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Diss Factsheets

Toxicological information

Specific investigations: other studies

Currently viewing:

Administrative data

Endpoint:
behavioural effects
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Guideline:
other: none
Principles of method if other than guideline:
suppression of Epileptic seizures (convulsions) in cats and rats by dapsone doses normally used for anti-leprosy therapy.
GLP compliance:
no
Type of method:
in vivo
Endpoint addressed:
neurotoxicity

Test material

Constituent 1
Chemical structure
Reference substance name:
Dapsone
EC Number:
201-248-4
EC Name:
Dapsone
Cas Number:
80-08-0
Molecular formula:
C12H12N2O2S
IUPAC Name:
4,4'-sulfonyldianiline
Details on test material:
Dapsone , pharmaceutical grade

Test animals

Species:
other: Rat and Cat
Sex:
male/female
Details on test animals or test system and environmental conditions:
13 male Wistar rats,
9-10 weeks of age

5 adults cats : 3 males and 2 females
Weighing 3.5-5.8 kg

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
polyethylene glycol
Details on exposure:
RATS : single injection of 6.25, 9.375, 12.5 and 25.0 mg/kg body weight.
CATS : daily oral dose initiated with 7-23 mg/kg/day ; when the seizure suprressing effect was not obtained following 7-11 daily doses of Dapsone, doses were increased up to 40 mg/kg/day. A second Dapsone trial was conducted in 3 cats with a different initial dose. A total of 8 Dapsone trials were made in 5 cats.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
none
Duration of treatment / exposure:
single treatment
Frequency of treatment:
single treatment
Post exposure period:
none
Doses / concentrations
Remarks:
Doses / Concentrations:
see above
Basis:

No. of animals per sex per dose:
2-12 rats (maximum dose was tested in only 2 rats, while other doses were assessed in 6-12 rats)
cats: individual cats received 7 - 40 mg/kg body weight
Details on study design:
Electrodes were implanted into the animal brain two weeks prior to treatment. Bipolar stimulation was delivered through a constant current unit to stimulate seizures. Clinical signs, serum dapsone levels, hematology and behavior were observed.

Examinations

Examinations:
Anticonvulsive properties were assessed by monitoring of seizure length and frequency and comparison to untreated animals.
Animals were assessed for clinical and behavioral signs and hematological changes.

Results and discussion

Details on results:
Acute anticonvulsive effects of dapsone in rats:
The rats developed stage 5 seizures with an average of 10.3 stimulations. Mean ADT for daily kindling and GST of kindled rats were 24.2 and 15.6 uA, respectively. Mean stimulus intensity for the control was 18.3 (6-36) uA; mean stimulus intensities for the 6.25, 9.375 and 12.5 mg/kg doses of dapsone were 21.7 (6-36), 24.8 (16-30), and 17.7 (6-28) uA, respectively. Mean numbers of stage 5 seizures before each treatment were 32.0 (13-51), 39.3 (10-53), 30.0 (9-51) and 37.6 (10-67), respectively.
the inhibitory efficacy of dapsone on stage 5 seizures or secondarily generalized convulsions increased with increasing dose. Regression of seizures to stage 4 was observed in 1 rat, but regression to stage 2 or 3 was not observed. regression to stage 1 focal seizures was obstered in 7 sessions and complete electro-clinical seizure supression occurred in 1 of 6 sessions (16.7%) at 6.25 mg/kg, 3 of 8 sessions (37.5%) at 9.375 mg/kg, and 8 of 12 sessions (66.7%) at 12.5 mg/kg. In 1 rat, in which 12.5 mg.kg dapsone was ineffective, a dose of 25 mg/kg brought about complete inhibition of the kindled suizure. Stage 5 seizures were induced in all the control rats.

There was a linear correlation between the dapsone dose and the serum level with single doses. The minimum serum dapsone level for suppression of secondarily generalized seizures was 4.9 ug/ml, and the maximum dapsone level that failed to suppress stage 5 seizures was 11.7 ug/ml. The ED50 and confidence limits of 95% probability for suppression of secondarily generalized seizures and focal seizures were 7.3 (5.8-9.2) and 10.4 (8.1 - 13.4) mg/kg, respectively, and the corresponding serum levels were 6.4 and 10.5 ug/ml.
Acute neurotoxic signs such as sedation and ataxia were not recognized at any dose level throughout the experiments. Hemolysis was not observed in any blood samples, however preliminary data indicate some hematological alterations. Doses of dapsone administered intraperitoneally to rats over a period of 9 days brought about a dose-dependent decrease in the RBC count and a lowering of hemoglobin levels. Simultaneously, reticulocyte counts increased.

