1125
Letters
to
ISONIAZID-INDUCED PELLAGRA DESPITE VITAMIN-B6 SUPPLEMENTATION
the Editor
MALE FERTILITY AFTER SUCCESSFUL CHEMOTHERAPY FOR LYMPHOBLASTIC LEUKÆMIA
SIR,-Boys with acute lymphoblastic leukaemia (ALL) have prognosis than girls,’ possibly because the testis acts as a sanctuary for residual disease. Prophylactic early radiotherapy to both testes has been advocated and is being assessed a worse
in clinical trials. Defenders of such radiotherapy argue that the inevitable sterility that ensues should be set against the high
probability of infertility being produced by the systemic chemotherapy alone, and, ignoring endocrine testicular function, that there is little to lose by wholesale irradiation. In fact, what little evidence there is suggests that, although
reproductive function of the testis can indeed be damaged by anti-ALL chemotherapy, this tends to be repaired in time,2 the
and at least one adult male who had had ALL has fathered a normal child shortly after completing a long programme of continuous treatment.3 The boy described below also achieved this, despite being around puberty at the time of diagnosis. ALL was diagnosed at the age of 14 years and 2 months. The patient attained a complete remission on the Medical Research Council combined therapy trial UKALL II (initial)’ in which he received no cyclophosphamide but did have 800 mg/m2 of cytarabine during a 2-year programme of therapy which finished in August, 1975. He married in July, 1978, at the age of 19 and announced his intention to start a family early in January, 1979. Fertility studies were planned but his wife conceived shortly afterwards so these were not done. Her uncomplicated pregnancy ended on Oct. 16 when a 3240 g female term baby was delivered without incident. The mother’s blood group was 0 RhD positive, the father’s was A RhD positive, and the baby’s was ARIR2’ While this offers no proof, there is little social reason to doubt paternity, and the A antigen plus one rhesus D antigen must be paternal in origin. The baby is well and apparently normal. Female fertility following ALL treatment has been shown to be adequate in several cases4 but the effect of such therapy on male fertility could well be different because the testis is apparently much more liable to damage around puberty.5 Despite this the young man described proved most effectively to have no lasting problems with spermatogenesis, and the rarity of such patients (he is apparently the first in the U.K.) may be due to the infrequency of long surviving adult males rather than to their oligospermia. On current evidence prophylactic testicular radiotherapy is hard to justify on a "nothing to lose" basis in all boys with ALL. While such radiotherapy may well prove to be valuable, its therapeutic role must be clearly defined before it is widely applied. Department of Hæmatology, Children’s Hospital,
J. S. LILLEYMAN
Sheffield S10 2TH
SIR,-Pellagra (niacin deficiency) is a side-effect of isoniazid unless supplementary vitamin-B6 is given.’ This is thought to result from inhibition of the enzyme kynureninase (EC 3.7.1.3) in the pathway of nicotinamide nucleotide synthesis from tryptophan, as a result of the formation of a complex between the drug and pyridoxal phosphate, the vitamin-B6derived cofactor of the enzyme. We have studied a patient in whom pellagra developed during isoniazid therapy despite adequate vitamin-B6 supplementation. A 31-year-old Kenyan Asian female with Behcet’s syndrome and severe colonic ulceration, had a darkened erythema and coarsened skin texture of light-exposed areas, at a time when her Behcet’s disease was in remission on prednisolone. She had been taking antituberculosis cover with ’Rimactazid’ (rifampicin 450 mg + isoniazid 300 mg daily) and pyridoxine hydrochloride 10 mg daily for the previous 3 months. Pellagra was suspected; the photosensitive dermatitis responded rapidly to nicotinamide 150 mg daily. The following investigations were done before the start of nicotinamide therapy: (a) Urinary N’-methyl nicotinamide excretion was measured.2 (b) The activation of plasma aspartate aminotransferase by added pyridoxal phosphate in vitro was measured3 with and without the addition of 1 mmol/1 pyridoxal phosphate to the incubation buffer. (c) A tryptophan load test was done. Urinary excretion of xanthurenic and kynurenic acids and kynurenine was determined in 24 h urine samples before and after the administration of 2 g L-tryptophan by mouth by our modification4of the method of Satoh and Price. The concentration of N’-methyl nicotinamide in a random urine was 0.25 mmol/mol creatinine (normal> 1); below 0-5 is considered evidence of niacin deficiency.5 The ratio of plasma aspartate aminotransferase activity with and without the addition of pyridoxal phosphate was 1-10 (normal 1-0—2-0’’). The results of the tryptophan load test are shown in the table.
