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EFFECT OF A.C.T.H. PEPTIDE FRAGMENT ON MUSCLE ACTION-POTENTIALS
919 ESSENTIAL FATTY ACIDS IN CYSTIC FIBROSIS
S)R,—I should like to comment on the hypothesis by Mr Rivers and Mr Hassam (Oct. 4, p. 642). Concerning the table (fatty-acid patterns in plasma-phospholipids in c.F., E.F.A. deficiency, and controls): (1) The ratio for 20.4/18-2 for Caren and Corbo’ should be 0.47 and 0.46 and not 0.61 and 0.56. (2) The first column headed "Total (weight)" has no meaning and certainly bears no relationship to concentrations of phospholipids (P.tin mg/100 ml as reported by Caren and Corbo’ (normals 78 +4.6 mg0;-, c.F. 81 +6.9 mg%) or Kuo and Huang2 (normals 211.8 i44.7 mgrlr, c.F. 178 +23.7 mg%). No values for total phospholipid concentrations were given by Rosenlund et aI.3 Following from this, the second sentence in the section headed "F.F.A. in c.F."--viz., "The phospholipid levels ofr.F.A. in c.F. are reduced to values comparable with these seen in dietary F.F.A. deficiency"-is nonsensical as, from these references, the P.I . levels in one case actually increase and the values from references 2 and 3 are so different as to be incomparable. It still remains for someone to measure the F.F.A. condition of c.F. and dietary F..F.A. deficiency using exactly the same methods, &c., before a true comparison can be made. (3) Kuo and Huang2 used serum and not plasma. In their last paragraph Rivers and Hassam say: "Although the evidence for a blocked or absent desaturase in c.F. is overwhelming ..." No "overwhelming" evidence is presented in the paper and desaturase activity could not be said to be absent until an attempt is made to directly measure such activity. Furthermore, given that linoleic acid (L.A.) can only be obtained from the diet and that arachidonic acid (A.A.) can be either dietary or synthesised from L.A., it is reasonable to expect that a drop in E.F.A. absorption would result in a greater decrease in A.A. levels than in L.A. levels if the desaturases in question were blocked or absent-i.e., the linoleic level would be comparatively raised because none would be transformed into A.A. and the A.A. level would be correspondingly lowered. In fact, the opposite happens. In three literature reportsl-3 the L.A. levels for c.F. compared to controls are always more significantly lower than A.A. Similarly the percentage lowering is also more for L.A. than A.A. There is, thus, no "overwhelming" evidence for a blocked or absent desaturase and the cause of the E.F.A. deficiency must be elsewhere. Rivers and Hassam noted that Bennett4 commented on the absence of C20:3(ù9 in C.F. patients. This is contrary to our observations:’ we have found up to 2.5% of the total fatty acids in both serum and red cells to be C20:39. All of our c.F. patients have shown this acid at some stage and, for most, it is a permanent feature of their fatty acid profile. It has been reported that C20:3oj9 would probably act as an inhibitor of prostaglandin formation from A.A.6 and it is interesting to conjecture on whether this could account for some of the symptoms of c.F. C20:39 would also be incorporated into p.). and could then alter membrane properties. Finally, in our paper on the use of ’Intralipid’ in the treatment of c.F.’ we did not claim that "dietary deficiency of E.F.A. is... the cause of c.F." nor did we attribute the improvements in the case reported "to the linoleic acid provided by this soybean emulsion". What we did say was that "It is possible that defective absorption of E.F.A. occurs in c.F." and that "Correction of the results of this hypothetical defect might correct some of the clinical manifestations of the disease." Rivers and Hassam consider it more likely that the derived F..F.A. in the lecithin is the beneficial agent and suggest that a more controlled trial be carried out. Plans for this are already well under way. It should also be pointed out that intralipid contains a number of vitamins (e.g., vitamin E.) and trace metals and the effects of these would also have to be considered. Aside from these comments, many of the points raised by 1 Caren, R., Corbo, L. J. clin. Endocr. Metab. 1966, 26, 470. 2 Kuo, P. T., Huang, N. N. J. clin. Invest. 1965, 44, 1924. 3 Rosenlund, M. L., Kim, H. K., Kritchevsky, D. Nature, 1974, 251, 719. 4 Bennett, M. J., Medwadowski, B. F. Am J. clin. Nutr. 1967, 20, 415 5 Robinson, P. G., Elliott, R. B. Unpublished 6. Nutr Revs, 1974, 32, 19 7 Elliolt, R. B., Robinson, P. G. Archs Dis Childh. 1975, 50, 76.