Effects of chronic dapsone administration in cats;
The cats developed stage 6 seizures with a mean of 24.2 stimulations. Regression of seizures to the earlier stages was observed in 7 of 8 dapsone trials in all animals. Complete electro-clinical seizure suppression occured in 4 trials in 3 cats. When seizures regressed to stage 1 or 2, they were always associated with continuation of localized AD for less than 10s. On the other hand, upon seizure regression only to stage 4 or 5, AS was prolonged for over 50s with inevitable propagation. On the basis of these differences, regression to stages 1 or 2 was also included in complete seizure suppression for scoring purposes, while regressions to stage 4 and 5 were scored as incomplete seizure suppression.
In the first trial 4 of 5 cats showed complete seizure suppression. The effects appeared on the first day or second day with serum dapsone levels of 8.9 - 15.8 ug/ml, and the anticonvulsive effects continues throughout the trials in 3cats for up to 12 days. In 1 cat complete suppression was achieved only on the first day. Subsequently, seizures recurred with stage 4 and even with stage 6, despite an increase of dapsone up to 40 mg/kg/d, resulting in a serum level of 68.0 ug/ml. in the remaining cat, seizure stage regression was not achieved even when the dapsone dose was increased to 26 mg/kg/day and the serum level reached 74.9 ug/ml. However, in these 2 animals, considerable reductions of AD durations were noted at stage 6 seizures.
In the second trial, dapsone was commenced with a higher initial dose of 28 mg/kg/d. As a result, incomplete seizure suppression occurred on the first day and was followed by complete suppression beginning on the 4th day, with serum levels of 19.9 and 45.9 ug/ml, respectively. These values were apparently lower than the maximal level obtained on the first trial. Since seizures were suppressed completely on the first trial, lower initial doses of dapsone were used in the second trial. Complete seizure suppression occurred abruptly when the dapsone doses were increased to as much in the first trial. However, serum levels were higher than those observed in the first trial.

Upon continuation of dapsone, animals abruptly began to respond with stage 6 seizures within 2-8 days. At this time, serum dapsone levels were lower than those observed at the beginning of complete seizure suppression in all cats except one. The serum levels measured 1-3 days before the seizure recurrence were also lower than the latter in 4 of 6 dapsone treatment sessions.

Restlessness characterized by continuous mewing was observed consistently during the early stages of each trial. This was noted when the serum dapsone levels reached approximately 20 ug/ml. Subsequently, the animals became immobile. They would squat down on the floor and lost interest in food. Consequently, their weight decreased progressively; at the end of the trials, an 8-24% reduction in body weight was observed. Ataxia, muscle weakness and lethargy were not observed. Distinct hemolysis was not observed in all the blood samples, although hematological determinations were not undertaken. Three cats recovered completely and proceeded to the second trials, however 2 animals failed to recover, even after the wash out period of 20 days.

Any other information on results incl. tables

12.5 mg Dapsone/kg bw reduced seizure activity by 91 % in rats.
13-23 mg/kg bw caused partial reduction of seizures in cats but not as efficient as in rats.

Applicant's summary and conclusion

Conclusions:
Single doses of a dapsone given to rats (doses 6.25 - 12.5 mg/kg, i.p.) containing epilepsy drug suppressed kindled seizures in a dose-dependent manner without overt behavioral toxicity. With repeated oral administration in cats, relatively higher initial doses (13-23 mg/kg) were required to obtain seizure suppression and neurotoxic signs occurred within a few days with serum drug levels of approx. 20 ug/ml. although dapsone showed anticonvulsive effects in both animal species, the effective serum levels overlapped the toxic levels reported in clinical treatment of leprosy. In the majority of cats, however, seizure suppression was maintained even after the discontinuation of dapsone with lower serum levels than those observed at the beginning of the seizure suppression. Therefore, dapsone would be useful as an antiepileptic drug only when long-term anticonvulsive efficacy is demonstrated using smaller doses comparable to those used in the treatment of leprosy.