AMINOPHYLLINE INHIBITION OF DIAZEPAM SEDATION: IS ADENOSINE BLOCKADE OF GABA-RECEPTORS THE MECHANISM?

463 sites at about 2 and 24 kilobases. In two other hepatoblastomas examined on the same occasion, no HBA DNA integration was observed. Radioimmunoassays of the patient’s serum revealed HBsAb and a questionable amount of HBcAb, but no HBsAg, HBeAg, or HBeAb. HBsAg was also not detectable, either in tumorous or nontumorous tissues, by Victoria-blue staining.8 The maternal serum was also negative for HBsAg and HBsAb by reverse phase and passive haemagglutination tests done twice before and after the delivery. The route of HBV infection in the baby is thus not clear. This case is important not only because it strengthens the hypothesis of a direct causal role for HBV in the induction of HCC (including hepatoblastomas) but also because it raises the possibility of transplacental transmission of HBV to the hepatocyte during

embryogenesis. This work was supported by grant-in-aid for Japanese Government.

cancer

research from the

2

(with doses up to 1’ 2 g per day) has not been demonstrated in man but patients with chronic renal failure may be prone to severe allopurinol hypersensitivity reactions.3Captopril itself has not been reported to cause the Stevens-Johnson syndrome but is well known to be associated with rashes. Wilkin et al4 have suggested that captopril-induced rashes may be the result of potentiation of kinin-mediated cutaneous reactions, especially in patients with a history of allergic or cutaneous disease. We are aware of two other patients in the world who, while on long-term captopril, acquired Stevens-Johnson syndrome 3-5 weeks after introduction of allopurinol (E. R. Squibb, personal communication). Our patient, who had no history of allergy or cutaneous disease, had a skin eruption which, we suggest, was secondary to the introduction of allopurinol potentiated by the presence of captopril. Whilst no firm conclusions can be drawn from one case, the drug combination of captopril and allopurinol should be prescribed with care, especially in patients with chronic renal failure.

Department of Pathology, Cancer Institute,

Kami-Ikebukuro, Toshima-ku,

Tokyo 170, Japan Departments of Surgery and Pathology, Hokkaido Children’s Hospital and Medical Centre

OKIO HINO TOMOYUKI KITAGAWA

St Thomas’ Hospital, London SE 1 7EH

TOSHINORI HIRAMA SHIGEAKI YOKOYAMA

FATAL STEVENS-JOHNSON SYNDROME IN A PATIENT ON CAPTOPRIL AND ALLOPURINOL

StR,-A 71-year-old man presented in March, 1983, with hypertension, chronic renal failure, congestive cardiac failure, and mild polyarthritis, reasonably controlled with piroxicam. The hypertension was poorly controlled on bendrofluazide, propranolol, and hydralazine, and his antihypertensive drugs were changed to prazosin, spironolactone, and frusemide with some clinical improvement. In July, 1983, he complained of increasing right hip pain. His blood pressure was 170/110 mm Hg and there third heart sound, bilateral basal crackles, and a hard prostate. Investigations revealed normochromic normocytic anaemia, a raised ESR (64 mm/h), raised alkaline phosphatase 20 KingArmstrong units (normal 2-11) and acid phosphatase 14U/1 (normal <10), blood urea (26 mmol/1), and serum creatinine (253 J.lmolll). Radiology demonstrated an enlarged heart, pulmonary congestion, bilateral small kidneys with no obstruction, and sclerosis of the right superior pubic ramus, which was hot on a radionuclide bone scan. Radiotherapy to the right hip region provided rapid relief of pain. Congestive cardiac failure persisted with marked postural hypotension attributed to prazosin. On Aug 19, 1983, he was started on captopril 25 mg twice daily (creatinine clearance of 29 mllmin) with good control of heart failure and hypertension. Because of a raised serum urate (0 -8mmol/1) and chronic renal failure he was started on allopurinol 100 mg twice daily on Aug 23. On Oct 3 he was readmitted with a 4 day history of a widespread rash, dry cough, malaise, and facial swelling. He had a fever, a confluent erythematous maculopapular eruption with oedema of the eyelids, face, lips, and mouth and conjunctival ulceration. Progressive balanitis led to urinary retention. The white cell count was 9 - 7 x 109/1 with 75% neutrophils and 11 % eosinophils. ESR Skin was 38 mm/h and alanine transaminase 178 IU (normal <20). multiforme. confirmed erythema Repeated Mycoplasma and biopsy Herpes simplex antibody titres were negative. Stevens-Johnson syndrome was diagnosed. All drugs were stopped. He was started on high dose corticosteroids. Severe oral pain, diarrhoea, and rapidly worsening renal failure developed, and, he died on Oct 17. Necropsy confirmed prostatic carcinoma with bone metastases. The kidneys were small and finely scarred and the heart was hypertrophied. Allopurinol is associated with toxic epidermal necrolysis and some reports refer to Stevens-Johnson-like manifestations. The two skin conditions may be related.’ Dose related toxicity of allopurinol was a

