Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study

Bakker, J., Thuesen, L. R., Braskamp, G., Skaanild, M. T., Ouwerling, B., Langermans, J. A. M., Bertelsen, M. F. Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study. J. vet. Pharmacol. Therap. 34 , 464–468. Cefovecin is a third‐generation cephalosporin approved for antibacterial treatment with a 14‐day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C_max) of cefovecin was 78 μg/mL and was achieved after 57 min. The mean apparent long elimination half‐life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 μg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C_max which however was lower than most of the MIC levels and with a very short t½. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys.     

Pharmacokinetics of buprenorphine following intravenous and intramuscular administration in male rhesus macaques (Macaca mulatta)

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (i.v.) and intramuscular (i.m.) administration. Four healthy, opioid‐naïve, socially housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, postadministration. Serum buprenorphine concentrations were analyzed with liquid chromatography–mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the i.v. study as compared to the i.m. study was 177 (159–189) vs. 185 (174–214) min, respectively [median (range)]. In the i.v. study, concentration back‐extrapolated to time zero was found to be 33.0 (16.8–57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the i.m. study was 11.8 (6.30–14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations >0.10 ng/mL for over 24 h in the i.v. study and over 12 h in the i.m. study. Bioavailability was found to be 68.1 (59.3–71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.     

Effects of social and climatic factors on birth sex ratio in Macaca mulatta in Mount Taihangshan area

Sex allocation theory predicts the optimal investment to male and female offspring. However, a biased sex ratio requires explanations as to why the deviation occurs. Rhesus macaque (Macaca mulatta) is the most widely distributed nonhuman primate species and the Taihangshan macaque (Macaca mulatta tcheliensis) occupies the northern limit of all rhesus macaque natural populations worldwide. We observed one macaque troop (Wangwu‐1 [WW‐1]) inhabiting Taihangshan Macaque National Nature Reserve and recorded all birth events and the sex of newborn macaques from 2004 to 2013. Our aim was to apply the Trivers–Willard hypothesis to this free‐ranging rhesus macaque troop, and to understand the relationship between climatic parameters (precipitation and temperature) and birth sex ratio. We found that the total newborn macaques showed a female‐biased sex ratio at birth in the WW‐1 troop, but there were no significant biased birth sex ratios in all matriarchs and in high‐ranking and middle‐ranking matrilineal units. However, the low‐ranking macaque matrilineal unit was significantly female‐biased. Moreover, we found that the annual precipitation of the previous year was positively associated with the birth sex ratio, and there was an interactive effect of troop size and current winter temperature on the birth sex ratio. The underlying mechanisms for the effects of social and climatic factors on birth sex ratio could be complex, and we discuss several plausible explanations.     

Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma

Background: Cyclophosphamide is an alkylating chemotherapeutic drug administered IV or PO. It is currently assumed that exposure to the active metabolite, 4‐hydroxycyclophosphamide (4‐OHCP), is the same with either route of administration.

Objectives:

To characterize the pharmacokinetics of cyclophosphamide and 4‐OHCP in dogs with lymphoma when administered PO or IV. Animals: Sixteen client‐owned dogs with substage A lymphoma were enrolled in the study. Eight dogs received cyclophosphamide IV and 8 received it PO. Methods: Prospective randomized clinical trial was performed. Blood was collected from each dog at specific time points after administration of cyclophosphamide. The serum was evaluated for the concentration of cyclophosphamide and 4‐OHCP with mass spectrometry and liquid chromatography. Results: Drug exposure to cyclophosphamide measured by area under the curve (AUC)_0–inf is significantly higher after intravenous administration (7.14 ± 3.77 μg/h/mL) compared with exposure after oral administration (P‐value < .05). No difference in drug exposure to 4‐OHCP was detected after IV (1.66 ± 0.36 μg/h/mL) or PO (1.42 ± 0.64 μg/h/mL) administered cyclophosphamide. Conclusions and Clinical Importance: Drug exposure to the active metabolite 4‐OHCP is equivalent after administration of cyclophosphamide either PO or IV.     

