- Email: [email protected]
ADVERSE REACTIONS TO PIPERACILLIN IN CYSTIC FIBROSIS
1070 COMPLEMENT-MEDIATED ANTIBODY-DEPENDENT LYSIS OF MYELOID CELL LINES
*From patient A on admission, 5 days after admission, and 1 month after recovery (WCC 7600/1), from patient B; from a patient (control X) on procainamide therapy, with normal WCC; from a normal donor with normal WCC (control Y); and from patient A on admission but IgG depleted. Each value represents the average ofthree determmations±SD (pooled). Final serum dilution 1:4
Inhibition of colony formation in the presence of patient’s serum 7 has been described in agranulocytosis related to amidopyrine,7 quinidine,and phenytoin,9 but not procainamide. Although attempts to demonstrate antigranulocyte activity in the sera of patients with agranulocytosis-related to procainamide have all been negative it could be that an antibody-mediated mechanism is directed against myeloid cells early in differentiation, hence our choice of cell lines at an early stage of differentiation. Both patients had cytotoxic antibodies against the myeloid cell lines (table), especially HL-60. The K-562 line was less susceptible but this cell line may in fact be an erythroleukaemia line. 10,11There was some cytotoxic activity against the Daudi (B cell) line (not
shown). No control serum, including the one from a patient on procainamide therapy but with a normal WCC, was cytotoxic against any cell line tested. The results suggest that antibody against granulocyte precursor cells causes procamamide-associated agranulocytosis. In patient A, when the WCC had recovered, antimyeloid activity in the serum was no longer detectable (table). The bone marrow findings suggest that the rate of recovery from agranulocytosis may depend on the ability of the stem cells to proliferate and differentiate until all the circulating antibody has been absorbed by the emerging myeloid cells. This would be possible if the antibody was active against antigens expressed at the promyelocyte or earlier state, but not on the stem cells themselves,
for all bone marrow elements derived from stem cells would then be destroyed, resulting in an aplastic bone marrow. The technique described here may help to detect anti-myeloid antibodies when
immune-mediated agranulocytosis is suspected. The antibody responsible seems to be an IgG that is susceptible to be removed by
abnormality complex produced by the extra chromosome 18 overlaps the abnormality complex of cystic fibrosis (CF), so that trisomy 18 cases could be regarded as exhibiting a partial form of CF. We report here features associated with CF in children with trisomy of other chromosomes. CF is usually diagnosed by measuring sweat sodium or chloride concentration or osmolality. We studied sweat osmolality in 20 children with trisomy 21 confirmed by chromosome analysis. Sweat testing was done by the Wescor technique for induction of sweat by pilocarpine iontophoresisl and osmolality was measured on a vapour pressure osmometer. Sweat osmolality was higher in the children with trisomy 21 (mean 164 mmo I/kg) than published values for normal children (mean 97 mmol/kg).1 4 children had sweat osmolality values within the ranged 200 mmol/kg)’ normally considered to be diagnostic off.’ In 2 cases the sweat osmolality was hypertonic, also plasma, as has previously been observed in children with CF.2Increased salivary sodium, a feature of CF, has also previously been shown in trisomy 21.3,4 Chromosomal abnormalities may also cause confusion in interpreting the results of early prenatal tests for CF. The phenylalanine-inhibitable isoenzyme of amniotic fluid alkaline phosphatase, which is deficient in CF, may also be abnormal in trisomy 18 and trisomy 21.5y-glutamyltranspeptidaseactivity in early amniotic fluid has also been described as decreased in chromosomal abnormalities, including 21, trisomy 18, We have recently trisomy 13, and XXY syndromeas well as seen a case in which a fetus from a pregnancy terminated because of suspected CF was found to have the pathological and cytogenetic features of trisomy 18. While attempting antenatal diagnosis of CF in a mother with a previously affected child, we suspected a chromosome abnormality in the fetus and found that the clinically normal mother carried a balanced translocation between chromosomes 6 and 13. The family then left our area and the results of further investigation in Oxford are reported by Professor Edwards and his colleagues (May 5, p 1020). In this case CF is associated with both trisomy for the chromosomal segment 6q25-6qter and monosomy for 13q34. There is evidence to link features of CF with trisomy of various different chromosomes, including 6, 13, 18, and 21. Chromosomal imbalance is associated with multisystem abnormalities which exhibit considerable interindividual variation and there is no definite evidence that any of these chromosomes is the site of the gene for CF. However, the association, as Edwards et al note, between confirmed CF and a very small chromosome imbalance8 suggests a stronger association of the CF gene with chromosome 13 or possibly even chromosome 6.
trisom CF.