sample of
EXCRETION OF TRYPTOPHAN METABOLITES AFTER TRYPTOPHAN LOAD
Pellagra
suspected clinically and was confirmed by the of NI-methyl nicotinamide, the major metabolite of nicotinamide nucleotides in man. The finding of normal activation of plasma aspartate aminotransferase by added pyriwas
low excretion
doxal was
phosphate indicates that the patient’s vitamin B6 status adequate-i.e., that she was taking her pyridoxine supple-
ments. to
Inhibition of kynureninase by isoniazid would be expected lead to approximately equal increases in the excretion of all
1. Biehl JP, Vilter RW. Effect of isoniazid on vitamin B6 metabolism; its possible significance in producing isoniazid neuritis. Proc Soc Exp Biol Med
1954; 85: 389-95. 1. Medical Research Council
Working Party on Leukæmia in Childhood. Effects of varying radiation schedule, cyclophosphamide treatment, and duration of treatment in acute lymphoblastic leukæmia. Br Med J 1978;
ii: 787-91. 2. Lendon M, Hann IM, Palmer MK, Shalet SM, Morris Jones PH. Testicular histology after combination chemotherapy in childhood for acute lymphoblastic leukæmia. Lancet 1978; ii: 439-41. 3. Hmkes E, Plotkin D. Reversible drug-induced sterility in a patient with acute
leukæmia. JAMA 1973;223:1490-91. Estiu M. Successful pregnancy in leukæmia. Lancet 5 Editorial. Treatment of childhood cancer: effects
4
1978; ii: 785-86.
1977; i: 433. the gonads. Br Med J
on
E. The fluorimetric estimation of N1-methyl nicotinamide and its differentiation from coenzyme I. Biochem J 1950; 46: 421—26. 3. Schuster L, Bates A, Hirsch CA. A sensitive radiochemical assay for serum glutamic-oxaloacetic transaminase. Analyt Biochem 1978; 86: 648-54. 4. Bender DA, Earl CJ, Lees AJ. Niacin depletion in parkmsonian patients treated with L-dopa, benserazide and carbidopa. Clin Sci 1979; 56: 89-93. 5. Gontzea I, Rujinski A, Sutzesco P. Rapide évaluation biochimique de l’état de nutrition niacinique. Biblioth Nutrio Dieta 1976; 23: 95-104. 6. Sauberlich HE, Canham JE, Baker EM, Raica N, Herman YF. Biochemical assessment of the nutritional status of vitamin B6 in the human Am J Clin Nutr 1972; 25:629-42. 2.
