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WITHDRAWAL OF HUMAN PITUITARY GROWTH HORMONE
1324
Letters to the Editor
Safeguarding purified pituitary extract from virus transmission has probably been or could be achieved, and this would give more time for the careful study of long-term side-effects ofbiosynthetic growth hormone.
WITHDRAWAL OF HUMAN PITUITARY GROWTH HORMONE
SiR,-The US Government (New York Times, April 20) has halted the distribution of the natural human growth hormone (HGH)
produced by the National Pituitary Agency (NPA), and the Canadian Pituitary Agency, KabiVitrum, and now the UK authorities (Lancet, May 18, p 1172) have taken similar action. This has worried all those who treat GH-deficient children, for whom HGH is the only therapy available. The ban on HGH was based on the deaths from Creutzfeldt-Jakob disease, a rare and incurable virus infection affecting the nervous system, of three patients who had received HGH prepared by the NPA before 1977. The treatment had stopped 5-16 years ago. The US Food and Drug Administration argues that the preparation of HGH from human pituitaries may not prevent the transfer of any slow-acting pathogenic virus that may be present in the donor pituitaries.
Paediatric endocrinologists are naturally very concerned. Is the evidence that HGH preparations before the mid-1970s are harmful universal? Are current pituitary HGH preparations (which undergo better purification) unsafe? Three large reviews from 1982-831-3 contain no reports of progressive brain disease after HGH therapy. We have been treating GH-deficient patients with pituitaryextracted HGH since 1964. Between 1964 and 1974 we prepared HGH in our laboratory from pituitaries collected in acetone, essentially following Raben’s methodsAs a result of pressure from religious groups, the pituitary collection was discontinued in 1974, and since then commercial HGH from Nordisk (’Nanormon’), Serono (’Grorm’), and Kabi (’Crescormon’) has been used. We have treated 166 children and adolescents (52 of them between 1964 and 1974). Among our patients with organic multiple pituitary hormone deficiencies (MPHD), there were-22 deaths, but these did not appear to have been caused by a pathogenic virus. Patient 1, a male born in 1951, had had craniopharyngioma diagnosed at age 6. After partial excision of the tumour, and irradiation, he remained blind in one eye and deficient in most of the pituitary hormones. Between 1964 and 1966 he received HGH, thyroid extract, and antidiuretic hormone. At age 21 severe headaches and vomiting developed and angiography revealed a large cystic tumour extending from the pituitary area to the frontal lobe. After a transfrontal operation he did not regain consciousness, despite large doses ofcorticosteroids, and he died 6 weeks later. Necropsy was not done. Patient 2 was a female born by breech delivery in 1946 and diagnosed as having MPHD at age 19, having received thyroid extract since childhood. Between 1965 and 1968 she received intermittent HGH therapy with thyroxine and cyclic sex hormones. At age 29 she was admitted because of sudden convulsions followed by deep coma. Arteriography was non-revealing and there was no definite neurological lesion. There was no fever. Despite intensive corticosteroid therapy and antibiotics she died 12 days later. Permission for necropsy was refused. Both patients had received HGH prepared in our laboratory. All the other patients treated at that time and since then are alive and well.
Biosynthetic HGH still causes appreciable titres of antibodies against either the slightly altered HGH molecule or Escherichia coli impuritiesand at present its use is experimental and limited to few patients in selected clinics. Is there any evidence that there will soon be enough pure, safe biosynthetic HGH at a reasonable price? Can we take the responsibility of switching therapy to these new preparations which might be approved without sufficient followup ? The ways of giving GH-releasing hormone therapy long term6 yet clear, and even if this agent proves to be useful, it will be applicable to only 20-30% of GH-deficient children. An international exchange of opinions is urgently needed. It might be helpful if all the groups would report whether they have encountered neurological disease and deaths during HGH therapy. are not
Sackler Faculty of Medicine, Tel Aviv University and Institute of Paediatric and Adolescent Beilinson Medical Centre, Petah Tikva 49 100, Israel
Endocrinology,
Z. LARON
Z. JOSEFSBERG
1. Preece MA. Diagnosis and treatment of children with growth hormone deficiency. Clin Endocrinol Metab 1982; ii: 1-24. 2. Frasier SD. Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocrinol Rev 1983; 4: 155-70. 3. Laron Z. Deficiencies of growth hormone and somatomedins in man. In: Cohen MP, Foa PP, eds. Special topics in endocrinology and metabolism: Vol V. New York: Alan R. Liss, 1983: 149-99. 4. Raben MS. Preparation of growth hormone from pituitaries of man and monkey. Science 1957; 125: 883-84. 5. Kaplan S. Report on the use of biosynthetic hGH. In: Raiti S, ed. Human growth hormone. (NIH Symposium, Baltimore, 1983) (in press). 6. Thorner MO, Reschke J, Chitwood J, et al. Acceleration of growth in two children treated with human growth hormone releasing factor. N Engl J Med 1985; 312: 4-9
REVERSAL OF HEPATIC COMA BY BENZODIAZEPINE ANTAGONIST (Ro 15-1788)
