- Email: [email protected]
ABSORPTION AND SUSTAINED RELEASE THEOPHYLLINE
966 led to the
following distribution of assay results when a
Woodruff and colleagues’ argument seems to be based on three aetiological factors-mothers not washing breasts before feeding,
second
failure to control flies, and mothers not boiling water given to babies or not cleaning utensils after use. Evidence is scanty that failure to wash breasts is a cause of disease in infants; the baby will probably have passive immunity to most maternal organisms, and the washing will in any case be limited by availability of water. Fly control would also require facilities outside the mother’s reach. Extra water is not required for most breast-fed babies, despite common advice to the contrary, and boiling water may be imprac" ticable where fuel is scarce. Water quantity is more important than 2 water quality in preventing childhood diarrhoea. Insufficient information is given on feeding and immunisation status. Presumably all the infants were breast fed but did any receive formula in addition? At what age were solids started, and what kind? These factors are crucial to the risk of infection and to weight gain in the first six months of life and there is still controversy over the right age to introduce solids because of the interrelationship between diarrhoea and contamination of weaning foods.3-5 Were any of the babies immunised? Whooping cough is characteristically followed
subtherapeutic 25%, therapeutic 70%, and toxic 5%. Theophylline concentrations at a steady state in adults are easy to act on because, for all practical purposes, an x% change in concentration will be achieved by an x% change in dosage. In nonsteady-state situations, interpretation is not so simple but Bayes’ statistical theory can be applied 1-3 and microcomputer programs have been developed to make this easier. Essentially, the approach is to estimate pharmacokinetic variables (most important, clearance, volume of distribution, and rate of absorption) from one or two concentration measurements, provided that adequate clinical and dosage information is also available. The bayesian estimates can then be used to calculate a dosage regimen which will achieve desired plasma concentrations, or a target concentration profile. In the measurement and interpretation of drug levels, this is a very useful tool-for example, it produces unbiased, precise theophylline concentration predictions associated with sets of indices that are unique to the individual patient.44 Using similar ideas it is possible to predict the response to
by marked weight lossand many more cases than the one described may have been pertussis, which could be prevented by early
theophylline in chronic bronchitis that will be achieved at any steady state concentration.On average forced vital capacity will increase linearly by 40 ml for each mg/1 increase in steady state theophylline concentration over the range of concentrations normally encountered in clinical practice. This response varies
immunisation. The use of anti-influenza vaccine would seem much less relevant. The following remedies, in addition to the better water and more latrines recommended by Woodruff and colleagues, might be more effective, more specific, and easier to put into practice than "health education" in tackling the problems of Juba babies: (1) tetanus immunisation of pregnant mothers; (2) training of birth attendants in safe delivery techniques, and the provision of a
delivery pack; (3) encouragement of breast feeding as the sole nutrient for the first four to six months (often mothers give water and/or solids too early on inappropriate medical advice); (4) provision of oral rehydration salts and advice on their use through clinics and
mass
media;
(5) diphtheria-pertussis-tetanus and polio immunisation for all babies from two
months;
(6) provision of road-to-health cards to all mothers, and regular weighing and charting of all babies. Such measures, which would make it easier for good mothers to be better mothers, require a health infrastructure which may not exist in Juba. These measures are the essence of primary health care and would depend on the training of village level health workers and on a political commitment at the highest level in government. I am sure that Woodruff and colleagues would agree that this commitment is necessary, and that to "encourage knowledge on good motherhood" may be a platitude for the peasant farming family. Department of Child Health, Ninewells Hospital and Medical School, Dundee DD19SY
TONY WATERSTON
CONTROLLING THEOPHYLLINE THERAPY
SIR,-Theophylline therapy can be controlled more rationally safely than in the manner discussed by Dr Woodcock and colleagues (Sept 10, p 610). Our hospital’s clinical pharmacokinetics laboratory has measured serum theophylline concentrations for the past four years. Over a representative six month period in the first year (145 patients) pattern of results changed strikingly. At the outset, 60% of theophylline levels were subtherapeutic (<10 mg/1), 29% were therapeutic (10-20 mg/1), and 11% were toxic (>20 mg/1) with symptoms attributable to toxicity always occurring at concentrations >25 mg/l. Careful interpretation of each concentration, followed by a laboratory report with advice and
Goldberg NM, Adams E. Supplementary water for breast-fed babies in a hot and dry climate-not really a necessity. Arch Dis Child 1983; 58: 73-74. 2. Feachem R. Oral rehydration with dirty water? Diarrhoea Dialogue 1981; 4: 7. 3. Waterlow JC, Thomson AM. Observations on the adequacy of breast feeding. Lancet 1.