Caudal epidural injection of lidocaine,tramadol, and lidocaine–tramadol for epidural anesthesia in cattle

Bigham, A. S., Habibian, S., Ghasemian, F., Layeghi, S. Caudal epidural injection of lidocaine, tramadol, and lidocaine–tramadol for epidural anesthesia in Cattle. J. vet. Pharmacol. Therap. 33 , 439–443. Caudal epidural anesthesia is commonly utilized in veterinary medicine to allow diagnostic, obstetrical, and surgical intervention, in the perineal region of large animal. The aim of this study is to directly compare the time of onset and duration of analgesia produced by a tramadol and lidocaine–tramadol combination with that produced by lidocaine administration in the epidural space of Cattle. Five healthy adult Holstein dairy cows were selected to this study. Epidural anesthesia was produced in all cows by lidocaine, with 2 weeks intervals repeated by a combination of lidocaine–tramadol and tramadol. Time to onset and duration of analgesia were recorded. Heart rate, respiratory rate and body temperature were recorded at 0 min and at 5, 10, 15, 30, 60, and 75 min after the epidural administrations of each treatments. The tramadol produced a significant (P < 0.05) longer duration of analgesia (306.8 ± 8.58 min) than lidocaine (69.40 ± 8.96 min) alone and lidocaine–tramadol combination (174 ± 4.84 min). Also, lidocaine–tramadol combination produced a significant (P < 0.05) longer duration of analgesia than lidocaine alone. Complete analgesia began at 14.10 ± 1.57 min in the tramadol treatment, being more delayed than in the treatments with lidocaine–tramadol (4.84 ± 0.68 min) and lidocaine (3.90 ± 0.89 min). Body temperatures, heart rates, and respiratory rates were not significantly different in comparison with baseline values throughout the study in the all treatments. The combination of lidocaine–tramadol produced anesthesia of longer duration than lidocaine and the onset time was approximately same as for the lidocaine group. Utilizing this combination, long duration of anesthesia could commence relatively soon after epidural injection and might be used without re‐administration of anesthetic agent in long‐duration obstetrical and surgical procedures.     

Pharmacokinetics of dexamethasone following intra‐articular,intravenous, intramuscular,and oral administration in horses and its effects on endogenous hydrocortisone

Soma, L. R., Uboh, C. E., Liu, Y., Li, X., Robinson, M .A., Boston, R. C., Colahan, P. T. Pharmacokinetics of dexamethasone following intra‐articular, intravenous, intramuscular, and oral administration in horses and its effects on endogenous hydrocortisone. J. vet. Pharmacol. Therap.  36 , 181–191. This study investigated and compared the pharmacokinetics of intra‐articular (IA) administration of dexamethasone sodium phosphate (DSP) into three equine joints, femoropatellar (IAS), radiocarpal (IAC), and metacarpophalangeal (IAF), and the intramuscular (IM), oral (PO) and intravenous (IV) administrations. No significant differences in the pharmacokinetic estimates between the three joints were observed with the exception of maximum concentration (C_max) and time to maximum concentration (T_max). Median (range) C_max for the IAC, IAF, and IAS were 16.9 (14.6–35.4), 23.4 (13.5–73.0), and 46.9 (24.0–72.1) ng/mL, respectively. The T_max for IAC, IAF, and IAS were 1.0 (0.75–4.0), 0.62 (0.5–1.0), and 0.25 (0.08–0.25) h, respectively. Median (range) elimination half‐lives for IA and IM administrations were 3.6 (3.0–4.6) h and 3.4 (2.9–3.7) h, respectively. A 3‐compartment model was fitted to the plasma dexamethasone concentration–time curve following the IV administration of DSP; alpha, beta, and gamma half‐lives were 0.03 (0.01–0.05), 1.8 (0.34–2.3), and 5.1 (3.3–5.6) h, respectively. Following the PO administration, the median absorption and elimination half‐lives were 0.34 (0.29–1.6) and 3.4 (3.1–4.7) h, respectively. Endogenous hydrocortisone plasma concentrations declined from a baseline of 103.8 ± 29.1–3.1 ± 1.3 ng/mL at 20.0 ± 2.7 h following the administration of DSP and recovered to baseline values between 96 and 120 h for IV, IA, and IM administrations and at 72 h for the PO.     

