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Biomedical subjects

B Dahlström

Publications and source records attributed to B Dahlström.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacokinetics of ketotifen after oral administration to healthy male subjects.

The pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross-over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC-MS method. The limit of quantitation was 40 pg ml-1. Inter-day precision and accuracy calculated from quality control samples were 16.3 per cent (-1.9 per cent), 19.8 per cent (+4.5 per cent) and 23.6 per cent (+5.9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml-1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml-1 after the syrup formulations and 300 pg ml-1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half-life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.

Administration, Oral↗
PubMed1991

Dose-proportionality of eltoprazine. Pharmacokinetics of single oral doses in healthy subjects.

Eltoprazine. HCl belongs to a new class of psychotropic drug, the serenics. The dose-proportionality and pharmacokinetics of eltoprazine HCl has been investigated after single oral doses of 5, 10, 20 mg (18 subjects) and 30 mg (12 subjects) in a partly randomized, cross-over design. Eltoprazine was well tolerated and there were no relevant changes in safety parameters. All subjects showed irregular plasma-concentration-time profiles, some subjects demonstrating secondary peaks. The mean half-life was calculated to be about 6.5 h. The renal excretion of eltoprazine was characterized by net tubular secretion. AUC, peak plasma concentrations and the amount excreted unchanged in the urine were linearly related to the dose. Renal clearance and t1/2 were independent of dose. Thus, eltoprazine HCl was well tolerated orally and exhibited a linear pharmacokinetic profile.

Administration, Oral↗
PubMed1991

Inter- and intraindividual variability in the concentration-effect (sedation) relationship of flunitrazepam.

1. The relationship between plasma flunitrazepam concentrations and the degree of sedation was evaluated in 20 healthy subjects receiving two single oral doses of 1 mg flunitrazepam on two different occasions (1 week apart). The degree of sedation was rated blindly during the two treatment sessions in parallel with blood sampling (48 h). 2. A strong correlation between the concentrations of flunitrazepam in plasma and the degree of sedation was found according to the sigmoid Emax model. The plasma drug concentration producing 50% of maximal effect (EC50) was found to be 7.0 and 6.5 ng ml-1 on the two occasions, respectively. The variability in EC50 between subjects was larger (C.V. 39%) than the variability within subjects (C.V. 27%). 3. The steepness of the concentration-response curve as reflected in the slope factor(s) showed a virtual 'all or none' response to flunitrazepam with s values ranging from 3 to 30 with a mean of about 14. 4. The results in young healthy subjects suggest that the present dosage recommendations for temporary insomnia (1-2 mg) may be inappropriate; the dose can probably be reduced to 0.5 mg in some patients to achieve moderate sedation.

Dose-Response Relationship, Drug↗
PubMed1990

Pharmacokinetics of oral noscapine.

The relative bioavailability in 20 healthy volunteers of 100 mg, 200 mg and 300 mg tablets of noscapine and 200 mg as a solution has been assessed in a four-way cross-over study, with repeated administration of the 200 mg dose to assess intraindividual variability. There was a disproportionate increase in the AUC of noscapine tablets, as a 3-fold increase in dose produced a 9-fold rise in AUC. This dose-dependency could mainly be attributed to saturable first-pass metabolism of the drug. Administration of noscapine as a solution resulted in a significantly higher maximal concentration at an earlier time-point and a higher AUC than the corresponding dose as tablets. Repeated administration of noscapine tablets and solution yielded higher AUC on the second dosing occasion. No cause for this carry-over effect was found, and the contribution of remaining noscapine was negligible. The terminal half-life of noscapine, which was independent of formulation or dose size was 4.5 h. Both inter- and intraindividual variability in noscapine kinetics were very high, e.g. 73% and 51% CV of the AUC for the 200 mg tablet.

Administration, Oral↗
PubMed1990

Serum protein binding of noscapine: influence of a reversible hydrolysis.

The binding of the antitussive drug noscapine to human serum, pure albumin and alpha 1-acid glycoprotein has been investigated by ultrafiltration and equilibrium dialysis, using radiolabelled noscapine. The binding in serum pooled from volunteers was 93 +/- 0.2% (at 100 ng mL-1). After incubation for 24 h the binding decreased to about 85% (ultrafiltration 87.0 +/- 1.0%; equilibrium dialysis 84.3 +/- 1.2%), because of the conversion of noscapine to noscapinic acid. Only unbound drug underwent this hydrolysis, and as noscapine is extensively bound in healthy volunteers, this elimination process is probably unimportant. The major binding protein of noscapine was albumin (K = 3060 M-1, n = 5.62), but the binding to alpha 1-acid glycoprotein was also substantial (K = 31,500 M-1, n = 1.73). The interindividual variation in binding was low and binding was linear at the concentrations observed after therapeutic doses (0-500 ng mL-1).

