Læknaneminn - 01.10.1995, Page 142

ABSTRAKTAR
THE PHARMACOKINETIC-PHARIVIACODYNAMIC
INTERRELATIONSHIP OF DOXAPRAM AFTER
CONTINLOUS INTRAVENOUS AND ORAL
ADMINISTRATION.
Sieurður Sverrir Stephensen'.
Ruben M. Kleppestö2, Nico G. Hartwig2, John N. van den Anker2.
‘LHI, 2Department of Pediatrics, Erasmus University and the
University Hospital / Sophia Children’s Hospital, Rotterdam, The
Netherlands.
Introduction: Apnoea is a problem frequently encountered in the
neonatal intensive care unit. Doxapramhydrochloride is a respiratory
stimulant that has proved useful as a second-line drug in the treatment of
idiopathic apnoea of prematurity unresponsive to caffeine. A good
correlation has been reported between dose and serum concentration
when given I.V. and the efficacy of doxapram is directly related to its
serum concentration. The ideal plasma therapeutic concentraions are
thought to be at least 1.5 pg/mL and not exceeding 5.0 pg/mL to avoid
adverse effects. An intravenous line is necessary if the infant is being
treated with intravenous infusion of doxapram, but apart from being
technically difficult to put in, a prolonged intravenous cannulation raises
the risk of catheteral related septicemia. There is little information on
the use of doxapram via oral route, but two reports show bioavailability
of 50-60% in preterm infants. This mode of administration seems to be
as effective in controlling apnoea as the intravenous route. Our purpose
was to study the pharmacokinetic-pharmacodynamic interrelationship
of doxapram after continuous intravenous and continuous oral
administration.
Materials and Methods: Ten preterm infants with gestational
ages of less than 34 weeks, with apnoea of prematurity were studied.
Apnoeic episodes were detected during continuous cardio-respiratory
monitoring and were recorded by well-trained staff. A standard period
of apnoea was not used, but apnoeic spells were defined as cessation of
breathing with an associated bradycardia of <100 beats/min. Infants
with more than 4 apnoeic episodes per 6 hours, despite receiving
therapeutical doses of caffeine, were eligible in the study. They must
have normal serum sodium, potassium, calcium and glucose values.
Furthermore they were not allowed to have hepatic or renal dysfunction,
signs of infection, anaemia or intracranial bleeding.
The eligible infants were treated with a loading dose of doxapram
(2.5 mg/kg/hour during 15 minutes), followed by a continuous infusion
of 1 mg/kg/hour. After 24 hours the continuous intravenous
administration of doxapram was changed to continuous oral
administration of doxapram, using the same dose of 1 mg/kg/hour. This
could only be instituted if at least 50% reduction in apnoea rate was seen
during the I.V. doxapram treatment. The oral route was continued
provided that there was no rise in apnoea rate to pre-treatment values.
Blood samples were collected 24 hours after the start of both the
intravenous and the oral route. The serum was separated and kept
frozen at -20°C until the serum concentration of doxapram was
determined with HPLC-assay. Clinical responses to the drug were
closely monitored and also possible side-effects, such as gastric
residuals, abdominal distension, elevated blood pressure, jitteriness,
nausea and vomiting. Gastric pH-values were also determined to
investigate whether changes in pH-values interfere with oral absorption
of doxapram.
Results: At this moment four patients have proved eligible in the
study. The median gestational age was 26.64 weeks (range 24.71-28.00)
and the median studyweight was 1258.0 grams (range 85-1385). Before
the doxapram treatment the median apnoea rate per 6 hours was 9.5
(range 5-21). However, once doxapram treatment was started the
median apnoea rate decreased to 1.75 (range 0.3-4.3) during I.V.
infusion and to 1.25 during the following oral administration. The
median plasma level of doxapram after 24 hours continuous I.V infusion
was 1.72 pg/mL (range 0.99-4.80) and had decreased to 0.91 pg/mL
(range 0.43-3.12) after 24 hours oral administration. This suggests a
bioavailability of 53% after oral administration.
