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Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema
Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema Albert
L. Sheffer,
M.D., Douglas
T. Fearon, M.D., and K. Frank Austen,
M.D.
Boston, Muss.
Daily therapy and alternate-day therapy with the attenuuted androgen oxymetholone were compared in patients tvith hereditary angioedema (HAE). Fifteen of 16 patients who experienced Lit leust monthly attucks of HAE without treatment tvere asymptomatic on administration of 5 mg oxymrtholene daily. When 13 of the patients who had been maintained asymptomutitnlly on 5 mg oxymetholone duily were advanced to a treatment schedule of 5 mg every other day, seven clttclc,ks occurred during a cumulative 50 mo of therupy. The adL)erse effects that occurred with duily oxymetholone therapy largely subsided when the patients received ulternute-duy therapy. Stati.stically signi$cunt meun increases in serum levels of CiINH occurred with daily therapy ~md \c‘ere maintained with alternnte-day therupy. while a signijic,unt meun rise in C4 protein and fi*nction oc,curred only on daily therapy. Clinic,& benejit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise CilNH to the lower limit of normal. The jnding that ulternate-day therapy diminished the side eflects of’the drug while uffording a substantial reduction in the incidence and severity of trttucks indicates the,feasibility of this therapeutic, approach.
Prophylactic administration of androgens’, ’ or anabolic steroids with impeded androgenic effects”-” prevents spontaneous attacks of angioedema in patients with hereditary angioedema (HAE). Partial correction of the deficiency in serum of the inhibitor of the activated first component of complement (CiINH) and some reversal of the secondarily depressed serum levels of C4 occur during such treatment. Therapy with these agents over long periods of time requires consideration of their side effects,6 which include an impairment of growth rate,6 virilization,7. 8 and hepatic dysfunction.” Since these adverse effects appear to be dose related,‘” a study was initiated to establish the lowest dosage schedule of oxymetholone, an impeded androgen, required to eliminate attacks in affected individuals. Serum levels of CiINH and C4 __From the Departmentsof Medicine, Harvard Medical School and the Robert B. Brigham Division of the Affiliated Hospitals Center, Inc. Supported by Grants AI-07722, AI-10356, AM-05577, and RR05669 from the National Institutes of Health. Received for publication Jan. 18, 1979. Accepted for publication May 2, 1979. Reprint requeststo: Albert L. Sheffer, M.D., Robert B. Brigham Hospital, 125 Parker Hill Ave., Boston, MA 02120.
were assessed to determine if these parameters could be predictive of a clinical response. MATERIALS
AND METHODS
Oxymetholone [ 17-beta-hydroxy-2-(hydroxymethylene)17-methyl-5-alpha-androstan-3-one] was supplied by Dr. G. H. Tarr, Jr., Parke, Davis & Co., Detroit, Mich. All patients received an initial daily doseof 5 mg. If symptoms were controlled for at least 2 to 3 mo, patients were advancedto 5 mg oxymetholone every other day. Patientswho were asymptomaticon this dosageschedule were advanced to 5 mg oxymetholone every third day. The population consisted of eight male and eight female patients of postpubertalage (Table I) who, when untreated, experiencedat least monthly attacksof cutaneous or gastrointestinal angioedema.Patients 2, 5, 6, 9, and 11, and Patients 3, 5. 6, and 10 had previously participated in two double-blind, crossover studies in which the monthly attack rate with placebo was compared with the less frequent incidence of attacks with tranexamic acid” and methyltestosterone therapy,’ respectively. Twelve unrelated patients had reduced CiINH protein levels; two brothers (Patients 5 and 6) as well as two unrelated women (Patients 4 and 15) had the variant form of the disease with nonfunctional CiINH.” Each patient maintained a daily diary indicating the occurrence, severity, and duration of cutaneous, gastrointestinal, and/or upper respiratory attacks.
0091-6749179/100275+06$00.60/0 0 1979 The C. V. Mosby Co.
Vol. 64, No. 4, pp. 275-280
276
Sheffer
J. ALLERGY
et al.
TABLE I. Symptoms accompanying for management of HAE
daily dosage
and altered
dosage
schedules
Attackslmo. Patient No. 1
2 3 4 5 6 7 8 9
IO II 12 13 14 15 16
Sex
F F M F M M F M M M F F M F F M
Age (vr)
30 33 47 19 30
45 30
36 27 31 51 56 25
32 43 61
Attack without
frequency treatment
Monthly; C, GI, UR Monthly; C, GI, UR Monthly; C, GI Weekly; C, GI Monthly; C, Gl Monthly; C, GI Weekly; C, GI Weekly; C Monthly; C, GI Monthly; C, GI Monthly; C, GI Monthly; C, GI Monthly; C, GI, UR Monthly; C, GI Every 2 wk; C, GI Every 2 wk; C, GI
*
Treatment duration (mo)
Daily treatment
I1 12
O/IO o/3
15 1.5 16
o/10
16 3 6 13
O/8 o/9 o/9 o/3 C/6 O/8
14
O/l I
12 8
o/4 O/l o/4 o/3 o/2
10 5 8
II
Total
of oxymetholone
of treatment
Alternateday treatment
C/l O/I o/2 o/4 c, GI’F/7 O/7
Increasedto IO mg/day GI/5 O/l O/7 C/1 C/6 c/2 C/6
CLIN. IMMUNOL OCTOBER 1979
Every-third-day treatment
c, G11/8 C, GIt/3 c, GIf/3
c/2 C/l
O/I 1 l/108
7/50
5/17
*C: Cutaneous attacks; GI: gastrointestinal attacks; UR: upper respiratory attacks. tconcurrent manifestations.
