Biochemical and Pharmacologic Effects of Α-Methyltyrosine in Man

Biochemical and pharmacologic effects of α-methyltyrosine in man

Karl Engelman, … , Eric Jéquier, Albert Sjoerdsma

J Clin Invest. 1968;47(3):577-594. https://doi.org/10.1172/JCI105754.

Research Article

Alpha methyltyrosine (α-MPT) was administered to 52 patients from 4 days to 10 months; 22 patients were cases of pheochromocytoma and 20 had essential hypertension. Inhibition of catecholamine synthesis in the range of 50-80% was achieved with divided daily drug dosage of from 1.0 to 4.0 g. Striking clinical benefit was noted in patients with pheochromocytoma in whom the drug was used in preparation for surgery and during chronic medical management. The drug appeared to have limited usefulness when used in essential hypertension, unless added to existing therapy with conventional agents. No beneficial effects were noted in thyrotoxicosis, glaucoma, and Raynaud's phenomenon. Untoward effects in order of decreasing incidence were: sedation (with insomnia on withdrawal), anxiety, tremor, diarrhea, and galactorrhea. Drug crystalluria, which has been observed in animals and is currently restrictive of clinical trials, was not observed in these studies. Evidence is presented that the minor conversion of α-MPT to methyldopa probably does not contribute significantly to the central and peripheral effects of the drug.

Find the latest version: https://jci.me/105754/pdf Biochemical and Pharmacologic Effects of a -Methyltyrosine in Man

KARL ENGELMAN, DAvm HORWITZ, ERIc JEQUER, and ALBERT SJoERDsMA From the Experimental Therapeutics Branch, National Heart Institute, Bethesda, Maryland

A B S T R A C T Alpha methyltyrosine (a-MPT) previous paper (4) have indicated that the drug was administered to 52 patients from 4 days to is adequately absorbed from the gastrointestinal 10 months; 22 patients were cases of pheo- tract and that the degree of inhibition achieved in chromocytoma and 20 had essential hypertension. man approximates the values which could be Inhibition of catecholamine synthesis in the range predicted from the plasma levels of the drug. of 50-80%o was achieved with divided daily drug In the earlier clinical studies (2, 3), maximal dosage of from 1.0 to 4.0 g. Striking clinical doses of drug generally were not administered. benefit was noted in patients with pheochromo- Nonetheless, the drug seemed to have therapeutic cytoma in whom the drug was used in preparation potential in patients with pheochromocytoma, for surgery and during chronic medical manage- whereas the results in cases of essential hyper- ment. The drug appeared to have limited useful- tension did not suggest beneficial effects. ness when used in essential hypertension, unless This paper presents the results of our total added to existing therapy with conventional clinical experience with a-MPT and includes agents. No beneficial effects were noted in thyro- findings with larger doses of drug and longer toxicosis, glaucoma, and Raynaud's phenomenon. durations of therapy than used previously. In Untoward effects in order of decreasing incidence addition to cases of pheochromocytoma and essen- were: sedation (with insomnia on withdrawal), tial hypertension, patients with open angle glau- anxiety, tremor, diarrhea, and galactorrhea. Drug coma, thyrotoxicosis, migraine, and Raynaud's crystalluria, which has been observed in animals phenomenon were studied since it seemed that and is currently restrictive of clinical trials, was alteration of catecholamine synthesis in these dis- not observed in these studies. Evidence is pre- orders might lead to therapeutic benefit. Selected sented that the minor conversion of a-MPT to pharmacological studies were performed which methyldopa probably does not contribute signifi- bear on the mechanism of action of a-MPT. Due cantly to the central and peripheral effects of to limitations imposed on clinical use of a-MPT the drug. some of the observations were necessarily preliminary. INTRODUCTION METHODS Of various methods employed for modifying the The subjects were patients hospitalized with the following functions of the sympathetic nervous system, a diseases: (a) pheochromocytoma: 15 patients with benign unique and recently successful one has been the and 7 with malignant tumors; (b) essential hypertension: 20 patients with uncomplicated disease; (c) other dis- inhibition of catecholamine biosynthesis by orders: 1 patient with thyrotoxicosis, 1 with migraine a-methyl-para-tyrosine (a-MPT) (1-3). Studies headache, 6 patients with Raynaud's phenomenon (5 defi- on the metabolic fate of a-MPT reported in the nite, 1 suspected to be related to scleroderma), and 2 with open angle glaucoma. Identical capsules containing Received for publication 9 August 1967. 100 or 250 mg of alpha methyl-L-para-tyrosine--or placebo The Journal of Clinical Investigation Volume 47 1968 577 material 1 were administered orally to the patients every for estimation of radioactivity in various metabolites 6-8 hr for periods of 4 days to 10 months; total daily (4). doses were as high as 4000 mg. The majority of patients received the drug for 2-4 wk. Some patients with pheo- RESULTS chromocytoma were receiving phenoxybenzamine to con- Effects on catecholamine production trol symptoms, and this drug was usually not withdrawn until definite therapeutic effects of the a-MPT were ob- The effect on catecholamine production of the served. The antihypertensive effects of a-MPT were in- maximal dosage of a-MPT employed in 22 pa- vestigated adequately in 13 of the patients with essential tients with pheochromocytoma was determined by hypertension. In these patients drug dosage was increased from initial levels of 0.5-1.0 g daily to a maxi- comparing the urinary excretion of the naturally mum of 3.0 g as required for reduction of blood pressure occurring catecholamines (norepinephrine plus unless limited by untoward effects. Pretreatment con- epinephrine) and their major metabolites during trol periods in these cases varied from 7 to 21 days, control periods and during drug administration treatment periods from 6 to 21 days (average of 12), and indices it may post-treatment observations were made through at least (Table I). Using the sum of these 5 days after loss of drug effect if hospitalization time be seen that we reduced catecholamine production permitted. Placebo capsules were administered during the by 20-79% by a-MPT dosage ranging from 600 pre and posttreatment periods in the same doses as ini- to 4000 mg (11-73 mg/kg)/day. In seven patients tial and final doses of a-MPT. (T. W., R. K., A. A., S. M., D. S., J. L., and Blood pressure (arm/cuff) and pulse rate were measured routinely four times daily after 15 min of recum- E. W.) the total excretion of catecholamines plus bency and again after 2 min of quiet standing. Pressor re- metabolites was reduced to normal or near normal sponses to tyramine hydrochloride (dosage expressed as (< 10 mg) levels. Patients with benign and malig- the base) infused intravenously in isotonic NaCl solu- nant tumors responded similarly. In individual tion at varying rates for 15-min periods were determined patients stepwise increments of dosage up to 1500 in two patients with essential hypertension and one with scleroderma in the resting (recumbent) state during mg/day produced marked increases in inhibition, placebo and treatment periods. Basal metabolic rate but at higher doses the decreases in catecholamine (BMR) was determined as previously reported (5). production generally were proportionally less. In patients with Raynaud's phenomenon we measured Catecholamine production was determined daily responses to cold stimuli objectively by determining in a number of patients to indicate that finger pad skin temperatures with a skin thermocouple sufficient after a standard cooling stimulus; subjective responses to the maximum effect of a given dosage regimen exposure in an environment at 40C and 50% humidity in a occurred within 2-3 days and catecholamine pro- walk-in refrigerator were also recorded. In the two pa- duction returned to control levels within 3-4 days tients with glaucoma, intraocular pressures, fluid dy- after withdrawal of drug (2, 3). namics, and outflow' indices were determined by Dr. Vernon Wong, Ophthalmology Branch, National In- In 18 other patients in whom the biochemical stitute of Neurological Disease and Blindness. The sedi- effects of a-MPT were studied catecholamine pro- ment of freshly voided urine specimens was examined duction was normal, and the sole index used to microscopically for a-MPT crystals. Routine hematologi- ascertain drug effect was the level of urinary cal and chemical tests were performed by the Clinical Pathology Section of the Clinical Center. VMA excretion. As shown in Table II, percent- The urinary excretion of catecholamines, total meta- age reductions (20-74%o) produced by a-MPT in nephrines, and vanillylmandelic acid (VMA) was deter- these patients were comparable to those observed mined as cited previously (4, 6). All three excretory in- in cases of pheochromocytoma, though the quan- dices of catecholamine production were measured in the titative changes were much smaller. Generally, patients with pheochromocytoma, but only VMA was measured in other patients. To rule out an effect of the doses exceeding 1000 mg/day resulted in a de- drug on the pattern of urinary metabolite excretion, the crease of VMA excretion of more than 50%. fate of 1000 ,tc of D,L-norepinephrine-7-3H hydrochloride Several assays for total metanephrines indicated a (2.2 c/mmole)2 given intravenously over a 30-min pe- similar reduction in excretion values, but the low riod to a patient (S. M., Table I) with pheochromocytoma levels of urinary catecholamines during drug ther- was studied both before and during treatment with 4000 mg of a-MPT/day. 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Effects of a-Methyltyrosine 581 TABLE I I Effect of a-MPT on Urinary Excretion of VMA in Patients with Normal Catecholamine Production

