- Email: [email protected]
ACE inhibitors and anaphylactoid reactions to high-flux membrane dialysis
370
The legislation proposed would have very little application to the real world of managing the natural process of dying. Any possible additional rights would be restricted to those citizens who were prepared, at a time when they must by definition still be reasonably well (of sound mind and able to write), to make a decision about how they would like to be managed when in a state of terminal illness. The Act would have no application to citizens under the age of 18 years, an area where the toughest decisions have to be made by physicians. The citizens of South Australia have, with rare exceptions, disregarded their rights under the 1983 Act and trust their doctors. A most worrying aspect of the proposed legislation is the final clause which reads "There will be no authorisation for an act that causes or accelerates death as distinct from an act that permits the dying process to take its natural course". This would unwittingly prevent any further use of narcotics, tranquillisers, and so on in dying patients; it would make it almost impossible to withhold unending transfusions from patients with incurable and uncontrolled haemorrhage. If the Crown Solicitor’s advice were to be upheld by the courts, almost every doctor (and public-spirited lay member of a hospital board) in New South Wales would be in gaol. Patients do not need legislated rights to dictate the terms of management for their care when dying-they simply need well-educated and compassionate doctors in whom they can trust. Until now doctors in New South Wales thought they had the right to care sensibly and compassionately for their dying patients. It now looks as though they may need statutory protection to continue to give this care without risk of criminal liability. This protection will patently not be available through the proposed Natural Death Act. Alan McGuinness
Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
CHARLES A. DINARELLO
Bingel M, Lonnemann G, Shaldon S, Koch KM, Dinarello CA. Human interleukin-l production during hemodialysis. Nephron 1986; 43: 161-63. 2. Lonnemann G, Bingel M, Floege J, Koch KM, Shaldon S, Dinarello CA. Detection of endotoxin-like interluekin-1-inducing activity during in vitro dialysis Kidney 1.
Int 1988; 33: 29-35. JE, Parker MM, Natanson C, et al Septic shock in humans advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 277-39
3 Parrillo
Gastroenterology Unit,
Sydney Hospital, Sydney, NSW 2000, Australia
challenged by endotoxin added to the dialysate compartment, PBMC circulating in the blood compartment provided interleukin1.1 When the dialysate compartment was challenged with a filtrate of Escherichia coli and 10% plasma was circulated on the blood side, subsequent incubation of plasma samples stimulated interleukin-1 synthesis in PBMC. Neither experiment was designed to test the hypothesis that passage of endotoxin-like molecules from dialysate through a membrane could explain acute anaphylactoid reactions of a "first use" type described by Verresen et al. Dr Jadoul and colleagues (Jan 12, p 112) and Dr van Es and colleagues (Jan 12, p 112) also report data suggesting that anaphylactoid reactions associated with AN69 membranes are not due to the dialysate. Furthermore, I know of no report showing that introduction of gram-negative bacteria, or their products, into blood results in acute anaphylactoid shock. Verresen et al are confusing acute anaphylactoid shock with gram-negative bacteraemic shock. Although both are associated with a fall in blood pressure, this fall is delayed in gram-negative shock3and is commonly associated with fever. The hypotension that accompanies anaphylaxis is virtually immediate and rarely associated with fever. was
JOHN R. GRAHAM
SIR,-From January to December, 1990, 34 patients have been treated with
Deceptive dysphagia SiR,—Dysphagia for solids is a potentially serious symptom. Although patients with dysphagia often point to the supposed site of their obstruction, which may lie anywhere between the throat and epigastrium, I describe the risk associated with accepting their suggestion unchallenged. A 48-year-old female was referred to an ear, nose, and throat surgeon in January, 1990, with a history of food sticking in the back of her throat. Her only medical history was recent mild depression after her mother’s death. She was overweight and careful examination showed her pharynx, larynx, and hypopharynx to be normal. Despite reassurance, her dysphagia continued, and she began to lose weight and complained of regurgitation. Her general condition deteriorated and she was admitted to hospital in May, 1990. A barium swallow examination revealed extensive carcinoma of the distal oesophagus, and subsequent histological examination showed a moderately differentiated squamous cell carcinoma. The tumour was inoperable. A tube prosthesis was inserted and radiotherapy given. Accordingly, patients with dysphagia, who indicate the throat as the site of obstruction and in whom no abnormality is detected in the mouth or pharynx, require further 1
investigation.’ Cumberland Infirmary, Carlisle CA2 7HY, UK
R. H. SALTER
DAW, Lobello R. Site of referral of the sense of obstruction to swallowing Gut 1982, 23: A435-36.
