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Biomedical subjects

A Nergårdh

Publications and source records attributed to A Nergårdh.

At least 19 recordsLinked to original sources
PubMed1998

The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study.

PURPOSE: We report a double-blind, placebo-controlled crossover study of lamotrigine (LTG) as add-on treatment in therapy-resistant, generalized epilepsy in children and adolescents (n = 30). METHODS: Twenty patients had Lennox-Gastaut syndrome. Each patient acted as his or her own control. LTG and placebo were randomly added to existing antiepileptic medication (AEDs). The LTG dosage was individualized in an open phase preceding the placebo/treatment phase. Patients who responded to LTG in the open phase went on to the double-blind phase. "Responders " were defined as patients with a >50% seizure reduction or less severe seizures or both, or improved behavior or improved motor skills or both. "Nonresponders" were defined as children who showed no positive effects of LTG with plasma levels of < or = 10 microg/ml or children who had adverse events during the open phase. RESULTS: There was a clear statistically significant reduction of seizure frequency in LTG compared with placebo treatment. None of the children studied showed abnormal biochemical or hematologic findings, or changes in plasma levels of concomitantly administered AEDs. CONCLUSIONS: LTG is a well-tolerated and effective treatment in children with intractable generalized epilepsies, including those with Lennox-Gastaut syndrome. The study design allowed a double-blind placebo-controlled assessment of LTG although the participating children used 19 different AED combinations at entry.

Adolescent↗
PubMed1996

Pharmacokinetic interactions between lamotrigine and other antiepileptic drugs in children with intractable epilepsy.

PURPOSE: We wished to determine the oral pharmacokinetics of lamotrigine LTG and to assess possible interactions with other AEDs in an unselected population of children. Concentration data in plasma and in CSF for lamotrigine as well as for the other AEDs are presented. METHODS: Thirty-one children, children and young adults aged > 2 years with intractable generalized epilepsy despite adequate duration and dose of at least three conventional AEDs were studied. RESULTS: There was a linear relation between the dose administered and the maximal plasma concentration, indicating that saturation of absorption or elimination mechanisms did not occur in the dose range studied. The median elimination half-life (t1/2) in patients receiving concomitant valproate (VPA) was 43.3 h; in patients receiving carbamazepine (CBZ) and/or phenobarbital (PB), it was 14.1 h; and in patients receiving both VPA and CBZ/ PB or other antiepileptic drugs (AEDs), it was 28.9 h. No clinically important changes in the plasma levels of CBZ, VPA, valproate, ethosuximide, or PB were observed in the follow-up period (2-12 months). No dose adjustments of concomitant AEDs were necessary. The plasma concentration of clonazepam (CZP) was reduced when LTG was introduced. CONCLUSIONS: The complex interaction between LTG and other AEDs in children with intractable epilepsy makes therapeutic drug monitoring (TDM) desirable.

Administration, Oral↗
PubMed1993

Treatment of spasticity in children with low dose benzodiazepine.

In an attempt to investigate whether benzodiazepines at low dosage have a significant effect in reducing spasticity among children with cerebral palsy, we carried out a double-blind, placebo-controlled, cross-over study. Twelve children with either spastic diplegia or hemiplegia participated in this study. The mean age was 14 years. The restraint of passive knee movements was determined with a dynamic dynamometer and spastic stretch reflexes were measured as EMG activity in muscles stretched. Clonazepam was given at low dosage (0.02 mg/kg body weight). In each child measurements of passive restraint were made on 2 different days immediately before and 3 h after an i.m. injection of either clonazepam or placebo in randomized order. Clonazepam significantly reduced spastic restraint (P < 0.001) compared to non-significant reduction with placebo. The mean plasma concentration of clonazepam at time of spasticity evaluation was 21 mmol/l which is in the low dose range, far below conventional doses. The study thus shows a positive effect of low dose clonazepam in reducing spasticity in children when given as a single dose.

Adolescent↗
PubMed1992

Receptor function studies in specimens from the proximal human urethra obtained by transurethral resection.

During transurethral resection (TUR) for prostatic hyperplasia, specimens were taken from the proximal urethra. Muscle strips thus obtained were mounted in an organ bath and muscle contraction was induced by adding increasing concentrations of noradrenaline (NA), methoxamine (alpha 1-agonist) and clonidine (alpha 2-agonist). NA and methoxamine induced a dose-dependent muscle contraction, but clonidine had no effect. The influence of prazosin (alpha 1-antagonist) and yohimbine (alpha 2-antagonist) on the NA-induced muscle contraction was also evaluated. Both antagonists had an inhibitory effect, which was much more potent with prazosin. The specimens taken during TUR were found to be suitable for in vitro receptor function studies. The alpha-adrenergic receptor function in the proximal human urethra was found to be mainly of the alpha-type.

Adrenergic alpha-Agonists↗
PubMed1992

Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases.

