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Biomedical subjects

L O Boréus

Publications and source records attributed to L O Boréus.

At least 19 recordsLinked to original sources
PubMed1997

Effects of routinely given pethidine during labour on infants' developing breastfeeding behaviour. Effects of dose-delivery time interval and various concentrations of pethidine/norpethidine in cord plasma.

A standard dose of 100 mg of pethidine was given im to 13 healthy primiparae during labour. The aim of the study was to investigate whether developing breastfeeding behaviour in the newborn infant was associated with the dose-delivery time interval (DDI) or with the plasma concentration of pethidine and norpethidine in mixed cord blood at birth. The DDI was found to be unevenly distributed with no pethidine exposures in the time interval 5.4-8 h. The material was therefore divided into a "short DDI" group (1.1-5.3 h) and a "long DDI" group (8.1-9.9 h). The infants in the "short DDI" group had a depressed sucking behaviour in 15-45 min of observation and a delayed initiation of lip and mouth movements when compared with the infants in the "long DDI" group. Six of the thirteen infants did not suck their mothers' breasts during the observation period. These infants had higher median plasma concentrations of pethidine at birth than the seven infants who did start sucking. No differences wer found between the plasma levels of norpethidine and the behaviour. It was concluded that 100 mg of pethidine im as an analgesic given under routine conditions may have unfavourable effects on infants' developing breastfeeding behaviour if the DDI is short.

Analgesia, Obstetrical↗
PubMed1995

Flunarizine of limited value in children with intractable epilepsy.

Fourteen ambulatory children and adolescents with intractable epilepsy were studied in an open phase II study to investigate the pharmacokinetics and pharmacodynamics of flunarizine as an add-on treatment. Flunarizine was given in increasing doses starting with 0.1-0.3 mg/kg/day until effect was observed or a steady-state plasma concentration of 50-60 ng/ml was reached. Treatment was continued for 3 months at steady state. Pharmacokinetics were determined during the immediate posttreatment period. Positive antiepileptic effect (> or = 50% reduction in seizure frequency) was observed in 4 of 14 patients (29%; 95% CI: 52-5). Independently of antiepileptic effect, 10 of 14 parents (71.4%; 95% CI: 95-48) observed positive cognitive effects. In all patients treatment was withdrawn due to either lack of effect or weight gain. Flunarizine was rapidly absorbed; mean time of peak concentration (Tmax) was 2.7 hours (range: 1-8). The mean terminal half-life was 23.2 days (range: 7-48), the total plasma clearance of flunarizine per fraction of the dose absorbed (CLp/F) was 0.28 ml/min/kg (range: 0.07-042), and the volume of distribution of flunarizine per fraction of the dose absorbed (Vd/F) was 187 L/kg (range: 99-348). We conclude that flunarizine (0.1-0.3 mg/kg/day) seems to be of limited antiepileptic value in children with intractable epilepsy. The pharmacokinetic profile of flunarizine complicates its clinical use.

Adolescent↗
PubMed1994

Plasma acetylsalicylic acid and salicylic acid levels during aspirin provocation in aspirin-sensitive subjects.

The ability of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit the cyclo-oxygenase which catalyzes formation of prostaglandins appears to be central to the mechanisms involved in aspirin sensitivity. We have investigated whether the plasma levels of acetylsalicylic acid (ASA) and its main metabolite salicylic acid (SA) at the time of intolerance reactions correspond with the concentrations required for enzyme inhibition in vitro. Twelve aspirin-sensitive and 15 aspirin-tolerant subjects were followed during provocation with aspirin. ASA and SA concentrations in plasma were determined by HPLC. After oral provocation (up to 460 mg cumulative dose), the levels of ASA and SA in plasma were equivalent in aspirin-sensitive and aspirin-tolerant subjects. For the aspirin-sensitive subjects, at the time of adverse reaction, the concentration range was 2.9-33.3 microM for ASA and 18.1-245 microM for SA. Oral provocation with sodium salicylate yielding 10-fold higher SA levels did not elicit intolerance reactions. Statistically significantly lower levels of ASA and SA (P < or = 0.01) evoked airway obstruction, as compared with merely extrapulmonary symptoms. Bronchial absorption of aspirin was found after inhalation of lysine-aspirin and was comparable in asthmatic and nonasthmatic subjects. In three aspirin-sensitive subjects who developed airway obstruction, the plasma levels for ASA and SA were 0.9-2.6 microM and 0.0-6.7 microM, respectively. In conclusion, the plasma levels of ASA reached at the time of a positive reaction are of the magnitude known to inhibit cyclo-oxygenases. Neither differences in bioavailability of ASA nor the formation of SA seems to contribute to the aspirin-elicited reactions.

