Biomedical subjects

P Hartvig

Publications and source records attributed to P Hartvig.

246 records · Page 14Linked to original sources

PubMedDate not supplied

Pharmacokinetics and effects of 9-amino-1,2,3,4-tetrahydroacridine in the immediate postoperative period in neurosurgical patients.

STUDY OBJECTIVE: To determine the effects of intravenous (IV) 9-amino-1,2,3,4-tetrahydroacridine (THA) on postoperative somnolence in comparison to its pharmacokinetics. DESIGN: Open-label study of the pharmacokinetics and effects of THA. SETTING: Postoperative intensive care ward at the Department of Neurosurgery, Uppsala University Hospital, Sweden. PATIENTS: Ten neurosurgical patients immediately after their operations were given 30 mg of THA for reversal of postoperative somnolence. INTERVENTIONS: Plasma concentrations of THA and, in seven cases, the metabolite 1-hydroxy-THA were assayed using high-performance liquid chromatography. The pharmacokinetic data were compared to the degree of sedation and pain relief. After an IV dose of 30 mg THA, plasma concentrations were fit to an open two- or three-compartment model. MEASUREMENTS AND MAIN RESULTS: The antagonistic effect of THA on sedation occurred immediately following IV administration and lasted 60 to 90 minutes. At a mean plasma THA concentration of 44 +/- 18 ng/ml, patients were resedated. There was no obvious relation between analgesia and plasma THA concentrations. Side effects such as nausea, salivation, and lower heart rate (HR) were observed in several patients. Plasma clearance (C1) was high and showed a twofold inter-individual variation, with a mean of 2.64 +/- 1.17 L/h. Volume of distribution (Vd gamma) varied between 300 and 850 liters, with a mean of 477 +/- 185 liters. The plasma half-lives of rapid and slow distribution, and elimination were 2.1 +/- 0.7 minutes, 26 +/- 18 minutes, and 133 +/- 48 minutes, respectively. Maximum plasma concentrations of 1-hydroxy-THA were 27 to 90 ng/ml in five patients; the concentration was below 1 ng/ml in two other patients. CONCLUSIONS: The duration of the effects of THA as an antagonist of postoperative sedation was only about double that seen previously after the IV administration of physostigmine in a similar group of patients, although the elimination half-life of THA was six times longer than that of physostigmine. A larger dose of THA possibly could have been given to prolong the period of antagonism of sedation, but the profile of adverse effects seen even at the doses used precluded that option.

Adult↗

PubMedDate not supplied

Clinical pharmacokinetics of propofol given as a constant-rate infusion and in combination with epidural blockade.

STUDY OBJECTIVES: To investigate the pharmacokinetics of propofol in combination with epidural anesthesia or with intravenous (i.v.) alfentanil infusion, and to investigate the clinical feasibility of this anesthetic technique in lower abdominal surgery. DESIGN: Randomized, open clinical study. SETTING: Operating theaters and postanesthesia recovery unit at the department of gynecology of a university medical center. PATIENTS: 20 healthy, consenting ASA physical status I and II adult female patients undergoing lower abdominal surgery. INTERVENTIONS: A total i.v. anesthetic technique was used in all patients. In Group 1, a continuous infusion of propofol was combined with an epidural block with bupivacaine. Group 2 patients received a combination of propofol and alfentanil infusions. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of propofol are best fitted to a two-compartment open model and were similar in both patient groups. Propofol blood clearance was 29.8 +/- 6.51 ml/min/kg, and volume of distribution was 3.60 +/- 1.34 L/kg, resulting in a blood elimination half-life of 144 +/- 46 minutes. The entire period of anesthesia was stable in the alfentanil group. In the epidural group, the initial period of anesthesia was too light as judged by the autonomic response to tracheal intubation, which also correlated in time to a lower propofol blood concentration than was seen in the alfentanil group. No evidence was found that an epidural block induced a change in propofol kinetics, apart from the lower blood concentration during the initial period of anesthesia. CONCLUSIONS: We could not show any statistically significant influence of an epidural blockade on the pharmacokinetic parameters of propofol. Nevertheless, the concentration-time profile changed during infusion, rendering the described infusion regimen, in combination with epidural anesthesia, unsatisfactory for adequate hypnosis. The propofol infusion regimen combined with alfentanil provided immediate and stable blood concentrations that were adequate for surgery.

