Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fuscata fuscata). [corrected

ObjectiveTo describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model.Study designProspective experimental trial.AnimalsFour male macaques (5-6 years old, 8.0-11.2 kg).MethodsThe macaque was restrained and 8 mg kg^?1 of propofol was administrated intravenously at 6 mg kg^?1 minute^?1. Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI.ResultsMacaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5) minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute^?1 and 72-144 beats minute^?1, respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V₁ = 10.4 L, V₂=8.38 L, V₃=72.7 L, CL₁= 0.442 L minute^?1, CL₂= 1.14 L minute^?1, CL₃= 0.313 L minute^?1, (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively).ConclusionsIntravenous administration of propofol (8 mg kg^?1) at 6 mg kg^?1 minute^?1 to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours.Clinical relevanceThe developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.     

Effects of buprenorphine,butorphanol or tramadol premedication on anaesthetic induction with alfaxalone in common marmosets (Callithrix jacchus)

Objective

To investigate the clinical and physiological effects of intravenous (IV) alfaxalone alone or in combination with buprenorphine, butorphanol or tramadol premedication in marmosets.

Pharmacokinetics and pharmacodynamic effects in koi carp (Cyprinus carpio) following immersion in propofol

Objective

To test the hypothesis that plasma propofol concentration (PPC) is associated with anesthetic effect in koi carp administered propofol by immersion.

Congenital malformation of the vaginal orifice,imperforate vagina,in the common marmoset (Callithrix jacchus)

The following is a report on a congenital vaginal malformation, imperforate vagina, in the common marmoset (Callithrix jacchus). This anomaly was observed for the first time in an adult female in our research colony. There was no uterine and vaginal aplasia or atresia in her grossly normal genital tract. The plasma progesterone concentration suggested that the ovarian cycle had ceased. However, this may not be related to a functional anomaly, but rather to suppressed ovulation resulting from subordination to cagemates considering the various stages of follicular development observed.     

Fatal Herpes simplex infection in a group of common marmosets (Callithrix jacchus)

An outbreak of classical herpetic infection causing vesicoulcerative stomatitis in a family group (eight animals) of Callithrix jacchus is described. In all eight infected animals, human herpesvirus 1 (HHV-1) was identified as the causative agent. This was confirmed by histologic, immunohistologic, and molecular biologic investigations, as well as by virus isolation. The clinical picture, the macroscopic appearance, and the histologic results indicated a herpes infection as the cause of mortality. Alterations of the oral mucous membranes were erosive to ulcerative with typical intranuclear inclusions. Immunohistologic and molecular biologic techniques clearly identified the HHV-1 virus and excluded other possible primate herpesviruses such as B-virus, SA8, HVP-2, and Herpes tamarinus. The significance of this herpesvirus infection for colony management is discussed.     

Fatal lymphoproliferative disease in a common marmoset (Callithrix jacchus) following inoculation of Ag876 strain of Epstein-Barr virus and a tumor-promoting agent: Preliminary report

We report here the development of a fatal lymphoproliferative disease in a common marmoset (Callithrix jacchus) following inoculation of the Ag876 strain of Epstein-Barr virus (EBV) and of the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). The marmoset showed antibodies against EBV capsid and early antigens (VCA, EA) but not against nuclear antigen (EBNA). EBNA was detected in impression smears from lymph nodes and liver, and the presence of the EBV genome was detected from the same organs by hydridization techniques. To our knowledge this is the first report of the oncogenicity of this strain of EBV. The need for further studies to assess the in vivo interaction between EBV and tumor promoting agents in the development of malignancies is stressed.     

Spontaneous Malignant T Cell Lymphoma in a Young Male Common Marmoset (Callithrix jacchus)

We histopathologically and immunohistochemically investigated a case of malignant lymphoma that spontaneously developed in a male common marmoset at two years of age. Beginning at two years four months of age, the animal had an enlargement of the submandibular and inguinal lymph nodes, small subcutaneous nodules near the right breast and an approximately fivefold increase in peripheral lymphocyte count compared with the previous examination value. The postmortem findings at two years eight months of age showed lymphadenopathy with enlargement of the thymus and spleen. Small- to intermediate-sized neoplastic lymphocytes had diffusely proliferated in the enlarged nodes. The neoplastic cells were pleomorphic and had irregularly shaped nuclei. The nuclear chromatin staining revealed hyperchromatism in the small-sized cells, and the intermediate-sized cells exhibited vesicular staining. An immunohistochemical examination indicated that the neoplastic lymphocytes were positive for CD3 and negative for CD20, thus suggesting that they had originated from T cells. In addition, the proliferation of high endothelial venules and reactive epithelioid histiocytes was observed. Scattered tingible body-laden macrophages were infrequently detected. Neoplastic lymphocytes were also observed in the thymus, spleen, heart, lungs, liver, kidneys, adrenal glands and femoral and sternal bone marrow. This malignant lymphoma in a young male common marmoset was considered to fit the category of “peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)” according to the new WHO system of classification.     

Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats

ObjectiveTo compare the pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol administered intravenously (IV) as a single induction dose in cats.Study designProspective experimental study.AnimalsSix healthy adult cats, three female intact, three male castrated, weighing 4.8 ± 1.8 kg.MethodsCats received 8 mg kg⁻¹ IV of propofol (P) or propofol with 2% benzyl alcohol (P28) using a randomized crossover design. Venous blood samples were collected at predetermined time points to 24 hours after drug administration to determine drug plasma concentrations. Physiologic and behavioral variables were also recorded. Propofol and benzyl alcohol concentrations were determined using high pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were described using a 2-compartment model. Pharmacokinetic and pharmacodynamic parameters were analyzed using repeated measures anova (p < 0.05).ResultsPlasma concentrations of benzyl alcohol were below the lower limits of quantification (LLOQ) at all time points for two of the six cats (33%), and by 30 minutes for the remaining four cats. Propofol pharmacokinetics, with or without 2% benzyl alcohol, were characterized by rapid distribution, a long elimination phase, and a large volume of distribution. No differences were noted between treatments with the exception of clearance from the second compartment (CLD2), which was 23.6 and 38.8 mL kg⁻¹ minute⁻¹ in the P and P28 treatments, respectively. Physiologic and behavioral variables were not different between treatments with the exception of heart rate at 4 hours post administration.Conclusions and clinical relevanceThe addition of 2% benzyl alcohol as a preservative minimally altered the pharmacokinetics and pharmacodynamics of propofol 1% emulsion when administered as a single IV bolus in this group of cats. These data support the cautious use of propofol with 2% benzyl alcohol for induction of anesthesia in healthy cats.     

A case of nontraumatic gas gangrene in a common marmoset (Callithrix jacchus)

The common marmoset is widely used in neuroscience and regenerative medicine research. However, information concerning common marmoset disorders, particularly infectious diseases, is scarce. Here, we report a case of a female common marmoset that died suddenly due to gas gangrene. The animal presented with gaseous abdominal distention at postmortem, and Clostridium perfringens type A was isolated from several tissues. Vacuoles, a Gram-positive bacteremia and intravascular hemolysis were observed microscopically in the muscles, liver and lungs. On the basis of these findings, we diagnosed nontraumatic gas gangrene caused by Clostridium perfringens type A in this common marmoset.     

Plasma vitamins A and E and hydrogen peroxide-induced in vitro erythrocyte haemolysis in common marmosets (Callithrix jacchus)

Plasma total lipid, cholesterol, all-trans retinol (vitamin A) and alpha-tocopherol (vitamin E) concentrations, and the susceptibility of erythrocytes to hydrogen peroxide-induced haemolysis in vitro were investigated in healthy laboratory-bred common marmosets (Callithrix jacchus). The concentrations of alpha-tocopherol and total cholesterol were similar to those of control human subjects. The mean lipid concentration was higher (P less than 0.025) and the retinol concentration lower (P less than 0.001) in the marmosets. The susceptibility of the erythrocytes of the marmosets to hydrogen peroxide-induced haemolysis was high, both in absolute value and relative to the controls. Changes in phospholipid and fatty acid composition might have rendered the red cells susceptible to oxidative stress.     

Pharmacokinetics of ceftiofur sodium in cats following a single intravenous and subcutaneous injection

Ceftiofur, a third‐generation cephalosporin antibiotic, is being extensively used by pet doctors in China. In the current study, the detection method was developed for ceftiofur and its metabolites, desfuroylceftiofur (DCE) and desfuroylceftiofur conjugates (DCEC), in feline plasma. Then, the pharmacokinetics studies were performed following one single intravenous and subcutaneous injection of ceftiofur sodium in cats both at 5 mg/kg body weight (BW) (calculated as pure ceftiofur). Ceftiofur, DCE, and DCEC were extracted from plasma samples, then derivatized and further quantified by high‐performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetics parameters. The terminal half‐life (t_1/2λz) was calculated as 11.29 ± 1.09 and 10.69 ± 1.31 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady‐state (V_SS) were determined as 14.14 ± 1.09 ml hr^‐1 kg^‐1 and 241.71 ± 22.40 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 14.99 ± 2.29 μg/ml) was observed at 4.17 ± 0.41 hr, and the absorption half‐life (t_1/2ka) and absolute bioavailability (F) were calculated as 2.83 ± 0.46 hr and 82.95%±9.59%, respectively. The pharmacokinetic profiles of ceftiofur sodium and its related metabolites demonstrated their relatively slow, however, good absorption after subcutaneous administration, poor distribution, and slow elimination in cats. Based on the time of drug concentration above the minimum inhibitory concentration (MIC) (T>MIC) calculated in the current study, an intravenous or subcutaneous dose at 5 mg/kg BW of ceftiofur sodium once daily is predicted to be effective for treating feline bacteria with a MIC value of ≤4.0 μg/ml.     

