Enoximone pharmacokinetics in infants

P. D. Booker1,*, S. Gibbons1, J. I. M. Stewart2,3, A. Selby2, E. Wilson-Smith2 and M. Pozzi2

1University of Liverpool, Liverpool, 2Royal Liverpool Children’s NHS Trust, Alder Hey, Eaton Road, Liverpool L12 2AP, UK. 3Present address: Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, UK

Accepted for publication: March 5, 2000


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Enoximone and enoximone sulphoxide concentrations were measured in plasma of 20 infants, median age 6.0 (range 0.6–49.7) weeks, during and after prolonged continuous infusions. Patients were given enoximone 1 mg kg–1 and an infusion at 10 µg kg–1 min–1 just before being weaned from cardiopulmonary bypass (CPB). The infusion was stopped when clinically indicated, after a median 97 (range 24–572) h. Arterial blood samples were taken 30 min and 12 h after CPB, every 24 h during the infusion, and then 2, 4, 8, 12 and 24 h after the infusion was stopped. Pharmacokinetic non-compartmental analysis was performed using TOPFIT software. Fourteen patients who retained normal hepatic function had a median (95% confidence intervals) clearance of 9.7 (6.3–14.1) ml min–1 kg–1, elimination half-life of 5.2 (2.4–6.8) h and a volume of distribution of 3.6 (2.0–5.7) litre kg–1. The six patients with significant hepatic dysfunction had a lower clearance, 5.7 (2.4–14.5) ml min–1 kg–1, and significantly longer elimination half-life, 7.6 (6.5–10.9) h (P=0.02). Enoximone sulphoxide elimination half-life was significantly prolonged in three patients with renal dysfunction, 16.2 (10.5–17.7) h versus 6.9 (6.1–9.4) h (P=0.03). These results confirm that enoximone pharmacokinetics in infants is similar to that found in adults. The infusion rate of enoximone should be reduced if hepatic or renal dysfunction supervenes.

Br J Anaesth 2000; 85: 205–10

Keywords: pharmacokinetics; enoximone; infants; cardiac surgery


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Enoximone, a selective phosphodiesterase inhibitor, has significant inotropic and vasodilating properties that have proved useful in the postoperative management of infants and children having cardiac surgery.1 The inotropic effects produced by enoximone are additive to ß1-adrenoreceptor agonists such as dobutamine2 and epinephrine.3 4 Enoximone does not require adrenergic receptors for its action so is particularly useful in patients with heart failure, who may have ß1-adrenoreceptor downregulation. One clinical study involving six adults in severe congestive heart failure who were given a single injection of enoximone, found a median steady-state volume of distribution of the parent drug of 4.2 (range 2.1–8.0) litres kg–1 and a median terminal elimination half-life of 6.2 (3.0–8.1) h.5 Another study of adults in heart failure who received enoximone by infusion for 24 h, followed by a 12 h washout period, has demonstrated similar results.6 There are no comparative data available for infants or children.

Enoximone is primarily metabolized in the liver by oxidation to enoximone sulphoxide. In a study of six adult patients with severe congestive heart failure, 74% of a single intravenous dose of enoximone was excreted in urine over the following 24 h as the sulphoxide metabolite, together with 0.5% of the parent drug.5 The median terminal elimination half-life for the sulphoxide metabolite in these patients was 7.6 (range 6–11) h. Accurate in vivo determination of metabolite potency in humans is made somewhat problematic by the reversibility of enoximone metabolism, as reduction of enoximone sulphoxide to enoximone can occur both in kidney and liver. An experimental study in dogs suggests that the potency of the metabolite is about one-seventh that of the parent drug.7