Pharmacokinetics and analgesic efficacy of intranasal administration of tramadol in dogs after ovariohysterectomy

ObjectiveTo assess analgesic efficacy and the pharmacokinetics of intranasal (IN) tramadol in dogs following ovariohysterectomy.Study designRandomized, blinded clinical study.AnimalsA total of 30 bitches undergoing elective ovariohysterectomy.MethodsDogs were randomly assigned to one of three experimental groups (10 dogs per group): IN tramadol 4 mg kg^–1 (group T-IN), intravenous (IV) tramadol 4 mg kg^–1 (group T-IV) and IV methadone 0.2 mg kg^–1 (group M). Drugs were administered at extubation. At established time points (before surgery and up to 8 hours after drug administration) analgesia was assessed using the Italian version of the Glasgow Composite Measure Pain Scale Short Form and physiological variables were recorded. To determine the pharmacokinetics of IN tramadol, blood samples were collected at predetermined time points. Shapiro–Wilk test was used to assess whether data were normally distributed and consequently parametric or non parametric tests were applied. A p value < 0.05 was considered significant.ResultsNo significant intergroup differences were observed in the dogs that were administered rescue analgesia and time of its administration. Excluding dogs that were administered rescue analgesia, no significant intergroup differences emerged in pain scores and physiological variables, except for a lower rectal temperature in group M compared with the tramadol groups. After IN administration, tramadol was rapidly absorbed into the systemic circulation, reaching its maximum concentration (range 74.74–200.29 ng mL^–1) within 30–60 minutes, it then decreased rapidly and was detectable in plasma for up to 2 hours after treatment in all dogs.Conclusions and clinical relevanceIN tramadol administration appears to be as effective as IV tramadol and methadone treatments in pain management of dogs after elective ovariohysterectomy. Given its low concentrations and short detection time in plasma after the IN route, systemic tramadol action appears unlikely.     

Pharmacokinetics of levosulpiride after single‐dose administration in goats (Capra hircus) by different routes of administration

Levosulpiride (LSP) is the l‐enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross‐over design (3 × 3 Latin‐square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5–4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.     

The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses

Davis, J. L., Marshall, J. F., Papich, M. G., Blikslager, A. T., Campbell, N. B. The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses. J. vet. Pharmacol. Therap. 34 , 12–16. The purpose of this study was to determine the pharmacokinetics of deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, deracoxib had a long elimination half‐life (t_1/2k₁₀) of 12.49 ± 1.84 h. The average maximum plasma concentration (C_max) was 0.54 μg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that deracoxib was selective for COX‐2 with a COX‐1/COX‐2 ratio of 25.67 and 22.06 for the IC₅₀ and IC₈₀, respectively. Dosing simulations showed that concentrations above the IC₈₀ for COX‐2 would be maintained following 2 mg/kg PO q12h, and above the IC₅₀ following 2 mg/kg PO q24h. This study showed that deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti‐inflammatory treatment of various conditions in the horse.     

Pharmacokinetic/pharmacodynamic assessments of 10 mg/kg tramadol intramuscular injection in yellow‐bellied slider turtles (Trachemys scripta scripta)