Urinary VMA Avg daily % Re- Patient Age Sex Wt a-MPT dose Control* a-MPT* duction kg mg mg/kg mg/24 hr Essential hypertension F. D. 55 F 81 0.8 10 4.1 2.2 46 A. N. 38 F 66 0.8 12 4.2 2.6 38 V. G. 56 F 56 0.8 14 3.0 2.4 20 D. F. 52 M 65 1.2 18 3.1 1.2 61 F. B. 48 F 56 1.6 29 3.5 1.5 57 S. C. 58 F 50 1.6 32 3.4 0.9 74 E. B. 59 F 48 1.7 35 2.2 0.8 64 G. D. 29 F 54 2.0 37 4.2 2.0 53 G. E. 47 F 71 3.0 42 4.3 1.9 66 D. E. 43 F 46 2.0 43 3.7 2.1 43 E. H. 53 F 68 3.0 44 4.8 2.3 52 A. M. 50 F 57 3.0 53 4.2 1.7 60

Open angle glaucoma K. G. 56 M 78 1.0 13 4.3 3.0 30 Thyrotoxicosis F. A. 23 M 67 3.0 45 3.1 1.2 61

Raynaud's phenomenon L. I. 67 F 70 2.0 29 4.0 1.7 58 J. S. 43 F 64 2.0 31 3.2 1.7 47 L. P. 23 F 45 2.0 44 3.2 1.6 50 J. M. 28 F 52 2.0 48 4.4 1.7 61

