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.     

Excavating sponges that are destructive to farmed pearl oysters in Western and Northern Australia

Species of the family Clionaidae (Porifera: Demospongiae) that excavate shell of the silver‐lip pearl oyster, Pinctada maxima, in north Western and Northern Australia are described. Two species belong to the genus Cliona and one species to the closely related genus Pione. Cliona orientalis has only recently been reported from Australia in living and dead coral on the Great Barrier Reef, and this is the first report of this species from north Western and Northern Australia. Cliona dissimilis is reported from Australia for the first time. Pione velans was first described from Shark Bay, Western Australia and this study extends its distribution from Albany, south Western Australia to Port Bremer in the Northern Territory. The most common species found was C. dissimilis. Pione velans and C. orientalis were also present, although the latter species was rare. Cliona dissimilis and P. velans were found to be sexually reproductive in some shells with specimens of C. dissimilis with oocytes in May and P. velans in September 1999. Egg development was synchronous, indicating that the sponges were oviparous and would broadcast gametes in a spawning event.