1 Edwards
anaphylactoid reactions high-flux membrane dialysis
ACE inhibitors and to
StR,—Dr Verresen and colleagues (Dec 1, p 1360) write that "several studies have shown transfer of bacterial products across dialysis membranes (AN69) and their role in the induction of anaphylactoid reactions", and cite two references in which I am the senior author.1.2 Their statement is misleading. Our experimental work was designed to show passage of endotoxin through dialysis membranes with human peripheral blood mononuclear cells (PBMC) as target cells. We found that when the dialysis membrane
a
parallel-plate
and hollow-fibre
polyacrylonitrile
(AN69) dialyser in our haemodialysis unit. 4 patients showed repeated anaphylactoid reactions (severe hypotension with flushing and swelling of face and/or tongue associated with dyspnoea) within 5 minutes of onset of haemodialysis. All patients were dialysed with acetate and the dialyers were sterilised with ethylene oxide. Dialysers were not reused and antihistamine drugs were unable to prevent these reactions. After each anaphylactoid reaction the dialyser was changed for another sterilised with gamma radiation. Back-filtration was prevented by delaying the connection of dialysate after blood had begun circulating into the extracorporeal circuit. However, patients continued to show the same reactions. All 4 patients were receiving captopril; only 1 of 30 unaffected patients had received this drug. Patients treated with captopril and dialysed with other membranes (cuprophane or polysulphone) did not show reactions. Anaphylactoid reactions ceased after drug withdrawal in 1 case and after changing the dialysis membrane for cuprophane or polysulphone in the other 3 patients. Our fmding that captopril may induce anaphylactoid reactions during haemodialysis with AN69 membranes supports that of Dr Verresen and colleagues (Dec 1, p 1360) and others.’ The different absorptive properties of high-flux membranes for bacterial proteins, together with the possible influences of kinins, deserves further study. M. A. ALVAREZ-LARA A. MARTIN-MALO M. ESPINOSA Nephrology Service, D. CASTILLO Reina Sofia, Hospital these
14004 Cordoba, Spain
P. ALJAMA
1 Tielemans
C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem J-L Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors Kidney Int 1990, 38: 982-84.
SIR,-Before the article by Dr Verresen and colleagues, we had already drawn attention to anaphylactoid reactions m patients treated with angiotensin-converting-enzyme (ACE) inhibitors during haemodialysis (HD) with high-flux membranes.’ Our cases were seen only in patients dialysed with the polyacrylonitrile membrane (AN69, Hospal, France), and we suggested that ACE
371
inhibition potentiates the inflammatory response triggered by the interaction between blood and the AN69 polymer. Verresen et al suggest that this reaction is mediated by some dialysate-borne endotoxin-like material that crosses high-flux membranes by back-diffusion. They cite the observation that anaphylactoid reactions did not take place during haemofiltration on the same membrane in 3 ACE-inhibitor-treated patients as supportive evidence. We believe that the AN69 membrane per se is involved in the pathogenesis of these anaphylactoid reactions. Therefore, we completed a retrospective multicentre study of the epidemiology of anaphylactoid reactions associated with ACE-inhibitor treatment in patients on maintenance HD. Nine HD units (seven in Belgium, one in France, and one in Switzerland) contributed 521 patients, of whom 70 were treated with an ACE inhibitor (captopril, enalapril, lisinopril, or ramipril). 11of these 70 had eighteen anaphylactoid reactions during the first minutes of the HD session. These reactions were characterised by facial swelling and hypotension. All Ipatients were dialysed with AN69 membranes (n 98, of whom 16 received ACE inhibitors). By contrast, among 45 patients dialysed with cellulosic membranes (n 354) and 9 dialysed with non-AN69 high-flux membranes (n = 69), and who were receiving ACE inhibitors, no anaphylactoid reactions were seen. These epidemiological data strongly suggest that anaphylactoid reactions during HD in patients on ACE inhibitors are specifically related to the use of AN69 membranes. The explanation for these observations remains a matter of debate. ACE inhibition leads to an amplification of the inflammatory response by decreasing bradykinin breakdownActivation of the kallikrein-bradykinin system could result in anaphylaxis. Only further investigations will identify the cause, but clinicians must be aware of the danger of adverse reaction from combined ACE-inhibitor treatment and use of AN69 membranes during HD.
