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Additive effect of indomethacin and methotrexate on suppression of growth in rats
M P Iqbal1, S A Saeed, S Pertani
1Department of Biochemistry, The Aga Khan University, PO Box 3500, Stadium Road, Karachi, Pakistan. perwaiz.iqbal@aku.edu
Abstract:
The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth.
Insights
Methotrexate (MTX) and indomethacin combined significantly suppressed growth in young rats, leading to minimal weight gain and reduced organ size. This additive effect may pose risks for patients on long-term therapy.
Area of Science:
- Pharmacology
- Toxicology
- Pediatric Rheumatology
Background:
- Methotrexate (MTX) and indomethacin are commonly used in treating conditions like juvenile rheumatoid arthritis and acute lymphoblastic leukemia.
- The potential for combined drug effects on growth, particularly in young individuals, warrants investigation.
Purpose of the Study:
- To investigate the medium-term effects of concurrent methotrexate and indomethacin administration on the growth of young rats.
- To assess the impact of these drugs on body weight, organ weights, food consumption, and biochemical markers related to DNA synthesis.
Main Methods:
- Four groups of Sprague-Dawley male rats were treated with MTX, indomethacin, both, or saline (control) for 10 weeks.
- Body weight, food/water consumption were monitored regularly.
- Liver, spleen, and kidney weights were measured, and MTX levels and dihydrofolate reductase activity were analyzed.
Main Results:
- The group receiving both MTX and indomethacin exhibited minimal body weight increase (17+/-11 g) compared to control and single-drug groups (p=0.001).
- Significantly reduced liver and spleen weights (p<0.01) and decreased food consumption (p<0.05) were observed in the combined treatment group.
- Increased MTX accumulation and decreased dihydrofolate reductase activity suggested enhanced inhibition of DNA synthesis.
Conclusions:
- Methotrexate and indomethacin demonstrate an additive effect in suppressing growth in young rats.
- Concurrent long-term use of these drugs may pose a risk of short-term growth suppression in pediatric patients.