Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis.

Omaveloxolone is a potent activator of Nrf2, a master transcriptional regulator of a multitude of cytoprotective functions, including antioxidative, anti-inflammatory, and mitochondrial bioenergetic effects. Some of the most potent known effects of Nrf2 involve hepatoprotective functions. The purpose of this study was to evaluate the effects of omaveloxolone and TX63682, a closely related structural analog with similar oral bioavailability, in the STAM mouse model of nonalcoholic steatohepatitis (NASH).

Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice.

Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates.

Background: Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich's ataxia.

Methods: The present study evaluated the pharmacokinetics (PK) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich's ataxia patients. Pharmacodynamic (PD) evaluations in monkeys consisted of Nrf2 target gene mRNA expression in peripheral blood mononuclear cells (PBMCs), liver, lung, and brain.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

Background: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity.

Methods: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer.

Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers.

Background: Topical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated clinically.

Methods: In vitro, RTA 408 (3-1000 nM) was incubated with primary human keratinocytes for 16 h.

Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis.

Free radicals produced during cancer radiotherapy often leads to dermatitis, with the insult ranging from mild erythema to moist desquamation and ulceration. This toxicity can be dose limiting and promote chronic complications, such as fibrosis and wound recurrence. The purpose of this study was to evaluate if RTA 408, a synthetic triterpenoid that potently activates the antioxidative transcription factor Nrf2 and inhibits the proinflammatory transcription factor nuclear factor-kappa b (NF-κB), could protect skin from radiation-induced dermatitis.

Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin.

RTA 408 is a member of the synthetic oleanane triterpenoid class of compounds known to potently activate the cytoprotective transcription factor Nrf2. Because skin is constantly exposed to external oxidative stress, such as that from ultraviolet radiation, from chemical exposure, during improper wound healing, and throughout the course of cancer radiation therapy, it may benefit from activation of Nrf2. This study was conducted to evaluate the transdermal penetration properties and Nrf2 activation potential of RTA 408 in normal rat skin.

The use of the African green monkey as a preclinical model for ocular pharmacokinetic studies.

Purpose: This investigation evaluated the ocular and systemic pharmacokinetics of besifloxacin in African green monkeys compared with cynomolgus monkeys following topical ocular dosing.

Methods: A suspension formulation containing 0.6% besifloxacin was administered to African green and cynomolgus monkeys.

Human aqueous humor concentrations of besifloxacin, moxifloxacin, and gatifloxacin after topical ocular application.

Purpose: To determine the concentrations of besifloxacin, moxifloxacin, and gatifloxacin in human aqueous humor after topical instillation of commercially available besifloxacin ophthalmic suspension 0.6%, moxifloxacin ophthalmic solution 0.5%, and gatifloxacin ophthalmic solution 0.

Ocular pharmacokinetics of mapracorat, a novel, selective glucocorticoid receptor agonist, in rabbits and monkeys.

Mapracorat is a selective glucocorticoid receptor agonist in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat after topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.

Ocular pharmacokinetics/pharmacodynamics of besifloxacin, moxifloxacin, and gatifloxacin following topical administration to pigmented rabbits.

Purpose: The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR).

Methods: Rabbits received a topical instillation of Besivance™ (besifloxacin ophthalmic suspension, 0.6%), Vigamox (moxifloxacin hydrochloride ophthalmic solution, 0.

Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration.

Purpose: To evaluate the pharmacokinetic properties of besifloxacin, gatifloxacin, and moxifloxacin in the conjunctival tissue of healthy volunteers after topical application.

Methods: One-hundred eight (108) subjects were randomly assigned to receive one drop of besifloxacin (0.6% suspension), gatifloxacin (0.

Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans.

Purpose: Studies were conducted to evaluate the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans.

Methods: Besifloxacin ophthalmic suspension (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects.

A rapid and sensitive LC/MS/MS assay for the quantitation of brimonidine in ocular fluids and tissues.

We report here the development and validation of an LC/MS/MS method for the rapid and accurate quantitation of brimonidine in ocular tissues and fluids using brimonidine-d(4) as an internal standard (IS). Brimonidine was extracted from retina, iris/ciliary body, and vitreous humor samples with an acetonitrile:water (1:1) solution followed by sonication and vortexing. Aliquots of aqueous humor, iris/ciliary body, retina, and vitreous humor samples were diluted with acetonitrile containing IS and were separated on a reverse-phase HPLC column under isocratic conditions.

Nonclinical safety and pharmacokinetics of intravitreally administered human-derived plasmin in rabbits and minipigs.

The use of plasmin for pharmacologic vitreolysis and the creation of a posterior vitreous detachment offers several potential advantages over surgery. The nonclinical pharmacokinetics and safety of human-derived plasmin was evaluated following single or multiple intravitreal injections to rabbits and minipigs. Single intravitreal injections of plasmin at 45-900 microg resulted in a no adverse effect level (NOAEL) of 45 microg in both species; effects at higher doses included chemosis, mucopurulent discharge, mononuclear cell infiltrates in the iris-ciliary body, and reversible changes in electroretinogram waveforms and parameters.

Quantitative determination of besifloxacin, a novel fluoroquinolone antimicrobial agent, in human tears by liquid chromatography-tandem mass spectrometry.

A rapid and sensitive method was developed using high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) for the quantification of besifloxacin in human tears using sparfloxacin as the internal standard (IS). Besifloxacin was extracted from human tear samples using an ammonium formate buffer at pH 3.25.

Cassette dosing pharmacokinetic studies for evaluation of ophthalmic drugs for posterior ocular diseases.

The purpose of this investigation was to evaluate the utility of cassette dosing as a means for increasing throughput and decreasing animal usage for intravitreal ocular pharmacokinetic studies. Pigmented rabbits received a single intravitreal injection of test article containing either a single compound or a mixture of up to five compounds. Samples of vitreous, choroid and retina were collected at predetermined intervals through 7 or 28 days after dosing.

Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey.

The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization. We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction. In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor.

A single dose of monoclonal anti-phencyclidine IgG offers long-term reductions in phencyclidine behavioral effects in rats.

These studies tested the hypothesis that a single dose of high-affinity anti-phencyclidine monoclonal antibody (anti-PCP mAb) provides long-term protection against behavioral effects of repeated PCP administration in rats. Rats were treated with saline, nonspecific bovine IgG (NS-IgG), or anti-PCP mAb (1.0 g/kg).