308
delayed ANF inactivation. Several known actions of the endogenous hormone (vasorelaxation, natriuresis, inhibition of the renin-angiotensin system’) might account for this activity. P.
Hôpital de Pontorson
LEFRANÇOIS
J. DUCHIER
Innopharm, Paris Laboratoire
Bioprojet,
G. CLERC
Paris
INSERM Neurobiology and Pharmacology Unit, Centre Paul Broca d’INSERM, 75014 Paris, France
C. LIM
J. M. LECOMTE
C. GROS
J. C. SCHWARTZ
Lang RE, Unger T, Ganten D. Atrial natnuretic peptide a new factor in blood pressure control. J Hypertension 1987; 5: 255-78. 2. Northridge DB, Alabaster CT, Connell CT, et al. Effects of UK 69578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 3. Gros C, Souque A, Schwartz JC, et al. Protection of atrial natriuretic factor against degradation, diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan. Proc Natl Acad Sci USA 1989; 86: 1.
7580-84. 4. Kahn JC, Patey M, Dubois-Rande JL, et al. Sinorphan, an orally-active enkephalinase inhibitor, enhances plasma atrial natriuretic factor in severe congestive heart failure. Lancet 1990; 335: 118-19. 5. Lecomte JM, Baumer Ph, Lim C, et al. Stereoselective protection of exogenous and endogenous ANF by enkephalinase inhibitors in mice and humans. Eur J
Pharmacol 1990; 179: 65-73
IM-
I
SINORPHAN(mg/day) Changes in systolic and diastolic BP in 12 patients with essential hypertension receiving placebo for two weeks, followed bysinorphan twice a day in increasing oral dosage. concentrations of the circulating hormone in healthy volunteers and in patients with congestive heart failure.2-5 These changes are accompanied by characteristic ANF-like responses such as diuresis, natriuresis, increase in urinary cyclic GMP excretion, or decrease in plasma renin activity. Since constant infusion of exogenous ANF in low dosage reduces blood pressure in hypertensive patients,! we have studied the effects of sinorphan, an orally active and well-tolerated atriopeptidase inhibitory in patients with mild-to-moderate essential hypertension. This open, controlled trial was done, with their informed consent, in 12 patients (5 males, 7 females, aged 55 [SD 10] years) exhibiting supine diastolic BP of 95-115 mm Hg and systolic BP below 200 mm Hg. Patients were either not previously treated or had stopped treatment for hypertension for 2 weeks before the trial. The trial lasted for 2 months: after a 2-week placebo period patients took sinorphan in increasing dosages (capsules of 25, 50, and 100, and then 200 mg, twice daily) each dosage being maintained for a week except for the last which was taken for 3 more weeks (figure). Sinorphan (or placebo) was given as monotherapy, diuretics, vasodilators, and other agents being avoided throughout the trial. Patients were examined every week, just before the dosage increase, and at day 42 (after 6 weeks of active treatment). Supine BP was measured with a mercury sphygmomanometer in duplicate with an interval of 3 min after 10 min in supine position, and heart rate was recorded. Electrocardiograms (ECG) were recorded on days - 14 and + 28. Supine diastolic or systolic BP (102-3 [1’7] and 166[4.7] mm Hg on day -14) did not change significantly during the placebo period. However, both systolic and diastolic BP decreased significantly during the sinorphan period (p < 0-001, analysis of variance). Compared with mean values at the end of the placebo session, systolic and diastolic BP decreases were significant from day 28 and at day 42. Decreases were maintained during the last 2 weeks to reach 12 mm Hg on both systolic (median fall 9%) and diastolic BP (10%) at the end of the trial. Heart rates, with the patient standing or supine, were not significantly modified. The treatment was well tolerated: there was no significant change in ECG or blood indices and no side-effect clearly attributable to the treatment was reported by the patients or detected clinically. This small open trial suggests that antihypertensive activity persists after atriopeptidase inhibition, presumably as a result of