Department
of Child Health,
protein A.
University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD
Venezuelan Institute of Scientific
Department of Genetics, University of Aberdeen
Investigations (IVIC), Apartado 1827, Caracas 101, Venezuela
Raeden Centre, Aberdeen
JOSÉ AZÓCAR S.
CYSTIC FIBROSIS AND CHROMOSOMAL ABNORMALITIES
SIR,-Dr Heeley and Dr Fagan (Jan 21, p 169) report increased levels of immunoreactive trypsin in trisomy 18 and suggest that a possible explanation for their findings may be that part of the Rozengurt N, Longhurst P, Humble JG. Amidopyrine agranulocytosis: Drug inhibition of granulocyte colonies in the presence of patient’s serum. Br Med J 1976; ii 850-51. 8. Kelton JG, Huang AT, Mod N, Logue GL, Rosse WF. The use of in vitro techniques to study drug induced pancytopenia. N Engl J Med 1979; 301: 621-24. 9. Taetle R, Lane TA, Mendelsohn J. Drug-induced agranulocytosis: In vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody. 7. Barrett AJ, Weller E,
Blood 1979; 54: 501-12. 10.
Anderson LC, Jokinen M, Gahmberg CG. Induction of erythroid differentiation in the
human leukaemic cell line K-562. Nature 1979; 278: 364-65. 11. Rutherford TR, Clegg JB, Weatherall DJ. K-562 human leukaemic cells synthesize embryonic haemoglobin in response to haemin. Nature 1979; 280: 164-65
DAVID N. K. SYMON GEORGE RUSSELL DAVID A. COUZIN LESLEY STEWART
ADVERSE REACTIONS TO PIPERACILLIN IN CYSTIC FIBROSIS
SIR,—We thank Dr Stead and his colleagues (April 14, p 857) for reporting the details of their nine cystic fibrosis patients who exhibited febrile reactions while being treated with piperacillin. HL, Barlow WK New approach to cystic fibrosis diagnosis by use of an improved sweat-induction/collection system and osmometry. Clin Chem 1981; 27:
1 Webster
385-87. 2 Shwachman
H, Mahmoodian A. Pilocarpine iontophoresis
sweat
testing. Results of
years experience. In: Rossi E, Stoll E, eds. Cystic fibrosis. Physiology and pathophysiology of serous secretion, clinical investigations and therapy. Part 1.
seven
Basel: Karger, 1967: 158-82. Chapman MJ, Donoghue EC, Saggers BA, Stern J Parotid saliva sodium in Down’s disease. J Ment Def Res 1967; 11: 185-93. 4. Winer RA, Cohen MM, Feller RP, Chauncey HH Composition of human saliva, parotid gland secretory rate, and electrolyte concentration in mentally subnormal persons. J Dent Res 1965; 44: 632-34 5. Brock DJ H. Amniotic fluid alkaline phosphatase isoenzymes in early prenatal diagnosis of cystic fibrosis. Lancet 1983; ii: 941-43. 6. Jalanko H, Aula P. Decrease in gamma-glutamyl transpeptidase activity in early amniotic fluid in fetal trisomy 18 syndrome. Br Med J 1982; 284: 1593-94. 7. Carbarns NJB, Gosden C, Brock DJH. Microvillar peptidase activity in amniotic fluid: possible use in the prenatal diagnosis of cystic fibrosis. Lancet 1983, i: 329-31. 3.
