Solanum malacoxylon poisoning in pigs.

Solanum malacoxylon was given orally to four pigs. The animals were examined clinically and subjected to post mortem examination. Macroscopic lesions were not seen with the exception of a small calcified plaque in the endocardium of one animal. Microscopic examinations revealed slight calcification of elastic fibres in the soft tissues. The pathological changes in the bones were extensive and are described in detail. The pigs showed minimal lesions at dose levels which cause considerable systemic calcification in cattle and sheep.     

The effect of the administration of Solanum malacoxylon on the chick.

Replacement of the drinking water of chicks maintained on a normal mixed protein diet with an aqueous extract containing the equivalent of 5 g of the dried leaves of Solanum malacoxylon (DLSM) per 100 ml for one month produces a hypercalcaemia (23-49 per cent), hypomagnesamia (28-37 per cent), hypophosphataemia (26-34 per cent), hypouricaemia (29-34 per cent) and a decrease in plasma alkaline phosphatase activity (54-98 per cent). The ash content of the defatted, dried tibiae and the body weight of the DLSM treated chicks were also significantly lower (37-7 per cent and 17-79 per cent respectively) than the corresponding values for the untreated birds. The results obtained are similar to those reported for hypervitaminosis D3 in the chick.     

Evaluation in Rabbits of the Fetal Effects of Maternal Ingestion of Solanum malacoxylon

A study was performed to determine the possible toxic effects on the young of does that had been fed during the gestational period on a ration containing Solanum malacoxylon (Sm), a calcinogenic plant that contains a vitamin D₃-glycoside conjugate. Experimental animals received a ration containing 0.03% or 0.04% of Sm leaves on days 6 to 30 of gestation. The levels of calcium, phosphorus and alkaline phosphatase in their sera, as well as their feed intake and body weight, were evaluated weekly. The does were euthanized 3 days after parturition and paraffin sections stained with haematoxylin and eosin were prepared from their heart, lungs, kidneys and aorta for histopathological examination. The young from does in the Sm 0.03% group were euthanized 3 days after birth and biochemical and histopathological determinations were performed, as described for the does. The does in both experimental groups showed decreased feed consumption and those in the Sm 0.04% group showed lower body weights throughout their gestation. Animals treated with Sm 0.04% presented a high incidence of abortion and stillbirth. There were biochemical and histopathological alterations in both experimental groups, which were more prominent in the does in the Sm 0.04% group. Litters from does treated with Sm 0.03% showed mineralization of soft tissue and an increase in phosphorus and calcium levels. These findings indicate that the vitamin D₃-glycoside passes through the placental barrier to the fetus.     

Effect of cytochrome P450 inhibition on toxicity of diclofenac in chickens: Unravelling toxicity in Gyps vultures

Diclofenac was responsible for the decimation of Gyps vulture species on the Indian subcontinent during the 1980s and 1990s. Gyps vultures are extremely sensitive (the lethal dose 50 [LD_50] ~ 0.1 mg/kg – 0.2 mg/kg), with toxicity appearing to be linked to metabolic deficiency, demonstrated by the long T_1/2 (~12 h – 17 h). This is in striking comparison to the domestic chicken (Gallus gallus domesticus), in which the LD₅₀ is ~10 mg/kg and the T_1/2 is ~1 h. The phase 1 cytochrome P450 (CYP) 2C subfamily has been cited as a possible reason for metabolic deficiency. The aim of this study was to determine if CYP2C9 homolog pharmacogenomic differences amongst avian species is driving diclofenac toxicity in Gyps vultures. We exposed each of 10 CYP-inhibited test group chickens to a unique dose of diclofenac (as per the Organisation for Economic Co-operation and Development [OECD] toxicity testing guidelines) and compared the toxicity and pharmacokinetic results to control group birds that received no CYP inhibitor. Although no differences were noted in the LD₅₀ values for each group (11.92 mg/kg in the CYP-inhibited test group and 11.58 mg/kg in the control group), the pharmacokinetic profile of the test group was suggestive of partial inhibition of CYP metabolism. Evaluation of the metabolite peaks produced also suggested partial metabolic inhibition in test group birds, as they produced lower amounts of metabolites for one of the three peaks demonstrated and had higher diclofenac exposure. This pilot study supports the hypothesis that CYP metabolism is varied amongst bird species and may explain the higher resilience to diclofenac in the chicken versus vultures.     

The hypocalcemic response to protamine as a measure of bone resorption

The heparin antagonist protamine inhibits bone resorption. In the present study protamine was given i.v. at a dose of 10 mg/kg to goats and sheep in various stages of pregnancy and lactation. It is known that bone resorption increases as pregnancy progresses. In sheep maximum in bone resportion is reached at early lactation. The hypocalcemic response to protamine followed a similar course. The slightest decrease in serum calcium was obtained during early pregnancy and the greatest during late pregnancy and early lactation. Protamine increased serum inorganic phosphorus. The increase was most pronounced during early pregnancy. Protamine did not significantly change serum magnesium.Five lactating ewes were given 25000 i.u./kg of vitamin D3. Serum calcium increased and the hypocalcemic response to protamine was greater after vitamin D₃ administration than before.The results showed that the hypocalcemic response to protamine can be used as an indicator of the role of bone resorption in calcium homeostasis in various physiological situations.     