Adult↗

PubMedDate not supplied

Dopamine receptors in pituitary adenomas: PET visualization with 11C-N-methylspiperone.

Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.

Adenoma↗

PubMedDate not supplied

Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment.

Functional imaging techniques offer new possibilities for further understanding of changes in functional correlates of structural and biological changes in dementia disorders like Alzheimer's disease (AD). Regional disturbances in glucose metabolism and cerebral blood flow are known to occur in AD brains and probably roughly correlate to changes in neurotransmitter activities. A proper estimate would be to visualize the neuroreceptors themselves. In this study the cholinergic nicotinic and muscarinic receptors were studied in brain by positron emission tomography (PET). The rate constant k2* (s) (-)11C-nicotine was significantly higher (+43%) in temporal cortex of AD patients compared to controls (p < 0.017) indicating a lower binding of 11C-nicotine in AD brains compared to controls. Treatment with the cholinesterase inhibitor tacrine (80 mg daily) during 3 months to AD patients resulted in a mean plasma concentration of 7.7 +/- 0.8 ng/ml and a corresponding inhibition of the cholinesterase activity in plasma by 34 +/- 5%. A significantly lower k2* (increased binding) for 11C-nicotine binding (-15%; p < 0.006) was obtained in the temporal cortex after 3 months of treatment compared to prior treatment. The muscarinic antagonist 11C-benztropine was used to visualize muscarinic receptors and the binding capacity of 11C-benztropine (KR) was found to be decreased in the temporal cortex after 3 months of tacrine treatment.

Aged↗

PubMedDate not supplied

Regional brain distribution and binding of the muscarinic receptor agonist CI-979 studied by positron emission tomography in the monkey.

The regional brain distribution and selective binding of the cholinergic muscarinic receptor agonist CI-979 labelled with 11C was studied in rhesus monkeys by means of positron emission tomography. The selective binding was measured as displacement of [11C]CI-979-derived radioactivity following constant-rate infusion of CI-979 at doses of 0.5-10 micrograms/kg/h. An extensive and rapid distribution of [11C]CI-979 was observed to the basal ganglia and temporal occipital cortices, i.e., regions of the brain with a high density of muscarinic receptors. The radioactivity was dose-dependently decreased in cortical regions following infusions of unlabelled CI-979 (0.5-10 micrograms/kg/h), indicating selective receptor binding of [11C]CI-979 in these brain regions. The binding of [11C]CI-979 was unaltered or even higher in the striatum following unlabelled CI-979 infusion. The high densities of autoreceptors in the striatum may explain the inhibitory feedback mechanism on endogenous acetylcholine induced by the muscarinic receptor agonist. Since muscarinic receptor agonists release acetylcholine, the higher releasable pool of acetylcholine in the stratum will induce feedback inhibition of acetylcholine release and less competition between acetylcholine and CI-979 at the muscarinic receptors. This may explain the differences between cortex and striatum in [11C]CI-979 binding. The cerebral blood flow was not changed by the infusion of unlabelled CI-979, supporting the assumption that effects of CI-979 in brain may be due to the interaction with brain muscarinic receptors. Despite a relative rapid clearance of [11C]CI-979 radioactivity from binding in the brain characteristic of a receptor agonist, the radioligand might be useful in positron emission tomography studies to reveal changes in cholinergic receptors and functional activity in Alzheimer patients treated with muscarinic agonists.

Animals↗

PubMedDate not supplied

Patient-controlled analgesic therapy. Part I: Pharmacokinetics of pethidine in the per- and postoperative periods.