Patients were assessedevery 2 to 4 mo for serum levels of CIINH and C4 protein and function.‘. ” Urinalysis, complete blood count, serum glutamic-pyruvic transaminase, urea nitrogen, glucose, total protein, albumin, calcium, lactic dehydrogenase,alkaline phosphatase,cholesterol, creatine phosphokinase (CPK), and uric acid were determinedwhen patients entered the study and during subsequentintervals of 2 to 4 mo for possible toxic alterations. Complete physical examination with particular notation of breast, hepatic, and prostatic assessmentswas performed before, at periodic intervals during, and at the conclusion of the study. This experimental design was approved by the Hospital Human Study Committee, and informed consent was obtained from each patient.
RESULTS The study was initiated in May, 1976, and completed in October, 1977. Of the 16 patients entering the study (Table I), 15 had no attack of angioedema when receiving 5 mg oxymetholone daily. One symptomatic patient (Patient 8) required 10 mg daily for complete freedom from attacks, and the 5-mg dose of oxymetholone was discontinued in one asymptomatic patient (Patient 7) because of depression. One patient (Patient 16) elected to maintain a daily dose of 5 mg because of complete relief of a 35yr history of abdominal pain. Thirteen patients, asymptomatic on 5 mg daily, were advanced to 5 mg oxymetholone every other day. Six of the 13 remained asymptomatic
at this lower dose while seven had mild attacks. In only one patient (Patient 1) was therapy with 5 mg oxymetholone daily reinstituted, and another (Patient 14) interrupted therapy because of the inconvenience of traveling from another country. Five of the 6 who were asymptomatic on alternate-day therapy were advanced to 5 mg oxymetholone every third day. None of the patients remained free of attacks of angioedema while receiving every-third-day treatment. This dosage was maintained, however, because of the reduced severity and duration of attacks. The effect of dosage schedule on the occurrence of adverse reactions is presented in Table II. Three patients ( 1, 8, and 12) experienced no adverse effects from daily therapy. Adverse effects of daily oxymetholone therapy in 13 patients for periods of 2 to 1 1 mo included depression, elevations in serum CPK and alkaline phosphatase, menstrual changes, and weight gain. Seven male patients had elevated serum levels of CPK, and the eighth man (Patient 8) consistently had normal values despite a maintenance dose of 10 mg oxymetholone. Isoenzyme analysis conducted in one instance (Patient 10) revealed that CPK was of skeletal muscle origin. CPK values returned to normal on alternate-day therapy in five patients and on daily therapy in one, but remained elevated in one patient when analyzed during an every-third-day treatment period. No CPK elevation occurred in women. Al-
VOLUME NUMBER
Effects of oxymetholone
64 il
TABLE II. Adverse effects treatment of HAE Patient No.
Sex
2
F F
3 4
M F
5 6
M M
7
F
8 9
M M
IO
M
I
II 12 13 14
F F M F
15 16
F M
with
daily dosage
and altered
Daily treatment
None Depression Oligomenorrhea CPKt = 228 Gained 9 lb Deepening voice Acne CPK = 294 Gained 1I lb CPK = 202 Amenorrhea Depression None Gained 17 lb Alk. phos.$ = 12.4 CPK = 310 Gained I2 lb Alk. phos. = 12.2 CPK = 534 Deepening voice None CPK = 312 Gained 5 lb Menorrhagia Gained 13 lb Gained 7 lb CPK = 312
dosage
schedules
on angioedema
therapy
277
of oxymetholone
Alternate-day treatment
None* None None None Gained 5 lb Deepening voice Less acne None Unchanged None
None None None None Not determined Not determined Deepening voice None None None None None
Every-third-day treatment
None None None None Deepeningvoice
Alk.phos. = 10.2 CPK = 262 None
*None:No abnormalityappearedor an abnormalitypresenton the morefrequentdosageschedulesubsided. TCPK:Creatinephosphokinase; normalrange,50 to 180IU. iAlk phos.: Alkaline phosphotase; normal range, 2.5 to 9.7 IU.