Carpenter KJ, Kodicek
1126 three metabolites after a tryptophan load. However, the rise in xanthurenic acid was only 42%, compared with a six-fold rise in excretion of kynurenic acid and kynurenine, which is compatible with inhibition of kynureninase. This suggests inhibition of kynurenine hydroxylase (EC 1.14.13.9) as well as inhibition of kynureninase. A similar effect has been observed in rats fed on a high tryptophan diet; animals given isoniazid excreted more kynurenine ’and less xanthurenic acid, with unchanged kynurenic acid, than did drug-free animals (unpublished). This apparent inhibition of kynurenine hydroxylase by isoniazid is not due to a direct interaction between the drug and the enzyme. Isoniazid added to rat liver preparations has no effect on the activity of kynurenine hydroxylase, even at concentrations considerably greater than those likely to be encountered clinically.7 It is possible that the inhibition is due to an isoniazid metabolite that accumulates only slowly after long-term administration, although there is no evidence for this from preliminary animal experiments (unpublished). Alternatively, the reduced activity of kynurenine hydroxylase may be a result of depletion of cofactor NADPH in the liver-i.e., an early result of nicotinamide nucleotide depletion is a reduction in further synthesis from tryptophan, because of cofactor lack.8 Depletion of liver nicotinamide nucleotide coenzymes may have occurred in this patient as a result of her marginally low intake of tryptophan and niacin (see below), together with reduced synthesis of NAD from tryptophan because of inhibition of tryptophan oxygenase by isoniazid, an effect which has been observed in vitro.7 The patient is a vegan, and had a low intake of tryptophan (below 70 mg/day) and of niacin (12 mg/day, recommended daily intake 15 mg). It is therefore prhaps not surprising that, with the additional factor of inhibition of endogenous synthesis of nicotinamide nucleotides from tryptophan, pellagra developed. There may be many strict vegetarians in Britain who have a similarly marginal intake of tryptophan and niacin, in whom isoniazid therapy, even with supplementary vitamin B6, might lead to clinical pellagra. This should respond to nicotinamide. We thank Dr Etain Cronin for her care.
allowing us to study a patient under
Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, London W1P 7PN
DAVID A. BENDER
of Dermatology, Central Middlesex Hospital, London NW10 7NS
ROBIN RUSSELL-JONES
Department
INCREASED INTRACELLULAR GLUTATHIONE DURING PENICILLAMINE TREATMENT FOR RHEUMATOID ARTHRITIS a slow-acting anti-rheumatic know how it but we do not works, although many mechdrug’ anisms (e.g., involvement of its SH group) have been proposed.2 No in-vivo intracellular effect of PCA has been described and no convincing relation between a possible biological effect of PCA and the clinical response to the drug in RA has yet been demonstrated. The thio tripeptide glutathione (GSH) is the most important intracellular source of SH apart from protein-SH. Glutathione seems to play an important role in the stability of lysosomal and other cell membranes, in protection against damage from
SIR,-Penicillamine (PCA) is
7. Bender DA. Inhibition in vitro of the enzymes of the oxidative pathway of tryptophan metabolism and of nicotinamide nucleotide synthesis by benserazide, carbidopa and isoniazid. Biochem Pharmacol (in press). 8. Price JM, Brown RR, Yess, N. Testing the functional capacity of the tryptophan: niacin pathway in man by analysis of urinary metabolites. In: Levine R, Loft R, eds. Advances in metabolic disorders: vol 2. New York: Academic Press, 1965: 159-225. 1. Munthe E, ed. Penicillamine research in rheumatoid disease: Proceedings of Symposium in Spåtind, Norway. Oslo: Fabritius/MSD, 1977. 2. Felthamp TEW, ed. Fundamental studies on penicillamine for rheumatoid diseases: Proceedings of second Bertine Koperberg conference. Scand J Rheumatol 1979; suppl 28.
Relation between ESR, E-GSH, penicillamine dose and clinical improvement in a 67-year-old female with RA.