1979; ii: 338-42. 4. Jelliffe DB, Jelliffe EFP. Adequacy of breast feeding. Lancet 1979; ii: 691-92. 5. Rowland GM, Barrell RAE, Whitehead RG. Bacterial contamination of traditional Gambian weaning foods. Lancet 1978; i: 136-38. 6. Morley DC, Woodland M. See how they grow. London: Macmillan. 1979: 94.
on
dosage,
measurement
was
made
after
about
four weeks:
to individual so that at a steady state concentration mg/l, for example, increases of 280-1120 ml can be anticipated in a population of chronic bronchitics. Predicting response in an individual patient from one or two measurements of response at different steady state concentrations, can be done quickly on a programmable calculator. Such techniques could remove some of the empiricism in drug therapy which results in a high proportion of unnacceptable and sometimes potentially lethal drug levels. Moreover, as Woodcock and colleagues indirectly point out, the confident achievement of therapeutic, safe levels would at least ensure that a drug such as theophylline is given the best possible chance before alternative strategies are considered.
from individual of 17-55
Department of Materia Medica, University of Glasgow, Stobhill General Hospital, Glasgow G21 3UW
BRIAN WHITING
ABSORPTION AND SUSTAINED RELEASE THEOPHYLLINE
SIR,-Dr Whyte and Dr Addis (Sept 10, p 618) reported a case of theophylline intoxication in a patient 24 h after the intake ofa large dose of a sustained release theophylline (SRT) preparation. They concluded that the remarkably long period of absorption was severe
probably due more to the size of the initial dose and its retention as a bezoar of tablets in the stomach than to the sustained release characteristics of the preparation. Very long periods of absorption of theophylline, with peak serum theophylline levels 16-24 h after medication, may also be seen when normal daily doses of SRT are taken with a substantial meal.6 LB, Beal SL, Rosenberg B, Marathe VV. Forecasting individual pharmacokinetics. Clin Pharmacol Ther 1979; 26: 294-305. 2. Peck CC, Brown DD, Sheiner LB, Schuster BG. A microcomputer drug (theophylline) dosing program which assists and teaches physicians. In: O’Neill JT, ed Proccedings of 4th annual conference on Computers in Medical Care, 1980: volII, 1. Sheiner
988-91.
AW, Whiting B, Bryson SM. OPT: a package of computer programs for parameter optimisation in clinical pharmacokinetics. Br J Clin Pharmacal 1982, 14: 247-56. 4. Fothenngham GH, Whiting B, Kelman AW, Bryson SM. Evaluation of kinetic parameter estimation from routine clinical pharmacokinetic data. Br J Clin Pharmacol 1982; 14: 595-96. 5. Whiting B, Kelman AW, Struthers AD. Prediction of response to theophylline in chronic bronchitis. Br J Clin Pharmacol (in press). 6. Pedersen S, Møller-Petersen J. Influence of food on the absorption rate and bioavailability of a sustained release theophylline preparation. Allergy 1982; 37: 531-34. 3. Kelman
967 When we studied the influence of food on the absorption of different SRT preparations we often found absorption profiles like the one reported by Whyte and Addis (fig 1).6,7 The time of serum
theophylline measurement and the frequency of dosing are normally recommended on the basis of fasting absorption curves. It is our experience, however, that the absorption profiles after food cannot be predicted from these fasting curves. Recently we studied the SRT preparation ’Theo-Dur Sprinkle,’ which has pHindependent dissolution pattern. In contrast to the fasting conditions substantial variability was found in absorption profiles when the drug was taken with food. In some patients no theophylline could be detected in the serum for as long as 6 h after medication (fig 2).
dosage adjustments are made otherwise there will be appreciable risk of toxic serum concentration. We agree with Woodcock et al,8 that theophyllines are difficult to use. However, in the 2112 years we started intensive education of patients and agreed with other doctors that patients treated with SRT should only be given extra theophylline at hospital by experienced doctors, we have in mind when an
not seen
any case of
levels above 25
theophylline intoxication or serum theophylline
mg/1.