Administration, Oral↗
PubMed1993

Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery.

A double blind randomised cross over investigation was carried out in 25 male patients undergoing two oral surgical extractions, one for each lower wisdom tooth. The two extractions were performed about 6 weeks apart and were carried out under local anaesthesia. One hour after each extraction the patients randomly received 90 or 45 mg codeine. During the following 5 h the patients rated the intensity of their pain on a visual analogue scale. Blood was simultaneously sampled and assayed for codeine and its metabolite morphine. Mean pain intensity difference was just significantly higher after 90 mg codeine compared to 45 mg. The mean plasma concentrations of codeine and morphine were significantly higher after the 90 mg dose. However, for the two dose levels of codeine there was no obvious relationship between the difference in analgesic effect and the difference in the plasma concentration of codeine or morphine. The plasma concentrations of morphine were 2-3% of those of codeine and the levels were relatively low. Local formation of morphine from codeine within the human brain should therefore be investigated. Four patients were unable to demethylate codeine to a detectable plasma concentration of morphine after 90 mg codeine. In those patients the analgesic effect during the first hours was better after 90 mg codeine than after 45 mg. This suggests some analgesic effect of codeine itself.

Administration, Oral↗
PubMed1990

Monitoring of phenytoin in epileptic children: value of the single morning sample.

The intra-individual variation in plasma concentration of phenytoin was studied in ten clinically well controlled children on monotherapy. The drug concentration was determined in routine pre-dose samples taken on three to five different mornings. On two of these occasions, plasma phenytoin was also determined at 0.5, 1, 2, 3, 5 and 7 h after the dose. The difference between the highest and lowest morning concentrations in a patient varied between 7.5 and 40 mumol/l (mean 20.1 mumol/l). Half of all morning concentration values were lower than 40 mumol/l. This often-recommended lower limit for good seizure control should therefore be reconsidered. The two concentration versus time curves in each patient during 7 h after administration differed considerably in shape, and the first curve could not be used for prediction of the second curve. The ratio between unbound and total drug was very stable and amounted to 9.4, SD 0.94% (n = 168). It is concluded that the conventional single morning sample is satisfactory for routine monitoring in well-controlled children on monotherapy with phenytoin. In problem patients, and during combination therapy, however, more extensive investigation will be necessary, including repeated morning samples as well as determination of dose-interval curves and protein binding.

Adolescent↗
PubMed1990

Pain in the newborn--pharmacodynamic aspects.

Pain is subjective and can be quantitated in others only through cognitive cooperation between the sufferer and the observer. The newborn infant can neither describe pain nor remember it later in life. Thus, strictly speaking, we will never know if a pain experience can occur in the newborn period. However, many observations suggest that a nociceptive function exists at birth: (1) the neuronal pathways and transmitter systems required for pain conduction in adults seem to be present already during fetal life: (2) noxious stimulation of the newborn leads to behavioural responses and stress-related biochemical changes, and (3) the use of anaesthetic and analgesic drugs may improve the clinical outcome following surgery. The main features of the pharmacokinetics in the newborn period of both peripherally and centrally acting analgesics are now relatively well known and at least the short-term side effects are predictable and generally avoidable. Even if long-term adverse drug effects due to impaired imprinting have been suggested it appears that nociceptive stimuli in the newborn should be considered being disadvantageous to the patient. If they cannot be avoided, they should be treated.

Analgesics↗
PubMed1989

The role of therapeutic drug monitoring in children.

Routine use of therapeutic drug monitoring in children is helpful in individualizing the dosage during long term treatment (e.g. theophylline and antiepileptic drugs) and in checking against toxic accumulation of drug in neonates (e.g. digoxin, theophylline/caffeine and aminoglycoside antibiotics). In individual patients, measurements of drug concentrations in plasma may be the only way to elucidate clinically unexpected drug effects or to handle interaction phenomena. Knowledge of the pharmacokinetic and pharmacodynamic changes during development is a prerequisite for a correct interpretation of the concentration values. Unfortunately, the quantitative relation between kinetics and clinical effect is still relatively poorly known for many drugs in the paediatric age groups. Apart from the pharmacokinetic informative value, therapeutic drug monitoring also has some merit as an aid to the physician in explaining to the patient and the parents why the drug should be taken as instructed. This may improve compliance.

Adolescent↗
PubMed1988

CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine.