Visiting and immunisation policies on a regional neonatal unit SiR.—The experience of Dr White and Dr Mackie (April 21, p 979) prompts us to report 19 cases of respiratory syncytial virus (RSV) infection diagnosed by the Cell Tech Diagnostic kit. During the winter of 1988/89 we diagnosed 15 cases of RSV infection on our neonatal unit. Between November, 1989, and April, 1990, we had only 4 cases of RSV infection in three infants. All three infants had been extubated into headbox oxygen shortly before respiratory symptoms developed (table). The presence of a cough, an unusual symptom in infants on a neonatal unit, prompted a suspicion of RSV infection. The increased handling of the babies after extubation and the greater time spent in their parents’ arms and in closer contact with siblings may have been responsible for the spread of RSV in these infants. Although RSV infections are disseminated by both adults1 and children, we adopted a policy of limiting visits from siblings under five years of age during the winter of 1989/90, and this may have helped to reduce the number of RSV infections on the neonatal unit. Whooping cough, like RSV infection, is generally felt to be an infection of older children and has been reported only in newborn babies after discharge from hospital.2 However, in June, 1989, a premature baby on the unit acquired pertussis. She was born at 28 weeks’ gestation, the first of twins weighing 920 g, and had been ventilated for 59 days. Bronchopulmonary dysplasia developed and she remained oxygen-dependent at 10 months when a coryzal illness arose and ventilation was again required. Bordetella pertussis was grown from a pernasal swab, but the source of infection remains CLINICAL DETAILS OF RSV INFECTIONS ON NEONATAL UNIT
*I P PV intermittent positive-pressure ventilation. All I had hyaline membrane disease and patent ductus arteriosus. tBronchopulmonary dysplasia, still on neonatal unit tDeath from respiratory infection Details of second RSV infection in parentheses.
309
unknown. She
was
ventilated for 26 days and had the added
complications of cardiac arrest, acute renal failure, candida septicaemia, and secondary lung infection with pseudomonas. She has recovered but has persistent lung damage. We are now more diligent in immunising newborn babies against pertussis and do not delay immunisation until discharge or until they are two months from expected date of delivery. 3,4 We also try to ensure that all under-5s visiting the unit have been immunised against pertussis. Department of Paediatrics,
K. D. BLAKE
London Hospital (Whitechapel), London E1 1BB, UK
D. C. JELLINEK
Kopeland MD, Douglas GR, Geiman JM, Meagher PM. Neonatal respiratory syncitial virus infection. N Engl J Med 1979; 300: 393-96. 2. McGregor J, Ogle JW, Curry-Kane G. Perinatal pertussis. Obstet Gynecol 1986; 64: 1 Hall CB,
582-86.
3. Department of Health. Immunisation against infectious Stationery Office, 1990. 4. Anon. Routine immunisation of preterm infants. Lancet
disease. London: HM
1990; 335: 23-24.
