- Email: [email protected]
ARTHROPATHIES AND SCHIZOPHRENIA
536 241 ±28 mg when tetracycline was given alone compared to 172 ±13 mg when administered with cimetidine, a decrease of
INTERACTION OF CIMETIDINE WITH TETRACYCLINE ABSORPTION
approximately 30% (p<0.05, paired t-test). In contrast, when tetracycline was given in solution, the mean cumulative amount excreted was 264±21 mg compared to 236±11 mg when given in conjunction with cimetidine. This difference was not significant. Dissolution of tetracycline in the stomach is a prerequisite for absorption in the small intestine because the mildly alka-
SIR,-Gastric acidity may influence absorption of drugs, especially those whose dissolutionis pH dependent.’·2 The that -cimetidine increases blood salicylate concentrations when coadministered with aspirin suggests that by inhibiting gastric acid secretion, cimetidine increases the dissolution rate and, thus, the absorption of aspirin. We have investigated the effect of cimetidine on the bioavailability of tetracycline, a basic antibiotic requiring low pH for optimum dissolution and absorption.
report3
Three men and two women (age 18-26 years, weight 47-60 kg) took part. After an overnight fast, tetracycline hydrochloride (’Achromycin’) was administered as 2x250 mg capsules with 200 ml water. On a different occasion, each subject was also given cimetidine (’Tagamet’), 200 mg three times daily and 400 mg at bedtime, for three consecutive days beginning the day before tetracycline administration. The treatments were allocated according to a randomised crossover design, treatments being separated by a washout period of at least 7 days. As a control, the above procedures were repeated except that the contents of the tetracycline hydrochloride capsules were dissolved in 200 ml water just before administration. Food was not permitted for four hours after tetracycline administration when normal diet could be resumed. Dairy products, vitamins, antacids, and any other medication were not permitted during the study. The volunteers also refrained from alcohol and tobacco. Urine was collected immediately before tetracycline administration’ (blank), then hourly up to twelve hours and then as necessary up to seventy-two hours. Each volunteer noted his urine collection times and volumes. A portion of each urine sample was frozen and assayed for tetracycline by high performance liquid chromatography. The amount of tetracycline excreted in the urine was calculated for each subject in each of the four treatments.
The results are presented in the figure. The coadministration of cimetidine with tetracycline decreased absorption of tetracycline from capsules. The mean (±SEM) cumulative amount of tetracycline excreted up to seventy-two hours was
1.
Mayersohn M. Physiological factors that modify systemic drug availability and pharmacologic response in clinical practice. In: Blanchard J, Sawchuk RJ, Brodie BB, eds. Principles and perspectives in drug bioavailability. Basel: Karger, 1979; 211-73. 2. Barr WH, Adir J, Garrettson L. Decrease of tetracycline absorption in man by sodium bicarbonate. Clin Pharmacol Ther 1971; 12: 779-84. 3. Khoury W, Geraci K, Askari A, Johnson M. The effect of cimetidine on aspirin absorption. Gastroenterology 1979; 76: 1169.
Mean cumulative urinary excretion of tetracycline after administration to five subjects as capsules and as solution, with and without coadministration of cimetidine. 0= tetracycline HCI (500 mg) capsules.
+
cimetidine (800
mg/day).
+
cimetidine (800
mg/day).
_
line conditions of the small intestine tend to inhibit further dissolution of tetracycline once undissolved drug particles reach this point in the gastrointestinal tract. Our results indicate that therapeutic doses of cimetidine substantially reduce the absorption of tetracycline when the antibiotic is administered orally, as capsules. The insignificant effect of cimetidine on the absorption of tetracycline from solution indicates that cimetidine per se, does not affect the absorption of the antibiotic, but that by lowering gastric acidity, it establishes an unfavourable environment for gastric dissolution and, subsequently, absorption in the small intestine. Bioavailability is a well recognised problem with oral tetracycline preparations, and the reduced absorption in the presence of cimetidine is of special concern since it could lead to therapeutic failure. Now that cimetidine is frequently prescribed, often for long periods, its interaction with drugs whose absorption is related to gastric acidity should be investigated
further.