The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg; n = 6) or lumbar intrathecal (25 mg; n = 5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45,000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml.kg-1 and clearance from the CSF was 15 microliters.kg-1.min-1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng.ml-1 and 14 to 210 ng.ml-1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1988

Liquid-chromatographic quantification compared with gas-chromatographic-mass-spectrometric determination of verapamil and norverapamil in plasma.

A high-performance liquid chromatographic (HPLC) method for determining verapamil and norverapamil in plasma is presented and compared with gas chromatography/mass spectrometry (GC-MS). The plasma samples were extracted at alkaline pH with hexane containing 2-butanol (20 mL/L) and then back-extracted into phosphate buffer (0.1 mol/L, pH 3.0). For chromatography we used a reversed-phase column (Supelcosil LC-18 DB) with a mobile phase of the phosphate buffer and acetonitrile (70/30 by vol). Fluorescence detection was used (excitation at 203 nm, emission at 320 nm). Overall analytical recovery was 85%. Standard curves were linear from 1 to 1000 micrograms/L. The detection limit was 1 microgram/L. The assays are accurate and precise. We found no interferences by those substances tested. Results by HPLC and GC-MS agreed well (r = 0.99) for both verapamil and norverapamil determinations.

Chromatography, High Pressure Liquid↗
PubMed1986

Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration.

Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2-3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.

Administration, Oral↗
PubMed1985

Comparison of renal excretion of pethidine (meperidine) and its metabolites in old and young patients.

In a previous study old subjects were found to eliminate pethidine and its active metabolite norpethidine more slowly than young people. To investigate whether this was due to the decline in renal function with age, the urinary output of pethidine and its metabolites pethidinic acid, norpethidine and norpethidinic acid was compared in old and young patients. The cumulative urinary excretion of pethidine and pethidinic acid over 24 h was similar in old and young patients. The slower elimination rate of pethidine from plasma might therefore be due to slower biotransformation of pethidine to norpethidine and norpethidinic acid. The cumulative urinary excretion of norpethidine and norpethidinic acid during 24 h was significantly lower in old patients than in young: 2.7% versus 7.1% (p less than 0.001), and 5.5% versus 10.5% (p less than 0.001). The renal clearance of norpethidine was inversely correlated with age. Thus, the slower disappearance of norpethidine from plasma in old patients is due to slower renal excretion of this metabolite. The renal clearance of pethidine showed pH-dependence and was usually smaller than the creatinine clearance. In contrast, renal clearance of norpethidine was correlated with creatinine clearance and was of the same magnitude. The difference in renal handling may be explained by the more polar character of norpethidine compared to its parent compound. The present study shows that not only the excretion of unchanged drugs may decline with increasing age but also that of drug metabolites, which may therefore reach higher plasma levels in old patients. If they are pharmacologically active they will increase and prolong the response to medication and possibly increase the risk of side effects.

Adolescent↗
PubMed1984

Phenobarbital prophylaxis for hyperbilirubinemia in preterm infants. A controlled study of bilirubin disappearance and infant behavior.

Phenobarbital (PB) has been used at several pediatric centers for prophylaxis against neonatal hyperbilirubinemia. However, few attempts have been made to evaluate this procedure quantitatively, and a variety of dose schedules has been proposed. Therefore, a randomized, controlled clinical trial was performed in which the effects on bilirubin disposition and on neonatal behavior was quantitated. Forty-three preterm infants were randomized into one of four dose groups and given 0, 4, 8, or 12 mg of PB per kg in a single dose within the first few hours after birth (mean 2.2 h). The total serum bilirubin disappearance rate was found to be significantly increased (p less than 0.01) only in the 12 mg/kg group. This effect was not evident until postnatal day 7. The 4 and 8 mg/kg groups were not significantly different from the control group at any time. Infant behavior was monitored by a non-invasive time-lapse filming technique. The time spent in quiet sleep was found to be proportional to the plasma PB concentration at one day of age (r = 0.61). The infants in the 12 mg group spent a larger proportion of time in quiet sleep than the other groups (p less than 0.05). The plasma half-lives, plasma clearances and volumes of distribution of PB were similar in the three dose groups. No correlation was found between the pharmacokinetics and the gestational age of the infant. It is concluded that in order to enhance the bilirubin disappearance rate, PB has to be administered in doses that will affect behavior.

Bilirubin↗
PubMed1984

Transfer of terbutaline into breast milk.