For over 10 years, enoximone has been used as one of our first line inotropic drugs in infants and children recovering from cardiac surgery, though our dosage regimen has until now been based solely on paediatric clinical studies and published adult pharmacokinetic data. However, as no pharmacokinetic studies have been carried out in children, there remains some uncertainty as to the optimal loading dose and subsequent infusion rates of the drug. It is a tribute to the drug’s wide therapeutic ratio that we continue to use it, despite knowing so little about its distribution and clearance in sick children. Nevertheless, there are potential dangers in giving too much enoximone: reported adverse effects include hyperosmolality8 and hypotension.9 One study of healthy adults demonstrated a significant correlation between the plasma concentration of both enoximone and its sulphoxide metabolite and effects on contractility.10 Subsequent clinical studies have been unable to confirm this relationship in adults with cardiac failure6 or in patients recovering from cardiac surgery,11 12 though plasma concentrations between 1000 and 2000 ng ml–1 appear to be related with maximal clinical effects. One aim of our study was to discern whether we were achieving similar therapeutic plasma concentrations when using our standard dosage regimen. We also wished to determine whether enoximone pharmacokinetic values in infants were significantly different from those previously described in adults.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
With local Ethics Committee approval and informed written parental consent, 20 infants who required inotropic support following cardiac surgery were studied. All infants had amethocaine gel applied to two small areas of skin 45 min preoperatively, but no other premedication was given. Anaesthesia was induced with thiopental 4 mg kg–1 and neuromuscular block produced with vecuronium 0.2 mg kg–1 h–1. Alfentanil 10 µg kg–1 was given over 5 min before commencing an i.v. infusion at 2 µg kg–1 min–1. Midazolam 0.2 mg kg–1 was injected into the bypass pump prime. Isoflurane (0.5%), in a mixture of air and oxygen, was given before and after cardiopulmonary bypass (CPB). Femoral arterial and central venous cannulae, a urinary catheter, temperature and oximeter probes were placed before surgery commenced.

A 1-ml arterial blood sample was taken during rewarming on CPB (zero control). Approximately 10 min before the anticipated discontinuation of CPB, a loading dose of enoximone 1 mg kg–1 was given over 2 min into a central vein. An infusion of enoximone 10 µg kg–1 min–1 was then started. A 1-ml blood sample was taken 30 min after successful weaning from CPB. Further samples were taken 12 and 24 h after CPB, and then every 24 h until the infusion was stopped. Clinical criteria determined when the enoximone infusion was discontinued. Another blood sample was taken immediately before stopping the infusion, and then at 2, 4, 8, 12 and 24 h. All blood samples were obtained from the arterial cannula, centrifuged, the serum separated and stored at –22°C until assay.

In addition to routine haemodynamic, haematological and biochemical monitoring, serum osmolality was measured each day in patients receiving infusions lasting > 48 h. This was compared to calculated values and the osmolal gap recorded. From the second postoperative day and thereafter, all patients had liver function tests measured daily for the duration of their enoximone infusion. Patients who had alanine aminotransferase and unconjugated bilirubin concentrations more than twice the normal values for >24 h were deemed to have significant hepatic dysfunction. Patients were deemed to have significant renal dysfunction if their serum creatinine concentration increased to more than twice the normal values for >24 h, and their urine output was <0.5 ml kg–1 h–1 for >6 h despite diuretic therapy and a normal blood pressure for their age.

The concentrations of enoximone and enoximone sulphoxide in the serum samples were determined using a high-performance liquid chromatographic (HPLC) technique, as described previously by Chan and co-workers.13 The method involves addition of internal standard and organic solvent extraction, followed by separation with HPLC and detection by ultraviolet absorption. The assay range for both enoximone and enoximone sulphoxide was 50–3000 ng ml–1. The coefficients of variation for enoximone at the level of the lowest and highest standards were 2.4% and 2.8%, respectively. The coefficients of variation for enoximone sulphoxide at the level of the lowest and highest standards were 0.4% and 2.4%, respectively. The lower limit of quantification (LLQ) for both enoximone and enoximone sulphoxide was 50 ng ml–1.

Pharmacokinetic parameters for enoximone and enoximone sulphoxide were determined by non-compartmental analysis using TOPFIT computer software (Gustav Fischer Verlag, Stuttgart, Germany). The elimination rate constant ({lambda}z) was calculated by log linear regression of the terminal portion of the plasma drug concentration–time curve using the method of least squares. The terminal elimination half-life (t1/2z) for enoximone and enoximone sulphoxide was calculated from ln 2/{lambda}z. The area under the drug–time curve (from time=0 to infinity; AUC) was determined by the log-linear trapezoidal rule. Clearance (Cl) of enoximone was calculated from dose/AUC, where dose is the product of infusion rate, infusion duration and weight of individual. Calculation of the volume of distribution at steady-state required an accurate calculation of mean residence time. However, our data set was too complex to be analysed by normal non-compartmental analysis, and our calculations of mean residence time produced many obviously anomalous results. Hence, we have simply reported the volume of distribution during the elimination phase, calculated as the product of Cl and 1/{lambda}z.