kaline phosphatase levels were elevated in two men (Patients 9 and 10) on daily therapy and remained elevated in one of these on every-third-day treatment. Two women (Patients 2 and 7) experienced oligomenorrhea on daily therapy. Patient 7 stopped treatment, and in Patient 2 a normal cycle developed on an alternate-day schedule. The only instance of menorrhagia (Patient 14) occurred on daily therapy, with normal cycles reappearing on alternate-day therapy. Depression occurred in two instances (Patients 2 and 7) and prompted discontinuation of therapy in one (Patient 7). The other patient was continued on alternate-day therapy. Two patients (4 and 11) experienced masculinizing effects characterized by deepening of the voice, and this symptom was not altered by alternate-day treatment. Acne, which was present in Patient 4, diminished on alternate-day treatment. Weight gain occurred during daily treatment in seven patients and averaged 10.6 pounds. In five the gain was maintained on alternate-day therspy, while there
was a further weight gain in Patient 4 and a 4-pound weight loss in Patient 9 on alternate-day therapy. The mean serum level of CiINH function during daily (Fig. 1, Table III) and alternate-day therapy increased 129% (t = 4.49, p < 0.001) and 83% (t = 2.29, p < 0.05), respectively, over the mean serum level obtained during symptom-free intervals prior to therapy. Mean plasma levels of C4 function increased 158% (t = 2.84, p < 0.01) on daily and 52% (t = 1.07, p > 0.10) on alternate-day therapy, whereas mean serum levels of C4 protein demonstrated less marked increases of 85% (t = 4.88, p < 0.001) and 22% (t = 1.46, p > 0. lo), respectively. Normal serum levels for C iINH and C4 were uncommon during daily therapy with oxymetholone, and the mean functional concentrations for all patients were less than half the lower limit for normal individuals. There were no significant differences in CiINH function and C4 protein and function between patients having mild attacks of angioedema on alter-
278 Sheffer et al.
J. ALLERGY
FIG. 1. Serum complement component levels with daily dosage and altered dosage oxymetholone for management of HAE. o = No therapy; A = daily therapy; n = therapy. Shaded areas represent the mean rt 1 SEM for each treatment regimen. of normal are: 19,700 U/ml for CilNH function, 130,000 U/ml for C4 function, and C4 protein.
TABLE III. Mean levels of serum complement schedules of oxymetholone therapy for HAE Treatment
schedule
C4 function
component
(U/ml)
with daily dosage
C4 protein
(pglml)
CLIN. IMMUNOL OCTOBER 1979
schedules of alternate-day Lower limits 258 pgiml for
and altered
CilNH
dosage
function
(U/ml)
Daily
61,017
Alternate day Every third day
36,800 11,000
235 157 121
9,690 6,970 4,360
Normal ranges
130,000-391,000
258-832
19,700-55,000
nate-day therapy and those who had no attacks. Five serum samples available from three patients receiving oxymetholone every third day demonstrated complement levels no different from those of untreated patients (Table III). DISCUSSION The findings of Spaulding’ that administration of androgens to patients with HAE prevents spontaneous attacks have recently been confirmed* and extended by demonstrating the efficacy of anabolic steroids with impeded androgenic effects.“-j Although the utilization of the latter agents minimizes the virilizing side effects of this therapeutic approach, it does not exclude the other complications observed with these agents in other clinical circumstances, such as hepatic toxicity,g depression, and disorders of the menstrual cycle.’ As these side effects are dose related, their containment can be approached by identifying the minimal dosage schedule affording symptomatic relief. In the present study, 1.5of 16 patients who experienced monthly attacks of angioedema without treatment or during previous studies when given placebo (Patients 2, 3, 5, 6, 9, 10, and 11) were asymptomatic while receiving 5 mg oxymetholone daily, an
amount found effective by Davis et al.” The sixteenth (Patient 8) was asymptomatic on 10 mg daily, which was the dose utilized in the controlled study of Rosse et al.” Thirteen of the patients who were maintained in an asymptomatic state on 5 mg oxymetholone daily (Table I) were advanced to 5 mg every other day. Six remained asymptomatic on alternate-day therapy, while each of the other seven experienced an attack of angioedema which was milder than that encountered during periods without therapy. Five of the six who were asymptomatic on alternate-day therapy advanced to every-third-day therapy. None of these maintained an asymptomatic state, and each experienced an attack of angioedema of an intensity milder than that during control or placebo therapy. The cumulative number of attacks relative to the number of months of treatment was one attack per 108 mo for 16 patients receiving 5 mg oxymetholone daily, seven in 50 mo for 13 patients on alternate-day therapy, and five in 17 mo for the five patients on every-third-day therapy. Since all these patients entered the study because of historical data of attacks occurring at least monthly, as confirmed in previous double-blind cross-over studies in seven patients,“. ”
VOLUME NUMBER
64 4
