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Insulin-like growth factor I for growth hormone therapy
Insulin-like growth factor I for growth hormone therapy Sir—In a commentary, B Å Bengtsson (Oct 23),1 discusses the effects of growth-hormone therapy in critically ill patients. Growth hormone is an anabolic hormone that spares protein storage at the expense of fat in caloric restriction. This hormone stimulates the synthesis and secretion of insulinlike growth factor I (IGF-I), which mediates many effects of growth hormone, including the anabolic effect. Growth-hormone therapy has been used to treat children with short stature and adults with growthhormone deficiency, and is clearly beneficial in these situations. High doses of growth hormone have been used to improve protein metabolism in critical illness. Growth hormone has several immunomodulatory effects, and is required for the normal development and maintenance of important components of the immune system. However, this treatment may trigger severe side-effects. We have found that growth-hormone infusion is detrimental when given to rats injected with endotoxin. 2,3 T h i s treatment has also been shown to potentiate the effects of Escherichia coli in pigs.4 The clinical significance in human beings of these animal experiments became evident when Takala and colleagues5 reported increased mortality after high-dose growthhormone treatment of critically ill patients. In two prospective trials involving 247 Finnish patients and 285 patients from other European countries, who had been in intensive care for 5–7 days, significantly increased mortality was noted in the treated group (42%) compared with the placebo group (18%). The reason for this increased mortality is unclear, but the presence of multiple-organ failure and septic shock suggests that a mechanism similar to that in rats may operate in human beings. Although IGF-I mediates many effects of growth hormone, the detrimental effects seen after growthhormone treatment of animals that have received endotoxin or E coli have not been reported in animals treated with IGF-I instead of growth hormone.3,4 Therefore, IGF-I therapy may be an alternative in patients who might benefit from anabolic treatment, such as critically ill patients. However, whether the effects of IGF-I in rats are valid in human
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beings is not clear. Results from clinical trials of IGF-I would therefore be of interest. *Wei Liao, Mats Rudling, Bo Angelin *Department of Molecular and Cellular Biology 55E, Baylor College of Medicine, Houston, TX 77030, USA; and Center for Metabolism and Endocrinology, and Department of Medicine, Karolinska Institutet at Huddinge Hospital, Huddinge, Sweden 1
Bengtsson B Å. Rethink about growthhormone therapy for critically ill patients. Lancet 1999; 354; 1403–04. 2 Liao W, Rudling M, Angelin B. Growth hormone potentiates the in vivo biological activities of endotoxin in the rat. Eur J Clin Invest 1996; 26: 254–58. 3 Liao W, Rudling M, Angelin B. Contrast effects of growth hormone and insulin-like growth factor I on the biological activities of endotoxin in the rat. Endocrinology 1997; 138: 289–95. 4 Unnenberg K, Balteskard L, Mjaaland M, Sager G, Revhaug A. Growth hormone increases and IGF-I reduces the response to Escherichia coli infusion in injured pigs. Eur J Surg 1997; 163: 779–88. 5 Takala J, Ruokonen E, Webster NR, et al. Increased mortality with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341: 785–95.
