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Unresectable pheochromocytoma: Response to α-methyl-dihydroxy-l -phenylalanine
J. &on.
Dis. 1963, Vol. 16, pp. 217-222. Pergamon Press Ltd. Printed in Great Britain
UNRESECTABLE
PHEOCHROMOCYTOMA:
RESPONSE
TO
a-METHYL-DIHYDROXY-L-PHENYLALANINE N.
A. GELFMAN*, S. J. LANDAU?, P. J. MULROW:, W. T. FRIEDEWALD$ and D. J. DALESSIO~
The VA Hospital, West Haven, Connecticut, and the Departments of Pathology and Medicine, Yale University School of Medicine, New Haven, Connecticut (Received
5 August
1962)
UNRESECTABLE pheochromocytoma presents a rare [l, 21 and difficult problem of medical management. Roentgen therapy has not proved effective [3]. The most troublesome symptoms are related to the over-production of catecholamines by the tumor. This report describes the results of drug therapy directed at catecholamine production. Decarboxylation of dihydroxyphenylalanine (DOPA) to its amine (dopamine) is an important step in the synthesis of epinephrine and norepinephrine by adrenal medullary tissue (Fig. 1). Recently, compounds have been described which are capable of inhibiting decarboxylase reactions in man and animals [4]. One of these is an analogue of DOPA in which a methyl group is substituted for the hydrogen on the alpha carbon (Fig. 2). This compound, a-methyl-3,4-dihydroxy-L-phenylalanine, (a-methyl-DOPA, AMD**) was synthesized by STEIN, BRONNER and PFISTER [5] in 1955, and was demonstrated by SOURKES [6] to be an effective inhibitor of decarboxylation in vitro. OATES, SJOERDSMA, and their coworkers have confirmed the ability of AMD to inhibit aromatic amino acid decarboxylation in man, and in addition, have commented extensively on its hypotensive properties [4, 71. On the basis of the above mentioned work, it was decided to administer this AMD to a patient with an unresectable, actively secreting pheochromocytoma in order to inhibit his production of catecholamines. Repeated measurements of urine vanillyl mandelic acid (VMA) excretion before, during and after the administration of AMD were made, as well as careful recording of the patient’s blood pressures in the erect and supine positions, notations of his subjective and objective sensations (including
*Department of Pathology, VA Hospital, West Haven, Corm., and Clinical Instructor, Department of Pathology, Yale University School of Medicine, New Haven, Conn. TPuhnonary Disease Service, VA Hospital, West Haven, GM., and Clinical Instructor in Medicine, Yale University School of Medicine, New Haven, Corm. $Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Conn. §Third year Medical Student, Yale University School of Medicine, New Haven, Conn. a Resident in Medicine, VA Hospital, West Haven,Conn., and Instructor in Medicine, Yale University School of Medicine, New Haven, COM. * *AMD (aldomet, a-methyl-3, 4-dihydroxy-L-phenylalamine) generously supplied by Merck, Sharp & Dohme. 217
218
N. A. GELPMAN,S. J. LANDAU, P. J. M~LROW, W. T. FRIBDEWALDand D. J.
H \
HO
I ‘: ‘: C-C-NH,
\
HO
Ii
HO
HO
&Hz
/
xl-
DOPA
HO
H
&::--COOH I:
HO
DALWSIO
I!
/ xlDOPAMINE
II\
I
‘: “:
C;-C-NH, AH
lh
/
NOREPINEPHRINE FIG.
1.
Steps in the synthesis of norepinephrine
from DOPA
HO HO AMD
FIG. 2.