and free radicals, and for aminoacid transport cell membranes and other membrane-bound functions.3 20-30% of glutathione in the cells is protein bound.4 We have been studying the glutathione content (by an enzymatic method5) of erythrocytes (E-GSH) in rheumatic diseases, in several cases before and during PCA treatment. We tested 95 patients with rheumatoid arthritis (RA) in different disease stages, 4 with RA or ankylosing spondylitis with secondary amyloidosis, 9 with ankylosing spondylitis, 3 with systemic lupus erythematosus (SLE), 3 with dermatopolymyositis, 2 with juvenile chronic arthritis, 1 with Reiter’s disease, 1 with psoriasis arthropathy, 1 with vasculitis and hypogammaglobulinsemia, and 2 with persistent arthralgias. Control values in healthy blood-donors and medical personnel were in the range 2.2 + 0-5 mol/1 in accordance with the literature.3Low levels (< 1 - p.moVI) were found in 7 RA patients, all with active disease of short duration (< 2 years). High levels (>2.7 p.mo11961) were found in 6 RA patients with long-standing, severe disease (usually functional stage iu or iv), in 1 case of secondary amyloidosis, in 1 case with severe ankylosing spondylitis, and in 1 with active SLE and pericarditis. All the others had normal values. Patients with stable disease had remarkably constant values. In periods of high disease activity E-GSH values fell; they rose during remissions. Because PCA can undergo SH/SS exchange with GSH in vitro, we measured E-GSH in 18 RA patients just before PCA was given and weekly or monthly during treatment. 12 showed a steady increase in E-GSH from low or low-normal levels up to high or high-normal after 2-3 months of treatment: a slight drop was then usual (see figure). 7 of these patients were in definite remission after 3 months; 5 had improved slightly (but 2 had not been followed up for more than 2 months). The increase in E-GSH was usually observed 2-8 weeks after PCA was introduced and long before any clinical effect was evident. 6 patients showed either no increase or only a slight increase in E-GSH in the first 4-6 weeks. None of these responded clinically. Cysteine 500-1000 mg per day was given in addition to PCA to 4 of the 6 patients who did not respond and to 2 other known non-responders to PCA. In 3 of these, E-GSH then increased in parallel with a slow, but definite subjective and slight objective improvement of their clinical condition. In the other 3 cases’ cysteine supplementation did not prompt any increase in E-GSH or response to PCA. Our observations indicate that an increase in free E-GSH during penicillamine treatment may be an indication of a response to treatment. Is the increase a specific drug action or secondary to clinical improvement? The fact that it often happened long before any clinical effect was seen indicates a specific drug action. Treatment of RA patients with gold or corticosteroids gave no similar"constant increase in E-GSH, despite
superoxides across
3. Arias IM, Jakoby WB, eds. Gluthathione: Metabolism and function (Kroc Found Ser 6). New York: Raven Press, 1976. 4. Révész L. In: Radiation damage and sulfhydryl compounds: Panel proceedings series. International Atomic Energy Agency, Vienna, 1969:125. 5. Tietze S. Analyt Biochem 1969; 27: 502.
Letters
to
ISONIAZID-INDUCED PELLAGRA DESPITE VITAMIN-B6 SUPPLEMENTATION
the Editor
MALE FERTILITY AFTER SUCCESSFUL CHEMOTHERAPY FOR LYMPHOBLASTIC LEUKÆMIA
SIR,-Boys with acute lymphoblastic leukaemia (ALL) have prognosis than girls,’ possibly because the testis acts as a sanctuary for residual disease. Prophylactic early radiotherapy to both testes has been advocated and is being assessed a worse
in clinical trials. Defenders of such radiotherapy argue that the inevitable sterility that ensues should be set against the high
probability of infertility being produced by the systemic chemotherapy alone, and, ignoring endocrine testicular function, that there is little to lose by wholesale irradiation. In fact, what little evidence there is suggests that, although
reproductive function of the testis can indeed be damaged by anti-ALL chemotherapy, this tends to be repaired in time,2 the