* Values are averages of determinations on at least two separate 24-hr collections. the patient during placebo and treatment periods. In patients who were receiving phenoxybenzamine The possibility that a-MPT might alter over-all it was usually possible to reduce or discontinue metabolism of circulating catecholamines and use of this drug coincident with administration of thereby distort urinary excretory patterns was a-MPT. As reported previously (2, 3), blood eliminated by a study of the fate of radioactive pressure decreased progressively during the first norepinephrine given intravenously on two occa- 2 days of therapy with a-MPT and, except for sions to a patient with pheochromocytoma. As those patients who received a-MPT to the day of shown in Fig. 1, the excretion pattern of the surgery, there was a gradual increase to pretreat- radioactive metabolites during control and treatment values within 2-3 days after withdrawal of ment periods was similar. the drug. Therapeutic evaluation 13 patients received a-MPT to the time of surgery. It was our clinical impression that these effects were observed in Striking beneficial patients presented fewer intraoperative problems of the with many patients pheochromocytoma with blood pressure control than other similar (Table I). Most patients experienced a decreased frequency and severity of hypertensive attacks, patients who had not been so treated, and the sweating, and palpitations. Blood pressure reduc- surgeon was able to handle the tumor directly tion of varying degrees was evident in all of the with less hazard of hypertensive crisis. Because patients with pheochromocytoma who were hyper- of the marked variability in clinical features of the tensive during control periods (18 of 22 cases). patients with pheochromocytoma, four cases will 582 K. Engelman, D. Horwitz, E. Jequier, and A. Sjoerdsma 100 times, and the level of urinary VMA excretion S.M. 25 M a-MPT 4000mg/day Pheochromocytoma CONTROL was diagnostic of pheochromocytoma. On admis- 90 sion to the N.I.H. she was found to be an anxious, perspiring, woman with blood press~ure of 160/102 ACIDS mm Hg while supine and 145/100 mm Hg while NEUTRALS 80s (VMA) standing. Therapy with a-MPT was started at a daily dose of 1000 mg; the patient reported a t 70 _- marked decrease in sweating within 24 hr. At a dose of 1500 mg/day she noted a decrease in anxiety as well as a marked reduction in the o 60 _- r4 incidence of attacks. While receiving a dose of 2500 mg/day for 4 days she experienced the onset 350 of a mild tremor of her hands and some "tight- A. ness" of her mouth; the dose was reduced to 2000 mg/day and these symptoms disappeared within 24-36 hr. During a predrug placebo period of 3 40 wk her blood pressure ranged from 140-225/80- ww 30 _ 140 mm Hg with a mean value of 184/108 mm Hg, wL AMINES (NMN) and while receiving 2500 mg of a-MPT daily it ranged from 120-200/80-130 mm Hg with a 20 _ AMINES mean value of 167/107 mm Hg. Three measure- (NE) ACIDS + ments of BMR during the placebo period were NEUTRALS o - at + 35, + 38, and + 45%, and two determinations while she was receiving 2000 mg of a-MPT per day were normal at + 7 and + 8%o. During CATECHOLS NONCATECHOLS therapy with a-MPT her urinary excretion of catecholamines plus metabolites was reduced by FIGURE 1 Excretion of radioactivity in various column chromatographic fractions of a urine specimen collected 68%o to only slightly abnormal values (Table I). for 24 hr after infusion of norepinephrine-'H in a patient The patient received 2000 mg/day to the time with pheochromocytoma. Two studies were done, one dur- of surgery. No phentolamine was required during ing a control period and the other during treatment with the intraoperative period, and the highest blood 4000 mg of a-MPT daily. Total excretion of radioactivity pressure observed during removal of a pheo- was 75-80%o in 24 hr, and the percentage of this distributed in various fractions was not altered by drug treatment. chromocytoma of the left adrenal was 180/105 As indicated, the catecholamine fraction is composed pri- mm Hg. marily of norepinephrine (NE), the noncatechol acids Comment. a-MPT controlled attacks and re- plus neutral fraction is largely vanillymandelic acid duced sweating and BMR in this case. Though (VMA) and the noncatechol amines represent normeta- nephrine (NMN). blood pressure was reduced only moderately, the drug apparently prevented the occurrence of hypertensive attacks during surgery. At a dose of be described in detail to illustrate specific re- 2.5 g/day, there was early evidence of neuro- sponses. toxicity (tremor and "tightness" of mouth) which Illustrative cases of pheochromocytoma disappeared on reduction of dosage. Case 2. A 63 yr old man (E. H.) probably Case 1. A 42 yr old female house painter had symptoms of pheochromocytoma since 1927 (E. L. H.) had a 2%2 yr history of "spells" char- when he had recurrent headaches, hypertension, acterized by a feeling of weakness, faintness, pal- and a subarachnoid hemorrhage. He was treated pitations, sweating, and nervousness. These attacks symptomatically over the interim despite two other were noted especially when she stretched to paint episodes of subarachnoid hemorrhage in 1944 and high above her head or in tight places. Her blood 1949. In 1955 he developed "diabetes" requiring pressure was found to be markedly elevated at insulin therapy, and in 1958 the diagnosis of pheo- Effects of a-Methyltyrosine 583 chromocytomia was made; all signs and symptoms atonic large bowel. The blood pressure wvas 180/ including those of "diabetes" disappeared after 120 mm Hg despite phenoxybenzamine therapy, surgical resection of his right adrenal gland which and he was confused mentally. Striking peripheral contained a pheochromocytoma. 6 yr later re- cyanosis of the hands, feet, and prepatellar regions exploration because of recurrent hypertensive at- wras observed, and the skin of some of these areas tacks and glycosuria revealed metastatic pheo- wlas ulcerated and sloughing due to intense cutane- chromocytoma. His condition deteriorated, and in ous vasoconstriction (Fig. 2). Small doses of January 1966 he was transferred to the N.I.H. a-AIPT were started several days after admission because of intractable hypertension and a 30 kg and within 24 hr striking clinical changes were weight loss due to nausea and vomiting with noted. The peripheral cyanosis disappeared and abdominal bloating and obstipation. On admission the ulcers began to heal rapidly (Fig. 2 ). He the patient appeared moribund; his abdomen was became much more alert mentally, and his blood massively distended with huge feces-filled loops of pressure decreased from 180/125 mmi Hg to

FIGURE 2 Appearance of the lower extremities of a 63 yr old man (E. H.) with malignant pheochromocytoma, before (upper) and 2 days after (lower) institution of treatment with a-MPT in a dose of 750 mg/day. After starting a-MPT cyanosis disappeared and healing of the ulcerated areas was apparent.

584 K. Engelman, D. Horwitz, E. Jequier, and A. Sjoerdsma H- E;63Yr c' 2000 MoligrInOnt phe o Uf) o 10 1000 _ -Os -~0 200 EE 180 160K I 140 1 20 °b g) 100 E O-J m al 80 _ 680 L ~Ln-- 60_ 7 70 , UJ La 40 60 m 2 200 -1 50 ;K 0 'r 8 9 l 1 4040 1 2 3 4 2 3 4 5 6 7 8 9 10 1 WEEKS MONTHS FIGURE 3 Effects of therapy with a-MPT in a 63 yr old man (E. H.) with malignant pheochromocytoma. Prompt lowering of blood pressure and pulse rate to normal levels was achieved and maintained for 10 months, accompanied by an eventual weight gain of almost 20 kg.