it is concluded that daily therapy is almost uniformly effective at the 5 mg dose. Alternate-day therapy is efficacious in maintaining some patients in an asymptomatic state, and in ameliorating the severity and duration of those attacks that do occur. The adverse effects of daily oxymetholone treatment (Table 11) included weight gain in three female (4, 14, and IS) and four male patients (6, 9, 10, and 16). This problem was substantially diminished on alternate-day therapy in that there was no further weight gain in six of the patients. The elevation in CPK occurred only in the male patients, appearing in seven of eight, and disappeared in five of these on alternate-day therapy and in one while continuing daily therapy (Patient 16). Two male patients (9 and 10) experienced a rise in alkaline phosphatase, which persisted in one on the altered dosage schedule. There were no other abnormalities of liver function parameters. Three (Patients 2, 7, and 14) of the eight female patients experienced disorders of the menstrual cycle on daily therapy, and in two instances (Patients 2 and 14) the irregularity subsided with alternate-day treatment. Depression occurred in two of these same patients and was alleviated in one by alternate-day therapy, while the other patient elected to discontinue using the drug. The reduced toxicity observed on alternate-day therapy could be a result of the altered schedule, or the diminished total dosage for 48 hr, or both. Biochemical support for the clinical efficacy of this type of therapeutic approach23‘. Rwas afforded by the immunochemical evidence that CiINH as well as C4 protein and function rose during periods of effective management with androgens or with anabolic steroids with impeded androgenic effect. The capacity of anabolic steroids to increase the serum concentration of CiINH in patients with HAE is thought to be secondary to stimulation of synthesis of the protein, although this has not been proven. As the disease is expressed in the heterozygous state, patients are presumed to be synthesizing the equivalent of one normal gene product. The reduction of normal serum level to less than half may reflect a non-concentrationdependent consumption of a constant amount of CiINH by stoichiometric interaction with “spontaneously” activated Ci. Danazol treatment of patients with the variant form of the diseaseI increases serum levels of normal CiINH only but not of the nonfunctional, antigenically detectable CiINH.13 These studies were interpreted as suggesting that anabolic agents augment synthesis only by the normal gene. This interpretation still leaves open the question of how much stimulation is required to achieve a satisfactory clinical response and whether or not that response is
Effects of oxymetholone
on angioedema
therapy
279
related to a specific serum concentration of ClINH. The statistically significant mean increases in serum levels of functional CiINH were 129% on daily therapy and 83% on alternate-day therapy (Fig. 1, Table III). Five of the six patients who were asymptomatic on alternate-day therapy had mean increases in serum CiINH levels that were less than those observed for the seven patients who experienced attacks while on this dosage schedule. Thus, it was not possible to predict the clinical response based on this biochemical measurement. The mean rise in C4 function and protein was statistically significant on daily therapy, but was not significant for the 13 patients on alternate-day therapy. There was no difference between the mean levels of C4 function or protein in those patients who were asymptomatic and those who had symptoms on alternate-day therapy. Thus, clinical benefit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise C iINH function to the lower limit of normal. In all likelihood, even a modest rise in CiINH controls the episodic increases in Ci so as to either prevent generation of the putative pathogenetic cleavage peptide’” or permit the other regulatory mechanisms to inactivate this product at a rate that prevents clinically apparent disease. Since the side effects of these agents are dose related in therapy for other disorders as well as in the management of HAE (Table II), it is important to realize that a modest biochemical increment in the level of CiINH alone is associated with a marked clinical benefit that can be achieved on alternate-day therapeutic programs. REFERENCES 1. Spaulding WB: Hereditary angioneurotic edema in two families. Can Med Assoc J 73: 1815, 1955. 2. Sheffer AL, Fearon DT, Austen KF: Methyltestosterone therapy in hereditary angioedema. Ann Intern Med 86: 306, 1977. 3. Davis PS, Davis FB, Charache P: Long-term therapy of hereditary angioedema (HAE). Johns Hopkins Med J 1357~391. 1914. 4. Gelfand JA, Sherins R, Ailing DW, Frank MM: Treatment of hereditary angioedema with Danazol: Reversal of clinical and biochemical abnormalities. N Engl J Med 295: 1444, 1976. 5. Rosse WF, Logue GL, Silberman HR, Frank MM: The effect of synthetic androgens in hereditary angioneurotic edema: Alteration of C 1 inhibitor and C4 levels. Trans Assoc Am Physicians 89: 122, 1976. 6. Keele DK, Woriey JW: Study of an anabolic steroid: Certain effects of oxymetholone on small children. Am J Dis Child 113422, 1967. I. Belch OH Jr, Warren JC: Induction of premature menstruation with catatoxic steroids. Am J Obstet Gynecol 111: 1107, 1971. 8. Drobeck HP, Coulston F, Beyler AL, Potts GO: Evaluation of the anabolic, hormonal, hematopoietic and pathologic properties of Stanozolol. Exp Mol Path01 2 (suppl.): 115, 1963.
280
Sheffer
et
at
J ALLERGY
9. Westaby D, Paradinas FJ, Ogle SJ, Randell JB, Murray-Lyon IM: Liver damage from long-term methyltestosterone. Lancet 1:261. 1911. 10. Daniel WA Jr, Bennett DL: The use of anabolic-androgenic steroids in childhood and adolescence, in Kochakian CD, editor: Handbook of experimental pharmacology, Vol. 43. Berlin, 1976. Springer-Verlag, p. 441. 1 I. Sheffer AL, Austen KF, Rosen FS: Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 287~452, 1972. 12. Rosen FS. Charache D, Pensky J. Donaldson V: Hereditary
Information
CLIN. IMMUNOL OCTOBER 1979
angioneurotic edema: Two genetic variants. Science 148:957. 1965. 13. Gadek JE, Hoaea SW, Gelfand JA, Frank MM: Cl inhibitor phenotypes in hereditary angioedema: Genetic implications of successful danazol therapy. Clin Res 25:357. 1977. 14. Donaldson VH, Rosen FS, Bing DH: Role of the second cow ponent of complement (C,) and plasmm in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Tram Aasoc Am Physicians 90: 174, 1977.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1. 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: “The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors.” Authors will be consulted, when possible, regarding republication of their material. I
I
L. Sheffer,
M.D., Douglas
T. Fearon, M.D., and K. Frank Austen,
M.D.