Screening donors for hepatitis C virus antibody SIR,-In their contribution to the debate on screening donors for antibody to hepatitis C virus (HCV) Dr Finlayson and Mr Tankersley (May 26, p 1274) note that the prevalence of anti-HCV positive donations in the US is between 5% and 10%. This figure is 10-20 times higher than that in most European countries and presumably refers to US paid plasma donors. It seems that the US Food and Drug Administration (FDA) concerns about the virus load in plasma pools should be more appropriately directed to the use of paid donors. The proposed experiments are not described in detail by Finlayson and Tankersley but our understanding is that tests will be done on chimpanzees and that the results will probably not be available until next year. The chimpanzee model has been shown, in the context of validating virus-inactivating procedures on coagulation factor concentrates, to give false-negative results. Products which would not transmit non-A, non-B hepatitis to the chimpanzee have infected patients. The proposed FDA experiments may not provide the assurances required, and one wonders what, in the face of negative results, our FDA colleagues will then propose. The chimpanzee will not resolve the issues. Improved confirmatory tests for HCV are emerging; we urgently need to know how they perform in designating infectivity. We certainly need studies on patients. If virus-inactivation steps (already in place for many coagulation factor concentrates) are introduced into the manufacture of immunoglobulin preparations, and if validated confirmatory tests are used, such studies could be planned quickly. Dr Thomas (June 9, p 1531), writing from the National Institute for Biological Standards and Control, an institution which advises the UK Medicines Control Agency, advises us to leave these scientific matters to the FDA and industry. In the expectation that North American industry, with its paid plasma donors, will have a rapdily diminishing role in the provision of plasma products in Europe in the 1990s (as a result of EC directive 89/38 P) the reliance of Europeans on the FDA needs to be challenged. New arrangements are likely to emerge from forthcoming EC directives. In the meantime should not the non-industrial European plasma fractionation centres liaise with the FDA? The newly established European Plasma Fractionation Association could provide a useful focal point for liaison, both for animal experiments and for clinical
Infectivity of blood that is immunoblot intermediate reactive on hepatitis C virus antibody testing SiR,—Dr Ebeling and colleagues (April 21, p 982) reported that only reactivity for both antigens in the Chiron-Ortho recombinant immunoblot assay (RIBA) for hepatitis C virus antibody (antiHCV) is associated with infectivity. This does not quite match our experience. Since January, 1986, our hospital has had a surveillance programme for hepatitis in transfused surgical patients. Transaminases are monitored monthly for at least 6 months after transfusion. When blood donor screening for anti-HCV by ELISA (Ortho Diagnostic Systems) began in January, 1990, we traced patients who had been transfused in the previous 6-24 months with blood from anti-HCV reactive donors. We identified 15 patients who had received blood from 13 anti-HCV reactive donors and had completed the follow-up (median 14 months). Anti-HCV ELISA tests and (for ELISA reactive sera) RIBA were done on samples collected during follow-up and a RIBA test was also done on all donors (table). SEROCONVERSIONS IN RECIPIENTS OF RIBA REACTIVE (OR
INDETERMINATE) BLOOD
*Non-A, non-B post-transfusion hepatitis, defined
higher than 2.5 times upper reference limit
as
confirmed
increase
of ALT
previously ALT-normal patient, after exclusion of other viral causes or any other cause of liver damage m
Of the 13 donors examined, 6 were RIBA reactive for both 5-1-1 and c-100 (RIBA positive) and 7 were reactive for c-100 alone. 4 of the 7 recipients of blood from RIBA positive donors seroconverted and post-transfusion hepatitis developed in 3. Of the 9 recipients of blood from the 7 donors who were RIBA reactive for c-100 alone, 3 (transfused with blood from donor H) seroconverted and posttransfusion hepatitis ensued in 2. These data suggest that, albeit infrequently, blood donors who are RIBA reactive for anti-c-100 alone may transmit HCV.
Immunology Centre, Ospedale Policlinico, 20122 Milan, Italy
Transfusion and
Detction of
ANTONIO BELLOBUONO FULVIO MOZZI GIANNA PETRINI ALBERTO ZANELLA GIROLAMO SIRCHIA
hepatitis C virus RNA in serum
trials. Scottish National Blood Transfusion Service, Edinburgh EH1 1JR, UK
JOHN D. CASH
1. Colombo M, Gamelli V, Gazengel C, Mannucci P, Savidge G, Schimpf K. Transmission of non-A, non-B hepatitis by heat treated factor VIII concentrate. Lancet 1985; ii: 1-4. 2. Cash JD. Blood transfusion services and the European Community. Br Med J 1990; 300: 481-82
SiR,—Dr Kaneko and colleagues (April 21, p 976) use the polymerase chain reaction (PCR) to detect hepatitis C virus (HCV) RNA in the sera of patients with chronic non-A, non-B hepatitis. They found that nested PCRI with primers for sequences of the clones they have obtained gave a higher detection rate (6/6) than PCR with primers derived from the HCV sequence of the Chiron Corporation2 (0/6). They attribute this to sequence diversity, a known property of single-stranded RNA viruses.
delayed ANF inactivation. Several known actions of the endogenous hormone (vasorelaxation, natriuresis, inhibition of the renin-angiotensin system’) might account for this activity. P.