subjects gave their informed consent and inhaled rIFN-alpha 2a (Roche; specific activity 200 x 106 IU/mg protein) via a metered jet nebuliser.’ Single doses of 18 x 106 (5 patients), 54 x 106 (7), 126 x 106 (5), and 216 x 106 IU (2) of IFN were given as single doses on separate days with an interval of one to two days. Serum IFN concentration was measured by vesicular stomatitis virus plaque reduction both before and at 2, 5, 10, 14, and 24 hours after each inhalation. Heart rate, blood pressure, axial temperature, peak expiratory flow rate (PEF), and subjective symptoms were recorded every 2 h. IFN was detected (6 to 11 IU/ml) in only 3 of 114 serum samples-in 1 patient, 10 and 14 h after inhalation of 126 x 106 IU of IFN and in another patient 5 h after inhalation of 216 x 106 IU. Fever, influenza-like symptoms (4 patients), nausea (3), flush (1), and headache (1) were observed. Fever was dose-dependent: 2 of 5 patients became febrile at the lowest dose and 6 of 7 patients at the two highest doses. PEF fell by over 15% and by over 50 ml/min in half of the patients at all doses. All symptoms were reversible after stopping IFN. The pharamcokinetics of inhaled IFN-alpha and rIFN-alpha seem to differ. In our previous study half of those patients who inhaled 60 x 106 IU ofnIFN, and all patients who inhaled 120 x 106 IU, had measurable serum IFN for at least 12 h; whereas in this study only 1 patient had measurable serum IFN in two samples after inhalation of 126 x 106 ; 216 X 106 IU rIFN produced measurable serum IFN in only one sample. Side-effects were milder but similar in character to those seen after inhalation of nIFN-alpha. Further work must assess whether these pharmacokinetic disparities are reflected in differences in clinical efficacy.
=
=
Department of Nephrology, Hôpital Erasme, 1070 Bruxelles, Belgium
C. TIELEMANS
J.
L. VANHERWEGHEM
Polyclinique
KARI CANTELL
V, Mattson K, Cantell K Pharmacokinetics and toxicity of inhaled human interferon-&agr; in patients with lung cancer. J Interferon Res 1989; 9: 419-23. 2. Bocci V, Pessina GP, Pacini A, Paulesu L, Muscettola M, Mogensen KE. Pulmonary catabolism of interferons. alveolar absorption of 125I-labelled human interferon alpha is accompanied by partial loss of biological activity Antiviral Res 1984; 4:
A. BLUMBERG
Clinique du Refuge, Belgium
National Public Health Insitute, Helsinki 1 Kinnula
Kantonsspital Aarau, Switzerland
00290 Helsinki, Finland
PAULA MAASILTA MAIJA HALME KARIN MATTSON
Department of Pulmonary Medicine, Helsinki University Central Hospital,
R. CUVELIER
211-22
Saint Come,
J. F.
France
DE FREMONT
Flecainide-associated interstitial
Hôpital Civil de Charleroi, Belgium
F. DEHOUT
Centre Hospitalier Universitaire de Tivoli
P. DUPONT
pneumonitis SIR,-Professor Akoun and his colleagues (Jan 5, p 49) report a of interstitial pneumonitis probably induced by flecainide. We
case
C. RICHARD
Institute Edith Cavell
J.