Boston, Muss.
Daily therapy and alternate-day therapy with the attenuuted androgen oxymetholone were compared in patients tvith hereditary angioedema (HAE). Fifteen of 16 patients who experienced Lit leust monthly attucks of HAE without treatment tvere asymptomatic on administration of 5 mg oxymrtholene daily. When 13 of the patients who had been maintained asymptomutitnlly on 5 mg oxymetholone duily were advanced to a treatment schedule of 5 mg every other day, seven clttclc,ks occurred during a cumulative 50 mo of therupy. The adL)erse effects that occurred with duily oxymetholone therapy largely subsided when the patients received ulternute-duy therapy. Stati.stically signi$cunt meun increases in serum levels of CiINH occurred with daily therapy ~md \c‘ere maintained with alternnte-day therupy. while a signijic,unt meun rise in C4 protein and fi*nction oc,curred only on daily therapy. Clinic,& benejit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise CilNH to the lower limit of normal. The jnding that ulternate-day therapy diminished the side eflects of’the drug while uffording a substantial reduction in the incidence and severity of trttucks indicates the,feasibility of this therapeutic, approach.
Prophylactic administration of androgens’, ’ or anabolic steroids with impeded androgenic effects”-” prevents spontaneous attacks of angioedema in patients with hereditary angioedema (HAE). Partial correction of the deficiency in serum of the inhibitor of the activated first component of complement (CiINH) and some reversal of the secondarily depressed serum levels of C4 occur during such treatment. Therapy with these agents over long periods of time requires consideration of their side effects,6 which include an impairment of growth rate,6 virilization,7. 8 and hepatic dysfunction.” Since these adverse effects appear to be dose related,‘” a study was initiated to establish the lowest dosage schedule of oxymetholone, an impeded androgen, required to eliminate attacks in affected individuals. Serum levels of CiINH and C4 __From the Departmentsof Medicine, Harvard Medical School and the Robert B. Brigham Division of the Affiliated Hospitals Center, Inc. Supported by Grants AI-07722, AI-10356, AM-05577, and RR05669 from the National Institutes of Health. Received for publication Jan. 18, 1979. Accepted for publication May 2, 1979. Reprint requeststo: Albert L. Sheffer, M.D., Robert B. Brigham Hospital, 125 Parker Hill Ave., Boston, MA 02120.
were assessed to determine if these parameters could be predictive of a clinical response. MATERIALS
AND METHODS
Oxymetholone [ 17-beta-hydroxy-2-(hydroxymethylene)17-methyl-5-alpha-androstan-3-one] was supplied by Dr. G. H. Tarr, Jr., Parke, Davis & Co., Detroit, Mich. All patients received an initial daily doseof 5 mg. If symptoms were controlled for at least 2 to 3 mo, patients were advancedto 5 mg oxymetholone every other day. Patientswho were asymptomaticon this dosageschedule were advanced to 5 mg oxymetholone every third day. The population consisted of eight male and eight female patients of postpubertalage (Table I) who, when untreated, experiencedat least monthly attacksof cutaneous or gastrointestinal angioedema.Patients 2, 5, 6, 9, and 11, and Patients 3, 5. 6, and 10 had previously participated in two double-blind, crossover studies in which the monthly attack rate with placebo was compared with the less frequent incidence of attacks with tranexamic acid” and methyltestosterone therapy,’ respectively. Twelve unrelated patients had reduced CiINH protein levels; two brothers (Patients 5 and 6) as well as two unrelated women (Patients 4 and 15) had the variant form of the disease with nonfunctional CiINH.” Each patient maintained a daily diary indicating the occurrence, severity, and duration of cutaneous, gastrointestinal, and/or upper respiratory attacks.
0091-6749179/100275+06$00.60/0 0 1979 The C. V. Mosby Co.
Vol. 64, No. 4, pp. 275-280
276
Sheffer
J. ALLERGY
et al.
TABLE I. Symptoms accompanying for management of HAE
daily dosage
and altered
dosage
schedules
Attackslmo. Patient No. 1
2 3 4 5 6 7 8 9
IO II 12 13 14 15 16
Sex
F F M F M M F M M M F F M F F M
Age (vr)
30 33 47 19 30
45 30
36 27 31 51 56 25
32 43 61
Attack without
frequency treatment
Monthly; C, GI, UR Monthly; C, GI, UR Monthly; C, GI Weekly; C, GI Monthly; C, Gl Monthly; C, GI Weekly; C, GI Weekly; C Monthly; C, GI Monthly; C, GI Monthly; C, GI Monthly; C, GI Monthly; C, GI, UR Monthly; C, GI Every 2 wk; C, GI Every 2 wk; C, GI
*
Treatment duration (mo)
Daily treatment
I1 12
O/IO o/3
15 1.5 16
o/10
16 3 6 13
O/8 o/9 o/9 o/3 C/6 O/8
14
O/l I
12 8
o/4 O/l o/4 o/3 o/2
10 5 8
II
Total
of oxymetholone
of treatment
Alternateday treatment
C/l O/I o/2 o/4 c, GI’F/7 O/7
Increasedto IO mg/day GI/5 O/l O/7 C/1 C/6 c/2 C/6
CLIN. IMMUNOL OCTOBER 1979
Every-third-day treatment
c, G11/8 C, GIt/3 c, GIf/3
c/2 C/l
O/I 1 l/108
7/50
5/17
*C: Cutaneous attacks; GI: gastrointestinal attacks; UR: upper respiratory attacks. tconcurrent manifestations.