Terbutaline has been determined in milk and plasma from 4 nursing mothers treated with Bricanyl tablets (2.5 or 5 mg, 3 times daily) because of obstructive lung disease. Both doses produced milk concentrations of terbutaline in the range 2.5-4.6 ng/mL, which were similar to or higher than the concentrations found in plasma. The highest milk:plasma concentration ratios (up to 2.9) were observed at the beginning and end of the dosage interval. The infants in this study were estimated to have ingested about 0.4-0.6 micrograms/kg/day of terbutaline base, which corresponds to 0.2-0.7% of the daily dose per kg taken by the mothers. Terbutaline was not detectable in plasma when samples were taken from one of the infants and no symptoms of beta-adrenoceptor stimulation could be found in any of the babies.

Biological Transport↗
PubMed1983

Appearance of pethidine and norpethidine in cerebrospinal fluid of man following intramuscular injection of pethidine.

The plasma and cerebrospinal fluid (CSF) concentrations of pethidine and its main metabolite in plasma, norpethidine, were determined in 20 patients undergoing minor surgery who had received pethidine chloride as premedication in a standard dose of 100 mg intramuscularly. The disposition of pethidine and norpethidine in plasma was followed for 3-8 h after administration. The rate of transfer of the drug and its metabolite from plasma to CSF was assessed on the basis of a single sample of CSF taken from each patient. Pethidine appeared within less than 18 min in the CSF, reaching a maximum after about 90 min. After that, the pethidine concentration ratio CSF/plasma was relatively stable at 0.4-0.5. This is in agreement with the concept that the concentration of a drug in CSF is correlated with the concentration of unbound drug in plasma at equilibrium. Norpethidine which was present in rapidly increasing concentrations in plasma after a delay of 30 min, appeared in CSF in a slower and more erratic fashion as compared to the parent compound. However, after 240 min, the CSF/plasma concentration ratio was similar for pethidine and norpethidine. Thus, transfer from plasma to CSF occurs relatively rapidly. There is little evidence for a functionally significant blood-brain barrier for pethidine and norpethidine.

Adult↗
PubMed1983

Digoxin therapy and left ventricular performance in premature infants with patent ductus arteriosus.

Left ventricular systolic time intervals were assessed in 16 preterm infants with symptomatic left-to-right ductal shunts, before, during and after digoxin therapy. An intravenous loading dose of digoxin, 20 micrograms/kg, resulted in a serum digoxin concentration of 1.94 +/- 0.44 nmol/l (mean +/- 1 SD) but in no significant change in heart rate or systolic time intervals. Digoxin maintenance, 2.5 micrograms/kg/12 h, led 3-7 days later to serum concentrations of 2.57 +/- 1.06 nmol/l with an associated shortening of left ventricular ejection time (p less than 0.05) which probably reflected a reduced ductal shunt. Digoxin therapy was withdrawn after ductal closure. The terminal serum half-life was 87 +/- 17 h. Decreasing digoxin concentrations were associated with prolongation of left ventricular ejection time (p less than 0.01). Digoxin therapy did not seem to influence left ventricular systolic time intervals while ductal patency persisted. This may be attributed to limitations of the method or the left ventricle already working at its maximum.

Digoxin↗
PubMed1983

Drug binding to plasma proteins during human pregnancy and in the perinatal period. Studies on cloxacillin and alprenolol.

Plasma protein binding of one acidic drug, cloxacillin, and one basic drug, alprenolol, was determined by equilibrium dialysis at +37 degrees C during pregnancy and the 1st postnatal week in 12 women and their newborn infants and in 7 nonpregnant women (controls). A significant increase in fraction free cloxacillin in maternal plasma occurred during pregnancy already from the 2nd trimester compared to the controls (p less than 0.01) and was most pronounced at delivery (median values 0.126 and 0.069, respectively). A similarly increased fraction free cloxacillin was found in cord blood (median value 0.108) which further increased during the 1st postnatal week (range 0.112-0.164). In maternal plasma the binding capacity returned to the values of the controls during the same time period. The binding of cloxacillin was significantly correlated with the concentration of albumin (p less than 0.01). High correlation was also found between binding of the basic drug alprenolol and concentration of orosomucoid (p less than 0.005). This was most obvious in the newborn infants with low concentrations (range 0.1-0.3 g/l) and in the mothers during the puerperium with high concentrations of orosomucoid (range 0.7-2.5 g/l). On the basis of plasma protein binding data in the mother and her child, a maternal to fetal plasma concentration ratio was calculated. For cloxacillin this ratio was close to unity (1.03), while it was significantly above unity for alprenolol (1.72). At equilibrium, therefore, the total plasma concentration of alprenolol in the mother can be expected to exceed the concentration in her infant.

Adolescent↗