- Email: [email protected]
On the shoulders of giants
64
Pralidoxime for organophosphorus
poisoning de Silva and
SIR,-Dr colleagues’ report (May 9, p 1136) may well confirm widespread prejudice that nothing is to be gained in cases of severe acute organophosphorus (OP) insecticide poisoning by the addition of oxime reacdvators to the standard regimen of atropine plus mechanical ventilation. The apparent lack of efficacy of oxime therapy as used in their patients may divert attention from the fact that overall 29% of them died. The need for more effective treatment for OP poisoning is undeniable and we should not dismiss the value of oximes unless they have been found wanting after correct use.
0
n
n
1000
2000
IVIG/patient’s IgG (moles/moles) Inhibition of C3NeF activity by intact IVIG (closed and Fab’ fragments of IVIG (open squares).
squares)
associated with the presence in IVIG of anti-idiotypic antibodies against autoantibodies.4,5 IVIG has been shown to contain antiidiotypes against various disease-related autoantibodies, including anti-factor VIII, anti-thyroglobulin, anti-intrinsic factor, antiDNA, and anti-neutrophil cytoplasmic antigen antibodies.6 Antiidiotypic antibodies to C3NeF have been described in normal human serum and in serum from patients with MPGN.7 We have investigated the capacity of IVIG to neutralise C3NeF activity in vitro. IgG containing C3NeF activity was purified from the serum of three patients with partial lipodystrophy and incubated with intact IVIG (Sandoglobulin) or with Fab’ fragments of IVIG in veronal buffer containing 0.1 % gelatin and 0-04 mol/1 EDTA for 2 h at 20°C and 1 h at 4°C. C3NeF activity was assessed by measuring the ability of the autoantibody to stabilise the function of C3bBb convertase.3 IVIG inhibited C3NeF activity in a concentration-dependent manner (figure). IVIG alone did not express C3NeF activity. On a molar basis, Fab’2 fragments of IVIG were as efficient as intact IVIG in inhibiting C3NeF function, indicating that neutralisation of autoantibody activity was mediated by interactions between variable regions of IVIG and of C3NeF-containing IgG. Affinity chromatography of C3NeF-containing IgG on Sepharose-bound Fab’2 fragments of IVIG decreased C3NeF activity five fold whereas chromatography of the same C3NeF preparation on sepharose-C3b did not affect C3NeF function. Thus, IVIG contains antibodies capable of neutralising C3NeF activity. These observations extend the clinical spectrum of disease-associated autoantibodies that are inhibited by IVIG in vitro and may represent potential targets for IVIG therapy in vivo.
Immunology Service, Hôpital Broussais, 75014 Paris, France
V. FREMEAUX BACCHI F. MAILLET L. BERLAN M. D. KAZATCHKINE
Spitzer RE, Vallota EH, Forristal J, et al. Serum C’3 lyric system in patients with glomerulonephritis. Science 1969; 164: 436-37. 2. Peters DK, Charlesworth JA, Sissons JGP, et al. Mesangiocapillary nephritis, partial lipodystrophy and hypocomplementemia. Lancet 1973; ii: 535-38. 3. Daha MR, Fearon DT, Austen KF. C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 1976; 116: 1-7. 4. Kaveri SV, Dietrich G, Hurez V, Kazatchkine MD. Intravenous immunoglobulins in the treatment of autoimmune diseases. Clin Exp Immunol 1991; 86: 192-98. 5. Dwyer JD. Manipulating the immune system with immune globulin. N Engl J Med 1.
1992; 326: 107-16. Rossi F, Dietrich G, Kazatchkine MD Antiidiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses. Immunol Rev 1989; 110: 135-49. 7. Spitzer RE, Stitzel AE, Tsokos GC. Human antudiotypic antibody responses to autoantibody against the alternative pathway C3 convertase. Clin Immunol Immunopathol 1990; 57: 19-31.
6.
We have arguedl that failure of oxime therapy does not indicate ineffectiveness of the drug nor, necessarily, does it indicate delay in administration; failure of treatment is usually a function of inadequate dosing. On the basis of available data it seems that to maintain adequate therapeutic concentrations of pralidoxime (about 4 mg/1) in a severely poisoned adult about 500 mg/h should be infused. We emphasise that dosage should be maintained continuously until clear, irreversible, clinical improvement is achieved; this may take many days while residual insecticide is cleared from body stores. de Silva et al infused 4 g in the first 24 h and 1 g daily thereafter. In our view this low level of maintenance dosing accounts for the lack of therapeutic benefit observed. It would be a clinical tragedy if potentially lifesaving therapy were dismissed because of an inadequate study. We believe the report from de Silva et al does no more than confirm the known substantial morbidity and mortality in OP poisoned patients treated supportively without the benefit of adequate oxime therapy. MRC
Toxicology Unit, Carshalton, Surrey SM5 4EF, UK
M. K.
JOHNSON
West Midlands Poisons Unit, Dudley Road Hospital,
J. A. VALE
Birmingham HEF(M) Division, Department of Health, London SE1
1.