-
J. J. COLE
Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
B. G. CHARLES P. J. RAVENSCROFT
ARTHROPATHIES AND SCHIZOPHRENIA
SIR,-We have previously reported an association between HLA-B27 and chronic paranoid schizophrenia.’ Using similar diagnostic and laboratory methods, - Mendlewicz and Linkowski2 also found an increased frequency of HLA-B27 in schizophrenic patients, although the difference was not significant when compared with a control group. Bearing in mind (a) that HLA-B27 is highly correlated with some forms of arthropathies3 and (b) that arthropathies and schizophrenia rarely occur together,4-7 we wondered if HLAB27 could serve as a genetic marker for both arthropathy and schizophrenia. To investigate this point we carried out the following studies: (1) 16 patients with chronic schizophrenia bearing HLA-B27 were investigated with clinical, radiological, and laboratory tests for any form of arthropathy. (2) HLA antigens were typed in 288 patients with clinical, radiological, and laboratory features of an arthropathy (ankylosing spondylitis, Reiter’s syndrome, juvenile rheumatoid 131 carried HLA-B27 and 157did not. By arthritis, &c). means of the cumulative psychiatric case register at this institute we compared the incidence of psychiatric diagnoses between these two subgroups (with and without HLA-B27). The methods are described in detail elsewhere.8 1. Gattaz WF, Beckmann H. HLA-antigens and schizophrenia. Lancet 1980, i: 98-99. 2. Mendlewicz J, Linkowski P. HLA-antigens and schizophrenia. Lancet 1980; i: 765. 3. Svejgaard A, Platz P, Ryder LP, Staub-Nielsen L, Thomsen M. HLA and disease association: a survey. Transplant Rev 1975; 22: 3-43. 4. Nissen HA, Spencer KA. The psychogenic problem (endocrinal and metabolic) in chronic arthritis. N Engl J Med 1936; 214: 576-81. 5. Mellsop GW, Whittingham S, Ungar B. Schizophrenia and autoimmune serological reactions. Arch Gen Psychiat 1973; 28: 194-96. 6. Mellsop GW, Koadlow L, Syme J, Whittingham S. Absence of rheumatoid arthritis in schizophrenia. Aust NZ J Med 1974; 4: 274-352. 7. Österberg E. Schizophrenia and rheumatic disease. Acta Psychiat Scand
1978; 58: 339-59. WF, Ewald RW, Beckmann H. The HLA system and schizophrenia.
8. Gattaz a
study
205-11.
in a
German
population.
Arch
Psychiat
Nervenkr
1980; 228:
537 In 16 chronic-paranoid patients with HLA-B27 no form of arthropathy was seen, and in 288 patients with arthropathies no case of schizophrenia was detected. Furthermore, in 131 HLA-B27-positive patients with arthropathies the only cases of psychiatric disorder were one subnormal patient and one with alcohol problems. On the other hand, in the group of HLAB27-negative patients with arthropathies the incidence of psychiatric diseases was five times higher than in the group with and so comparable to the psychiHLA-B27 (=5.7; p<0.02) atric morbidity of the general population. These data agree with the hypothesis that schizophrenia and arthropathies tend to be mutually exclusive. It is conceivable that HLA-B27 isa genetic marker for some arthropathies as well as for a defined subgroup of schizophrenia. HLA-B27 could perhaps predispose to both diseases, the development of either an arthropathy or schizophrenia depending on the inter-
action of the genetic marker with other biological and environmental factors. The possibility that HLA-B27-positive arthropathy is negatively correlated not only with schizophrenia but with other psychiatric disorders should be investigated further. Zentralinstitut für Seelische,
Gesundheit, 6800 Mannheim
1-J.5,
West Germany
WAGNER F. GATTAZ SIEGFRIED KASPER ROLF W. EWALD HELMUT BECKMANN
ADDITION OF HEPATITIS-B IMMUNOGLOBULIN TO CLOTTING FACTORS
SIR,-Dr Tabor and his colleagues (July 12,