Natural occurrence of amyloid-Abeta deposits in the brain of young common marmosets (Callithrix jacchus): a morphological and immunohistochemical evaluation

The spontaneous incidence and distribution of beta-amyloid (Abeta) peptide and argyrophilic deposits were extensively investigated in the common marmoset (Callithrix jacchus). In 12 young marmosets, up to 67 coronal step sections were evaluated in the brain. One brain hemisphere was stained by a silver method and also immunohistochemically with a primary antibody directed against Abeta. Argyrophilic deposits were observed in 4 (33%) of 12 animals with silver stain, and Abeta was seen in 4 (33%) of 12 animals with anti-4G8 antibody. The overall incidence was 6 (50%) of 12 affected animals. These results show that the young marmoset brain displays Abeta deposits at a low incidence and that immunohistochemistry is more suitable than silver staining to reveal rare amyloid plaques. These findings also provide evidence for the early onset of amyloid deposits in marmoset brain.     

The effect of preanaesthetic oral trazodone hydrochloride on the induction dose of propofol: a preliminary retrospective study

ObjectiveTo determine whether the administration of trazodone to dogs 2 hours prior to radiotherapy treatment reduced the dose of propofol required to induce anaesthesia.Study designRetrospective, crossover, case-matched study.AnimalsRecords of 30 client-owned dogs.MethodsAnaesthetic records from all dogs undergoing weekly radiotherapy treatment between January 2020 and December 2020 were retrospectively assessed. All dogs were premedicated with 10 μg kg^–1 alfentanil and 12 μg kg^–1 atropine intravenously (IV) and anaesthesia was induced with IV propofol. In part 1, the propofol induction dose was compared between anaesthetics when trazodone was administered prior to the anaesthetic (T) versus not (NT). For part 2, control dogs not administered trazodone during the treatment course were case-matched based on bodyweight and tumour location and type. The propofol induction dose was compared between the first (C1) and last (C2) anaesthetic to identify the effects of confounding factors. A Wilcoxon signed-rank test for repeated measurements was performed to identify any significant differences in the propofol induction dose between NT and T in the study dogs and between C1 and C2 in the control dogs.ResultsIn part 1, 15 study dogs that were administered trazodone prior to at least one anaesthetic were identified. A significant difference in propofol induction dose between groups NT and T was identified [3.3 (2.1–7.4) and 2.0 (1.5–5.0) mg kg^–1, respectively; p = 0.003]. In part 2, 15 dogs were case-matched to the study cohort. The dose of propofol administered did not differ between the first and last anaesthetic [2.5 (1.6–6.4) and 2.6 (1.9–8.9) mg kg^–1, respectively; p = 0.638].Conclusions and clinical relevancePreanaesthetic trazodone administration reduced the induction dose of propofol compared to when it was not administered to dogs following premedication with IV atropine and alfentanil.     

Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection

The present study aimed to determine the pharmacokinetic profiles of ceftiofur (as measured by ceftiofur and its active metabolites concentrations) in a small-size dog breed, Peekapoo, following a single intravenous or subcutaneous injection of ceftiofur sodium. The study population comprised of five clinically healthy Peekapoo dogs with an average body weight (BW) of 3.4 kg. Each dog received either intravenous or subcutaneous injection, both at 5 mg/kg BW (calculated as pure ceftiofur). Plasma samples were collected at different time points after the administration. Ceftiofur and its active metabolites were extracted from plasma samples, derivatized, and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetic parameters. The terminal half-life (t_1/2λz) was calculated as 7.40 ± 0.79 and 7.91 ± 1.53 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (V_SS) were determined as 39.91 ± 4.04 ml hr⁻¹ kg⁻¹ and 345.71 ± 28.66 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 10.50 ± 0.22 μg/ml) was observed at 3.2 ± 1.1 hr, and the absorption half-life (t_1/2ka) and absolute bioavailability (F) were calculated as 0.74 ± 0.23 hr and 91.70%±7.34%, respectively. The pharmacokinetic profiles of ceftiofur and its related metabolites demonstrated their quick and excellent absorption after subcutaneous administration, in addition to poor distribution and slow elimination in Peekapoo dogs. Based on the time of concentration above minimum inhibitory concentration (T > MIC) values calculated here, an intravenous or subcutaneous dose at 5 mg/kg of ceftiofur sodium once every 12 hr is predicted to be effective for treating canine bacteria with a MIC value of ≤4.0 μg/ml.     