The influence of anaesthesia and surgery on the pharmacokinetics of pethidine (meperidine) was studied in 12 patients. Plasma pethidine concentrations in central venous blood collected during anaesthesia and the ensuing postoperative hours were by gas chromatography with electron capture detection. Postoperative analgesia was accomplished by patient-controlled intravenous administration of small doses of pethidine. The NONLIN program was used to calculate pharmacokinetic parameters for each individual. A single dose study of pethidine kinetics was carried out in all patients 3 to 5 days postoperatively. Mean +/- SD for peroperative Vd area was 4.3 +/- 1.7L/kg and for the elimination half-life was 6.1 +/- 3.6h. In the postoperative period Vdarea was 3.2 +/- 0.8L/kg and the elimination half-life was 3.2 +/- 1.4h. Plasma clearance increased from a peroperative value of 8.9 +/- 1.9 ml/min/kg to a postoperative value of 12 +/- 3.0 ml/min/kg. The changes in elimination half-life and plasma clearance are significant. The postoperative pharmacokinetics of pethidine were in accordance with those reported for healthy volunteers. The fraction of unbound pethidine was significantly reduced postoperatively - from 0.26 +/- 0.10 (peroperatively) to 0.18 +/- 0.10 (3 to 5 days later).

Adult↗

PubMedDate not supplied

Patient-controlled analgesic therapy, Part II: Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain.

20 survival patients were allowed to self-administer small intravenous doses of pethidine to relieve pain after major abdominal surgery. Pethidine injections were given by means of a programmable drug injector. Pethidine consumption varied from 12 to 50mg/h with a mean +/- SD of 26 +/- 10mg/h. The mean measured plasma concentration of pethidine during self-administration was 551 +/- 182 ng/ml, with a range of 132 to 896 ng/ml. Minimum effective concentrations averaged 455 +/- 174 ng/ml. Individual pethidine consumption and mean plasma concentrations did not differ between men and women, and were not correlated to variations in age, anthropometric factors, plasma clearance or elimination rate constant for pethidine. Individual consumption of pethidine was consistent, with stable plasma concentrations throughout most of the trial period. Pseudo-steady-state plasma concentrations of pethidine were established and maintained at widely different levels. 19 of the 20 patients obtained subjectively satisfactory analgesia.

Adult↗

PubMedDate not supplied

Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone.

The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(area) decreased to 3.7 +/- 0.4L/kg and the terminal half-life to 2.1 +/- 0.4 h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18 +/- 4.3 ml/min/kg and postoperative Clp being 22 +/- 7.5 ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation 'Ketogin'. Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 +/- 0.8 mg/h, which produced a mean plasma concentration of 28 +/- 11 mg/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 +/- 11 ng/ml. Ketobemidone 'plain' and 'Ketogin' did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

Abdomen↗

PubMedDate not supplied

Patient-controlled analgesic therapy, Part IV: pharmacokinetics and analgesic plasma concentrations of morphine.

The influence of anaesthesia and surgery on the pharmacokinetics of morphine was studied in 10 patients. Plasma concentrations of morphine were assayed by gas chromatography with electron capture detection. All patients were studied on the day of surgery and again 3 to 7 days later. Mean +/- SD for peroperative Vd(area) was 6.3 +/- 3.6 L/kg and for the terminal half-life was 3.8 +/- 2.3 h. In the postoperative period, Vd(area) decreased to 3.7 +/- 1.4L/kg and the terminal half-life to 2.2 +/- 1.1 h. Plasma clearance (Clp) remained constant, peroperative Clp being 20 +/- 7.0 ml/min/kg and postoperative Clp 21 +/- 6.0 ml/min/kg. Postoperative pain was relieved by patient-controlled administration of intravenous doses of morphine by means of a programmable drug injector. The mean morphine consumption was 2.6 +/- 1.2 mg/h, which produced a mean plasma concentration of 21 +/- 12 ng/ml with a calculated mean minimum effective concentration (MEC) of 16 +/- 9 ng/ml. In 1 patient, temporary hypercapnia was seen during a period of hypovolaemia. Analgesia was considered satisfactory by all patients.

Abdomen↗

PubMedDate not supplied

Clinical pharmacokinetics of cholinesterase inhibitors.