68) have revived an old theme. The addition of immunoglobulin to prevent post-transfusion hepatitis (PTH) risk in preparations capable of transmitting hepatitis-B virus (HBV) parenterally, is certainly not a new idea.’ In the early 1970s, with the advent of preparations of hepatitis-B immunoglobulin (HBIgG), there has been some discussion in Edinburgh about the possibility of adding a high-titre anti-HBs preparation to certaiii fractions, but this was not pursued seriously because of logistic difficulties (J. G. Watt, personal communication). In the past decade a major shift in prevalence of type and incidence of post-transfusion hepatitis has been observed, especially in the high-risk group of haemophiliacs. Non-A, non-B hepatitis is now the major risk in transfusion. Careful screening of individual donations for HBsAg, as recommended by the W.H.O.,z and control protocols have contributed to the reduction of post-transfusion HBV infection. An international forum’ was in favour of a "small-pool concept", especially for the preparation of fraction i and cryoprecipitate for the treatment of new hemophiliacs, but we fear that the rapidly increasing demand for these concentrates will prevent this concept from being put into practice. If the transmission of HBV infection should be solved by adding anti-HBs immunoglobulin to fractionation products, it
ing of the patients with immune complexes, possible effects of the immunoglobulin and immune complexes on specific clotting properties and on organs such as kidneys,s the availability of large amounts of high-titre anti-HBs serum, and the costs -all unpredictable complications for the treatment of an almost controllable disease. We leave it
to our
fractionatiori
colleagues to deal with the possible effects such an additional ,step might have on the purity, yield, and efficacy of factor-VIII and factor-IX preparations, and on the thrombogenicity of the latter. The
of ultraviolet light and betapropiolactone (BPL) to HBV infectivity is safe and harmless to heat-labile plasma proteins,6-9 and such products are commercially available in Europe. BPL and ultraviolet light together have a strong synergistic viricidal effect.’"’" In long-term studies it has proved to be a most valuable technique not only for prevention of HBV infection but also for inactivation of non-A, non-B virus infectivity. 12-15 We believe that the addition of hepatitis-B immunoglobulin to human plasma or its products is neither feasible nor desirable. Instead a good-quality plasma pool should be collected from blood from healthy donors, individual donations being tested for HBV carrier state. In the future a vaccine for HBV will be available, which can be used for the high-risk patient populations, such as haemophiliacs. At present our greatest hope lies with a test that will detect carriers of non-A; non-B hepatitis-now the major cause of post-transfusion hepatitis. use
remove
Red Cross Bloodbank Groningen-Drenthe Groningen, Netherlands Division of Hæmatology, Department of Medicine, University of Groningen
C. TH. SMIT SIBINGA P. C. DAS
H. O. NIEWEG
p.
’
should be realised that most patients treated with such products will be chronically exposed to these concentrates with an increased IgG content, received via i.v. infusion. It is, however, known that ordinary factor-VIII preparations, containing a small amount of IgG (1-3 mg/ml), can cause antibody formation against IgG.’ Other considerations are: the chronic loadRodriguez J, Ward R. Post-transfusion hepatitis, effect of modified gammaglobulin added to blood in vitro. N Engl J Med 1971; 285: 925. 2. World Health Organisation. Requirements for the collection, processing and quality control of human blood and blood products. Tech Rep Ser no. 626. 1. Katz M,
Geneva, 1978. 3. International Forum. What is the importance of the "small-pool concept" in the preparation of fraction I and cryoprecipitates for the prevention of post-transfusion hepatitis? Vox Sang 1980; 38: 106. 4. Allain JP, Jones P, Martin-Villar J, de Vreker R, Taub R. Management of the hemophilias. Scand J Hœmatol 1980; 24: suppl. 35, 72.