1071 There has been considerable discussion between ourselves and Stead et al during the collation of these data. Since the extended spectrum of activity of piperacillin over other penicillins is advantageous when treating mixed infections or organisms resistant to other antipseudomonal agents, we have evaluated other reportsl-3 of similar reactions in cystic fibrosis patients. Patients with cystic fibrosis have a greater incidence of atopy than the general population, their siblings, or their parents,4and are considered to be particularly prone to allergy. Skin testing produced reactions in 88% of cystic fibrosis patients compared with 36% of controls, and those with cystic fibrosis had higher levels of IgG4 and IgE and higher eosinophil counts.5The abnormal concentration of immunoglobulins is particularly pertinent because IgG antibodies are responsible for at least some of the late reactions to penicillins, and rashes are generally mediated by IgE.Patients with cystic fibrosis who demonstrate positive immediate skin tests are also more likely to be persistently colonised by pseudomonas than are those with negative tests; hence anti-pseudomonal penicillins are likely to be used in those cystic fibrosis patients at greatest risk of allergic reaction. A high incidence of allergic manifestations is seen in patients with cystic fibrosis treated with other semisynthetic penicillins. For example, intensive carbenicillin therapy produced reactions in 16/84 such patients8 and azlocillin resulted in symptoms of serum sickness in 5/18.1 The suggestion that long-term treatment with high doses of semisynthetic penicillins in patients with cystic fibrosis may provoke a febrile response needs to be resolved. PETER G. BROCK MARYANNE ROACH
Lederle Laboratories,
Gosport, Hampshire
PO13 0AS
RANITIDINE AND CONFUSION
SIR,-Acute mental confusion is a well-recognised side-effect of cimetidine therapy, being more frequent in cases of renal or hepatic failure. 9, 10 Ranitidine, however, has been claimed to be free of some of the side-effects of cimetidine, including confusion, and has been given safely to patients who had had confusion when taking cimetidine.ll,12However, two cases of confusion in patients taking ranitidine for chronic gastric ulceration have been reported.13,14 I describe here a case of ranitidine causing a confusional state in a patient with liver failure. A 56-year-old woman with alcoholic liver disease and oesophageal varices was given ranitidine 150 mg twice daily, having previously been on cimetidine prophylaxis for 3 months. Cimetidine was stopped 2 weeks before ranitidine was started. Her only concurrent Hoiby N. Antibiotic treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. Scand J Infect Dis 1981; (suppl 24): 87-91. 2. Agostini M, Barlocco G, Bonomi U, et al. Alternative antibiotics against pseudomonas infections in cystic fibrosis: In vitro activity, pharmacokinetics, and double blind randomised clinical trial with azlocillin, piperacillin, cefoperazone, ceftazidime, cefsulodin, cefotaxime and moxalactam. Preliminary results. Drug Expl Clin Res 1983; 9: 671-86. 3 Blumer JL, Reed MD. Role of piperacillin in the treatment of gram negative infections in children. In: Proceedings of 13th International Congress of Chemotherapy 1. Moller NE,
(Vienna, 1983).. DJ, Carson J, Maguire O, et al Atopy and cystic fibrosis: a study of CF sibling pairs and their families. Clin Allergy 1981; 11: 571-77. 5. Tobin MJ, Maguire O, Reen D, et al. Atopy and bronchial reactivity in older patients with cystic fibrosis. Thorax 1980; 35: 807-13. 6. Beeley L. Allergy to penicillin. Br Med J 1984; 288: 511-21. 7. Pitcher-Wilmott RW, Levinsky RJ, Gordon I, et al. Pseudomonas infection, allergy and cystic fibrosis. Arch Dis Child 1982; 57: 582-86. 8. Moller NE, Ahlstedt S, Skoo PS, et al. Allergological examination of cystic fibrosis patients with skin reactions during carbenicillin treatment. Allergy 1980; 35: 4. Reen
135-38.
9. Schentag JJ, Cerra FB, Calleri G,
De
Glopper E,
Rose
JQ,
Bernhard H.
Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet 1979; i: 177-81. 10. Kimelblatt BJ, Cerra FB, Calleri G, Berg MJ, McMillen MA, Schentag JJ. Dose and serum concentration relationship in cimetidine-associated mental confusion. Gastroenterology 1980; 78: 791-95. 11. Bones P, Michel H, Duclos B, Beraud JJ, Mirouze J. Use of ranitidine without mental confusion, in patient with renal failure. Lancet 1980; ii: 755. 12. Pedrazzoli S, Petrin P, Pasquali C, Militello C, Sperti C, Fregonese V, Simmi G. Ranitidine reverses cimetidine-induced mental confusion in a patient withZolingerEllison syndrome. Arch Surg 1983; 118: 875. 13. Hughes JD, Reed WD, Serjeant CS. Mental confusion associated with ranitidine. Med J Aust 1983; ii: 12-13. 14. Davies WA. Mental confusion associated with ranitidine. Med J Aust 1984; i: 478.
medication was magnesium trisilicate. 3 days after the start of ranitidine she became acutely confused and disoriented in time and space, agitated, excited, and increasingly aggressive with very labile mood changes. Stools for occult blood were repeatedly negative and her cardiovascular status remained constant. Ranitidine was stopped after 6 days because it was suspected to be causing the confusion. The patient’s mental state gradually improved over a 4 day period, to the point where she was no longer confused and her conversation became rational and lucid. In the initial clinical evaluation of ranitidine the frequency of confusion was 0-09% of 7380 patients treated. By comparison the early studies with cimetidine, involving 2182 patients, revealed no cases of acute confusion. As suggested by Flind and Rowley-Jones 15 increasing usage of ranitidine may reveal that confusion is as common with this newer H2-blocker as it is with cimetidine. Medical Unit, Gravesend and North Kent Hospital, Kent DA11 0DG
SIR,—Ranitidine
is
thought
P. H. SILVERSTONE to
lack the central nervous system I describe here a case during two separate courses of
side-effects ascribed to earlier Hrblockers.I,2 of mental confusion developing
ranitidine. A 87-year-old banker had continued working and driving until the autumn of 1983, when bleeding gastritis developed. He was put on ranitidine 150 mg twice daily and was admitted to hospital 2 weeks later with a complaint offlank pain, difficulty in walking, and recent onset of confusion. He remained confused for the following week in hospital, during which he also received diazepam, an average of two doses daily at 2. 5 mg. Formal neurological examination done 6 days after admission showed that he was disoriented. He did not remember that the Thanksgiving holiday had been the day before, could not give the name of the private nurse who had been with him since the day of admission, did not know the hospital floor where he had been for 6 days, and could not estimate the time. When the physician returned to the room after 10 minutes, the patient did not recall that he had been there shortly before. Diazepam and ranitidine were discontinued. By midnight that evening he was alert and oriented. Six weeks later the patient was readmitted under the care of a different physician. The same nurse looked after him and reported that his mental status was normal. But on Jan 5, 1984, ranitidine was restarted at 150 mg twice daily. Over the ensuing 3 days the patient received, in addition, three doses of maprotiline hydrochloride, 25-50 mg at night. The nurse noted that his mental status deteriorated within 24-48 h of the first ranitidine dose. He became irritable and cooperated poorly with medical evaluation. Mental status examination on Jan 9 showed that he was again disoriented to the time and to his location in the hospital. The patient’s home had been a few miles from the hospital for many years, but he was unable to describe a route by which he might get from one to the other. Computerised tomography of the head revealed mild atrophy, compatible with age, and an EEG was normal. Maprotiline hydrochloride was continued but ranitidine was stopped, and his confusion cleared within 2 days. Repeat neurological examination showed that he was once more cooperative, oriented, and able to describe in detail four different routes between home and hospital. Subsequent medical evaluation revealed the presence of myeloma and hepatoma, but his mental status remained normal. Early reports of "no mental confusion" with ranitidine were based upon trials in healthy young adults, and not upon extensive use in the elderly or in the sort of patient who had experienced most of the difficulties ascribed to earlier H2 antagonists.3,4 In a similar setting ranitidine seems capable of producing similar neurological
side-effects. Section
of Neurology,
Emory University Clinic, Atlanta, Georgia 30322, USA 15. Flind AC, Rowley-Jones
CHARLES M. EPSTEIN D. Cimetidine and ranitidine. Lancet
1982, i: 749
1. Editorial. Cimetidine and ranitidine. Lancet 1982; i: 601-02. 2. Strum WB. Ranitidine. JAMA 1983; 250: 1894-96
3. Freston JW. Cimetidine II Adverse reactions and patterns of use. Ann Intern Med 1982; 97: 728-34. 4. Sawyer D,Conner CS, Scalley R. Cimetidine: Adverse reactions and acute toxicity. Am
J Hosp Pharm 1981; 38: 188-97.