A case of intestinal mucormycosis in a common marmoset (Callithrix jacchus)

A 3-year-old female common marmoset was euthanatized because of wasting. Grossly, a perforating lesion was present in the jejunum and hemorrhagic lesions in the cecum and colon. Histopathologically, these gross lesions were a perforated jejunal ulcer and necrotizing colitis, respectively. Necrotizing colitis was characterized by extensive mucosal necrosis along with numerous ribbon-shaped aseptate hyphae. These aseptate hyaline hyphae were positively stained with PAS and GMS, and reacted immunohistochemically with the antibody against the family Mucoraceae. This case was diagnosed as intestinal mucormycosis. This is the first report on mucormycosis in a common marmoset.     

The effects of diazepam or midazolam on the dose of propofol required to induce anaesthesia in cats

ObjectivesAssess effects of benzodiazepine administration on the propofol dose required to induce anaesthesia in healthy cats, investigate differences between midazolam and diazepam, and determine an optimal benzodiazepine dose for co-induction.Study designProspective, randomised, blinded, placebo-controlled clinical trial.AnimalsNinety client-owned cats (ASA I and II) with a median (interquartile range) body mass of 4.0 (3.4–4.9) kg.MethodsAll cats received 0.01 mg kg⁻¹ acepromazine and 0.2 mg kg⁻¹ methadone intravenously (IV). Fifteen minutes later, sedation was scored on a scale of 1–5, with 5 indicating greatest sedation. Propofol, 2 mg kg⁻¹, administered IV, was followed by either midazolam or diazepam at 0.2, 0.3, 0.4 or 0.5 mg kg⁻¹ or saline 0.1 mL kg⁻¹. Further propofol was administered until endotracheal intubation was possible. Patient signalment, sedation score, propofol dosage and adverse reactions were recorded.ResultsMidazolam and diazepam (all doses) significantly reduced the propofol dose required compared with saline (p < 0.001). There was no difference between midazolam and diazepam in propofol dose reduction (p = 0.488). All individual doses of midazolam reduced propofol requirement compared with saline (0.2 mg kg⁻¹, p = 0.028; 0.3 mg kg⁻¹, p = 0.006; 0.4 mg kg⁻¹, p < 0.001; 0.5 mg kg⁻¹, p = 0.009). Diazepam 0.2 mg kg⁻¹ did not reduce the propofol dose compared with saline (p = 0.087), but the remaining doses did (0.3 mg kg⁻¹, p = 0.001; 0.4 mg kg⁻¹, p = 0.032; 0.5 mg kg⁻¹, p = 0.041). Cats with sedation scores of 3 required less propofol than cats with scores of 2 (p = 0.008). There was no difference between groups in adverse events.Conclusions and clinical relevanceMidazolam (0.2–0.5 mg kg⁻¹) and diazepam (0.3–0.5 mg kg⁻¹) administered IV after 2 mg kg⁻¹ propofol significantly reduced the propofol dose required for tracheal intubation.     

Serologic survey in a colony of captive common marmosets (Callithrix jacchus) after infection with herpes simplex type 1-like virus.

An outbreak of herpesvirus caused the death of four of five common marmosets (Callithrix jacchus) in a private colony. Gross lesions included acute ulcerative gingivitis, glossitis, and enlarged mandibular lymph nodes. Histologically, all fatal cases showed meningoencephalitis and eosinophilia with intranuclear inclusion bodies in neurons and glial cells. A herpes simplex-like virus was cultured from the brain and was identified as herpes simplex type 1 virus or a closely related virus by immunofluorescence. Serologic testing (complement fixation test) indicated that the surviving adult female was serologically positive for more than 4 yr and that the offspring she produced was seronegative. The most likely source of the outbreak was the owner who mouth fed hand-raised offspring.     

Oxalate nephropathy in a laboratory colony of common marmoset monkeys (Callithrix jacchus) following the ingestion of Eucalyptus viminalis

Seven common marmoset monkeys (Callithrix jacchus) from a laboratory colony of 17 died over a period of eight months. Death of six of these monkeys was attributed to kidney failure from an oxalate-induced nephropathy. The epidemiology of this outbreak suggested an exogenous source and there was strong evidence that the source was bark and leaves from an Eucalyptus viminalis tree. Branches of this tree were introduced one month before the first death. The branches were removed one month after deaths commenced, but deaths continued for another five months. Urinalysis of all surviving marmosets at 80 and 122 days after initial contact with the E viminalis branches suggested that these monkeys had renal impairment. In the cases described here, the eating behaviour of common marmosets apparently exposed the animals to toxic levels of oxalate in the bark and leaves of an E viminalis tree.