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. The aims of this study were to assess the pharmacokinetic/pharmacodynamic (PK/PD) properties of tramadol and its active metabolite M1 and to evaluate the effect of the renal portal system on the PK/PD parameters in yellow‐bellied slider turtles. Turtles (n = 19) were randomly assigned to four treatment groups, according to a masked, single‐dose, four‐treatment, unpaired, four‐period crossover design. Group A (n = 5) received a single i.m. dose of tramadol (50 mg/mL) at 10 mg/kg in the proximal hindlimb. Group B (n = 5) received the same i.m. dose but in the forelimb. Groups C (n = 5) and D (n = 4) received a single i.m. injection of saline (NaCl 0.9%) of equivalent volume to the volumes of tramadol injected in the hind‐ and forelimb, respectively. Groups were rotated (1‐month washout period) until the completion of the crossover study. Tramadol plasma concentrations were evaluated by a validated HPLC‐FL method. An infrared thermal stimulus was applied to the plantar surface of the turtles' hindlimbs to evaluate the thermal withdrawal latency (TWL). The two PK profiles of tramadol differed in the first 2 h following administration, but overlapped in the elimination phases. The metabolite M1 was formed in both the treatment groups, showing similar pharmacokinetic trends, although the amount of M1 was significantly higher (20%) in the hindlimb vs. forelimb group. Turtles given tramadol in the hind‐ and forelimb showed a significant increase in TWL over the periods of 0.5–48 and 8–48 h, respectively. The calculated % maximal possible response (% MPR) was low (about 24%). The PK/PD correlations between M1 plasma concentrations vs. % MPR appeared to show a counterclockwise hysteresis loop shape.     

Pharmacokinetics and efficacy of intravenous and extradural tramadol in dogs

Tramadol is a synthetic opioid agonist used extensively in human and, to a lesser extent, veterinary medicine throughout the world. The clinical efficacy and pharmacokinetic profile of intravenous (IV) and extradural (ED) tramadol (2 mg/kg) and its o-desmethyl metabolite were studied in dogs undergoing tibial plateau levelling osteotomy (TPLO). Intra-operative cardiorespiratory variables were monitored and post-operative pain was assessed using the short form of the Glasgow Composite Pain Scale. A rapid (<5 min) and effective production of o-desmethyl tramadol was recorded. The pharmacokinetic profile was similar for tramadol and its metabolite irrespective of the route of administration. ED tramadol provided sufficient intra- and post-operative analgesia without significant clinical side-effects, but the post-operative analgesia was comparable to that following IV administration and the ED route could therefore not be considered a practical alternative to the IV route.     

Genetic structure and recent population demographic history of Taihangshan macaque (Macaca mulatta tcheliensis), North China

Massive actions have been and are being taken into protecting the world's primates from extinction, while the study of the properties of genetic diversity, demographic history, and ecological relationships will benefit the understanding of the long-term survival of a species. The Taihangshan macaque (Macaca mulatta tcheliensis), a subspecies of rhesus macaque (Macaca mulatta), is endemic to China and currently restricted to southern Mt. Taihangshan area. Herein, we evaluated the genetic diversity, population structure, and demographic history of this subspecies using mitochondrial (Cytb and high variable region I: HVR I) and nuclear markers (microsatellite loci) of 131 individuals collected from 9 localities covering the distribution range of this subspecies. Both phylogenetic analyses and genetic assignment revealed that the wild populations of Taihangshan macaques could be divided into 2 major highly divergent clades, THS-east and THS-west. Low genetic diversity (π: 0.00266 ± 0.00016) but high haplotype diversity (H_d: 0.80352 ± 0.015) were detected in the Taihangshan macaques, particularly in THS-east. Analyses of demographic history suggested that the Taihangshan macaques experienced first a stable historical population size from Holocene to early 19th century but a subtle decline and then slight growth in the recent 200 years. We suggest that bridging the neighbor populations (i.e. setting corridors) would facilitate the male-mediated gene flow and subsequently increase the genetic diversity of the Taihangshan macaque populations.     

Evaluation of the predictive performance of a pharmacokinetic model for propofol in Japanese macaques (Macaca fuscata fuscata)