SIR,-The mechanism for the central nervous system derangement responsible for hepatic coma remains unknown. However, clinical and electroencephalographic (EEG) observations point to increased sensitivity to benzodiazepines (BZ) in the brain of patients with liver disease. Furthermore BZ receptors increase in number in rats with galactosamine-induced hepatic coma.’ It thus seemed logical to evaluate in hepatic coma the therapeutic activity of a new BZ antagonist (Ro 15-1788; Hoffman-La Roche, Basel), previously shown to be effective in benzodiazepine overdose. A 25-year-old female heroin addict with severe hepatic dysfunction due to hepatitis B became progressively more comatose. On the study day she was totally unresponsive to painful stimuli and was motionless. The EEG showed flat periods interspersed with triphasic slow wave complexes. Intravenous injectio. i of 0 -5mg Ro 15-1788 over 1 min resulted in a remarkable improve iient: the patient opened her eyes, reacted to verbal comman,is, and moved spontaneously and in response to painful stimuli, but she did not speak. This improvement lasted for an hour and during this period two EEGs showed more normal background activity and a decrease in triphasic slow wave complexes. This effect was reproducible with additional injections of Ro 15-1788 but not with naloxone or physostigmine injections. She had not been pretreated with benzodiazepines. The patient died 2 weeks later. Whether this effect was related to an increase in BZ receptors or to of y-aminobutyric acid (GABA) neurotransmission,
overactivity
mediated by an endogenous benzodiazepine, or was merely a reversal of non-specific CNS damping in hepatic coma, cannot be ascertained from this clinical experience. However, this case, together with a previous one,2suggests that further investigation would be rewarding.
was
University Neurological Clinic, Kantonsspital, 4031
Basle, Switzerland
Department of Medicine, University Hospital, Basle
G. SCOLLO-LAVIZZARI E. STEINMANN
1. Baraldi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat; reversal by a benzodiazepine antagonist. Clin Sci 1984; 67: 167. 2. Scollo-Lavizzari G. First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. Eur Neurol 1983; 22: 7.
SIR,-The inhibitory GABA neurotransmitter system seems to an important role in the pathogenesis of hepatic encephalopathy.1-3 In patients with decompensated acute and chronic liver disease, particularly in the presence of hepatic
play
encephalopathy, serum levels of GABA-like activity4 and the density of the postsynaptic GABA receptors in the brain are increased.The GABA receptor is located on a postsynaptic
Letters to the Editor
Safeguarding purified pituitary extract from virus transmission has probably been or could be achieved, and this would give more time for the careful study of long-term side-effects ofbiosynthetic growth hormone.
WITHDRAWAL OF HUMAN PITUITARY GROWTH HORMONE
SiR,-The US Government (New York Times, April 20) has halted the distribution of the natural human growth hormone (HGH)
produced by the National Pituitary Agency (NPA), and the Canadian Pituitary Agency, KabiVitrum, and now the UK authorities (Lancet, May 18, p 1172) have taken similar action. This has worried all those who treat GH-deficient children, for whom HGH is the only therapy available. The ban on HGH was based on the deaths from Creutzfeldt-Jakob disease, a rare and incurable virus infection affecting the nervous system, of three patients who had received HGH prepared by the NPA before 1977. The treatment had stopped 5-16 years ago. The US Food and Drug Administration argues that the preparation of HGH from human pituitaries may not prevent the transfer of any slow-acting pathogenic virus that may be present in the donor pituitaries.
Paediatric endocrinologists are naturally very concerned. Is the evidence that HGH preparations before the mid-1970s are harmful universal? Are current pituitary HGH preparations (which undergo better purification) unsafe? Three large reviews from 1982-831-3 contain no reports of progressive brain disease after HGH therapy. We have been treating GH-deficient patients with pituitaryextracted HGH since 1964. Between 1964 and 1974 we prepared HGH in our laboratory from pituitaries collected in acetone, essentially following Raben’s methodsAs a result of pressure from religious groups, the pituitary collection was discontinued in 1974, and since then commercial HGH from Nordisk (’Nanormon’), Serono (’Grorm’), and Kabi (’Crescormon’) has been used. We have treated 166 children and adolescents (52 of them between 1964 and 1974). Among our patients with organic multiple pituitary hormone deficiencies (MPHD), there were-22 deaths, but these did not appear to have been caused by a pathogenic virus. Patient 1, a male born in 1951, had had craniopharyngioma diagnosed at age 6. After partial excision of the tumour, and irradiation, he remained blind in one eye and deficient in most of the pituitary hormones. Between 1964 and 1966 he received HGH, thyroid extract, and antidiuretic hormone. At age 21 severe headaches and vomiting developed and angiography revealed a large cystic tumour extending from the pituitary area to the frontal lobe. After a transfrontal operation he did not regain consciousness, despite large doses ofcorticosteroids, and he died 6 weeks later. Necropsy was not done. Patient 2 was a female born by breech delivery in 1946 and diagnosed as having MPHD at age 19, having received thyroid extract since childhood. Between 1965 and 1968 she received intermittent HGH therapy with thyroxine and cyclic sex hormones. At age 29 she was admitted because of sudden convulsions followed by deep coma. Arteriography was non-revealing and there was no definite neurological lesion. There was no fever. Despite intensive corticosteroid therapy and antibiotics she died 12 days later. Permission for necropsy was refused. Both patients had received HGH prepared in our laboratory. All the other patients treated at that time and since then are alive and well.
