OCE-205, a novel, selective vasopressin V1a receptor mixed agonist/antagonist with no V2 receptor activity, may treat the portal hypertension-related complications of end-stage liver disease with an improved therapeutic profile over currently utilized nonselective full-agonist vasopressin analogs. This Phase 1, double-blind, placebo-controlled, within-dose-group randomized trial investigated the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of OCE-205 in healthy adults. Subjects received a single intravenous dose of OCE-205 0.1, 0.3, 0.45, 0.6, or 0.9 mg, or placebo infused over 6 h. Safety and tolerability were assessed, and blood samples were obtained for pharmacokinetic analyses. Sixty-four subjects were randomized and treated. Area under the concentration–time curve (AUC) and maximum plasma concentrations (Cmax) were approximately dose-proportional across doses from 0.1 to 0.9 mg. OCE-205 terminal half-life was 1.5 h. Diastolic, and to a lesser extent systolic, blood pressure increased in all OCE-205 dose groups; pulse rate decreased. Overall changes in mean arterial pressure were similar to changes in diastolic blood pressure. Absolute changes in cardiac output, by echocardiogram, were somewhat dose-dependent, with mean reductions of 3–12

Abstract Background Keratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes. Results Voriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 μg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment. Conclusions Voriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.

Abstract Background Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs. Objectives To perform a LC pharmacokinetic (PK) study when administered SC in dogs. Animals Five healthy female beagles. Methods Three‐period, 3‐treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m2 SC and FC was administered at 25 and 50 mg/m2 SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra‐high‐performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration‐time profiles were evaluated by noncompartmental analysis. Results Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration‐time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC. Conclusions and Clinical Importance In healthy dogs, SC LC administration at 50 mg/m2 results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.

Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs. To perform a LC pharmacokinetic (PK) study when administered SC in dogs. Five healthy female beagles. Three-period, 3-treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m 2 SC and FC was administered at 25 and 50 mg/m 2 SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra-high-performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration-time profiles were evaluated by noncompartmental analysis. Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration-time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC. In healthy dogs, SC LC administration at 50 mg/m 2 results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.

Voriconazole (VRC) is a potential treatment for pneumomycosis in horses. The objectives of this study were to determine if the delivery of Vfend using a Flexineb nebulizer produced clinically significant [VRC] in lower airways. The hypothesis was that [VRC] after delivery by nebulization would be greater in the pulmonary epithelial lining fluid than plasma. A secondary objective was to determine [VRC] in upper airways through the collection of nasopharyngeal wash (NPW) samples. Voriconazole solution [Vfend-6.25 mg/mL, 100 (n = 2), 200 (n = 3), 500 (n = 1) mg] was nebulized once in 6 healthy geldings. Clinical responses, duration of nebulization, and [VRC] at various time points (up to 8 hours) in plasma, bronchoalveolar lavage fluid (BALF) supernatant and cell pellet, and NPW samples were recorded. Voriconazole (Vfend-6.25 mg/mL, 200 mg) was nebulized in 5 additional, healthy geldings, and [VRC] was measured in NPW samples pre- and postnebulization at time points up to 8 hours. The antifungal activity of BALF and NPW samples was determined using agar disk diffusion. Concentrations of voriconazole were below detection in plasma, BALF supernatant, and cell pellets for all time points and doses except the BALF cell pellet (0.4 μg/g) immediately after nebulization of 500 mg. For 5 horses, administered 200 mg of Vfend, mean [VCR] in NPW at the end of nebulization and 1, 6, and 8 hours postnebulization were: 30.8 ± 29, 1.0 ± 0.84, 0.2 ± 0.19, and 0.34 ± 0.67 μg/mL, respectively. Only NPW samples obtained immediately postnebulization showed antifungal activity. A nebulized Vfend solution is not recommended for the treatment of pneumomycosis in horses.