The Mann–Whitney test (SPSS for Windows, version 10.0) was used to compare pharmacokinetic parameters in patients with severe hepatic or renal dysfunction with those in patients with no evidence of organ dysfunction. Kendall’s tau-b rank-order correlation coefficient was used to assess associations between age and calculated pharmacokinetic parameters. Partial correlations, controlling for hepatic dysfunction, were used to assess associations between duration of infusion or age and calculated pharmacokinetic parameters, and between age and peak concentration.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Individual patient details are given in Table 1. Six patients had significant hepatic dysfunction and three patients significant renal dysfunction during the course of the infusion. Although there was no significant correlation between age and any calculated pharmacokinetic parameters, we found a significant correlation between age and peak concentration, after controlling for hepatic dysfunction (P=0.03). There were no significant correlations between duration of infusion and any calculated pharmacokinetic parameters, when controlling for hepatic dysfunction. The plasma concentration of enoximone 30 min after discontinuation of CPB, peak concentration of enoximone, and calculated pharmacokinetic parameters for each patient are given in Table 2. At 30 min after discontinuation of CPB, plasma concentrations of enoximone ranged between 440 and 1316 ng ml–1. Enoximone concentrations measured 12 h after CPB reached our target ‘therapeutic’ range (1000–2000 ng ml–1) in 10/12 patients (samples were unobtainable at this time in eight patients due to logistical problems). In those 14 patients who retained normal hepatic function throughout the duration of their infusion, plasma concentrations of enoximone measured just before stopping the infusion were not significantly different to those measured after just 24 h of infusion, that is there was no evidence of drug accumulation. The median plasma concentrations (with 95% confidence intervals) of enoximone and enoximone sulphoxide measured at 24 h intervals during the infusions, for all patients, are given in Table 3.


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Table 1 Details of individual patients. Organ ‘dysfunction’ signifies that biochemical markers of hepatic function were markedly deranged (H, hepatic) or that the patient was oliguric and serum creatinine was high (R, renal). TGA, transposition of the great arteries; TAPVC, total anomalous pulmonary venous connection; VSD, ventricular septal defect; ASD, atrial septal defect; HLHS, hypoplastic left heart syndrome; COR, cor triatriatum; FALLOT, tetralogy of Fallot; PA, pulmonary atresia; MVD, mitral valve disease. IQR, interquartile range
 

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Table 2 Enoximone concentration 30 min after weaning from cardiopulmonary bypass (CPB), peak enoximone concentration, and calculated pharmacokinetic parameters for each individual patient. NS, not sampled; IS, insufficient samples. IQR, interquartile range. 95% CI = 95% confidence intervals for the median
 

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Table 3 Median (95% confidence intervals) plasma concentrations of enoximone and enoximone sulphoxide during constant rate infusion at 10 µg kg–1 min–1. Duration of infusion was determined by clinical criteria alone. Sampling was not performed at all possible times in all patients for logistical reasons
 
Enoximone pharmacokinetics for those patients with organ dysfunction are compared to those who retained normal hepatic and renal function throughout their infusion in Table 4. There was no significant difference between the median volume of distribution during the elimination phase in patients with and without hepatic dysfunction. Although the median clearance in patients with hepatic dysfunction was lower than in those retaining normal hepatic function, this difference did not achieve statistical significance. Elimination half-life was significantly prolonged in patients with hepatic dysfunction compared to the other patients (P=0.02). The median peak enoximone concentration in the six patients with hepatic dysfunction (2974 ng ml–1) was much higher than in the other patients (1483 ng ml–1), though this did not achieve a statistically significant difference. Only patients with hepatic dysfunction had peak enoximone concentrations that exceeded 3000 ng ml–1. An illustration of the marked difference between the enoximone concentrations measured in a patient with hepatic dysfunction, and one with normal hepatic function is given in Fig. 1. The median elimination half-life for enoximone sulphoxide in the three patients with renal dysfunction (16.2 h) was significantly longer than in the other patients (6.9 h, P=0.03).