Rivers and Hassam are very valid and we investigations into the role ofn.F.A. in c.F. University Department
are
continuing
our
of Pædiatrics,
Auckland 3, New Zealand.
PETER G. ROBINSON
EFFECT OF A.C.T.H. PEPTIDE FRAGMENT ON MUSCLE ACTION-POTENTIALS
SIR,- The treatment of myasthenia gravis with corticotrophin (A.C.T.H.) is complicated by its corticotrophic for the effect of the adrenocortical steroids on muscle is controversial.l -3 The use of a peptide fragment of A.C.T.H., A.C.T.H. 4-10, which is without adrenocortical stimulating activity,4 permits separation of the effects on muscle function of the peptide hormone and the cortical steroids. Animal studies have shown that both A.C.T.H. and A.C.T.H. 4-10 increase the amplitude of muscle actionpotentials (M.A.P.S) and reduce fatigue.5.G Since A.C.T.H. 4-10 has no known toxicity in man, a pilot study was undertaken to investigate the effect of this peptide on evoked M.A.P.s in an 18-year-old female with myasthenia gravis and in a 24-year-old male with progressive spinal muscular
activity,
atrophy (Kugelberg-Welander type). Using a standardised test based on the fall in amplitude of the first 5 M.A.P.s evoked by median-nerve stimulation,7 found in control tests that the M.A.P.S of the myasthenic patient declined to 80% of the initial value. M.A.P. testing following the infusion of 3 mg A.C.T.H. 4-10 showed no decline in M.A.P. amplitude. This maintenance of amplitude was retained for at least 2 h after peptide infusion. The administration of 15 mg A.C.T.H. 4-10 resulted in a similar, but slightly less effective, response. Control evoked M.A.P.S in the patient with the KugelbergWelander syndrome showed an average decrease of 55%ê) of the initial amplitude. Following the infusion of either 3 mg or 6 mg A.C.T.H. 4-10 all test M.A.P.S rose above 100%. This retention of M.A.P. amplitude was demonstrable 10 days after infusion of 6 mg A.C.T.H. 4-10. Tests made following saline infusions showed essentially no deviation from control tests. A.C.T.H. 4-10, like certain other polypeptides, may influence transmitter synthesis8 or release at the neuromuscular junctionand/or it may modulate synaptic transmissionrestoring depressed synapses to normal.’,, The effect of this peptide fragment of A.C.T.H. on muscle function is presently being investigated in larger groups of myasthenic patients.
it
was
FLEUR L. STRAND* H. STOBOY FRIEDEBOLD KRIVOY HEYCK VAN RIEZEN
University Orthopædic Clinic, Freie Universitat Berlin, Clayallec 229, 1000 Berlin 33. *
Present address: New York University, Washington Square, College of Arts and Science, Department of Biology, New York, N.Y. 10003, U.S.A. 1.
Shapiro, M. S., Namba, T., Grob, 18, 1018.
2. 3.
Strand, F. L., Stoboy, H. Pflugers Arch. 1969, 312, 97. Johns, T. R., Mann, J. D., Campa, J. F. Excerpta med. int. Congr. Ser. 1974, no. 334, p. 15. Greven, H. M., De Wied, D. Eur. J. Pharmac. 1967, 2, 14. Strand, F. L., Stoboy, H., Cayer, A. Neuroendocristology, 1973, 74, 13, 1. Strand, F. L., Cayer, A. in Hormones, Homeostasis and the Brain: Progress in Brain Research, vol. 42 (edited by W. H. Gispen, T. B. van Wimersma Greidanus, B. Bohus, and D. deWied). Amsterdam (in the press). Roberts, D. V., Wilson, A. in Myasthenia Gravis (edited by R. Greene); ch. 2. Philadelphia, 1969. Torda, C., Wolff, H. G. Am. J. Physiol. 1952, 169, 140. Barker, J. L., Gainer, H. Science, 1974, 184, 1371. Krivoy, W., Zimmerman, E. in Chemical Modulation of Brain Function (edited by H. C. Sabelli); p. 111. New York, 1973.
