- Email: [email protected]
REACTIONS TO TRIAZOLAM
526 between the actions of FSH and LH
on
the tests.8-11 Clomi-
phene produces an increase in serum-testosterone which may explain the blunting of the LH response to GnRH after clomiphene had been stopped. If clomiphene had been unsuccessful we might have tried
(’Purgonal’) long-term GnRH. 12 FSH alone
or
in combination with LH3
We thank Mrs N. Furness and staff for technical
help
or
with
and Mrs R.
Pembry for typing the manuscript. Departments of Medicine and Surgery, Peel Memorial Hospital, Brampton, Ontario, Canada, and Wellesley Hospital, Toronto, and University of Toronto
JOSEPH MCCONNON DONALD KILLINGER WILLIAM GRACEY FRANK GHANY
REACTIONS TO TRIAZOLAM
SIR,-During the past nine months I have been confronted psychiatric practice with a syndrome which is almost certainly induced by the benzodiazepine triazolam (’Halcion’). I have made a close study of 25 patients. Triazolam can produce the following symptoms: severe malaise; depersonalisation and derealisation; paranoid reactions ; acute and chronic anxiety; continuous fear of going insane; depression and deterioration of existing depressions; hypermsthesia, especially for sound, but also for smell, taste and light; sometimes hypoaesthesia for the same stimuli; nightmares ; restlessness; inability to concentrate; verbal and physical aggression; conflicts with entourage; severe suicidal tendencies ; hypnagogic hallucinations; impulse actions; amnxsia; dysphagia, accompanied by nasty taste, painful tongue and mucous membranes, dry mouth, loathing of food, rigid feeling in the throat and emaciation up to 2tstone; cervical pains; headaches that are often extremely sensitive to sound; pressure on the ears; numb and cold feeling in fingers and toes, extending to the distal parts of the extremities; tingling feeling, muscular cramps and paralyses, often at the sinistral side; catatonically impaired motor functioning; reading complaints and blurred vision; dysfunctional speaking and writing; sweating. This syndrome must be classified with the exogenous syndrome of Bonhoeffer. Symptoms usually disappear within a couple of days after stopping triazolam; sometimes there are withdrawal symptoms, such as rapidly mounting panic and heavy sweating. These side-effects appear in patients who are taking other drugs and in those who are not and in patients who have never had psychiatric treatment as well as in those with a psychiatric history. Patients with this syndrome may be admitted on suspicion of brain tumour or schizophrenia. They impress the observer as seriously ill and the patients themselves often feel desperate and have to fight an almost irresistible impulse to commit suicide. I know of one patient who did commit suicide. The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has received several reports of patients with similar features while on triazolam and the centre issued (July 16) a letter to Dutch doctors, dealing with this matter. in my
199 Bezuidenhoutseweg, The Hague,
Netherlands
C.
VAN DER
KROEF
8. Odell W, Swerdloff RS, Bain J, Wollesen F, Grover P. The effect of sexual maturation on testicular response to L.H. stimulation of testosterone secretion in the intact rat. Endocrinology 1974; 95: 1380-84. 9. Odell W, Swerdloff RS, Jacobs HS, Hescox MA. F.S.H. induction of sensitivity to L.H. One cause of sexual maturation in the male rat. Endocrinology 1973; 92: 160-65. 10. Nelson WO. Some factors involved in the control of gameto-genetic and endocrine functions of the testis. Cold Spring Harbor Symp Quant Biol 1937; 5: 123-35. 11. VonBerswordt-Wallrabe R, Mehring MJ. Steroid Biochem 1974; 5: 380
(abstract 352). 12. Mortimer C, McNeilly A, Fisher R, Murray M, Besser G. Gonadotrophinreleasing hormone therapy in hypogondal males with hypothalamic or pituitary dysfunction. Br Med J 1974; iv: 617-21.
TEMPORARY AGEUSIA RELATED TO CAPTOPRIL
SIR,-Captopril is under investigation for the treatment of various forms of hypertension’°2and refractory congestive heart-failure.3 Dr J. C. Alexander (E. R. Squibb and Sons, Inc.) has told us that during these trials temporary loss of taste (ageusia) has been noted in a small percentage of patients. The mechanism of this side-effect is unknown, but one hypothesis is a lingual interaction between captopril and concomitantly administered beta-adrenergic blocking agents that possess local anaesthetic properties. We have seen a case of temporary ageusia in a patient treated with captopril where this hypothesis was not confirmed after rechallenge with propranolol. Our patient was a 56-year-old man with severe hypertension refractory to large doses ’of antihypertensive medications. His treatment had included propranolol for about a year. Because of the resistance of his blood-pressure to standard therapy, the investigational agent captopril was tried. 1 month later, after treatment with maximal doses (600 mg) of captopril and the addition of hydrochlorothiazide, his blood-pressure remained high (174/108 mm Hg, supine) and propranolol was reinstituted. Within 24 h, the patient reported an abrupt loss of taste, which he had never experienced previously. Because his bloodpressure responded, the regimen was not altered; however, the ageusia persisted for the next 6 weeks and the patient lost 2.5 kg of weight. Propranolol was then discontinued and the ageusia resolved over several days. Because the patient’s bloodpressure again rose to 180/110 mm Hg supine, over several days, metoprolol, a beta, selective blocking agent with weak local anaesthetic action was tried. The blood-pressure was again controlled and ageusia did not recur; the patient regained his previous weight. To test the interaction of captopril and propranolol in the previous episode of ageusia, the metoprolol was discontinued, with the patient’s consent, and propranolol was again reinstituted. The ageusia did not reappear and 5 months later the patient’s blood-pressure was well controlled on captopril, hydrochlorothiazide, and pro-
pranolol. Thus, the ageusia during the initial reinstitution of propranolol seems to have been a chance association; it could not be reproduced on rechallenge. The temporary ageusia is most probably due to captopril therapy alone, but the mechanism is unknown. We thank Dr John C. advice in this case.