Discussion: These results reveal that apnoea of prematurity can
successfully be treated with continuous oral administration of
doxapram, following a loading dose and 24 hours intravenous infusion.
We observed that a median plasma level of only 0.91 pg/mL proved to
be effective, which is considerably less than previously recommended.
We did not detect any known adverse effects to doxapram in these four
patients during the study. This suggests that an intravenous line can
possibly be avoided in the treatment of idiopathic apnoea of prematurity.
LYFHRIF PENISILLÍNS OG CEFTRÍAXÓNS GEGN
ÓNÆMUM PNEUMOKOKKUM IN VITRO.
Sólev Omarsdóttir* 1.
Viðar Magnússon1, Helga Erlendsdóttir2, Sigurður
Guðmundsson3.
1LHI, 2Sýkladeild Landspítalans, 3Lyflœkningadeild
Landspítalans.
Inngangur: Bakterían Streptococcus pneumoniae er mikill
meinvaldur í nútímaþjóðfélagi. Hún er algengasta orsök lungnabólgu,
eyrnabólgu og skútabólgu, en veldur einnig öðrum fátíðari kvillum svo
sem blóðsýkingu og heilahimnubólgu. Penisillín var lengi kjörlyf við
sýkingum af völdum pneumokokka en síðastliðin 25 ár hefur tíðni
penisillínónæmra pneumokokka (PÓP) farið vaxandi um allan heim.
Meðferð sýkinga af völdum PÓP krefst því annarra lyija og eru þriðju
kynslóðar cefalósporín meðal þeirra sem notuð hafa verið.
Lyflirifafræði lýsir samspili lyfs og sýkils og hefur klínískt gildi tengt
skömmtun sýklalyfja.
Efniviður og aðferðir: Lyflirif penisillíns og ceftríaxóns in vitro
voru borin saman í næmum (MIC penisillíns 0,012 mg/ml) og ónæmum
(MIC 1,0 mg/ml) pneumokokkastofnum, báðum af hjúpgerð 6B.
Athuguð voru hammörk (MIC), drápshraði við mismunandi margfeldi
af MIC og eftirvirkni (PAE) við mismunandi lyfjastyrk og
verkunarlengd lyfs.
Niðurstöður og efnisskil: Drápsmynstrið var eins fyrir bæði lyf
gegn báðum stofnum, þ.e. dráp breyttist lítið er lyfjastyrkur jókst úr 2 í
128 MIC. Marktækt meira dráp fékkst gegn næma stofninum heldur en
gegn ónæma stofninum við sama margfeldi af MIC lyfjanna. Fyrir
penisillín var meðaldráp (loglO CFU/ml/4 klst) fyrir næma stofninn
50% meira en gegn ónæma stofninum og fyrir ceftríaxón var meðaldráp
næma stofnsins fimmfalt meira. PAE beggja lyfja lengdist með auknum
Iyfjastyrk gegn báðum stofnum t.d. lengdist PAE penisillíns gegn næma
stofninum úr 0,01 klst. í 3,83 klst. við aukningu styrks lyfsins úr 2 MIC
í 8 MIC. Lengingin var meiri gegn næma stofninum fyrir penisillín, en
fyrir ceftríaxón var lengingin meiri gegn ónæma stofninum. Aukin
verkunarlengd ceftríaxóns lengdi PAE gegn báðum stofnum og reyndist
lengingin meiri gegn næma stofninum. Lengri verkun penisillíns
framkallaði lengra PAE gegn báðum stofnum en gegn næma stofninum
styttist PAE á ný eftir að penisillínið hafði verkað í ákveðinn tíma.
Munur á in vitro lyflirifum penisillíns og ceftríaxóns gegn næmum og
ónæmum pneumokokkum fólst í lægra MIC, meira drápi og lengra PAE
gegn næma stofninum. Eftir fylgja in vivo rannsóknir sem skera úr um
klínískt notagildi þessara niðurstaðna.
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LÆKNANEMINN 2. tbl. 1995 48. árg.