INTRODUCTION: Hyperuricemia has been identified as an independent risk factor for coronary artery disease (CAD). Uric acid lowering therapy could potentially lower the risk of CAD. Conventional treatments have been effective in treating acute gout flares in most patients, but certain options, like NSAIDs could increase the risk of CAD. Area covered: This review covers the aspect of cardiac safety with traditional and new medications used in treating both acute flares and chronic gout according to the most recent international guidelines. Expert opinion: All NSAIDs, not just selective Cox 2 inhibitors, have associated with them different degrees of cardiac risk; therefore, NSAIDs should be avoided when treating patients with underlying CAD. Interleukin-1 inhibitors appear to be safe alternatives for treating cardiac patients who are contraindicated to conventional treatment. Presently, there is a paucity of evidence concerning whether treatment of hyperuricemia could lower the risk of CAD and this must be explored further. It is also important to explore the cardiac safety of plegloticase to better ascertain its safety in CAD patients.
ETHNOPHARMACOLOGICAL RELEVANCE: Lippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling.
AIM OF THE STUDY: The present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model.
MATERIALS AND METHODS: The mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis.
RESULTS: Oral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7-O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2 mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3 mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200mg/kg. No toxic effect was observed in rats administered with 5000 mg/kg of methanol extract or F3.
CONCLUSION: The potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities.
KEYWORDS: Antihyperuricemic; Hypoxanthine-induced hyperuricemic rat; Lippia nodiflora; Liver xanthine oxidase and xanthine dehydrogenase; Serum uric acid; Uric acid excretion
ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri Linn. (Euphorbiaceae) is used as folk medicine in South America to treat excess uric acid. Our initial study showed that the methanol extract of Phyllanthus niruri and its lignans were able to reverse the plasma uric acid of hyperuricemic animals.
AIM OF THE STUDY: The study was undertaken to investigate the mechanisms of antihyperuricemic effect of Phyllanthus niruri and its lignan constituents.
MATERIAL AND METHODS: The mechanisms were investigated using xanthine oxidase assay and uricosuric studies in potassium oxonate- and uric acid-induced hyperuricemic rats.
RESULTS: Phyllanthus niruri methanol extract exhibited in vitro xanthine oxidase inhibition with an IC50 of 39.39 microg/mL and a moderate in vivo xanthine oxidase inhibitory activity. However, the lignans display poor xanthine oxidase inhibition in vitro and a relatively weak in vivo inhibitory activity at 10mg/kg. On the other hand, intraperitoneal treatment with Phyllanthus niruri methanol extract showed 1.69 folds increase in urinary uric acid excretion when compared to the hyperuricemic control animals. Likewise, the lignans, phyllanthin, hypophyllanthin and phyltetralin exhibited up to 2.51 and 11.0 folds higher in urinary uric acid excretion and clearance, respectively. The co-administration of pyrazinamide with phyllanthin exhibited a significant suppression of phyllanthin's uricosuric activity resembling that of pyrazinamide with benzbromarone.
CONCLUSIONS: The present study showed that the antihyperuricemic effect of Phyllanthus niruri methanol extract may be mainly due to its uricosuric action and partly through xanthine oxidase inhibition, whereas the antihyperuricemic effect of the lignans was attributed to their uricosuric action.
Hypoadiponectinemia is characterized by low plasma adiponectin levels that can be caused by genetic factors, such as single nucleotide polymorphisms (SNPs) and mutations in the adiponectin gene or by visceral fat deposition/obesity. Reports have suggested that hypoadiponectinemia is associated with dyslipidemia, hypertension, hyperuricemia, metabolic syndrome, atherosclerosis, type 2 diabetes mellitus and various cardiovascular diseases. Previous studies have highlighted several potential strategies to up-regulate adiponectin secretion and function, including visceral fat reduction through diet therapy and exercise, administration of exogenous adiponectin, treatment with peroxisome proliferator-activating receptor gamma (PPARγ) agonists (e.g., thiazolidinediones (TZDs)) and ligands (e.g., bezafibrate and fenofibrate) or the blocking of the renin-angiotensin system. Likewise, the up-regulation of the expression and stimulation of adiponectin receptors by using adiponectin receptor agonists would be an effective method to treat obesity-related conditions. Notably, adiponectin is an abundantly expressed bioactive protein that also exhibits a wide spectrum of biological properties, such as insulin-sensitizing, anti-diabetic, anti-inflammatory and anti-atherosclerotic activities. Although targeting adiponectin and its receptors has been useful for treating diabetes and other metabolic-related diseases in experimental studies, current drug development based on adiponectin/adiponectin receptors for clinical applications is scarce, and there is a lack of available clinical trial data. This comprehensive review discusses the strategies that are presently being pursued to harness the potential of adiponectin up-regulation. In addition, we examined the current status of drug development and its potential for clinical applications.
Plumeria rubra Linn of the family Apocynaceae is locally known in Malaysia as "Kemboja". It has been used by local traditional medicine practitioners for the treatment of arthritis-related disease. The LCMS/MS analysis of the methanol extract of flowers (PR-ME) showed that it contains 3-O-caffeyolquinic acid, 5-caffeoquinic acid, 1,3-dicaffeoquinic acid, chlorogenic acid, citric acid, 3,3-di-O-methylellagic acid, kaempferol-3-O-glucoside, kaempferol-3-rutinoside, kaempferol, quercetin 3-O-α-l-arabinopyranoside, quercetin, quinic acid and rutin. The flower PR-ME contained high amounts of phenol and flavonoid at 184.632 mg GAE/g and 203.2.2 mg QE/g, respectively. It also exhibited the highest DPPH, FRAP, metal chelating, hydrogen peroxide, nitric oxide superoxide radical scavenging activity. Similarly, the XO inhibitory activity in vitro assay possesses the highest inhibition effects at an IC50 = 23.91 μg/mL. There was no mortality or signs of toxicity in rats at a dose of 4 g/kg body weight. The administration of the flower PR-ME at doses of 400 mg/kg to the rats significantly reduced serum uric acid 43.77%. Similarly, the XO activity in the liver was significantly inhibited by flower PR-ME at doses of 400 mg/kg. These results confirm that the flower PR-ME of P. rubra contains active phytochemical compounds as detected in LCMS/MS that contribute to the inhibition of XO activity in vitro and in vivo in reducing acid uric level in serum and simultaneously scavenging the free radical to reduce the oxidative stress.