METHEMALBUMIN. II. EFFECT OF PAMAQUINE AND QUININE ON PATHWAYS OF HEMOGLOBIN METABOLISM William D. Blake J Clin Invest. 1948;27(3):144-150. https://doi.org/10.1172/JCI101954. Research Article Find the latest version: https://jci.me/101954/pdf METHEMALBUMIN. II. EFFECT OF PAMAQUINE AND QUININE ON PATHWAYS OF HEMOGLOBIN METABOLISM 1, 2 By WILLIAM D. BLAKE 8 (From the Department of Medicine, New York University College of Medicine, and the Research Service, Third [New York University] Medical Division, Goldwater Memorial Hospital, New York City) (Received for publication March 12, 1947) INTRODUCTION laria during the study but the period immediately fol- lowing malaria was avoided because of the questionable Methemalbuminemia has been described in as- status of certain functions of the liver (10, 11, 12). sociation with massive intravascular hemolysis Serunm bilirubin and bromsulfalein retention tests were (1, 2, 3, 4) or with limited hemolysis in the pres- normal, unless specifically mentioned. ence of liver disease (1, 5). Similarly, the in- Pamaquine naphthoate and quinine sulfate were admin- istered orally, the dosage in each case being expressed jection of large amounts of hemoglobin may result in terms of the free base. Plasma pamaquine (13) and in methemalbuminemia (1), whereas smaller quinine concentrations (14) were estimated at intervals amounts do so only in the presence of a damaged to ascertain reliability of drug intake. Pamaquine dosage liver (6). Hematin injected intravenously rapidly regimens were either 15 mg. every four hours or 10 mg. combines with serum albumin to form methemal- every eight hours. Quinine was given as the sulfate in 0.6 gram doses every eight hours. bumin (7) which is then converted to bilirubin Commercial hemin' was recrystallized (15) prior to and is largely recoverable as fecal urobilinogen being prepared for intravenous injection (8). One of five (8). patients receiving hematin suffered dizziness and ab- It has been noted that the concurrent adminis- dominal and back pain of short duration. The injection and quinine also leads to was discontinued and the patient withdrawn from the tration of pamaquine study. Uncomplicated thrombophlebitis was encountered methemalbuminemia, whereas neither drug alone following some of the slower injections. No other un- produces this effect (9). The reproducibility of toward effects were noted. the phenomenon suggested the use of these drugs Hemoglobin solution 5 for intravenous injection was as a means of investigating methemalbumin metab- received and stored in 500 cc. sterile flasks at a concen- the tration of 7.5 ± 0.5 grams per cent. More than 98 per olism. Studies were directed toward relation- cent was present as oxyhemoglobin. One of the four ship of methemalbuminemia to the degree and patients receiving hemoglobin intravenously experienced duration of hemolysis and hemoglobinemia, to the abdominal cramps, nausea and vomiting and another, disappearance rate of methemalbumin as affected transient back pain. No hyperpyrexia or other untoward by drug action, and to the possible role of liver effects were encountered. The estimation of methemalbumin concentration has function. been described in full in the preceding paper (9). Hemo- globin was estimated by the method of Evelyn (16). MATERIALS AND METHODS Serum hemoglobin was estimated on the Beckman photo- White patients with central nervous system syphilis electric spectrophotometer by a method similar to the were used as subjects. Some received therapeutic ma- one used for methemalbumin, except that optical densi- ties were recorded at 415 mnv wave-length, the absorp- 1 The work described in this paper was done under a tion maximum of oxyhemoglobin. At this wave-length, contract, recommended by the Committee on Medical after the correction blank had been subtracted, an optical Research between the Office of Scientific Research and density of 0.076 (1 cm. cell) was estimated as equivalent Development and New York University. to a hemoglobin concentration of 1.0 mg. per cent. 2 The authors express their thanks to the Malaria Serum bilirubin was estimated by the method of Study Section of the National Institute of Health for Malloy and Evelyn (17), fecal urobilinogen by a modi- editorial assistance and for arrangements in regard to the fication of Watson's method (18) yielding 90-100 per publication of this paper. They are also grateful to the cent recovery, coproporphyrin by the method of Dobriner Abbott Laboratories, E. I. du Pont de Nemours and and Rhoads (19), and bromsulfalein retention in per cent Company, Inc., E. R. Squibb and Sons, Eli Lilly and Company, Sharp and Dohme, and Wyeth, Inc., for con- 4 Eastman Kodak Company. tributing toward the publication costs. 