Vitamin A toxicity: comparative changes in bone of the broiler and leghorn chicks

Severe skeletal lesions were produced in both broilers and leghorns orally administered toxic levels of vitamin A (330 or 660 IU vit. A/g body weight X day) for 21 consecutive days. Hypervitaminosis A in broilers produced an osteodystrophy characterized by abnormal thickening of the proliferative-maturation zone, metaphyseal sclerosis, hyperosteoidosis, decreased number of osteoclasts, and parathyroid gland hyperplasia. In leghorns, the osteodystrophic lesions were characterized by a thin proliferative-maturation zone, a relatively thickened hypertrophy zone, flattened spindle-shaped osteoblasts, and osteoporosis. In both broilers and leghorns given excessive vitamin A, the osteogenic layer of periosteum in all bones was thin.     

Evaluation of bone toxicity in various bones of aged rats

The aim of the present study was to provide a method for evaluating bone toxicity induced by drugs in various bones in aged rats. Male Crl:CD (SD) rats at 46 weeks of age were administered 15 mg/m(2) body surface area of doxorubicin, which effects the growth plate in weanling rats, weekly for 9 weeks by intravenous injection, and the femur, sternum, humerus and tibia were examined histopathologically. In the doxorubicin-treated group, thinning of the growth plate was remarkably observed in the proximal tibia and humerus; however, these changes were not observed in other regions. In addition, the osteoclast number per bone perimeter in the proximal tibia was significantly higher than others in control aged rat. Thus, recognizing the various histological reactions related to the time of epiphyseal closure is important for evaluating bone toxicity in aged rats.     

Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover

Our investigations evaluated the effect of VEL‐0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX‐1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX‐1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX‐1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases.     

Dietary supplementation of 25-hydroxycholecalciferol increases tibial mass by suppression bone resorption in meat ducks

Leg problems often result from the rapid weight gain and poor bone quality in modern ducks, leading to a high risk of fractures and continuous pain. We hypothesized that improving bone quality in combination with delaying weight gain via a low nutrient density (LND) diet probably reverses these skeletal abnormalities. Studies indicated that 25-hydroxycholecalciferol (25-OH-D₃), a vitamin D₃ metabolite, is effective in treating bone-related disorders. Therefore, Exp. 1 evaluated the effects of 25-OH-D₃ on tibial mass of meat ducks. Male meat ducklings were fed a standard nutrient density diet (containing a regular vitamin regimen) without or with 25-OH-D₃ at 0.069 mg/kg for 35 d. The results showed that 25-OH-D₃ supplementation improved the mineral content, microarchitecture and mechanical properties of tibias, and this companied by a decreased serum bone resorption marker and a concomitant decrement in osteoclast-specific marker genes expression. Subsequently, Exp. 2 was conducted to examine the impacts of 25-OH-D₃ incorporating an LND diet on tibial quality of ducks under 2 different vitamin regimens (regular and high). Ducklings were allocated to a 2 × 2 factorial arrangement with 2 kinds of vitamin premixes and without or with 25-OH-D₃ at 0.069 mg/kg in LND diets. The high premix had higher levels of all vitamins except biotin than the regular premix. The results demonstrated that high vitamin diets exhibited more significant effects than regular vitamin diets on inhibiting bone turnover and increasing minerals deposition. Tibial mineral content, microarchitecture, and strength of birds under the regular vitamin regimen were increased by 25-OH-D₃ supplementation; However, these positive effects were not observed in ducks under the high vitamin regimen. To conclude, 25-OH-D₃ supplementation improves tibial mass by suppressing osteoclast-mediated bone resorption in meat ducks, and this positive impact only was observed in regular but not high vitamin regimen when birds fed an LND diet.     

Effects of Solanum glaucophyllum toxicity on cell proliferation and apoptosis in the small and large intestine of rabbits

Vitamin D regulates mineral homeostases and enterocyte proliferation and differentiation. Hypervitaminosis D generates changes in cell proliferation, differentiation and apoptosis in several organs. We analysed morphometric parameters and proliferative and apoptotic indices in the intestinal epithelium of rabbits with hypervitaminosis D induced by the chronic treatment with the calcinogenic plant Solanum glaucophyllum. Rabbits were treated for 15 or 30 days. A group was treated for 15 days and led to possible recovery for 30 days. Another group was nutritionally restricted for 30 days. Morphological, morphometric, proliferative and apoptotic changes were found in the treated animals. Mild atrophy and reduced proliferation was found in the jejunum and ileum. Apoptosis increased in the crypts of the ileum and in the superficial epithelium and crypts of the rectum. Most of the alterations were partially recovered. The possible involvement in these changes of the hypervitaminosis D-like state induced by S. glaucophyllum is discussed.