SIR,-Dr Tabor and his colleagues have shown that hepatitis B virus (HBV) infectivity can be removed from a factor IX concentrate by the addition of hepatitis B immunoglobulins. This observation is of considerable theoretical and practical importance, but most cases of chronic liver disease in haemophiliacs transfused with large-pool clotting factor concentrates are thought to be related to non-A, non-B viruses.1,2 5. Zuckerman AJ. Human viral hepatitis. Hepatitis associated antigen and viruses. Amsterdam: North-Holland Publishing Company, 1975: 377. 6. Kotitschke R, Stephan W. Kombinierte Behandlung von Gerinnungsfaktoren in humanplasma mit beta-propiolacton und UV. In: Schröer H, Hauck G, Zimmermann WF, eds. Struktur und funktion des fibrinogens. Stuttgart: Schattauer Verlag, 1976: 222. 7. Kotitschke R, Stephan W. In vivo recovery Studien von Prothrombinekomplex Konzentraten an Ratten. In: Heene DL, ed. Immunologische probleme der blutgerinnung. Stuttgart: Schattauer Verlag, 1978: 317. 3. Stephan W. Hepatitis-free and stable human serum for intravenous therapy. Vox Sang 1971; 20: 442. 9. Stephan W. Undegraded human immunoglobulin for intravenous use. Vox
10.
Sang 1975; 28: 422. LoGrippo GA, Hartman FW. Chemical
and combined methods for plasma sterilization. Bibl Hœmatol 1958; 7: 225. 11. LoGrippo GA. Status of betaprone for cold sterilization of biologic products.
Vox Sang 1969; 17: 52. LoGrippo GA. Serum hepatitis and the clinical evaluation of blood compounds sterilized with beta-propiolactone. In: Proc 8th Congr Int. Soc. Blood Transfusion, Tokyo 1960. 1962: 504. 13. LoGrippo GA, Wolfram BR, Rupe CE. Human plasma treated with ultraviolet and propiolactone, six years clinical evaluation. JAMA 1964; 187: 12.
722. 14. Kornhuber B. Intravenöse Immunoglobulin-langzeit-therapie bei Kinder. Msch Kinderheilk 1979; 127: 20. 15. Prince AM, Stephan W, Brotman B, van der Ende MC. Evaluation of safety of beta-propiolactone/ultraviolet treated factor IX complex in chimpanzees. XIII Int Congr World Fed Hemophilia, Tel Aviv 1979 (abstract). 1. Gerety RJ, Tabor E, Eyster ME, Drucker JA. Serological markers of hepatitis viruses in hæmophiliacs. Thrombosis Hœmostas 1979; 42: 265
(abstr). J, Dilling N, Stern D. An outbreak of hepatitis associated with intravenous injection of factor VIII concentrate. Lancet 1975; ii. 221-23.
2. Craske
INTERACTION OF CIMETIDINE WITH TETRACYCLINE ABSORPTION
approximately 30% (p<0.05, paired t-test). In contrast, when tetracycline was given in solution, the mean cumulative amount excreted was 264±21 mg compared to 236±11 mg when given in conjunction with cimetidine. This difference was not significant. Dissolution of tetracycline in the stomach is a prerequisite for absorption in the small intestine because the mildly alka-
SIR,-Gastric acidity may influence absorption of drugs, especially those whose dissolutionis pH dependent.’·2 The that -cimetidine increases blood salicylate concentrations when coadministered with aspirin suggests that by inhibiting gastric acid secretion, cimetidine increases the dissolution rate and, thus, the absorption of aspirin. We have investigated the effect of cimetidine on the bioavailability of tetracycline, a basic antibiotic requiring low pH for optimum dissolution and absorption.
report3
Three men and two women (age 18-26 years, weight 47-60 kg) took part. After an overnight fast, tetracycline hydrochloride (’Achromycin’) was administered as 2x250 mg capsules with 200 ml water. On a different occasion, each subject was also given cimetidine (’Tagamet’), 200 mg three times daily and 400 mg at bedtime, for three consecutive days beginning the day before tetracycline administration. The treatments were allocated according to a randomised crossover design, treatments being separated by a washout period of at least 7 days. As a control, the above procedures were repeated except that the contents of the tetracycline hydrochloride capsules were dissolved in 200 ml water just before administration. Food was not permitted for four hours after tetracycline administration when normal diet could be resumed. Dairy products, vitamins, antacids, and any other medication were not permitted during the study. The volunteers also refrained from alcohol and tobacco. Urine was collected immediately before tetracycline administration’ (blank), then hourly up to twelve hours and then as necessary up to seventy-two hours. Each volunteer noted his urine collection times and volumes. A portion of each urine sample was frozen and assayed for tetracycline by high performance liquid chromatography. The amount of tetracycline excreted in the urine was calculated for each subject in each of the four treatments.