135/100 mm Hg (Fig. 3). To establish that these with a complete absence of hypertensive attacks or striking changes were drug-related, we discon- sweating. 2 months later his condition gradually tinued the a-MPT and substituted it with placebo. and then rapidly deteriorated because of complica- His clinical condition reverted promptly to pre- tions of tumor growth, though no effects of excess treatment status. Therapy with a-MPT was catecholamine production were manifest at any quickly reinstituted and the patient again im- time while receiving a-MPT. The patient died 10 proved remarkably. The previously sluggish bowel months after starting therapy with a-MPT. sounds became more active, and the patient Comment. This response to a-MPT was the evacuated more than 5 kg of feces, reestablished most impressive of any observed in patients treated normal alimentation, and gradually became ambu- with this drug. The clinical improvement corre- latory. While receiving 2000 mg of a-MPT per lated well with a reduction of catecholamine pro- day his urinary VMA excretion was reduced by duction and persisted for the duration of therapy 75%o from 72.8 to 18.2 mg/24 hr, and his fasting until just before death. The 10 months during blood sugars were reduced from over 200 mg/100 which this patient received a-MPT was by far ml to 70-100 mg/100 ml. During the next 31/2 the longest course of therapy in any patient to months he improved steadily with a net weight date; no evidence of toxicity or drug crystalluria gain of more than 12 kg, and he was discharged was detected at any time. The experience in this on 2000 mg of a-MPT per day, having a normal patient revealed a-MPT to be potentially an excel- blood pressure and pulse rate (Fig. 3). He con- lent medical means of treating patients with valesced briefly at home, and then returned to inoperable pheochromocytoma. work as a regional sales manager for a large Case 3. A 27 yr old minister (E. W.) had a corporation, rapidly increasing his time in the left adrenalectomy for pheochromocytoma in Janu- office from a mere daily appearance to 5-6 hr/day. ary 1965. Because his blood pressure did not 6 months after starting a-MPT and while still return to normal postoperatively and because of showing evidence of continued improvement he a progressive increase in blood 'pressure with returned to the N.I.H. for further study. He had recurrence of excessive sweating and headaches he gained an additional 5 kg in weight since dis- was referred to the N.I.H. in April 1966. On ad- charge, and his blood pressure was still normal mission the patient was a well developed anxious Effects of a-Methyltyrosine 585 man who perspired excessively and who had a before in patients with pheochromocytoma, and the marked rubor of the palmar and dorsal aspects of change in this condition was the first manifestation his hands. This rubor had been present before of clinical improvement. Though the patient had his previous surgery and had disappeared tem- residual tumor and mild hypertension after surgery porarily after resection of his tumor. His blood it was elected to treat him with small doses of pressure was 196/130 mm Hg supine and 160/108 phenoxybenzamine rather than a- M1PT because of mm Hg standing. During a placebo control period inadequate experience with the long-term effects the supine blood pressure ranged from 150-228/ of the new drug. Reinstitution of a-MPT therapy 50-150 mm Hg. aMPT was started, and after may be necessary as the tumor grows and cate- the 2nd day of therapy at 2000 mg/day he noted cholamine production continues to increase. a marked diminution of sweating and disappear- Case 4. A 59 yr old retired porter (T. \V.) ance of the erythema of his hands. The blood pres- was well until August 1965 when he noted the sure responded favorably to a-MPT administration onset of severe symptoms of congestive heart fail- and was reduced from an average control value ture followed a week later by the development of of 185/118 mm Hg to 146/99 mm Hg during aphasia and severe diaphoresis and headaches for treatment with 4000 mg of the drug (Fig. 4). His which he was hospitalized elsewhere. A diagnosis catecholamine production was decreased by 70% of pheochromocytoma was made, and a large right (Table I). At the time of surgery he was found superior mediastinal mass found on chest roent- to have metastatic tumor which was resected genography was thought to represent an intra- from around the left renal pelvis and the aorta. thoracic neurofibroma. 1 wk later he had the After surgery, urinary catecholamines and metabo- sudden onset of left hemiparesis and expressive lites were still higher than normal, and his blood aphasia which cleared within a week despite the pressure remained elevated in the range of 150/ finding on carotid arteriogram of a complete occlu- 115 mm Hg, which indicated residual tumor. He sion of the right middle cerebral artery. Hyper- was discharged on phenoxybenzamine (20 mg tensive crises were controlled with oral phenoxy- daily) which maintained his blood pressure at benzamine but because the patient developed about 135/90 mm Hg. congestive heart failure refractory to salt restric- Comment. This patient also demonstrated an tion and potent diuretics, he was referred to the excellent response to inhibition of catecholamine N.I.H. for possible treatment with a-MPT in an synthesis with a-MPT. The striking rubor of the attempt to reverse his presumed catecholamine hands was a finding which we had not noted cardiomyopathy (6). On admission the patient

230 E. 27 Yr 0 220 W. -~210 Malignant pheochromocytoma 200 E Operation Lt 190 S 180 70 iUi 160 c 50 14 -- 130 - \ ... Vrnitos. 120 110 - 100- *b;..l- /

80 c 70- 60 4000 6 / Cr 50 / Uj40 / 2000 FIGURE 4 Blood pressure response to 1 / 30a-P z/ j ~. "a-MPT therapy in a 27 yr old man 20 0 (E. with 10 W.) 'malignant pheochromocy- I I ffr toma. 0 5 10 15 20 25 DAYS