*From patient A on admission, 5 days after admission, and 1 month after recovery (WCC 7600/1), from patient B; from a patient (control X) on procainamide therapy, with normal WCC; from a normal donor with normal WCC (control Y); and from patient A on admission but IgG depleted. Each value represents the average ofthree determmations±SD (pooled). Final serum dilution 1:4
Inhibition of colony formation in the presence of patient’s serum 7 has been described in agranulocytosis related to amidopyrine,7 quinidine,and phenytoin,9 but not procainamide. Although attempts to demonstrate antigranulocyte activity in the sera of patients with agranulocytosis-related to procainamide have all been negative it could be that an antibody-mediated mechanism is directed against myeloid cells early in differentiation, hence our choice of cell lines at an early stage of differentiation. Both patients had cytotoxic antibodies against the myeloid cell lines (table), especially HL-60. The K-562 line was less susceptible but this cell line may in fact be an erythroleukaemia line. 10,11There was some cytotoxic activity against the Daudi (B cell) line (not
shown). No control serum, including the one from a patient on procainamide therapy but with a normal WCC, was cytotoxic against any cell line tested. The results suggest that antibody against granulocyte precursor cells causes procamamide-associated agranulocytosis. In patient A, when the WCC had recovered, antimyeloid activity in the serum was no longer detectable (table). The bone marrow findings suggest that the rate of recovery from agranulocytosis may depend on the ability of the stem cells to proliferate and differentiate until all the circulating antibody has been absorbed by the emerging myeloid cells. This would be possible if the antibody was active against antigens expressed at the promyelocyte or earlier state, but not on the stem cells themselves,
for all bone marrow elements derived from stem cells would then be destroyed, resulting in an aplastic bone marrow. The technique described here may help to detect anti-myeloid antibodies when
immune-mediated agranulocytosis is suspected. The antibody responsible seems to be an IgG that is susceptible to be removed by
abnormality complex produced by the extra chromosome 18 overlaps the abnormality complex of cystic fibrosis (CF), so that trisomy 18 cases could be regarded as exhibiting a partial form of CF. We report here features associated with CF in children with trisomy of other chromosomes. CF is usually diagnosed by measuring sweat sodium or chloride concentration or osmolality. We studied sweat osmolality in 20 children with trisomy 21 confirmed by chromosome analysis. Sweat testing was done by the Wescor technique for induction of sweat by pilocarpine iontophoresisl and osmolality was measured on a vapour pressure osmometer. Sweat osmolality was higher in the children with trisomy 21 (mean 164 mmo I/kg) than published values for normal children (mean 97 mmol/kg).1 4 children had sweat osmolality values within the ranged 200 mmol/kg)’ normally considered to be diagnostic off.’ In 2 cases the sweat osmolality was hypertonic, also plasma, as has previously been observed in children with CF.2Increased salivary sodium, a feature of CF, has also previously been shown in trisomy 21.3,4 Chromosomal abnormalities may also cause confusion in interpreting the results of early prenatal tests for CF. The phenylalanine-inhibitable isoenzyme of amniotic fluid alkaline phosphatase, which is deficient in CF, may also be abnormal in trisomy 18 and trisomy 21.5y-glutamyltranspeptidaseactivity in early amniotic fluid has also been described as decreased in chromosomal abnormalities, including 21, trisomy 18, We have recently trisomy 13, and XXY syndromeas well as seen a case in which a fetus from a pregnancy terminated because of suspected CF was found to have the pathological and cytogenetic features of trisomy 18. While attempting antenatal diagnosis of CF in a mother with a previously affected child, we suspected a chromosome abnormality in the fetus and found that the clinically normal mother carried a balanced translocation between chromosomes 6 and 13. The family then left our area and the results of further investigation in Oxford are reported by Professor Edwards and his colleagues (May 5, p 1020). In this case CF is associated with both trisomy for the chromosomal segment 6q25-6qter and monosomy for 13q34. There is evidence to link features of CF with trisomy of various different chromosomes, including 6, 13, 18, and 21. Chromosomal imbalance is associated with multisystem abnormalities which exhibit considerable interindividual variation and there is no definite evidence that any of these chromosomes is the site of the gene for CF. However, the association, as Edwards et al note, between confirmed CF and a very small chromosome imbalance8 suggests a stronger association of the CF gene with chromosome 13 or possibly even chromosome 6.
trisom CF.