This study reports the microemulsion (ME) effects on the permeation of genistein across normal (intact) and microporated human skin. The genistein formulation was optimized to know the stable ME region in the pseudo-ternary phase diagrams and to maximize the skin permeation and retention of genistein. The phase diagrams were constructed with different oil phases, surfactants, and their combinations. The influence of formulation factors on the permeation through intact and microporated human skin was determined. Based on its wide ME region, as well as permeation enhancement effects, oleic acid was used as an oil phase with various surfactants and co-surfactants to further maximize the ME region and skin permeation. The water content in the formulation played an important role in the ME stability, droplet size, and flux of genistein. For example, the ME with 20% water exhibited 4- and 9-fold higher flux as compared to the ME base (no water) and aqueous suspension, respectively. Likewise, this formulation had demonstrated 2- and 4-fold higher skin retention as compared to the ME base (no water) and aqueous suspension, respectively. The skin microporation did not significantly increase the skin permeation of genistein from ME formulations. The ME composition, water content, and to a lesser extent the ME particle size played a role in improving the skin permeation and retention of genistein.

BackgroundDiuretic treatment is the mainstay for management of congestive heart failure in horses, and its use has been restricted to injectable medications because no currently data supports the use of PO administered loop diuretics.ObjectivesTo determine the pharmacokinetic and pharmacodynamic properties of PO administered torsemide and, determine if PO administered torsemide, could be used as an alternative to injectable diuretics in the horse.AnimalsSix healthy adult mares.MethodsA 2‐phase, prospective study, that consisted of pharmacokinetic profiling of a single dose (6 mg/kg PO) and pharmacodynamic effects of long‐term torsemide administration (2 mg/kg PO q12h) for 6 days in healthy horses.ResultsPharmacokinetic analysis identified a peak concentration (Cmax) of 10.14 µg/mL (range, 6.79–14.69 µg/mL) and elimination half‐life (T1/2) 9.2 hours (range, 8.4–10.4 hours). The area under the plasma drug concentration over time curve (AUC) was 80.7 µg × h/mL (range, 56.5–117.2 µg × h/mL). A statistically significant increase in urine volume and decrease in urine specific gravity were found from day 0 (baseline) to day 6 (P < .0001). Significant alterations in biochemical variables included hyponatremia, hypokalemia, hypochloremia, and increased serum creatinine concentration. Mean arterial blood pressure significantly decreased on day 6 (57.7 ± 8.8 mm Hg, P = .001) as compared with baseline (78 ± 6.1 mm Hg). Serum aldosterone concentrations significantly increased after 6 days of torsemide administration (P = .0006).Conclusions and Clinical ImportancePO administered torsemide (4 mg/kg/day) successfully reached therapeutic concentrations in blood, induced clinically relevant diuresis, and resulted in moderate pre‐renal azotemia and electrolyte disturbances.

Objective: To characterize the pharmacokinetics (PK) of SBECD (sulfobutylether-β-cyclodextrin sodium salt, Capitsol) in carbamazepine(CBZ)-treated patients with epilepsy by renal function status. Background: SBECD solubilizes oral CBZ for intravenous use when oral administration is not feasible. IV CBZ is bioequivalent to oral CBZ infused at 70% of the total daily dose (TDD) every 6 hours (q6h). SBECD is eliminated unchanged by renal excretion, and half-life (t ½ ), mean AUC, and C max are increased in patients with moderate renal impairment (RI). Design/Methods: In a phase 1 open-label trial (NCT01079351), adults with epilepsy receiving stable oral CBZ (400–2,000 mg/day) were converted to IV CBZ (70% oral TDD) administered as 15- or 30-min infusions q6h on Days 1–7 of an inpatient period. SBECD PK following single-dose (Day 1) and multiple-dose (Day 7) IV CBZ administration were assessed by renal function (RF) and infusion duration. Results: On Day 1, SBECD exposure was similar for both infusion groups independent of renal function (normal RF, n=35: mean AUC 0–∞ , 782–881 μg·h/mL; mild RI, n=16: mean AUC 0–∞ , 808–905 μg·h/mL). Mean C max was notably greater in the 15-min groups (normal RF, 779 μg/mL; mild RI, 725 μg/mL) versus the 30-min groups (normal RF, 520 μg/mL; mild RI, 478 μg/mL). On Day 7, steady-state SBECD exposures were similar in patients with normal RF (30- and 15-min) and mild RI (15-min) (mean AUC τ : 830–1015 μg·h/mL). Steady-state mean C max was greater in the 15-min groups versus the 30-min groups, but similar for patients with normal RF and mild RI with the same infusion duration. Conclusions: Steady-state SBECD PK was similar to single-dose PK following IV CBZ infusions, indicating linear PK. Accumulation of SBECD, a potentially nephrotoxic ingredient of IV CBZ, was comparable between patients with normal RF and mild RI after 7 days of treatment. Study Supported by: Lundbeck LLC Disclosure: Dr. Tolbert has received personal compensation for activities with Lundbeck LLC. Dr. Ravis has received personal compensation for activities with Fast-Track Drugs & Biologics, LLC. Dr. Ravis has received research support from Fast-Track Drugs & Biologics, LLC and War Eagle Labs. Dr. Karim has received personal compensation for activities with Lundbeck LLC and Aptinyx as a consultant.