586 K. Engelman, D. Horwitz, E. Jequier, and A. Sjoerdsma was an elderly, chronically ill Negro male who pulse rate and rhythm returned to normal within had a moderate expressive aphasia and residual 24 hr. The watery diarrhea which persisted was weakness of the left leg and arm. His blood treated symptomatically as before, and the patient, pressure was 100/60 mm Hg supine and 96/44 free of congestive heart failure, underwent surgery mm Hg standing; the pulse rate was irregular at for an intrathoracic pheochromocytoma 3 months 120/minute. The external jugular veins were dis- after starting on a-MPT therapy. During the tended 5 cm above the clavicle at 450, and there postoperative period the patient had mild diarrhea were prominent A waves in the venous pulse. Dull- for the first 10-14 days, and this then gradually ness to percussion and egophony were present over abated. The excretion of catecholamines and the mid and upper paravertebral areas of the right metabolites returned to normal postoperatively. thorax, and rales were heard at both lung bases. Comment. a-MPT produced an excellent The heart was enlarged to the anterior axillary line therapeutic response in this patient with cate- and a loud protodiastolic gallop was heard. A cholamine cardiomyopathy due to an intrathoracic tender liver edge was felt 3 cm below the right pheochromocytoma. Tachycardia and arrhythmias costal margin; there was a trace of ankle edema. which were controlled by a-MPT recurred during Because of persistent hypotension in the range of temporary substitution of phenoxybenzamine, per- 80-90/50-60 mm Hg the phenoxybenzamine was haps because the beta adrenergic effects of circu- discontinued, digoxin dosage of 0.5 mg/day was lating catecholamines were unaffected by the a- discontinued because of multiple atrial and nodal adrenergic-blocking drug. Diarrhea occurred in arrhythmias, and a-MPT therapy was started. this patient in association with a-MPT treatment. When the evidence of digitalis toxicity disap- This patient was most unusual in that his tumor, peared, digoxin was resumed in a maintenance arising remote from the adrenal glands, produced dose of 0.125 mg/day. On an a-MPT dose of large amounts of epinephrine (30%c of urinary 500-750 mg/day the patient's blood pressure was catecholamine excretion, Table I) as well as nor- in the range of 100-120/60-80 mm Hg, and he epinephrine. was free of hypertensive attacks and excessive In addition to the aforementioned therapeutic sweating. Diuretic therapy was discontinued and evaluation of a-MPT in pheochromocytoma, it salt restriction was ended without the recurrence seemed important to ascertain whether the drug of congestive failure. During his first 2 months in might be a useful antihypertensive agent in cases the hospital the a-MPT dose varied between 500- of essential hypertension. As noted previously 1500 mg/day. 2 months after starting a-MPT (Table II) in patients with the latter condition and while receiving a dose of 1500 mg/day the in whom catecholamine production is normal, the patient noted the onset of watery bowel move- drug produces a degree of inhibition of cate- ments. An extensive search for the etiology of the cholamine biosynthesis (as indicated by urinary diarrhea was unsuccessful and he was treated VMA) comparable to that observed in pheo- symptomatically with anticholinergic and opiate chromocytoma. Nonetheless, the effects of a-MPT drugs and a low roughage diet. It was then de- on the blood pressure of patients with essential cided to withdraw the a-MPT. Within 24-36 hr hypertension was much less striking than in the patient developed dyspnea, tachycardia, sweat- pheochromocytoma. While the effects of a-MPT ing, and blood pressure elevation to 142/112 mm were studied in 20 cases of essential hypertension, Hg, the highest blood pressure observed thus far the results in 7 patients will not be presented during his hospitalization. The diarrhea decreased since they were inconclusive either because of over the next several days, and phenoxybenzamine relatively low dosage (< 1500 mg/day) or brief was given to control the blood pressure although duration of treatment (< 1 wk). Effects of the drug it did not control his heart rate which had risen as sole treatment in eight patients, and on addition from 84 to 140 beats/min after the withdrawal of to existing suboptimal treatment with an accepted a-MPT. Because he still was having 2-3 loose antihypertensive drug in six patients, are sum- bowel movements daily and had a nodal tachy- marized in Table III. A convincing antihyper- cardia at 130-140 beats/min a week after with- tensive effect was noted in only three patients in drawal of a-MPT, the drug was reinstituted. The whom the drug was used alone (patients M. D., Effects of a-Methyltyrosine 587 TABLE I II Blood Pressure Effects in Patients with Essential Hypertension Given a-MPT Alone, or in Combination with Standard Antihypertensive Drugs Average blood pressure* Supine Standing Avg dose Other antihypertensive Patient a-MPT Precontrol a-MPT Postcontrol Precontrol a-MPT Postcontrol therapy, all periods mg/day mm Hg mg/day Sole therapy M. D. 2000 150/105 130/88 141/105 155/112 126/94 147/106 G. D. 1700 177/116 159/107 168/115 164/115 144/101 149/112 G. E. 3000 166/115 141/99 150/107 151/110 137/101 145/108 E. F. 1500 188/123 168/108 186/122 166/122 128/85 158/113 F. D. 3000 192/120 187/121 174/114 170/118 - R. L. 3000 166/116 157/109 - 152/114 154/116 E. B.T 1700 158/113 143/101 175/130 120/87 - A. M. 3000 174/113 171/106 181/117 162/109 160/113 169/113 Combined therapy E. B.1 900 151/107 132/96 147/106 151/116 119/95 149/116 Methyldopa 750 J. P. 1600 209/99 196/95 204/101 145/79 115/66 151/85 Guanethidine 87.5 R. R. 3000 154/109 147/100 159/111 142/108 118/94 138/108 Reserpine 0.25 W. S. M. 700 181/123 175/121 183/123 155/113 131/92 145/108 Methyldopa 500 A. B. 2500 161/110 147/99 144/105 133/96 Methyldopa 500 A. L. 3000 173/122 144/98 153/106 169/126 127/91 145/109 Hydrochloro- thiazide 100

* Each value is average of four daily determinations for the last 5 days of each period. t Same patient.

240 - E. F. 52 Yr S-_upine 230 i 220 - Essential hypertension Slonding 210 200 crw 190 = 180 170 u 160 2 150 2 140 a_ 130 m 120 B 1 10 m 1 00 < 90 or 8 0 w 7 0 60 50 40

30 - C15IO IK 20 CU - FIGURE 5 Comparison of the effects of 10 - 10 equivalent doses of a-MPT and methyldopa 0 (a-MD) on the blood pressure of a woman with essential hypotension. 0 5 10 15 20 25 30 35 40 DAYS