and at least one adult male who had had ALL has fathered a normal child shortly after completing a long programme of continuous treatment.3 The boy described below also achieved this, despite being around puberty at the time of diagnosis. ALL was diagnosed at the age of 14 years and 2 months. The patient attained a complete remission on the Medical Research Council combined therapy trial UKALL II (initial)’ in which he received no cyclophosphamide but did have 800 mg/m2 of cytarabine during a 2-year programme of therapy which finished in August, 1975. He married in July, 1978, at the age of 19 and announced his intention to start a family early in January, 1979. Fertility studies were planned but his wife conceived shortly afterwards so these were not done. Her uncomplicated pregnancy ended on Oct. 16 when a 3240 g female term baby was delivered without incident. The mother’s blood group was 0 RhD positive, the father’s was A RhD positive, and the baby’s was ARIR2’ While this offers no proof, there is little social reason to doubt paternity, and the A antigen plus one rhesus D antigen must be paternal in origin. The baby is well and apparently normal. Female fertility following ALL treatment has been shown to be adequate in several cases4 but the effect of such therapy on male fertility could well be different because the testis is apparently much more liable to damage around puberty.5 Despite this the young man described proved most effectively to have no lasting problems with spermatogenesis, and the rarity of such patients (he is apparently the first in the U.K.) may be due to the infrequency of long surviving adult males rather than to their oligospermia. On current evidence prophylactic testicular radiotherapy is hard to justify on a "nothing to lose" basis in all boys with ALL. While such radiotherapy may well prove to be valuable, its therapeutic role must be clearly defined before it is widely applied. Department of Hæmatology, Children’s Hospital,
J. S. LILLEYMAN
Sheffield S10 2TH
SIR,-Pellagra (niacin deficiency) is a side-effect of isoniazid unless supplementary vitamin-B6 is given.’ This is thought to result from inhibition of the enzyme kynureninase (EC 3.7.1.3) in the pathway of nicotinamide nucleotide synthesis from tryptophan, as a result of the formation of a complex between the drug and pyridoxal phosphate, the vitamin-B6derived cofactor of the enzyme. We have studied a patient in whom pellagra developed during isoniazid therapy despite adequate vitamin-B6 supplementation. A 31-year-old Kenyan Asian female with Behcet’s syndrome and severe colonic ulceration, had a darkened erythema and coarsened skin texture of light-exposed areas, at a time when her Behcet’s disease was in remission on prednisolone. She had been taking antituberculosis cover with ’Rimactazid’ (rifampicin 450 mg + isoniazid 300 mg daily) and pyridoxine hydrochloride 10 mg daily for the previous 3 months. Pellagra was suspected; the photosensitive dermatitis responded rapidly to nicotinamide 150 mg daily. The following investigations were done before the start of nicotinamide therapy: (a) Urinary N’-methyl nicotinamide excretion was measured.2 (b) The activation of plasma aspartate aminotransferase by added pyridoxal phosphate in vitro was measured3 with and without the addition of 1 mmol/1 pyridoxal phosphate to the incubation buffer. (c) A tryptophan load test was done. Urinary excretion of xanthurenic and kynurenic acids and kynurenine was determined in 24 h urine samples before and after the administration of 2 g L-tryptophan by mouth by our modification4of the method of Satoh and Price. The concentration of N’-methyl nicotinamide in a random urine was 0.25 mmol/mol creatinine (normal> 1); below 0-5 is considered evidence of niacin deficiency.5 The ratio of plasma aspartate aminotransferase activity with and without the addition of pyridoxal phosphate was 1-10 (normal 1-0—2-0’’). The results of the tryptophan load test are shown in the table.
sample of
EXCRETION OF TRYPTOPHAN METABOLITES AFTER TRYPTOPHAN LOAD
Pellagra
suspected clinically and was confirmed by the of NI-methyl nicotinamide, the major metabolite of nicotinamide nucleotides in man. The finding of normal activation of plasma aspartate aminotransferase by added pyriwas
low excretion
doxal was
phosphate indicates that the patient’s vitamin B6 status adequate-i.e., that she was taking her pyridoxine supple-
ments. to
Inhibition of kynureninase by isoniazid would be expected lead to approximately equal increases in the excretion of all
1. Biehl JP, Vilter RW. Effect of isoniazid on vitamin B6 metabolism; its possible significance in producing isoniazid neuritis. Proc Soc Exp Biol Med
1954; 85: 389-95. 1. Medical Research Council
Working Party on Leukæmia in Childhood. Effects of varying radiation schedule, cyclophosphamide treatment, and duration of treatment in acute lymphoblastic leukæmia. Br Med J 1978;
ii: 787-91. 2. Lendon M, Hann IM, Palmer MK, Shalet SM, Morris Jones PH. Testicular histology after combination chemotherapy in childhood for acute lymphoblastic leukæmia. Lancet 1978; ii: 439-41. 3. Hmkes E, Plotkin D. Reversible drug-induced sterility in a patient with acute
leukæmia. JAMA 1973;223:1490-91. Estiu M. Successful pregnancy in leukæmia. Lancet 5 Editorial. Treatment of childhood cancer: effects
4
1978; ii: 785-86.