Department
of Child Health,
protein A.
University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD
Venezuelan Institute of Scientific
Department of Genetics, University of Aberdeen
Investigations (IVIC), Apartado 1827, Caracas 101, Venezuela
Raeden Centre, Aberdeen
JOSÉ AZÓCAR S.
CYSTIC FIBROSIS AND CHROMOSOMAL ABNORMALITIES
SIR,-Dr Heeley and Dr Fagan (Jan 21, p 169) report increased levels of immunoreactive trypsin in trisomy 18 and suggest that a possible explanation for their findings may be that part of the Rozengurt N, Longhurst P, Humble JG. Amidopyrine agranulocytosis: Drug inhibition of granulocyte colonies in the presence of patient’s serum. Br Med J 1976; ii 850-51. 8. Kelton JG, Huang AT, Mod N, Logue GL, Rosse WF. The use of in vitro techniques to study drug induced pancytopenia. N Engl J Med 1979; 301: 621-24. 9. Taetle R, Lane TA, Mendelsohn J. Drug-induced agranulocytosis: In vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody. 7. Barrett AJ, Weller E,
Blood 1979; 54: 501-12. 10.
Anderson LC, Jokinen M, Gahmberg CG. Induction of erythroid differentiation in the
human leukaemic cell line K-562. Nature 1979; 278: 364-65. 11. Rutherford TR, Clegg JB, Weatherall DJ. K-562 human leukaemic cells synthesize embryonic haemoglobin in response to haemin. Nature 1979; 280: 164-65
DAVID N. K. SYMON GEORGE RUSSELL DAVID A. COUZIN LESLEY STEWART
ADVERSE REACTIONS TO PIPERACILLIN IN CYSTIC FIBROSIS
SIR,—We thank Dr Stead and his colleagues (April 14, p 857) for reporting the details of their nine cystic fibrosis patients who exhibited febrile reactions while being treated with piperacillin. HL, Barlow WK New approach to cystic fibrosis diagnosis by use of an improved sweat-induction/collection system and osmometry. Clin Chem 1981; 27:
1 Webster
385-87. 2 Shwachman
H, Mahmoodian A. Pilocarpine iontophoresis
sweat
testing. Results of
years experience. In: Rossi E, Stoll E, eds. Cystic fibrosis. Physiology and pathophysiology of serous secretion, clinical investigations and therapy. Part 1.
seven
Basel: Karger, 1967: 158-82. Chapman MJ, Donoghue EC, Saggers BA, Stern J Parotid saliva sodium in Down’s disease. J Ment Def Res 1967; 11: 185-93. 4. Winer RA, Cohen MM, Feller RP, Chauncey HH Composition of human saliva, parotid gland secretory rate, and electrolyte concentration in mentally subnormal persons. J Dent Res 1965; 44: 632-34 5. Brock DJ H. Amniotic fluid alkaline phosphatase isoenzymes in early prenatal diagnosis of cystic fibrosis. Lancet 1983; ii: 941-43. 6. Jalanko H, Aula P. Decrease in gamma-glutamyl transpeptidase activity in early amniotic fluid in fetal trisomy 18 syndrome. Br Med J 1982; 284: 1593-94. 7. Carbarns NJB, Gosden C, Brock DJH. Microvillar peptidase activity in amniotic fluid: possible use in the prenatal diagnosis of cystic fibrosis. Lancet 1983, i: 329-31. 3.
