5 September 1962 Ind. Jour. Med. Res. Vol.50 pp.715-719

by R. D. Kukarni, B. B. Gaitonde, (with tech. Assistance of Shri N. K. Dadkar)
Some measure of success has been achieved in the oral treatment of Diabetes mellitus with some introduction of the sulphonylurea…

 

Potentiation of Tolbutamide Action by Jasad Bhasma and Karela (Momordica charantia)

Author: R. D. Kukarni, B. B. Gaitonde, (with tech. Assistance of Shri N. K. Dadkar)

Type of Publication: Pre-clinical

Date of Publication: September 5, 1962

Publication: Ind. Jour. Med. Res. Vol.50 pp.715-719, 5 September 1962

Organization: Department of Pharmacology, Grant Medical College, Bombay

Some measure of success has been achieved in the oral treatment of Diabetes mellitus with some introduction of the sulphonylurea derivatives in its therapy. However, usefulness of these agents is limited to the treatment of the elderly obese diabetes without ketosis. The safest of the series, Tolbutamide, is the eldest potent also. Several indigenous drugs have been tested for their antidiabetic action both in the laboratory (Aiman, 1955; 1956; Shrotri and Aiman, 1960; Mukerji, 1957) and in the clinic (Sathe et al., 1960; Vad, 1960). The effectiveness of such indigenous drugs, where it has been demonstrated, is far less as compared with the synthetic compounds. Two indigenous drugs- Jasad Bhasma (J.B.) and Karela (K)- have been shown to be effective in large number of diabetes by Sathe et al. (loc. cit.) and Vad (loc. cit.), respectively. The present investigation was planned to test the effect of these drugs on blood sugar of rabbits and also to see whether these drugs could potentiate the action of Tolbutamide.

MATERIAL AND METHODS

The work was carried out on rabbits weighing between 1 kg. and 2 kg. The rabbits were fasted over a period of 48 hours as this period is necessary to obtain a true fasting state (Kulkarni et al., 1959). Blood samples were collected from marginal ear vein for glucose estimation which was done by Somogyi’s method.

The experiments were performed to study the effects of single administration of the drug on the blood sugar profile of rabbits (acute experiments) and to study the effect of the chronic administration of the drugs on the fasting blood sugar level. In the acute experiments the blood samples were collected initially and then 2 hours, 4 hours, 6 hours, and 8 hours after the drug administration. In chronic experiments blood samples were collected before the initiation of therapy and then at weekly intervals before the administration of the drug on that day. In chronic experiments the drug was administered twice a day. In all cases the drugs were given orally through a stomach tube.

Jasad Bhasma was prepared for us by the Himalaya drug Co., Bombay. The same sample was used throughout the studies. It satisfied the test for the Bhasmas, viz, that floated on water as a thin transparent film. The market samples tried earlier, contained a variable amount of zinc oxide as impurity. In acute experiments the doses used were 100 mg., and 500 mg. per kg. In chronic experiments 500 mg./kg. given in two divided doses daily.

The dried juice of Karela was supplied by the Himalaya Company, Bombay. The doses used were similar to those of Jasad Bhasma.

Tolbutamide powder supplied by the Hoechst Fedco Pharma, Ltd., Bombay, was used. It was administered in the doses of 250 mg. and 500 mg./kg., earlier alone or together with 200 mg. each of Karela and Jasad Bhasma.

The dosage range used here is found to be optimum from the various pilot experiments which are not included in this report.

RESULTS

Jasad Bhasma in the dose of 500 m./kg. does not cause any fall in the fasting blood sugar level at the end of 8 hours after administration (t=0.26,P>0.5). Karela also, in the dose of 500 mg./kg. does not cause significant fall in the fasting blood glucose level (t=0.26, P>0.5). Combination of two drugs like wise does not cause a significant fall in the blood sugar of rabbits (t=0.9, P>0.5).

On chronic administration, Jasad Bhasma causes a fall in fasting blood sugar of rabbits. The fall is evident at about 2 weeks and goes on progressively increasing till at the end of 6 weeks there is an average of 22 per cent fall in the fasting blood sugar. This fall, though moderate, is statistically highly significant (t=9; P<0.01). Karela has no such effect on chronic administration. When Jasad Bhasma and Karela administered together there is a progressive fall of blood sugar over six weeks but the fall at the end of 6 weeks is little over 28 per cent which is slightly more than that obtained with Jasad Bhasma alone. This small difference is also statistically highly significant (t=3.2; P<0.01).

Tolbutamide in the dose of 500 mg./kg. causes a fall in the blood sugar with a maximum of 20 per cent reaching at 4 hours. The blood sugar then gradually returns to the normal level at 8 hours. When Tolbutamide is given together with Jasad Bhasma and Karela, a similar degree of fall of blood sugar occurs in 4 hours but thereafter the blood sugar remains at the same level and even at the end of 8 hours is appreciably lower than the initial level. The difference in the blood sugar levels of the rabbits goven Tolbutamide and those given Tolbutamide + J. B. + K, 8 hours after the administration, is statistically significant (t=5.6; P<0.01).