The results are presented in the figure. The coadministration of cimetidine with tetracycline decreased absorption of tetracycline from capsules. The mean (±SEM) cumulative amount of tetracycline excreted up to seventy-two hours was
1.
Mayersohn M. Physiological factors that modify systemic drug availability and pharmacologic response in clinical practice. In: Blanchard J, Sawchuk RJ, Brodie BB, eds. Principles and perspectives in drug bioavailability. Basel: Karger, 1979; 211-73. 2. Barr WH, Adir J, Garrettson L. Decrease of tetracycline absorption in man by sodium bicarbonate. Clin Pharmacol Ther 1971; 12: 779-84. 3. Khoury W, Geraci K, Askari A, Johnson M. The effect of cimetidine on aspirin absorption. Gastroenterology 1979; 76: 1169.
Mean cumulative urinary excretion of tetracycline after administration to five subjects as capsules and as solution, with and without coadministration of cimetidine. 0= tetracycline HCI (500 mg) capsules.
+
cimetidine (800
mg/day).
+
cimetidine (800
mg/day).
_
line conditions of the small intestine tend to inhibit further dissolution of tetracycline once undissolved drug particles reach this point in the gastrointestinal tract. Our results indicate that therapeutic doses of cimetidine substantially reduce the absorption of tetracycline when the antibiotic is administered orally, as capsules. The insignificant effect of cimetidine on the absorption of tetracycline from solution indicates that cimetidine per se, does not affect the absorption of the antibiotic, but that by lowering gastric acidity, it establishes an unfavourable environment for gastric dissolution and, subsequently, absorption in the small intestine. Bioavailability is a well recognised problem with oral tetracycline preparations, and the reduced absorption in the presence of cimetidine is of special concern since it could lead to therapeutic failure. Now that cimetidine is frequently prescribed, often for long periods, its interaction with drugs whose absorption is related to gastric acidity should be investigated
further.
-
J. J. COLE
Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
B. G. CHARLES P. J. RAVENSCROFT
ARTHROPATHIES AND SCHIZOPHRENIA
SIR,-We have previously reported an association between HLA-B27 and chronic paranoid schizophrenia.’ Using similar diagnostic and laboratory methods, - Mendlewicz and Linkowski2 also found an increased frequency of HLA-B27 in schizophrenic patients, although the difference was not significant when compared with a control group. Bearing in mind (a) that HLA-B27 is highly correlated with some forms of arthropathies3 and (b) that arthropathies and schizophrenia rarely occur together,4-7 we wondered if HLAB27 could serve as a genetic marker for both arthropathy and schizophrenia. To investigate this point we carried out the following studies: (1) 16 patients with chronic schizophrenia bearing HLA-B27 were investigated with clinical, radiological, and laboratory tests for any form of arthropathy. (2) HLA antigens were typed in 288 patients with clinical, radiological, and laboratory features of an arthropathy (ankylosing spondylitis, Reiter’s syndrome, juvenile rheumatoid 131 carried HLA-B27 and 157did not. By arthritis, &c). means of the cumulative psychiatric case register at this institute we compared the incidence of psychiatric diagnoses between these two subgroups (with and without HLA-B27). The methods are described in detail elsewhere.8 1. Gattaz WF, Beckmann H. HLA-antigens and schizophrenia. Lancet 1980, i: 98-99. 2. Mendlewicz J, Linkowski P. HLA-antigens and schizophrenia. Lancet 1980; i: 765. 3. Svejgaard A, Platz P, Ryder LP, Staub-Nielsen L, Thomsen M. HLA and disease association: a survey. Transplant Rev 1975; 22: 3-43. 4. Nissen HA, Spencer KA. The psychogenic problem (endocrinal and metabolic) in chronic arthritis. N Engl J Med 1936; 214: 576-81. 5. Mellsop GW, Whittingham S, Ungar B. Schizophrenia and autoimmune serological reactions. Arch Gen Psychiat 1973; 28: 194-96. 6. Mellsop GW, Koadlow L, Syme J, Whittingham S. Absence of rheumatoid arthritis in schizophrenia. Aust NZ J Med 1974; 4: 274-352. 7. Österberg E. Schizophrenia and rheumatic disease. Acta Psychiat Scand
1978; 58: 339-59. WF, Ewald RW, Beckmann H. The HLA system and schizophrenia.