Hôpital Universitaire Brugmann
R. WENS
C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem JL Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int 1990; 38: 982-84. 2. Proud D Kinin formation mechanisms and role of inflammatory disorders. Ann Rev Immunol 1988, 6: 49-83
Pharmacokinetics of inhaled recombinant and natural alpha interferon SIR,-Clinical trials have shown biological activity of interferons (IFN) against several malignant and viral diseases. Inhalation is a theoretically advantageous method of delivery to the airways. We have previously reported that natural human leucocyte IFN-alpha given by inhalation at high doses (above 60 x 106
IU).1 However, experimental data suggest that the pharmacokinetics of natural (n) and recombinant (r) IFN-alpha may differ in the airways.2 We have studied the pharmacokinetics of inhaled rIFN-alpha in 7 patients with cancer (6 non-small-cell lung cancers, 1 breast cancer), who had not received any anticancer treatment during the previous 4 weeks. Patients had a mean age of 68 years and 5 were females. All patients had adequate ventilatory function for effective
inhalation (forced vital
Kamofsky
index above
capacity [FVC] 50% 60%, and
no
other
of
predicted),
seen
unusual
who had been
1 Tielemans
enters blood when
pulmonary complications in a 49-year-old man receiving flecainide (150 mg twice daily) since October, 1988, for ventricular arrhythmias. The patient had moderate dyspnoea. He was admitted on Oct 9, 1989 (day 1), for severe dyspnoea, non-productive cough, and pyrexia. Chest radiography showed diffuse bilateral interstitial changes. The erythrocyte sedimentation rate was 127 mm after the first hour and the white cell blood count was normal. Bacteriological and serological investigations and fibreoptic bronchoscopy were unremarkable. Empirical antibiotherapy with cefuroxime and amikacin was started and flecainide was stopped. Because of a positive tuberculin response and a lack of clinical and radiological improvement, and despite negative Ziehl stain of sputum, antituberculous therapy was started on day 7. The patient was admitted to University Hospital on day 9 to receive mechanical ventilation for progressive respiratory failure. Bilateral fine crackles were noted and the patient remained febrile. Viral, bacterial, and fungal cultures from bronchoalveolar lavage and various biological and serological analyses were not informative. Acute respiratory distress syndrome (ARDS) with multiple barotrauma complications developed during mechanical ventilation despite intermittent use of high-jet ventilation. Antibiotics were stopped on day 25 and empirical corticotherapy (methylprednisolone 1 mg/kg daily) was started on day 27. A possible toxic origin of ARDS was considered. A serum sample obtained on day 9 (9 days after withdrawal of the drug) and a bronchoalveolar lavage sample on day 27 did not have detectable concentrations (less than 0-07 ug/ml) of flecainide. A pronounced
have
C. STOLEAR
Institute Médico-chirurgical de Tournai
a
major disease. All
The legislation proposed would have very little application to the real world of managing the natural process of dying. Any possible additional rights would be restricted to those citizens who were prepared, at a time when they must by definition still be reasonably well (of sound mind and able to write), to make a decision about how they would like to be managed when in a state of terminal illness. The Act would have no application to citizens under the age of 18 years, an area where the toughest decisions have to be made by physicians. The citizens of South Australia have, with rare exceptions, disregarded their rights under the 1983 Act and trust their doctors. A most worrying aspect of the proposed legislation is the final clause which reads "There will be no authorisation for an act that causes or accelerates death as distinct from an act that permits the dying process to take its natural course". This would unwittingly prevent any further use of narcotics, tranquillisers, and so on in dying patients; it would make it almost impossible to withhold unending transfusions from patients with incurable and uncontrolled haemorrhage. If the Crown Solicitor’s advice were to be upheld by the courts, almost every doctor (and public-spirited lay member of a hospital board) in New South Wales would be in gaol. Patients do not need legislated rights to dictate the terms of management for their care when dying-they simply need well-educated and compassionate doctors in whom they can trust. Until now doctors in New South Wales thought they had the right to care sensibly and compassionately for their dying patients. It now looks as though they may need statutory protection to continue to give this care without risk of criminal liability. This protection will patently not be available through the proposed Natural Death Act. Alan McGuinness
Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
CHARLES A. DINARELLO
Bingel M, Lonnemann G, Shaldon S, Koch KM, Dinarello CA. Human interleukin-l production during hemodialysis. Nephron 1986; 43: 161-63. 2. Lonnemann G, Bingel M, Floege J, Koch KM, Shaldon S, Dinarello CA. Detection of endotoxin-like interluekin-1-inducing activity during in vitro dialysis Kidney 1.
