Citroflavonoids as Promising Agents for Drug Discovery in Diabetes and Hypertension: A Systematic Review of Experimental Studies.

Flavonoids are naturally occurring compounds widely distributed in the Citrus genus. These natural compounds have many health benefits, mainly for metabolic and cardiovascular diseases. In fact, some these compounds are components of drug products with approved indications for peripheral vascular insufficiency and hemorrhoids. However, information on pharmacological effects of these compounds remains disperse and there is scarce comprehensive analysis of whole data and evidence. These kinds of evidence analyses could be necessary in drug design and the development of novel and innovate drug products in diabetes and hypertension. We aimed to systematically search for evidence on the efficacy of citroflavonoids in diabetes and hypertension in in vivo models. We searched four literature databases based on a PICO strategy. After database curation, twenty-nine articles were retrieved to analyze experimental data. There was high heterogeneity in both outcomes and methodology. Naringenin and hesperetin derivates were the most studied citroflavonoids in both experimental models. More investigation is still needed to determine its potential for drug design and development.

A Pharmacokinetic Study of Mix-160 by LC-MS/MS: Oral Bioavailability of a Dosage Form of Citroflavonoids Mixture.

This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes' activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.

Data sources for drug utilization research in Latin American countries-A cross-national study: DASDUR-LATAM study.

PURPOSE: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region. METHODS: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed. RESULTS: We identified 125 data sources for DUR in nine LatAm countries. Thirty-eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient-level data. CONCLUSIONS: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol-driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication-related problems that need further exploration.

Toxicological Screening of Four Bioactive Citroflavonoids: In Vitro, In Vivo, and In Silico Approaches.

Many studies describe different pharmacological effects of flavonoids on experimental animals and humans. Nevertheless, few ones are confirming the safety of these compounds for therapeutic purposes. This study aimed to investigate the preclinical safety of naringenin, naringin, hesperidin, and quercetin by in vivo, in vitro, and in silico approaches. For this, an MTT-based cytotoxicity assay in VERO and MDCK cell lines was performed. In addition, acute toxicity was evaluated on Wistar rats by OECD Guidelines for the Testing of Chemicals (Test No. 423: Acute Oral Toxicity-Class Method). Furthermore, we used the ACD/Tox Suite to predict toxicological parameters such as hERG channel blockade, CYP450 inhibition, and acute toxicity in animals. The results showed that quercetin was slightly more cytotoxic on cell lines (IC50 of 219.44 ± 7.22 mM and 465.41 ± 7.44 mM, respectively) than the other citroflavonoids. All flavonoids exhibited an LD50 value > 2000 mg/kg, which classifies them as low-risk substances as OECD guidelines established. Similarly, predicted LD50 was LD50 > 300 to 2000 mg/kg for all flavonoids as acute toxicity assay estimated. Data suggests that all these flavonoids did not show significant toxicological effects, and they were classified as low-risk, useful substances for drug development.

Pharmacological characterization of the cardiovascular effect of Nibethione: ex vivo, in vivo and in silico studies.

OBJECTIVE: This work describes the vasorelaxant and antihypertensive effects and the mechanism of action on vascular smooth muscle cells of Nibethione, a synthetic thiazolidinedione derivative. Additionally, evidence of its cytotoxicity is assessed. METHODS: Nibethione (NB) was synthesized, and its vasorelaxant effect and mechanism of action were assessed through ex vivo experiments. Molecular docking studies were used to predict the mode of interaction with L-type Ca2+ channel, and in vivo antihypertensive activity was assayed on spontaneously hypertensive rats (SHR). The cytotoxicity potential was evaluated in porcine aortic endothelial cells (PAECs) from primary explants. KEY FINDINGS: Nibethione vasorelaxant effect was efficient on KCl (80 mm) and NE-contraction. This effect was deleteriously modified in the presence of potassium channel block drugs, while the maximal contraction induced with NE was significantly decreased by NB; the CaCl2 -induced contraction was abolished entirely. In vivo experiments showed that NB decreased diastolic blood pressure in 20.3 % after its administration on SHR. The molecular docking showed that NB blocks L-type Ca2+ channel, and in vitro tests showed that NB did not produce cytotoxic activity on PAECs (IC50 >1000 µm). CONCLUSIONS: Nibethione showed in vivo antihypertensive and ex vivo vasorelaxant effects with implication of voltage-dependent L-type Ca2+ channel blocking, and this may contribute to the research of novel antihypertensive drugs.

Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches.

Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.

Systematic search for benzimidazole compounds and derivatives with antileishmanial effects.

Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold. Our analysis revealed that a limited number of studies had investigated the antileishmanial effects of benzimidazoles. Among this limited number, L. major was the species most commonly used to evaluate the antileishmanial effects of these compounds, whereas L. amazonensis and L. braziliensis were used least often in the reported studies. The antileishmanial activities of benzimidazole derivatives were notably variable, a fact that may depend on the substitution pattern of the scaffold. In addition, we investigated the effects of a benzimidazole derivative on promastigotes and amastigotes of L. infantum and L. amazonensis using a novel fluorometric method. Significant antileishmanial effects were observed on both species, with L. amazonensis being the most sensitive. To the best of our knowledge, this chemoinformatic analysis represents the first attempt to determine the relevance of benzimidazole scaffolds for antileishmanial drug discovery using the ChEMBL database. The present findings will provide relevant information for future structure-activity relationship studies and for the investigation of benzimidazole-derived drugs as potential treatments for leishmaniasis.

Spasmolytic effect of Mentha pulegium L. involves ionic flux regulation in rat ileum strips.

Mentha pulegium is common known as "poleo" and used for the treatment of diarrhea, headache and cough in Mexican traditional medicine. Organic extracts from aerial parts were evaluated to determine their spasmolytic action on rat isolated ileum test. Hexanic (HEMp), dichloromethanic (DEMp) and methanolic (MEMp) extracts induced a concentration-dependent (0.97 to 1000 microg/mL) antispasmodic effect on spontaneous contractions. DEMp was the most active extract; therefore, spasmolytic mechanism was investigated. This extract (200 microg/mL) induced a significant depression on cumulative concentration-response curve for carbachol and serotonin (P<0.05). Besides, extract decreased and shifted to the right KCl- and CaCl2-induced contraction curves. Moreover, pre-incubation with chlorpromazine (0.001 mM) shifted to the left the relaxant curve. Pre-treatment with L-NAME (1 mM), papaverine (0.01 mM), teophylline (0.01 mM), TEA (1 mM) and glybenclamide (0.1 mM) did not produced any changed of the relaxant curves of DEMp. Findings indicate that dichloromethanic extract of M. pulegium induced its spasmolytic effect through Ca2+-influx blockade, which may explain its traditional use against diarrhea.

Cochlospermum vitifolium induces vasorelaxant and antihypertensive effects mainly by activation of NO/cGMP signaling pathway.

AIM OF THE STUDY: Cochlospermum vitifolium is a medicinal plant used for the treatment of diabetes, hepatobilary and cardiovascular illnesses. The aim of current study was to determine the in vivo antihypertensive and in vitro functional vasorelaxant mechanism of methanol extract of Cochlospermum vitifolium (MECv) and naringenin (NG). MATERIALS AND METHODS: Test material was assayed on rat isolated aorta rings test with- and without-endothelium to determine their vasorelaxant mechanism. Also, the in vivo antihypertensive effect was evaluated on spontaneously hypertensive rat (SHR) model. In addition, presence of NG into the extract was confirmed by reverse phase high performance liquid chromatography (RP-HPLC) analysis. RESULTS: MECv (120 mg/kg) and NG (50 and 160 mg/kg) showed acute antihypertensive effects on SHR when systolic and diastolic pressure were decreased at 1 h and 24 h after administration, respectively. Vasorelaxant effect of MECv and NG was shifted to the right when endothelium-intact aortic rings were pre-incubated with L-NAME (10 microM) and ODQ (1 microM). Also, NG relaxant curves were displaced to the right in the presence of tetraethylammonium (TEA, 1 mM) and 2-aminopyridine (2-AP, 100 microM) on endothelium-denuded aortic rings. CONCLUSION: Experiments described above showed that MECv play an important role in hypertension regulation through NO synthesis and may be PGI(2) production and potassium channel activation on excessive endothelial dysfunction conditions. Unfortunately, presence of NG into the extract is not significant on bioactivity of the extract; however, this compound could be tested and evaluated as structural scaffold for future drug design for development of antihypertensive agents.