Department of Paediatrics, Aalborg Hospital North, Aalborg, Denmark
S. PEDERSEN
HAEMORRHAGIC SHOCK, ENCEPHALOPATHY, AND THE PANCREAS
1- Serum concentrations of theophylline (mean and SD) in six children taking a single dose of the SRT preparation ’Theolair’ under fasting conditions (* ) and after food ()
Fig
SiR,—I am struck by the similarity between the syndrome of haemorrhagic shock and encephalopathy in infancy described by Dr Levin and colleagues (July 9, p 64) and the pancreatitis syndrome we have seen in the United States. 1,2 These children, who were older than Levin’s, had fever, encephalopathy, hepatic dysfunction, coagulation abnormalities or frank haemorrhage, acidosis, and renal abnormalities. Hypotension was variable and was thought to be due to encephalopathy or its treatment. We noted the similarity of our cases to Reye Other investigators have reported syndrome. additional cases.3 Adult cases of pancreatic encephalopathy arise from the circulation of pancreatic enzymes.6 Levin et al do not specifically mention examination of the pancreas in the six necropsies they present. However, their patients did have raised serum trypsin and depressed serum calcium values. Although their cases differed from ours in having diarrhoea and disseminated intravascular coagulation (which we did not test for), these are aspects of disease that could be attributed to interaction of digestive enzymes with the vascular system. -
Department of Tropical Medicine and Medical Microbiology, University of Hawaii School of Medicine, Honolulu, Hawaii 96816, USA
DAVID M. MORENS
IRON IN FLOUR
SIR,-Your editorial on proposals for new bread and flour regulations (Sept 24) states that in Sweden fortification offlour with iron led to "a striking decline in iron deficiency anaemia in women increase in iron overload". However, this be fully ascribed to the fortification of flour with iron. Other factors shown to be important are increased consumption of iron tablets and of ascorbic acid and greater use of oral contraceptives, thus reducing menstrual blood losses.7These three factors accounted for two-thirds of the improvement in iron deficiency anaemia. While we have no evidence of an increase in iron overload no data are available on the effect of iron fortificationon patients with haemochromatosis and thalassaemia.
and
no
evidence of
improvement
Fig 2-Serum concentrations of theophylline in a patient taking a single dose of the SRT preparation theo-dur sprinkle under fasting conditions (Q) and after food ( + ).
possibility of a delay in absorption or very sustained absorption of theophylline should always be taken into account when patients treated with SRT require emergency treatment with additional intravenous theophylline at hospital. Furthermore, a single serum theophylline measurement 4-6 h after medication, as The
suggested by others in the same issue of The Lancet, 8,9 may not be sufficient in such situations since the steady-state serum concentration at that time may be the trough rather than the peak, if the medicine was taken with food. 6,10 This fact should also be borne 7. Pedersen S.
Delay in the absorption rate of theophylline from a sustained release theophylline preparation caused by food. Br J Clin Pharmacol 1981; 12: 904-05. 8. Woodcock AA, Johnson MA, Geddes DM. Theophylline prescribing, serum concentrations, and toxicity. Lancet 1983; ii: 610-13. 9. Editorial. Theophylline benefits and difficulties. Lancet 1983; ii: 607-09. 10. Sommer B, Pedersen SE, Nathan E. Serum concentrations of theophylline in children treated with two daily doses ofa sustained-release theophylline preparation. Allergy 1981; 36: 507-11.
an
cannot
Kingston Hospital, Kingston upon Thames, Surrey St
S. LAKHANI
George’s Hospital,
London SW17
R. SONDHI
DM, Hammar SL, Heicher DA. Idiopathic acute pancreatitis in children: Association with a clinical picture resembling Reye syndrome. Am J Dis Child 1974;
1. Morens
128: 401-04.
Idiopathic acute pancreatitis in children. Am J Dis Child 1975; 129: 984-85. 3. Glassman M, Tahan S, Hillemeier C, Rothstein P, Shaywitz BA, Gryboski J. Pancreatitis in patients with Reye syndrome. J Clin Gastroenterol 1981; 3: 165-69. 4. Ellis GH, Mirkin D, Mills MC. Pancreatitis and Reye’s syndrome. Am J Dis Child 1979; 133: 1014-16. 5. Stover SL, Wanglee P, Kennedy C. Acute hemorrhagic pancreatitis and other visceral changes associated with acute encephalopathy. JPediatr 1968, 73: 235-41 6. Sharf B, Bental E. Pancreatic encephalopathy. J Neurol Neurosurg Psychiatr 1971; 34: 357-61. 7. Hallberg L, Bengtsson C, Garby L, Lennartsson J, Rossander L, Tibblin E. Bull WHO 1979; 57: 947-54.