Nine horses received 20 mg/kg of intravenous ( LEV IV ); 30 mg/kg of intragastric, crushed immediate release ( LEV CIR ); and 30 mg/kg of intragastric, crushed extended release ( LEV CER ) levetiracetam, in a three‐way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEV CIR and LEV CER were 50.72 ± 10.60 and 53.58 ± 15.94 μg/ml, respectively. The y ‐intercept for IV administration was 64.54 ± 24.99 μg/ml. The terminal half‐life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEV CIR , LEV CER , and LEV IV , respectively. Volume of distribution at steady‐state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg −1 hr −1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEV CIR and LEV CER , respectively. A single dose of Levetiracetam ( LEV ) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

PurposeTo determine in vitro release profiles, transcorneal permeation, and ocular injection characteristics of a voriconazole-containing thermogel suitable for injection into the subconjunctival space (SCS).MethodsIn vitro release rate of voriconazole (0.3% and 1.5%) from poly (DL-lactide-co-glycolide-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.ResultsVoriconazole 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.ConclusionsVoriconazole-containing thermogels have potential application in treatment of keratomycosis. Further research is required to evaluate their performance in vivo.

Objective: To compare the pharmacokinetics of oral carbamazepine (CBZ) and intravenous CBZ (IV CBZ) in patients by renal function (RF) status. Background: IV CBZ has been developed as a short-term replacement when oral administration is temporarily intractable. IV CBZ has been shown to be well tolerated and bioequivalent to oral CBZ when infused at 70% of the total daily dose (TDD) every 6 hours (q6h). Design/Methods: In a phase 1, open-label trial (OV-1015; NCT01079351), adults with epilepsy receiving stable oral CBZ (400–2,000 mg/day) were converted to IV CBZ (infused at 70% oral TDD) administered as 15- or 30-min infusions q6h on Days 1–7, and 2- to 5-min infusions on Day 8 for a subset of 15-min infusion patients. Pharmacokinetic parameters of oral and IV CBZ were estimated through non-compartmental analysis. Creatinine clearance (CL CR ) was calculated by the Cockroft-Gault equation. Results: Mean AUC 0–24 was similar between oral and IV CBZ at 70% TDD. In patients with normal RF (n=55, CL CR ≥90 mL/min), mean AUC 0–24 was 11.87% higher in the 30-min group vs the rapid (2- to 5-min) infusion group; in patients with mild renal impairment (n=20, CL CR =60–89 mL/min), mean AUC 0–24 was 33.35% higher in the rapid infusion group vs the 30-min group. C max was higher after rapid infusion versus 15-min or 30-min infusions. In patients with mild renal impairment, CL/F marginally decreased by 5.71% and 3.01% in the 15-and 30-min infusion groups, respectively. Similar analyses could not be performed for patients with moderate renal impairment (CL CR =30–59 mL/min) due to the small number of participants (n=2). Conclusions: Mild renal impairment had no clinically meaningful effects on oral or IV CBZ pharmacokinetics. The effects of moderate (CL CR 30–59 mL/min) and severe (15–29 mL/min) renal impairment on CBZ PK are untested. Study Supported by: Lundbeck LLC Disclosure: Dr. Ravis has received personal compensation for activities with Fast-Track Drugs & Biologics, LLC. Dr. Ravis has received research support from Fast-Track Drugs & Biologics, LLC and War Eagle Labs. Dr. Tolbert has received personal compensation for activities with Lundbeck LLC. Dr. Karim has received personal compensation for activities with Lundbeck LLC and Aptinyx as a consultant. Dr. Cloyd has received personal compensation for activities with Neurelis, Inc., UCB, Inc., Upsher Smith, Xeris, Lundbeck LLC, and Mitsubishi Tanabe. Dr. Cloyd holds stock and/or stock options with Epalex. Dr. Dr. Cloyd has received licensing fees from the University of Minnesota. Dr. Cloyd has received research support from Pfizer, Sanofi Genzyme, and Allaysis.

