Safety, tolerability, and pharmacokinetics of l‐ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/1/hep29621.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/2/hep29621-sup-0001-suppinfo1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/3/hep29621_am.pd

Development of a sustained-release voriconazole-containing thermogel for subconjunctival injection in horses

PURPOSE. To determine in vitro release profiles, transcorneal permeation, and ocular injection characteristics of a voriconazole-containing thermogel suitable for injection into the subconjunctival space (SCS). METHODS. In vitro release rate of voriconazole (0.3% and 1.5%) from poly (DL-lactide-coglycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) thermogel was determined for 28 days. A Franz cell diffusion chamber was used to evaluate equine transcorneal and transscleral permeation of voriconazole (1.5% topical solution, 0.3% and 1.5% voriconazole-thermogel) for 24 hours. Antifungal activity of voriconazole released from the 1.5% voriconazole-thermogel was determined via the agar disk diffusion method. Ex vivo equine eyes were injected with liquid voriconazole-thermogel (4°C). Distension of the SCS was assessed ultrasonographically and macroscopically. SCS voriconazole-thermogel injections were performed in a horse 1 week and 2 hours before euthanasia and histopathologic analysis of ocular tissues performed. RESULTS. Voriconazole was released from the PLGA-PEG-PLGA thermogel for more than 21 days in all groups. Release followed first-order kinetics. Voriconazole diffused through the cornea and sclera in all groups. Permeation was greater through the sclerae than corneas. Voriconazole released from the 1.5% voriconazole-thermogel showed antifungal activity in vitro. Voriconazole-thermogel was easily able to be injected into the dorsal SCS where it formed a discrete gel deposit. Voriconazole-thermogel was easily injected in vivo and did not induce any adverse reactions. CONCLUSIONS. Voriconazole-containing thermogels have potential application in treatment of keratomycosis. Further research is required to evaluate their performance in vivo

Transdermal Iontophoretic Delivery of Ketoprofen Through Human Cadaver Skin and in Humans

Transdermal iontophoretic delivery of ketoprofen in cadaver skin and healthy volunteers was examined. In vitro anodic and cathodic iontophoresis (0.5 mA/cm2, 3 h) of ketoprofen (75 mg/ml) resulted in equivalent intracutaneous ketoprofen permeation (232.1 ± 27.1 vs. 275.0 ± 141.0 μg/cm2, respectively), which in turn was higher than passive intracutaneous uptake of ketoprofen (40.7 ± 42.1 μg/cm2). In contrast, only cathodic iontophoresis resulted in transcutaneous ketoprofen permeation across cadaver skin, under these conditions. The in vitro study was then repeated to achieve transcutaneous permeation of ketoprofen at clinical iontophoretic parameters (0.28 mA/cm2, 40 min) by increasing drug concentration to 300 mg/ml. No stereo-selective permeation of R- and S-ketoprofen enantiomers was observed in vitro. In humans, cathodic iontophoresis of 300 mg/ml ketoprofen (0.28 mA/cm2, 40 min) was performed at the wrist. Ketoprofen was detected at 40 min (0.88 ± 0.42 μg/ml) from the forearm veins of the ipsilateral arm. Urinary excretion of ketoprofen totaled 790 ± 170 μg at 16 h post iontophoresis. This investigation is the first to clearly demonstrate transcutaneous iontophoresis of an antiinflammatory agent in humans utilizing a commercially cleared iontophoretic device. The investigation also adds to the very limited number of publications in the area of iontophoretic delivery of drugs to humans

Pharmacokinetics and Absorption of Paromomycin and Gentamicin from Topical Creams Used To Treat Cutaneous Leishmaniasis

This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin (“paromomycin alone”) and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC0–24) was 2,180 +/- 2,621 ng · h/ml (mean +/- standard deviation [SD]) for the paromomycin-alone group and 975.6 +/- 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC0–24 and maximum concentration of drug (Cmax) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC0–24 was 8,575 +/- 7,268 ng · h/ml and the Cmax was 1,000 +/- 750 ng/ml, compared with 6,037 +/- 3,956 ng · h/ml and 660 +/- 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences (P\u3e0.05) in the AUC0–24 or Cmax were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% +/- 6.26% and 9.68% +/- 6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.