Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation

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ic parameters and without signs of left ventricular failure. Thus the acute pulmonary hypertension seemed to be a major factor only in the contralateral, but not in the ipsilateral, reexpansion pulmonary edema. The identity of bilateral pressure measurements in our patient makes doubtful the earlier hypothesis concerning the inequalities in capillary or venous pressures in the two sides of the lungs.14,I5 We also ruled out positional-gravitational factors15, I6 by changing our patient’s position frequently, which did not influence the chest x-ray findings. As mentioned above, only rarely was a postpneumothorax pulmonary edema associated with the clinical picture of marked respiratory distress. Our patient, however, exhibited clinical symptoms of severe respiratory insufficiency and extremely low Pa,+ values, the x-ray picture revealed pulmonary edema, and there was no left ventricular failure. Thus the criteria for adult respiratory distress syndrome were fulfilled.13 The importance of hemodynamic measurements for diagnosing this syndrome in patients with bilateral pulmonary edema and for application of proper therapy is well established.‘3,17 Our report not only presents a new and unusual form of unilateral noncardiac edema alternating sequentially in the two lungs but stresses again the importance of hemodynamic measurements in a clinical entity in which the pathophysiology may be obscure.@ REFERENCES 1.

2.

3. 4. 5. 6. 7. 8. 9. 10.

11.

12. 13.

14.

Calenoff L, Kruglick GD, Woodruff A: Unilateral pulmonary edema. Radiology 126:19, 1978. Ziskind MM, Weill H, George RA: Acute pulmonary edema following the treatment of spontaneous pneumothorax with excessive negative intrapleural pressure. Am Rev Respir Dis 92:632, 1965. Waqaruddin M, Bernstein A: Reexpansion pulmonary edema. Thorax 30:54, 1975. Mahajan VK, Simon M, Huber GL: Reexpansion pulmonary edema. Chest 75:192, 1979. Miller WC, Toon R, Palat H, Lacroix J: Experimental pulmonary edema following reexpansion of pneumothorax. Am Rev Respir Dis 108:654, 1973. Steckel RJ: Unilateral nulmonarv edema after tmeumothorax. N Engl J Med 289:621, 1973: Ravin CE, Dahmash NS: Reexpansion pulmonary edema (Letter to the Editor). Chest 77:709, 1980. Sherman S, Ravikrishnan KP: Unilateral pulmonary edema following reexpansion of pneumothorax of brief duration (Letter to the Editor). Chest 77:714, 1980. Humphreys RL, Berne AS: Rapid reexpansion of pneumothorax. Radiology 96:509, 1970. Hublitz UF, Shapiro JH: Atypical pulmonary patterns of congestive failure in chronic lung disease. Radiology 93:995, 1969. Albers WH, Nadas AS: Unilateral chronic pulmonary edema and pleural effusion after systemic-pulmonary artery shunts for cyanotic congenital heart disease. Am J Cardiol 19:861, 1967: Richman SM, Godar TJ: Unilateral pulmonary edema. N Engl J Med 264:1146, 1961. Petty TL, Ashbaugh DG: The adult respiratory distress syndrome: Clinical features, factors influencing prognosis and principles of management. Chest 60:233, 1971. Goodrich WA: Pulmonary edema: A correlation of x-ray ;;;;.arance and physiological changes. Radiology 51:58,

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15. Gleason DC, Steiner RE: The lateral roentgenogram in pulmonary edema. Am J Roentgen01 98:279, 1966. 16. Leeming BWA: Gravitational edemaof the lungs observed during assisted respiration. Chest 64:719, 1973. 17. Keren A, Klein J, Stern S: Adult respiratory distress syndrome in the course of acute myocardial infarction. Chest 77:161, 1980. 18. Nessa CB, Rigler LG: The roentgenological manifestations of pulmonary edema. Radiology 37:35, 1941.

Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation Rashmi R. Shah, B.Sc., M.R.C.P., Nicholas S. Oates, Ph.D., Jeffrey R. Idle, Ph.D., Robert L. Smith, D.Sc., and J. Dennis F. Lockhart, M.B.B.Ch., D.P.H. Paddington and Middleser, England