Alpha-methyldihydroxy-r-phenylalanine
flushing, sweating, palpitations, and headache), and response to oral and parenteral phentolamine (Regitine). MATERIALS
AND
METHOD
Clinical iizforination
R. W. is a 31-year old Negro male admitted to the West Haven Veterans Administration Hospital for therapy of early cavitary tuberculosis. Because of a history of episodic flushing, sweating and headache, and observed marked fluctuations in his blood pressures associated with electrocardiographic abnormalities, a pheochromocytoma was suspected. Two intravenous phentolamine tests were performed and were positive. Urinary VMA excretions were 39 mg, 60 mg, and 57 mg/day (normal range less than 5 mg/day). Urinary catecholamine excretion was 436 pg/24 hr (normal less than 200 pg/24 hr). Ninety per cent of the total catecholamine was norepinephrine.* The site of the tumor was located radiologically by means of presacral air insufflation. At operation a large mass arising in the area of the right adrenal gland was found. *Catecholamine determination and fractionation at the Grace-New Haven Hospital.
were performed in Dr.
DAVID SELIGSON’S laboratory
Unresectable
Pheochromocytoma:
Response to a-methyldihydroxy-L-phenylalanine
219
This tumor involved the liver, the porta hepatis, and the right diaphragm, and was invading the tenth dorsal vertebra; it was not resectable. A decompression laminectomy was subsequently performed (DIO and DII), and extradural compression of the spinal cord by the tumor was observed. Histologic sections of this tumor were typical of pheochromocytoma. The patient was thereafter given phentolamine by mouth in gradually increasing amounts up to 450 mg/day with a negligible effect on his blood pressure. AMD was then administered, initially 1.0 g/day; the dose was gradually increased to 3.0 g/day. The medication was dispensed in divided doses, either four or six times each day. Laboratory studies
Twenty-four hour urinary VMA excretion was determined chromatographically using a modification of the technique described by ARMSTRONG et al. [8] for chromatography of phenolic acids in urine. Twenty-four hour urine samples were collected in brown bottles containing 25 ml of 6 N-HCl. A 2 ml aliquot of urine was saturated with NaCl and further acidified with two drops of concentrated HCl. This aliquot was extracted twice with 5 ml of ethyl acetate. The combined extract was air dried. The residue was dissolved in 100 pl of absolute ethyl alcohol and spotted on 8 in. x 20 in. Whatman No. 1 filter paper for two dimensional chromatography. Papers were run overnight in isopropanol-ammonia-water (8: 1: 1 by vol.) using a descending technique. The appropriate 8 in. portion was then run for 4 hr in n-butanol-acetic acidwater (4: 1: 1 by vol.) using an ascending technique. Papers were sprayed with diazotized sulfanilic acid. The appropriate spot was eluted in water and compared colorimetrically in a Spectronic 20 at 475 mp with a 25 pg standard run concurrently. Twenty-four hour urine VMA has been measured by this method in 33 patients with and without hypertension, but without pheochromocytoma. Thirty had values less than 5 mg/24 hr. Three had values of 6. 7 and 8 mg/24 hr. RESULTS
VMA excretion varied widely from day to day; it was near normal some days, markedly elevated on others (Fig. 3). This pattern was not affected by AMD therapy nor by X-ray therapy started on the 108th hospital day. EFFECT OF AMD ON VMA EXCRETION “% mp CREPT 40 . 30 I 20
IO
--
1
.. .
.
.
.
.
-
.
*
.
*a
.-
._
.
.
_*
.
- .* .
..
. .
. .
.
-
.
* *.
.
. . .
-
.
.
. .
.
HOSPITAL
DAYS
FIG. 3. Twenty-four hour VMA excretion expressed as pg of VMA per mg of creatinine in order to compensate for possible inaccuracy in urine collection.
. ..
M. A. GELFMAN, S. J. LANDAU,P. J. Mumow, W. T. FRIEDEWALD and D. J. D-IO
220
RESPONSE OF BLOOD PRESSURE TO AMD
.__.,
I lDf5m
1
1
5
IO
I
15
20
I
25
30 HOSPITAL
FIG. 4.
.
