Showing papers by "Gary M. Brittenham published in 1990"

Variation in hemoglobin concentration among samples of high-altitude natives in the Andes and the Himalayas.

Abstract: This paper presents data on hemoglobin concentration in a rural Andean sample at 3,800-3,900 m and incorporates them into a review intended to evaluate possible sources of the range of variation in mean hemoglobin concentration among samples obtained at high altitude. Between 3,400 and 4,000 m, rural Himalayan highlanders average 1.4 gm/dl lower mean hemoglobin concentration than rural Andean highlanders. With respect to potential causes of anemia, it is concluded that the relatively low values of rural Himalyan populations are not explicable by lower hypoxic stress or different techniques of obtaining and analyzing blood samples and are probably not explicable by nutritional deficiency and disease. With respect to potential causes of polycythemia within Andean populations, it is concluded that the somewhat higher values of some mining and urban samples of Andean higlanders may not be due to the mining occupation per se but may be due partly to the inclusion of European and mestizo (with at most 500 years of high-altitude ancestry) along with Amerindian highlanders (with millenia of high-altitude ancestry) as well as to the inclusion of highlanders living well above their own habitual altitudes of residence. The Andean polycythemia is probably not due to obesity, high androgen levels, or frequent intermittent hypoxemia during sleep. The effect of heavy smoking cannot be evaluated. Further work on hematological adaptation to high altitude must pay special attention to sample characteristics.

Pyridoxal Isonicotinoyl Hydrazone

Abstract: Both the quality and t h e length of life of patients with Cooky's anemia could be substantially improved by the developrncnt of a safe, inexpcnsivc chelating agent that cffectively promotes the excretion of iron after oral administration. Without therapy, potentially lethal amounts of iron accumulate in patients with refractory anemia who require regular blood transfusions, absorb excessive amounts of dietary iron, or both. Because the body lacks an effective means to eliminate excess iron, the iron contained in transfused red cells or derived from dietary absorption is progressively deposited in the liver, heart, pancreas, and other organs. Cirrhosis, heart disease, diabetes, and other disorders develop; death is usually the result of cardiac failure. New rncans of treating and preventing these complications of iron overload may soon become available with the continued development of several orally active ironchelating agents that are now in or near clinical trial.'-f' The results of preclinical and clinical studies with one of these agents, pyridoxal isonicotinoyl hydrazone (PIH), will be reviewed here. Both the distinctive pharmacokinetic profile of PIH and the extcnsivc experience in the use of its constituents, isoniazid (INH) and pyridoxal (vitamin BJ, in the chronic therapy of tuberculosis suggest that this chelator may he ii safe and non-toxic agent that is particularly well suited for prolonged use in the treatment of iron overload in Cooky's anemia.

The Interference of Pyridoxal Isonicotinoyl Hydrazone with Intestinal Iron Absorption

Abstract: A number of new oral iron-chelating compounds have been developed for the treatment of iron overload. Among thcse, acute and subacute toxicity tests suggest that pyridoxal isonicotinoyl hydrazone (PIH) has very low toxicity in both animals and humans.’ Phase I1 clinical trials are now being conducted. Although some chelators showed high efficiency in iron excretion, long-term oral administration at low dose failed to show any reduction in hepatic iron in animals.’ It has been proposed that the “low-dose effect” is due to their capacity to transport dietary iron across the gastrointestinal (GI) barrier. The aim of this study is to determine whether PIH has any enhancing effect on intestinal iron absorption, a criterion for furthcr clinical evaluation. Studies were performed in 6 adult male patients, aged 15-31 years, with P-thalassemia/Hb E disease who were not regularly transfused. All were in steadystate without complication or recent blood transfusion at the time of study. They were markedly anemic with moderate degrees of iron overload. No medication was given three days before and during the four-week study period except as described below. Two iron absorption measurements were performed in each patient by the whole-body counting te~hnique ,~ one with oral PIH plus radioiron ascorbate, the other as a control of radioiron absorption. To prevent acid hydrolysis of PIH, 150 mg of ranitidine was given twice a day, at 6 A.M. and 6 P.M., for five days (days -2,0, +2). Overnight-fasted subjects were fed with 1 pCi (5 mg) [59Fe]ferrous ulfate with 50 mg ascorbic acid plus 3 capsules of 200 mg PIH. The percent radioiron retention was evaluated on day 14, when the same dose of radioiron ascorbate was readministered; and iron absorption was measured on day 28 as the control. Hematologic examina-