances in HFrEF therapeutics.

Alzheimer’s disease (AD) is one of the most complicated neurodegenerative diseases causing dementia in human beings. Aside from that, the incidence of AD is increasing and its treatment is very complicated. There are several known hypotheses regarding the pathology of Alzheimer’s disease, including the amyloid beta hypothesis, tau hypothesis, inflammation hypothesis, and cholinergic hypothesis, which are investigated in different researches to completely elucidate the pathology of AD. Besides, some new mechanisms, such as immune, endocrine, and vagus pathways, as well as bacteria metabolite secretions, are being explained as other causes to be somehow related to AD pathogenesis. There is still no definite treatment for Alzheimer’s disease that can completely cure and eradicate AD. Garlic (Allium sativum) is a traditional herb used as a spice in different cultures, and due to the organosulfur compounds, like allicin, it possesses highly anti-oxidant properties; the benefits of garlic in cardiovascular diseases, like hypertension and atherosclerosis, have been examined and reviewed, although its beneficiary effects in neurodegenerative diseases, such as AD, are not completely understood. In this review, we discuss the effects of garlic based on its components, such as allicin and S-allyl cysteine, on Alzheimer’s disease and the mechanisms of garlic components that can be beneficiary for AD patients, including its effects on amyloid beta, oxidative stress, tau protein, gene expression, and cholinesterase enzymes. Based on the literature review, garlic has been revealed to have beneficiary effects on Alzheimer’s disease, especially in animal studies; however, more studies should be done on humans to find the exact mechanisms of garlic’s effects on AD patients.

Cardiac involvement is the leading cause of death in patients with cardiac amyloidosis. Early recognition is crucial as it can significantly change the course of the disease. Until now, the imaging modality of choice for diagnosing cardiac amyloidosis has been cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). LGE-CMR in patients with cardiac amyloidosis reveals characteristic LGE patterns that lead to a diagnosis while also correlating well with disease prognosis. However, LGE-CMR has numerous drawbacks that the newer CMR modality, T1 mapping, aims to improve. T1 mapping can be further subdivided into native T1 mapping, which does not require the use of contrast, and ECV measurement, which requires the use of contrast. Numerous T1 mapping techniques have been developed, each one with its own advantages and disadvantages when it comes to procedure difficulty and image quality. A literature review to identify relevant published articles was performed by two authors. This review aimed to present the value of T1 mapping in diagnosing cardiac amyloidosis, quantifying the amyloid burden, and evaluating the prognosis of patients with amyloidosis with cardiac involvement.

Background: Naturally occurring bioactive compounds have a plethora of biological effects. Objective: In this study, we examined a pharmacological screening of natural products on the human umbilical artery (HUA). Methods: HUA preparations were used to follow contractions by KCl (60 mM) and tested at different concentrations (1-5000 μg/mL and μM) of the Lippia alba (EOLa) and Lippia origanoides (EOLo) essential oils, terpenes (citral, limonene perilic alcohol) and phenylpropanoids (eugenol, methyl eugenol). Results: The reduction corresponded to approximately 100%, except for limonene (80 ± 1.2%). When evaluating the concentration of the natural product that promotes 50% relaxation of the HUA contracted by KCL, EC50 values were: 424.3 μg/mL (EOLa); 468.7 ± 6.7 μg/mL (EOLo); 264.2 ± 8.2 μM (citral); 677.8 ± 5.4 μM (limonene); 186.3 ± 6.4 μM (peryl alcohol); 986.4 ± 7.9 μM (eugenol); and 279.1 ± 4.4 μM (methyl-eugenol). Perillyl alcohol had a lower EC50 (consequently it has a higher pharmacological potency). Conclusion: The plant extracts have a promising vasorelaxing effect in HUAs, paving the way for future investigations: as applications in diseases related to these vessels, such as preeclampsia.

Aims: A network pharmacological analysis combined with experimental validation was used to investigate the neuroprotective mechanism of the natural product Tetramethylpyrazine (TMP). Background: Protecting neurons is critical for acute ischemic stroke treatment. Tetramethylpyrazine is a bioactive component extracted from Chuanxiong. The neuroprotective potential of TMP has been reported, but a systematic analysis of its mechanism has not been performed. Objective: Based on the hints of network pharmacology and bioinformatics analysis, the mechanism by which TMP alleviates oxygen-glucose deprivation-induced neuronal damage through inhibition of the HIF-1α/BNIP3 pathway was verified. Methods: In this study, we initially used network pharmacology and bioinformatics analyses to elucidate the mechanisms involved in TMP's predictive targets on a system level. The HIF-1α/BNIP3 pathway mediating the cellular response to hypoxia and apoptosis was considered worthy of focus in the bioinformatic analysis. An oxygen-glucose deprivation (OGD)-induced PC12 cell injury model was established for functional and mechanical validation. Cell viability, lactate dehydrogenase leakage, intracellular reactive oxygen species, percentage of apoptotic cells, and Caspase-3 activity were determined to assess the TMP's protective effects. Transfection with siRNA/HIF-1α or pcDNA/HIF-1α plasmids to silence or overexpress hypoxia-inducible factor 1α (HIF-1α). The role of HIF-1α in OGD-injured cells was observed first. After that, TMP's regulation of the HIF-1α/BNIP3 pathway was investigated. The pcDNA3.1/HIF-1α-positive plasmids were applied in rescue experiments. Results: The results showed that TMP dose-dependently attenuated OGD-induced cell injury. The expression levels of HIF-1α, BNIP3, and the Bax/Bcl-2 increased significantly with increasing OGD duration. Overexpression of HIF-1α decreased cell viability, increased BNIP3 expression, and Bax/Bcl-2 ratio; siRNA-HIF-1α showed the opposite effect. TMP treatment suppressed HIF-1α, BNIP3 expression, and the Bax/Bcl-2 ratio and was reversed by HIF-1α overexpression. Conclusion: Our study shows that TMP protects OGD-damaged PC12 cells by inhibiting the HIF-1α/BNIP3 pathway, which provides new insights into the mechanism of TMP and its neuroprotective potential.