1071 There has been considerable discussion between ourselves and Stead et al during the collation of these data. Since the extended spectrum of activity of piperacillin over other penicillins is advantageous when treating mixed infections or organisms resistant to other antipseudomonal agents, we have evaluated other reportsl-3 of similar reactions in cystic fibrosis patients. Patients with cystic fibrosis have a greater incidence of atopy than the general population, their siblings, or their parents,4and are considered to be particularly prone to allergy. Skin testing produced reactions in 88% of cystic fibrosis patients compared with 36% of controls, and those with cystic fibrosis had higher levels of IgG4 and IgE and higher eosinophil counts.5The abnormal concentration of immunoglobulins is particularly pertinent because IgG antibodies are responsible for at least some of the late reactions to penicillins, and rashes are generally mediated by IgE.Patients with cystic fibrosis who demonstrate positive immediate skin tests are also more likely to be persistently colonised by pseudomonas than are those with negative tests; hence anti-pseudomonal penicillins are likely to be used in those cystic fibrosis patients at greatest risk of allergic reaction. A high incidence of allergic manifestations is seen in patients with cystic fibrosis treated with other semisynthetic penicillins. For example, intensive carbenicillin therapy produced reactions in 16/84 such patients8 and azlocillin resulted in symptoms of serum sickness in 5/18.1 The suggestion that long-term treatment with high doses of semisynthetic penicillins in patients with cystic fibrosis may provoke a febrile response needs to be resolved. PETER G. BROCK MARYANNE ROACH
Lederle Laboratories,
Gosport, Hampshire
PO13 0AS
RANITIDINE AND CONFUSION
SIR,-Acute mental confusion is a well-recognised side-effect of cimetidine therapy, being more frequent in cases of renal or hepatic failure. 9, 10 Ranitidine, however, has been claimed to be free of some of the side-effects of cimetidine, including confusion, and has been given safely to patients who had had confusion when taking cimetidine.ll,12However, two cases of confusion in patients taking ranitidine for chronic gastric ulceration have been reported.13,14 I describe here a case of ranitidine causing a confusional state in a patient with liver failure. A 56-year-old woman with alcoholic liver disease and oesophageal varices was given ranitidine 150 mg twice daily, having previously been on cimetidine prophylaxis for 3 months. Cimetidine was stopped 2 weeks before ranitidine was started. Her only concurrent Hoiby N. Antibiotic treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. Scand J Infect Dis 1981; (suppl 24): 87-91. 2. Agostini M, Barlocco G, Bonomi U, et al. Alternative antibiotics against pseudomonas infections in cystic fibrosis: In vitro activity, pharmacokinetics, and double blind randomised clinical trial with azlocillin, piperacillin, cefoperazone, ceftazidime, cefsulodin, cefotaxime and moxalactam. Preliminary results. Drug Expl Clin Res 1983; 9: 671-86. 3 Blumer JL, Reed MD. Role of piperacillin in the treatment of gram negative infections in children. In: Proceedings of 13th International Congress of Chemotherapy 1. Moller NE,
(Vienna, 1983).. DJ, Carson J, Maguire O, et al Atopy and cystic fibrosis: a study of CF sibling pairs and their families. Clin Allergy 1981; 11: 571-77. 5. Tobin MJ, Maguire O, Reen D, et al. Atopy and bronchial reactivity in older patients with cystic fibrosis. Thorax 1980; 35: 807-13. 6. Beeley L. Allergy to penicillin. Br Med J 1984; 288: 511-21. 7. Pitcher-Wilmott RW, Levinsky RJ, Gordon I, et al. Pseudomonas infection, allergy and cystic fibrosis. Arch Dis Child 1982; 57: 582-86. 8. Moller NE, Ahlstedt S, Skoo PS, et al. Allergological examination of cystic fibrosis patients with skin reactions during carbenicillin treatment. Allergy 1980; 35: 4. Reen
135-38.
9. Schentag JJ, Cerra FB, Calleri G,
De
Glopper E,
Rose
JQ,
Bernhard H.
Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet 1979; i: 177-81. 10. Kimelblatt BJ, Cerra FB, Calleri G, Berg MJ, McMillen MA, Schentag JJ. Dose and serum concentration relationship in cimetidine-associated mental confusion. Gastroenterology 1980; 78: 791-95. 11. Bones P, Michel H, Duclos B, Beraud JJ, Mirouze J. Use of ranitidine without mental confusion, in patient with renal failure. Lancet 1980; ii: 755. 12. Pedrazzoli S, Petrin P, Pasquali C, Militello C, Sperti C, Fregonese V, Simmi G. Ranitidine reverses cimetidine-induced mental confusion in a patient withZolingerEllison syndrome. Arch Surg 1983; 118: 875. 13. Hughes JD, Reed WD, Serjeant CS. Mental confusion associated with ranitidine. Med J Aust 1983; ii: 12-13. 14. Davies WA. Mental confusion associated with ranitidine. Med J Aust 1984; i: 478.