The progressive myoclonus epilepsies (PME) are a heterogeneous group of rare genetic disorders. Unverricht-Lundborg disease and Lafora's disease are two major classic forms of PME. We recently assigned the gene for Unverricht-Lundborg disease (EPM1) to human chromosome 21 band q22.3. We have now refined the localization of EPM1 by linkage analysis between the disease phenotype and nine DNA markers in 13 Finnish families. Loci MX1 and CD18 flank the EPM1 interval, which spans a distance of about 3.5 megabases. In this 20-centimorgan interval, no recombinations were detected between EPM1 and marker loci BCEI, D21S19, D21S42, D21S113, D21S154, and PFKL. Within this interval a maximum multipoint lod score of 11.04 was reached at loci D21S154-PFKL. In two Swedish families with Unverricht-Lundborg disease no recombinations were detected. In three Italian families with Lafora's disease the linkage results suggested that EPM1 is not the locus for Lafora's disease.

Chromosome Mapping↗
PubMed1991

Pharmacokinetics of total and free valproic acid during monotherapy in infants.

The pharmacokinetics of free and total valproic acid (VPA) in plasma and whole blood after oral administration during steady state was investigated in seven infants (mean age 10.7 months) receiving monotherapy. The VPA concentrations in whole blood closely followed those in plasma but at a reduced level. A positive correlation was found between dose and mean plasma concentration (r = 0.71). Mean terminal half-lives were similar in plasma and whole blood (12.5 and 15.5 h, respectively), but were considerably longer than for free VPA (6.4 and 6.5 h, respectively; P less than 0.01). There was a significant decrease in half-lives with increasing age (P less than 0.05). Plasma and whole blood clearance for total VPA was higher than reported in older infants and adults (17.8 and 28.9 ml/kg per hour) and was considerably higher for free VPA (127.6 and 188.8 ml/kg per hour, respectively). The increase in clearance compared with that in older subjects is well in concordance with a lower protein binding of VPA (mean 85.3%). Of special importance is that the percentage of unbound VPA increased with increasing concentrations of total VPA. The fraction of unbound VPA in plasma increased even more in subjects with low albumin concentrations (P less than 0.01).

Blood Proteins↗
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↗
PubMed1989

Lidocaine treatment of neonatal convulsions, a therapeutic dilemma.

Three infants with neonatal convulsions were given lidocaine infusions for three days, three weeks and three months, respectively, and the plasma concentrations of lidocaine and its metabolites were analyzed by HPLC. After a prolonged infusion there was considerable accumulation of the metabolites. This may account for the difficulty of stopping the infusion without relapse of the seizures.

Female↗
PubMed1988

Pharmacokinetics of free and total sodium valproate in adolescents and young adults during maintenance therapy.

The pharmacokinetics of total and free valproic acid (VPA) in plasma and whole blood was investigated in seven adolescents and young adults (mean age 17.3 years) during a dosage interval at steady state. The concentration curves of VPA in whole blood after an oral morning dose (mean 8.2 mg/kg body wt.) closely followed those in plasma but at a reduced level. The apparent volume of distribution (Vd) of total VPA was 0.150-0.197 l/kg body wt. and of free VPA 0.911-1.58 l/kg body wt., which indicates considerable distribution of unbound VPA as well as drug binding to extravascular proteins. The terminal half-life of free VPA (6.4-6.7 h) was significantly shorter (P less than 0.05) than the half-life of total VPA (10.4-11.9 h). The binding of VPA in plasma was concentration dependent and fluctuated considerably within the individual dosage intervals. Concentrations of unbound VPA in plasma water of whole blood varied to a corresponding degree, since distribution to blood cells was low (mean 2.2%). It is concluded that there are substantial differences in the pharmacokinetics of free and total VPA. This may contribute to the well-known poor correlation between dose, plasma concentrations and effect of VPA.

Adolescent↗
PubMed1987

Changes in cholinergic innervation and neuropharmacologic properties in idiopathic hypotonic urinary bladders.

Tissue specimens from hypotonic and normotonic human urinary bladders were investigated histochemically, chemically and neuropharmacologically. In hypotonic bladders the density of acetylcholinesterase (AChE)-positive nerves was markedly reduced and the nerve AChE staining intensity was weak. The concentration of acetylcholine was significantly lower than in specimens from normotonic bladders. At field stimulation the contractions were weak. The observations indicated that sparse cholinergic innervation and reduced acetylcholine synthesis are important for the impaired contractility in idiopathic dystonic bladder.

Acetylcholine↗
PubMed1986

Influence of valproic acid on the gonadotropin-releasing hormone test in puberty.

