Takuma Harada

Changes in hematology, biochemical values, and restraint ECG of rhesus monkeys (Macaca mulatta) following 6‐month laboratory acclimation

Abstract:  The aim of this study was to determine if 6‐month acclimation would enable accurate evaluation of hematological, biochemical data, and ECG recorded under restraint for conscious rhesus monkeys of both sexes. Periodic evaluation of these parameters was made during the 6‐month period of acclimation. The platelet count, alkaline phosphatase, glucose, and sodium levels significantly decreased, whereas creatinine increased, compared with pre‐acclimation values. The heart rate was significantly reduced compared with pre‐acclimation values. QT–RR relation followed the square root regression function, which means modification of Bazetts QTc formula can be applied even if the ECG is recorded under restraint. In conclusion, 6‐month acclimation was effective for stabilizing the blood data and for allowing accurate evaluation of the ECG even under restraint. Current results show that an acclimation period at least 3 months may be necessary prior to using rhesus monkeys for chronic studies.

Spontaneous adrenal and hepatic myelolipomas in the common marmoset

Myelolipomas occurring simultaneously in the adrenal and liver were found in a 2.7-yr-old, bred female common marmoset (Callithrix jacchus). The animal bore single adrenal and multiple hepatic myelolipomas. The adrenal myelolipoma consisted of mature adipose cells and focal collections of normal hematopoietic elements and was unencapsulated. In the liver, the myelolipomas, which were partially encapsulated, included a large amount of hematopoietic tissue and adipose cells that resembled normal bone marrow cells in various ways. Additionally, one of the multiple nodules contained several bony spicules with osteoblasts. Furthermore, there were invasive figures of hematopoietic cells, such as myeloblasts, erythroblasts, and megakaryocytes, in the hepatic sinusoids around the lesions. Thus, this case has some unusual morphological characteristics and is the first report, to our knowledge, on multiorganic myelolipomas in common marmosets.

QT prolongation and torsades de pointes induced by an antifungal agent, D0870, in conscious dogs.

D0870 ((R)-2-(2,4-difluoro-phenyl)-1-[3-[(E)-4-(2,2,3,3-tetrafluoropropoxy+ ++)-styryl]-1H-1,2,4-triazol-1-yl]-3-(1H-1,2,4-triazole-1-yl) propan-2-ol), a novel bis-triazole antifungal agent, induced sudden deaths at a high dose of 5 mg/kg/day in a 6-month toxicity study in dogs. In the present study, we intended to elucidate the cause of the sudden death in dogs. When used in a single dose, D0870 induced prolongation of QTc intervals in proportion to its plasma concentration, and the threshold plasma concentration of the drug causing 10% QTc prolongation was estimated to be 3.8 microg/ml. Then, we conducted a study to induce sudden death in dogs using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring. Marked QTc prolongation (52-96%), ventricular premature contractions, and T-wave alternans were observed in all 10 animals treated with the drug, and seven out 10 animals died of ventricular fibrillation (VF) associated with torsades de pointes (TdP) when the dogs were treated with D0870 for 14 or 16 days. The TdPs were elicited in both tachycardia and bradycardia, and some of them in the former proceeded to VF. Consequently, we clarified that D0870-induced sudden death is primarily attributable to the development of TdP preceding VF and may be enhanced by sympathetic nervous tone produced by emotional or physical stress.

Influences of Catecholamines on the Sudden Death Induced in Dogs by an Antifungal Agent, D0870☆

We previously reported the occurrence of QT prolongation and sudden death owing to torsades de pointes (TdP) in dogs treated with D0870, an antifungal agent. In the present study, we evaluated the influences of epinephrine and isoproterenol on the onset of TdP each time D0870 was given to 6 anesthetized open-chest dogs at a dosage of 20 mg/kg, 5 times every 40 minutes, by the simultaneous measurements of surface electrocardiogram and epicardial monophasic action potential (MAP). D0870 alone induced noticeable prolongation of the QT interval and action potential duration (APD), but neither ventricular premature contraction (VPC) nor sudden death. In contrast, the additional administration of the catecholamines induced a greater shortening of APD during the later phase of repolarization than during its earlier one and VPCs in all dogs tested, and sudden deaths owing to TdPs in 4 of the 6 dogs treated with D0870. These results suggest that D0870 alone does not induce TdP but that catecholamines play an important part in the development of sudden death induced by D0870 in dogs.