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[General pharmacological studies on human natural tumor necrosis factor (MHR-24)]
1Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan.
Abstract:
The general pharmacological properties of MHR-24 were studied in various experimental animals. Intravenously (i.v.)-administered MHR-24 at 8.6 x 10(2) JRU/kg or more produced fever in rabbits. MHR-24 at 3 x 10(4) JRU/kg or more caused tachycardia; and at 1 x 10(5) JRU/kg or more, it lowered arterial blood pressure in anesthetized monkeys. In rats, MHR-24 at 2.9 x 10(4) JRU/kg or more showed a diuretic action and inhibitory effects on gastric juice secretion and carrageenin-induced paw edema. Furthermore, MHR-24 at a large dose (8.6 x 10(4) or 2.9 x 10(5) JRU/kg, i.v.) decreased spontaneous locomotor activity, had an inhibitory effect on acetic acid-induced writhing and potentiated intestinal propulsion in mice; and it caused the appearance of rest wave on acute spontaneous electroencephalograms in rabbits. Pretreatment of the animals with the cyclooxygenase inhibitor indomethacin abolished the fever and potentiation of intestinal propulsion caused by MHR-24. Therefore, these data seem to indicate that some of the effects of MHR-24 are mediated via cyclooxygenase pathways. The results suggested that, except for the above results, MHR-24 has no noticeable effects on the central nervous, autonomic nervous, respiratory and cardiovascular systems and others in general pharmacological studies.
Insights
MHR-24 administration in animals induced fever, tachycardia, and lowered blood pressure. Some effects, like fever and enhanced intestinal propulsion, were blocked by indomethacin, suggesting cyclooxygenase pathway involvement.
Area of Science:
- Pharmacology
- Drug Discovery
Background:
- Understanding the general pharmacological properties of novel compounds is crucial for drug development.
- MHR-24 is a compound with potential therapeutic applications requiring comprehensive safety and efficacy evaluation.
Purpose of the Study:
- To investigate the general pharmacological effects of MHR-24 in various experimental animal models.
- To elucidate the potential mechanisms of action for observed MHR-24 effects, particularly concerning cyclooxygenase pathways.
Main Methods:
- Administration of MHR-24 via intravenous (i.v.) route to rabbits, anesthetized monkeys, rats, and mice at varying dosages.
- Observation of physiological responses including body temperature, heart rate, arterial blood pressure, diuresis, gastric secretion, and edema.
- Assessment of central nervous system effects, locomotor activity, pain response, and electroencephalograms (EEGs).
- Evaluation of MHR-24's mechanism of action through pretreatment with the cyclooxygenase inhibitor, indomethacin.
Main Results:
- MHR-24 induced fever in rabbits, tachycardia and hypotension in monkeys, and diuretic and anti-secretory effects in rats.
- In mice, MHR-24 reduced locomotor activity, inhibited writhing, and potentiated intestinal propulsion. In rabbits, it induced rest waves on EEGs.
- Indomethacin pretreatment abolished MHR-24-induced fever and potentiation of intestinal propulsion, indicating involvement of cyclooxygenase pathways.
Conclusions:
- MHR-24 exhibits a range of pharmacological effects across different physiological systems in animal models.
- The findings suggest that certain effects of MHR-24 are mediated through cyclooxygenase pathways.
- MHR-24 demonstrated no significant adverse effects on the central nervous, autonomic nervous, respiratory, or cardiovascular systems in general pharmacological studies.