Current Pharmaceutical Design - Volume 27, Issue 40, 2021

The presence of hypertension among the population with human immunodeficiency virus (HIV) has become a new threat to the health and well-being of people living with this disease, in particular, among those who received antiretroviral therapy. The estimated prevalence of high blood pressure in HIV128;infected patients is significantly higher than the rate observed in HIV128;uninfected subjects. The approach to the HIV-positive patient requires the assessment of individual cardiovascular risk and its consideration when designing the individualized target. On the other hand, the numerous pharmacological interactions of antiretroviral (ARV) drugs are essential elements to take into account. Serum levels of any kind of antihypertensive drugs may be influenced by the coadministration of protease inhibitors, non-nucleoside reverse transcriptase inhibitor, or other antiretroviral. Similarly, plasma concentrations of antiretroviral drugs can be increased by the concomitant use of calcium channel blockers or diuretics. In this regard, the treatment of high blood pressure in HIV patients should be preferentially based on ACE inhibitors or thiazide/thiazide-like diuretics or their combination.

Beta blockers (BBs) have important side effects that contribute to low adherence and persistence. Therefore, the optimal choice of BB is an important mode to prevent BB’s side effects, leading to an increase in compliance, which can improve the outcomes in BBs' evidence-based indications, such as acute myocardial infarction, heart failure, etc. The aim of the paper is to suggest an improved method of reporting contraindications for BBs. We used a search of the following indexing databases: SCOPUS and PubMed, and web search engine Google Scholar to identify guidelines on arterial hypertension (HTN). HTN guidelines published during the last 2 decades were analyzed (from 2000 to 2020). Some of the contraindications (e.g., bradycardia, acute heart failure) are true for every BB. However, some contraindications do not belong to the whole BB class. For example, propranolol and carvedilol are contraindicated in chronic obstructive lung disease, but nebivolol and bisoprolol are not. We suggest that contraindications which are specific for some BBs (i.e., not for the whole class) ought to be listed with the exact name(s) of the individual BBs. In this way, we may decrease the number of wrong choices among BBs and consequently increase drug adherence (which is currently worse for the class of BBs than for most of the other antihypertensive drugs). To our knowledge, there is a lack of guidelines citing contraindications for individual BBs, because they vary a lot within-the-class of BBs. This is an approach to improve both basic medical education and guidelines.

Background: It has been suggested that hydroxychloroquine may have positive effects on LDL-C, HDL-C, and triglyceride levels; however, the hypolipidemic activities of this drug are still uncertain. Objective: The aim of this meta-analysis of randomized controlled trials was to explore the effect of hydroxychloroquine on circulating lipid concentrations. Methods: Randomized controlled trials examining the impact of hydroxychloroquine on lipid parameters were searched in PubMed, Web of Science, Scopus, and Google Scholar databases. Meta-analysis was performed using a random-effects model and sensitivity analysis through the leave one-out method. Results: Meta-analysis showed that patients receiving hydroxychloroquine therapy significantly decreased total cholesterol (WMD: 0.18 mmol/L, 95% CI: -0.28, -0.08, I² = 6%, p = 0.0004), LDL-C (WMD: -0.21 mmol/L, 95% CI: -0.36, -0.06, I² = 75%, p = 0.006), triglycerides (WMD: -0.09 mmol/L, 95% CI: -0.15, -0.04, I² = 22%, p = 0.001), and non-HDL-C (WMD: -0.28 mmol/L, 95% CI: -0.45, -0.12, I² = 0%, p = 0.0009), and increased HDL-C concentrations (WMD: 0.03 mmol/L, 95% CI: 0.00, 0.06, I² = 0%, p = 0.03). Conclusion: Our results suggest that hydroxychloroquine improves lipid parameters by reducing total cholesterol, LDL-C, triglycerides, non-HDL-C, and increasing HDL-C levels.