T. C. MARRS T. J. MEREDITH
Johnson MK, Vale JA. Clinical management of acute organophosphorus poisoning: an overview. In: Marrs TC, Ballantyne B, eds. Basic and clinical toxicology of organophosphates and carbamates. Oxford: Butterworth Heinemann, 1992: 528-35.
On the shoulders of giants SIR,-Today’s progress has its historic roots in Latin civilisation. We are thus like dwarves on the shoulders of giants. Dr Hoogendijk and colleagues (May 2, p 1081), and many others, incorrectly use the Latin term "de novo" instead of "ex novo".2 We inherited from Latin civilisation not only linguistic roots but also an appreciation for precision. I wish that editors of scientific journals would correct this error, which represents a small thorn even for us dwarves. IRCCS, Neurological Institute, C. Mondino Foundation, 27100 Pavia, Italy
DIEGO FRANCIOTTA
1. Merton R. On the shoulders of giants. New York: The Free Press, 1965. 2. Calonghi F. Dizionario della lingua Latina, vol 1, 3rd ed. Torino: Rosenberg & Sellier, 1950.
CORRECTIONS Coronary Atheroma Regression Trials.-The edited version of Professor Oliver’s letter (May 16, p 1241) wrongly gave the impression that the Multi-Center Anti-Atheroma Study was originally planned to last four years. MAAS was a two-year study that has been extended. Interim analyses of the two-year angiographic data did not show an unequivocal effect on the primary endpoints, according to predefined criteria. Thus, it was decided to perform a third coronary angiogram after a further two years.
Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease.-In this article by Dr Smith and colleagues Qune 6, p 1375), the name of the sixth author should have read D. M. Maraganore.
Pralidoxime for organophosphorus
poisoning de Silva and
SIR,-Dr colleagues’ report (May 9, p 1136) may well confirm widespread prejudice that nothing is to be gained in cases of severe acute organophosphorus (OP) insecticide poisoning by the addition of oxime reacdvators to the standard regimen of atropine plus mechanical ventilation. The apparent lack of efficacy of oxime therapy as used in their patients may divert attention from the fact that overall 29% of them died. The need for more effective treatment for OP poisoning is undeniable and we should not dismiss the value of oximes unless they have been found wanting after correct use.
0
n
n
1000
2000
IVIG/patient’s IgG (moles/moles) Inhibition of C3NeF activity by intact IVIG (closed and Fab’ fragments of IVIG (open squares).
squares)
associated with the presence in IVIG of anti-idiotypic antibodies against autoantibodies.4,5 IVIG has been shown to contain antiidiotypes against various disease-related autoantibodies, including anti-factor VIII, anti-thyroglobulin, anti-intrinsic factor, antiDNA, and anti-neutrophil cytoplasmic antigen antibodies.6 Antiidiotypic antibodies to C3NeF have been described in normal human serum and in serum from patients with MPGN.7 We have investigated the capacity of IVIG to neutralise C3NeF activity in vitro. IgG containing C3NeF activity was purified from the serum of three patients with partial lipodystrophy and incubated with intact IVIG (Sandoglobulin) or with Fab’ fragments of IVIG in veronal buffer containing 0.1 % gelatin and 0-04 mol/1 EDTA for 2 h at 20°C and 1 h at 4°C. C3NeF activity was assessed by measuring the ability of the autoantibody to stabilise the function of C3bBb convertase.3 IVIG inhibited C3NeF activity in a concentration-dependent manner (figure). IVIG alone did not express C3NeF activity. On a molar basis, Fab’2 fragments of IVIG were as efficient as intact IVIG in inhibiting C3NeF function, indicating that neutralisation of autoantibody activity was mediated by interactions between variable regions of IVIG and of C3NeF-containing IgG. Affinity chromatography of C3NeF-containing IgG on Sepharose-bound Fab’2 fragments of IVIG decreased C3NeF activity five fold whereas chromatography of the same C3NeF preparation on sepharose-C3b did not affect C3NeF function. Thus, IVIG contains antibodies capable of neutralising C3NeF activity. These observations extend the clinical spectrum of disease-associated autoantibodies that are inhibited by IVIG in vitro and may represent potential targets for IVIG therapy in vivo.