588 K. Engelman, D. Horwitz, E. Jgquier, and A. Sjoerdsma E. F., and E. B.), blood pressure lowering occur- as control period) occurred coincident with ad- ring in both the supine and standing positions. A ministration of a-MPT in a dosage range of 0.5- comparison of the effects of 1.5 g of a-MPT with 0.75 g for 17 days. The patient was also obviously that of an equivalent daily dose of methyldopa in sedated during this time. Migraine attacks re- patient E. F. is shown in Fig., 5. Blood pressure curred within 1 wk as drug dosage was decreased lowering with the two drugs was comparable in to 0.1 g/day and then discontinued. A patient who this case, with an orthostatic effect predominating. had severe thyrotoxicosis (serum protein bound In contrast to the situation when the drug was iodine of 16.3 Ig/100 ml and 131I uptake of 60% used alone, each of the six patients who was at 24 hr) was treated with up to 4000 mg of receiving guanethidine, reserpine, methyldopa, or a-MPT daily for a total of 12 days. Neither the hydrochlorothiazide exhibited a blood pressure average daily resting pulse rate nor the BMR response when a-MPT was added to the ongoing was altered significantly by this therapy despite a drug regimen (Table III). Under these circum- reduction of VMA excretion of 61% (Fig. 6). stances, blood pressure lowering was evident with This patient was moderately sedated, but there doses as low as 700 mg/day and was generally was no other sign of beneficial effect. Four of the greater in the standing than supine position. six patients with Raynaud's phenomenon initially No convincing therapeutic effect of a-MPT showed suggestive beneficial effects while receiv- could be established in the patients with glaucoma, ing 1.0-2.0 g of a-MPT per day. Subjectively migraine, thyrotoxicosis, or Raynaud's phenome- these patients claimed an increase in tolerance to non and none of these normotensive subjects be- cold exposure in that a longer exposure elapsed came hypotensive on a-MPT. The two patients before the development of pain in the hands. This with open angle glaucoma received daily drug effect tended to persist on switching to placebo doses of 500 and 1000 mg respectively, for up to medication, however, and it was impossible to 4 wk. In the patient with migraine headache (a demonstrate any increase in skin temperature. 49 yr old woman), a complete cessation of migraine attacks (usual frequency two times per Other drug effects week as an outpatient, two attacks also occurring Central nervous system effects were noted al- during the 1st wk of hospitalization which served most uniformly in patients of all categories. Seda-

FA. 23M THYROTOXICOSIS 3000 2000 3 - 1000110 I- A////////M _) -_ 120

J 100 CLf 90 I-%- ' 80 - 70 LU r- 5 I- 4 - 3 3 "Cl 2 .r- _ FIGURE 6 Effects of therapy with a-MPT o+80 in a 23 yr old male with severe thyrotoxi- g @+60 4-- - @+40 cosis. Though the VMA excretion was re- -+ 20 duced by 60% to levels of only 1 mg/day, C 0 D12N110 14 1 there was no effect on resting pulse rate I or I0 F I' the basal metabolic rate. 5 10 15 20 DAYS

Effects of a-Methyltyrosine 589 tion, generally mild but of varying degree, was matology at a dose of 2.0 g/day (W. L., Table I). observed in 44 of the 46 subjects in this study who As with mood changes, neuromuscular effects dis- received a dose of 1000 mg or more a-MPT appeared rapidly with cessation or reduction of daily; several patients experienced sedation with drug dose. Patients exhibiting neuromuscular ef- daily doses as low as 300-600 mg. Sedative effects fects had deep tendon reflexes and plantar re- began within 18-24 hr of institution of treatment sponses unchanged from control status. with divided daily dosage, were maximal at 2-3 Other side effects observed were diarrhea (five days, waned during the next few days, and usually cases), galactorrhea (1 case), and decreased sali- were not obvious after 1 wk unless dosage was vation with "dry" mouth (one case). Diarrhea increased. At doses greater than 2.0 g/day some was of minimal degree except in one of the degree of sedation or feeling of fatigue tended patients with pheochromocytoma (T. WV., Case 4) to persist. Interestingly, patients who received and in a patient with scleroderma who had a single 1.0 g oral doses for study of the drug's history of mucus colitis and developed flatulence metabolism (4) did not experience sedation with frequent, watery bowel movements while though this effect occurred uniformly when the receiving 2.0 g of a-MIPT per day. Symptoms same total dose was divided over a 24 hr period. abated in the latter subject when the drug was Other central effects observed included an stopped for 3 days, but diarrhea recurred on anxiety or agitated depression and changes in rechallenge with a-NIPT. Galactorrhea occurred sleep pattern after withdrawal of medication. in a 43 yr old woman with Raynaud's phenomenon Anxiety was noted in four cases of pheochromo- at an a-MPT dose of 2.0 g; the patient had two cytoma (F. M., S. M., J. D., and W. L., Table I) children, 18 and 15 yr of age, and was menstru- at doses of 2.0-4.0 g of a-MPT per day, which ating normally at the time of study. Fluid could necessitated reduction of dosage or cessation of no longer be expressed from her breasts 10 days treatment. The study group of patients with essen- after discontinuing a-MPT. tial hypertension was unusual in that six subjects No other clinical findings could lbe attributed to had a history of psychic depression. Three of these a-MIPT. There was no crystalluria even at a dose six patients became sufficiently agitated on 1.0- of 4.0 g daily and no evidence of renal, hepatic, 2.0 g of drug daily to require stopping treatment. or henmatological toxicity by the usual monitoring. One patient with Raynaud's phenomenon became studies anxious at the 2.0 g dose level. Temporary changes Special in sleep pattern on withdrawal of drug occurred The question exists whether any of the effects in most patients who had experienced sedative of a-IPT can be attributed to the minor degree effects; these changes consisted of a pleasant of metabolism of the drug to a-methyldopa (4). A feeling of alertness and ambition accompanied by few observations were made which bear on this insomnia for 4872 hr. question. Since the changes in sleep pattern after In addition to changes in mood and mental a-MPT administration and withdrawal are very activity, adverse effects related to neuromuscular reminiscent of those observed with methyldopa activity appeared in three patients with pheo- (7), it may be pertinent that in three hyper- chromocytoma (two of whom were also quite tensive patients (E. B., W. S. M., and A. B., anxious) and two of the patients with essential Table III) central effects occurred with a-NIPT hypertension who had manifested an agitated that were seemingly independent of ongoing ther- state. The mildest alterations consisted of fine apy with methyldopa. Patients W. S. M. and A. B. tremor of the hands first manifest as a change in both became markedly sedated for the first few handwriting and in severest form consisted of days of a-MPT administration and then showed gross tremor of the hands and legs unaffected by striking insomnia after its withdrawal despite the rest or movement and accompanied by tightening continuation of methyldopa therapy. The responses of the jaw with trismus and plastic resistance to of E. B. differed in that she was sedated initially passive movement. The patient who had the most on 750-1000 mg of a-MPT, but as the dose was severe reaction had intracranial metastases from a continued she developed insomnia and anxiety pheochromocytoma and developed severe sympto- which regressed when a-MPT was discontinued; 590 K. Engelman, D. Horwitz, E. Jequier, and A. Sjoerdsma 80r