35
40
45
50
55
60
65
DAYS
Postural hypotension during AMD therapy
Postural hypotension was noted during AMD therapy (Fig. 4). This effect disappeared promptly with cessation of drug therapy on day-47, and reappeared promptly with resumption of therapy on day-54. During therapy the patient noted less restlessness and anxiety. Palpitations and profuse sweating, frequent and troublesome symptoms before therapy, were markedly diminished. The most striking and unexpected response to therapy was the patient’s marked sensitivity to oral phentolamine. When it became apparent that recumbent blood pressure was not lowered by AMD therapy, oral phentolamine was added to the regimen. Following oral administration of the fist 50 mg dose, the patient complained of weakness and dizziness. Within 2 hr supine blood pressure was 130/90 and with the patient supported in the erect position, blood pressure was unobtainable. Three and one-half hours after this single dose the blood pressure was 110/90 and 0.25 ml of adrenaline (l/1000) was given. Symptoms subsided within 30 min. Two days later this phenomenon was cautiously retested under careful supervision. A stable baseline blood pressure was determined, and 12.5 mg of phentolamine was given by mouth (Table 1). Whereas previously the patient was refractory to oral phentolamine in 75 mg doses, he was now unable to tolerate 12.5 mg. DISCUSSION
HESSet al. [9], in a recent study, demonstrated that the synthesis of norepinephrine continues in AMD-treated animals at the same time that tissue levels of norepinephrine are maximally suppressed. They discuss the reaction rates of the three enzyme steps involved in the transformation of tyrosine to norepinephrine, and state that the decarboxylation step is so rapid that “a 50 per cent reduction of the enzyme activity would result in much less than a 50 per cent reduction of product.” They conclude
Unresectable Pheochromocytoma: TABLE 1.
Response to a-methyl-dihydroxy+phenylalanine
221
EXAGGERATEDBLEND PFWSURJZ RESPONSE TO ORAL PHENTOLAMINE WHILE ON AMD THERAPY
(3 &!/day)
Time (a.m.)
LYiW
Standing
8:00
2261180
8: 15
210/170
140/100 12.5 mg phentolamine p.o. lOO/SO
8:30 8~45 9:Oo 9: 15 9: 30
154/100 150/100 150/110 152/110 2201148
9:45
220/l 50
unable to stand unable to stand unable to stand unable to stand ? 80 tachycardia, weakness loo/90
Sitting
Barely heard-pt. weak 118/90 138/110 114/90 130/90 140/90 -
170/120
that in vivo effects of decarboxylase inhibition become apparent only when the amount of DOPA in the tissues is increased, and attribute the marked reduction in tissue catecholamine in AMD-treated animals to a reserpine-like action of the a-methyl amino acid or its decarboxylation product which is formed in vivo. The results of AMD treatment in our patient are consistent with the conclusions of HESS et al. Norepinephrine production as measured by VMA excretion was not significantly suppressed by AMD administration. It is possible that a slight inhibition (lo-30 per cent) was missed because of the wide daily variation and the semiquantitative nature of chromatographic methods. During therapy there was significant postural hypotension and striking sensitivity to small doses of phentolamine. Whereas previously the patient had been refractory to oral phentolamine, there was evidence of a synergistic response when phentolamine and AMD were administered together. Postural hypotension persisted 90 min after the patient received only 12.5 mg of phentolamine by mouth. These effects may be related to the depletion of tissue stores of norepinephrine, not through blockade of DOPA decarboxylation, but rather by interference at tissue binding sites through a reserpine-like action of AMD or its metabolite [9]. However, the rather prompt disappearance of the hypotensive effect after cessation of therapy is somewhat against tissue depletion as the only mechanism of action. Phentolamine is thought to block the peripheral action of circulating norepinephrine and to have a direct histamine-like vasodilatory effect on small vessels [lo]. Although we could not inhibit norepinephrine production as measured by urinary VMA, the AMD therapy seemed to relieve some of the troublesome symptoms associated with excessive norepinephrine and may have a place in the long term management of unresected pheochromocytoma. SUMMARY a-Methyl-DOPA, an aromatic L-amine decarboxylase inhibitor, was administered to a patient with an actively secreting, unresectable pheochromocytoma. Sweating, flushes, palpitations and headache diminished. The blood pressure was decreased in the erect position. Urinary excretion of VMA was not significantly depressed. Marked sensitivity to oral phentolamine was noted. These effects may be due to depletion of tissue norepinephrine by AMD or its decarboxylation product.