8 Tanaka

D. J. PENNELL T. O. NUNAN M. J. O’DOHERTY D. N. CROFT

K, Mori W, Suwa K. Victoria blue-nuclear fast red stain for HBs antigen detection in paraffin section. Acta Pathol Jap 1981; 31: 93-98. 1. Assad D, From L, Ricciatti D, Shapero H. Toxic epidermal necrolysis in StevensJohnson syndrome. Can Med Assoc J 1978; 118: 154-56.

AMINOPHYLLINE INHIBITION OF DIAZEPAM SEDATION: IS ADENOSINE BLOCKADE OF GABA-RECEPTORS THE MECHANISM?

SIR,-In a 1981 case-report Stirt5 suggested that aminophylline at very modest dose counteracted deep diazepam sedation. We have shown that low-dose aminophylline (60 mg intravenously) rapidly reverses the sedative effect of diazepam a

postoperatively.6,7

given to achieve deep sedation, analgesia being maintained by spinal or topical anaesthesia. Another case of a reversal of diazepam sedation by low-dose aminophylline has recently been reported in The Lancet by Kleindienst and Usinger,8 in a healthy volunteer evaluated psychometrically. The reversal in this case was not complete. We have tried to evaluate possible mechanisms for this effect. is Aminophylline is a general adenosine blocking a very potent endogenous CNS-depressant. 0 Aminophyllineinduced adenosine blockade may therefore explain the CNS stimulation after the xanthines aminophylline and caffeine. This might also be the mechanism behind the inhibition of diazepam sedation found in our previous study. Unfortunately, no pure adenosine receptor antagonist is available to test the physiological role of adenosine in man. However, enprofylline, a novel xanthine derivative, is devoid of adenosine-blocking properties. Even so it is about five times as potent as aminophylline in respect of all antiasthmatic effects. I By comparing equipotent anti-asthmatic doses of enprofylline and aminophylline the importance of adenosine blockade in the interference with diazepam sedation has been Diazepam

was

aflent. 9 Adenosine

evaluated.

Twenty men gave their informed consent to a randomised doublestudy. They were scheduled for transurethral surgery under spinal anaesthesia. Premedication was given with 10 mg diazepam

blind

2. Yu

TF, Gutman AB. Effect of allopurinol (4-hydroxy pyrazolo-(3, 4,-d) pyrimidine) and urinary acid in primary and secondary gout. Am J Med 1964; 37:

on serum

885-98.

Young JL, Boswell RB, Nies AS. Severe allopurinol hypersensitivity: association with thiazides and prior renal compromise. Arch Intern Med 1974; 134: 553-58. 4. Wilkin JK, Hammond JJ, Kirkendall WM. The captopril-induced eruption. Arch Dermatol 1980; 116: 902-05. 5. Stirt JA. Aminophylline is a diazepam antagonist. Anesth Analg 1981; 60: 767-68. 6. Arvidsson SB, Ekström-Jodal B, Martinell SAG, Niemand D. Aminophylline antagonises diazepam sedation. Lancet 1982; ii: 1467. 7. Arvidsson SB, Niemand D, Martinell SAG, Ekström-Jodal B. Aminophylline for reversal of diazepam sedation. Anaesthesia (in press). 8. Kleindienst G, Usinger P. Diazepam sedation is not antagonised completely by aminophylline. Lancet 1984; i: 113. 9. Fredholm BB. Are Methylxanthine effects due to antagonism of endogenous adenosine? Trends in Pharmacol Sci 1980; 1: 129-32. 10. Fredholm BB. Adenosine receptors: focus on research. Med Biol 1982; 60: 289-93. 11. Lunell E, Svedmyr N, Andersson K-E, Persson CGA. Effects of enprofylline, a xanthine lacking adenosine receptor antagonism, in patients with chronic obstructive lung disease. EurJ Clin Pharmacol 1982; 22: 395-402 3.