Patients were assessedevery 2 to 4 mo for serum levels of CIINH and C4 protein and function.‘. ” Urinalysis, complete blood count, serum glutamic-pyruvic transaminase, urea nitrogen, glucose, total protein, albumin, calcium, lactic dehydrogenase,alkaline phosphatase,cholesterol, creatine phosphokinase (CPK), and uric acid were determinedwhen patients entered the study and during subsequentintervals of 2 to 4 mo for possible toxic alterations. Complete physical examination with particular notation of breast, hepatic, and prostatic assessmentswas performed before, at periodic intervals during, and at the conclusion of the study. This experimental design was approved by the Hospital Human Study Committee, and informed consent was obtained from each patient.
RESULTS The study was initiated in May, 1976, and completed in October, 1977. Of the 16 patients entering the study (Table I), 15 had no attack of angioedema when receiving 5 mg oxymetholone daily. One symptomatic patient (Patient 8) required 10 mg daily for complete freedom from attacks, and the 5-mg dose of oxymetholone was discontinued in one asymptomatic patient (Patient 7) because of depression. One patient (Patient 16) elected to maintain a daily dose of 5 mg because of complete relief of a 35yr history of abdominal pain. Thirteen patients, asymptomatic on 5 mg daily, were advanced to 5 mg oxymetholone every other day. Six of the 13 remained asymptomatic
at this lower dose while seven had mild attacks. In only one patient (Patient 1) was therapy with 5 mg oxymetholone daily reinstituted, and another (Patient 14) interrupted therapy because of the inconvenience of traveling from another country. Five of the 6 who were asymptomatic on alternate-day therapy were advanced to 5 mg oxymetholone every third day. None of the patients remained free of attacks of angioedema while receiving every-third-day treatment. This dosage was maintained, however, because of the reduced severity and duration of attacks. The effect of dosage schedule on the occurrence of adverse reactions is presented in Table II. Three patients ( 1, 8, and 12) experienced no adverse effects from daily therapy. Adverse effects of daily oxymetholone therapy in 13 patients for periods of 2 to 1 1 mo included depression, elevations in serum CPK and alkaline phosphatase, menstrual changes, and weight gain. Seven male patients had elevated serum levels of CPK, and the eighth man (Patient 8) consistently had normal values despite a maintenance dose of 10 mg oxymetholone. Isoenzyme analysis conducted in one instance (Patient 10) revealed that CPK was of skeletal muscle origin. CPK values returned to normal on alternate-day therapy in five patients and on daily therapy in one, but remained elevated in one patient when analyzed during an every-third-day treatment period. No CPK elevation occurred in women. Al-
VOLUME NUMBER
Effects of oxymetholone
64 il
TABLE II. Adverse effects treatment of HAE Patient No.
Sex
2
F F
3 4
M F
5 6
M M
7
F
8 9
M M
IO
M
I
II 12 13 14
F F M F
15 16
F M
with
daily dosage
and altered
Daily treatment
None Depression Oligomenorrhea CPKt = 228 Gained 9 lb Deepening voice Acne CPK = 294 Gained 1I lb CPK = 202 Amenorrhea Depression None Gained 17 lb Alk. phos.$ = 12.4 CPK = 310 Gained I2 lb Alk. phos. = 12.2 CPK = 534 Deepening voice None CPK = 312 Gained 5 lb Menorrhagia Gained 13 lb Gained 7 lb CPK = 312
dosage
schedules
on angioedema
therapy
277
of oxymetholone
Alternate-day treatment
None* None None None Gained 5 lb Deepening voice Less acne None Unchanged None
None None None None Not determined Not determined Deepening voice None None None None None
Every-third-day treatment
None None None None Deepeningvoice
Alk.phos. = 10.2 CPK = 262 None
*None:No abnormalityappearedor an abnormalitypresenton the morefrequentdosageschedulesubsided. TCPK:Creatinephosphokinase; normalrange,50 to 180IU. iAlk phos.: Alkaline phosphotase; normal range, 2.5 to 9.7 IU.