Int 1988; 33: 29-35. JE, Parker MM, Natanson C, et al Septic shock in humans advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 277-39
3 Parrillo
Gastroenterology Unit,
Sydney Hospital, Sydney, NSW 2000, Australia
challenged by endotoxin added to the dialysate compartment, PBMC circulating in the blood compartment provided interleukin1.1 When the dialysate compartment was challenged with a filtrate of Escherichia coli and 10% plasma was circulated on the blood side, subsequent incubation of plasma samples stimulated interleukin-1 synthesis in PBMC. Neither experiment was designed to test the hypothesis that passage of endotoxin-like molecules from dialysate through a membrane could explain acute anaphylactoid reactions of a "first use" type described by Verresen et al. Dr Jadoul and colleagues (Jan 12, p 112) and Dr van Es and colleagues (Jan 12, p 112) also report data suggesting that anaphylactoid reactions associated with AN69 membranes are not due to the dialysate. Furthermore, I know of no report showing that introduction of gram-negative bacteria, or their products, into blood results in acute anaphylactoid shock. Verresen et al are confusing acute anaphylactoid shock with gram-negative bacteraemic shock. Although both are associated with a fall in blood pressure, this fall is delayed in gram-negative shock3and is commonly associated with fever. The hypotension that accompanies anaphylaxis is virtually immediate and rarely associated with fever. was
JOHN R. GRAHAM
SIR,-From January to December, 1990, 34 patients have been treated with
Deceptive dysphagia SiR,—Dysphagia for solids is a potentially serious symptom. Although patients with dysphagia often point to the supposed site of their obstruction, which may lie anywhere between the throat and epigastrium, I describe the risk associated with accepting their suggestion unchallenged. A 48-year-old female was referred to an ear, nose, and throat surgeon in January, 1990, with a history of food sticking in the back of her throat. Her only medical history was recent mild depression after her mother’s death. She was overweight and careful examination showed her pharynx, larynx, and hypopharynx to be normal. Despite reassurance, her dysphagia continued, and she began to lose weight and complained of regurgitation. Her general condition deteriorated and she was admitted to hospital in May, 1990. A barium swallow examination revealed extensive carcinoma of the distal oesophagus, and subsequent histological examination showed a moderately differentiated squamous cell carcinoma. The tumour was inoperable. A tube prosthesis was inserted and radiotherapy given. Accordingly, patients with dysphagia, who indicate the throat as the site of obstruction and in whom no abnormality is detected in the mouth or pharynx, require further 1
investigation.’ Cumberland Infirmary, Carlisle CA2 7HY, UK
R. H. SALTER
DAW, Lobello R. Site of referral of the sense of obstruction to swallowing Gut 1982, 23: A435-36.
1 Edwards
anaphylactoid reactions high-flux membrane dialysis
ACE inhibitors and to
StR,—Dr Verresen and colleagues (Dec 1, p 1360) write that "several studies have shown transfer of bacterial products across dialysis membranes (AN69) and their role in the induction of anaphylactoid reactions", and cite two references in which I am the senior author.1.2 Their statement is misleading. Our experimental work was designed to show passage of endotoxin through dialysis membranes with human peripheral blood mononuclear cells (PBMC) as target cells. We found that when the dialysis membrane
a
parallel-plate
and hollow-fibre
polyacrylonitrile
(AN69) dialyser in our haemodialysis unit. 4 patients showed repeated anaphylactoid reactions (severe hypotension with flushing and swelling of face and/or tongue associated with dyspnoea) within 5 minutes of onset of haemodialysis. All patients were dialysed with acetate and the dialyers were sterilised with ethylene oxide. Dialysers were not reused and antihistamine drugs were unable to prevent these reactions. After each anaphylactoid reaction the dialyser was changed for another sterilised with gamma radiation. Back-filtration was prevented by delaying the connection of dialysate after blood had begun circulating into the extracorporeal circuit. However, patients continued to show the same reactions. All 4 patients were receiving captopril; only 1 of 30 unaffected patients had received this drug. Patients treated with captopril and dialysed with other membranes (cuprophane or polysulphone) did not show reactions. Anaphylactoid reactions ceased after drug withdrawal in 1 case and after changing the dialysis membrane for cuprophane or polysulphone in the other 3 patients. Our fmding that captopril may induce anaphylactoid reactions during haemodialysis with AN69 membranes supports that of Dr Verresen and colleagues (Dec 1, p 1360) and others.’ The different absorptive properties of high-flux membranes for bacterial proteins, together with the possible influences of kinins, deserves further study. M. A. ALVAREZ-LARA A. MARTIN-MALO M. ESPINOSA Nephrology Service, D. CASTILLO Reina Sofia, Hospital these
14004 Cordoba, Spain
P. ALJAMA
1 Tielemans
C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem J-L Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors Kidney Int 1990, 38: 982-84.