4. 5.
6.
7. 8. 9.
10.
D.
Neurology, Minneap. 1968,
S)R,—I should like to comment on the hypothesis by Mr Rivers and Mr Hassam (Oct. 4, p. 642). Concerning the table (fatty-acid patterns in plasma-phospholipids in c.F., E.F.A. deficiency, and controls): (1) The ratio for 20.4/18-2 for Caren and Corbo’ should be 0.47 and 0.46 and not 0.61 and 0.56. (2) The first column headed "Total (weight)" has no meaning and certainly bears no relationship to concentrations of phospholipids (P.tin mg/100 ml as reported by Caren and Corbo’ (normals 78 +4.6 mg0;-, c.F. 81 +6.9 mg%) or Kuo and Huang2 (normals 211.8 i44.7 mgrlr, c.F. 178 +23.7 mg%). No values for total phospholipid concentrations were given by Rosenlund et aI.3 Following from this, the second sentence in the section headed "F.F.A. in c.F."--viz., "The phospholipid levels ofr.F.A. in c.F. are reduced to values comparable with these seen in dietary F.F.A. deficiency"-is nonsensical as, from these references, the P.I . levels in one case actually increase and the values from references 2 and 3 are so different as to be incomparable. It still remains for someone to measure the F.F.A. condition of c.F. and dietary F..F.A. deficiency using exactly the same methods, &c., before a true comparison can be made. (3) Kuo and Huang2 used serum and not plasma. In their last paragraph Rivers and Hassam say: "Although the evidence for a blocked or absent desaturase in c.F. is overwhelming ..." No "overwhelming" evidence is presented in the paper and desaturase activity could not be said to be absent until an attempt is made to directly measure such activity. Furthermore, given that linoleic acid (L.A.) can only be obtained from the diet and that arachidonic acid (A.A.) can be either dietary or synthesised from L.A., it is reasonable to expect that a drop in E.F.A. absorption would result in a greater decrease in A.A. levels than in L.A. levels if the desaturases in question were blocked or absent-i.e., the linoleic level would be comparatively raised because none would be transformed into A.A. and the A.A. level would be correspondingly lowered. In fact, the opposite happens. In three literature reportsl-3 the L.A. levels for c.F. compared to controls are always more significantly lower than A.A. Similarly the percentage lowering is also more for L.A. than A.A. There is, thus, no "overwhelming" evidence for a blocked or absent desaturase and the cause of the E.F.A. deficiency must be elsewhere. Rivers and Hassam noted that Bennett4 commented on the absence of C20:3(ù9 in C.F. patients. This is contrary to our observations:’ we have found up to 2.5% of the total fatty acids in both serum and red cells to be C20:39. All of our c.F. patients have shown this acid at some stage and, for most, it is a permanent feature of their fatty acid profile. It has been reported that C20:3oj9 would probably act as an inhibitor of prostaglandin formation from A.A.6 and it is interesting to conjecture on whether this could account for some of the symptoms of c.F. C20:39 would also be incorporated into p.). and could then alter membrane properties. Finally, in our paper on the use of ’Intralipid’ in the treatment of c.F.’ we did not claim that "dietary deficiency of E.F.A. is... the cause of c.F." nor did we attribute the improvements in the case reported "to the linoleic acid provided by this soybean emulsion". What we did say was that "It is possible that defective absorption of E.F.A. occurs in c.F." and that "Correction of the results of this hypothetical defect might correct some of the clinical manifestations of the disease." Rivers and Hassam consider it more likely that the derived F..F.A. in the lecithin is the beneficial agent and suggest that a more controlled trial be carried out. Plans for this are already well under way. It should also be pointed out that intralipid contains a number of vitamins (e.g., vitamin E.) and trace metals and the effects of these would also have to be considered. Aside from these comments, many of the points raised by 1 Caren, R., Corbo, L. J. clin. Endocr. Metab. 1966, 26, 470. 2 Kuo, P. T., Huang, N. N. J. clin. Invest. 1965, 44, 1924. 3 Rosenlund, M. L., Kim, H. K., Kritchevsky, D. Nature, 1974, 251, 719. 4 Bennett, M. J., Medwadowski, B. F. Am J. clin. Nutr. 1967, 20, 415 5 Robinson, P. G., Elliott, R. B. Unpublished 6. Nutr Revs, 1974, 32, 19 7 Elliolt, R. B., Robinson, P. G. Archs Dis Childh. 1975, 50, 76.