Methy/dopo I0' E E U-w 60k

(n w

0 m pre -a-MPT 0aJ 40k in 0o- FIGURE 7 Alterations pressor responsiveness to tyramine produced by equivalent doses of cn a-MPT and methyldopa in a hypertensive pa- z tient (E. F.). Individual values represent sys- w tolic pressure increments produced by 15-min en 201- intravenous infusions of tyramine at the rates w indicated. The protocol of drug administration z is that depicted in Fig. 5; tyramine testing was done on the 9th and 11th days of a-MPT treatment and on the 7th and 10th days of methyl- | dopa therapy. 0 500 1000 1500 2000 TYRAMINE INFUSION RATE (ig/min) on the other hand, 12 days later when methyldopa degree of inhibition is similar with equivalent doses was discontinued the patient again experienced of drug in both circumstances. transient pronounced insomnia. Reductions of catecholamine synthesis over the Evidence against the participation of methyldopa wide range of 36-79% resulted in clear-cut im- in the peripheral sympathetic effects of a-MPT provement in the clinical condition of patients was obtained by the demonstration that pressor with pheochromocytoma. In most cases the results responses to the indirectly acting pressor amine, compared favorably with those achieved by admin- tyramine, were reduced by a-MPT treatment in istration of adrenergic-blocking drugs, and in some the three subjects studied. An illustrative study notable instances (Cases 2 and 4, above), the is depicted in Fig. 7. The patient was a hyper- effects of a-MPT were superior to those attainable tensive subject (E. F.) who was studied during with other drugs. Despite current availability of placebo periods and during periods of treatment potent alpha and beta adrenergic-blocking drugs, with 1.5 g of a-MPT and 1.5 g of methyldopa, it appears preferable and simpler to antagonize the respectively, with comparable reductions in blood wide range of "effects" of the catecholamines by pressure being achieved with the two drugs (see actually reducing their production. With such an Fig. 5). As shown in Fig. 7, systolic pressor approach it is possible to achieve a balanced over- responses to varying rates of infusion of tyramine all effect with maximum therapeutic benefit using were decreased by approximately 50%c during a single drug. a-MPT treatment. In contrast, treatment with In contrast to the situation in pheochromo- methyldopa was accompanied by an enhanced cytoma, in which symptomatology is directly re- responsiveness (300-400%) to tyramine. lated to catecholamine production rate, the sensitivity and specificity of response in conditions DISCUSSION associated with normal rates of catecholamine It is clear from the data presented that a-MPT synthesis were less apparent. Thus, it appears that is effective in inhibiting catecholamine synthesis inhibition of catecholamine biosynthesis to the in man. This is true whether the rate of synthesis extent of 50-70% in patients with essential hyper- is high, as in pheochromocytoma, or normal as in tension was insufficient to result in consistent cases of essential hypertension. Furthermore, the reduction of blood pressure. In contrast to our Effects of a-Methyltyrosine 591 initial impression (2), however, these additional was inhibited. As with symptoms of sedation and studies indicate that blood pressure effects clearly anxiety, tremors disappeared within a few days occur in some patients. Furthermore, lowering of of reduced drug dose, a period during which cate- blood pressure can be produced consistently if the cholamine synthesis rate would have reverted to- drug is added to ongoing therapy with an accepted wards normal. The appearance of lactation in a antihypertensive agent. premenopausal patient probably also represented Preliminary studies of a-MPT effects in other an effect of a-MPT on the central nervous system. conditions in which antagonism of sympathetic A wide variety of centrally acting anti-adrenergic function has been used in therapy, but in which drugs, including methyldopa, reserpine, and the over-all catecholamine metabolism is normal, failed phenothiazines have been reported to induce galac- to reveal any therapeutic effects. No appreciable torrhea in women (13), presumably by interrupt- beneficial effects accrued to a single patient with ing adrenergic mechanisms which normally inhibit thyrotoxicosis, a condition reported to be possibly release of prolactin from hypothalamic centers. associated with an increased sensitivity to cate- The most troublesome untoward effect of the cholamines (8) and reported to be partially drug was severe diarrhea occurring in two pa- responsive to certain adrenergic antagonists (9- tients. Ordinarily one might tend to attribute such 11). Results in two patients with open angle diarrhea to diminished sympathetic neural control glaucoma and in one patient with migraine were of the bowel, as occurs with guanethidine and difficult to interpret, and apparent subjective bene- similar drugs. However, one of the two patients fit in patients with Raynaud's phenomenon was still had excessive amounts of catecholamines due considered to be no greater than that achievable to pheochromocytoma, and diarrhea in both pa- with placebo. Further evaluation of patients with tients seemed to persist after drug withdrawal these and other diseases has been prohibited at beyond the time required for return of catechola- least temporarily pending evaluation of results mine synthesis to control levels. The possibility of toxicity studies in animals (see below). of a direct irritant effect of the drug seems likely A number of untoward effects were encountered at this time since studies in dogs have shown that in patients given a-MPT. Persistent sedation or a-MPT orally in a dose of 150 mg/kg per day the development of an anxiety state, while not of may produce ulcerating lesions of the intestinal serious consequence, limited the level of dosage tract in as little as 2 wk.3 which could be tolerated by some patients. This Because of drug crystalluria and urolithiasis was not a serious problem in cases of pheochromo- occurring in dogs receiving as little as 50 mg/kg cytoma, but was a significant deterrent in cases of a-MPT per day,3 therapeutic evaluation of of essential hypertension, possibly because our a-MPT has been markedly restricted. This ac- study group was somewhat biased toward patients counts for the fact that our studies in essential with a past history of psychic