medication was magnesium trisilicate. 3 days after the start of ranitidine she became acutely confused and disoriented in time and space, agitated, excited, and increasingly aggressive with very labile mood changes. Stools for occult blood were repeatedly negative and her cardiovascular status remained constant. Ranitidine was stopped after 6 days because it was suspected to be causing the confusion. The patient’s mental state gradually improved over a 4 day period, to the point where she was no longer confused and her conversation became rational and lucid. In the initial clinical evaluation of ranitidine the frequency of confusion was 0-09% of 7380 patients treated. By comparison the early studies with cimetidine, involving 2182 patients, revealed no cases of acute confusion. As suggested by Flind and Rowley-Jones 15 increasing usage of ranitidine may reveal that confusion is as common with this newer H2-blocker as it is with cimetidine. Medical Unit, Gravesend and North Kent Hospital, Kent DA11 0DG
SIR,—Ranitidine
is
thought
P. H. SILVERSTONE to
lack the central nervous system I describe here a case during two separate courses of
side-effects ascribed to earlier Hrblockers.I,2 of mental confusion developing
ranitidine. A 87-year-old banker had continued working and driving until the autumn of 1983, when bleeding gastritis developed. He was put on ranitidine 150 mg twice daily and was admitted to hospital 2 weeks later with a complaint offlank pain, difficulty in walking, and recent onset of confusion. He remained confused for the following week in hospital, during which he also received diazepam, an average of two doses daily at 2. 5 mg. Formal neurological examination done 6 days after admission showed that he was disoriented. He did not remember that the Thanksgiving holiday had been the day before, could not give the name of the private nurse who had been with him since the day of admission, did not know the hospital floor where he had been for 6 days, and could not estimate the time. When the physician returned to the room after 10 minutes, the patient did not recall that he had been there shortly before. Diazepam and ranitidine were discontinued. By midnight that evening he was alert and oriented. Six weeks later the patient was readmitted under the care of a different physician. The same nurse looked after him and reported that his mental status was normal. But on Jan 5, 1984, ranitidine was restarted at 150 mg twice daily. Over the ensuing 3 days the patient received, in addition, three doses of maprotiline hydrochloride, 25-50 mg at night. The nurse noted that his mental status deteriorated within 24-48 h of the first ranitidine dose. He became irritable and cooperated poorly with medical evaluation. Mental status examination on Jan 9 showed that he was again disoriented to the time and to his location in the hospital. The patient’s home had been a few miles from the hospital for many years, but he was unable to describe a route by which he might get from one to the other. Computerised tomography of the head revealed mild atrophy, compatible with age, and an EEG was normal. Maprotiline hydrochloride was continued but ranitidine was stopped, and his confusion cleared within 2 days. Repeat neurological examination showed that he was once more cooperative, oriented, and able to describe in detail four different routes between home and hospital. Subsequent medical evaluation revealed the presence of myeloma and hepatoma, but his mental status remained normal. Early reports of "no mental confusion" with ranitidine were based upon trials in healthy young adults, and not upon extensive use in the elderly or in the sort of patient who had experienced most of the difficulties ascribed to earlier H2 antagonists.3,4 In a similar setting ranitidine seems capable of producing similar neurological
side-effects. Section
of Neurology,
Emory University Clinic, Atlanta, Georgia 30322, USA 15. Flind AC, Rowley-Jones
CHARLES M. EPSTEIN D. Cimetidine and ranitidine. Lancet
1982, i: 749
1. Editorial. Cimetidine and ranitidine. Lancet 1982; i: 601-02. 2. Strum WB. Ranitidine. JAMA 1983; 250: 1894-96
3. Freston JW. Cimetidine II Adverse reactions and patterns of use. Ann Intern Med 1982; 97: 728-34. 4. Sawyer D,Conner CS, Scalley R. Cimetidine: Adverse reactions and acute toxicity. Am
J Hosp Pharm 1981; 38: 188-97.