Rivers and Hassam are very valid and we investigations into the role ofn.F.A. in c.F. University Department
are
continuing
our
of Pædiatrics,
Auckland 3, New Zealand.
PETER G. ROBINSON
EFFECT OF A.C.T.H. PEPTIDE FRAGMENT ON MUSCLE ACTION-POTENTIALS
SIR,- The treatment of myasthenia gravis with corticotrophin (A.C.T.H.) is complicated by its corticotrophic for the effect of the adrenocortical steroids on muscle is controversial.l -3 The use of a peptide fragment of A.C.T.H., A.C.T.H. 4-10, which is without adrenocortical stimulating activity,4 permits separation of the effects on muscle function of the peptide hormone and the cortical steroids. Animal studies have shown that both A.C.T.H. and A.C.T.H. 4-10 increase the amplitude of muscle actionpotentials (M.A.P.S) and reduce fatigue.5.G Since A.C.T.H. 4-10 has no known toxicity in man, a pilot study was undertaken to investigate the effect of this peptide on evoked M.A.P.s in an 18-year-old female with myasthenia gravis and in a 24-year-old male with progressive spinal muscular
activity,
atrophy (Kugelberg-Welander type). Using a standardised test based on the fall in amplitude of the first 5 M.A.P.s evoked by median-nerve stimulation,7 found in control tests that the M.A.P.S of the myasthenic patient declined to 80% of the initial value. M.A.P. testing following the infusion of 3 mg A.C.T.H. 4-10 showed no decline in M.A.P. amplitude. This maintenance of amplitude was retained for at least 2 h after peptide infusion. The administration of 15 mg A.C.T.H. 4-10 resulted in a similar, but slightly less effective, response. Control evoked M.A.P.S in the patient with the KugelbergWelander syndrome showed an average decrease of 55%ê) of the initial amplitude. Following the infusion of either 3 mg or 6 mg A.C.T.H. 4-10 all test M.A.P.S rose above 100%. This retention of M.A.P. amplitude was demonstrable 10 days after infusion of 6 mg A.C.T.H. 4-10. Tests made following saline infusions showed essentially no deviation from control tests. A.C.T.H. 4-10, like certain other polypeptides, may influence transmitter synthesis8 or release at the neuromuscular junctionand/or it may modulate synaptic transmissionrestoring depressed synapses to normal.’,, The effect of this peptide fragment of A.C.T.H. on muscle function is presently being investigated in larger groups of myasthenic patients.
it
was
FLEUR L. STRAND* H. STOBOY FRIEDEBOLD KRIVOY HEYCK VAN RIEZEN
University Orthopædic Clinic, Freie Universitat Berlin, Clayallec 229, 1000 Berlin 33. *
Present address: New York University, Washington Square, College of Arts and Science, Department of Biology, New York, N.Y. 10003, U.S.A. 1.
Shapiro, M. S., Namba, T., Grob, 18, 1018.
2. 3.
Strand, F. L., Stoboy, H. Pflugers Arch. 1969, 312, 97. Johns, T. R., Mann, J. D., Campa, J. F. Excerpta med. int. Congr. Ser. 1974, no. 334, p. 15. Greven, H. M., De Wied, D. Eur. J. Pharmac. 1967, 2, 14. Strand, F. L., Stoboy, H., Cayer, A. Neuroendocristology, 1973, 74, 13, 1. Strand, F. L., Cayer, A. in Hormones, Homeostasis and the Brain: Progress in Brain Research, vol. 42 (edited by W. H. Gispen, T. B. van Wimersma Greidanus, B. Bohus, and D. deWied). Amsterdam (in the press). Roberts, D. V., Wilson, A. in Myasthenia Gravis (edited by R. Greene); ch. 2. Philadelphia, 1969. Torda, C., Wolff, H. G. Am. J. Physiol. 1952, 169, 140. Barker, J. L., Gainer, H. Science, 1974, 184, 1371. Krivoy, W., Zimmerman, E. in Chemical Modulation of Brain Function (edited by H. C. Sabelli); p. 111. New York, 1973.
4. 5.
6.
7. 8. 9.
10.
D.
Neurology, Minneap. 1968,