Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys

CS-1008, a humanized monoclonal antibody that is agonistic to human death receptor 5, was intravenously administered to cynomolgus monkeys twice a week for 13 weeks at 3 different dose levels (5, 15 and 42 mg/kg) in order to evaluate its potential toxicity. A control group received phosphate buffered saline containing 0.01% polysorbate 80. Each of the 4 groups consisted of 3 male and 3 female cynomolgus monkeys. No animal in any group died during the dosing period. No toxic changes in clinical signs, food consumption, body weight, electrocardiography, ophthalmology, urinalysis, hematology, blood chemistry, gross pathology, organ weights or histopathology were noted in any group during the dosing period. In the toxicokinetic analysis, the values for the maximum concentration of CS-1008 in plasma and the area under the curve generally increased with increasing dose. No clear differences in the toxicokinetic parameters or profiles were observed between the sexes. Development of anti-CS-1008 antibodies was not detected in any sample. The no-observed adverse-effect level (NOAEL) of CS-1008 in cynomolgus monkeys under the conditions of this study was concluded to be 42 mg/kg in both sexes, when administered intravenously twice a week for 13 weeks. This study supports the development of CS-1008 as a therapeutic biopharmaceutical

Mechanism of Voriconazole-Induced Transient Visual Disturbance: Reversible Dysfunction of Retinal ON-Bipolar Cells in Monkeys

PURPOSE. To investigate the mechanism of voriconazole-induced transient visual disturbance in humans. METHODS. Standard full-field electroretinograms (ERGs) were recorded from monkeys treated intravenously with voriconazole. In addition, photopic ERGs elicited by long-duration stimuli (ON-OFF response) were also recorded from monkeys receiving intravenous voriconazole or intravitreal 2-amino-4-phosphonobutyric acid (APB). RESULTS. Characteristic changes were observed in the waveform of the standard full-field ERGs obtained immediately after dosing of voriconazole as follows: electronegative combined rod-cone response (markedly attenuated b-wave and oscillatory potentials), undetectable rod response (eliminated b-wave); slightly abnormal single-flash cone response (flattened appearance in the bottom of the a-wave, mildly attenuated b-wave); and slightly abnormal 30 Hz flicker (mildly attenuated b-wave). The above changes fully recovered to baseline 24 hours after each dosing, along with a decrease in plasma voriconazole concentration. In addition, the change in the waveform of the ON-OFF response recorded in voriconazole-treated monkeys was quite similar to that recorded in APB-treated monkeys as follows: the b-wave was eliminated or prominently attenuated; and the a-and d-waves were not apparently attenuated. V oriconazole is a triazole antifungal agent with potent activity against a broad spectrum of clinically significant pathogens. 1-3 Voriconazole has been generally well tolerated in clinical trials 4 and postmarketing surveillances 5-7 with frequently reported adverse events of transient visual disturbances, which are described as enhanced/altered light perception, photopsia, photophobia, blurred vision, or color vision changes without any abnormality in the fundus oculi. Very few studies have focused on the detailed effect of voriconazole on retinal function, although the retina is generally considered to be the site of the visual disturbances because reversible decreases in the amplitude of the electroretinogram (ERG) were noted in voriconazole-treated humans. METHODS Animals A total of ten cynomolgus monkeys (Macaca fascicularis) between three and eight years of age were used in this study. The animals were housed individually in stainless steel cages in an animal study room where the environmental condition was set as follows: room temperature, 24°C; relative humidity, 60%; illumination, 12-hour lighting (7:00 to 19:00) at 150 to 300 luces. The animals were fed 100 g per animal per day of pellet food for monkeys (PS; Oriental Yeast Co., Ltd., Tokyo, Japan). Tap water from a feed-water nozzle was supplied ad libitum to the animals. All experimental procedures adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and were approved by the Institutional Animal Care Committee of DaiichiSankyo Co. Ltd. Drug Administration Voriconazole (VFEND for Intravenous Use; Pfizer Inc., New York, NY) was dissolved in physiologic saline. The dose formulation was administered intravenously at a rate of 0.2 mL/kg per minute for ten minutes to six animals with increasing doses of 0, 3, 6 and 12 mg/kg at intervals of one week or more, and the standard full-field ERGs were recorded as described below. Several months after the 12 mg/kg dosing, voriconazole was administered to three animals at 0 mg/kg and to another three animals at 6 mg/kg in the same manner, and the photopic ERG elicited by a long-duration stimulus (the ON-OFF response) was recorded as described below. Intravitreal injection of 2-amino-4-phosphonobutyric acid (APB) (Sigma-Aldrich; St. Louis, MO) was also conducted in two animals several weeks after the last dosing of voriconazole mentioned above. The techniques for intravitreal injection have been described in detail elsewhere

Isoprenaline increases the slopes of restitution trajectory in the conscious rabbit with ischemic heart failure

Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25–2.0 ml of 1 μmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (− 0.81 ± 0.52 vs − 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients