J. Mark Christensen

Human pharmacokinetics of xanthohumol, an antihyperglycemic flavonoid from hops

SCOPE Xanthohumol (XN) is a bioactive prenylflavonoid from hops. A single-dose pharmacokinetic (PK) study was conducted in men (n = 24) and women (n = 24) to determine dose-concentration relationships. METHODS AND RESULTS Subjects received a single oral dose of 20, 60, or 180 mg XN. Blood was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 h. Plasma levels of XN and its metabolites, isoxanthohumol (IX), 8-prenylnaringenin (8PN), and 6-prenylnaringenin (6PN) were measured by LC-MS/MS. Xanthohumol (XN) and IX conjugates were dominant circulating flavonoids among all subjects. Levels of 8PN and 6PN were undetectable in most subjects. The XN PK profile showed peak concentrations around 1 h and between 4-5 h after ingestion. The maximum XN concentrations (C(max)) were 33 ± 7 mg/L, 48 ± 11 mg/L, and 120 ± 24 mg/L for the 20, 60, and 180 mg dose, respectively. Using noncompartmental modeling, the area under the curves (AUC(0→∞)) for XN were 92 ± 68 h × μg/L, 323 ± 160 h × μg/L, and 863 ± 388 h × μg/L for the 20, 60, and 180 mg dose, respectively. The mean half-life of XN was 20 h for the 60 and 18 h for the 180 mg dose. CONCLUSION XN has a distinct biphasic absorption pattern with XN and IX conjugates being the major circulating metabolites.

Precipitate Analysis from an Indwelling Total Parenteral Nutrition Catheter

The composition of a precipitate obtained from a silastic right atrial catheter was determined. The precipitate was collected and washed with deionized water thoroughly before subjecting portions of it to organic and inorganic analysis. Inorganic analysis was conducted using scanning electron microscopy and x-ray spectroscopy for sodium, aluminum, silicone, sulfur, chlorine, and calcium. Phosphorus analysis was conducted by a commercial laboratory. Organic analysis was conducted by thin layer chromatography with cholesterol, phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine, and sphingomyelin as standards. Silicone, calcium, and phosphorus and three organic compounds, which could not be conclusively identified, were found. The precipitate was most likely calcium phosphate intermixed with silicone oil lubricant and residual total parenteral nutrition (TPN) solution. This formed in the catheter at body temperature probably due to incomplete catheter flushing.

PHARMACOKINETICS OF ORALLY ADMINISTERED TERBINAFINE IN AFRICAN PENGUINS (SPHENISCUS DEMERSUS) FOR POTENTIAL TREATMENT OF ASPERGILLOSIS

Abstract The objective of this study was to determine the pharmacokinetic parameters of orally administered terbinafine hydrochloride based on 3, 7, and 15 mg/kg single- as well as multiple-dosage trials in order to calculate dosing requirements for potential treatment of aspergillosis in African penguins (Spheniscus demersus). Ten adult African penguins were used in each of these trials, with a 2-wk washout period between trials. Mean plasma concentrations of terbinafine peaked in approximately 4 hrs at 0.11 ± 0.017 µg/ml (mean ± SD) following administration of 3 mg/kg terbinafine, while 7 mg/kg and 15 mg/kg dosages resulted in peak plasma concentrations of 0.37 ± 0.105 and 0.33 ± 0.054 µg/ml, respectively. The volume of distribution increased with increasing dosages, being 37 ± 28.5, 40 ± 28.1, and 52 ± 18.6 mg/L for 3, 7, and 15 mg/kg doses, respectively. The mean half-life was biphasic with initial terminal half-life (t½) values of 9.9 ± 4.5, 17.2 ± 4.9 and 16.9 ± 5.4 hrs, for 3, 7, and 15 mg/kg doses, respectively. A rapid first elimination phase was followed by a slower second phase, and final elimination was estimated to be 136 ± 9.7 and 131 ± 9.9 hrs, for 7 and 15 mg/kg doses, respectively. Linearity was demonstrated for area under the curve but not for peak plasma concentrations for the three dosages used. Calculations based on pharmacokinetic parameter values indicate that a 15 mg/kg terbinafine q24h dosage regimen would result in steady-state trough plasma concentrations above the minimum inhibitory concentration (0.8–1.6 µg/ml), and this dosage is recommended as a potential treatment option for aspergillosis in penguins. However, additional research is required to determine both treatment efficacy and safety.