Hôpital de Pontorson
LEFRANÇOIS
J. DUCHIER
Innopharm, Paris Laboratoire
Bioprojet,
G. CLERC
Paris
INSERM Neurobiology and Pharmacology Unit, Centre Paul Broca d’INSERM, 75014 Paris, France
C. LIM
J. M. LECOMTE
C. GROS
J. C. SCHWARTZ
Lang RE, Unger T, Ganten D. Atrial natnuretic peptide a new factor in blood pressure control. J Hypertension 1987; 5: 255-78. 2. Northridge DB, Alabaster CT, Connell CT, et al. Effects of UK 69578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 3. Gros C, Souque A, Schwartz JC, et al. Protection of atrial natriuretic factor against degradation, diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan. Proc Natl Acad Sci USA 1989; 86: 1.
7580-84. 4. Kahn JC, Patey M, Dubois-Rande JL, et al. Sinorphan, an orally-active enkephalinase inhibitor, enhances plasma atrial natriuretic factor in severe congestive heart failure. Lancet 1990; 335: 118-19. 5. Lecomte JM, Baumer Ph, Lim C, et al. Stereoselective protection of exogenous and endogenous ANF by enkephalinase inhibitors in mice and humans. Eur J
Pharmacol 1990; 179: 65-73
IM-
I
SINORPHAN(mg/day) Changes in systolic and diastolic BP in 12 patients with essential hypertension receiving placebo for two weeks, followed bysinorphan twice a day in increasing oral dosage. concentrations of the circulating hormone in healthy volunteers and in patients with congestive heart failure.2-5 These changes are accompanied by characteristic ANF-like responses such as diuresis, natriuresis, increase in urinary cyclic GMP excretion, or decrease in plasma renin activity. Since constant infusion of exogenous ANF in low dosage reduces blood pressure in hypertensive patients,! we have studied the effects of sinorphan, an orally active and well-tolerated atriopeptidase inhibitory in patients with mild-to-moderate essential hypertension. This open, controlled trial was done, with their informed consent, in 12 patients (5 males, 7 females, aged 55 [SD 10] years) exhibiting supine diastolic BP of 95-115 mm Hg and systolic BP below 200 mm Hg. Patients were either not previously treated or had stopped treatment for hypertension for 2 weeks before the trial. The trial lasted for 2 months: after a 2-week placebo period patients took sinorphan in increasing dosages (capsules of 25, 50, and 100, and then 200 mg, twice daily) each dosage being maintained for a week except for the last which was taken for 3 more weeks (figure). Sinorphan (or placebo) was given as monotherapy, diuretics, vasodilators, and other agents being avoided throughout the trial. Patients were examined every week, just before the dosage increase, and at day 42 (after 6 weeks of active treatment). Supine BP was measured with a mercury sphygmomanometer in duplicate with an interval of 3 min after 10 min in supine position, and heart rate was recorded. Electrocardiograms (ECG) were recorded on days - 14 and + 28. Supine diastolic or systolic BP (102-3 [1’7] and 166[4.7] mm Hg on day -14) did not change significantly during the placebo period. However, both systolic and diastolic BP decreased significantly during the sinorphan period (p < 0-001, analysis of variance). Compared with mean values at the end of the placebo session, systolic and diastolic BP decreases were significant from day 28 and at day 42. Decreases were maintained during the last 2 weeks to reach 12 mm Hg on both systolic (median fall 9%) and diastolic BP (10%) at the end of the trial. Heart rates, with the patient standing or supine, were not significantly modified. The treatment was well tolerated: there was no significant change in ECG or blood indices and no side-effect clearly attributable to the treatment was reported by the patients or detected clinically. This small open trial suggests that antihypertensive activity persists after atriopeptidase inhibition, presumably as a result of
