Studies on the Chemotherapy of the Human Malarias. Ix. Effect of Pamaquine on the Blood Cells of Man 123

Abstract

Pamaquine (6-methoxy-8-amino [N-diethylaminoisopentyl] quinoline) is recognized to be a potentially dangerous drug. However, a definitive appraisal of its hazard had not been achieved at a time when the further exploration of the antimalarial activity of the 8-aminoquinolines was considered advisable. Pamaquine toxicity can involve the gastro-intestinal tract, the central nervous system, and the circulating blood. Symptoms referable to the gastro-intestinal tract and the central nervous system may be annoying, but there is no evidence that they constitute a hazard to life or persist beyond the termination of therapy. Effects on the blood do constitute a serious hazard and are considered in this paper. MATERIALS AND METHODSMost of the patients utilized as subjects either were having malaria at the time of the observations or had had the disease from one to six weeks previously. None of the patients had malaria long enough to be considered likely subjects for the development of blackwater fever. Most subjects were suffering from asymptomatic neurosyphilis and many had received prior antiluetic therapy. (e) Fragility of erythrocytes to hypotonic saline. A 2 per cent suspension of erythrocytes in sterile physiological saline was prepared from blood containing one drop of saturated potassium oxalate per 5 ml. of blood. 0.5 ml. of the cell suspension was added as soon as possible to 2 ml. each of 0.9 per cent sodium chloride (control), to distilled water (total hemoglobin), and to a series of sodium chloride dilutions usually ranging from 0.48 per 121

Studies on the Chemotherapy of the Human Malarias. Viii. The Physiological Disposition of Pamaquine 123

“…Data presented in another paper (6) support this statement as far as leukopenia and methemoglobinemia are concerned. It is, therefore, proposed that the modification of pamaquine disposition effected by quinacrine represents a specific example of a mechanism whereby one drug (quinacrine) potentiates the activity (toxic) of another (pamaquine).…”

Determinants of relapse periodicity in Plasmodium vivax malaria

“…It was noted that haemolytic reactions occurred sporadically with plasmoquine in patients of Asian, African or South European descent, but were uncommon in Caucasians originating further north [88]. This was explained later by the epidemiology of glucose-6-phosphate dehydrogenase deficiency.…”

“…Furthermore resistance arose readily to the antifol anti-malarials in P. vivax . Although plasmoquine was moderately effective it was relatively poorly tolerated in the dose regimens necessary to prevent relapse (radical cure) [83-88]. The more effective and better tolerated 8-aminoquinolines pentaquine and then primaquine were developed and evaluated between 1944 and 1955 [122-126].…”

Pharmacogenetics begins to deliver on its promises

“…Furthermore, black patients were more susceptible to this adverse effect. 3 Similar observations in the 1950s led to the birth of pharmacogenetics; the study of hereditary influences on drug response with Mendel's laws of inheritance and Garrod's "inborn errors of metabolism" providing the theoretical framework.…”