222
N. A. GELFMAN,S. J. LANDAU, P. J. MULROW, W. T. FRIEDEWALDand D. J. DAL~~~IO
REFERENCES with volun1. RANSON,C. L., LANDER,R. R. and GADDY, C. G.: Malignant pheochromocytoma tary ability to elevate blood pressure, J. Ural. 79,368, 1958. and hypertension, Znt. Abstr. Surg. 92,105,1951. 2. GRQXM,J. B. : Pheochromocytoma Langenbecks Arch. klin. 3. SCHWARZHOFF,E. : Klinik und Behandhmg des Phaeochromocytoms, Chir. 275,232, 1953. A. : Decarboxylase inhibition and 4. OATES,J. A., GILLESPIE,L., UDENFRIEND,S. and SJOERDSMA, blood pressure reduction by a-methyl-3,4dihydroxy-oL-phenylalanine, Science 131, 1890, 1960. 5. STEIN, G. A., BRONNER,H. A. and PFLPTER,K.: a-Methyl a-amino acids. Derivatives of DLphenylalanine, J. Amer. them. Sot. 77,700,1955. decarboxylase by derivatives of phenyl6. SOURKES, T. L.: Inhibition of dihydroxyphenylalanine alanine Arch. Biochem. 51,444,1954. 7. SJOERDSMA, A., OATES,J. A., ZALTMAN,P. and UDENPRIEND,S. : Serotonin synthesis in carcinoid patients, New Engl. J. Med. 263,585, 1960. 8. ARMSTRONG,M. D., SHAW, K. N. F. and WALL, P. E.: The phenolic acids of human urine, J. biol. Chem. 218,293, 1955. 9. HELW,S. M., CONNAMACHER, R. H., OZAKI, M. and UDENFIUEND,S.: The effects of cc-methyldopa and a-methyl-m-tyrosine on the metabolism of norepinephrine and serotonin in viva, J. Pharmacol. 134,129,1961. 10. GOODMAN,L. S. and GDLMAN,A.: Pharmacologicial Basis of Therapeutics, 2nd Ed., p. 584,
Macmillan, New York, 1955.
Dis. 1963, Vol. 16, pp. 217-222. Pergamon Press Ltd. Printed in Great Britain
UNRESECTABLE
PHEOCHROMOCYTOMA:
RESPONSE
TO
a-METHYL-DIHYDROXY-L-PHENYLALANINE N.
A. GELFMAN*, S. J. LANDAU?, P. J. MULROW:, W. T. FRIEDEWALD$ and D. J. DALESSIO~
The VA Hospital, West Haven, Connecticut, and the Departments of Pathology and Medicine, Yale University School of Medicine, New Haven, Connecticut (Received
5 August
1962)
UNRESECTABLE pheochromocytoma presents a rare [l, 21 and difficult problem of medical management. Roentgen therapy has not proved effective [3]. The most troublesome symptoms are related to the over-production of catecholamines by the tumor. This report describes the results of drug therapy directed at catecholamine production. Decarboxylation of dihydroxyphenylalanine (DOPA) to its amine (dopamine) is an important step in the synthesis of epinephrine and norepinephrine by adrenal medullary tissue (Fig. 1). Recently, compounds have been described which are capable of inhibiting decarboxylase reactions in man and animals [4]. One of these is an analogue of DOPA in which a methyl group is substituted for the hydrogen on the alpha carbon (Fig. 2). This compound, a-methyl-3,4-dihydroxy-L-phenylalanine, (a-methyl-DOPA, AMD**) was synthesized by STEIN, BRONNER and PFISTER [5] in 1955, and was demonstrated by SOURKES [6] to be an effective inhibitor of decarboxylation in vitro. OATES, SJOERDSMA, and their coworkers have confirmed the ability of AMD to inhibit aromatic amino acid decarboxylation in man, and in addition, have commented extensively on its hypotensive properties [4, 71. On the basis of the above mentioned work, it was decided to administer this AMD to a patient with an unresectable, actively secreting pheochromocytoma in order to inhibit his production of catecholamines. Repeated measurements of urine vanillyl mandelic acid (VMA) excretion before, during and after the administration of AMD were made, as well as careful recording of the patient’s blood pressures in the erect and supine positions, notations of his subjective and objective sensations (including
*Department of Pathology, VA Hospital, West Haven, Corm., and Clinical Instructor, Department of Pathology, Yale University School of Medicine, New Haven, Conn. TPuhnonary Disease Service, VA Hospital, West Haven, GM., and Clinical Instructor in Medicine, Yale University School of Medicine, New Haven, Corm. $Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Conn. §Third year Medical Student, Yale University School of Medicine, New Haven, Conn. a Resident in Medicine, VA Hospital, West Haven,Conn., and Instructor in Medicine, Yale University School of Medicine, New Haven, COM. * *AMD (aldomet, a-methyl-3, 4-dihydroxy-L-phenylalamine) generously supplied by Merck, Sharp & Dohme. 217
