Explore the vast range of titles available.

Background Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug–drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout. Methods sUA levels, fractional excretion of uric acid (FE UA ), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity. Results After 6 hours, a single 200-mg dose of lesinurad elevated FE UA 3.6-fold ( p  < 0.001) and reduced sUA levels by 33 % ( p  < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting. Conclusion The pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout.

The rapidly evolving nanotechnology field highlights the need of better understanding the relationship between nanoparticle (NP) properties and NP transport in solid tumors. The present study tested the hypothesis that the diffusive transport and spatial distribution of NP can be predicted based on the following parameters: interstitial NP diffusivity, NP–cell interaction parameters (cell surface binding capacity, rate constants of association, dissociation, and internalization). We (a) established the models and equations; (b) experimentally measured, in monolayer pharynx FaDu cells, the model parameters for three NP formulations (negatively charged polystyrene beads, near-neutral liposomes, and positively charged liposomes, with respective diameter of 20, 110, and 130 nm); and (c) used the models and parameters to simulate NP diffusion in 3-dimensional (3D) systems. We next measured the NP concentration–depth profiles in tumor cell spheroids, an avascular 3D system, and found good agreement between model-simulated and experimental data in spheroids for the negative and neutral NP (>90% predicted data points at three NP concentrations and three treatment times were within the 95% confidence intervals of experimental data). Model performance was inferior for positive liposomes containing a fusogenic lipid. The present study demonstrated the possibility of using in vitro NP–cell biointerface data in monolayer cultures with in silico studies to predict the NP diffusive transport and concentration–time–depth profiles in 3D systems, as functions of NP concentrations and treatment times. Extending this approach to include convective transport may yield a cost-effective means to predict the NP delivery and residence in solid tumors.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10-12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (C ) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; C occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and C by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.

Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapies after surgical transurethal resection, while systemic therapy is typically reserved for higher stage, muscle-invading, or metastatic diseases. The goal of intravesical therapy is to eradicate existing or residual tumors through direct cytoablation or immunostimulation. The unique properties of the urinary bladder render it a fertile ground for evaluating additional novel experimental approaches to regional therapy, including iontophoresis/electrophoresis, local hyperthermia, co-administration of permeation enhancers, bioadhesive carriers, magnetic-targeted particles and gene therapy. Furthermore, due to its unique anatomical properties, the drug concentration-time profiles in various layers of bladder tissues during and after intravesical therapy can be described by mathematical models comprised of drug disposition and transport kinetic parameters. The drug delivery data, in turn, can be combined with the effective drug exposure to infer treatment efficacy and thereby assists the selection of optimal regimens. To our knowledge, intravesical therapy of bladder cancer represents the first example where computational pharmacological approach was used to design, and successfully predicted the outcome of, a randomized phase III trial (using mitomycin C). This review summarizes the pharmacological principles and the current status of intravesical therapy, and the application of computation to optimize the drug delivery to target sites and the treatment efficacy.

Percutaneous vaccine delivery offers an advantageous mode of immunization due to the unique ability of cutaneous immune cells, especially Langerhans cells, to present antigens to the immune system. Langerhans cells, upon activation, migrate to the regional lymph nodes and lead to the generation of systemic and mucosal immune responses. However, simple topical application of vaccines does not deliver sufficient amounts of antigen in the skin to generate an adequate immune response. Co-administration of strong adjuvants such as cholera toxin or invasive skin abrasion is usually necessary to induce an adequate immune response by topical vaccine application. Here, we report on the use of low-frequency ultrasound as a potent physical adjuvant for successful transcutaneous immunization (TCI). Using tetanus toxoid as a model vaccine, we show that low-frequency ultrasound enhances the immune response induced by topical application of tetanus toxoid. The adjuvant effect of ultrasound is partly explained by the enhanced delivery of tetanus toxoid into the skin after ultrasound application and partly by the activation of immune cells after ultrasonic TCI. These studies demonstrate generation of a potent systemic immune response through TCI without using toxin adjuvants or skin abrasion. Ultrasonic TCI offers a needle-free and painless mode of immunization.

Background and Objectives Lesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major liver and kidney transporters in vitro and evaluated the drug–drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies. Methods Lesinurad interaction with membrane transporters was evaluated in validated transporter-expressing cell systems and analyzed by liquid scintillation counting. Healthy male subjects (ages 18–65 years; body mass index 18–32 kg/m 2 ) received atorvastatin (40 mg; n  = 28) with or without lesinurad 200 or 400 mg, or received metformin (850 mg; n  = 12) or furosemide (40 mg; n  = 11) with or without lesinurad 400 mg. Plasma concentrations of each concomitant drug were determined by validated liquid chromatography with tandem mass spectrometry methods. Results Lesinurad interacted in vitro with OATP1B1, OCT1, and OAT1/3 transporters. Co-administration of lesinurad 200 mg did not significantly alter plasma exposure (maximum concentration [ C max ] and area under the concentration–time curve [AUC]) of total atorvastatin (atorvastatin + hydroxyl-metabolites) or atorvastatin, while co-administration of lesinurad 400 mg increased the C max of total atorvastatin and atorvastatin by 17–26 %, but had no effect on AUC. Co-administration of lesinurad 400 mg had no effect on the plasma exposure of metformin. Furosemide plasma AUC was reduced by 31 % in the presence of lesinurad 400 mg, but furosemide renal clearance and diuretic activity were unchanged. Conclusions No clinically relevant DDIs were observed between lesinurad and substrates of major liver or kidney transporters.

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration-time curve by 34%, 54%-65%, and 102%, respectively. Lesinurad plasma was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects. This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5-15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data. Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration ( ) and area under the plasma concentration-time curve (AUC) increased in a near dose-proportional manner. Time to ( ) was ~1.25-2.0 hours with fasting. A moderate-fat meal delayed (range 3.0-5.0 hours) and had a variable effect on AUC (0%-97% increase) and (0%-26% increase) across the dose groups. Following multiple verinurad 10 mg doses, and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses. Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia.

Oral route offers an attractive mode of drug administration, although its applications are limited by poor stability of peptides and proteins in the gastrointestinal tract. In this article, we report a novel method based on intestinal patches for oral drug delivery. This method involves the use of millimeter size mucoadhesive patches that adhere to the intestinal wall and direct solute diffusion towards the wall similar to that observed in the case of a transdermal patch. Intestinal patches were prepared by sandwiching a film of cross-linked bovine serum albumin microspheres between a film of ethyl cellulose and Carbopol/pectin. Delivery of three model drugs, sulforhodamine B. phenol red, and dextran was assessed in vitro using rat intestine. In vitro tests confirmed substantial unidirectional diffusion of model drugs from the patch across the intestinal wall. The presence of ethyl cellulose layer minimized release from the edges as well as from the back side of the patch into the intestinal lumen. In vitro experiments with rat intestine showed that patches were effective in delivering model drugs across the intestine. Trans-lumenal flux of model drugs from intestinal patches was about 100-fold higher compared to that from a solution due to localization of the solute near the intestinal wall and due to minimization of drug loss into the intestinal lumen. Intestinal patches offer a novel approach for oral drug delivery.