Paul E. Carson

BIOCHEMICAL AND GENETIC ASPECTS OF PRIMAQUINE-SENSITIVE HEMOLYTIC ANEMIA

Excerpt Acute hemolysis, which may destroy half the red cells within a few days, occurs in approximately 10% of otherwise healthy American Negroes, very rarely in Caucasians,1, 2, 3when 30 mg. prim...

Host Failure in Treatment of Malaria with Sulfalene and Pyrimethamine

An individual infected with a multidrug-resistant strain of Plasmodium falciparum failed to respond to treatment with sulfalene and pyrimethamine. Subinoculation studies showed that parasite resistance to the drug combination was not present. Plasma levels of sulfalene and pyrimethamine in this individual were similar to those of three individuals, subinoculated from him, who were cured by the drug combination. Erythrocyte levels of sulfalene in this individual were similar to those in an individual, subinoculated from him, who was cured by the drug combination. After treatment with the drug combination, in vitro tests showed similar antimalarial activity in the serum of this individual in comparison with the serum of this individual in comparison with the serum of an individual subinoculated from him. The failure of this individual to respond to treatment with sulfalene and pyrimethamine is attributed to an undefined host factor (or factors) that appear(s) to be present in his erythrocytes.

HEMOLYSIS DUE TO INHERITED ERYTHROCYTE ENZYME DEFICIENCIES

The term, pharmacogenetics, is especially apt when applied to the development of our knowledge of the inherited erythrocyte enzyme deficiencies which result in increased hemolytic susceptibility. We discovered glucose-6-phosphate dehydrogenase (G6PD) deficiency in this context as part of the study of primaquineinduced hemolysis.1.2 Subsequently, several genetically determined erythrocytic deficiencies have been reported in association with increased hemolytic susceptibility and representative examples are given in TABLE l.3-12 The discovery of additional deficiencies is readily predictable. The division into two groups shown in TABLE 1 is a clinical rather than a biochemical distinction, although as indicated both in the Table and in FIGURE 1, showing the biochemical relationships, the groups naturally fall into disorders of the pentose phosphate pathway as opposed to those of the glycolytic pathway. Normally, the pentose phosphate pathway is relatively inactive and hexokinase deficiency would be expected, therefore, to present like other deficiencies of the glycolytic pathway. Although glutathione (GSH) is not an enzyme, its deficiency is considered to be an enzymatic defect of synthesis. The clinical distinction between the two groups arises from the following considerations. All of the deficiencies so far reported for enzymes of the glycolytic pathway have, to the best of my knowledge, been sought for and found in patients with chronic nonspherocytic hemolytic anemia. Furthermore, there is apparently no evidence that deficiencies of the glycolytic pathway result in increased susceptibility to drug-induced hemolysis, and, whether these deficiencies can occur without spontaneous hemolytic anemia is questionable. Certainly if a genetic defect in the glycolytic pathway were to be found in an individual without clinical evidence of hematological abnormality, testing the blood from this subject for increased hemolytic susceptibility to pharmacological agents would be very important. On the other hand, with the possible exception of glutathione deficiency, the elements of the oxidative reactions of the pentose phosphate pathway can be deficient in individuals who do not have clinically evident hematological abnormality. In G6PD deficiency this is the rule rather than the exception. In these individuals the increased hemolytic susceptibility is revealed even during health by ingestion of agents such as primaquine, various other drugs, or fava beans.2 From the pharmacological point of view we can say, therefore, that most of the results of the last few years which might appropriately be discussed in this monograph have been found in the conditions associated with defects of the pentose phosphate pathway rather than those of the glycolytic pathway and the remainder of this paper will be devoted primarily to the pentose phosphate pathway. Until recently the inclusion of 6-phosphogluconic dehydrogenase (6PGD) deficiency in the list of those susceptible to primaquine-induced hernolysis was tentative. In the case reported by Dern, et d . l 3 only partial deficiency was found and the patient was also heterozygous for G6PD deficiency. We have now had an opportunity, however, to test the hemolytic susceptibility of blood from the

Intravenous Glucose Tolerance in Negro Men Deficient in Glucose-6-Phosphate Dehydrogenase

Abstract Standard intravenous, cortisone-modified intravenous and oral glucose tolerance tests were carried out in 10 Negro men with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and in 10 normal Negro men. The mean age and weight were identical in the G-6-PD-deficient and the normal men. No significant differences were demonstrated between mean blood glucose levels in the G-6-PD-deficient men and those in the normal men during standard oral glucose tolerance tests. In contrast, the results of both the standard and the cortisone-modified intravenous glucose tolerance tests revealed significantly higher blood glucose levels in the G-6-PD-deficient men at 20, 30, 40, 50 and 60 minutes. Despite the higher blood glucose levels, mean serum immunoreactive insulin levels in the G-6-PD-deficient men were not significantly different from those in the normal men. Additional evidence of altered glucose metabolism associated with G-6-PD deficiency is thus provided.

The Metabolic Basis of Inherited Disease

The second edition of this book follows the first by six years. The advances in genetics have been so extensive in this time that total revision has been necessary; not only has each chapter been rewritten due to advances within each subject, but several new chapters have been added. Some idea of this expansion may be gained from the fact that this edition weighs 7 lb compared to a little over 4 lb for the first. The quality of this edition, however, is also markedly improved. The book is divided into 12 parts and a short appendix. The introductory part has been expanded to three chapters covering basic principles of inherited variation and metabolic abnormality, coding, information transfer and protein synthesis, and the cytologie bases of human heredity. There is great emphasis on the newer knowledge of genetics in terms of regulatory processes expressed in current genetic nomenclature, eg, structural genes, operator genes,