Richard D. Propper

Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH.

Fifty-eight patients with severe, progressive multiple sclerosis were prospectively randomized to one of three treatments: 20 received intravenous ACTH, 20 received high-dose intravenous cyclophosphamide plus ACTH, and 18 were placed on a regimen consisting of plasma exchange, low-dose oral cyclophosphamide, and ACTH. The three groups were similar in age, sex, duration and type of disease, and degree of disability. Before treatment and six months and one year after treatment, a disability-status score, ambulation index, and functional-status score were determined, and a quantitative neurologic examination was performed. In the ACTH group, the number of patients stabilized or improved was 8 of 20 at six months and 4 of 20 at one year; in the cyclophosphamide-ACTH group, 18 of 20 at six months and 16 of 20 at one year; and in the plasma exchange group, 11 of 18 at six months and 9 of 18 at one year. High-dose cyclophosphamide plus ACTH was most effective in halting progression of the disease at both 6 and 12 months (at 12 months, cyclophosphamide-ACTH vs. ACTH, P = 0.0004; cyclophosphamide-ACTH vs. plasma exchange, P = 0.087). Thus, progressive multiple sclerosis may be stabilized by short-term, intensive immunosuppression with cyclophosphamide plus ACTH.

Continuous Subcutaneous Administration of Deferoxamine in Patients with Iron Overload

Since deferoxamine B, when administered as a single daily intramuscular injection of 0.75 g, is unable to promote sufficient urinary iron excretion to achieve net negative iron balance in siderosis, we evaluated its administration as a constant infusion over 24 hours. We compared intravenous and subcutaneous routes in 24 siderotic patients who had excreted 420 to 630 mg (mean, 480 mg) of iron per month on intramuscular therapy. With the intravenous route urinary iron excretions increased to 570 to 3690 mg (mean, 1595 mg) per month. Constant subcutaneous delivery was 90 per cent as effective as intravenous administration on a dose-for-dose basis. Noteworthy net cumulative urinary iron excretions (urinary iron excretions minus transfused iron), often in excess of 1 g per month, have been maintained in all patients. Constant subcutaneous deferoxamine administration may prove to be an effective and practical means of eliminating large quantities of iron in siderosis.

Prevention of Cardiac Disease by Subcutaneous Deferoxamine in Patients with Thalassemia Major

We examined the efficacy of long-term subcutaneous deferoxamine therapy in the prevention of iron-related cardiac disease in patients with thalassemia major who began treatment after the age of 10 years. Of 36 such patients without preexisting cardiac disease, 19 did not comply with the program of chelation therapy. Over the course of treatment (1977 to 1983) serum ferritin and aspartate aminotransferase levels fell in the compliant group, from mean values (+/- S.D.) of 4765 +/- 2610 to 2950 +/- 1850 ng per milliliter and 58.1 +/- 22 IU to 30 +/- 20 IU per liter, respectively (P less than 0.05), but rose in the noncompliant group, from 5000 +/- 2316 to 6040 +/- 2550 ng per milliliter and 56.6 +/- 20 to 90 +/- 35 IU per liter, respectively. Only one patient in the compliant group acquired cardiac disease and died of fulminant congestive heart failure. In contrast, 12 noncompliant patients acquired cardiac disease, and 7 died. In addition, the mean age of the compliant population (18.9 +/- 4.5 years) now approaches the mean age of acquisition of cardiac disease in the noncompliant group (19 +/- 4.3). These data demonstrate that compliance with treatment with deferoxamine may protect patients from cardiac disease induced by iron overload.

Reassessment of the use of desferrioxamine B in iron overload

Treatment of transfusion-induced iron overload by daily intramuscular injection of the chelator desferrioxamine has not produced impressive urinary iron excretion. We attempted to augment net iron excretion by altering both the route and quantity of chelator administered. Two ascorbic acid-replete patients excreted a mean of 14.5 mg of iron per 24 hours after a single intramuscular injection of 750 mg of desferrioxamine. Excretion increased to a mean of 44.9 mg when this dose was delivered by a continuous 24-hour intravenous infusion. When the intravenous dose of chelator was increased incrementally to as high as 16,000 mg per 24 hours, iron excretion increased up to 180 mg per day. At these high-dose levels, efficiency of binding of iron to chelator was compromised. Constant exposure of the labile iron pool to a chelating agent markedly enhances net iron excretion in splenectomized transfusion-dependent patients.

Thalassemia Major: Molecular and Clinical Aspects

Abstract Thalassemia major is a severe and transfusion-dependent anemia that occurs in persons homozygous for a mutation that affects the capacity for synthesis of the β- globin subunit of hemoglob...