464

rectally. When analgesia had been established, deep sedation (to loss response) was induced and maintained throughout surgery by repeated intravenous injections of diazepam. Sedation was assessed postoperatively on an arbitrary six-point scale from I (fully alert) to VI (totally unresponsive to auditory stimuli). Thereafter the patients received 0’22 ml/kg bodyweight from coded ampoules randomly containing aminophylline (corresponding to 4- 5 mg/kg) or enprofylline (1-55 mg/kg). Sedation was assessed at 5, 10, 20, 60, and 120 min after this injection. Ten patients were given aminophylline and ten were given enprofylline. The two groups did not differ significantly in age, weight, or dose of diazepam given intraoperatively (the mean total intraoperative dose of diazepam was 0-65 mg/kg in the aminophylline group, with a range of 0’ 47-1 - 00 mg/kg, and 0’ 69 of verbal

in the enprofylline group, with a range of 0.59-0’ 83 mg/kg). Sedation grade was not significantly different in the two groups before the test injection. 10 min after the injections nine of the ten patients in the aminophylline group were fully alert and the remaining patient was giving adequate verbal response but was slightly drowsy. At 20 min this patient was also fully alert. There was no tendency to relapse into sleep. Neither did there seem to be any unpleasant arousal effects. In the enprofylline group no patient was fully alert after 10 min although eight of the patients were rather less deeply sedated. The difference between the groups was significant (Wilcoxon rank sum test; p<0’01). Even after 120 min only four of the patients in the enprofylline group were fully alert. Patients in the enprofylline group, more lightly sedated after injection, showed a pronounced tendency to relapse into sleep. None of the patients in either group had any abnormal electrolyte disturbances postoperatively. Benzodiazepines are thought to exert their CNS effects through stimulating the y-aminobutyric acid (GABA) receptor complex by binding to a specific receptor.12 Adenosine seems to be at least as potent a CNS-depressing mediator as GABA and may have an amplifying effect on the GABA-receptor complex. Diazepam sedation seems to be reversed by low doses of aminophylline but not by enprofylline, a drug which lacks adenosine blocking properties. Thus it is likely that aminophylline antagonises diazepam sedation by blocking adenosine receptors. Department of Anaesthesiology, Östra Sjukhuset, S-416 85 Göteborg, Sweden; and Department of Clinical Pharmacology, Sahlgrenska Sjukhuset, Göteborg

D. NIEMAND S. MARTINELL S. ARVIDSSON N. SVEDMYR B. EKSTRÖM-JODAL

ANGIOTENSIN CONVERTING ENZYME INHIBITION IN RENOVASCULAR HYPERTENSION: FAILURE OF THE STENOTIC KIDNEY

99’Tc-DTPA in fourteen patients with unilateral renal artery 107±7 mol/1 (mean±SEM) before 3-5 weeks on captopril. DTPA uptake on the affected side, however, became almost zero in seven patients, indicating severe reduction of glomerular filtration rate; serum creatinine in these patients rose from 100±6 mol/1 to only DTPA uptake and serum creatinine 122±9 µmol/l (p<0.01). returned to pretreatment levels within 1-2 weeks of captopril withdrawal. Captopril had little or no effect on the stenotic kidney in the remaining seven patients. It also had little effect on the opposite kidney or on the kidneys of seventeen patients with essential hypertension. As in Jackson’s series the fall in blood pressure in patients who responded with serious impairment of function of the stenotic kidney was not greater than it was in patients whose renal function was maintained on both sides. Thus failure of the stenotic kidney is probably not a rare complication of ACE inhibition. However, the effect is reversible, at least after 3-5 weeks of treatment, and ACE inhibitors are very effective antihypertensive agents in patients with renovascular hypertension who are often difficult to treat with other drugs. We believe, therefore, that ACE inhibitors are still useful in these patients but that clinicians should not rely on measurements of serum creatinine for monitoring the effect on renal function. In unilateral renal artery stenosis, scintillation camera renography is more diagnostic. When the split renal uptake of the isotope falls, it would be prudent to stop ACE inhibition, since serious and longlasting impairment of glomerular filtration is associated with an irreversible harmful effect of ACE inhibition on the kidney.