218
N. A. GELPMAN,S. J. LANDAU, P. J. M~LROW, W. T. FRIBDEWALDand D. J.
H \
HO
I ‘: ‘: C-C-NH,
\
HO
Ii
HO
HO
&Hz
/
xl-
DOPA
HO
H
&::--COOH I:
HO
DALWSIO
I!
/ xlDOPAMINE
II\
I
‘: “:
C;-C-NH, AH
lh
/
NOREPINEPHRINE FIG.
1.
Steps in the synthesis of norepinephrine
from DOPA
HO HO AMD
FIG. 2.
Alpha-methyldihydroxy-r-phenylalanine
flushing, sweating, palpitations, and headache), and response to oral and parenteral phentolamine (Regitine). MATERIALS
AND
METHOD
Clinical iizforination
R. W. is a 31-year old Negro male admitted to the West Haven Veterans Administration Hospital for therapy of early cavitary tuberculosis. Because of a history of episodic flushing, sweating and headache, and observed marked fluctuations in his blood pressures associated with electrocardiographic abnormalities, a pheochromocytoma was suspected. Two intravenous phentolamine tests were performed and were positive. Urinary VMA excretions were 39 mg, 60 mg, and 57 mg/day (normal range less than 5 mg/day). Urinary catecholamine excretion was 436 pg/24 hr (normal less than 200 pg/24 hr). Ninety per cent of the total catecholamine was norepinephrine.* The site of the tumor was located radiologically by means of presacral air insufflation. At operation a large mass arising in the area of the right adrenal gland was found. *Catecholamine determination and fractionation at the Grace-New Haven Hospital.
were performed in Dr.
DAVID SELIGSON’S laboratory
Unresectable
Pheochromocytoma:
Response to a-methyldihydroxy-L-phenylalanine
219
This tumor involved the liver, the porta hepatis, and the right diaphragm, and was invading the tenth dorsal vertebra; it was not resectable. A decompression laminectomy was subsequently performed (DIO and DII), and extradural compression of the spinal cord by the tumor was observed. Histologic sections of this tumor were typical of pheochromocytoma. The patient was thereafter given phentolamine by mouth in gradually increasing amounts up to 450 mg/day with a negligible effect on his blood pressure. AMD was then administered, initially 1.0 g/day; the dose was gradually increased to 3.0 g/day. The medication was dispensed in divided doses, either four or six times each day. Laboratory studies
Twenty-four hour urinary VMA excretion was determined chromatographically using a modification of the technique described by ARMSTRONG et al. [8] for chromatography of phenolic acids in urine. Twenty-four hour urine samples were collected in brown bottles containing 25 ml of 6 N-HCl. A 2 ml aliquot of urine was saturated with NaCl and further acidified with two drops of concentrated HCl. This aliquot was extracted twice with 5 ml of ethyl acetate. The combined extract was air dried. The residue was dissolved in 100 pl of absolute ethyl alcohol and spotted on 8 in. x 20 in. Whatman No. 1 filter paper for two dimensional chromatography. Papers were run overnight in isopropanol-ammonia-water (8: 1: 1 by vol.) using a descending technique. The appropriate 8 in. portion was then run for 4 hr in n-butanol-acetic acidwater (4: 1: 1 by vol.) using an ascending technique. Papers were sprayed with diazotized sulfanilic acid. The appropriate spot was eluted in water and compared colorimetrically in a Spectronic 20 at 475 mp with a 25 pg standard run concurrently. Twenty-four hour urine VMA has been measured by this method in 33 patients with and without hypertension, but without pheochromocytoma. Thirty had values less than 5 mg/24 hr. Three had values of 6. 7 and 8 mg/24 hr. RESULTS
VMA excretion varied widely from day to day; it was near normal some days, markedly elevated on others (Fig. 3). This pattern was not affected by AMD therapy nor by X-ray therapy started on the 108th hospital day. EFFECT OF AMD ON VMA EXCRETION “% mp CREPT 40 . 30 I 20
IO
--
1
.. .