Treatment of iron overload in adults with continuous parenteral desferrioxamine

Adult patients with transfusional hemosiderosis were given ascorbic acid and treated with the iron chelator, desferrioxamine B. The drug was administered by continuous subcutaneous or intravenous infusions using a light weight portable constant infusion device. On this regimen, four of the five patients studied were able to excrete significant amounts of iron (greater than 35 mg/da) when receiving a daily desferrioxamine dose of 1.5 to 2.2 g. Continuous subcutaneous infusion was well tolerated and about 80 per cent as effective as intravenous therapy in chelating iron. The number of prior transfusions, the hepatic iron content and the serum ferritin levels appear to be useful in predicting which patients will respond to iron chelation therapy, especially if there is little bone marrow erythropoietic activity. One patient with ineffective erythropoiesis did not have significantly increased hepatic iron stores but responded to the administration of desferrioxamine. Continuous subcutaneously administered desferrioxamine may prove to be adaptable for long-term outpatient therapy, allowing patients with ongoing transfusion requirements to go into negative iron balance. Long-term studies will be needed to demonstrate reversal of endocrine, hepatic and cardiac dysfunction secondary to iron deposition in these patients.

Qualitative deferoxamine color test for iron ingestion.

types of galactosemia in infants screened at birth, J Med Gen 10:27, 1973. 4. Levy HL, Sepe S J, Walton DS, Shih VE, Hammersen G, Houghton S, and Beutler E: Galactose-l-phosphate uridyl transferase deficiency due to Duarte/galactosemia combined variation: Clinical and biochemical studies, J I~DIATR 92:390, 1978. 5. Beutler E, and Mitchell M: New rapid method for estimation of red cell galactose-l-phosphate uridyl transferase activity, J Lab Clin Med 72:527, 1968. Ng W, Bergren WR, Fields M, and Donnell GN: An improved electrophoretic procedure for galactose-l-phosphate uridyl transferase: demonstration of multiple activity bands with the Duarte variant, Biochem Biophys Res Commun 37:354, 1969.

CHELATION THERAPY IN OLDER PATIENTS WITH THALASSEMIA MAJOR

To determine the utility of chronic subcutaneous Desferal (SCDF) therapy (Rx) in the prevention of cardiac disease in patients with thalassemia major who began treatment after the age of 10, we evaluated 36 patients; all of whom were started on SCDF when they were 10 years of age or older and had no pre-existing cardiac disease (defined as clinical congestive heart failure or abnormal left ventricular function). There were 17 compliant patients (mean age 12.3 years at onset of Rx) who used SCDF at least 5 days a week; 8-12 hours each day. Nineteen patients were noncompliant (mean age 16.6 years), they used SCDF periodically. In the group of compliant patients, the mean number of years on Desferal Rx was 4.8 years, in the noncompliant group, 4.0 years. All patients have been on a hypertransfusion regimen (maintaining a hemoglobin of 11%), at least since they began SCDF. Only one patient in the compliant group developed cardiac disease (at age 11) and she died of congestive heart failure at age 18. In contrast, 12 in the noncompliant group developed cardiac disease. Two of these patients have died. The mean age of development of cardiac disease in the noncompliant patients was 20.3 years ± 4.2 years. Therefore, the lack of cardiac complications in the compliant group suggests that compliance with SCDF Rx may reduce the risk of cardiac disease in older patients.

116 DETECTION OF PRECLINICAL LEFT VENTRICULAR DYSFUNCTION USING METHOXAMINE AFTERLOAD CHALLENGE IN PATIENTS WITH THALASSEMIA MAJOR

Cardiomyopathy is the major cause of death in patients(pt) with Thalassemia Major(TM). Standard tests of left ventricular(LV) function have not dependably identified pts with TM and cardiac dysfunction. Methoxamine afterload challenge with assessment of end systolic pressure(ESP)-dimension(ESD) relationships has been used to identify subclinical cardiac dysfunction in pts with structural heart disease. In an effort to detect early abnormalities in LV contractile reserve, 8 pts with TM, ages 6-18 years, underwent echocardiography(echo) during Methoxamine infusion. ESD was measured using standard methods. ESP was estimated from the dicrotic notch of a calibrated carotid pulse recording. All pts were asymptomatic with normal resting systolic time intervals, LV percent fractional shortening by echo and treadmill exercise capacity. ESP-D values were determined for each pt at various levels of afterload. The slope of the ESP-D curve was abnormal in 3/8 pts as defined by values > 2SD below the mean for 17 control pts. These 3 pts were the oldest subjects in the TM group. The use of Methoxamine to increase afterload in combination with readily available noninvasive techniques, offers a sensitive method of unmasking LV dysfunction not evident on standard resting or dynamic exercise tests. Serial studies using this technique may identify pts at risk for the development of cardiomyopathy.

817 SUBCUTANEOUS DEFEROXAMINE (ScDF) PLUS HYPERTRANSFUSION (HiTx) IN THALASSEMIA MAJOR (TM): A THREE YEAR FOLLOW-UP

12 TM patients (pts.) aged 5-25 yrs. on moderate Tx protocol were begun on HiTx and ScDF with yearly monitoring of serum ferritin (SF), height age (HA), bone age (BA), cardiac function (CF [eccho, EKG, treadmill, Holter]), and GTT. Net negative iron balance was maintained. Results are tabulated.Comparison of Initial and 3 Yr. Follow-Up Study by PresentingThe above data suggests that young pts. with TM may be protected from iron overload sequelae by the early administration of HiTx and ScDF. Similar therapy in older patients does not seem to prevent the development of or improve existing overt pathology.