8. Gattaz a
study
205-11.
in a
German
population.
Arch
Psychiat
Nervenkr
1980; 228:
537 In 16 chronic-paranoid patients with HLA-B27 no form of arthropathy was seen, and in 288 patients with arthropathies no case of schizophrenia was detected. Furthermore, in 131 HLA-B27-positive patients with arthropathies the only cases of psychiatric disorder were one subnormal patient and one with alcohol problems. On the other hand, in the group of HLAB27-negative patients with arthropathies the incidence of psychiatric diseases was five times higher than in the group with and so comparable to the psychiHLA-B27 (=5.7; p<0.02) atric morbidity of the general population. These data agree with the hypothesis that schizophrenia and arthropathies tend to be mutually exclusive. It is conceivable that HLA-B27 isa genetic marker for some arthropathies as well as for a defined subgroup of schizophrenia. HLA-B27 could perhaps predispose to both diseases, the development of either an arthropathy or schizophrenia depending on the inter-
action of the genetic marker with other biological and environmental factors. The possibility that HLA-B27-positive arthropathy is negatively correlated not only with schizophrenia but with other psychiatric disorders should be investigated further. Zentralinstitut für Seelische,
Gesundheit, 6800 Mannheim
1-J.5,
West Germany
WAGNER F. GATTAZ SIEGFRIED KASPER ROLF W. EWALD HELMUT BECKMANN
ADDITION OF HEPATITIS-B IMMUNOGLOBULIN TO CLOTTING FACTORS
SIR,-Dr Tabor and his colleagues (July 12,
68) have revived an old theme. The addition of immunoglobulin to prevent post-transfusion hepatitis (PTH) risk in preparations capable of transmitting hepatitis-B virus (HBV) parenterally, is certainly not a new idea.’ In the early 1970s, with the advent of preparations of hepatitis-B immunoglobulin (HBIgG), there has been some discussion in Edinburgh about the possibility of adding a high-titre anti-HBs preparation to certaiii fractions, but this was not pursued seriously because of logistic difficulties (J. G. Watt, personal communication). In the past decade a major shift in prevalence of type and incidence of post-transfusion hepatitis has been observed, especially in the high-risk group of haemophiliacs. Non-A, non-B hepatitis is now the major risk in transfusion. Careful screening of individual donations for HBsAg, as recommended by the W.H.O.,z and control protocols have contributed to the reduction of post-transfusion HBV infection. An international forum’ was in favour of a "small-pool concept", especially for the preparation of fraction i and cryoprecipitate for the treatment of new hemophiliacs, but we fear that the rapidly increasing demand for these concentrates will prevent this concept from being put into practice. If the transmission of HBV infection should be solved by adding anti-HBs immunoglobulin to fractionation products, it
ing of the patients with immune complexes, possible effects of the immunoglobulin and immune complexes on specific clotting properties and on organs such as kidneys,s the availability of large amounts of high-titre anti-HBs serum, and the costs -all unpredictable complications for the treatment of an almost controllable disease. We leave it
to our
fractionatiori
colleagues to deal with the possible effects such an additional ,step might have on the purity, yield, and efficacy of factor-VIII and factor-IX preparations, and on the thrombogenicity of the latter. The
of ultraviolet light and betapropiolactone (BPL) to HBV infectivity is safe and harmless to heat-labile plasma proteins,6-9 and such products are commercially available in Europe. BPL and ultraviolet light together have a strong synergistic viricidal effect.’"’" In long-term studies it has proved to be a most valuable technique not only for prevention of HBV infection but also for inactivation of non-A, non-B virus infectivity. 12-15 We believe that the addition of hepatitis-B immunoglobulin to human plasma or its products is neither feasible nor desirable. Instead a good-quality plasma pool should be collected from blood from healthy donors, individual donations being tested for HBV carrier state. In the future a vaccine for HBV will be available, which can be used for the high-risk patient populations, such as haemophiliacs. At present our greatest hope lies with a test that will detect carriers of non-A; non-B hepatitis-now the major cause of post-transfusion hepatitis. use
remove
Red Cross Bloodbank Groningen-Drenthe Groningen, Netherlands Division of Hæmatology, Department of Medicine, University of Groningen
C. TH. SMIT SIBINGA P. C. DAS
H. O. NIEWEG
p.