When Tolbutamide is given in the dose of 250 mg./kg., there is a mean fall of 11 per cent in the fasting blood sugar at the end of 4 hours. When the same dose of Tolbutamide is given together with Jasad Bhasma and karela, there is a fall of 28 per cent in the fasting blood sugar level at the end of 4 hours. This difference in the percentage fall of blood sugar is significant (t=4.2; P<0.01).

DISCUSSION

Jasad Bhasma used in this study did not cause any fall in the blood sugar level of the fasting rabbits. On prolonged administration, the same preparation caused a progressive fall in the fasting blood sugar of the rabbits over a period of 6 weeks. Though the extent of the fall was not very great, it was appreciable. This finding is consistent with the clinical observation of sathe et al.(loc. cit.) that the effect of Jasad Bhasma is progressively greater on prolonged administration. The commercial preparations of Jasad Bhasma do not give satisfy the requirements of a Bhasma. A few studies with zinc oxide revealed that it did not possess the activity of Jasad Bhasma.

Dried Karela juice used in these studies did not have any hypoglycaemic activity on acute or chronic administration. However, when Karela juice was admistered together with Jasad Bahsma over a prolonged period, hypoglyceamic effect was greater than when Jasad Bhasma was administered alone. However,the difference is very small and only suggest the synergistic action of the two drugs. At the stage it cannot, however, be definitely said that such an action does exist.

When Tolbutamide is administered in the dose of 250 mg./kg., it produces a fall of about 10 per cent in the fasting blood sugar. However, when this same dose is given with Jasad bahsma and Karela there is a fall of about 28 per cent. Since sugar in acute experiments, this definitely suggests a potentiation of Tolbutamide action by the two indigenous drugs. When Tolbutamide is given in the dose of 500 mg./kg., it produces a fall of 24 per cent in the fasting blood sugar over 4 hours and the blood sugar returns to normal in about 8 hours. When this dose is given together with Jasad Bhasma and Karela the extent of fall does not increase but the duration of the hypoglycaemic action is prolonged.

This leaves no doubt regarding the enhancement of Tolbutamide action by Jasad bahsma and Karela. However, the mechanism of this enhancement is not clear. It appears from the results obtained so far that the two indigenous drugs might be interfering with the excretion of Tolbutamide. It has also been observed that while a single dose of 100 mg. of Tolbutamide is without effect on the blood sugar, the combination of this dose with the two indigenous drugs causes a small but definite fall in the blood sugar. This makes it possible that there may be a true potentiation of the action of Tolbutamide. The detailed wok on the mechanism of this enhancement of action is in progress.

This observations of ours various therapeutic possibilities. Tolbutamide which is the safest of the oral antidiabetic drugs has the drawback of being least potent. It is also rapidly excerted from the body. If the activity of this compounds is enhanced and its duration of action prolonged, it might be the ideal drug for the treatment of the type of diabetes for which the oral antidiabetic drugs are now useful.

SUMMARY

The work was undertaken to investigate the place of some indigenous antidiabetic drugs in therapy vis-à-vis Tolbutamide. Rabbits starved over a period of 48 hours were used for fasting blood sugar estimation. Jasad Bhasma, dried Karela juice and Tolbutamide were given either individually or in combination orally. The effect of single administration on the fasting blood sugar of rabbits was studied over an eight-hour period. The drugs were administered chronically and the effect on blood sugar estimated over 6 weeks period. Jasad Bhasma and Karela had no effect on single adminstration. But Jasad Bhasma potentiated the hypoglycaemic action of single dose of Tolbutamide. Jasad Bhasma caused some fall in fasting blood sugar on prolonged administration and enhanced the effect of Tolbutamide. Karela had no such effect.

REFERENCE

Aiman, R. (1955). Enquiry into the antidiabetic property of indigenous drugs. Technical Report of I. C. M. R.

Idem (1956). Ibid.

Kulkarni, R. D., Shrotre, D. S., and Aiman, R. (1959). Period of fasting and testing of hypoglycaemic agents in rabbits. Ind. Jour. Phys. & Pharma., 3, 67.

Mukerji, B. (1957). Indigenous antidiabetic drug: A review. Jour. Sci. & indust. Res., 16A.

Sathe, R. V., Talwalkar, N. G., and Ajagaonkar, S. S. (1960). Investigations in the use of Jasad bhasma: An Ayurvedic preparation of zinc in the treatment of Diabetes mellitus. Ind. Jour. Med. Res., 48, 720.

Shrotri, D. S., and Aiman, R. (1960). The relationship of the post absorptive state to the hypoglycaemic action: Studies on Ficus bengalensis and Ficus glomerata. Ibid., 48, 162.

Vad, B. G. (1960). Place of Momordica charantia in the treatment of Diabetes mellitus. Maharashtra Med. Jour., 6, 734.