Perhexiline is an effective antianginal agent.’ Its use however, has been associatedwith occasionalseriousside effects, notably peripheral neuropathy: severe weight loss,’and effects on hepatic function, including cirrhosis.3 Perhexiline is metabolized by oxidation to more polar hydroxylated metabolites prior to its elimination.4 Recently, human studiesof debrisoquinemetabolismhave shown the occurrence of a genetic polymorphism in drug oxidation, approximately 9% of British white persons being defective in this respect.5Furthermore, individuals with impaired debrisoquine oxidizing ability cannot metabolize normally a number of other drugs.5 As a consequence,they are susceptibleto various adversedrug reactions such asdebrisoquine-inducedpostural hypotension, phenformin-induced lactic acidosis, phenacetininduced methemoglobinemia,and nortriptyline-induced vertigo, dizziness, and confusional state6 We describe a patient for whom the determination of debrisoquine hydroxylation status wasof value in alerting us to investigating and demonstrating the existence of subclinical peripheral neuropathy, which might otherwise have escapedrecognition until it had developed to the point of becoming clinically overt. G.A., a 60-year-old man with a past medical history of duodenalulcer and treatment with cimetidine, wasadmitted in 1978 with extensive anterior myocardial ischemia. His ECG showedsevereST-T changeswithout any accompanying changesin serumenzyme levels. Following recovery, he continued to experience angina at rest, during From the Department of Biochemical and Experimental Pharmacology, Mary’s Hospital Medical School, and Merrell Pharmaceuticals Limited. Received

for publication

Reprint

requests:

Oct. 7, 1981; Rashmi

Biochemical/Experimental School,

Paddington,

0002.8703/83/010159

London

R.

Shah,

accepted

Nov.

M.R.C.P., Pharmacology, St. Mary’s W2 lPG, England.

+ 03$00.30/O

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Hrief Communications

Sensory conduction Right median nerve Latency (msec) Amplitude (PV) Right ulnar nerve Latency (msec) Amplitude (pV) Motor conduction Velocity (m/set) EMG conclusion

4.x 3.0 CY

3.4

:1.4

2.H

0

2.6

13.0

8.0

51.0 Neuropathic changes, particularly sensory, resolving

n.d. No evidence of neuropathy

55.0 No evidence of neuropathy

50.0 Demyelinating, predominantly sensory, neuropathy

md. = not determined; CY= action potentials *Debrisoquine metabolic ratio. iDuration of perhexiline treatment. tAfter stopping treatment with perhexiline.

'A,.) ) r 1 r, ( I n.d. No evidence of neuropathy

".:I 10.0 n.d. No evidence of neuropathl

undetectable.

emotional stress,and at night, with a total of about I2 to 15 episodesdaily. Beta blockers and nifedipine did not prove to be of substantial benefit. There were no abnormal cardiovascular, respiratory, or neurologic physical signs, and his routine hepatic and renal biochemical tests were normal. Coronary angiography revealed normal left ventricular function without major coronary arterial obstruction. The patient began receiving perhexiline, 100 mg twice daily, and in view of encouragingtherapeutic responseand normal liver function tests 4 weeks later, the dose was increasedto 100 mg three times a day. At regular followup visits, he reported considerable reduction in angina1 episodesand had no neurologic complaints. During this follow-up, he maintained normal liver function tests on five occasionsapart from one minor elevation of serum aspartate aminotransferaseconcentration to 75 U/L (normal range 7 to 40 U/L), which dropped to 46 U/L during continued perhexiline therapy. Following a total of 33 weeksof perhexiline therapy, the patient’s phenotype was determined with 10 mg oral debrisoquinefor his hydroxylation status.” Treatment continued with atenolol, cimetidine, perhexiline, and isosorbidedinitrate. He wasfound to have a metabolic ratio of 18.1,confirming that he wasof poor metabolizer phenotype. In view of this finding, an electromyogram (EMG) was obtained 3 days later, and it revealed definite evidence of subclinical demyelinating, predominantly sensory, neuropathy. Perhexiline was therefore discontinued and replaced by prenylamine lactate, 60 mg three times a day, although this agent has not proved equally beneficial. The plasma elimination halflife of perhexiline in this patient was estimated to be 9.5 days. A repeat EMG 16 weeks later confirmed consider-

able resolution of neuropathy, the improvement being particularly marked in the sensorycomponent. The patient’s EMG data are summarized in Table I, which, for comparison,also contains the results of EMGs of two other patients (K.B., M.C.) of extensive metabolizer phenotype, both of whom have debrisoquinemetabolic ratios of 0.6 each. Thesetwo patients have been receiving perhexiline, 100 mg three times a day, without any evidence of sideeffects for more than 40 weeks.A previous study reported high plasma perhexiline levels as well as high ratios of plasmaperhexiline to 4-hydroxy-perhexiline in neuropathic patients compared to non-neuropathic contro1s.7Wide interindividual variations in the rate of its oxidative metabolism in healthy volunteers have been noted,’ and the plasma half-life of perhexiline has been shown to be longer in neuropathic patients than in non-neuropathic patients.7 It has been suggestedthat the neuropathic reaction associated with perhexiline usage represents an individual susceptibility secondary to a latent inborn metabolic disorder.?The finding of impaired debrisoquine oxidation status in our patient is of great interest when viewed with all other available evidenceand compared to the status of the two patients with normal oxidative ability. The phenotype of our first-mentioned patient was again determined on two separate occasions, and his ratios were 27.4 (5 weeksafter stopping perhexiline) and 24.2 (after discontinuing cimetidine for 5 days 12 weeks later). It is also worth noting that liver function tests in our patient remained essentially normal, thereby excluding initial hepatic damage to account for the impaired debrisoquine, and by inference perhexiline, hydroxylation. The ability to oxidize many drugs hasbeen shownto be controlled by the samepair of gene allelesas