Blood Proteins↗
PubMed1988

Characterization of high-affinity binding sites for the antitussive [3H]noscapine in guinea pig brain tissue.

We have characterized the binding of the antitussive alkaloid [3H]L-alpha-noscapine ([3H]noscapine) to guinea pig brain. Binding of [3H]noscapine to brain homogenate is stereospecific, saturable, reversible, heat-sensitive and manifests high affinity (Kd = 7 nM). Binding sites are present in all major brain areas, with the thalamus exhibiting the highest density. Subcellular localization studies showed an enrichment of binding sites in the synaptosomal fraction. Some structurally related compounds with antitussive properties (narceine, hydrastine, narcotoline and papaverine) were potent competitors, while other antitussives did not inhibit [3H]noscapine binding. Various ligands that bind to known neurotransmitter receptors failed to displace [3H]noscapine binding or had IC50 values in the micromolar range. It was concluded that the noscapine binding sites are different from those previously described for antitussives such as codeine and other opiates, or dextromethorphan.

Animals↗
PubMed1986

Excretion of noscapine in human breast milk.

The excretion of noscapine in human breast milk was studied in 8 lactating women given a single oral dose of 100 or 150 mg after a light breakfast. Serum and milk samples were collected for 24 h after drug intake. Although noscapine is a weak base, only a small amount was excreted in the milk. The median milk/serum ratio was 0.29, range 0.15-0.88. The noscapine dose received by a child during a 24 hour period, when the maternal dose is 50 mg t.i.d., was calculated to be 0.8 (0.4-1.9) micrograms/kg (median and range).

Adult↗
PubMed1986

Influence of naloxone infusion on analgesia and respiratory depression following epidural morphine.

The influence of two different concentrations of iv naloxone infusion on the analgesia and adverse effects of epidural morphine were compared in a double-blind, placebo-controlled study. Forty-five patients undergoing gallbladder surgery were provided postoperative analgesia by 4 mg epidural morphine; they then received an iv infusion over a 12-h period consisting of either 5 micrograms X kg-1 X h-1 naloxone, 10 micrograms X kg-1 X h-1 naloxone, or saline. Pain relief was assessed by hourly visual analog scoring (VAS) and by direct questioning of the patient. Requirement of additional analgesia was noted. Respiratory frequency was monitored every 15 min and arterial blood gases were analyzed every 2 h for 24 h. Peak expiratory flow (PEF) was recorded 6 and 24 h postoperatively. Steady-state kinetics of naloxone were determined by a modified radioimmunoassay (RIA) method. All patients had good to excellent postoperative pain relief. Naloxone, 5 micrograms X kg-1 X h-1, did not appear to have any effect on epidural morphine analgesia. However, naloxone infusion at the rate of 10 micrograms X kg-1 X h-1 reduced the duration of analgesia by about 25%, and more frequent injections of epidural morphine were required to give effective analgesia. Complete reversal of analgesia was not seen in any patient. A dose-related stimulatory effect on respiratory frequency was noted in the groups receiving naloxone. PaCO2 values also were better in these groups as compared to values in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Pharmacokinetics and pharmacodynamics of epidural and intrathecal morphine.

Spinal opiate analgesia has opened an exciting new field of research and has also rapidly gained widespread clinical acceptance. This mode of administration has obvious and definite advantages over conventional pain therapy; however, the field is still at an early stage of development. More research is clearly needed to provide methods for coping with some of the drawbacks of this method of pain relief. Important areas for future research include (1) the CSF kinetics of opiates; (2) the physiological mechanisms underlying the rostral spread of drugs within the CSF compartment; (3) a search for safer and more selective drugs; and (4) an evaluation of the extent to which pain-modulating systems at different levels in the CNS can be regulated by opiates and drugs interfering with other neurotransmitters. In this context it is essential to emphasize the importance of simultaneous study of the pharmacokinetics and the pharmacodynamic/clinical effects in providing a rational basis for a better understanding of the mechanisms of actions underlying spinal opiate analgesia.