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Table 4 Median (95% confidence intervals) values of calculated pharmacokinetic parameters and peak enoximone concentration in patients with and without hepatic and renal dysfunction. Hepatic dysfunction was deemed to have occurred when concentrations of both alanine aminotransferase and unconjugated bilirubin were more than twice normal values for >24 h. Renal dysfunction was defined as a rising serum creatinine concentration >100 µmol litre–1 for >24 h, together with a urine output of <0.5 ml kg–1 h–1 for >6 h despite diuretic therapy and a normal arterial pressure. We were unable to obtain sufficient samples in one patient to perform the ES t1/2z calculation. Vd, volume of distribution; Cl, clearance; EN t1/2z, elimination half-life of enoximone, ES t1/2z, elimination half-life of enoximone sulphoxide. *Significant difference between groups (P<0.05)
 


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Fig 1 Plasma concentrations of enoximone in two infants receiving a constant infusion of enoximone 10 µg kg–1 min–1 after cardiac surgery. One patient (squares) had severe hepatic dysfunction for 3 days after surgery, causing a temporary increase in plasma enoximone concentration. These very high concentrations are in contrast to those measured in the other patient (circles) who retained normal hepatic function throughout.

 
The platelet count of all patients decreased after surgery, from a median value of 108 000 ml–1 24 h post-CPB to a low of 73 000 ml–1 by day 4, but returning back spontaneously to >95 000 ml–1 by day 5 of the infusion. Measured serum osmolality exceeded 330 mOsm kg–1, and the osmolal gap increased transiently to between 20 and 44 mOsm kg–1 in all six patients with hepatic or renal dysfunction for up to 72 h. There were no other adverse effects that could reasonably be attributed to the enoximone therapy. All patients in the study made a full recovery from their surgery and were subsequently discharged from hospital.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The median values calculated for enoximone clearance and elimination half-life in infants in this study were very similar to those previously found in adults. Although there are no directly comparable adult data, enoximone clearance in adults in chronic congestive cardiac failure ranged between 7 and 16 ml min–1 kg–1 and the elimination half-life between 4 and 7 h.6 14 Although we were unable to calculate the volume of distribution at steady-state in our patients, our median value for volume of distribution during the elimination phase, 3.8 (95% CI 2.1–5.2) litres kg–1 is very similar to previously documented adult values (range 3.5–9.2 litres kg–1).

This is the first study to examine enoximone pharmacokinetics in infants, and also the first to examine drug concentrations during and after prolonged infusions in any age group. Previous adult pharmacokinetic studies have been performed only after single intravenous injections or short infusions (<48 h).6 10 11 15 16 In our study, the enoximone infusion was stopped when the patient’s general condition, and ventricular function in particular, had improved sufficiently such that inotropic support was no longer required. If a patient required more than one inotropic drug, enoximone was always the last one to be discontinued. Inevitably, therefore, the patients receiving the most prolonged infusions of enoximone were, by definition, the patients who were sickest for the longest time period. However, there was no significant correlation between duration of infusion and calculated pharmacokinetic parameters. Nevertheless, we observed very high plasma drug and metabolite concentrations in some sick patients at various times during their infusion. However, by the time the infusion was stopped, drug concentration had usually returned to near target levels. We observed no significant increase in plasma concentration during infusions of 72–144 h duration in those infants retaining normal hepatic and renal function. This suggests that an enoximone infusion rate of 10 µg kg–1 min–1 does not usually result in drug accumulation in neonates or infants who have normal hepatic function.