Background: Evidence about the use of dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitors in patients with acute minor ischemic stroke or transient ischemic attack (TIA) is emerging. The aim of our study was to provide an updated and comprehensive analysis about the risks and benefits of DAPT versus aspirin monotherapy in this setting. Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov databases, main international conference proceedings were searched for randomized controlled trials comparing DAPT versus aspirin monotherapy in patients with acute ischemic stroke or TIA not eligible for thrombolysis or thrombectomy presenting in the first 24 hours after the acute event. Data were pooled by meta-analysis using a random-effects model. The primary efficacy endpoint was ischemic stroke recurrence, and the primary safety outcome was major bleeding. Secondary endpoints were intracranial hemorrhage, hemorrhagic stroke, and allcause death. Results: A total of 4 studies enrolling 21,459 patients were included. DAPT with clopidogrel was used in 3 studies, DAPT with ticagrelor in one study. DAPT duration was 21 days in one study, 1 month in one study, and 3 months in the remaining studies. DAPT was associated with a significant reduction in the risk of ischemic stroke recurrence (relative risk (RR), 0.74; 95% confidence interval (CI), 0.67-0.82, P<0.001, number needed to treat 50 (95% CI 40-72), while it was associated with a significantly higher risk of major bleeding (RR, 2.59; 95% CI 1.49-4.53, P=0.001, number needed to harm 330 (95% CI 149-1111), of intracranial hemorrhage (RR 3.06, 95% CI 1.41-6.66, P=0.005), with a trend towards higher risk of hemorrhagic stroke (RR 1.83, 95% CI 0.83-4.05, P=0.14), and a slight tendency towards higher risk of all-cause death (RR 1.30, 95% CI 0.89-1.89, P=0.16). Conclusion: Among patients with acute minor ischemic stroke or TIA, DAPT, as compared with aspirin monotherapy, might offer better effectiveness in terms of ischemic stroke recurrence at the expense of a higher risk of major bleeding. The trade-off between ischemic benefits and bleeding risks should be assessed in tailoring the therapeutic strategies.

Background: Long non-coding RNAs (lncRNAs) has no protein-coding potential due to the lack of an apparent open reading frame. There is growing evidence that lncRNA DGCR5 has a vital regulatory role in human illnesses' pathological development, particularly in the digestive system's carcinogenesis and progression. Abnormal DGCR5 expression affects different cellular functions such as proliferation, aggression, and metastasis. This paper aims to probe into the pathophysiological functions and molecular mechanisms of DGCR5 in cancers of the digestive system. Methods: This review summarizes and analyzes the biological functions and mechanisms of lncRNA DGCR5 in digestive system cancers occurrence. Relevant studies were conducted and reviewed by searching PubMed for articles with lncRNA DGCR5 and digestive system cancer as keywords in recent years. Results: DCGR5, as a novel tumor-related lncRNA, is recently identified to be abnormally expressed in digestive system cancers, such as pancreatic ductal adenocarcinoma, pancreatic cancer, gastric cancer, gallbladder cancer, colorectal cancer, and hepatocellular carcinoma. The role played by DCGR5 is vital and varies in different digestive cancers. Taken together, aberrant expression of DCGR5 regulates the progression of digestive cancers by affecting cancer cell proliferation, aggression, metastasis, and drug resistance. Conclusion: LncRNA DGCR5 might be a viable marker or a promising therapeutic target in digestive system cancers.

Background: As it is known, long non-coding RNA (lncRNA) affects tumor progression, which has caused a great upsurge in recent years. It can also affect the growth, migration, and invasion of tumors. The abnormal expression of lncRNA is associated with malignant tumors. In addition, it has been proved that lncRNA is a key targeted gene for the treatment of some diseases. PART1, a member of lncRNA, has been reported as a regulator in the process of tumor occurrence and development. This study aims to reveal the biological functions, specific mechanisms, and clinical significance of PART1 in various tumor cells. Methods: Through the careful search of PUBMED, the mechanisms of the effect of PART1 on tumorigenesis and development are summarized. Results: On the one hand, the up-regulated expression of PART1 plays a tumor-promoting role in tumors, including lung cancer, prostate cancer, bladder cancer, and so on. On the other hand, PART1 is down-regulated in gastric cancer, glioma, and other tumors to play a tumor inhibitory role. In addition, PART1 regulates tumor growth mainly by targeting microRNA, such as miR-635, directly regulating the expression of proteins, such as FUS/EZH2, affecting signal pathways, such as Toll-like receptor pathway, or regulating immune cells. Conclusion: PART1 is closely related to tumors by regulating a variety of molecular mechanisms. In addition, PART1 can be used as a clinical marker for the early diagnosis of tumors and plays an important role in tumortargeted therapy.

