Thalidomide pharmacokinetics in sheep

AIM: To determine the half life (T_1/2), time taken to reach maximum plasma concentration (T_max) and maximum plasma concentration (C_max) of thalidomide in sheep following I/V, oral and topical treatment with a single dose of thalidomide.

METHOD: Three groups of 4–6-month-old ram lambs were treated with thalidomide dissolved in dimethylsulphoxide (DMSO). The first group (n=10) was treated I/V with 100?mg thalidomide in 2?mL DMSO; the second group (n=8) received 400?mg thalidomide in 2?mL DMSO orally, and the third group (n=8) had 400?mg thalidomide in 4?mL DMSO applied topically. Plasma samples were collected up to 36 hours after treatment, snap-frozen at ?80°C and analysed for concentrations of thalidomide using high performance liquid chromatography.

RESULTS: Following I/V administration, T_1/2 was 5.0 (SEM 0.4) hours, volume of distribution was 3,372.0 (SEM 244.3) mL/kg and clearance was 487.1 (SEM 46.1) mL/hour.kg. Topical application of 400?mg thalidomide did not increase plasma concentrations. Following oral administration, thalidomide bioavailability was 89%, with T_1/2, T_max, and C_max being 7.2 (SEM 0.8) hours, 3.0 (SEM 0.4) hours and 1,767.3 (SEM 178.1) ng/mL, respectively.

CONCLUSION: Topical administration using DMSO as a solvent did not increase concentrations of thalidomide in plasma. The mean pharmacokinetic parameters determined following oral treatment with 400?mg of thalidomide were similar to those reported in humans receiving a single 400?mg oral dose (T_1/2 7.3 hours; T_max 4.3 hours and C_max 2,820?ng/mL). There is potential for thalidomide to be used as a model for the treatment of chronic inflammatory conditions in sheep, such as Johne's disease, where tumour necrosis factor alpha plays a pathogenic role.     

Bilateral Sertoli and Interstitial Cell Tumours in Abdominal Testes of a Goat with Polled Intersex Syndrome (PIS)

An 8‐year‐old, mixed breed, polled goat was presented for evaluation of male‐like behaviour. Clinical findings included clitoromegaly, a heavily muscled neck, pronounced beard, and erect dorsal guard hairs, which are phenotypic characteristics commonly observed in intersex animals. Transrectal ultrasonography revealed the presence of two abdominal masses caudolateral to the uterine horns. Serum concentration of estradiol was elevated. Genetic evaluation was compatible with polled intersex syndrome defined by an XX karyotype without a Y chromosome or SRY gene. Based on gross and histologic evaluation, the abdominal masses were determined to be intra‐abdominal testes, each of which was effaced by Sertoli cell and interstitial (Leydig) cell tumours. The Sertoli cell tumours (SCTs) represented two unique histologic patterns. Regardless of pattern, neoplastic Sertoli cells were consistently lipid laden and positive for vimentin. Interstitial cell tumours (ICTs) were negative for vimentin. Clinical and histopathologic findings suggest that prolonged exposure to steroids secreted by neoplastic Sertoli cells contributed to virilization. In addition, results from immunohistochemistry indicated that vimentin may be a valuable immunodiagnostic tool for differentiation between interstitial and Sertoli cell tumours in goats.     

Dermatoses caused by infestations of immature Ixodes spp. on dogs and cats in Sydney, Australia

Infestations of larval and nymphal Ixodes spp. were identified in 16 dogs and 16 cats from several small animal clinics in Sydney. Cases occurred in late summer or autumn, peaking in February, and were seasonally recurrent in some individuals. Clinical signs of infestation included a papular dermatitis and irritation or pruritus that ranged from severe to mild or absent. The distribution of tick attachment tended to be cranial and ventral, with the face, legs, axillae and ventrum the most commonly affected sites. The estimated number of ticks in each infestation varied from less than 10 to more than 100. Basic morphological examination of ticks collected from affected animals was performed by attending veterinarians using light microscopy, and larvae and nymphs belonging to the Ixodes genus were identified. Ticks collected from 17 animals and submitted to the Department of Medical Entomology, Westmead Hospital were putatively identified as I. trichosuri (57%) and I. holocyclus (25%) larvae. Histopathological samples of attachment sites collected from three dogs and one cat were characterised by ticks attached in well-demarcated invaginations of the skin ('tick craters') associated with variable epidermal and/or dermal necrosis, focal eosinophilic intraspinous pustules, mild to marked eosinophilic and neutrophilic, superficial to deep, dermal perivascular to interstitial inflammation, and moderate to marked superficial dermal oedema and red cell extravasation. A range of topical acaricidal preparations, including fipronil and synthetic pyrethroids, were used for treatment.     

