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.     

Morphological characterization and notes on the life cycle of a newly discovered variant of Loma salmonae (Putz, Hoffman & Dunbar) from a natural infection of chinook salmon, Oncorhynchus tshawytscha (Walbaum)

Two variants of Loma salmonae occur in net-pen reared chinook salmon, Oncorhynchus tshawytscha. The typical variant (OA) has a host specificity for salmonids of the genus Oncorhynchus whereas the atypical variant (SV) has a host specificity for brook trout, Salvelinus fontinalis, and in this study, the ultrastructure of the two are compared. In fish at 8 weeks post-exposure xenomas of the SV variant have a very high proportion of mature spores compared with other developmental stages, while in xenomas of the OA variant there are fewer spores and many other developmental stages. Spores of the SV variant had up to 20 turns of their polar tube whereas those of the OA variant only had 17. Furthermore, the spores of the SV variant were significantly larger than those of the OA variant. The sporophorous vesicle for both variants appears to form around a sporogonial plasmodia, which results in many spores developing within the vesicle.     

Impact of vegetation management on macroinvertebrates in chalk streams

Dense growths of macrophytes are a characteristic feature of chalk streams which may cause problems both to farmers and anglers. Weed is frequently cut to reduce flooding of surrounding land and provide open water for anglers. The objective of this study was to examine short-term responses of macroinvertebrate faunal assemblages in main flow and marginal samples to both weed-cutting and the application of herbicide and to compare these with untreated controls. No statistically significant effect could be demonstrated on such faunal parameters as biotic score, richness and abundance and a multivariate analysis of all available data showed that the weed-cut and herbicide treated sites could not be distinguished from the control sites III and V on the basis of their fauna. It is suggested that for conservation purposes small-scale management with ‘recovery strips’ separating the treated reaches can achieve the desired objectives of avoiding flooding and providing open water for anglers with minimal effects on the river biota.     

Ammonia distribution and excretion in fish

This paper reviews the literature concerning ammonia production, storage and excretion in fish. Ammonia is the end product of protein catabolism and is stored in the body of fish in high concentrations relative to basal excretion rates. Ammonia, if allowed to accumulate, is toxic and is converted to less toxic compounds or excreted. Like other weak acids and bases, ammonia is distributed between tissue compartments in relation to transmembrane pH gradients. NH₃ is generally equilibrated between compartments but NH₄ ⁺ is distributed according to pH. Ammonia is eliminated from the blood upon passage through the gills. The mechanisms of branchial ammonia excretion vary between different species of fish and different environments, and primarily involves NH₃ passive diffusion and NH₄ ⁺/Na⁺ exchange. Water chemistry near the gill surface may also be important to ammonia excretion, but a more accurate measurement of the NH₃ gradient across the gill epithelium is required before a more detailed analysis of NH₃ and NH₄ ⁺ excretion can be made.     

促性腺激素诱发大西洋鲑卵黄发生期卵巢滤泡释放性类固醇激素的离体研究

提要应用大麻哈鱼(Oncovhynchus keta)促性腺激素(GTH)诱发大西洋鲑(Salmosalar)卵黄发生期的离体卵巢滤泡(直径为3．4毫米)产生性类固醇激素的研究表明，不论用0．1或1微克／毫升GTH刺激，经培育10天后，未出现卵母细胞卵核消失的现象，卵核偏位也不明显。对培养液中17α，20β-双羟孕酮(17α20βP)的积累浓度测定结果，仅1微克／毫升GTH组含少量的17α20βP；0．1微克／毫升GTH组，培养液中雌二醇的积累浓度明显高于对照组和1微克／毫升GTH组，并为后者的两倍。除雌二醇外，孕酮，17α-羟孕酮，17α20βP，雄烯二酮和睾酮的产生，都呈现对GTH剂量的依赖关系，1微克／毫升GTH组的产生量明显高于0．1微克／毫升GTH组和对照组。离体研究的结果表明，处于卵黄发生期的卵巢滤泡对低剂量(0．1微克／毫升)和高剂量(1微克／毫升)GTH的反应不同。低浓度的GTH，引起性类固醇激素生物合成的途径沿着形成雌二醇的方向进行，雄激素被芳香化成雌激素，雌二醇再而刺激肝脏合成卵黄物质的前体，从而促进卵黄发生。高浓度的GTH，有抑制雌二醇合成的作用，而是促使卵母细胞向着最终成熟的方向发展，使性类固醇生物合成的途径转向形成大量雄激素和孕激素，特别是17α20βP。这与已充分生长和卵黄积累完成的卵巢滤泡离体试验的结果一致，与活体观察以上各种性类固醇激素的变化一致。     