Alexander, E.
Clinical Pharmacology Unit, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, U.S.A.
R.
Squibb
&
Sons, Inc., for his
PETER H. VLASSES ROGER K. FERGUSON
NEPHROTOXICITY WITH GENTAMICIN OR TOBRAMYCIN
SIR,-Although nephrotoxic reactions associated with aminoglycoside antibiotics may be reduced if the drug dose is adjusted for change in renal function,4 Wade et a1.5 recorded a rate of 16.6% for gentamicin or tobramycin nephrotoxicity even when such dose adjustments were made. In our prospective trial in adults given gentamicin or tobramycin we defined nephrotoxicity as a rise in the serum-creatinine of 0.5 mg/dl or more during therapy. The rise in creatinine was ascribed to
1. Brunner 2.
HR, Gavras H, Waeber B, Kershaw GR, Turini GA, Vukovich RA, McKinstry DN, Gauras I. Ann Intern Med 1979; 90: 19. Cody RJ, Tarazi RC, Bravo EL, Fouad FM. Clin Sci Mol Med 1978, 55:
453. 3. Turini GA, Brunner HR, Gribic M, Waeber B, Gavras H. Lancet 1979, 1: 1213. 4. Appel GB, Neu HC. Gentamicin in 1978. Ann Intern Med 1978, 89: 528-38. 5. Wade JC, Petty BG, Conrad G, Smith CR, Lipsky JJ, Ellner J, Lietman PS. Cephalothin plus an aminoglycoside is more nephrotoxic then methicillin plus an aminoglycoside. Lancet 1978; ii: 604-06.
on
the tests.8-11 Clomi-
phene produces an increase in serum-testosterone which may explain the blunting of the LH response to GnRH after clomiphene had been stopped. If clomiphene had been unsuccessful we might have tried
(’Purgonal’) long-term GnRH. 12 FSH alone
or
in combination with LH3
We thank Mrs N. Furness and staff for technical
help
or
with
and Mrs R.
Pembry for typing the manuscript. Departments of Medicine and Surgery, Peel Memorial Hospital, Brampton, Ontario, Canada, and Wellesley Hospital, Toronto, and University of Toronto
JOSEPH MCCONNON DONALD KILLINGER WILLIAM GRACEY FRANK GHANY
REACTIONS TO TRIAZOLAM
SIR,-During the past nine months I have been confronted psychiatric practice with a syndrome which is almost certainly induced by the benzodiazepine triazolam (’Halcion’). I have made a close study of 25 patients. Triazolam can produce the following symptoms: severe malaise; depersonalisation and derealisation; paranoid reactions ; acute and chronic anxiety; continuous fear of going insane; depression and deterioration of existing depressions; hypermsthesia, especially for sound, but also for smell, taste and light; sometimes hypoaesthesia for the same stimuli; nightmares ; restlessness; inability to concentrate; verbal and physical aggression; conflicts with entourage; severe suicidal tendencies ; hypnagogic hallucinations; impulse actions; amnxsia; dysphagia, accompanied by nasty taste, painful tongue and mucous membranes, dry mouth, loathing of food, rigid feeling in the throat and emaciation up to 2tstone; cervical pains; headaches that are often extremely sensitive to sound; pressure on the ears; numb and cold feeling in fingers and toes, extending to the distal parts of the extremities; tingling feeling, muscular cramps and paralyses, often at the sinistral side; catatonically impaired motor functioning; reading complaints and blurred vision; dysfunctional speaking and writing; sweating. This syndrome must be classified with the exogenous syndrome of Bonhoeffer. Symptoms usually disappear within a couple of days after stopping triazolam; sometimes there are withdrawal symptoms, such as rapidly mounting panic and heavy sweating. These side-effects appear in patients who are taking other drugs and in those who are not and in patients who have never had psychiatric treatment as well as in those with a psychiatric history. Patients with this syndrome may be admitted on suspicion of brain tumour or schizophrenia. They impress the observer as seriously ill and the patients themselves often feel desperate and have to fight an almost irresistible impulse to commit suicide. I know of one patient who did commit suicide. The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has received several reports of patients with similar features while on triazolam and the centre issued (July 16) a letter to Dutch doctors, dealing with this matter. in my
199 Bezuidenhoutseweg, The Hague,
Netherlands
C.