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defined by debrisoquinet and the high metabolic ratio in the patient described suggeststhat impaired drug oxidation may be the inborn metabolic disorder predisposingan individual to perhexiline accumulation and the associated neurotoxic sequelae. REFERENCES 1. Pilcher

2.

3.

4.

5.

6.

7.

J, Chandrasekhar KP, Russell Rees J, Boyce MJ, Pence TH, Ikram H: Long-term assessment of perhexiline maleate in angina pectoris. Postgrad Med J 49(suppl 31:115, 1973. L’Hermitte F, Fardeau M, Chedru F, Mallecourt J: Polyneuropathy after perhexiline maleate therapy. Br Med J 1:1256, 1976. Pessayre D, Bichara M, Feldman G, Degott C, Potet F, Benhamou J: Perhexiline maleate-induced cirrhosis. Gastroenterology 76:170, 1979. Wright GJ, Leeson GA, Zeiger AV, Lang JF: The absorption, excretion and metabolism of perhexiline maleate by the human. Postgrad Med J 49(suppl 3):8, 1973. Idle JR, Oates NS, Ritchie JC, Shah RR, Sloan TP, Smith RL: New perspectives of genetic polymorphism in drug metabolism. In Bellingham AJ, editor: Advanced Medicine. Vol. 16. Bath, 1980, Pitman Medical, p 227. Bertilsson L, Mellstriim B, Sjijqvist F, Martensson B, Asberg M: Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: Clinical implications. Lancet 1:561, 1981. Singlas E, Goujet MA, Simon P: Pharmacokinetics of perhexiline maleate in angina1 patients with and without peripheral neuropathy. Eur J Clin Pharmacol 14:195, 1978.

Fulminant acute rheumatic multisystem involvement

1. Chest x-ray film shows cardiomegaly with predominanceof left-heart chambers,signsof pulmonary and

Fig.

venocapillary

hypertension,

and an area of consolidation

at the right basewith pleural effusion.

fever with

Jorge Escudero, M.D., Estanislao Stanislawsky, M.D., and Xavier Escudero, M.D. Mexico City, Mexico A 14-year-old boy admitted to our institution had no history of pharyngitis or rheumatic fever. Four months prior to admissionhe developed malaise, arthritis, and weight loss without fever. Shortly thereafter, exerciserelated dyspnea occurred, progressingto orthopnea, nocturnal paroxysmal episodes,cough with blood-streaked sputum, pain in the right hypochondrium, and malleolar edema. At physical examination he was afebrile with a heart rate of lOO/min and blood pressureof 140/Omm Hg, cachectic, dehydrated, and jaundiced. The jugular veins were distended with hepatojugular reflux. Cardiac examination revealed a hyperdynamic apex, gallop rhythm, pericardial rub, systolic and diastolic apical murmurs, systolic murmur at the tricuspid area, ejection systolic From the Hospital de Cardiologia y Neumologia, National Medical Center, Mexican Institute of Social Security. Received for publication April 6, 1981; revision received Nov. 1, 1981; accepted Dec. 3, 1981. Reprint requests: Jorge Escudero, M.D., Hospital de Cardiologia y Neumologia, National Medical Center, Mexican Institute of Social Security, Avenida Cuauhtemoc 330, Mexico 7. D.F., Mexico.

0002-8703/83/010161

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Mosby

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2. Trivalvular rheumatic valvulitis as viewed from above with the atria removed. The aortic valve is in the midcenter field, the mitral valve in the upper right, and the tricuspid valve in the upper left. The mitral and aortic valves are thickened with commissural fusion and small vegetations.The tricuspid valve displayssimilar, although milder, changes. Fig.

murmur with soft diastolic murmur at the base, and a reinforced or loud pulmonary secondsound. There were pulmonary rales, painful moderate hepatomegaly, peripheral pulses of the Corrigan type, and marked malleoiar edema.An ECG showedfour-chamber enlargement.Chest x-ray films revealed marked cardiomegaly, pulmonary and venocapillary hypertension, and right pleural effusion (Fig. 1). Laboratory findings were asfollows: hemoglobin,