Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation

Table 1 Effect of cyclosporin A or castanospermine or both upon cardiac allograft survival

No. of subjects and (number alive at 100 d) for each dose group of cyclosporin A by castanospermine1,2
	Castanospermine dose3,4
		0	50	100	150	200	300
Cyclosporin A dose4	0.0	14 (0)	7 (0)	7 (0)	7 (1)	6 (1)	6 (4)
	0.5	7 (0)		7 (2)		6 (4)
	2.0	10 (0)	7 (0)	11 (7)		6 (5)
	3.0	6 (0)	6 (1)	6 (6)
	4.0	6 (5)

¹PVG donor into DA recipient;

²The syngeneic control, DA into DA, was 4 (4);

³Survival times are truncated at 100 d;

⁴Drug doses are given in mg/kg per day body weight.

Table 2 Effect of cyclosporin A or castanospermine or both upon cardiac allograft survival

Mean survival for each dose group of cyclosporin A by castanospermine1,2
	Castanospermine dose3,4
		0	50	100	150	200	300
Cyclosporin A dose4	0.0	7.5	9.7	13.1	31.7	45	75.7
	0.5	7.4		38.9		73.8
	2.0	8.4	13.2	75.5		99.3
	3.0	10.7	30.7	100
	4.0	85.2

¹PVG donor into DA recipient;

²The mean survival of the syngeneic control (DA into DA) was 100 d;

³Survival times are truncated at 100 d;

⁴Drug doses are given in mg/kg per day body weight.

Table 3 Analysis of the interaction between cyclosporin A and castanospermine upon cardiac allograft survival

Output from the accelerated failure time model with weibull distribution for cyclosporin A doses of 0 to 2 mg/kg per day and castanospermine doses of 0 to 200 mg/kg per day
Variable	HR	95%CI	P value
Cyclosporin A dose	0.958	0.668-1.374	0.817
Castanospermine dose	0.982	0.976-0.988	< 0.001
Interaction	0.986	0.981-0.992	< 0.001

Table 4 Analysis of the interaction between cyclosporin A and castanospermine upon cardiac allograft survival

Output from the accelerated failure time model with weibull distribution for cyclosporin A doses of 0 to 3 mg/kg per day and castanospermine doses of 0 to 100 mg/kg per day
Variable	HR	95%CI	P value
Cyclosporin A dose	0.852	0.662-1.0954	0.211
Castanospermine dose	0.978	0.968-0.987	< 0.001
Interaction	0.986	0.981-0.992	< 0.001

Table 5 Effect of the dose of castanospermine delivered by a pump on the blood level of cyclosporin A

Blood level of CsA1
CsA dose2	d	Castanospermine dose2	No.	Mean	SD
23,4	3	0	5	189.2	73.34
	3	100	5	299.8	53.53
	3	200	5	313.0	131.56
	6	0	5	477.0	78.97
	6	100	5	326.6	110.48
	6	200	5	280.2	126.69
33,5	3	0	5	520.6	177.18
	3	100	5	450.2	218.76
	3	200	4	506.5	271.96
	6	0	5	1061.80	256.22
	6	100	5	784.80	107.83
	6	200	4	439.75	160.51
43,6	3	0	5	711.80	184.61
	3	100	5	601.40	121.33
	3	200	5	1031.60	287.18
	6	0	5	1110.20	252.20
	6	100	5	1152.20	127.67
	6	200	5	556.20	192.41

¹CsA levels are given in μmol/L;

²CsA and CAST doses are given in mg/kg per day body weight;

³No significant increase in CsA level for no CAST vs CAST at day 3 or day 6;

⁴For each CsA dose the difference in trend of day 6 values compared with day 3 was significant: CsA 2 mg/kg per day P = 0.02;

⁵CsA 3 mg/kg per day P = 0.04;

⁶CsA 4 mg/kg per day P = 0.001. CAST: Castanospermine; CsA: Cyclosporin A.

Table 6 Effect of removal of the pump delivering castanospermine on blood level of cyclosporin A

Blood level of CsA1
CsA dose2	On pump	Castanospermine dose2	No.	Mean	SD
23	Yes	0	10	333.10	167.84
		100	10	313.20	83.06
		200	10	296.60	122.98
	No	0	5	513.20	170.76
		100	5	560.00	254.00
		200	5	355.40	105.29
34	Yes	0	10	791.20	352.83
		100	10	617.50	239.87
		200	8	473.13	209.79
	No	0	5	849.40	455.77
		100	5	671.20	421.57
		200	4	824.50	153.44
44	Yes	0	10	911.00	295.81
		100	10	876.80	313.14
		200	10	793.90	340.42
	No	0	5	968.80	429.26
		100	5	1188.60	453.13
		200	5	589.40	290.93

¹CsA levels are given in μmol/L;

²CsA and CAST doses are given in mg/kg per day body weight;

³Off pump significantly increased compared with on pump (P = 0.02);

⁴No significant difference between on pump vs off pump values. CAST: Castanospermine; CsA: Cyclosporin A.