kaline phosphatase levels were elevated in two men (Patients 9 and 10) on daily therapy and remained elevated in one of these on every-third-day treatment. Two women (Patients 2 and 7) experienced oligomenorrhea on daily therapy. Patient 7 stopped treatment, and in Patient 2 a normal cycle developed on an alternate-day schedule. The only instance of menorrhagia (Patient 14) occurred on daily therapy, with normal cycles reappearing on alternate-day therapy. Depression occurred in two instances (Patients 2 and 7) and prompted discontinuation of therapy in one (Patient 7). The other patient was continued on alternate-day therapy. Two patients (4 and 11) experienced masculinizing effects characterized by deepening of the voice, and this symptom was not altered by alternate-day treatment. Acne, which was present in Patient 4, diminished on alternate-day treatment. Weight gain occurred during daily treatment in seven patients and averaged 10.6 pounds. In five the gain was maintained on alternate-day therspy, while there
was a further weight gain in Patient 4 and a 4-pound weight loss in Patient 9 on alternate-day therapy. The mean serum level of CiINH function during daily (Fig. 1, Table III) and alternate-day therapy increased 129% (t = 4.49, p < 0.001) and 83% (t = 2.29, p < 0.05), respectively, over the mean serum level obtained during symptom-free intervals prior to therapy. Mean plasma levels of C4 function increased 158% (t = 2.84, p < 0.01) on daily and 52% (t = 1.07, p > 0.10) on alternate-day therapy, whereas mean serum levels of C4 protein demonstrated less marked increases of 85% (t = 4.88, p < 0.001) and 22% (t = 1.46, p > 0. lo), respectively. Normal serum levels for C iINH and C4 were uncommon during daily therapy with oxymetholone, and the mean functional concentrations for all patients were less than half the lower limit for normal individuals. There were no significant differences in CiINH function and C4 protein and function between patients having mild attacks of angioedema on alter-
278 Sheffer et al.
J. ALLERGY
FIG. 1. Serum complement component levels with daily dosage and altered dosage oxymetholone for management of HAE. o = No therapy; A = daily therapy; n = therapy. Shaded areas represent the mean rt 1 SEM for each treatment regimen. of normal are: 19,700 U/ml for CilNH function, 130,000 U/ml for C4 function, and C4 protein.
TABLE III. Mean levels of serum complement schedules of oxymetholone therapy for HAE Treatment
schedule
C4 function
component
(U/ml)
with daily dosage
C4 protein
(pglml)
CLIN. IMMUNOL OCTOBER 1979
schedules of alternate-day Lower limits 258 pgiml for
and altered
CilNH
dosage
function
(U/ml)
Daily
61,017
Alternate day Every third day
36,800 11,000
235 157 121
9,690 6,970 4,360
Normal ranges
130,000-391,000
258-832
19,700-55,000
nate-day therapy and those who had no attacks. Five serum samples available from three patients receiving oxymetholone every third day demonstrated complement levels no different from those of untreated patients (Table III). DISCUSSION The findings of Spaulding’ that administration of androgens to patients with HAE prevents spontaneous attacks have recently been confirmed* and extended by demonstrating the efficacy of anabolic steroids with impeded androgenic effects.“-j Although the utilization of the latter agents minimizes the virilizing side effects of this therapeutic approach, it does not exclude the other complications observed with these agents in other clinical circumstances, such as hepatic toxicity,g depression, and disorders of the menstrual cycle.’ As these side effects are dose related, their containment can be approached by identifying the minimal dosage schedule affording symptomatic relief. In the present study, 1.5of 16 patients who experienced monthly attacks of angioedema without treatment or during previous studies when given placebo (Patients 2, 3, 5, 6, 9, 10, and 11) were asymptomatic while receiving 5 mg oxymetholone daily, an
amount found effective by Davis et al.” The sixteenth (Patient 8) was asymptomatic on 10 mg daily, which was the dose utilized in the controlled study of Rosse et al.” Thirteen of the patients who were maintained in an asymptomatic state on 5 mg oxymetholone daily (Table I) were advanced to 5 mg every other day. Six remained asymptomatic on alternate-day therapy, while each of the other seven experienced an attack of angioedema which was milder than that encountered during periods without therapy. Five of the six who were asymptomatic on alternate-day therapy advanced to every-third-day therapy. None of these maintained an asymptomatic state, and each experienced an attack of angioedema of an intensity milder than that during control or placebo therapy. The cumulative number of attacks relative to the number of months of treatment was one attack per 108 mo for 16 patients receiving 5 mg oxymetholone daily, seven in 50 mo for 13 patients on alternate-day therapy, and five in 17 mo for the five patients on every-third-day therapy. Since all these patients entered the study because of historical data of attacks occurring at least monthly, as confirmed in previous double-blind cross-over studies in seven patients,“. ”
VOLUME NUMBER
64 4