Oral cobalamin therapy Sir—Olaf Bodamer and Fernando Scaglia (Oct 30, p 1562) 1 rather confuse the issue between physiological cobalamin deficiency and the inborn errors of the metabolism of cobalamin that affect synthesis of the cofactors required for the function of methylmalonyl CoA mutase and methionine synthase. In cobalamin deficiency, only physiological concentrations (g) of hydroxocobalamin are required for therapy, and although injections of relatively large amounts of cyanocobalamin and hydroxocobalamin are widely used,2 adequate maintenance of blood cobalamin is obtained from use of oral preparations after initial intramuscular loading, with 500–1000 g per day achieving the required blood and tissue concentrations.2 Whether sublingual or chewable oral preparations are used, and whether these contain cyanocobalamin or hydroxocobalamin are irrelevant because sufficient absorbed cyanocobalamin from an adequate oral dosage will be hydrolysed to hydroxocobalamin for maintenance of therapy in such patients. Treatment of the inborn errors of cobalamin metabolism or, more correctly, of cobalamin cofactor synthesis, associated with methylmalonic aciduria is quite distinct and requires pharmacological concentrations (mg) of hydroxocobalamin
for those patients who respond to such therapy (not all patients with disorders of cobalamin cofactor synthesis do so—some 90% of cblA patients respond compared with only 40% of cblB patients 3). Oral hydroxocobalamin, in much higher dosages than those required for cobalamin-deficient states (10–15 mg per day or, preferably, 0·5 mg/kg bodyweight per day), is also most effective in these vitamin B12-responsive patients for maintenance therapy, after initial stabilisation on intramuscular hydroxocobalamin. Although we agree with Bodamer and Scaglia1 that few published data are available of clinical trials of oral hydroxocobalamin in the treatment of patients with inborn errors of cobalamin cofactor synthesis and methylmalonic aciduria, such treatment has certainly been reported from as early as 19763–5 (methylmalonic aciduria was first discovered in 1967). We studied a patient who had cblA variant 3 during withdrawal and reinstatement of oral cobalamin therapy at age 8 years5 and showed the efficacy of this treatment. Our patient is now a healthy young adult and we have successfully maintained another vitamin B12-responsive adult patient with methylmalonic aciduria on 10 mg oral hydroxocobalamin per day (taken concomitantly with oral L-carnitine) with good metabolic control. Oral hydroxocobalamin therapy has an important place in the maintenance therapy of patients with cobalamin deficiency syndromes and with cobalamin cofactor synthesis disorders (at least cblA variants), it is preferred to intramuscular injections by patients, and deserves to receive wider publicity and use. *Ronald A Chalmers, Murray D Bain, Ian Costello *Paediatric Metabolism Unit, Department of Child Health, St George’s Hospital Medical School, London SW17 0RE, UK; and St George’s Pharmacy, St George’s Hospital, London 1
Bodamer OAF, Scaglia F. Sublingual therapy for cobalamin deficiency. Lancet 1999; 354: 1562. 2 Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998; 352: 1721–22. 3 Chalmers RA, Bain MD, Mistry J, Tracey BM, Weaver C. Enzymologic studies on patients with methylmalonic aciduria: basis for a clinical trial of deoxyadenosylcobalamin in a hydroxocobalamin-unresponsive patient. Pediatr Res 1991; 30: 560–63. 4 Gordon BA, Carson RA. Methylmalonic acidemia controlled with oral administration of vitamin B12. Can Med Assoc J 1976; 115: 233–36. 5 Ninan TK, Thom H, Russell G. Oral vitamin B12 treatment of cobalaminresponsive methylmalonic aciduria. J Inherit Metab Dis 1992; 15: 939–40.
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beings is not clear. Results from clinical trials of IGF-I would therefore be of interest. *Wei Liao, Mats Rudling, Bo Angelin *Department of Molecular and Cellular Biology 55E, Baylor College of Medicine, Houston, TX 77030, USA; and Center for Metabolism and Endocrinology, and Department of Medicine, Karolinska Institutet at Huddinge Hospital, Huddinge, Sweden 1
Bengtsson B Å. Rethink about growthhormone therapy for critically ill patients. Lancet 1999; 354; 1403–04. 2 Liao W, Rudling M, Angelin B. Growth hormone potentiates the in vivo biological activities of endotoxin in the rat. Eur J Clin Invest 1996; 26: 254–58. 3 Liao W, Rudling M, Angelin B. Contrast effects of growth hormone and insulin-like growth factor I on the biological activities of endotoxin in the rat. Endocrinology 1997; 138: 289–95. 4 Unnenberg K, Balteskard L, Mjaaland M, Sager G, Revhaug A. Growth hormone increases and IGF-I reduces the response to Escherichia coli infusion in injured pigs. Eur J Surg 1997; 163: 779–88. 5 Takala J, Ruokonen E, Webster NR, et al. Increased mortality with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341: 785–95.
