Figure 1.
Pharmacokinetic analysis of PDE4D NAMs in female Cynomolgous monkeys.
(A–B) Plasma exposure of D159687 (A), or D159797 (B) in female Cynomolgus monkey plasma following a single intravenous administration at 1.0 mg/kg, and on day 1 and day 7 after repeated daily oral administration at 5.0 mg/kg.
Figure 2.
Object retrieval task schematic and baseline characterization.
(A) Order of object retrieval task sessions for easy and difficult trials. Drawings illustrate the position of the reward in the boxes. (*) Left position will become right and right position will become left and so on in weekly rotation throughout the study. (#) The bold side of the cube represents the open side of the cube. (**) Trial 17 was for reward purposes and was not included in the data analysis; (B) Box (line indicates median, * indicates mean, box represents upper and lower 25 percentiles) and whisker (maximum to minimum) plots of all animal performance during the 4 training sessions and to vehicle administration during the testing phase on both easy (grey) and difficult (black) trials. Dashed lines indicate targeted performance – performance in easy trials >50% correct first reach, and performance in difficult trials <40% correct first reach. (C) Same data as in (B) but with high performer animal 3939 excluded. Criteria are largely met by exclusion of this animal. The outlier value during the rolipram vehicle trial is due to animal 7A5D.
Table 1.
Summary of plasma pharmacokinetic parameters of D159687 following single intravenous administration at 1.0/kg, and on day 1 and day 7 after repeated daily oral administration at 5.0 mg/kg.
Table 2.
Summary of plasma pharmacokinetic parameters of D159797 following single intravenous administration at 1.0/kg, and on day 1 and day 7 after repeated daily oral administration at 5.0 mg/kg.
Figure 3.
Influence of the PDE4 inhibitor Rolipram on the percent correct first reaches for both ‘easy’ and ‘difficult’ level OR performance.
(A–B) Effects of rolipram on easy (open bars) versus difficult tasks (black bars) (A), and after exclusion of ‘high baseline performing animals’ 3939 and 7A5D (B). Values are shown as mean ± SEM. Asterisks denote significant differences from vehicle treatment (*p<0.05, **p<0.01) following repeat measures one-way ANOVA and Dunnett's post-hoc analysis. Individual animal performance plot in the easy trials is shown in (C) and in the difficult trials is shown in (D).
Figure 4.
Influence of D159687 on OR trial performance.
Effects of D159687 on easy (open bars) versus difficult task (black bars). Dose-dependent improvement in (A) mean percent correct first reach on difficult task performance, with modest improvement on easy trial performance. Individual animal performance plot in easy trials (B) and in difficult trials (C). (D–E) Dose-dependent reduction in the total number of reaches (D) and barrier reaches (E) on difficult taks. (A, D, E) Values are listed as mean ± SEM (n = 8 for vehicle, low and mid-dose groups, n = 7 for high dose group). Asterisks denote significant differences from vehicle treatment (* p<0.05, **p<0.01 and ***p<0.001) following repeat measures one-way ANOVA and Dunnett's post-hoc analysis (n = 7, due to non-completer 7A5D).
Figure 5.
Influence of D159797 on OR trial performance.
Effects of D159797 on easy (open bars) versus difficult tasks (black bars). Dose-dependent improvement in (A) mean percent correct first reach on difficult task performance. Individual animal performance plot in easy trials (B) and in difficult trials (C). (D–E) Dose-dependent reduction in the total number of reaches (D) and barrier reaches (E) on difficult tasks. (A, D, E) Values are listed as mean ± SEM (n = 8 for vehicle and low dose, and n = 7 for mid and high dose group). Asterisks denote significant differences from vehicle treatment (* p<0.05, **p<0.01 and ***p<0.001) following repeat measures one-way ANOVA and Dunnett's post-hoc analysis (n = 7, due to non-completer 7A5D).