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KMID : 0378019620050030035
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New Medical Journal
1962 Volume.5 No. 3 p.35 ~ p.82
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Studies on a Relationship between Dose, Time and Percentage of Occurrence of Response and on a Method of Evaluation of Combined Action in Drugs
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Abstract
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Various drugs, metrazol, coramin, strychnine nitrate, caffeine as central nervous system stimulants, evipan sodium as a central nervous system depressant, potassium cyanide as a general protoplasmic toxic substance, epinephrine hydrochloride as a sympatheticomimetic, acetylcholine chloride as a parasympatheticomimetic, ether and chloroform as general anesthetics were administered to 3,281 adult healthy, male and female mice of SM strain. Then general convulsion, respiratory arrest and anesthesia caused by drugs were observed. Relationships between dose, time and percentage of response in single and combined uses of the above described drugs were searched for and their mutual actions in combined administration were examined. The results obtained may be summarized as follows:
1. Formulas were presented to express the relationship between dose, time and percentage of response in single action of the above drugs in mice.
2. It is suggested that Chung´s general formula concerning stress can be applicable to biological assays of unknown drugs.
3. It is found that distributions of occurrence of response at relatively large doses in a single action of drugs become normal when the times after their administration are transformed to logarithms as suggested by Chung´s general formula.
4. Mathematical analysis appears possible in relationships between dose, time and percentage of occurrence of response in combined action of drugs as well as in single action; namely the evaluation of combined action of two kinds of drugs can be done and types of mutual action may be classified into serveral categories i. e., additively and potentiated synergistic, antagonistic, mutually independent and so on according to the following method.
The formulas (1) and (2) represent the relationship between dose, time and percentage of response in single action of two kinds of drugs, respectively.
I where D and Dz are dose of both drugs, ti and t2 are time after their administration a a2 b b2 c c
dl, d2, nl and n2 are constants dependent upon sorts of animals, drugs, observed responses and units etc. Pl´ and P2´ are ´modified probacents´, Pl and P2 ´probacents´(Chung´s abbreviation of probability percentage). Ptl and Pt2 are predicted percentage of occurrence of response in single action of both drugs, respectively.
Actually observed and theoretically calculated values of percentages of response are represented Pa and Pr, provided that additively synergistic action may occur.
If Pa ] Pr, the mutual action of both drugs is of potentiated synergistic action. If Pa=Pt, they are of additively synergistic action. If Pa < Pr and Pa > either Pt1 or Pte, they are synergistic. If Pa < Pr and Pa < either Pt, or Pte, they show antagonistic action. If Pa is independent of Pt but Pa=either Pt, or Pre, both drugs have no mutual action.
5 The relationship between dose, time and percentage of response in combined uses of anesthetics, ether and chloroform and central nervous system depressants, evipan sodium and the evaluation of their combined action can be mathematically analyzed.
6. Adaptation to anesthesia was observed in third day when mice were exposed to ether or chloroform of daily increasing concentration once a day.
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