2. Morens DM
following distribution of assay results when a
Woodruff and colleagues’ argument seems to be based on three aetiological factors-mothers not washing breasts before feeding,
second
failure to control flies, and mothers not boiling water given to babies or not cleaning utensils after use. Evidence is scanty that failure to wash breasts is a cause of disease in infants; the baby will probably have passive immunity to most maternal organisms, and the washing will in any case be limited by availability of water. Fly control would also require facilities outside the mother’s reach. Extra water is not required for most breast-fed babies, despite common advice to the contrary, and boiling water may be imprac" ticable where fuel is scarce. Water quantity is more important than 2 water quality in preventing childhood diarrhoea. Insufficient information is given on feeding and immunisation status. Presumably all the infants were breast fed but did any receive formula in addition? At what age were solids started, and what kind? These factors are crucial to the risk of infection and to weight gain in the first six months of life and there is still controversy over the right age to introduce solids because of the interrelationship between diarrhoea and contamination of weaning foods.3-5 Were any of the babies immunised? Whooping cough is characteristically followed
subtherapeutic 25%, therapeutic 70%, and toxic 5%. Theophylline concentrations at a steady state in adults are easy to act on because, for all practical purposes, an x% change in concentration will be achieved by an x% change in dosage. In nonsteady-state situations, interpretation is not so simple but Bayes’ statistical theory can be applied 1-3 and microcomputer programs have been developed to make this easier. Essentially, the approach is to estimate pharmacokinetic variables (most important, clearance, volume of distribution, and rate of absorption) from one or two concentration measurements, provided that adequate clinical and dosage information is also available. The bayesian estimates can then be used to calculate a dosage regimen which will achieve desired plasma concentrations, or a target concentration profile. In the measurement and interpretation of drug levels, this is a very useful tool-for example, it produces unbiased, precise theophylline concentration predictions associated with sets of indices that are unique to the individual patient.44 Using similar ideas it is possible to predict the response to
by marked weight lossand many more cases than the one described may have been pertussis, which could be prevented by early
theophylline in chronic bronchitis that will be achieved at any steady state concentration.On average forced vital capacity will increase linearly by 40 ml for each mg/1 increase in steady state theophylline concentration over the range of concentrations normally encountered in clinical practice. This response varies
immunisation. The use of anti-influenza vaccine would seem much less relevant. The following remedies, in addition to the better water and more latrines recommended by Woodruff and colleagues, might be more effective, more specific, and easier to put into practice than "health education" in tackling the problems of Juba babies: (1) tetanus immunisation of pregnant mothers; (2) training of birth attendants in safe delivery techniques, and the provision of a
delivery pack; (3) encouragement of breast feeding as the sole nutrient for the first four to six months (often mothers give water and/or solids too early on inappropriate medical advice); (4) provision of oral rehydration salts and advice on their use through clinics and
mass
media;
(5) diphtheria-pertussis-tetanus and polio immunisation for all babies from two
months;
(6) provision of road-to-health cards to all mothers, and regular weighing and charting of all babies. Such measures, which would make it easier for good mothers to be better mothers, require a health infrastructure which may not exist in Juba. These measures are the essence of primary health care and would depend on the training of village level health workers and on a political commitment at the highest level in government. I am sure that Woodruff and colleagues would agree that this commitment is necessary, and that to "encourage knowledge on good motherhood" may be a platitude for the peasant farming family. Department of Child Health, Ninewells Hospital and Medical School, Dundee DD19SY
TONY WATERSTON
CONTROLLING THEOPHYLLINE THERAPY
SIR,-Theophylline therapy can be controlled more rationally safely than in the manner discussed by Dr Woodcock and colleagues (Sept 10, p 610). Our hospital’s clinical pharmacokinetics laboratory has measured serum theophylline concentrations for the past four years. Over a representative six month period in the first year (145 patients) pattern of results changed strikingly. At the outset, 60% of theophylline levels were subtherapeutic (<10 mg/1), 29% were therapeutic (10-20 mg/1), and 11% were toxic (>20 mg/1) with symptoms attributable to toxicity always occurring at concentrations >25 mg/l. Careful interpretation of each concentration, followed by a laboratory report with advice and
Goldberg NM, Adams E. Supplementary water for breast-fed babies in a hot and dry climate-not really a necessity. Arch Dis Child 1983; 58: 73-74. 2. Feachem R. Oral rehydration with dirty water? Diarrhoea Dialogue 1981; 4: 7. 3. Waterlow JC, Thomson AM. Observations on the adequacy of breast feeding. Lancet 1.