1977; i: 433. the gonads. Br Med J
on
E. The fluorimetric estimation of N1-methyl nicotinamide and its differentiation from coenzyme I. Biochem J 1950; 46: 421—26. 3. Schuster L, Bates A, Hirsch CA. A sensitive radiochemical assay for serum glutamic-oxaloacetic transaminase. Analyt Biochem 1978; 86: 648-54. 4. Bender DA, Earl CJ, Lees AJ. Niacin depletion in parkmsonian patients treated with L-dopa, benserazide and carbidopa. Clin Sci 1979; 56: 89-93. 5. Gontzea I, Rujinski A, Sutzesco P. Rapide évaluation biochimique de l’état de nutrition niacinique. Biblioth Nutrio Dieta 1976; 23: 95-104. 6. Sauberlich HE, Canham JE, Baker EM, Raica N, Herman YF. Biochemical assessment of the nutritional status of vitamin B6 in the human Am J Clin Nutr 1972; 25:629-42. 2.
Carpenter KJ, Kodicek
1126 three metabolites after a tryptophan load. However, the rise in xanthurenic acid was only 42%, compared with a six-fold rise in excretion of kynurenic acid and kynurenine, which is compatible with inhibition of kynureninase. This suggests inhibition of kynurenine hydroxylase (EC 1.14.13.9) as well as inhibition of kynureninase. A similar effect has been observed in rats fed on a high tryptophan diet; animals given isoniazid excreted more kynurenine ’and less xanthurenic acid, with unchanged kynurenic acid, than did drug-free animals (unpublished). This apparent inhibition of kynurenine hydroxylase by isoniazid is not due to a direct interaction between the drug and the enzyme. Isoniazid added to rat liver preparations has no effect on the activity of kynurenine hydroxylase, even at concentrations considerably greater than those likely to be encountered clinically.7 It is possible that the inhibition is due to an isoniazid metabolite that accumulates only slowly after long-term administration, although there is no evidence for this from preliminary animal experiments (unpublished). Alternatively, the reduced activity of kynurenine hydroxylase may be a result of depletion of cofactor NADPH in the liver-i.e., an early result of nicotinamide nucleotide depletion is a reduction in further synthesis from tryptophan, because of cofactor lack.8 Depletion of liver nicotinamide nucleotide coenzymes may have occurred in this patient as a result of her marginally low intake of tryptophan and niacin (see below), together with reduced synthesis of NAD from tryptophan because of inhibition of tryptophan oxygenase by isoniazid, an effect which has been observed in vitro.7 The patient is a vegan, and had a low intake of tryptophan (below 70 mg/day) and of niacin (12 mg/day, recommended daily intake 15 mg). It is therefore prhaps not surprising that, with the additional factor of inhibition of endogenous synthesis of nicotinamide nucleotides from tryptophan, pellagra developed. There may be many strict vegetarians in Britain who have a similarly marginal intake of tryptophan and niacin, in whom isoniazid therapy, even with supplementary vitamin B6, might lead to clinical pellagra. This should respond to nicotinamide. We thank Dr Etain Cronin for her care.
allowing us to study a patient under
Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, London W1P 7PN
DAVID A. BENDER
of Dermatology, Central Middlesex Hospital, London NW10 7NS
ROBIN RUSSELL-JONES
Department
INCREASED INTRACELLULAR GLUTATHIONE DURING PENICILLAMINE TREATMENT FOR RHEUMATOID ARTHRITIS a slow-acting anti-rheumatic know how it but we do not works, although many mechdrug’ anisms (e.g., involvement of its SH group) have been proposed.2 No in-vivo intracellular effect of PCA has been described and no convincing relation between a possible biological effect of PCA and the clinical response to the drug in RA has yet been demonstrated. The thio tripeptide glutathione (GSH) is the most important intracellular source of SH apart from protein-SH. Glutathione seems to play an important role in the stability of lysosomal and other cell membranes, in protection against damage from
SIR,-Penicillamine (PCA) is
7. Bender DA. Inhibition in vitro of the enzymes of the oxidative pathway of tryptophan metabolism and of nicotinamide nucleotide synthesis by benserazide, carbidopa and isoniazid. Biochem Pharmacol (in press). 8. Price JM, Brown RR, Yess, N. Testing the functional capacity of the tryptophan: niacin pathway in man by analysis of urinary metabolites. In: Levine R, Loft R, eds. Advances in metabolic disorders: vol 2. New York: Academic Press, 1965: 159-225. 1. Munthe E, ed. Penicillamine research in rheumatoid disease: Proceedings of Symposium in Spåtind, Norway. Oslo: Fabritius/MSD, 1977. 2. Felthamp TEW, ed. Fundamental studies on penicillamine for rheumatoid diseases: Proceedings of second Bertine Koperberg conference. Scand J Rheumatol 1979; suppl 28.