Miyabe‐Nishiwaki, T., Masui, K., Kaneko, A., Nishiwaki, K., Nishio, T., Kanazawa, H. Evaluation of the predictive performance of a pharmacokinetic model for propofol in Japanese macaques (Macaca fuscata fuscata). J. vet. Pharmacol. Therap.  36 , 169–173. Propofol is a short‐acting intravenous anesthetic used for induction/maintenance anesthesia. The objective of this study was to assess a population pharmacokinetic (PPK) model for Japanese macaques during a step‐down infusion of propofol. Five male Japanese macaques were immobilized with ketamine (10 mg/kg) and atropine (0.02 mg/kg). A bolus dose of propofol (5 mg/kg) was administrated intravenously (360 mg/kg/h) followed by step‐down infusion at 40 mg/kg/h for 10 min, 20 mg/kg/h for 10 min, and then 15 mg/kg/h for 100 min. Venous blood samples were repeatedly collected following the administration. The plasma concentration of propofol (Cp) was measured by high‐speed LC‐FL. PPK analyses were performed using NONMEM VII. Median absolute prediction error and median prediction error (MDPE), the indices of prediction inaccuracy and bias, respectively, were calculated, and PE ? individual MDPE vs. time was depicted to show the variability of prediction errors. In addition, we developed another population pharmacokinetic model using previous and current datasets. The previous PK model achieved stable prediction of propofol Cp throughout the study period, although it underestimates Cp. The step‐down infusion regimen described in this study would be feasible in macaques during noninvasive procedures.     

Pharmacokinetics and pharmacodynamics of tramadol in horses following oral administration

Tramadol is a synthetic opioid used in human medicine, and to a lesser extent in veterinary medicine, for the treatment of both acute and chronic pain. In humans, the analgesic effects are owing to the actions of both the parent compound and an active metabolite (M1). The goal of the current study was to extend current knowledge of the pharmacokinetics of tramadol and M1 following oral administration of three doses of tramadol to horses. A total of nine healthy adult horses received a single oral administration of 3, 6, and 9 mg/kg of tramadol via nasogastric tube. Blood samples were collected at time 0 and at various times up to 96 h after drug administration. Urine samples were collected until 120 h after administration. Plasma and urine samples were analyzed using liquid chromatography–mass spectrometry, and the resulting data analyzed using noncompartmental analysis. For the 3, 6, and 9 mg/kg dose groups, C_max, T_max, and the t_1/2λ were 43.1, 90.7, and 218 ng/mL, 0.750, 2.0, and 1.5 h and 2.14, 2.25, and 2.39 h, respectively. While tramadol and M1 plasma concentrations within the analgesic range for humans were attained in the 3 and 6 mg/kg dose group, these concentrations were at the lower end of the analgesic range and were only transiently maintained. Furthermore, until effective analgesic plasma concentrations have been established in horses, tramadol should be cautiously recommended for control of pain in horses. No significant undesirable behavioral or physiologic effects were noted at any of the doses administered.     

Computed tomography is a feasible method for quantifying bone density in Macaca mulatta

Osteopathologies are a result of advanced age and decreased bone density and represent a global health problem. It is therefore important to generate models for longitudinal studies of the pathophysiology in order to improve early diagnosis and develop preventive therapies. For this kind of research, the use of computed tomography (CT) to evaluate bone health offers advantages over other techniques since it provides more complete information. The aim of this prospective, pilot study was to obtain measurements of the left femur from a population in captivity of 32 rhesus monkeys (Macaca mulatta) in order to standardize the model for future research. Healthy subjects from 5 to 28 years old were chosen. Three groups with different ages were formed as follows: (1) 5–9 years, (2) 10–19 years, and (3) 20–28 years. Semi‐automatic segmentation by threshold defined the regions of interest, which were subdivided in the range of 300–700 Hounsfield units (HU) for trabecular bone and >700 HU for cortical bone. Then, the proportional ratios of the volumes of trabecular bone and cortical bone were obtained. Significant differences (analysis of variance test) in the averages of Hounsfield units, cortical, and trabecular bone proportions from each age group proved that a decrease in bone density begins at approximately 20 years of age. The values presented here, as well as the method to obtain them from CT scans, can be used as a baseline in a primate model for long‐term research in bone pathology diagnosis and treatment.     

Pharmacokinetics of a controlled‐release liposome‐encapsulated hydromorphone administered to healthy dogs

The purpose of the study was to assess the pharmacokinetics of liposome‐encapsulated (DPPC‐C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14–28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC‐C formulation (half‐life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half‐life of hydromorphone after SC administration of DPPC‐C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C_MAX/D) ranged between 19.41–24.96 ng/mL occurring at 0.18–0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6–72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC‐C hydromorphone. Liposome‐encapsulated hydromorphone (DPPC‐C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.     