1979; ii: 338-42. 4. Jelliffe DB, Jelliffe EFP. Adequacy of breast feeding. Lancet 1979; ii: 691-92. 5. Rowland GM, Barrell RAE, Whitehead RG. Bacterial contamination of traditional Gambian weaning foods. Lancet 1978; i: 136-38. 6. Morley DC, Woodland M. See how they grow. London: Macmillan. 1979: 94.
on
dosage,
measurement
was
made
after
about
four weeks:
to individual so that at a steady state concentration mg/l, for example, increases of 280-1120 ml can be anticipated in a population of chronic bronchitics. Predicting response in an individual patient from one or two measurements of response at different steady state concentrations, can be done quickly on a programmable calculator. Such techniques could remove some of the empiricism in drug therapy which results in a high proportion of unnacceptable and sometimes potentially lethal drug levels. Moreover, as Woodcock and colleagues indirectly point out, the confident achievement of therapeutic, safe levels would at least ensure that a drug such as theophylline is given the best possible chance before alternative strategies are considered.
from individual of 17-55
Department of Materia Medica, University of Glasgow, Stobhill General Hospital, Glasgow G21 3UW
BRIAN WHITING
ABSORPTION AND SUSTAINED RELEASE THEOPHYLLINE
SIR,-Dr Whyte and Dr Addis (Sept 10, p 618) reported a case of theophylline intoxication in a patient 24 h after the intake ofa large dose of a sustained release theophylline (SRT) preparation. They concluded that the remarkably long period of absorption was severe
probably due more to the size of the initial dose and its retention as a bezoar of tablets in the stomach than to the sustained release characteristics of the preparation. Very long periods of absorption of theophylline, with peak serum theophylline levels 16-24 h after medication, may also be seen when normal daily doses of SRT are taken with a substantial meal.6 LB, Beal SL, Rosenberg B, Marathe VV. Forecasting individual pharmacokinetics. Clin Pharmacol Ther 1979; 26: 294-305. 2. Peck CC, Brown DD, Sheiner LB, Schuster BG. A microcomputer drug (theophylline) dosing program which assists and teaches physicians. In: O’Neill JT, ed Proccedings of 4th annual conference on Computers in Medical Care, 1980: volII, 1. Sheiner
988-91.
AW, Whiting B, Bryson SM. OPT: a package of computer programs for parameter optimisation in clinical pharmacokinetics. Br J Clin Pharmacal 1982, 14: 247-56. 4. Fothenngham GH, Whiting B, Kelman AW, Bryson SM. Evaluation of kinetic parameter estimation from routine clinical pharmacokinetic data. Br J Clin Pharmacol 1982; 14: 595-96. 5. Whiting B, Kelman AW, Struthers AD. Prediction of response to theophylline in chronic bronchitis. Br J Clin Pharmacol (in press). 6. Pedersen S, Møller-Petersen J. Influence of food on the absorption rate and bioavailability of a sustained release theophylline preparation. Allergy 1982; 37: 531-34. 3. Kelman
967 When we studied the influence of food on the absorption of different SRT preparations we often found absorption profiles like the one reported by Whyte and Addis (fig 1).6,7 The time of serum
theophylline measurement and the frequency of dosing are normally recommended on the basis of fasting absorption curves. It is our experience, however, that the absorption profiles after food cannot be predicted from these fasting curves. Recently we studied the SRT preparation ’Theo-Dur Sprinkle,’ which has pHindependent dissolution pattern. In contrast to the fasting conditions substantial variability was found in absorption profiles when the drug was taken with food. In some patients no theophylline could be detected in the serum for as long as 6 h after medication (fig 2).
dosage adjustments are made otherwise there will be appreciable risk of toxic serum concentration. We agree with Woodcock et al,8 that theophyllines are difficult to use. However, in the 2112 years we started intensive education of patients and agreed with other doctors that patients treated with SRT should only be given extra theophylline at hospital by experienced doctors, we have in mind when an
not seen
any case of
levels above 25
theophylline intoxication or serum theophylline
mg/1.
