Mepacrine and Falciparum Malaria: A Study of the Chemotherapeutic, Pharmacological, and Toxic Properties of the Drug

Reid, James (1946) Mepacrine and Falciparum Malaria: A Study of the Chemotherapeutic, Pharmacological, and Toxic Properties of the Drug. PhD thesis, University of Glasgow.

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1. Prevention of falciparum malaria in volunteers experimentally infected with sporozoites has been found to depend on the concentration of mepacrine in the blood. When the blood mepacrine is 100 mug. per litre or more, malaria does not appear. But, when the blood mepacrine is less than 100 mug. per litre, a fever develops that is almost certainly malarial in origin, though parasites are not usually found in the blood. Whether this fever is self-limiting, or whether it develops into a frank attack of malaria, depends on whether enough mepacrine is transferred from tissues to the blood to raise the blood mepacrine to a parasiticidal level. The transference of mepacrine from tissues to the blood is considered to be due to a diminution in the tissue: blood partition of the drug resulting from the change in pH. of tissues and blood that accompanies fever. 2. The dye properties of mepacrine are most important in determining the distribution of the drug in the body. The drug tends to concentrate in tissues rather than in internal body fluids. For this reason tissue mepacrine is the dominant pharmacological factor. It is largely responsible for the persistence of the drug in the body long after dosing has been stopped. Blood mepacrine is directly proportional to tissue mepacrine, and the partition of the drug between the two is determined by the pH of tissues and blood. In healthy men engaged in sedentary occupations, the tissue : blood partition is practically constant. In disease associated with diminution in pH of tissues and blood, the partition may be markedly diminished, with the result that blood mepacrine increases at the expense of tissue mepacrine. The blood- and tissue-mepacrine levels of healthy individuals depend mainly on dose. For each dose, an equilibrium between dose and blood- and tissue-mepacrine, is eventually reached. The greater the dose, the higher the blood- and tissue-mepacrines. Absorption of mepacrine is inversely proportional to the blood- and tissue-levels of the drug. That is, when blood- and tissue-levels are low, maximal adsorption takes palace; when blood and tissue-levels are in equilibrium with dose, absorption is minimal and is determined by the amount or drug degraded in the tissues. Dagradation of mepacrine which occurs in tissues, blood, and alimentary tract is probably an oxidative process in the first place. Evidence has been found suggesting that the rate of degradation in blood is proportional to the rate of degradation in tissues, and that both are proportional to the respective concentration in blood and tissues. Degradation by alimentary contents is considered to be mainly responsible for the fall in blood mepacrine from the initial peak, to the late stable level that has been observed after prolonged administration of the drug. Mepacrine is mainly excreted in urine and faeces, and the total excretion of the drug is determined by the blood- and tissue-mepacrine levels. When these are high, greater amounts are excreted than when they are low. After tablets by mouth, the blood mepacrine is much lower than after parenteral or rectal injection of the same dose. The difference is due, partly to the time required for solution of the tablets, partly to the pH effect of the gastric contents, and partly to diminished absorption resulting from degradation of mepacrine in the bowel. Combined parenteral and Oral administration may result in very high blood-mepacrine levels. Parenteral injection seems, in a way that is not understood, to increase subsequent absorption from the bowel. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Medicine, Pharmacology
Date of Award: 1946
Depositing User: Enlighten Team
Unique ID: glathesis:1946-79616
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 31 Mar 2020 09:09
Last Modified: 31 Mar 2020 09:09

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