6 Supplied through the courtesy of Dr. Robert B. 8 Captain, MC, AUS. Pennell of Sharp & Dohme, Inc. 144 PAMAQUINE-QUININE: EFFECT ON HEMOGLOBIN METABOLISM 145 by the estimation of serum bromsulfalein at five and 30 control, pamaquine, and combined pamaquine-qui- minutes after the intravenous injection of 5 mg. per kilo nine periods (Figure 1). Pamaquine dosage of body weight. was 90 mg. per day throughout in both patients. RESULTS Only during combined drug administration was Hemolysis during combined pamaquine-quinine urobilinogen output significantly increased over administration. Fecal urobilinogen excretion was the control period. A slightly increased output estimated in two individuals during successive of doubtful significance occurred during pama- quine alone in one patient. Total coproporphyrin excretion, estimated in one of the patients, also showed an increased output only during combined 20C _REP pamaquine-quinine administration (Figure 1). The administration of 400 mg. of hematin had no effect on coproporphyrin output in this individual. 100 Methemalbuminemia not a result of hemolysis CONT PAM PAM+QUIN alone. One of the patients mentioned above de- veloped methemalbuminemia on the third day of fl COPRO. combined drug administration. It was estimated nURO. from the increment in fecal urobilinogen excre- SOC0 0 G I tion that no more than 2.5 grams of hemoglobin was catabolized per day in excess of the patient's 40C ..CRAr- - control rate. A comparable amount of hemoglobin m(D r--- 2001 was administered intravenously to five patients a-6 who were receiving no drug to determine whether 300 rn _ _ _ an equivalent degree of hemolysis alone would II I produce methemalbumin. Two patients received, 0 I__n | respectively, single doses of 7.0 and 9.0 grams of Ix aoc 200- hemoglobin in one hour (Table I) and three re- 2 ceived multiple small injections of 4.5 - 6.5 grams 100 per day in divided doses for periods of two to four Tx days (Figure 2). None developed methemalbu- CONT PAM PAM + QUIN minemia. One of the latter patients subsequently I I I I 10 5 10 15 20 25 was given a large single dose of 15.0 grams of TIME IN DAYS hemoglobin. Methemalbumin was present in the FIG. 1. FECAL UROBILINOGEN AND TOTAL COPROPOR- serum of this patient at 24 hours, at which time PHYRIN ExCRETION AS AFFECTED BY THE ADMINISTRA- no free hemoglobin was demonstrable (Table I). TION OF PAMAQUINE AND COMBINED PAMAQUINE AND Methemalbuminemia following hemoglobin in- QUININE jection during pamaquine and/or quinine ad- The excretion per 24 hours of the two pigments was ministration.' Two patients were given intra- estimated during a control period (CONT), during the - a administration of 90 mg. of pamaquine base daily (PAM), venously 4.5 6.5 grams of hemoglobin day in and during the administration of 90 mg. of pamaquine divided doses for three days during pamaquine base and 1.8 gm. quinine base daily (PAM + QUIN). and for three days during quinine administration 48-96 hour stool specimens were pooled as indicated in (Figure 2), to ascertain whether either drug alone the figure. would promote methemalbumin formation if free The excretion on patient Cra was complicated by the intravenous administration of 400 mg. of hematin, as hemoglobin were available. No significant met- indicated by the arrows on the lower part of the figure. hemalbumin appeared in one patient during the The four-day period following each hematin injection pamaquine period, whereas in the other, there was includes a blocked off area which represents the uro- trace formation. Quinine caused clear-cut met- bilinogen excretion from 50 per cent of the injected hematin on the assumption that a minimum of 50 per hemalbumin formation under the same conditions cent is recoverable as fecal urobilinogen (8). of hemoglobin administration. 146 WILLIAM D. BLAKE TABLE I Serum optical density at 405 and 415 mp wave-lengths (the absorption maxima of methemalbumin and hemoglobin respectively) 24 hours after a single intravenous dose of hemoglobin Hemolysis resulting from the handling of the blood or hemoglobinemia is judged qualitatively by the shape of the absorption curve from 540 m," to 600 mr/ wave-length. Hemo- Optical density 405 mp Optical density 415 me& Serum PatientPatient glmobi __ __ ____ ____ ___ _-H mlss Methem- globid bilirubin aHemolysisnlbumi Actual Expected Difference Actual Expected Difference grams mg. % ROF 7.0 .42 .564 .565 - .001 .619 .595 + .024 0 0 KEN 9.0 .45 .669 .580 + .089 .707 .615 + .092 + 0 BRA 15.0 .47 1.860 .590 +1.270 1.683 .630 +1.053 0 +++ BRA .40 .905 .550 + .355 .895 .585 + .310 trace + + (at 48 hours) Two patients received a similar series of hemo- jected and was superimposed upon pre-existing globin injections during combined pamaquine- methemalbuminemia present as the result of pama- quinine therapy (Figure 2). Additional met- quine-quinine administration. The amount of ad- hemalbumin was formed from the hemoglobin in- ditional methemalbumin derived from the intra- venously injected hemoglobin was of the same CONTROL PAMAQUIN QUININE PAM*+ QUIA order of magnitude as that derived from hemo- globin during the administration of quinine alone. BRA UNSHAM~LRI~E AREAS - ME Disappearance rate of serum hemoglobin re- t-fo0 tt __ -To_RX lated to combined pamaquine-quinine administra- 2.