’
should be realised that most patients treated with such products will be chronically exposed to these concentrates with an increased IgG content, received via i.v. infusion. It is, however, known that ordinary factor-VIII preparations, containing a small amount of IgG (1-3 mg/ml), can cause antibody formation against IgG.’ Other considerations are: the chronic loadRodriguez J, Ward R. Post-transfusion hepatitis, effect of modified gammaglobulin added to blood in vitro. N Engl J Med 1971; 285: 925. 2. World Health Organisation. Requirements for the collection, processing and quality control of human blood and blood products. Tech Rep Ser no. 626. 1. Katz M,
Geneva, 1978. 3. International Forum. What is the importance of the "small-pool concept" in the preparation of fraction I and cryoprecipitates for the prevention of post-transfusion hepatitis? Vox Sang 1980; 38: 106. 4. Allain JP, Jones P, Martin-Villar J, de Vreker R, Taub R. Management of the hemophilias. Scand J Hœmatol 1980; 24: suppl. 35, 72.
SIR,-Dr Tabor and his colleagues have shown that hepatitis B virus (HBV) infectivity can be removed from a factor IX concentrate by the addition of hepatitis B immunoglobulins. This observation is of considerable theoretical and practical importance, but most cases of chronic liver disease in haemophiliacs transfused with large-pool clotting factor concentrates are thought to be related to non-A, non-B viruses.1,2 5. Zuckerman AJ. Human viral hepatitis. Hepatitis associated antigen and viruses. Amsterdam: North-Holland Publishing Company, 1975: 377. 6. Kotitschke R, Stephan W. Kombinierte Behandlung von Gerinnungsfaktoren in humanplasma mit beta-propiolacton und UV. In: Schröer H, Hauck G, Zimmermann WF, eds. Struktur und funktion des fibrinogens. Stuttgart: Schattauer Verlag, 1976: 222. 7. Kotitschke R, Stephan W. In vivo recovery Studien von Prothrombinekomplex Konzentraten an Ratten. In: Heene DL, ed. Immunologische probleme der blutgerinnung. Stuttgart: Schattauer Verlag, 1978: 317. 3. Stephan W. Hepatitis-free and stable human serum for intravenous therapy. Vox Sang 1971; 20: 442. 9. Stephan W. Undegraded human immunoglobulin for intravenous use. Vox
10.
Sang 1975; 28: 422. LoGrippo GA, Hartman FW. Chemical
and combined methods for plasma sterilization. Bibl Hœmatol 1958; 7: 225. 11. LoGrippo GA. Status of betaprone for cold sterilization of biologic products.
Vox Sang 1969; 17: 52. LoGrippo GA. Serum hepatitis and the clinical evaluation of blood compounds sterilized with beta-propiolactone. In: Proc 8th Congr Int. Soc. Blood Transfusion, Tokyo 1960. 1962: 504. 13. LoGrippo GA, Wolfram BR, Rupe CE. Human plasma treated with ultraviolet and propiolactone, six years clinical evaluation. JAMA 1964; 187: 12.
722. 14. Kornhuber B. Intravenöse Immunoglobulin-langzeit-therapie bei Kinder. Msch Kinderheilk 1979; 127: 20. 15. Prince AM, Stephan W, Brotman B, van der Ende MC. Evaluation of safety of beta-propiolactone/ultraviolet treated factor IX complex in chimpanzees. XIII Int Congr World Fed Hemophilia, Tel Aviv 1979 (abstract). 1. Gerety RJ, Tabor E, Eyster ME, Drucker JA. Serological markers of hepatitis viruses in hæmophiliacs. Thrombosis Hœmostas 1979; 42: 265
(abstr). J, Dilling N, Stern D. An outbreak of hepatitis associated with intravenous injection of factor VIII concentrate. Lancet 1975; ii. 221-23.
2. Craske