Biosynthetic HGH still causes appreciable titres of antibodies against either the slightly altered HGH molecule or Escherichia coli impuritiesand at present its use is experimental and limited to few patients in selected clinics. Is there any evidence that there will soon be enough pure, safe biosynthetic HGH at a reasonable price? Can we take the responsibility of switching therapy to these new preparations which might be approved without sufficient followup ? The ways of giving GH-releasing hormone therapy long term6 yet clear, and even if this agent proves to be useful, it will be applicable to only 20-30% of GH-deficient children. An international exchange of opinions is urgently needed. It might be helpful if all the groups would report whether they have encountered neurological disease and deaths during HGH therapy. are not
Sackler Faculty of Medicine, Tel Aviv University and Institute of Paediatric and Adolescent Beilinson Medical Centre, Petah Tikva 49 100, Israel
Endocrinology,
Z. LARON
Z. JOSEFSBERG
1. Preece MA. Diagnosis and treatment of children with growth hormone deficiency. Clin Endocrinol Metab 1982; ii: 1-24. 2. Frasier SD. Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocrinol Rev 1983; 4: 155-70. 3. Laron Z. Deficiencies of growth hormone and somatomedins in man. In: Cohen MP, Foa PP, eds. Special topics in endocrinology and metabolism: Vol V. New York: Alan R. Liss, 1983: 149-99. 4. Raben MS. Preparation of growth hormone from pituitaries of man and monkey. Science 1957; 125: 883-84. 5. Kaplan S. Report on the use of biosynthetic hGH. In: Raiti S, ed. Human growth hormone. (NIH Symposium, Baltimore, 1983) (in press). 6. Thorner MO, Reschke J, Chitwood J, et al. Acceleration of growth in two children treated with human growth hormone releasing factor. N Engl J Med 1985; 312: 4-9
REVERSAL OF HEPATIC COMA BY BENZODIAZEPINE ANTAGONIST (Ro 15-1788)
SIR,-The mechanism for the central nervous system derangement responsible for hepatic coma remains unknown. However, clinical and electroencephalographic (EEG) observations point to increased sensitivity to benzodiazepines (BZ) in the brain of patients with liver disease. Furthermore BZ receptors increase in number in rats with galactosamine-induced hepatic coma.’ It thus seemed logical to evaluate in hepatic coma the therapeutic activity of a new BZ antagonist (Ro 15-1788; Hoffman-La Roche, Basel), previously shown to be effective in benzodiazepine overdose. A 25-year-old female heroin addict with severe hepatic dysfunction due to hepatitis B became progressively more comatose. On the study day she was totally unresponsive to painful stimuli and was motionless. The EEG showed flat periods interspersed with triphasic slow wave complexes. Intravenous injectio. i of 0 -5mg Ro 15-1788 over 1 min resulted in a remarkable improve iient: the patient opened her eyes, reacted to verbal comman,is, and moved spontaneously and in response to painful stimuli, but she did not speak. This improvement lasted for an hour and during this period two EEGs showed more normal background activity and a decrease in triphasic slow wave complexes. This effect was reproducible with additional injections of Ro 15-1788 but not with naloxone or physostigmine injections. She had not been pretreated with benzodiazepines. The patient died 2 weeks later. Whether this effect was related to an increase in BZ receptors or to of y-aminobutyric acid (GABA) neurotransmission,
overactivity
mediated by an endogenous benzodiazepine, or was merely a reversal of non-specific CNS damping in hepatic coma, cannot be ascertained from this clinical experience. However, this case, together with a previous one,2suggests that further investigation would be rewarding.
was
University Neurological Clinic, Kantonsspital, 4031
Basle, Switzerland
Department of Medicine, University Hospital, Basle
G. SCOLLO-LAVIZZARI E. STEINMANN
1. Baraldi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat; reversal by a benzodiazepine antagonist. Clin Sci 1984; 67: 167. 2. Scollo-Lavizzari G. First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. Eur Neurol 1983; 22: 7.
SIR,-The inhibitory GABA neurotransmitter system seems to an important role in the pathogenesis of hepatic encephalopathy.1-3 In patients with decompensated acute and chronic liver disease, particularly in the presence of hepatic
play
encephalopathy, serum levels of GABA-like activity4 and the density of the postsynaptic GABA receptors in the brain are increased.The GABA receptor is located on a postsynaptic