SIR,-Before the article by Dr Verresen and colleagues, we had already drawn attention to anaphylactoid reactions m patients treated with angiotensin-converting-enzyme (ACE) inhibitors during haemodialysis (HD) with high-flux membranes.’ Our cases were seen only in patients dialysed with the polyacrylonitrile membrane (AN69, Hospal, France), and we suggested that ACE
371
inhibition potentiates the inflammatory response triggered by the interaction between blood and the AN69 polymer. Verresen et al suggest that this reaction is mediated by some dialysate-borne endotoxin-like material that crosses high-flux membranes by back-diffusion. They cite the observation that anaphylactoid reactions did not take place during haemofiltration on the same membrane in 3 ACE-inhibitor-treated patients as supportive evidence. We believe that the AN69 membrane per se is involved in the pathogenesis of these anaphylactoid reactions. Therefore, we completed a retrospective multicentre study of the epidemiology of anaphylactoid reactions associated with ACE-inhibitor treatment in patients on maintenance HD. Nine HD units (seven in Belgium, one in France, and one in Switzerland) contributed 521 patients, of whom 70 were treated with an ACE inhibitor (captopril, enalapril, lisinopril, or ramipril). 11of these 70 had eighteen anaphylactoid reactions during the first minutes of the HD session. These reactions were characterised by facial swelling and hypotension. All Ipatients were dialysed with AN69 membranes (n 98, of whom 16 received ACE inhibitors). By contrast, among 45 patients dialysed with cellulosic membranes (n 354) and 9 dialysed with non-AN69 high-flux membranes (n = 69), and who were receiving ACE inhibitors, no anaphylactoid reactions were seen. These epidemiological data strongly suggest that anaphylactoid reactions during HD in patients on ACE inhibitors are specifically related to the use of AN69 membranes. The explanation for these observations remains a matter of debate. ACE inhibition leads to an amplification of the inflammatory response by decreasing bradykinin breakdownActivation of the kallikrein-bradykinin system could result in anaphylaxis. Only further investigations will identify the cause, but clinicians must be aware of the danger of adverse reaction from combined ACE-inhibitor treatment and use of AN69 membranes during HD.
subjects gave their informed consent and inhaled rIFN-alpha 2a (Roche; specific activity 200 x 106 IU/mg protein) via a metered jet nebuliser.’ Single doses of 18 x 106 (5 patients), 54 x 106 (7), 126 x 106 (5), and 216 x 106 IU (2) of IFN were given as single doses on separate days with an interval of one to two days. Serum IFN concentration was measured by vesicular stomatitis virus plaque reduction both before and at 2, 5, 10, 14, and 24 hours after each inhalation. Heart rate, blood pressure, axial temperature, peak expiratory flow rate (PEF), and subjective symptoms were recorded every 2 h. IFN was detected (6 to 11 IU/ml) in only 3 of 114 serum samples-in 1 patient, 10 and 14 h after inhalation of 126 x 106 IU of IFN and in another patient 5 h after inhalation of 216 x 106 IU. Fever, influenza-like symptoms (4 patients), nausea (3), flush (1), and headache (1) were observed. Fever was dose-dependent: 2 of 5 patients became febrile at the lowest dose and 6 of 7 patients at the two highest doses. PEF fell by over 15% and by over 50 ml/min in half of the patients at all doses. All symptoms were reversible after stopping IFN. The pharamcokinetics of inhaled IFN-alpha and rIFN-alpha seem to differ. In our previous study half of those patients who inhaled 60 x 106 IU ofnIFN, and all patients who inhaled 120 x 106 IU, had measurable serum IFN for at least 12 h; whereas in this study only 1 patient had measurable serum IFN in two samples after inhalation of 126 x 106 ; 216 X 106 IU rIFN produced measurable serum IFN in only one sample. Side-effects were milder but similar in character to those seen after inhalation of nIFN-alpha. Further work must assess whether these pharmacokinetic disparities are reflected in differences in clinical efficacy.