Clinicopathologic features of suspected brevetoxicosis in double-crested cormorants (Phalacrocorax auritus) along the Florida Gulf Coast.

Outbreaks of morbidity and mortality in double-crested cormorants (Phalacrocorax auritus) along Florida's Gulf Coast have occurred sporadically for at least 30 yr. During these outbreaks, the Clinic for the Rehabilitation of Wildlife, located on Sanibel Island in Florida, has admitted a substantial number of cormorants with consistent presentation of primarily neurologic clinical signs. In order to investigate the association of these outbreaks in cormorants with exposure to brevetoxin, we compared the timing of admittance of cormorants with outbreak-specific clinical signs to blooms of the brevetoxin-producing marine algae, Karenia brevis (formerly Gymnodinium breve), around Sanibel Island from 1995 through 1999. The clinic admitted 360 out of 613 cormorants with the common clinical sign of severe cerebellar ataxia in six outbreaks occurring during this period. The ataxia was characterized by a broad-based stance, truncal incoordination, hypermetric gait, and intention tremors of the head. The histopathologic findings in 10 cormorants euthanized in 1997 were mild and nonspecific. An immunohistochemical staining technique for the detection of brevetoxin in cormorants documented the uptake of brevetoxin in tissues from four cormorants admitted during an outbreak in 1997, but a modified technique used on samples from 11 cormorants admitted during a K. brevis bloom in 2000 produced indeterminate results. Admittance of cormorants with outbreak-specific clinical signs was positively correlated (P < 0.05) with concurrent concentrations of K. brevis in local water. The cross-correlation coefficient was also significant when increased K. brevis levels preceded cormorant admittances by 2, 4, 6, and 8 wk. This delay in time between K. brevis blooms and cormorant admittance and our clinical finding of neurologic abnormalities in cormorants without overt histopathologic features suggest an association between K. brevis blooms and local cormorant morbidity.     

Toxicity of chlordimeform and amitraz to the egyptian cotton leafworm (Spodoptera littoralis) and the tobacco budworm (Heliothis virescens)

The relative toxicity (μg a.i. g^?1 body wt) of the formamidine insecticide chlordimeform (CDM) and the triazapentadiene insecticide amitraz was examined in two species of noctuid moth Spodoptera littoralis and Heliothis virescens. When applied topically, there was an unexpected and marked difference in the toxicity of CDM base and its hydrochloride to adults of both species, the salt being appreciably more toxic. For H. virescens at least, this difference in toxicity could not be explained by differences in penetration. This trend was reversed for larval instars of S. littoralis; while there was relatively little difference in the toxicity of the base to adult and larval stages, the salt was at least 1000-fold more toxic to adults than to larvae. N¹-Demethylchlordimeform (DCDM) was the only metabolite of CDM to show biological activity against either species, but was much less toxic than the parent compound. Amitraz was far less toxic than either CDM or DCDM; like the CDM salt, it appeared to be more toxic to adult than larval stages of S. littoralis. Application of piperonyl butoxide significantly increased the toxicity of the CDM salt, DCDM and amitraz to adult H. virescens, the synergist being particularly effective with DCDM and amitraz. In contrast, piperonyl butoxide had no significant effect on the toxicity of DCDM, and slightly antagonised the toxicity of DCDM to fourth-instar larvae of S. littoralis.