All patients who exhibited peak enoximone concentrations >3000 ng ml–1 demonstrated marked biochemical evidence of hepatic derangement. Clearance values of enoximone suggest that enoximone metabolism will be affected both by hepatic blood flow and by microsomal activity. A transient increase in drug plasma concentration during a constant rate infusion must reflect either a decrease in hepatic microsomal enzyme metabolic activity and/or a decrease in hepatic blood flow. The latter explanation seems more likely, as these perturbations usually occurred in the first 24–48 h after surgery, when cardiac output was particularly labile and vasoconstrictor inotropic drugs were also being used. Our criteria for a patient to be deemed as having hepatic dysfunction were relatively strict, though somewhat arbitrary: our measures of liver function had to rise to more than twice normal values for >24 h.17 One clinical study in adults has demonstrated that low sulphoxidation activity does not correlate with the degree of hyperbilirubinaemia or histological severity of liver disease, and may even occur in otherwise normal individuals.18 Nevertheless, the six patients who fulfilled our criteria for hepatic dysfunction had a reduced clearance rate and a significantly longer elimination half-life than the other 14 patients. As the neonate has reduced microsomal enzyme function compared to the older infant,17 we were not surprised to find a significant correlation between age and peak concentration, after controlling for hepatic dysfunction (P=0.03). However, we were unable to demonstrate any significant correlation between age and any calculated pharmacokinetic parameter, after controlling for hepatic dysfunction.

The criteria we used to determine whether a patient should be deemed as having renal dysfunction were similar to those we normally use as indications for peritoneal dialysis, that is a rising creatinine >100 µmol litre–1 and a urine output <0.5 ml kg–1 h–1 for >6 h despite diuretic therapy and a normal arterial pressure. Only patients who had very poor renal function and required peritoneal dialysis demonstrated serum concentrations of enoximone sulphoxide >10 000 ng ml–1 at any time during their infusion. Prolonged elimination of the metabolite was demonstrated in all three patients with severe renal dysfunction.

There is one case report of an infant becoming hyperosmolar secondary to an enoximone infusion given at 20 µg kg–1 min–1 for several days.8 This was thought to be due to propylene glycol accumulation, though the diluent also contains alcohol, which could have added to the problem. We both measured and calculated osmolality in all our patients who required prolonged infusions of enoximone, and found high transient osmolal gaps of 20–40 in six of our sickest patients, all of whom had hepatic dysfunction. No other patient exhibited an abnormal osmolal gap. Although this hyperosmolality may have been at least partially due to alcohol and propylene glycol, there were probably other contributing factors in these very sick infants. As vital organ function returned to normal, osmolal gaps similarly reduced to within normal limits, despite continuation of the same enoximone infusion rate.

In accordance with a previous adult study,15 we could not demonstrate that enoximone produced clinically significant thrombocytopaenia. We believe that the post-CPB decrease in platelet count that we observed was similar to that often seen in sick patients not given enoximone, though a formal matched-pair comparison was not performed. Furthermore, although platelet counts decreased initially after CPB, they all returned spontaneously to normal values during the time course of the infusion.

We have confirmed that a loading dose of enoximone is necessary to achieve therapeutic concentrations in the early post-CPB period. The administration of the loading dose to the patient while still on CPB avoided any drug-induced hypotension. This study has demonstrated that enoximone 1 mg kg–1 given to the patient in the final few minutes of CPB will produce near therapeutic plasma concentrations in most patients by 30 min post-CPB, if an infusion at 10 µg kg–1 min–1 is started at the same time. Adult data suggest that the optimum dosage regimen is one that achieves plasma concentrations ranging between 1000 and 2000 ng ml–1, though this has not been confirmed for the paediatric age group. Although worthwhile therapeutic effects can be achieved at lower plasma concentrations than these, we aim for the maximum possible inotropic effect. This is because enoximone has a wide therapeutic ratio and substantially reduces the likelihood of having to use other potentially more noxious agents at high dose. Nevertheless, there is no therapeutic benefit in producing very high plasma concentrations, although enoximone appears devoid of obvious adverse effects during short-term infusions.

We conclude, therefore, that our current dosage regimen for enoximone, a 1 mg kg–1 loading dose followed by an infusion at 10 µg kg–1 min–1, appears suitable for most patients. However, hepatic dysfunction may induce transient, very high concentrations in some individuals. Hence, we recommend that any clinical or biochemical indication of hepatic dysfunction should trigger a substantial reduction in the infusion rate. Similarly, isolated renal dysfunction resulting in oliguria should trigger a moderate reduction in the infusion rate.


