Mechanisms of theaflavins against gout and strategies for improving the bioavailability.

BACKGROUND: Gout is a crystal related arthropathy caused by monosodium urate deposition. At present, the identification of appropriate treatments and new drugs to reduce serum uric acid levels and gout risk is a major research area. PURPOSE: Theaflavins are naturally occurring compounds characterized by a benzodiazepine skeleton. The significant benefits of theaflavins have been well documented. A large number of studies have been carried out and excellent anti-gout results have been achieved in recent years. STUDY DESIGN: A comprehensive analysis of the mechanism of the anti-gout effect of theaflavins is presented through a literature review and network pharmacology prediction, and strategies for increasing the bioavailability of theaflavins are summarized. METHODS: In this review, the active components and pharmacological mechanisms of theaflavins in the treatment of gout were summarized, and the relationship between theaflavins and gout, the relevant components, and the potential mechanisms of anti-gout action were clarified by reviewing the literature on the anti-gout effects of theaflavins and network pharmacology. RESULTS: Theaflavins exert anti-gout effects by down regulating the gene and protein expression of glucose transporter 9 (GLUT9) and uric acid transporter 1 (URAT1), while upregulating the mRNA expression levels of organic anion transporter 1 (OAT1), organic cation transporter N1 (OCTN1), organic cation transporters 1/2 (Oct1/2), and organic anion transporter 2 (OAT2). Network pharmacology prediction indicate that theaflavins can regulate the AGE-RAGE and cancer signaling pathways through ATP-binding cassette subfamily B member 1 (ABCB1), recombinant mitogen activated protein kinase 14 (MAPK14), telomerase reverse tranase (TERT), signal transducer and activator of transcription 1 (STAT1), matrix metalloproteinase 2 (MMP2), B-cell lymphoma-2 (BCL2), and matrix metalloproteinase 14 (MMP14) targets for anti-gout effects. CONCLUSION: This review presents the mechanisms of anti-gout action of theaflavins and strategies for improving the bioavailability of theaflavins, as well as providing research strategies for anti-gout treatment measures and the development of novel anti-gout drugs.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

Enhanced oral bioavailability and anti-gout activity of [6]-shogaol-loaded solid lipid nanoparticles.

[6]-Shogaol, an alkylphenol compound purified from the root and stem of ginger (Zingiber officinale), has attracted considerable interest due to its potential anticancer, antioxidative and antirheumatic properties. However, the oral bioavailability of [6]-shogaol has been severely limited because of its poor solubility. In this study, a significant quantity of high-purity [6]-shogaol (yield: 3.6%; purity: 98.65%) was extracted and encapsulated in solid lipid nanoparticles (SLNs) via high-pressure homogenization (encapsulation efficiency: 87.67%) to improve its solubility and oral bioavailability. The resulting [6]-shogaol-loaded solid lipid nanoparticles (SSLNs) were stable, homogeneous and well-dispersed. Its mean particle size and zeta potential were 73.56 ±â€¯5.62 nm and -15.2 ±â€¯1.3 mV, respectively. Importantly, the in vitro release profile and in vivo oral bioavailability of SSLNs were significantly improved compared with the free drug. Furthermore, the SSLNs could remarkably lower the uric acid level via inhibiting the activity of xanthine oxidase and reduce the production of interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) in the hyperuricemia/gouty arthritis rat model, when compared to the free [6]-shogaol. Collectively, SLNs could serve as a promising drug delivery system to improve the oral bioavailability of [6]-shogaol for effective treatment of gouty arthritis.

HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.

The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.

Characterization, efficacy, pharmacokinetics, and biodistribution of 5kDa mPEG modified tetrameric canine uricase variant.

PEGylated uricase is a promising anti-gout drug, but the only commercially marketed 10kDa mPEG modified porcine-like uricase (Pegloticase) can only be used for intravenous infusion. In this study, tetrameric canine uricase variant was modified by covalent conjugation of all accessible ɛ amino sites of lysine residues with a smaller 5kDa mPEG (mPEG-UHC). The average modification degree and PEGylation homogeneity were evaluated. Approximately 9.4 5 kDa mPEG chains were coupled to each monomeric uricase and the main conjugates contained 7-11 mPEG chains per subunit. mPEG-UHC showed significantly therapeutic or preventive effect on uric acid nephropathy and acute urate arthritis based on three different animal models. The clearance rate from an intravenous injection of mPEG-UHC varied significantly between species, at 2.61 mL/h/kg for rats and 0.21 mL/h/kg for monkeys. The long elimination half-life of mPEG-UHC in non-human primate (191.48 h, intravenous injection) indicated the long-term effects in humans. Moreover, the acceptable bioavailability of mPEG-UHC after subcutaneous administration in monkeys (94.21%) suggested that subcutaneous injection may be regarded as a candidate administration route in clinical trails. Non-specific tissue distribution was observed after administration of (125)I-labeled mPEG-UHC in rats, and elimination by the kidneys into the urine is the primary excretion route.

Elastic liposomal formulation for sustained delivery of colchicine: in vitro characterization and in vivo evaluation of anti-gout activity.

Colchicine, an alkaloid found in extracts of the plants Colchicum autumnale and Gloriosa superb, is effective in the treatment of acute gout and dermatological conditions like leuko-cytoclastic vasculitis, psoriasis, and Sweet's syndrome. Oral administration of colchicine is associated with gastrointestinal side effects and its accumulation in the body leads to bone marrow suppression. In the present study, an attempt has been made for development and in vitro and in vivo evaluation of elastic liposomal formulation for topical delivery of colchicine. The in vitro skin permeation study across rat skin found transdermal flux for different elastic liposomal formulations to range between 32.8 +/- 1.2 and 44.4 +/- 1.9 microg h(-1) cm(-2), which was approximately seven to 11 times higher than obtained using drug solution (4.3 +/- 0.6 microg h(-1) cm(-2)). The results of skin deposition study showed that elastic liposomal formulation provide 12.5-fold higher skin deposition as compared to drug solution of colchicine. Confocal laser scanning microscopy also revealed better accumulation and deeper penetration (up to 200 microm) of elastic liposomes than drug solution (up to 12 microm). The biological evaluation of various vesicular formulations and drug solution was carried out using monosodium urate-induced air pouch model. The results of anti-gout activity in rats showed better and sustained biological effects in 24 h measured in terms of exudate volume (63.1 +/- 5.7% and 9.6 +/- 0.5% reduction with elastic liposomes and drug solution, respectively), reduction in leukocyte count (74.2 +/- 6.0% and 4.1 +/- 0.3% reduction with elastic liposomes and drug solution, respectively), decrease in inflammatory cells accumulation, and collagen deposition with elastic liposomal formulation than drug solution. Hence, the present study reveals that elastic liposomal formulation of colchicine possesses greater potential to enhance skin accumulation, prolong drug release, and improve the site-specificity of colchicine.

Pegloticase, a polyethylene glycol conjugate of uricase for the potential intravenous treatment of gout.

Savient Pharmaceuticals Inc (formerly Bio-Technology General Corp), under license from Duke University, is developing pegloticase, PEG conjugates of uricase (urate oxidase), for the potential treatment of gout. The in-life portion of the phase III trials have been completed.