Pharmacokinetics of Terbinafine After Single Oral Dose Administration in Red-Tailed Hawks (Buteo jamaicensis)

Abstract To determine pharmacokinetic parameters of orally administered terbinafine hydrochloride for potential treatment of aspergillosis in raptors, 10 adult red-tailed hawks (Buteo jamaicensis) were used in single dose trials by using 15, 30, and 60 mg/kg doses with a 2-week washout period between trials. After administration of 15 mg/kg terbinafine, mean (± SD) plasma concentration peaked in approximately 5 hours at 0.3 ± 0.24 µg/mL, whereas a 30 mg/kg dose resulted in peak mean (± SD) plasma concentration of 1.2 ± 0.40 µg/mL in 3 hours and a 60 mg/kg dose resulted in mean (± SD) concentration of 2.0 ± 0.75 µg/mL in 5 hours. The volume of distribution decreased with increasing doses, averaging 76.8 ± 38.06 mL/kg for the 15 mg/kg dose and falling to 55.2 ± 17.4 mL/kg for the 30 mg/kg dose. This suggests that terbinafine accumulated in deep tissues, limiting further distribution at higher doses. The harmonic mean (± SD) half-life was biphasic, with initial values of 14.7 ± 6.67 hours, 17.5 ± 8.7 hours, and 13.3 ± 5.03 hours for 15, 30, and 60 mg/kg doses, respectively. A rapid first-elimination phase was followed by a slower second phase, and final elimination was estimated to be 161 ± 78.2 and 147 ± 65.6 hours for 15 and 30 mg/kg doses, respectively. Linearity was demonstrated for the area under the curve but not for peak plasma concentrations for the 3 doses used. Calculations based on pharmacokinetic parameter values indicated that a dosage of 22 mg/kg terbinafine q24h would result in steady-state trough plasma concentrations above the minimum inhibitory concentration of terbinafine (0.8–1.6 µg/mL). This dosage is recommended as a potential treatment option for aspergillosis in raptors. However, additional research is required to determine both treatment efficacy and safety.

Age and gender dependent bioavailability of R- and R,S-α-lipoic acid: A pilot study

Lipoic acid (LA) shows promise as a beneficial micronutrient toward improving elder health. Studies using old rats show that (R)-α-LA (R-LA) significantly increases low molecular weight antioxidants that otherwise decline with age. Despite this rationale for benefiting human health, little is known about age-associated alterations in absorption characteristics of LA, or whether the commercially available racemic mixture of LA (R,S-LA) is equally as bioavailable as the naturally occurring R-enantiomer. To address these discrepancies, a pilot study was performed to establish which form of LA is most effectively absorbed in older subjects relative to young volunteers. Young adults (average age=32 years) and older adults (average age=79 years) each received 500 mg of either R- or R,S-LA. Blood samples were collected for 3h after supplementation. After a washout period they were given the other chiral form of LA not originally ingested. Results showed that 2 out of 6 elder males exhibited greater maximal plasma LA and area under the curve for the R-form of LA versus the racemic mixture. The elder subjects also demonstrated a reduced time to reach maximal plasma LA concentration following R-LA supplementation than for the racemic mixture. In contrast, young males had a tendency for increased bioavailability of R,S-LA. Overall, bioavailability for either LA isoform was much more variable between older subjects compared to young adults. Plasma glutathione levels were not altered during the sampling period. Thus subject age, and potential for varied response, should be considered when determining an LA supplementation regimen.

Development and in vitro evaluation of mesalamine delayed release pellets and tableted reservoir-type pellets

Background: The basic objective of this study was to develop a novel technique that aids in compaction of coated pellets into tablets and obtain a release pattern from compressed pellets resembling the same pattern before compression. Method: Multi-unit dosage forms of mesalamine targeted to the colon were formulated by extrusion-spheronization, and then coated with Eudragit S (30%). These pellets were filled into gelatin capsules or further formulated and compressed into tablets. Tablets for colonic delivery of mesalamine were prepared by mixing the coated beads with cushioning agents like stearic acid and Explotab, or by applying an additional coat of gelatin (4% weight gain) onto the Eudragit S coated pellets, and then compressing into tablets (tableted reservoir-type pellets). Then additional coating of the tablets prepared by the coating technique was applied utilizing Eudragit L 100-55 (5% weight gain). Results: This technique provides additive protection for the coated beads to withstand the compression force during tableting. Excellent in vitro dissolution results were obtained, which were comparable to the results of the release of mesalamine from uncompressed beads filled in capsules. Mesalamine release from the capsules was 0.3% after 2 hours in gastric pH, 0.37% was released after an additional 1 hour in pH 6, and 89% was released after 1.5 hours in colonic pH 7.2. Conclusion: Various formulation and process parameters have to be optimized in order to obtain tableted reservoir-type pellets having the same release properties as the uncompressed pellets. The coating technique delays the release of mesalamine until the beads reach the terminal ileum and colon. Once released in the colon, mesalamine is minimally absorbed and can act locally to treat ulcerative colitis.

Comparative in vitro activities of topical wound care products against community-associated methicillin-resistant Staphylococcus aureus

OBJECTIVES Community-associated methicillin-resistant Staphylococcus aureus is responsible for an increasing number of skin infections. Over-the-counter topical wound care products may play a role in the prevention of these infections, but limited data are available regarding their activity. The current study utilized a modified time-kill design to evaluate the activity of three over-the-counter topical wound care products (benzethonium chloride/essential oils, neomycin/polymyxin B and polymyxin B/gramicidin) against four unique isolates (three USA 300 and one USA 400). METHODS All experiments were performed using commercially available formulations. Bactericidal activity was defined as a sustained 3 log(10) reduction in cfu/mL from the initial inoculum. Reductions in bacterial counts between agents were determined using analysis of variance. RESULTS At 10 min, the reduction (mean +/- SD) in log(10) cfu/mL for all strains was 2.87 +/- 1.22, 1.86 +/- 0.76 and 0.143 +/- 0.82 for benzethonium chloride/essential oils, neomycin/polymyxin B and polymyxin B/gramicidin, respectively. By 24 h, bactericidal activity was observed against two strains each for neomycin/polymyxin B and polymyxin B/gramicidin. Benzethonium chloride/essential oils was bactericidal against all strains by 6 h. At 24 h, all three agents were superior to controls (P < 0.05). Benzethonium chloride/essential oils was more active at 24 h than polymyxin B/gramicidin versus all four strains (P < 0.05) and more active than neomycin/polymyxin B versus three of four strains (P < 0.05). CONCLUSIONS These topical agents demonstrated variable activity against the four strains tested. Benzethonium chloride/essential oils was more rapidly and completely active than the other agents tested.

New Dissolution Method for Mesalamine Tablets and Capsules

Dissolution methods are different for extended-release mesalamine capsules (pH 7.5 only) and delayed-release tablets (pH 1.4, 6.0, and 7.2). Mesalamine is used for the treatment of ulcerative colitis. The USP methods have several drawbacks in that they do not mimic gastrointestinal tract environments; tablets are removed from vessels to change dissolution medium; and neither method has been adopted to compare different formulations. This study proposed a method that reflects gastrointestinal transit time and pH, is easy to conduct, and may be used to test new delayed- or extended-release formulations and compare various dosage forms.

Sustained Delivery of Intact Drug to the Colon: Mesalamine Formulation and Temporal Gastrointestinal Transit Analysis

The goal was to use temporal gastrointestinal transit simulations and formulation to predict and provide sustained input of target-site directed oral drug delivery exclusively into the colon. Using mesalamine as the model drug for formulation coupled with stomach emptying rates (fed and unfed) plus intestinal transit times demonstrates concepts and provides a specific example for treatment in ulcerative colitis. Formulation involved extrusion and spheronization into beads which were then coated with aqueous Eudragit® S. Drug is released only at colonic pH and gastrointestinal transit predicts sustained drug input into the colon, especially when food effects are included.

Pharmacokinetic Modeling and Simulation of Gastrointestinal Transit Effects on Plasma Concentrations of Drugs from Mixed Immediate-Release and Enteric-Coated Pellet Formulations

Effects of gastrointestinal transit on plasma concentrations of drugs from mixed immediate–release and enteric-coated pellet formulation were simulated with models developed by including gastric emptying time and lag time of emptying. Models were evaluated by comparing simulated plasma concentrations of amphetamine from Monte Carlo simulations to available published data of a commercial mixed pellet formulation (Adderall XR™). Results show that the plasma profile from the mixed pellet formulation does not mimic that from two immediate-release doses administered at different times. Instead, the plasma profile from the mixed pellets of amphetamine is similar to a typical sustained-release formulation. The pharmacokinetic models presented herein describe plasma concentrations of amphetamine from mixed pellet formulation quite well. The models and assumptions are general and can be applied to other drugs in similar mixed pellet dosage forms.