OBJECTIVE: Assess the bioequivalence of oral to intravenous (IV) carbamazepine (CBZ) infused at 75[percnt] and 80[percnt] of the oral total daily dose (TDD) every 6 hours (q6h) using a pharmacokinetic (PK) model. BACKGROUND: Patients may be unable to take oral CBZ due to illness or surgery. Results from a clinical study showed IV CBZ infused at 70[percnt] of TDD q6h was bioequivalent to oral CBZ. DESIGN/METHODS: CBZ plasma concentration profiles and PK parameters were simulated for oral and IV CBZ infused for 15- or 30-minutes q6h at 75[percnt] or 80[percnt] of the oral TDD. Minimum, maximum, and average plasma concentrations (Cmin, Cmax, and Cavg, respectively), area under the time-concentration curve from 0-24 hours (AUC0-24), and partial 2 hour AUCs were determined. Bioequivalence between oral and IV CBZ was declared if the 90[percnt] confidence intervals (CIs) of the ratio of geometric LSMs for the PK parameters were between 80-125[percnt]. RESULTS: Simulated and observed values of IV CBZ infused over 15 minutes q6h at 70[percnt] of the oral TDD were similar and validated the model. Predicted steady-state estimates of Cmin and Cavg were within the 90[percnt] CIs for the 15 minute infusion rate; predicted Cmax was above the upper CI limit for both dose conversions. For 15-minute IV CBZ infusions, most predicted steady-state estimates of Cmin and Cavg were within and predicted Cmax values above the CI limit at 75[percnt] and 80[percnt] of the oral TDD. Partial AUC predictions for IV CBZ 15-minute infusions appeared to be better than the 30-minute infusions. CONCLUSIONS: PK simulations showed that the IV CBZ 15-minute infusion rate q6h at 75[percnt] and 80[percnt] of the oral TDD were bioequivalent to oral CBZ for Cmin, Cavg, and AUC0-24. IV CBZ infused over 15 minutes q6h appeared to better meet the 90[percnt] CI criteria for bioequivalence. Support: Lundbeck LLC

Background: Zoledronic acid, an inhibitor of osteoclast-mediated bone resorption, has been shown to have both direct and indirect antitumor activity. However, its use in extraskeletal malignancy is limited due to rapid uptake and accumulation within bone. Polyinosinic acid-polycytidylic acid [poly (I:C)] is a synthetic double-stranded RNA with direct antitumor cytotoxicity if it can be delivered to tumor cells intracellularly.Methods: Cationic lipid-coated calcium phosphate nanoparticles (LCP) were developed to enable intracellular codelivery of zoledronic acid and poly (I:C). LCP codelivering zoledronic acid and poly (I:C) were prepared using an ethanol injection method. Briefly, the ethanol solution of lipids was rapidly injected into newly formed calcium phosphate crystals containing poly (I:C) and zoledronic acid, and the mixture was then sonicated briefly to form LCP. The LCP were fully characterized for mean diameter size and zeta potential, efficiency in loading zoledronic acid, cytotoxic effect in a B16BL6 melanoma cell line in vitro, and antitumor effect in B16BL6 melanoma-bearing mice.Results: LCP with a mean diameter around 200 nm and a narrow size distribution (polydispersity index 0.17) and high zoledronic acid encapsulation efficiency (94%) were achieved. LCP loaded with zoledronic acid and poly (I:C) had significantly greater antitumor activity than the free drugs in the B16BL6 melanoma cell line (P<0.05). Furthermore, codelivery of zoledronic acid and poly (I:C) by LCP had higher cytotoxicity than delivering poly (I:C) alone by LCP (P, 0.05), indicating a synergism between zoledronic acid and poly (I:C). Finally, the antitumor study in melanoma-bearing mice also demonstrated synergism between zoledronic acid and poly (I:C) codelivered by LCP.Conclusion: Cationic lipid-coated calcium phosphate nanoparticles constructed for codelivery of zoledronic acid and double-stranded RNA poly (I:C) had better antitumor activity both in vitro and in vivo. Future preclinical development of LCP encapsulating zoledronic acid and poly (I:C) for the treatment of human cancer is under way.