Isolation and identification of a South China strain of Plasmodium inui from Macaca fascicularis

Southeast Asian macaques are hosts of a number of Plasmodium infections, some of which are transmittable to humans. During examination of blood films of five wild-caught long-tailed macaques Macaca fascicularis from South China, malaria infection was detected in one of the monkeys. In order to isolate this parasite for identification and characterization, we experimentally passed this parasite through both Assamese (M. assamensis) and rhesus (M. mulatta) monkeys by intravenous injection of infected blood. This parasite morphologically resembled Plasmodium inui, and had a typical 72 h quartan periodicity. This parasite was infective to Anopheles dirus mosquitoes, and salivary gland sporozoites appeared 13 days post feeding. Feeding by 20 infected An. dirus mosquitoes on another Assamese monkey produced infection with a prepatent period of 8 days. Molecular analysis of the small subunit rRNA genes and the mitochondrial genome confirmed this parasite as an isolate of P. inui. In spleen-intact macaques, the infection had a protracted duration with parasites being detected during the rearing of the infected monkeys for over two years. In summary, this study identified a P. inui isolate and successfully passed this parasite through Assamese monkeys by both intravenous inoculation and mosquito transmission.     

Pharmacokinetics of orally administered tramadol in Muscovy ducks (Cairina moschata domestica)

This study documents the pharmacokinetics of oral tramadol in Muscovy ducks. Six ducks received a single 30 mg/kg dose of tramadol, orally by stomach tube, with blood collection prior to and up to 24 hr after tramadol administration. Plasma tramadol, and metabolites O‐desmethyltramadol (M1), and N,O‐didesmethyltramadol (M5) concentrations were determined by high‐pressure liquid chromatography (HPLC) with fluorescence (FL) detection. Pharmacokinetic parameters were calculated using a one‐compartment model with first‐order input. No adverse effects were noted after oral administration. All ducks achieved plasma concentrations of tramadol above 0.10 μg/ml and maintained those concentrations for at least 12 hr. Elimination half‐life was 3.95 hr for tramadol in ducks, which is similar to other avian species. All ducks in this study produced the M1 metabolite and maintained plasma concentrations above 0.1 μg/ml for at least 24 hr.     

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady‐state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross‐over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one‐way anova ; P ≤ 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C_max was 14.4 ± 2.3 mcg/mL and elimination half‐life was 17.2 ± 3.6 h. After IV dosing, volume of distribution was 1.1 ± 0.25 L/kg, clearance was 58 ± 11 mL/h/kg and elimination t_1/2 was 12.9 ± 3.6 h. Oral bioavailability was 68 ± 12%; fraction of unbound drug approximated 60%. At steady‐state (4 days), differences occurred for for all parameters except C_max and C_min. Plasma C_max at steady‐state was 56 ± 12 mcg/mL, with 10% fluctuation between C_max and C_min. Plasma t_1/2 (h) was 23.52 ± 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 μg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.     

Hydatid Echinococcosis (Echinococcus granulosus) in a Laboratory Colony of Pig‐Tailed Macaques (Macaca nemestrina)

Several cases of hydatid echinococcosis were diagnosed in a laboratory colony of 19 pig‐tailed macaques (Macaca nemestrina) at the Paul Ehrlich Institute, Germany. Three hydatid cysts were found in the liver of an euthanized animal. The diagnosis of an Echinococcus granulosus infection was confirmed by histopathology and the results of a specific polymerase chain reaction. The serum of five of 14 other monkeys tested for Echinococcus antibodies using a genus‐specific enzyme‐linked immunosorbent assay (ELISA) was positive or weakly positive; none of the animals, however, showed specific reactions in an E. multilocularis‐specific ELISA. On ultrasonographic examination, alterations in the liver were found in four of the serologically positive monkeys, and two animals showed clinical signs such as progressive anorexia, apathy and icterus. The monkeys had most probably acquired the E. granulosus infection in their breeding colony in Slovenia.