    Acknowledgements
 
Financial support for this study was given by the Royal Liverpool Children’s NHS Trust Research Fund and RLCH Cardiac Fund.


    Footnotes
 
* Corresponding author Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Innes PA, Frazer RS, Booker PD, et al. Comparison of the haemodynamic effects of dobutamine with enoximone after open heart surgery in small children. Br J Anaesth 1994; 72: 77–81[Abstract]

2 Gilbert EM, Hershberger RE, Wiechmann RJ, Movsesian MA, Bristow MR. Pharmacologic and hemodynamic effects of combined beta-agonist stimulation and phosphodiesterase inhibition in the failing heart. Chest 1995; 108: 1524–32[Abstract/Free Full Text]

3 Boldt J, Kling D, Moosdorf R, Hempelmann G. Enoximone treatment of impaired myocardial function during cardiac surgery: combined effects with epinephrine. J Cardiothorac Anesth 1990; 4: 462–8[Medline]

4 Vincent JL, Leon M, Berre J, Melot C, Kahn RJ. Addition of enoximone to adrenergic agents in the management of severe heart failure. Crit Care Med 1992; 20: 1102–6[ISI][Medline]

5 Okerholm RA, Chan KY, Lang JF, Thompson GA, Ruberg SJ. Biotransformation and pharmacokinetic overview of enoximone and its sulfoxide metabolite. Am J Cardiol 1987; 60: 21C–6C[Medline]

6 Smith NA, Kates RE, Lebsack C, et al. Clinical pharmacology of intravenous enoximone: pharmacodynamics and pharmacokinetics in patients with heart failure. Am Heart J 1991; 122: 755–63[ISI][Medline]

7 Dage RC, Okerholm RA. Pharmacology and pharmacokinetics of enoximone. Cardiology 1990; 77: 2–13

8 Huggon I, James I, Macrae D. Hyperosmolality related to propylene glycol in an infant treated with enoximone infusion. BMJ 1990; 301: 19–20[ISI][Medline]

9 Patel A, Caldicott LD, Skoyles JR, Das P, Sherry KM. Comparison of the haemodynamic effects of enoximone and piroximone in patients after cardiac surgery. Br J Anaesth 1993; 71: 869–72[Abstract]

10 Belz GG, Meinicke T, Schafer-Korting M. The relationship between pharmacokinetics and pharmacodynamics of enoximone in healthy man. Eur J Clin Pharmacol 1988; 35: 631–5[ISI][Medline]

11 Desanger JP, Installe E, Harvengt C. Plasma enoximone concentrations in cardiac patients. Curr Ther Res 1990; 47: 743–52[ISI]

12 Gonzalez M, Desager J-P, Jaquemart J-L, Chenu P, Muller T, Installe E. Efficacy of enoximone in the management of refractory low-output states following cardiac surgery. J Cardiothorac Vasc Anesth 1988; 2: 409–18

13 Chan KY, Ohlweiler DF, Lang JF, Okerholm RA. Simultaneous analysis of a new cardiotonic agent, MDL 17043, and its major metabolite in plasma by high-performance liquid chromatography. J Chromat 1984; 306: 249–56[Medline]

14 Jahnchen E, Trenk D. Pharmacology and pharmacokinetics of enoximone. Z Kardiol 1991; 80: 21–6

15 Boldt J, Kling D, Dieterich HA, Marck P, Hempelmann G. The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery – pharmacokinetics and influence on parameters of coagulation. Intensive Care Med 1990; 16: 54–9[ISI][Medline]

16 Morita S, Sawai Y, Heeg JF, Koike Y. Pharmacokinetics of enoximone after various intravenous administrations to healthy volunteers. J Pharm Sci 1995; 84: 152–7[ISI][Medline]

17 Rosenthal P. Assessing liver function and hyperbilirubinaemia in the newborn. National Academy of Clinical Biochemistry. Clin Chem 1997; 43: 228–34[Abstract/Free Full Text]

18 Olomu AB, Vickers CR, Waring RH, et al. High incidence of poor sulfoxidation in patients with primary biliary cirrhosis. New Engl J Med 1988; 318: 1089–92[Abstract]





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