Oscillatory dynamics of Cdc42 GTPase in the control of polarized growth

Cells promote polarized growth by activation of Rho-family protein Cdc42 at the cell membrane. We combined experiments and modeling to study bipolar growth initiation in fission yeast. Concentrations of a fluorescent marker for active Cdc42, Cdc42 protein, Cdc42-activator Scd1, and scaffold protein Scd2 exhibited anticorrelated fluctuations and oscillations with a 5-minute average period at polarized cell tips. These dynamics indicate competition for active Cdc42 or its regulators and the presence of positive and delayed negative feedbacks. Cdc42 oscillations and spatial distribution were sensitive to the amounts of Cdc42-activator Gef1 and to the activity of Cdc42-dependent kinase Pak1, a negative regulator. Feedbacks regulating Cdc42 oscillations and spatial self-organization appear to provide a flexible mechanism for fission yeast cells to explore polarization states and to control their morphology.     

Partially Molten Middle Crust Beneath Southern Tibet: Synthesis of Project INDEPTH Results

INDEPTH geophysical and geological observations imply that a partially molten midcrustal layer exists beneath southern Tibet. This partially molten layer has been produced by crustal thickening and behaves as a fluid on the time scale of Himalayan deformation. It is confined on the south by the structurally imbricated Indian crust underlying the Tethyan and High Himalaya and is underlain, apparently, by a stiff Indian mantle lid. The results suggest that during Neogene time the underthrusting Indian crust has acted as a plunger, displacing the molten middle crust to the north while at the same time contributing to this layer by melting and ductile flow. Viewed broadly, the Neogene evolution of the Himalaya is essentially a record of the southward extrusion of the partially molten middle crust underlying southern Tibet.     

A comparison of two different ketamine and diazepam combinations with an alphaxalone and medetomidine combination for induction of anaesthesia in sheep

Abstract

AIMS: To investigate the perceived adverse effects of a particular batch of ketamine during induction of anaesthesia in sheep and to assess if any adverse effects would make intubation more difficult for the veterinary students.

METHODS: Thirty adult sheep (mean bodyweight 74.5 (SD 9.4) kg) were randomly assigned to one of six groups of five sheep. Sheep in Groups A and B received I/V 0.5 mg/kg diazepam and 10 mg/kg ketamine (Ketamine Injection; Parnell Laboratories NZ Ltd, of the suspect batch); those in Groups C and D received I/V 0.5 mg/kg diazepam and 10 mg/kg ketamine (Ketalar; Hospira NZ Ltd.), and those in Groups E and F received I/V 2 μg/kg medetomidine and 2 mg/kg alphaxalone. In Groups A, C and E, intubation was by an experienced anaesthetist, and in Groups B, D and F intubation was by a veterinary student. Time from injection to successful intubation, the ease of intubation, saturation of haemoglobin with oxygen (SpO₂) and partial pressure of oxygen in arterial blood (PaO₂) were measured before the sheep were connected to an anaesthetic machine and allowed to breath oxygen. Times to extubation, holding its head up and standing, maximum and minimum heart rates, respiratory rates, maximal end tidal CO₂, and the quality of recovery were then recorded.

RESULTS: There were no measurable differences in outcomes between sheep in Groups A and B compared with C and D. Time to intubation was slightly shorter for the experienced anaesthetist than the student, but the difference was not significant. The sheep in Groups E and F took less time to recover than those in Groups A?D (p<0.05), but there were no significant differences between the groups in either the ease of induction or quality of recovery. Most sheep in Groups E and F showed minor excitatory effects, mainly at induction, which did not interfere with induction. Respiratory rates were lower in Groups E and F than Groups A?D (p<0.01), but SpO₂ was higher in Groups E and F than A and B (p<0.05).

CONCLUSIONS: The clinical impression that the batch of Parnell ketamine produced unexpected effects was shown to be incorrect. All the combinations produced anaesthesia that allowed intubation by the veterinary student.

CLINICAL RELEVANCE: All the drug combinations produced satisfactory anaesthesia in sheep, but the alphaxaloneand medetomidine combination resulted in faster recovery.