Department of Paediatrics, Aalborg Hospital North, Aalborg, Denmark
S. PEDERSEN
HAEMORRHAGIC SHOCK, ENCEPHALOPATHY, AND THE PANCREAS
1- Serum concentrations of theophylline (mean and SD) in six children taking a single dose of the SRT preparation ’Theolair’ under fasting conditions (* ) and after food ()
Fig
SiR,—I am struck by the similarity between the syndrome of haemorrhagic shock and encephalopathy in infancy described by Dr Levin and colleagues (July 9, p 64) and the pancreatitis syndrome we have seen in the United States. 1,2 These children, who were older than Levin’s, had fever, encephalopathy, hepatic dysfunction, coagulation abnormalities or frank haemorrhage, acidosis, and renal abnormalities. Hypotension was variable and was thought to be due to encephalopathy or its treatment. We noted the similarity of our cases to Reye Other investigators have reported syndrome. additional cases.3 Adult cases of pancreatic encephalopathy arise from the circulation of pancreatic enzymes.6 Levin et al do not specifically mention examination of the pancreas in the six necropsies they present. However, their patients did have raised serum trypsin and depressed serum calcium values. Although their cases differed from ours in having diarrhoea and disseminated intravascular coagulation (which we did not test for), these are aspects of disease that could be attributed to interaction of digestive enzymes with the vascular system. -
Department of Tropical Medicine and Medical Microbiology, University of Hawaii School of Medicine, Honolulu, Hawaii 96816, USA
DAVID M. MORENS
IRON IN FLOUR
SIR,-Your editorial on proposals for new bread and flour regulations (Sept 24) states that in Sweden fortification offlour with iron led to "a striking decline in iron deficiency anaemia in women increase in iron overload". However, this be fully ascribed to the fortification of flour with iron. Other factors shown to be important are increased consumption of iron tablets and of ascorbic acid and greater use of oral contraceptives, thus reducing menstrual blood losses.7These three factors accounted for two-thirds of the improvement in iron deficiency anaemia. While we have no evidence of an increase in iron overload no data are available on the effect of iron fortificationon patients with haemochromatosis and thalassaemia.
and
no
evidence of
improvement
Fig 2-Serum concentrations of theophylline in a patient taking a single dose of the SRT preparation theo-dur sprinkle under fasting conditions (Q) and after food ( + ).
possibility of a delay in absorption or very sustained absorption of theophylline should always be taken into account when patients treated with SRT require emergency treatment with additional intravenous theophylline at hospital. Furthermore, a single serum theophylline measurement 4-6 h after medication, as The
suggested by others in the same issue of The Lancet, 8,9 may not be sufficient in such situations since the steady-state serum concentration at that time may be the trough rather than the peak, if the medicine was taken with food. 6,10 This fact should also be borne 7. Pedersen S.
Delay in the absorption rate of theophylline from a sustained release theophylline preparation caused by food. Br J Clin Pharmacol 1981; 12: 904-05. 8. Woodcock AA, Johnson MA, Geddes DM. Theophylline prescribing, serum concentrations, and toxicity. Lancet 1983; ii: 610-13. 9. Editorial. Theophylline benefits and difficulties. Lancet 1983; ii: 607-09. 10. Sommer B, Pedersen SE, Nathan E. Serum concentrations of theophylline in children treated with two daily doses ofa sustained-release theophylline preparation. Allergy 1981; 36: 507-11.
an
cannot
Kingston Hospital, Kingston upon Thames, Surrey St
S. LAKHANI
George’s Hospital,
London SW17
R. SONDHI
DM, Hammar SL, Heicher DA. Idiopathic acute pancreatitis in children: Association with a clinical picture resembling Reye syndrome. Am J Dis Child 1974;
1. Morens
128: 401-04.
Idiopathic acute pancreatitis in children. Am J Dis Child 1975; 129: 984-85. 3. Glassman M, Tahan S, Hillemeier C, Rothstein P, Shaywitz BA, Gryboski J. Pancreatitis in patients with Reye syndrome. J Clin Gastroenterol 1981; 3: 165-69. 4. Ellis GH, Mirkin D, Mills MC. Pancreatitis and Reye’s syndrome. Am J Dis Child 1979; 133: 1014-16. 5. Stover SL, Wanglee P, Kennedy C. Acute hemorrhagic pancreatitis and other visceral changes associated with acute encephalopathy. JPediatr 1968, 73: 235-41 6. Sharf B, Bental E. Pancreatic encephalopathy. J Neurol Neurosurg Psychiatr 1971; 34: 357-61. 7. Hallberg L, Bengtsson C, Garby L, Lennartsson J, Rossander L, Tibblin E. Bull WHO 1979; 57: 947-54.
2. Morens DM