disturbances. The hypertension are somewhat limited and those in development of tremor in several patients, accom- the other states, in which there is a normal cate- panied in two patients by "tightness of the cholamine production rate, are highly preliminary. mouth" or trismus, is of considerable interest. However, no evidence of a-MPT crystalluria has Though the clinical neurological states of these been found in any of our patients receiving up to patients were not entirely characteristic of an 4000 mg of a-MPT daily. There was no evidence extrapyramidal disorder, it seemed to us that of urolithiasis at postmortem examination of the there were similarities. Since depletion of 3,4- patient (E. H.) who received 2000 mg of a-MPT dihydroxyphenylethylamine (dopamine) in neu- daily for 10 months. One of our patients (D. B., rones of the basal ganglia has been found in Table I) was treated subsequently with consid- association with extrapyramidal syndromes (12), erably larger doses of a-MPT at another institu- it seems possible that we were observing such a tion; crystalluria was noted at a dose of 5000 circumstance as a result of a-MPT. Dopamine is mg/day.4 It should be noted that, in contrast with an intermediate in the biosynthesis of norepineph- 3 Bayne, G. M. Merck & Co. Personal communication. rine and would be expected to decrease in tissues 4 Melmon, K. Moffett General Hospital, San Francisco, of patients in whom tyrosine hydroxylase activity Calif. Personal communication. 592 K. Engelman, D. Horwitz, E. Jequier, and A. Sjoerdsma human subjects, dogs that developed evidence of hospital for the short periods of time required for a-MPT crystalluria and stones were heavily preoperative preparation of a patient with benign sedated and ate and drank poorly. Similar toxico- pheochromocytoma. Though a-MPT used alone logical studies in rats indicate that crystalluria appears not to be a safe and effective means of and renal damage may be prevented by forced controlling the blood pressure of patients with water intake (14). In vitro solubility studies essential hypertension, its effectiveness in combi- show that despite its general insolubility in nation with other antihypertensive drugs warrants aqueous solutions a-MPT is soluble in normal further study. It is likely that even partial control urine to the extent of slightly more than 1 mg/ml. of the rate of catecholamine biosynthesis with Since absorption averages 60-70%o of the oral a-MPT would favorably affect responsiveness to dose (4) and usual urine output exceeds 1000 other antihypertensive drugs which interact with ml/day, one would not expect crystalluria in sympathetic mechanisms in a different way. patients receiving up to 2000 mg/day. Further- Judging from studies in experimental animals more, it is possible that in common with a num- (16), increased sympathetic activity resulting in ber of other compounds, this drug may actually marked increases in rates of catecholamine syn- be excreted in urine in a supersaturated state with thesis is one of the reactions to stressful stimuli. a much higher apparent solubility coefficient. Such increases in synthesis rates can be eliminated Nevertheless, it is advised that any patients re- by use of a-MPT. Thus, insofar as variations in ceiving larger doses of a-MPT be encouraged to blood pressure may occur in reaction to "stress," ingest enough liquids to excrete a daily urine a-MPT might have application in placing a volume of 2000 ml or more. "damper" on an important sympathetic neural Though the primary effects of a-MPT are mechanism. For these reasons, we would recom- thought to be due to inhibition of catecholamine mend that a-MPT in doses up to 3.0 g/day be biosynthesis, a small conversion of the drug to evaluated further in combination with other drugs raises the methyldopa and its amine metabolites essential Pheo- question of the possible role of methyldopa in in patients with hypertension. the responses observed (4). The results of studies chromocytoma and essential hypertension repre- presented here tend to rule out a methyldopa sent the minimal clinical spectrum in which more effect. It seems noteworthy that the initial sedative potent inhibitors of tyrosine hydroxylase might and later withdrawal effects of a-MPT occurred be clinically useful. in the usual way when the drug was administered ACKNOWLEDGMENTS to patients who were already receiving amounts of methyldopa, 5004750 mg, that were massive The capable technical assistance of Mrs. Diane Warren, Mrs. Katherine Gvozdas, and Mrs. Jane Bell is appreci- compared to that which can originate from a-MPT ated. Dr. Charles J. Glueck offered valuable assistance (4). As to the peripheral effects of a-MPT, the in the studies on patients with Raynaud's phenomenon. demonstration that tyramine pressor responsiveness is decreased during a-MPT whereas it is REFERENCES typically enhanced during methyldopa. therapy 1. Spector, S., A. Sjoerdsma, and S. Udenfriend. 1965. (15) as confirmed here in one of the patients, Blockade of endogenous norepinephrine synthesis by of catechola- a-methyl-tyrosine, an inhibitor of tyrosine hydroxy- also argues strongly for inhibition Therap. 147: 86. of drug lase. J. Pharmacol. Exptl. mine synthesis as the primary mechanism 2. Sjoerdsma, A., K. Engelman, S. Spector, and S. action. Udenfriend. 1965. Inhibition of catecholamine synthe- A final consideration is what future exploration sis in man with alpha methyl-tyrosine, an inhibitor of should be made in human subjects of the effects of tyrosine hydroxylase. Lancet. 2: 1092. a-MPT itself, and of other drugs yet to be devel- 3. Engelman, K., and A. Sjoerdsma. 1966. Inhibition of which inhibit hydroxylase. Balanc- catecholamine biosynthesis in man. Circtulation Res. oped tyrosine 18 and 19(Suppl. 1): 1. ing the risks of toxicity vs. therapeutic benefit, it 4. Engelman, K., E. Jequier, S. 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Effects of oral and intramuscular admin- mine sensitivity in man. Nature. 200: 1107. istration of reserpine in thyrotoxicosis. New Engl. 16. Gordon, R., J. V. 0. Reid, A. Sjoerdsma, and S. J. Med. 257: 435. Udenfriend. 1966. Increased synthesis of norepineph- 10. Gaffney, T. E., E. Braunwald, and R. L. Kahler. rine in the rat heart on electrical stimulation of the 1961. Effects of guanethidine on tri-iodothyronine- stellate ganglia. Mol. Pharmacol. 2: 610.

594 K. Engelman, D. Horwitz, E. Mquier, and A. Sjoerdsma