it is concluded that daily therapy is almost uniformly effective at the 5 mg dose. Alternate-day therapy is efficacious in maintaining some patients in an asymptomatic state, and in ameliorating the severity and duration of those attacks that do occur. The adverse effects of daily oxymetholone treatment (Table 11) included weight gain in three female (4, 14, and IS) and four male patients (6, 9, 10, and 16). This problem was substantially diminished on alternate-day therapy in that there was no further weight gain in six of the patients. The elevation in CPK occurred only in the male patients, appearing in seven of eight, and disappeared in five of these on alternate-day therapy and in one while continuing daily therapy (Patient 16). Two male patients (9 and 10) experienced a rise in alkaline phosphatase, which persisted in one on the altered dosage schedule. There were no other abnormalities of liver function parameters. Three (Patients 2, 7, and 14) of the eight female patients experienced disorders of the menstrual cycle on daily therapy, and in two instances (Patients 2 and 14) the irregularity subsided with alternate-day treatment. Depression occurred in two of these same patients and was alleviated in one by alternate-day therapy, while the other patient elected to discontinue using the drug. The reduced toxicity observed on alternate-day therapy could be a result of the altered schedule, or the diminished total dosage for 48 hr, or both. Biochemical support for the clinical efficacy of this type of therapeutic approach23‘. Rwas afforded by the immunochemical evidence that CiINH as well as C4 protein and function rose during periods of effective management with androgens or with anabolic steroids with impeded androgenic effect. The capacity of anabolic steroids to increase the serum concentration of CiINH in patients with HAE is thought to be secondary to stimulation of synthesis of the protein, although this has not been proven. As the disease is expressed in the heterozygous state, patients are presumed to be synthesizing the equivalent of one normal gene product. The reduction of normal serum level to less than half may reflect a non-concentrationdependent consumption of a constant amount of CiINH by stoichiometric interaction with “spontaneously” activated Ci. Danazol treatment of patients with the variant form of the diseaseI increases serum levels of normal CiINH only but not of the nonfunctional, antigenically detectable CiINH.13 These studies were interpreted as suggesting that anabolic agents augment synthesis only by the normal gene. This interpretation still leaves open the question of how much stimulation is required to achieve a satisfactory clinical response and whether or not that response is
Effects of oxymetholone
on angioedema
therapy
279
related to a specific serum concentration of ClINH. The statistically significant mean increases in serum levels of functional CiINH were 129% on daily therapy and 83% on alternate-day therapy (Fig. 1, Table III). Five of the six patients who were asymptomatic on alternate-day therapy had mean increases in serum CiINH levels that were less than those observed for the seven patients who experienced attacks while on this dosage schedule. Thus, it was not possible to predict the clinical response based on this biochemical measurement. The mean rise in C4 function and protein was statistically significant on daily therapy, but was not significant for the 13 patients on alternate-day therapy. There was no difference between the mean levels of C4 function or protein in those patients who were asymptomatic and those who had symptoms on alternate-day therapy. Thus, clinical benefit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise C iINH function to the lower limit of normal. In all likelihood, even a modest rise in CiINH controls the episodic increases in Ci so as to either prevent generation of the putative pathogenetic cleavage peptide’” or permit the other regulatory mechanisms to inactivate this product at a rate that prevents clinically apparent disease. Since the side effects of these agents are dose related in therapy for other disorders as well as in the management of HAE (Table II), it is important to realize that a modest biochemical increment in the level of CiINH alone is associated with a marked clinical benefit that can be achieved on alternate-day therapeutic programs. REFERENCES 1. Spaulding WB: Hereditary angioneurotic edema in two families. Can Med Assoc J 73: 1815, 1955. 2. Sheffer AL, Fearon DT, Austen KF: Methyltestosterone therapy in hereditary angioedema. Ann Intern Med 86: 306, 1977. 3. Davis PS, Davis FB, Charache P: Long-term therapy of hereditary angioedema (HAE). Johns Hopkins Med J 1357~391. 1914. 4. Gelfand JA, Sherins R, Ailing DW, Frank MM: Treatment of hereditary angioedema with Danazol: Reversal of clinical and biochemical abnormalities. N Engl J Med 295: 1444, 1976. 5. Rosse WF, Logue GL, Silberman HR, Frank MM: The effect of synthetic androgens in hereditary angioneurotic edema: Alteration of C 1 inhibitor and C4 levels. Trans Assoc Am Physicians 89: 122, 1976. 6. Keele DK, Woriey JW: Study of an anabolic steroid: Certain effects of oxymetholone on small children. Am J Dis Child 113422, 1967. I. Belch OH Jr, Warren JC: Induction of premature menstruation with catatoxic steroids. Am J Obstet Gynecol 111: 1107, 1971. 8. Drobeck HP, Coulston F, Beyler AL, Potts GO: Evaluation of the anabolic, hormonal, hematopoietic and pathologic properties of Stanozolol. Exp Mol Path01 2 (suppl.): 115, 1963.
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et
at
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9. Westaby D, Paradinas FJ, Ogle SJ, Randell JB, Murray-Lyon IM: Liver damage from long-term methyltestosterone. Lancet 1:261. 1911. 10. Daniel WA Jr, Bennett DL: The use of anabolic-androgenic steroids in childhood and adolescence, in Kochakian CD, editor: Handbook of experimental pharmacology, Vol. 43. Berlin, 1976. Springer-Verlag, p. 441. 1 I. Sheffer AL, Austen KF, Rosen FS: Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 287~452, 1972. 12. Rosen FS. Charache D, Pensky J. Donaldson V: Hereditary
Information
CLIN. IMMUNOL OCTOBER 1979
angioneurotic edema: Two genetic variants. Science 148:957. 1965. 13. Gadek JE, Hoaea SW, Gelfand JA, Frank MM: Cl inhibitor phenotypes in hereditary angioedema: Genetic implications of successful danazol therapy. Clin Res 25:357. 1977. 14. Donaldson VH, Rosen FS, Bing DH: Role of the second cow ponent of complement (C,) and plasmm in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Tram Aasoc Am Physicians 90: 174, 1977.
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