.
.
.
.
-
.
*
.
*a
.-
._
.
.
_*
.
- .* .
..
. .
. .
.
-
.
* *.
.
. . .
-
.
.
. .
.
HOSPITAL
DAYS
FIG. 3. Twenty-four hour VMA excretion expressed as pg of VMA per mg of creatinine in order to compensate for possible inaccuracy in urine collection.
. ..
M. A. GELFMAN, S. J. LANDAU,P. J. Mumow, W. T. FRIEDEWALD and D. J. D-IO
220
RESPONSE OF BLOOD PRESSURE TO AMD
.__.,
I lDf5m
1
1
5
IO
I
15
20
I
25
30 HOSPITAL
FIG. 4.
.
35
40
45
50
55
60
65
DAYS
Postural hypotension during AMD therapy
Postural hypotension was noted during AMD therapy (Fig. 4). This effect disappeared promptly with cessation of drug therapy on day-47, and reappeared promptly with resumption of therapy on day-54. During therapy the patient noted less restlessness and anxiety. Palpitations and profuse sweating, frequent and troublesome symptoms before therapy, were markedly diminished. The most striking and unexpected response to therapy was the patient’s marked sensitivity to oral phentolamine. When it became apparent that recumbent blood pressure was not lowered by AMD therapy, oral phentolamine was added to the regimen. Following oral administration of the fist 50 mg dose, the patient complained of weakness and dizziness. Within 2 hr supine blood pressure was 130/90 and with the patient supported in the erect position, blood pressure was unobtainable. Three and one-half hours after this single dose the blood pressure was 110/90 and 0.25 ml of adrenaline (l/1000) was given. Symptoms subsided within 30 min. Two days later this phenomenon was cautiously retested under careful supervision. A stable baseline blood pressure was determined, and 12.5 mg of phentolamine was given by mouth (Table 1). Whereas previously the patient was refractory to oral phentolamine in 75 mg doses, he was now unable to tolerate 12.5 mg. DISCUSSION
HESSet al. [9], in a recent study, demonstrated that the synthesis of norepinephrine continues in AMD-treated animals at the same time that tissue levels of norepinephrine are maximally suppressed. They discuss the reaction rates of the three enzyme steps involved in the transformation of tyrosine to norepinephrine, and state that the decarboxylation step is so rapid that “a 50 per cent reduction of the enzyme activity would result in much less than a 50 per cent reduction of product.” They conclude
Unresectable Pheochromocytoma: TABLE 1.
Response to a-methyl-dihydroxy+phenylalanine
221
EXAGGERATEDBLEND PFWSURJZ RESPONSE TO ORAL PHENTOLAMINE WHILE ON AMD THERAPY
(3 &!/day)
Time (a.m.)