stenosis. Serum creatinine treatment and 116±8

Department of Internal Medicine I, University Hospital Dijkzigt, Rotterdam, Netherlands

M. A. D. H. SCHALEKAMP G. J. WENTING

AMITRIPTYLINE: LOOKING THROUGH THE THERAPEUTIC WINDOW

SIR,-The "therapeutic window" for nortriptyline was identified in 1971 when et all found in a two-week study in twentynine patients with endogenous depression on different doses of the drug that the best therapeutic results were achieved when plasma nortriptyline concentrations lay between 50 and 140 µg/l. Nortriptyline is not much used nowadays. At the Psychiatric Hospital, University of Munich, in 1981 only 3 patients were on treatment with nortriptyline compared with 247 on amitriptyline. Results achieved with amitriptyline are confusing :2 several groups

Åsberg

1.

Asberg M, Cronholm B, Sjöqvist F, Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 1971; iii: 331-34 G, Norman T. Psychotropic drugs: Plasma concentration and response. Basle: Marcel Dekker, 1981.

2. Burrows

Amitriptyline [µg/l]

SIR,-Dr Jackson and his colleagues (Jan 28, p 225) reported that renal failure was a rare complication of angiotensin converting enzyme (ACE) inhibition by captopril in renovascular hypertension. As in other reports 1-3 serum creatinine rose only in patients with stenosis of a solitary functioning kidney or with bilateral renal artery disease. This observation may not be all that assuring. In laboratory animals impairment of glomerular filtration of the stenotic kidney after ACE inhibition is the rule rather than the exception, an effect that is independent, at least in part, of the fall in blood pressure.4 Using scintillation camera renography we have studied5 the effect of captopril monotherapy (150 mg daily) on the renal uptake of 12. Braestrup C, Nielsen M. Neurotransmitters and CNS disease. Anxiety. Lancet 1030-34.

was

mol/1 after

clinical

Nortripty[ine [µg/l]

.&verba;

1982; ii:

1. Collste P, Haglund K, Lundgren G, Magnusson G, Ostman J. Reversible renal failure during treatment with captopril. Br Med J 1979; ii: 612-13. 2. Curtis JJ, Luke RG, Whelchel JD, Diethelm AG, Jones P, Dustan HP. Inhibition of angiotensin-converting enzyme in renal-transplant recipients with hypertension. N Engl J Med 1983; 308: 377-81. 3. Hricik DE, Browing PJ, Kopelman R, Goorno WE, Madias ME, Dzau VJ. Captopril-

induced functional renal insufficiency inpatients with bilateral renal-artery stenosis renal-artery stenosis in a solitary kidney. N Engl J Med 1983; 308: 373-76.

or

4. Helmchen U, Gröne HJ, Kirchertz EJ, Bader H, Bohle RM, Kreissler U, Khosla MC. Contrasting renal effects of different antihypertensive agents in hypertensive rats with bilateral constricted renal arteries. Kidney Int 1982; 22 (suppl 12): S198-S205. 5. Wenting GJ, Tan-Tjiong HL, Derkx FHM, de Bruyn JHB, Man in’t Veld AJ,

Schalekamp MADH. Split renal function after captopril in unilateral renal artery stenosis. Br Med J (in press).

N-Oxide Amitriptyline 150 mg 150mg Amitriptyline and nortriptyline intake.

Amitriptyline 150 mg

N-Oxide

150 mg drug

concentrations 12 h after last