Immunology Service, Hôpital Broussais, 75014 Paris, France
V. FREMEAUX BACCHI F. MAILLET L. BERLAN M. D. KAZATCHKINE
Spitzer RE, Vallota EH, Forristal J, et al. Serum C’3 lyric system in patients with glomerulonephritis. Science 1969; 164: 436-37. 2. Peters DK, Charlesworth JA, Sissons JGP, et al. Mesangiocapillary nephritis, partial lipodystrophy and hypocomplementemia. Lancet 1973; ii: 535-38. 3. Daha MR, Fearon DT, Austen KF. C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J Immunol 1976; 116: 1-7. 4. Kaveri SV, Dietrich G, Hurez V, Kazatchkine MD. Intravenous immunoglobulins in the treatment of autoimmune diseases. Clin Exp Immunol 1991; 86: 192-98. 5. Dwyer JD. Manipulating the immune system with immune globulin. N Engl J Med 1.
1992; 326: 107-16. Rossi F, Dietrich G, Kazatchkine MD Antiidiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses. Immunol Rev 1989; 110: 135-49. 7. Spitzer RE, Stitzel AE, Tsokos GC. Human antudiotypic antibody responses to autoantibody against the alternative pathway C3 convertase. Clin Immunol Immunopathol 1990; 57: 19-31.
6.
We have arguedl that failure of oxime therapy does not indicate ineffectiveness of the drug nor, necessarily, does it indicate delay in administration; failure of treatment is usually a function of inadequate dosing. On the basis of available data it seems that to maintain adequate therapeutic concentrations of pralidoxime (about 4 mg/1) in a severely poisoned adult about 500 mg/h should be infused. We emphasise that dosage should be maintained continuously until clear, irreversible, clinical improvement is achieved; this may take many days while residual insecticide is cleared from body stores. de Silva et al infused 4 g in the first 24 h and 1 g daily thereafter. In our view this low level of maintenance dosing accounts for the lack of therapeutic benefit observed. It would be a clinical tragedy if potentially lifesaving therapy were dismissed because of an inadequate study. We believe the report from de Silva et al does no more than confirm the known substantial morbidity and mortality in OP poisoned patients treated supportively without the benefit of adequate oxime therapy. MRC
Toxicology Unit, Carshalton, Surrey SM5 4EF, UK
M. K.
JOHNSON
West Midlands Poisons Unit, Dudley Road Hospital,
J. A. VALE
Birmingham HEF(M) Division, Department of Health, London SE1
1.
T. C. MARRS T. J. MEREDITH
Johnson MK, Vale JA. Clinical management of acute organophosphorus poisoning: an overview. In: Marrs TC, Ballantyne B, eds. Basic and clinical toxicology of organophosphates and carbamates. Oxford: Butterworth Heinemann, 1992: 528-35.
On the shoulders of giants SIR,-Today’s progress has its historic roots in Latin civilisation. We are thus like dwarves on the shoulders of giants. Dr Hoogendijk and colleagues (May 2, p 1081), and many others, incorrectly use the Latin term "de novo" instead of "ex novo".2 We inherited from Latin civilisation not only linguistic roots but also an appreciation for precision. I wish that editors of scientific journals would correct this error, which represents a small thorn even for us dwarves. IRCCS, Neurological Institute, C. Mondino Foundation, 27100 Pavia, Italy
DIEGO FRANCIOTTA
1. Merton R. On the shoulders of giants. New York: The Free Press, 1965. 2. Calonghi F. Dizionario della lingua Latina, vol 1, 3rd ed. Torino: Rosenberg & Sellier, 1950.
CORRECTIONS Coronary Atheroma Regression Trials.-The edited version of Professor Oliver’s letter (May 16, p 1241) wrongly gave the impression that the Multi-Center Anti-Atheroma Study was originally planned to last four years. MAAS was a two-year study that has been extended. Interim analyses of the two-year angiographic data did not show an unequivocal effect on the primary endpoints, according to predefined criteria. Thus, it was decided to perform a third coronary angiogram after a further two years.
Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease.-In this article by Dr Smith and colleagues Qune 6, p 1375), the name of the sixth author should have read D. M. Maraganore.