=
=
Department of Nephrology, Hôpital Erasme, 1070 Bruxelles, Belgium
C. TIELEMANS
J.
L. VANHERWEGHEM
Polyclinique
KARI CANTELL
V, Mattson K, Cantell K Pharmacokinetics and toxicity of inhaled human interferon-&agr; in patients with lung cancer. J Interferon Res 1989; 9: 419-23. 2. Bocci V, Pessina GP, Pacini A, Paulesu L, Muscettola M, Mogensen KE. Pulmonary catabolism of interferons. alveolar absorption of 125I-labelled human interferon alpha is accompanied by partial loss of biological activity Antiviral Res 1984; 4:
A. BLUMBERG
Clinique du Refuge, Belgium
National Public Health Insitute, Helsinki 1 Kinnula
Kantonsspital Aarau, Switzerland
00290 Helsinki, Finland
PAULA MAASILTA MAIJA HALME KARIN MATTSON
Department of Pulmonary Medicine, Helsinki University Central Hospital,
R. CUVELIER
211-22
Saint Come,
J. F.
France
DE FREMONT
Flecainide-associated interstitial
Hôpital Civil de Charleroi, Belgium
F. DEHOUT
Centre Hospitalier Universitaire de Tivoli
P. DUPONT
pneumonitis SIR,-Professor Akoun and his colleagues (Jan 5, p 49) report a of interstitial pneumonitis probably induced by flecainide. We
case
C. RICHARD
Institute Edith Cavell
J.
Hôpital Universitaire Brugmann
R. WENS
C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem JL Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int 1990; 38: 982-84. 2. Proud D Kinin formation mechanisms and role of inflammatory disorders. Ann Rev Immunol 1988, 6: 49-83
Pharmacokinetics of inhaled recombinant and natural alpha interferon SIR,-Clinical trials have shown biological activity of interferons (IFN) against several malignant and viral diseases. Inhalation is a theoretically advantageous method of delivery to the airways. We have previously reported that natural human leucocyte IFN-alpha given by inhalation at high doses (above 60 x 106
IU).1 However, experimental data suggest that the pharmacokinetics of natural (n) and recombinant (r) IFN-alpha may differ in the airways.2 We have studied the pharmacokinetics of inhaled rIFN-alpha in 7 patients with cancer (6 non-small-cell lung cancers, 1 breast cancer), who had not received any anticancer treatment during the previous 4 weeks. Patients had a mean age of 68 years and 5 were females. All patients had adequate ventilatory function for effective
inhalation (forced vital
Kamofsky
index above
capacity [FVC] 50% 60%, and
no
other
of
predicted),
seen
unusual
who had been
1 Tielemans
enters blood when
pulmonary complications in a 49-year-old man receiving flecainide (150 mg twice daily) since October, 1988, for ventricular arrhythmias. The patient had moderate dyspnoea. He was admitted on Oct 9, 1989 (day 1), for severe dyspnoea, non-productive cough, and pyrexia. Chest radiography showed diffuse bilateral interstitial changes. The erythrocyte sedimentation rate was 127 mm after the first hour and the white cell blood count was normal. Bacteriological and serological investigations and fibreoptic bronchoscopy were unremarkable. Empirical antibiotherapy with cefuroxime and amikacin was started and flecainide was stopped. Because of a positive tuberculin response and a lack of clinical and radiological improvement, and despite negative Ziehl stain of sputum, antituberculous therapy was started on day 7. The patient was admitted to University Hospital on day 9 to receive mechanical ventilation for progressive respiratory failure. Bilateral fine crackles were noted and the patient remained febrile. Viral, bacterial, and fungal cultures from bronchoalveolar lavage and various biological and serological analyses were not informative. Acute respiratory distress syndrome (ARDS) with multiple barotrauma complications developed during mechanical ventilation despite intermittent use of high-jet ventilation. Antibiotics were stopped on day 25 and empirical corticotherapy (methylprednisolone 1 mg/kg daily) was started on day 27. A possible toxic origin of ARDS was considered. A serum sample obtained on day 9 (9 days after withdrawal of the drug) and a bronchoalveolar lavage sample on day 27 did not have detectable concentrations (less than 0-07 ug/ml) of flecainide. A pronounced
have
C. STOLEAR
Institute Médico-chirurgical de Tournai
a
major disease. All