Oral cobalamin therapy Sir—Olaf Bodamer and Fernando Scaglia (Oct 30, p 1562) 1 rather confuse the issue between physiological cobalamin deficiency and the inborn errors of the metabolism of cobalamin that affect synthesis of the cofactors required for the function of methylmalonyl CoA mutase and methionine synthase. In cobalamin deficiency, only physiological concentrations (g) of hydroxocobalamin are required for therapy, and although injections of relatively large amounts of cyanocobalamin and hydroxocobalamin are widely used,2 adequate maintenance of blood cobalamin is obtained from use of oral preparations after initial intramuscular loading, with 500–1000 g per day achieving the required blood and tissue concentrations.2 Whether sublingual or chewable oral preparations are used, and whether these contain cyanocobalamin or hydroxocobalamin are irrelevant because sufficient absorbed cyanocobalamin from an adequate oral dosage will be hydrolysed to hydroxocobalamin for maintenance of therapy in such patients. Treatment of the inborn errors of cobalamin metabolism or, more correctly, of cobalamin cofactor synthesis, associated with methylmalonic aciduria is quite distinct and requires pharmacological concentrations (mg) of hydroxocobalamin
for those patients who respond to such therapy (not all patients with disorders of cobalamin cofactor synthesis do so—some 90% of cblA patients respond compared with only 40% of cblB patients 3). Oral hydroxocobalamin, in much higher dosages than those required for cobalamin-deficient states (10–15 mg per day or, preferably, 0·5 mg/kg bodyweight per day), is also most effective in these vitamin B12-responsive patients for maintenance therapy, after initial stabilisation on intramuscular hydroxocobalamin. Although we agree with Bodamer and Scaglia1 that few published data are available of clinical trials of oral hydroxocobalamin in the treatment of patients with inborn errors of cobalamin cofactor synthesis and methylmalonic aciduria, such treatment has certainly been reported from as early as 19763–5 (methylmalonic aciduria was first discovered in 1967). We studied a patient who had cblA variant 3 during withdrawal and reinstatement of oral cobalamin therapy at age 8 years5 and showed the efficacy of this treatment. Our patient is now a healthy young adult and we have successfully maintained another vitamin B12-responsive adult patient with methylmalonic aciduria on 10 mg oral hydroxocobalamin per day (taken concomitantly with oral L-carnitine) with good metabolic control. Oral hydroxocobalamin therapy has an important place in the maintenance therapy of patients with cobalamin deficiency syndromes and with cobalamin cofactor synthesis disorders (at least cblA variants), it is preferred to intramuscular injections by patients, and deserves to receive wider publicity and use. *Ronald A Chalmers, Murray D Bain, Ian Costello *Paediatric Metabolism Unit, Department of Child Health, St George’s Hospital Medical School, London SW17 0RE, UK; and St George’s Pharmacy, St George’s Hospital, London 1
Bodamer OAF, Scaglia F. Sublingual therapy for cobalamin deficiency. Lancet 1999; 354: 1562. 2 Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998; 352: 1721–22. 3 Chalmers RA, Bain MD, Mistry J, Tracey BM, Weaver C. Enzymologic studies on patients with methylmalonic aciduria: basis for a clinical trial of deoxyadenosylcobalamin in a hydroxocobalamin-unresponsive patient. Pediatr Res 1991; 30: 560–63. 4 Gordon BA, Carson RA. Methylmalonic acidemia controlled with oral administration of vitamin B12. Can Med Assoc J 1976; 115: 233–36. 5 Ninan TK, Thom H, Russell G. Oral vitamin B12 treatment of cobalaminresponsive methylmalonic aciduria. J Inherit Metab Dis 1992; 15: 939–40.
THE LANCET • Vol 355 • January 8, 2000