Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT_1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.     

Compensatory Growth of Pond-reared Hybrid Striped Bass, Morone chrysops × Morone saxatilis, Fingerlings

Compensatory growth (CG) or “catch‐up growth” is a period of super‐accelerated growth following a period of suboptimal conditions (i.e., lack of prey availability or overwintering). Little is known about the CG response in pond‐raised fish and whether hybrid striped bass (HSB), Morone chrysops × Morone saxatilis, might exhibit the rapid growth states or improvements in other production characteristics that may accompany the response. To evaluate the potential for CG in HSB culture, a 16‐wk growth trial in twelve 0.1‐ha earthen ponds was conducted. Approximately 2850 fish (mean weight ± SD = 3.2 g ± 1.1) were stocked into ponds and subjected to one of four cyclic feeding regimens. Treatment regimens included a control (0 wk, fed twice daily to apparent satiation) and cycles of 1, 2, or 4 wk of feed deprivation, followed by 1, 2, or 4 wk of feeding to apparent satiation. Fish in the 4‐wk feeding regimen were offered feed twice during the feed‐deprivation period (once every other week). Growth, specific growth rate (SGR), hepatosomatic index (HSI), intraperitoneal fat ratio, and condition factor (CF) were measured every other week, while overall growth, feed efficiency (FE) (FE = [weight gain/feed fed] × 100), and survival were calculated at the trial termination. The effect of these feeding regimens on water quality was examined by monitoring pH, turbidity, total ammonia nitrogen, nitrite–nitrogen, nitrate–nitrogen, soluble reactive phosphorus, and chlorophyll a weekly; total nitrogen and phosphorous biweekly; and dissolved oxygen and temperature twice daily. Cyclic feeding elicited CG; fish subjected to the 2‐wk regimen had a significantly higher SGR than 0‐wk controls during all but the final refeeding period. FE was higher for all fish in the cyclic regimens, although only FE for fish in the 2‐wk regimen was statistically greater (40%) than the controls. HSI was the most responsive measure and significantly decreased in the 2‐ and 4‐wk treatments during feed‐deprivation period and overcompensated during the refeeding period. CF also varied with feeding cycle and proved to be an effective nonlethal measure of predicting a CG response. No statistical differences in water quality parameters were observed. These data suggest that CG can be effectively induced in pond‐raised HSB and that the increase in FE warrants further research for practical application. Future pond studies with fingerling HSB fish should be conducted with emphasis on feed‐deprivation periods of 2 wk and refeeding periods of at least twice that of the feed‐deprivation period.     

Remedies for pseudoreplication

Pseudoreplication is the failure of a statistical analysis to properly incorporate the true structure of randomness present in the data. It has been well documented and studied in the ecological literature but has received little attention in the fisheries literature. Avoiding pseudoreplication in analyses of fisheries data can be difficult due to the complexity of the statistical procedures required. However, recent developments in statistical methodology are decreasing the extent to which pseudoreplication has to be tolerated. Seven examples are given here, beginning with simple design-based remedies and progressing to more challenging examples including the model-based remedies of mixed-effects modelling, generalized linear mixed models, state-space models, and geostatistics.     

Multifactorial resistance to transpermethrin in field-collected strains of the tobacco budworm Heliothis virescens F.

The penetration, degradation and excretion of [³H]transpermethrin were examined in susceptible and field-collected pyrethroid-resistant strains of the tobacco budworm Heliothis virescens. No consistent differences in labelled materials excreted or recovered in cuticle rinses were found between the resistant (R) and susceptible (S) larvae. Considerably lower levels of the parent compound were present internally in R compared with S larvae after 24h (P <0.01), clearly identifying a metabolic resistance mechanism in Meloland and Westmorland larvae. Moderate levels of absorbed permethrin accompanied by an absence of poisoning symptoms were observed in certain individuals of both R strains, suggesting a second resistance mechanism. Neurobioassays of R larvae showed a consistently lower sensitivity of the neuromuscular system to pyrethroids when compared with the S larvae, thus confirming the indication from metabolic studies of the additional (site-insensitive) mechanism. Toxicity values suggest a cross-resistance to other pyrethroids.     

Effects of stage of lactation, month, age, origin and heart girth on lameness in dairy cattle

Lameness in herds during one year was commonest in the first month of lactation (15 per cent of all cases). Leg lesions were particularly common at this time (24 per cent of all cases of leg lesions) but white line abscess and sole ulcer were more common a month later. Foul-in-the-foot was one of the two most common lesions at all stages of pregnancy and lactation, and white line abscess the most common (20 per cent of all lesions) in late lactation. Both sole ulcer and underrun heel had lower incidence in the second half of the year than the first. White line abscess was particularly common in March and November although there were significant interactions between month and veterinary practice; foul-in-the-foot was most common in October. Susceptibility to lameness increased with age; 10-year-old cows were over four times more likely to develop lameness than three-year-old cows. This was due particularly to increased incidence with age of white line abscess and sole ulcer and, to a lesser extent, underrun heel. In contrast, foul-in-the-foot and leg lesions showed little change with age. Whereas these lesions accounted for 68 per cent of the total in cows up to two years old, they accounted for only 15 per cent of all lesions in cows over 10 years old. White line abscess was slightly commoner in cows with large heart girths.     

Evaluation of Canine Red Blood Cells Stored in a Saline, Adenine, and Glucose Solution for 35 Days

An additive solution for the storage of red blood cells was evaluated for use in dogs. Blood collected from 6 dogs was processed into packed red blood cells and stored for 35 days in the additive solution Nutricel (Miles, Inc, Pharmaceutical Division, West Haven, CT). Packed red blood cells stored in citrate-phosphate-dextrose-adenine (CPDA-1; Fenwal Laboratories, Baxter Health Care Corp, Deerfield, IL) also were evaluated for comparison. Red blood cell 2,3-diphosphoglycerate (2,3-DPG) concentration, adenosine triphosphate (ATP) concentration, percentage hemolysis, and pH were determined. The red blood cell post-transfusion viability (PTV) after 35 days of storage was assessed with both single-labeled chromium 51 (⁵¹Cr) and double-labeled technetium 99m/chromium 51 (^99mTc/⁵¹Cr) techniques. Mean ATP concentration and percentage hemolysis of the cells stored in Nutricel were 1.1 μmol/g hemoglobin (Hb) and 0.28% respectively and did not differ significantly (P < .05) from the values of 1.0 μmol/g Hb and 0.33% from the CPDA-1-stored red blood cells. The mean pH of red blood cells stored in Nutricel was 6.19, which was significantly lower than the pH of 6.47 for cells stored in CPDA-1. The mean 2,3-DPG concentration of red blood cells stored in Nutricel was significantly higher at 10.1 μmol/g Hb than the 2,3-DPG concentration of 3.4μmol/g Hb for cells stored in CPDA-1. The mean PTV of canine red blood cells stored in Nutricel for 35 days was 85% with ⁵¹Cr and 90% with ^99mTc/⁵¹Cr. This was significantly higher than the mean PTVs of 38% and 36% for the CPDA-1 stored cells as assessed with ⁵¹Cr and ^99mTc/⁵¹Cr techniques, respectively. It was concluded that 35-day-old canine red blood cells stored in Nutricel are of acceptable quality for transfusion purposes.     

Treatment in the field of 27 horses with epiglottic entrapment

Twenty-seven horses were treated for epiglottic entrapment by using an oral, hand-assisted bistoury knife technique, under general anaesthesia; 26 of them returned successfully to racing, but one developed a permanently displaced soft palate. After the surgery 13 of the horses had an increased handicap rating and 13 had a decreased rating.