Disodium 3,3'-dithiobis[propanesulphonate]

Specific investigations: other studies

Administrative data

Endpoint:

mechanistic studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Studies on the Urotoxicity of Oxazaphosphorine Cytostatics and its Prevention. 2. Comparative Study on the Uroprotective Efficacy of Thiols and Other Sulfur Compounds

Author:

Brock, N., Pohl, J., Stekar, J.

Year:

1981

Bibliographic source:

Eur J. Cancer Clin. Oncol., Vol. 17, No. 11, pp, 1155-1163, 1981.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Sodium-3-mercapto-propane sulfonate (Asta 7100 = MPS) was tested for its uroprotective action in 5 (per dose level) Sprague Dawley rats treated with 68 mg/kg ifosfamide that is known to induce haemorrhagic cystitis. MPS was administered by i. v. administration 15 min before the injection of ifosfamide at dose levels of 21.5, 68.1 and 215 mg/kg bw. The uroprotective efficacy of MPS was evaluated 24 hours after the administration of ifosfamide. The rats were killed and the urinary bladder were evaluated (inflammation, bleeding and weight).

GLP compliance:

no

Type of method:

in vivo

Endpoint addressed:

basic toxicokinetics

Test material

Test material information

Constituent 1

Reference substance name:

Sodium 3-mercaptopropanesulphonate

EC Number:

241-620-3

EC Name:

Sodium 3-mercaptopropanesulphonate

Cas Number:

17636-10-1

Molecular formula:

C3H8O3S2.Na

IUPAC Name:

sodium 3-sulfanylpropane-1-sulfonate

Test material form:

other: i.v. solution

Details on test material:

- Name of test material (as cited in study report): sodium-3-mercapto-propane sulfonate (Asta 7100) (Asta Werke, Bielefeld, Germany)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Asta-Werke, Bielefeld, and Mus Rattus AG, Brunnthal
- Weight at study initiation: 250 g
- Housing: standard conditions
- Diet (e.g. ad libitum): ad libitum (altromin ® 1324, no deprivation)
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS: not reported

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

No details reported

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

single treatment

Frequency of treatment:

single treatment

Post exposure period:

24 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
screening dose: 100 mg/kg bw; 21.5, 68.1 and 215 mg/kg bw
Basis:
other: nominal dose

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

No details

Examinations

Examinations:

Urinary bladder weight; gross pathology (inflammation, bleeding).

Positive control:

Ifosfamide (68 mg/kg bw)

Results and discussion

Details on results:

Asta 7100 exerted a uroprotective effect at doses of 100 mg/kg bw and 215 mg/kg bw. The uroprotective efficacy of MPS was lesser than that of its short-chain homologue mesna.

Any other information on results incl. tables

The severity of the inflammation of the bladder after i.v. administration of ifosfamide was dose-dependent. An ifosfamide dose of 68 mg/kg always induced an approximately 2- fold increase in the wet weight of the bladder and a damage score of about 2. Some of the rats also showed bladder haemorrhages. The scoring system used takes into account two parameters: firstly, increased capillary permeability (which is demonstrable objectively by the extravasal occurrence of intravenously injected trypan blue) and secondly, the increase in the weight of the bladder, which can also be assessed macroscopically as a swelling of the bladder. In some selected groups the bladder damage and the extent of bladder protection were also investigated histologically. The uroprotective effect of MPS was dose-dependent. It was reflected in a reduced increase in the bladder weight and reduced extravasation of trypan blue, and it was also demonstrable histologically. In the case of the test compounds with a demonstrable uroprotective effect (i.e. mesna) the lowest dose ensuring reliable uroprotection was determined. The results of these investigations of the uroprotective efficacy of MPS and mesna (as well as it dimer dimesna) are summarized in the following table:

Table 1.  Uroprotective action of mercapto-alkane sulfonates and analogs
					Assessment of urinary bladder
Compound	Structural formula	Dose (mg/kg)		Animals (n)	Inflamm. (x/n)	Bleeding	Weight (mg)		Score (0-3)
						x/n	Mean + SE
Untreated controls		—		105	0	0	81.0±12.0		0
Ifosfamide		68.1	i.v.	100	100	63	165.0±35.0		2.3
Mesna	HS-CH2-CH2-SO3Na	6.81	i.v.	10	6	1	97.3±22.6		1.5
		10.0	i.v.	10	2	0	88.8±5.4		0.5
		14.7	i.v.	10	0	0	77.5±10.9		0.3
		21.5	i.v.	10	0	0	72.6±10.3		0
Dimesna	S-CH2CH2-S03Na S-CH2CH2-S03Na	21.5	i.v.	10	6	3	137.5±29.1		1.4
		31.6	i.v.	10	3	0	101.6±12.4		0.3
		46.4	i.v.	10	1	0	86.6±12.4		0.1
		68.1	i.v.	10	0	0	77.5±10.9		0
Asta 7100	HS-(CH2)3-SO3Na	21.5	i.v.	5	5	0	138.4±26.5		2.0
		68.1	i.v.	5	3	0	80.4±7.4		0.5
		215.0	i.v.	5	1	0	77.0±10.1		0.1

The uroprotective efficacy of MPS was less effective than that of its short-chain homologue mesna (CAS 19767-45-4).

Applicant's summary and conclusion

Conclusions:

MPS possesses uroprotective efficacy against ifosfamide induced haemorrhagic cystitis in rats at dose levels of 100 and 215 mg/kg bw.

Executive summary:

Sodium-3-mercapto-propane sulfonate (Asta 7100 = MPS) was tested for its uroprotective efficacy in 5 Sprague Dawley rats treated with 68 mg/kg ifosfamide that is known to induce haemorrhagic cystitis. MPS was administered by i. v. administration 15 min before the injection of ifosfamide at the screening dose of 100 mg/kg bw and thereafter was raised or lowered in steps with a factor of 2.15. The dose levels were 21.5, 68.1 and 215 mg/kg bw. The uroprotective efficacy of MPS was evaluated 24 hours after the administration of ifosfamide. The rats were killed and the urinary bladder was evaluated (inflammation, bleeding and weight). The severity of the inflammation of the bladder after i.v. administration of ifosfamide was dose-dependent. An ifosfamide dose of 68 mg/kg always induced an approximately 2- fold increase in the wet weight of the bladder and a damage score of about 2. Some of the rats also showed bladder haemorrhages. The scoring system used takes into account two parameters: firstly, increased capillary permeability (which is demonstrable objectively by the extravasal occurrence of intravenously injected trypan blue) and secondly, the increase in the weight of the bladder, which can also be assessed macroscopically as a swelling of the bladder. In some selected groups the bladder damage and the extent of bladder protection were also investigated histologically. The uroprotective effect of MPS was dose-dependent. It was reflected in a reduced increase in the bladder weight and a reduced extravasation of trypan blue, and it was also demonstrable histologically. MPS exerted its uroprotective effect at doses of 100 and 215 mg/kg bw. MPS was, however, less effective than its short-chain homologue mesna (CAS 19767-45-4).