Plasma pharmacokinetics, pulmonary disposition, and safety of subcutaneous gamithromycin in alpacas.

The study objective was to determine the disposition of gamithromycin in plasma, peripheral blood polymorphonuclear cells (PMNs), pulmonary epithelial lining fluid (PELF), and bronchoalveolar lavage (BAL) cells in alpacas. A single subcutaneous injection of gamithromycin (6.6 mg/kg) was administered to six healthy adult alpacas. At various time points after administration, gamithromycin concentrations were analyzed via LC-MS/MS in plasma, PMNs, PELF, and BAL cells until Day 14 post-injection. Plasma gamithromycin concentrations were measured in all six alpacas; the remaining three body compartments were analyzed in four alpacas. Gamithromycin rapidly concentrated in blood PMNs, BAL cells, and PELF. Shorter Tmax , and lower Cmax, and AUC were observed in plasma than in the other three compartments. Cmax was highest in BAL cells (26001.80 ± 12400.00 ng/ml) and PMNs (2573.00 ± 963.30 ng/ml) compared to PELF (660.80 ± 413.70 ng/ml) and plasma (452.30 ± 196.20 ng/ml). Mean terminal half-lives were 72.60 ± 14.10 h in plasma, 56.60 ± 10.60 h in PELF, 62.80 ± 85.30 h in PMNs, and 93.60 ± 124.80 h in BAL cells. No injection site reactions occurred. One alpaca developed colic but no other adverse reactions were noted. Overall, gamithromycin was highly concentrated in white blood cells and pulmonary fluids/cells. Clinical utilization of gamithromycin in alpacas should be done with caution until further investigation of potential for colic.

High particle counts in neonatal parenteral nutrition solutions with added cysteine: Relationship to crystal formation and effect of filtration on cysteine content.

BACKGROUND: Parenteral nutrition(PN) solutions containing calcium gluconate and cysteine have elevated particle counts when analyzed using laser light obscuration (LO) as recommended by the United States Pharmacopeia. It is unclear whether increased particle formation in these solutions results in decreased availability of cysteine to neonatal patients due to filtration. OBJECTIVE: The purpose of this study was to measure cysteine concentrations in neonatal PN solutions before and after filtration as well as analyze precipitates on filters. METHODS: Solutions of PN containing amino acids with and without cysteine that were compounded with calcium chloride or calcium gluconate plus potassium phosphate were analyzed using LO. Concentrations of cysteine were measured before and after filtration. The effect on particle formation of magnesium sulfate (MgSO4 ) and D70 was also evaluated. RESULTS: Multiple additives including the specific calcium or D70 additive, cysteine, and MgSO4 influenced particle formation of particles detected using LO. There was no significant decrease in cysteine concentration because of filtering and there was no difference in the amount of calcium on filters of various solutions after filtration regardless of LO particle counts. Scanning electron micrographic (SEM) analysis found no significant differences in crystal composition. Light microscopic and SEM examination did not show evidence of high particle counts on filters. CONCLUSION: The increased particle counts detected in neonatal PN solutions containing cysteine added at the time of compounding does not appear to result in increased precipitate or crystal formation. It is not associated witha decrease in cysteine delivery to patients.

Pharmacokinetics after subcutaneous administration of a single dose of cefovecin sodium in African lions (Panthera leo).

OBJECTIVE To determine the pharmacokinetics of cefovecin sodium after SC administration of a single dose to African lions (Panthera leo). ANIMALS 3 adult (9 to 10 years old; 1 male and 2 females) and 3 juvenile (2 years old; 1 male and 2 females) African lions. PROCEDURES A crossover study was conducted. A single dose of cefovecin was administered SC at 4 mg/kg (half dose) and 8 mg/kg (full dose) to African lions. Blood samples were collected daily for 14 days after cefovecin injection. Plasma drug concentrations were determined by use of high-performance liquid chromatography with UV detection. RESULTS Cefovecin had first-order elimination kinetics for doses of 4 and 8 mg/kg. Mean ± SD maximum plasma concentration was 9.73 ± 1.01 µg/mL and 18.35 ± 0.94 µg/mL after doses of 4 and 8 mg/kg, respectively. Time to maximum plasma concentration was approximately 4 hours for both doses. Mean elimination half-life was approximately 111 and 115 hours after doses of 4 and 8 mg/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Cefovecin was detected in lion plasma for 336 hours after administration at both 4 and 8 mg/kg at concentrations greater than the reported minimum inhibitory concentration (0.06 µg/mL) for common bacterial organisms in domestic cats. These results indicated that cefovecin administered at 4 mg/kg SC reached therapeutic concentrations for an extended period in African lions.

Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract.

SCOPE: Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. METHODS AND RESULTS: Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 µmol SFN daily, as a single dose and as two 100-µmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ∼3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). CONCLUSION: We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials.

Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration.

SCOPE: Xanthohumol (XN), a dietary flavonoid found in hops, may have health-protective actions against cardiovascular disease and type 2 diabetes. Yet, there are limited data on the pharmacokinetics (PK) of XN. This study provides PK parameters for XN and its major metabolites in rats. METHODS AND RESULTS: A PK study was conducted in male jugular vein-cannulated Sprague-Dawley rats. Rats (n = 12/group) received an intravenous (IV) injection (1.86 mg/kg BW) or an oral gavage of a low (1.86 mg/kg BW), medium (5.64 mg/kg BW), or high (16.9 mg/kg BW) dose of XN. Plasma samples were analyzed for XN and its metabolites using LC-MS/MS. The maximum concentration (C(max) ) and area under the curve (AUC(0-96 h) ) of total XN (free and conjugated) were 2.9±0.1 mg/L and 2.5±0.3 h* mg/L in IV group, 0.019±0.002 mg/L and 0.84±0.17 h* mg/L in the oral low group, 0.043±0.002 mg/L and 1.03±0.12 h* mg/L in the oral medium group, and 0.15±0.01 mg/L and 2.49±0.10 h* mg/L in the oral high group. CONCLUSION: The bioavailability of XN is dose-dependent and approximately 0.33, 0.13, and 0.11 in rats, for the low-, medium-, and high-dose groups, respectively.

Hydrocortisone Diffusion Through Synthetic Membrane, Mouse Skin, and Epiderm™ Cultured Skin.

OBJECTIVES: The penetration of hydrocortisone (HC) from six topical over-the-counter products along with one prescription cream through cultured normal human-derived epidermal keratinocytes (Epiderm™), mouse skin and synthetic nylon membrane was performed as well as the effect hydrating the skin by pre-washing was explored using the Upright Franz Cell. METHOD AND RESULTS: Permeation of HC through EpiDerm™, mouse skin and synthetic membrane was highest with the topical HC gel formulation with prewash treatment of the membranes among seven products evaluated, 198 ± 32 µg/cm(2), 746.32 ± 12.43 µg/cm(2), and 1882 ± 395.18 µg/cm(2), respectively. Pre-washing to hydrate the skin enhanced HC penetration through EpiDerm™ and mouse skin. The 24-hour HC released from topical gel with prewash treatment was 198.495 ± 32 µg/cm(2) and 746.32 ± 12.43 µg/cm(2) while without prewash, the 24-h HC released from topical gel was 67.2 ± 7.41 µg/cm(2) and 653.43 ± 85.62 µg/cm(2) though EpiDerm™ and mouse skin, respectively. HC penetration through synthetic membrane was ten times greater than through mouse skin and EpiDerm™. Generally, the shape, pattern, and rank order of HC diffusion from each commercial product was similar through each membrane.