Visiting and immunisation policies on a regional neonatal unit SiR.—The experience of Dr White and Dr Mackie (April 21, p 979) prompts us to report 19 cases of respiratory syncytial virus (RSV) infection diagnosed by the Cell Tech Diagnostic kit. During the winter of 1988/89 we diagnosed 15 cases of RSV infection on our neonatal unit. Between November, 1989, and April, 1990, we had only 4 cases of RSV infection in three infants. All three infants had been extubated into headbox oxygen shortly before respiratory symptoms developed (table). The presence of a cough, an unusual symptom in infants on a neonatal unit, prompted a suspicion of RSV infection. The increased handling of the babies after extubation and the greater time spent in their parents’ arms and in closer contact with siblings may have been responsible for the spread of RSV in these infants. Although RSV infections are disseminated by both adults1 and children, we adopted a policy of limiting visits from siblings under five years of age during the winter of 1989/90, and this may have helped to reduce the number of RSV infections on the neonatal unit. Whooping cough, like RSV infection, is generally felt to be an infection of older children and has been reported only in newborn babies after discharge from hospital.2 However, in June, 1989, a premature baby on the unit acquired pertussis. She was born at 28 weeks’ gestation, the first of twins weighing 920 g, and had been ventilated for 59 days. Bronchopulmonary dysplasia developed and she remained oxygen-dependent at 10 months when a coryzal illness arose and ventilation was again required. Bordetella pertussis was grown from a pernasal swab, but the source of infection remains CLINICAL DETAILS OF RSV INFECTIONS ON NEONATAL UNIT
*I P PV intermittent positive-pressure ventilation. All I had hyaline membrane disease and patent ductus arteriosus. tBronchopulmonary dysplasia, still on neonatal unit tDeath from respiratory infection Details of second RSV infection in parentheses.
309
unknown. She
was
ventilated for 26 days and had the added
complications of cardiac arrest, acute renal failure, candida septicaemia, and secondary lung infection with pseudomonas. She has recovered but has persistent lung damage. We are now more diligent in immunising newborn babies against pertussis and do not delay immunisation until discharge or until they are two months from expected date of delivery. 3,4 We also try to ensure that all under-5s visiting the unit have been immunised against pertussis. Department of Paediatrics,
K. D. BLAKE
London Hospital (Whitechapel), London E1 1BB, UK
D. C. JELLINEK
Kopeland MD, Douglas GR, Geiman JM, Meagher PM. Neonatal respiratory syncitial virus infection. N Engl J Med 1979; 300: 393-96. 2. McGregor J, Ogle JW, Curry-Kane G. Perinatal pertussis. Obstet Gynecol 1986; 64: 1 Hall CB,
582-86.
3. Department of Health. Immunisation against infectious Stationery Office, 1990. 4. Anon. Routine immunisation of preterm infants. Lancet
disease. London: HM
1990; 335: 23-24.