LYiW
Standing
8:00
2261180
8: 15
210/170
140/100 12.5 mg phentolamine p.o. lOO/SO
8:30 8~45 9:Oo 9: 15 9: 30
154/100 150/100 150/110 152/110 2201148
9:45
220/l 50
unable to stand unable to stand unable to stand unable to stand ? 80 tachycardia, weakness loo/90
Sitting
Barely heard-pt. weak 118/90 138/110 114/90 130/90 140/90 -
170/120
that in vivo effects of decarboxylase inhibition become apparent only when the amount of DOPA in the tissues is increased, and attribute the marked reduction in tissue catecholamine in AMD-treated animals to a reserpine-like action of the a-methyl amino acid or its decarboxylation product which is formed in vivo. The results of AMD treatment in our patient are consistent with the conclusions of HESS et al. Norepinephrine production as measured by VMA excretion was not significantly suppressed by AMD administration. It is possible that a slight inhibition (lo-30 per cent) was missed because of the wide daily variation and the semiquantitative nature of chromatographic methods. During therapy there was significant postural hypotension and striking sensitivity to small doses of phentolamine. Whereas previously the patient had been refractory to oral phentolamine, there was evidence of a synergistic response when phentolamine and AMD were administered together. Postural hypotension persisted 90 min after the patient received only 12.5 mg of phentolamine by mouth. These effects may be related to the depletion of tissue stores of norepinephrine, not through blockade of DOPA decarboxylation, but rather by interference at tissue binding sites through a reserpine-like action of AMD or its metabolite [9]. However, the rather prompt disappearance of the hypotensive effect after cessation of therapy is somewhat against tissue depletion as the only mechanism of action. Phentolamine is thought to block the peripheral action of circulating norepinephrine and to have a direct histamine-like vasodilatory effect on small vessels [lo]. Although we could not inhibit norepinephrine production as measured by urinary VMA, the AMD therapy seemed to relieve some of the troublesome symptoms associated with excessive norepinephrine and may have a place in the long term management of unresected pheochromocytoma. SUMMARY a-Methyl-DOPA, an aromatic L-amine decarboxylase inhibitor, was administered to a patient with an actively secreting, unresectable pheochromocytoma. Sweating, flushes, palpitations and headache diminished. The blood pressure was decreased in the erect position. Urinary excretion of VMA was not significantly depressed. Marked sensitivity to oral phentolamine was noted. These effects may be due to depletion of tissue norepinephrine by AMD or its decarboxylation product.
222
N. A. GELFMAN,S. J. LANDAU, P. J. MULROW, W. T. FRIEDEWALDand D. J. DAL~~~IO
REFERENCES with volun1. RANSON,C. L., LANDER,R. R. and GADDY, C. G.: Malignant pheochromocytoma tary ability to elevate blood pressure, J. Ural. 79,368, 1958. and hypertension, Znt. Abstr. Surg. 92,105,1951. 2. GRQXM,J. B. : Pheochromocytoma Langenbecks Arch. klin. 3. SCHWARZHOFF,E. : Klinik und Behandhmg des Phaeochromocytoms, Chir. 275,232, 1953. A. : Decarboxylase inhibition and 4. OATES,J. A., GILLESPIE,L., UDENFRIEND,S. and SJOERDSMA, blood pressure reduction by a-methyl-3,4dihydroxy-oL-phenylalanine, Science 131, 1890, 1960. 5. STEIN, G. A., BRONNER,H. A. and PFLPTER,K.: a-Methyl a-amino acids. Derivatives of DLphenylalanine, J. Amer. them. Sot. 77,700,1955. decarboxylase by derivatives of phenyl6. SOURKES, T. L.: Inhibition of dihydroxyphenylalanine alanine Arch. Biochem. 51,444,1954. 7. SJOERDSMA, A., OATES,J. A., ZALTMAN,P. and UDENPRIEND,S. : Serotonin synthesis in carcinoid patients, New Engl. J. Med. 263,585, 1960. 8. ARMSTRONG,M. D., SHAW, K. N. F. and WALL, P. E.: The phenolic acids of human urine, J. biol. Chem. 218,293, 1955. 9. HELW,S. M., CONNAMACHER, R. H., OZAKI, M. and UDENFIUEND,S.: The effects of cc-methyldopa and a-methyl-m-tyrosine on the metabolism of norepinephrine and serotonin in viva, J. Pharmacol. 134,129,1961. 10. GOODMAN,L. S. and GDLMAN,A.: Pharmacologicial Basis of Therapeutics, 2nd Ed., p. 584,
Macmillan, New York, 1955.