Læknaneminn


Læknaneminn - 01.10.1995, Qupperneq 142

Læknaneminn - 01.10.1995, Qupperneq 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. 132 LÆKNANEMINN 2. tbl. 1995 48. árg.
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