Anesthesia, Epidural↗
PubMed1984

Pharmacokinetic aspects of intrathecal morphine analgesia.

Fifteen patients undergoing thoracotomy were given 0.25 or 0.50 mg morphine intrathecally (L2-L3 or L3-L4) for an analgetic and pharmacokinetic study. Administration of morphine at the end of the operation resulted in a highly variable duration of analgesia ranging from 1-20.5 and 1-40 h for the 0.25 and 0.50 mg groups, respectively. Calculation of cumulative consumption pattern of additional analgesics given im indicated a dose-related analgesia lasting around 12 h. Morphine concentrations in the CSF were high and dose dependent. Thus, at 1 h, CSF concentrations (means +/- SEM) were 4,228 +/- 361 ng/ml and 10,447 +/- 1,538 ng/ml for the 0.25 and 0.50-mg groups, respectively. The plasma concentrations generally were very low, i.e., under 1 ng/ml. For the 0.50 and 0.25 mg groups, the terminal elimination half-life in CSF was 175 +/- 9 min and 196 +/- 13 min, respectively: the volume of CSF distribution was 0.88 +/- 0.16 ml X kg-1 and 1.06 +/- 0.17 ml X kg-1, respectively: and the clearance from CSF was 2.81 +/- 0.41 microliter X kg-1 X min-1 and 3.41 +/- 0.55 microliter X kg-1 X min-1, respectively (means +/- SEM). The study indicates that the significant pharmacokinetic parameter related to the long duration of analgesia after intrathecal morphine administration probably is the high CSF concentrations found, since the rate of elimination from CSF is similar to what is reported for morphine in plasma. Furthermore, modulation of nociceptive input in the thoracic region also may be achieved by lumbar administration, but a slower onset should be anticipated.

Aged↗
PubMed1984

Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: influence on postoperative ambulation and pulmonary function.

In a randomized double-blind study of thirty grossly obese patients undergoing gastroplasty for weight reduction, the effects of intramuscular and epidural morphine were compared as regards analgesia, ambulation, gastrointestinal motility, early and late pulmonary function, duration of hospitalization, and occurrence of deep vein thrombosis in the postoperative period. The patients were operated on under thoracic epidural block combined with light endotracheal anesthesia. A six-grade scale was devised to quantify postoperative mobilization. A radioactive isotope method using 99mTc -plasmin was employed to detect postoperative deep vein thrombosis. For 14 hr after the first analgesic injection, respiratory frequency was noted every 15 min and arterial blood gases were measured hourly. Peak expiratory flow was recorded daily until the patient was discharged from hospital. Spirometry was performed the day before and the day after surgery. Plasma concentrations of morphine were measured after both intramuscular and epidural administration. Both intramuscular and epidural morphine gave effective analgesia, but the average dose of intramuscular morphine was up to seven times greater than that required by the epidural route. A larger number of patients receiving epidural morphine postoperatively were able to sit, stand, or walk unassisted within 6, 12, and 24 hr, respectively. Being alert and more mobile as a result of superior postoperative analgesia from epidural morphine, patients in this group benefited more from vigorous physiotherapy routine, which resulted in fewer pulmonary complications. Furthermore, earlier postoperative recovery of peak expiratory flow and bowel function presumably contributed to a significantly shorter hospitalization in patients receiving epidural morphine. There was no evidence of prolonged respiratory depression in this high-risk category of patients. The 99mTc -plasmin tests revealed no significant difference between the two groups.

Adult↗
PubMed1983

Steady-state kinetics and analgesic effect of oral morphine in cancer patients.

The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20-40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7-240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.

Administration, Oral↗
PubMed1983

Pharmacokinetic aspects of epidural morphine analgesia.