This review deals mainly with the pharmacokinetics of the reversible quaternary cholinesterase inhibitors neostigmine, pyridostigmine and edrophonium, which are mainly used to antagonise non-depolarising neuromuscular blockade in general anaesthesia and in the symptomatic treatment of myasthenia gravis. Only in the last few years, since the introduction of highly sensitive and selective analytical procedures based on gas and liquid chromatography, have proper pharmacokinetic studies of these drugs become possible. Rapid cooling and addition of internal standard to samples before freezing are important precautions in view of the poor stability of the cholinesterase inhibitors in plasma and blood. Plasma clearances of the reversible quaternary cholinesterase inhibitors are in the range 0.5 to 1.0 L/h/kg and their apparent volumes of distribution range from 0.5 to 1.7 L/kg. Accordingly, the drugs have short plasma elimination half-lives, in the order of 30 to 90 minutes. One to two hours after oral administration of 60 mg pyridostigmine, peak plasma concentrations of 40 to 60 micrograms/L are observed, whereas the plasma concentrations of neostigmine after a 30 mg oral dose are only 1 to 5 micrograms/L. The oral bioavailability of these hydrophilic ionised compounds is low: that of pyridostigmine is approximately 10% and the value for neostigmine is even lower. In spite of the short elimination half-life of pyridostigmine, intraindividual variations in plasma concentration during a dose interval are small in myasthenic patients receiving oral maintenance therapy, probably as a result of slow absorption from the gastrointestinal tract. Severely impaired renal function has been shown to prolong the elimination of neostigmine and pyridostigmine, while methylcellulose has been reported to inhibit the absorption of the latter drug completely. Other pharmacokinetic drug interactions suggested so far do not seem to be of clinical significance. Although a positive correlation has been demonstrated between the plasma concentrations of these drugs and their pharmacological effects as measured by a decrement in muscle response to repetitive nerve stimulation in a single muscle, this relationship is less clear when a global evaluation of muscular function in myasthenia gravis is used. Pharmacokinetic studies of the tertiary reversible cholinesterase inhibitor physostigmine, an important tool in experimental cholinergic neuropharmacology, are still in their initial stages. This drug too is characterised by a short plasma elimination half-life of 20 to 30 minutes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗

PubMedDate not supplied

Dynamic study of supratentorial gliomas with L-methyl-11C-methionine and positron emission tomography.

The regional kinetics of intravenously injected L-methyl-11C-methionine (11C-L-methionine) in the brain was investigated by positron emission tomography (PET) in 14 patients with gliomas. In both tumor and unaffected brain the tracer uptake reached a nearly constant level in 5 min or less. The ratio between the uptake of 11C-L-methionine by high-grade tumors and the uptake by unaffected brain was 1.9-4.8. In two cases of low-grade astrocytoma the ratio was 0.8-1.0. High uptakes of 11C-L-methionine occurred in gliomas even in the absence of blood-brain barrier defects as observed by other methods. This indicates that besides active transport of amino acid, a larger extracellular space in tumor as compared with unaffected brain tissue may also contribute to the increased uptake of 11C-L-methionine--derived radioactivity. In some patients delineation of the tumors was improved by use of PET with 11C-L-methionine as compared with computed tomography, angiography, and, in some instances, PET with 68Ga-EDTA. PET with 11C-L-methionine permits better evaluation of the tumor extent and may affect preoperative grading.

Adult↗

PubMedDate not supplied

Quantitative determination of the urinary excretion of ketobemidone and four of its metabolites after intravenous and oral administration in man.

The urinary excretion of ketobemidone and its metabolites has been quantified in man after intravenous and oral administration. The metabolism of ketobemidone was found to proceed via 4 metabolic pathways: N-demethylation, ring-hydroxylation, O-methylation, and conjugation. The metabolites were isolated and identified after hydrolysis of the corresponding conjugates. A mean total recovery of about 80% of the dose was found in urine as ketobemidone and metabolites after oral and iv administration, conjugated metabolites amounted to 34-68% of the dose. After iv administration the recovery of unchanged ketobemidone in urine was 13-24%, and after oral administration it was 3-10%. Norketobemidone constituted 10-37% of the dose irrespective of route of administration. 4'-Hydroxyketobemidone amounted to 3-12% of the dose. Neither ketobemidone N-oxide nor metabolites formed after reduction of ketobemidone could be detected in the urine. Less than 2% of the dose was found in feces after iv administration.

Administration, Oral↗