Twelve epileptic adolescents on valproate (VPA) treatment were studied by means of clinical observation and gonadotropin-releasing hormone stimulation (GnRH) tests. Five patients were investigated before and during VPA treatment. Before treatment the basal and peak levels of gonadotropins were appropriate for age; during treatment both levels were depressed and the areas under the curves were significantly decreased. The long-term effect of VPA was studied in an additional seven patients. The basal levels of gonadotropins were as low and their response to GnRH as poor as in the second test of the first five patients--i.e., during VPA treatment. No recovery was noted in two patients after dose reduction or in a further two patients 10 months after the discontinuation of VPA treatment. In all the patients, however, the usual clinical signs of pubertal development and maturity were unaffected by VPA treatment. The significance of the results for sexual development and fertility is therefore uncertain.

Adolescent↗
PubMed1986

The effect of noradrenaline on the contractile response of the urinary bladder. An in vitro study in man and cat.

In this study, bladder muscle strips from the detrusor of man and cat were used to evaluate the modulating effects of adrenergic agonist and antagonists on the field stimulation induced contractile response. Noradrenaline (NA) inhibited and phentolamine enhanced the contraction in a dose-dependent manner. Propranolol did not influence the field stimulation response. When a study of the combined effect of adrenergic drug influence was performed, the NA-induced inhibition was partly reversed by propranolol but a further increase of the contractile response compared to the control was seen, when phentolamine was added. No species differences were found. The conclusion drawn from these results is, that the inhibiting effect of NA on the contractile response is mediated via alpha- and beta-adrenergic receptors. The former could be located on the short parasympathetic intramural neurons while the latter probably are located on muscle cells.

Aged↗
PubMed1983

Neurotransmission in activation of the contractile response in the human urinary bladder.

The endogenous contracting transmitter at the neuromuscular junction in strips from human urinary bladder has been investigated using field stimulation and selective antagonists. Atropine in low concentrations was found to inhibit bladder contractions whereas higher concentrations of the drug sometimes had the opposite effects. Indomethacin inhibited, phentolamine enhanced and methysergide had no dose-dependent effect on the field stimulation response. It is proposed that acetylcholine is one of the transmitter substances responsible for the contraction of the human detrusor. Species differences which could be responsible for the alleged atropine-resistance of the bladder are discussed. It is concluded that anticholinergic drugs should be of therapeutic value for treatment of muscular hyperactivity in the human urinary bladder.

Acetylcholine↗
PubMed1982

Plasma concentrations of valproate during maintenance therapy in epileptic children.

A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents. The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9 +/- 1.3 h (mean +/- SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a "therapeutic window" seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.

Adolescent↗
PubMed1982

Effects of narcotic analgesics, especially pethidine and norpethidine, on renal pelvic smooth muscle in patients with hydronephrosis.

Relaxation of the renal pelvic smooth muscle is usually attempted as a symptomatic treatment in painful colic of the upper urinary tract. The spasmolytic potency of morphine, pethidine, pentazocine, fentanyl, naloxone and papaverine was evaluated using noradrenaline-contracted pelvic strips from hydronephrotic patients. The order of spasmolytic potency was found to be fentanyl greater than pethidine = papaverine greater than pentazocine = naloxone. Morphine produced a dual effect, starting with contraction followed by relaxation. Norpethidine, which is the only metabolite of pethidine occurring in human plasma, had the same relaxing potency as its parent compound, pethidine. Thus, an active metabolite may play a role in the outcome of spasmolytic drug treatment.

Analgesics, Opioid↗
PubMed1982

Observations on the internal sphincter mechanism during the filling phase in children with hyperactive neurogenic bladder.

The internal sphincter mechanism in the urinary bladder was investigated in three groups of children. Two groups had neurogenic bladder, one of them with and one without detrusor hyperactivity. The third group had no myelodysplasia and normal detrusor activity in the filling phase. In this group the sphincter contractions were sustained at high pressure level, with superimposed waves of substantial amplitude. Myelodysplasia of segments below L3 was associated with hyperactivity of the detrusor. The general sphincter pattern in this condition was the same as in the normal group, but the behavior of the sphincter was not synchronized with the pressure fluctuations in the bladder. In the children with low thoracic or high lumbar level of lesion ther was no detrusor hyperactivity. Their sphincter mechanism could be characterized as passive, with low mean pressure and low amplitude of superimposed waves. When detrusor hyperactivity is present, it seems to be the main factor in leakage from neurogenic bladder. In the absence of detrusor hyperactivity in neurogenic bladder, passivity of the internal urethral sphincter due to dissociation from the spinal centers is proposed as the explanation of incontinence.

Adolescent↗
PubMed1981

Diagnosis of detrusor hyperactivity in children with neurogenic bladder.

Detrusor hyperactivity and its reproducibility was investigated in 22 patients with myelodysplasia and neurogenic bladder. The examinations were performed with microtransducers in the bladder, proximal urethra and rectum. Hyperactivity was found in 15 children all belonging to low lumbar and sacral neurological lesion groups. Patients without hyperactivity mostly had their levels of lesion higher in the spinal cord. In 6 children without neurologic disease no hyperactivity was found.

Adolescent↗