Twenty patients undergoing thoracotomy were given 2, 4, or 6 mg morphine epidurally in a double-blind, randomized study for postoperative analgesia. Administration at T12-L1 or L1-L2 resulted in a dose-related analgetic duration (514 +/- 118 min, 778 +/- 207 min, and 938 +/- 155 min; means +/- SEM, respectively, for the groups). For the three groups, peak plasma morphine concentrations (range 19-34 ng/ml) were reached within 15 min. The plasma curves had a similar appearance as after an intramuscular injection and pharmacokinetic calculations showed an elimination half-life (mean +/- SEM) of 173 +/- 24 min, 200 +/- 60 min, and 213 +/- 57 min for the groups, respectively. The morphine concentrations in the CSF were considerably higher compared with plasma (45-100 times the plasma concentration at 1 h, 100-250 times at 3 h, and 125-175 times at 5 h) but the elimination half-life of morphine in the cerebrospinal fluid (CSF) was similar to that in plasma. The lumbar approach was used with similar efficacy as reported for thoracic administration. Side effects were few and nonsignificant. The authors conclude that epidural morphine administration results in a dose-dependent analgesia, as well as concentrations in the CSF that are considerably higher than in plasma. With similar elimination half-lives for morphine in CSF and plasma, the long analgetic duration probably depends on the locally high morphine concentrations achieved. For safety purposes, one may use the lumbar approach to the epidural space even for thoracic pain without reducing the efficacy.

Aged↗
PubMed1982

Pharmacokinetic properties of noscapine.

Noscapine was administered to five healthy volunteers in a randomized crossover design, as an intravenous infusion of 66 mg, and as an oral 150 mg dose of either rapidly dissolving tablets or a tablet containing ion exchange resin-bound noscapine. After i.v. administration, the disposition of noscapine was bi-exponential with an elimination half-life of 2.6 h; the total plasma clearance was 22 ml/min/kg and the volume of distribution (Vdarea) was 4.7 l/kg. The absolute oral bioavailability was 30%, with a 3.6-fold interindividual variation. There was no pharmacokinetic evidence to support a prolonged action of the ion exchange resin tablet.

Administration, Oral↗
PubMed1982

Pharmacokinetics of pethidine during anaesthesia and patient-controlled analgesic therapy.

The pharmacokinetics of pethidine has been studied in 12 patients subjected to major intraabdominal surgery. Pethidine and norpethine were analyzed in plasma samples collected during anesthesia and during patient-controlled administration of small intravenous doses of pethidine in the early postoperative period. A second study on the pharmacokinetics of pethidine was performed on the 3-5th postoperative day. The plasma clearance of pethidine was significantly lower in the preoperative study (8.9 +/- 1.8 ml x kg x min-1) compared with the postoperative study (12.0 +/- 3.1 ml x kg x min-1). Volume of distribution (Vd) was not significantly influenced, being 4.25 +/- 1.72 l x kg-1 peroperatively and 3.14 +/- 0.84 l x kg-1 postoperatively. Elimination half-life decreased from 5.91 +/- 3.57 h peroperatively to 3.25 +/- 1.40 h postoperatively. The kinetics of pethidine in the postoperative study agreed with pethidine kinetics reported for healthy volunteers. The fraction of unbound pethidine decreased from 0.26 +/- 0.1 peroperatively to 0.18 +/- 0.1 postoperatively. Norpethidine, a metabolite of pethidine, has been claimed to be responsible for several side effects like respiratory depression and convulsions during pethidine therapy. No side effect attributable to norpethidine was observed in the self-administration period. Norpethidine plasma concentrations did not exceed 500 ng/ml. The altered pethidine pharmacokinetics during anesthesia and the ensuing postoperative hours and the interindividual differences of the disposition of the drug strongly suggest that pethidine should be given by individualized regimens in surgical patients.

Anesthesia↗
PubMed1982

Multiple dose kinetics of ketobemidone in surgical patients.

Twelve patients scheduled for major abdominal surgery were selected for a study of the kinetics of ketobemidone during the day of surgery and in a follow-up study 3-5 days after surgery. In six patients ketobemidone was administered as ketobemidone plain and in the other six, it was given as Ketogin, a combination formula containing a spasmolytic substance in addition to ketobemidone. Plasma samples were collected for approximately 24 h following induction of anesthesia, during which time multiple doses of ketobemidone were administered. A single-dose study was performed 3-5 days after surgery using the same drug. No significant differences were found between the two formulations of ketobemidone. Plasma clearance did not change significantly between the two periods of study, being 18.0 +/- 4.4 ml . kg-1 . min-1 peroperatively and 21.7 +/- 7.6 ml . kg-1 . min-1 postoperatively. Peroperative Vd area was significantly larger than post-operative Vd area, 5.84 +/- 2.62 l . kg-1 and 3.63 +/- 0.38 l . kg-1, respectively. T1/2 terminal decreased from 3.84 +/- 1.6 h peroperatively to 2.06 +/- 0.44 h postoperatively.

Analgesics, Opioid↗