Relation between ESR, E-GSH, penicillamine dose and clinical improvement in a 67-year-old female with RA.
and free radicals, and for aminoacid transport cell membranes and other membrane-bound functions.3 20-30% of glutathione in the cells is protein bound.4 We have been studying the glutathione content (by an enzymatic method5) of erythrocytes (E-GSH) in rheumatic diseases, in several cases before and during PCA treatment. We tested 95 patients with rheumatoid arthritis (RA) in different disease stages, 4 with RA or ankylosing spondylitis with secondary amyloidosis, 9 with ankylosing spondylitis, 3 with systemic lupus erythematosus (SLE), 3 with dermatopolymyositis, 2 with juvenile chronic arthritis, 1 with Reiter’s disease, 1 with psoriasis arthropathy, 1 with vasculitis and hypogammaglobulinsemia, and 2 with persistent arthralgias. Control values in healthy blood-donors and medical personnel were in the range 2.2 + 0-5 mol/1 in accordance with the literature.3Low levels (< 1 - p.moVI) were found in 7 RA patients, all with active disease of short duration (< 2 years). High levels (>2.7 p.mo11961) were found in 6 RA patients with long-standing, severe disease (usually functional stage iu or iv), in 1 case of secondary amyloidosis, in 1 case with severe ankylosing spondylitis, and in 1 with active SLE and pericarditis. All the others had normal values. Patients with stable disease had remarkably constant values. In periods of high disease activity E-GSH values fell; they rose during remissions. Because PCA can undergo SH/SS exchange with GSH in vitro, we measured E-GSH in 18 RA patients just before PCA was given and weekly or monthly during treatment. 12 showed a steady increase in E-GSH from low or low-normal levels up to high or high-normal after 2-3 months of treatment: a slight drop was then usual (see figure). 7 of these patients were in definite remission after 3 months; 5 had improved slightly (but 2 had not been followed up for more than 2 months). The increase in E-GSH was usually observed 2-8 weeks after PCA was introduced and long before any clinical effect was evident. 6 patients showed either no increase or only a slight increase in E-GSH in the first 4-6 weeks. None of these responded clinically. Cysteine 500-1000 mg per day was given in addition to PCA to 4 of the 6 patients who did not respond and to 2 other known non-responders to PCA. In 3 of these, E-GSH then increased in parallel with a slow, but definite subjective and slight objective improvement of their clinical condition. In the other 3 cases’ cysteine supplementation did not prompt any increase in E-GSH or response to PCA. Our observations indicate that an increase in free E-GSH during penicillamine treatment may be an indication of a response to treatment. Is the increase a specific drug action or secondary to clinical improvement? The fact that it often happened long before any clinical effect was seen indicates a specific drug action. Treatment of RA patients with gold or corticosteroids gave no similar"constant increase in E-GSH, despite
superoxides across
3. Arias IM, Jakoby WB, eds. Gluthathione: Metabolism and function (Kroc Found Ser 6). New York: Raven Press, 1976. 4. Révész L. In: Radiation damage and sulfhydryl compounds: Panel proceedings series. International Atomic Energy Agency, Vienna, 1969:125. 5. Tietze S. Analyt Biochem 1969; 27: 502.
