Acta pharmacol. el toxicol. 1977, 41,193-202.

From the Department of Pharmacology, Institute of Biomedicine, University of Turku, Finland, the Department of Clinical Pharmacology, Institute of Pharmacology, Arhus, Denmark, and the Departments of Neurosurgery and Paediatrics, University Hospital, Lund, Sweden

Passage of Digoxin into Cerebrospinal Fluid in Man BY H. Allonen, K.-E. Anderson, E. Iisalo, J. Kanto, L.-G. Striimblad and G. Wetlrell (Received February 23, 1977; Accepted March 14, 1977)

Abstract: The passage of digoxin into the cerebrospinal fluid (CSF) was studied in 8 infants on maintenance therapy with digoxin, 11 adult patients on long-term

digoxin therapy, and 15 patients, previously non-digitalized, who were given 0.5 mg digoxin orally 1 hr to 12 hrs prior to lumbar puncture. Digoxin in the serum and CSF was determined by radioimmunoassay. In the infants a mean serum concentration of 1.5 ng/ml (range 0.7-2.3 ng/ml) was found, and a simultaneous mean CSF concentration of 0.5 ng/ml (range 0.3-1.1 nglml). In the adults on long-term therapy, the corresponding figures were 1.1 nglml (range 0.5-2.2 nglml) and 0.3 nglml (range 0-0.6 nglml). Among the 15 patients given a single oral dose of digoxin, detectable CSF concentrations (0.2-0.3 ng/ml) were found in five, 1-12 hrs after the administration of the drug. In three paediatric patients with hydrocephalus (3 months - 5 years) digoxin therapy was started as an attempt to decrease CSF production. In these patients, the production of CSF was reduced by 17, 25 and 30 %, respectively. Key-words; Digoxin - cerebrospinal fluid - blood-brain-barrier - man.

It is known that the choroid plexus, both in mammals and man, has a magnesium-dependent, ouabain-sensitive, sodium-potassium activated ATPase, which is essential for the active production of cerebrospinal fluid (CSF) (VATESet ~ l 1964; . OPPELT & PALMER 1966; DAVSON 1967). Cardiac glycosides have a specific affinity for, and bind to, this enzyme which has been suggested to be the “digitalis receptor” (REPKE & PORTIUS 1963) It has also been shown in animal experiments that cardiac glycosides in small amounts

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H.ALLONEN ET AL.

increase and in large amounts inhibit CSF production (VATESet al. 1964; OPPELT& PALMER1966; DAVSON 1967). Probably because of binding to the ATPase, digoxin is accumulated in the choroid plexus both in man (BERTLERet al. 1973) and in animals (DAS GWTA & BINNON1974). NEBLETT et al. (1972) demonstrated that digoxin in "normal doses" could reduce the production of CSF by as much as 78 % in patients requiring ventricular drainage. As this might have important therapeutic implications, it was considered of interest to study further the passage of digoxin into the CSF and to evaluate its possible therapeutic effect in infants and in children with hydrocephalus.

Materials and Methods Patients. Infants and children. Ten infants and children, aged 1 month to 5 years were investigated. They were all on maintenance therapy with digoxin (0.006-0.020 mg/kg/ day) because of heart failure and/or because of hydrocephalus (table l), and were subjected to lumbar puncture for diagnostic purposes. This offered an opportunity to determine the concentrations of digoxin in simultaneously taken samples of senim and CSF. All the paediatric patients investigated had been on digoxin treatment for at least three days; the serum and CSF samples were taken at least four h after the last dose. In three paediatric patients, hospitalized for investigation and treatment of hydrocephalus, the effects of digoxin on the rate of production of CSF were studied. The method for determination of CSF production described by IMAssmuum (1934) was used in two patients; in one, the rate of CSF production was measured by means of et al. (1972). continuous drainage as described by NEBLETC Adults. Twenty-six hospitalized patients were selected for the study. They were going to be operated for various reasons in spinal anaesthesia. Most of them had more than one disease, and were on multiple drug therapy. All had normal serum creatinine values (below 120 pmol/l). Further characteristics are given in tables 2 and 3. Fifteen non-digitalized patients received 0.5 mg digoxin orally 1 to 12 hrs prior to the lumbar puncture. Eleven patients on long-term digoxin therapy because of heart failure, with daily doses of 0.125 to 0.25 mg, received their last dose 12 hrs prior to the lumbar puncture. Samples were obtained simultaneously from venous blood and CSF immediately prior to the injection of a local anaesthetic into the CSF. One male patient, aged 55 years, who suffered from a brain stem tumour and who had a continuous CSF-drainage, was digitalized because of incipient cardiac insufficiency. He received 0.5 mg digoxin intravenously and the glycoside concentrations in the serum and CSF were followed at regular intervals during a 12-hrs period. Analysis of digoxin. The concentrations of digoxin in the serum and CSF were determined by radioimmunoassay (SMITHet al. 1969) using antiserum prepared by the authors (ALLOWN et al. 1975), or a commercially available digoxin kit with tritiated digoxin as tracer (Schwarz/Mann, Orangeburg, New York, USA). The detection limit for both methods was 0.2 nglml. In some of the infants, the amounts of digoxin in CSF were also determined by an *'Rb assay (B~TLJ?.R& RZDFORS 1970).