Screening donors for hepatitis C virus antibody SIR,-In their contribution to the debate on screening donors for antibody to hepatitis C virus (HCV) Dr Finlayson and Mr Tankersley (May 26, p 1274) note that the prevalence of anti-HCV positive donations in the US is between 5% and 10%. This figure is 10-20 times higher than that in most European countries and presumably refers to US paid plasma donors. It seems that the US Food and Drug Administration (FDA) concerns about the virus load in plasma pools should be more appropriately directed to the use of paid donors. The proposed experiments are not described in detail by Finlayson and Tankersley but our understanding is that tests will be done on chimpanzees and that the results will probably not be available until next year. The chimpanzee model has been shown, in the context of validating virus-inactivating procedures on coagulation factor concentrates, to give false-negative results. Products which would not transmit non-A, non-B hepatitis to the chimpanzee have infected patients. The proposed FDA experiments may not provide the assurances required, and one wonders what, in the face of negative results, our FDA colleagues will then propose. The chimpanzee will not resolve the issues. Improved confirmatory tests for HCV are emerging; we urgently need to know how they perform in designating infectivity. We certainly need studies on patients. If virus-inactivation steps (already in place for many coagulation factor concentrates) are introduced into the manufacture of immunoglobulin preparations, and if validated confirmatory tests are used, such studies could be planned quickly. Dr Thomas (June 9, p 1531), writing from the National Institute for Biological Standards and Control, an institution which advises the UK Medicines Control Agency, advises us to leave these scientific matters to the FDA and industry. In the expectation that North American industry, with its paid plasma donors, will have a rapdily diminishing role in the provision of plasma products in Europe in the 1990s (as a result of EC directive 89/38 P) the reliance of Europeans on the FDA needs to be challenged. New arrangements are likely to emerge from forthcoming EC directives. In the meantime should not the non-industrial European plasma fractionation centres liaise with the FDA? The newly established European Plasma Fractionation Association could provide a useful focal point for liaison, both for animal experiments and for clinical
Infectivity of blood that is immunoblot intermediate reactive on hepatitis C virus antibody testing SiR,—Dr Ebeling and colleagues (April 21, p 982) reported that only reactivity for both antigens in the Chiron-Ortho recombinant immunoblot assay (RIBA) for hepatitis C virus antibody (antiHCV) is associated with infectivity. This does not quite match our experience. Since January, 1986, our hospital has had a surveillance programme for hepatitis in transfused surgical patients. Transaminases are monitored monthly for at least 6 months after transfusion. When blood donor screening for anti-HCV by ELISA (Ortho Diagnostic Systems) began in January, 1990, we traced patients who had been transfused in the previous 6-24 months with blood from anti-HCV reactive donors. We identified 15 patients who had received blood from 13 anti-HCV reactive donors and had completed the follow-up (median 14 months). Anti-HCV ELISA tests and (for ELISA reactive sera) RIBA were done on samples collected during follow-up and a RIBA test was also done on all donors (table). SEROCONVERSIONS IN RECIPIENTS OF RIBA REACTIVE (OR
INDETERMINATE) BLOOD
*Non-A, non-B post-transfusion hepatitis, defined
higher than 2.5 times upper reference limit
as
confirmed
increase
of ALT
previously ALT-normal patient, after exclusion of other viral causes or any other cause of liver damage m
Of the 13 donors examined, 6 were RIBA reactive for both 5-1-1 and c-100 (RIBA positive) and 7 were reactive for c-100 alone. 4 of the 7 recipients of blood from RIBA positive donors seroconverted and post-transfusion hepatitis developed in 3. Of the 9 recipients of blood from the 7 donors who were RIBA reactive for c-100 alone, 3 (transfused with blood from donor H) seroconverted and posttransfusion hepatitis ensued in 2. These data suggest that, albeit infrequently, blood donors who are RIBA reactive for anti-c-100 alone may transmit HCV.
Immunology Centre, Ospedale Policlinico, 20122 Milan, Italy
Transfusion and
Detction of
ANTONIO BELLOBUONO FULVIO MOZZI GIANNA PETRINI ALBERTO ZANELLA GIROLAMO SIRCHIA
hepatitis C virus RNA in serum
trials. Scottish National Blood Transfusion Service, Edinburgh EH1 1JR, UK
JOHN D. CASH
1. Colombo M, Gamelli V, Gazengel C, Mannucci P, Savidge G, Schimpf K. Transmission of non-A, non-B hepatitis by heat treated factor VIII concentrate. Lancet 1985; ii: 1-4. 2. Cash JD. Blood transfusion services and the European Community. Br Med J 1990; 300: 481-82
SiR,—Dr Kaneko and colleagues (April 21, p 976) use the polymerase chain reaction (PCR) to detect hepatitis C virus (HCV) RNA in the sera of patients with chronic non-A, non-B hepatitis. They found that nested PCRI with primers for sequences of the clones they have obtained gave a higher detection rate (6/6) than PCR with primers derived from the HCV sequence of the Chiron Corporation2 (0/6). They attribute this to sequence diversity, a known property of single-stranded RNA viruses.