VAN DER
KROEF
8. Odell W, Swerdloff RS, Bain J, Wollesen F, Grover P. The effect of sexual maturation on testicular response to L.H. stimulation of testosterone secretion in the intact rat. Endocrinology 1974; 95: 1380-84. 9. Odell W, Swerdloff RS, Jacobs HS, Hescox MA. F.S.H. induction of sensitivity to L.H. One cause of sexual maturation in the male rat. Endocrinology 1973; 92: 160-65. 10. Nelson WO. Some factors involved in the control of gameto-genetic and endocrine functions of the testis. Cold Spring Harbor Symp Quant Biol 1937; 5: 123-35. 11. VonBerswordt-Wallrabe R, Mehring MJ. Steroid Biochem 1974; 5: 380
(abstract 352). 12. Mortimer C, McNeilly A, Fisher R, Murray M, Besser G. Gonadotrophinreleasing hormone therapy in hypogondal males with hypothalamic or pituitary dysfunction. Br Med J 1974; iv: 617-21.
TEMPORARY AGEUSIA RELATED TO CAPTOPRIL
SIR,-Captopril is under investigation for the treatment of various forms of hypertension’°2and refractory congestive heart-failure.3 Dr J. C. Alexander (E. R. Squibb and Sons, Inc.) has told us that during these trials temporary loss of taste (ageusia) has been noted in a small percentage of patients. The mechanism of this side-effect is unknown, but one hypothesis is a lingual interaction between captopril and concomitantly administered beta-adrenergic blocking agents that possess local anaesthetic properties. We have seen a case of temporary ageusia in a patient treated with captopril where this hypothesis was not confirmed after rechallenge with propranolol. Our patient was a 56-year-old man with severe hypertension refractory to large doses ’of antihypertensive medications. His treatment had included propranolol for about a year. Because of the resistance of his blood-pressure to standard therapy, the investigational agent captopril was tried. 1 month later, after treatment with maximal doses (600 mg) of captopril and the addition of hydrochlorothiazide, his blood-pressure remained high (174/108 mm Hg, supine) and propranolol was reinstituted. Within 24 h, the patient reported an abrupt loss of taste, which he had never experienced previously. Because his bloodpressure responded, the regimen was not altered; however, the ageusia persisted for the next 6 weeks and the patient lost 2.5 kg of weight. Propranolol was then discontinued and the ageusia resolved over several days. Because the patient’s bloodpressure again rose to 180/110 mm Hg supine, over several days, metoprolol, a beta, selective blocking agent with weak local anaesthetic action was tried. The blood-pressure was again controlled and ageusia did not recur; the patient regained his previous weight. To test the interaction of captopril and propranolol in the previous episode of ageusia, the metoprolol was discontinued, with the patient’s consent, and propranolol was again reinstituted. The ageusia did not reappear and 5 months later the patient’s blood-pressure was well controlled on captopril, hydrochlorothiazide, and pro-
pranolol. Thus, the ageusia during the initial reinstitution of propranolol seems to have been a chance association; it could not be reproduced on rechallenge. The temporary ageusia is most probably due to captopril therapy alone, but the mechanism is unknown. We thank Dr John C. advice in this case.
Alexander, E.
Clinical Pharmacology Unit, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, U.S.A.
R.
Squibb
&
Sons, Inc., for his
PETER H. VLASSES ROGER K. FERGUSON
NEPHROTOXICITY WITH GENTAMICIN OR TOBRAMYCIN
SIR,-Although nephrotoxic reactions associated with aminoglycoside antibiotics may be reduced if the drug dose is adjusted for change in renal function,4 Wade et a1.5 recorded a rate of 16.6% for gentamicin or tobramycin nephrotoxicity even when such dose adjustments were made. In our prospective trial in adults given gentamicin or tobramycin we defined nephrotoxicity as a rise in the serum-creatinine of 0.5 mg/dl or more during therapy. The rise in creatinine was ascribed to
1. Brunner 2.
HR, Gavras H, Waeber B, Kershaw GR, Turini GA, Vukovich RA, McKinstry DN, Gauras I. Ann Intern Med 1979; 90: 19. Cody RJ, Tarazi RC, Bravo EL, Fouad FM. Clin Sci Mol Med 1978, 55:
453. 3. Turini GA, Brunner HR, Gribic M, Waeber B, Gavras H. Lancet 1979, 1: 1213. 4. Appel GB, Neu HC. Gentamicin in 1978. Ann Intern Med 1978, 89: 528-38. 5. Wade JC, Petty BG, Conrad G, Smith CR, Lipsky JJ, Ellner J, Lietman PS. Cephalothin plus an aminoglycoside is more nephrotoxic then methicillin plus an aminoglycoside. Lancet 1978; ii: 604-06.