195

DIGOXIN IN CSF

Table I . Distribution of digoxin (nglml) in serum and cerebrospinal fluid in infants during maintenance therapy. The samples were taken simultaneously at least 4 hrs after oral intake of the glycoside. Patient

Age (days) 25 81 31 43 120 50 23 155

Mean range

Digoxin dosage, Digoxin concentration in mglkglday serum CSF

CSF/serum ratio

0.010 0.020 0.010 0.008 0.015 0.009 0.008 0.006

2.3 2.3 1.5 1.6 1.2 0.9 0.7 1.4

1.1 0.3 0.5 0.4 0.4 0.5 0.3 0.5

0.48 0.13 0.33 0.25 0.33 0.56 0.18 0.36

0.011 0.0064.020

1.5 0.7-2.3

0.5 0.3-1.1

0.33 0.13-0.56

Results Infants and children. Table 1 gives the concentrations of digoxin in serum and CSF in the paediatric patients on maintenance therapy. A mean serum concentration of 1.5 ng/ml (range 0.7-2.3 ng/ml) was found. The mean concentration in CSF was 0.5 ng/ml, ranging from 0.3 to 1.1 ng/ml. In the three patients in whom the rate of CSF production was measured, digoxin decreased CSF production. Patient E H was a boy, 6 months old, with chondrodystrophy and a moderately active hydrocephalus. CSF production (measured according to IV~ASSERMAN) was 0.1 11 ml/min. before therapy. After digoxin therapy (maintenance dose, 0.016 mg/kg/day) was started, CSF production was reduced to 0.082 ml/min., i. e. a reduction of approximately 25 70.However, this reduction was not sufficient, and the patient was operated and received a ventriculo-atrial shunt one month later. Patient P E was a boy, 3 months old, with hydrocephalus due to delivery trauma and secondary basal arachnoiditis. He had moderate symptoms, but a marked increase of the circumference of the head. His CSF production before therapy (measured according to ~ ~ A S S E R M A Nwas ) 0.140 ml/min., and during digoxin therapy 0.116 mllmin., i. e. a reduction of 17 Vo. The results of the therapy (maintenance dose, 0.015 mg/kg/day) has been satisfactory, with no further abnormal increase in head circumference. Patient A B was a boy, 5 years old, with myoelomeningocele and hydro-

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H. ALLONEN ET AL.

Table 2. Patient characteristics and digoxin concentrations in serum and CSF 12 hrs after last dose in long-term therapy. Sex patient F=female Age Digoxin dosage =male (years) mglkglday 1 3

6 10 14 15 17

22 24 25 26

F F F F F F F F F F M

81 69 68 92 86 92 90 80 68

0.0025 0.0053 0.0047 0.0031 0.0025 0.0025 0.0050 00.038 0.0018 0.0017 0.0018

78 74

80

Mean range

68-92

Digoxin concentration, nglml Serum CSF

0.0032 0.0017-0.0053

0.31 0.27 0.30

1.3 1.1 1.o 0.8

0.4 0.3 0.3 0.2

1.2 1.4

0.5

2.2 1.4 0.5 0.6 0.7

0.5

0.25 0.42 0.29

0.4

0.23 0.21 0 0.33

0.3 0 0.2 0.6

1.1 0.5-2.2

CSFlserum ratio

0.86

0.3

0.31

S0.6

0-0.86

cephalus. He had previously been treated with a ventrimlo-atrial shunt ad modum Spitz-Hdter. Because of infection, the shunt was extirpated. Two days after the operation, the patient developed an acute increase in intracranial pressure and continuous CSF-drainage (at 15 mmHg) was instituted. j0I

A=infantr *=adults y = 0 . 2 1 4 ~ 0.122 r = 0.5225 p< 0.05

C

A

0

1 I

0

I

0.5

1 .o

1.5

2.0

2.5

SERUM DIGOXIN, ng/ml

Fig, 1. The correlation between serum and CSF digoxin concentrations.

197

DIGOXIN IN CSF

Table 3. Patients characteristics and digoxin concentrations in serum and CSF after a single dose of 0.5 mg.

Patient

4 13 16 18 20

Sex F=female M =male

F M F F M

mean range 5 8 19 23

M F M M

mean range 2 7 9 11 12 21 mean range

F M M F F

M

Digoxin concentration, nglml serum CSF

Age (years)

Weight kg

69 51 80 72 58

70 91 64 74 75

1.5 1.9 1.1 4.0 1.4

66 51-72

75 7&91

2.0 1.1-4.0

61 17 77 48

68 80 77 108

1.9 0.7 0.8 1.9

66 48-77

83 68-108

1.3 0.7-1.9

69 76 59 81 71 65

79 54 79 75 80 68

0.7 0.8 0.3 1.o 0.8 0.5

70 59-81

73 54-80

0.7 0.3-1.0

Time after digoxin intake hrs 1

0 0.3 0 0 0

1 1

0 0.2 0 0

2 4 3 2

0 0.2 0 0.2 0.3 0

12 12 12 12 12 12

1 1

During digitalization, the CSF production was approximately 140 ml/day. Some days after discontinued therapy (0.007 mg/kg/day), the CSF production rose to 170 ml/day. The reduction during glycoside intake was about 30 Yo. Adults. The patients on long-term therapy (table 2) had a mean serum concentration of 1.1 ng/ml, ranging from 0.5-2.2 ng/ml 12 hrs after the last dose was given. The corresponding mean CSF concentration was 0.3 ng/ml (range 0.0-0.6 nglml). The concentrations of digoxin in CSF correlated significantly with the levels in serum during maintenance therapy, r = 0.5 (P