Background: Vascular endothelial growth factor (VEGF) is a supergene family derived from a platelet growth factor. It plays a pivotal role in regulating angiogenesis and lymphangiogenesis. sFlt-1 is a soluble antagonist of VEGF with an essential effect of maintaining the balance of vascular growth. Recently, sFlt-1 has emerged as a new marker for early diagnosis and disease surveillance of angiogenesis-related diseases. However, few comprehensive reviews focus on the relationship between sFlt-1 and related diseases despite that many results have yielded. Methods: In this review, we analyzed the relationship between sFlt-1 and angiogenesis-related diseases by searching PubMed, Web of Science, and other databases, and summarized our current understanding of the role of sFlt-1 in angiogenesis-related diseases. Results: sFlt-1 is associated with pre-eclampsia, perinatal cardiomyopathy, diabetic nephropathy, hypertension, tumor, atherosclerosis, and other diseases. The mechanisms of sFlt-1 that regulate those diseases are mainly associated with the bioavailability of VEGF and vascular endothelial cell integrity. Conclusion: From the summary article, sFlt-1 is a double regulator in angiogenesis-related diseases; too much or too little may cause different diseases. Therefore, maintaining the stability of sFlt-1 content in the body is essential to control the development of related diseases.

Background: The purpose of this study was to assess the relationship between different dialysis modalities and depression in end-stage renal disease (ESRD) patients. Methods: We searched through the PsycINFO, PubMed, Cochrane Library, EMBASE, and CNKI for all related studies from 1 January 1990 through 30 June 2019 without restriction on language. We selected papers that compared depression levels among patients undergoing hemodialysis and peritoneal dialysis. Two authors independently selected studies, evaluated the quality of included studies, and extracted data according to Newcastle-Ottawa Scale (NOS). A discussion with a third author checked any disagreement to minimize the publication bias. PRISMA guidelines were used as the standards of reporting (PRISMA registration ID is 239172). Results: There was insufficient evidence to prove the relationship between different dialysis modalities and depression (OR: 2.37, 95% CI: 0.88-6.40). We also found no statistical significance between the mean difference of depression level and dialysis modalities (Std mean difference=0.69, 95% CI: -2.09-3.46). Conclusion: The available limited, deficient quality evidence assessed by ROBINS-I does not support an association between depression and dialysis modalities among ESRD patients. Further studies that provide data for different sex and age groups are needed to clarify whether a subgroup of dialysis modalities has a different risk of depression.

Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR.

Background: Elderly patients with multiple chronic conditions are closely linked to polymedication, a condition that is also highly associated with the presence of adverse effects, such as those observed by anticholinergic activity. Anticholinergic burden is defined in a very variable way and is described inconsistently using different scores and providing different interpretations of the risk of suffering from anticholinergic adverse effects. Objective: The objective is to analyse the anticholinergic risk exposure in elderly complex chronic patients. Methods: A observational multicentre study was performed for a cohort of complex chronic patients over 65 years who received treatment with at least one drug with anticholinergic activity. Anticholinergic exposure was assessed using ten scales included in the Anticholinergic Burden Calculator. Results: 473 patients were recruited, being 67.7% with excessive polypharmacy. 80 was the total number of anticholinergic drugs with any scale, with a median of 2 drugs with anticholinergic activity per patient (IQR=2). Three scales evaluated more than 70% of the patients (Chew: 79.1%; Drug Burden Index (DBI): 77.8%; Anticholinergic Cognitive Burden (ACB): 75.9%). The percentage of different drugs with anticholinergic properties evaluated ranged from 13.8% (Anticholinergic Burden Classification (ABC)) to 57.5% (DBI) and anticholinergic drugs prescriptions oscillated from 14% (Anticholinergic Risk Scale (ARS)) to 53.3% (DBI). 71.1% of patients were at risk (moderate and high risk) according to DBI vs. 9.7% by ARS at the opposite side. Important differences of anticholinergic risk in patients with excessive polypharmacy were in ACB, ABC and DBI scales. Conclusion: This study has highlighted clear differences between the scales used. DBI seems to be the scale that identifies a higher number of elderly chronic complex patients at risk of developing anticholinergic adverse effects.