ABSTRACT 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 (AUC 0–24 ) 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 AUC 0–24 and maximum concentration of drug ( C max ) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC 0–24 was 8,575 ± 7,268 ng · h/ml and the C max 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 ≥ 0.05) in the AUC 0–24 or C max 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.)

Edmondson, M. A., Duran, S. H., Boothe, D. M., Stewart, A. J., Ravis, W. R. Pharmacokinetics of tramadol and its major metabolites in alpacas following intravenous and oral administration. J. vet. Pharmacol. Therap. 35 , 389–396. Tramadol, a centrally acting opioid analgesic with monamine reuptake inhibition, was administered to six alpacas (43–71 kg) randomly assigned to two treatment groups, using an open, single‐dose, two‐period, randomized cross‐over design at a dose of 3.4–4.4 mg/kg intravenously (IV) and, after a washout period, 11 mg/kg orally. Serum samples were collected and stored at −80 °C until assayed by HPLC. Pharmacokinetic parameters were calculated. The mean half‐lives ( t 1/2 ) IV were 0.85 ± 0.463 and 0.520 ± 0.256 h orally. The Cp(0) IV was 2467 ± 540 ng/mL, and the C max was 1202 ± 1319 ng/mL orally. T max occurred at 0.111 ± 0.068 h orally. The area under the curve (AUC 0 ‐∞ ) IV was 895 ± 189 and 373 ± 217 ng*h/mL orally. The volume of distribution ( V d[area] ) IV was 5.50 ± 2.66 L/kg. Total body clearance (Cl) IV was 4.62 ± 1.09 h; Cl/F for oral administration was 39.5 ± 23 L/h/kg. The IV mean residence time (MRT) was 0.720 ± 0.264. Oral adsorption ( F ) was low (5.9–19.1%) at almost three times the IV dosage with a large inter‐subject variation. This may be due to binding with the rumen contents or enzymatic destruction. Assuming linear nonsaturable pharmacokinetics and absorption processes, a dosage of 6.7 times orally would be needed to achieve the same IV serum concentration of tramadol. The t 1/2 of all three metabolites was longer than the parent drug; however, O ‐DMT, N ‐DMT, and Di‐DMT metabolites were not detectable in all of the alpacas. Because of the poor bioavailability and adverse effects noted in this study, the oral administration of tramadol in alpacas cannot be recommended without further research.

The effect of a perfluorochemical blood substitute (Fluosol-DA 20%) on the disposition kinetics of digoxin in the dog was studied. An intravenous dose of digoxin was administered at either 0.25 or 24 hours following a 30% blood exchange with the dog’s own blood (SHAM group) or Fluosol-DA (treatment group). A significant change in the initial volume of distribution and mean residence time in the serum was noted when digoxin was administered 0.25 hours after the Fluosol-DA blood exchange. This volume of distribution change was not observed when digoxin was administered 24 hours after the Fluosol-DA blood exchange. No change in the t1/2, total body clearance, or volume of distribution at steady-state was observed in any of the treatments. No change in the partitioning of digoxin in the blood was noted following Fluosol-DA administration.