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Biomedical subjects

P Hartvig

Publications and source records attributed to P Hartvig.

At least 127 records · Page 7Linked to original sources
PubMed1989

Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing.

Antinociceptive effects have been demonstrated after systemic and spinal administration of the adrenoceptor agonist clonidine and cholinomimetic drugs in animals and human. The present investigation was undertaken in rats to study the possible interactions between spinal noradrenergic and cholinergic mechanisms in modulating the reaction to nociceptive stimuli. Using the tail immersion test, an additive antinociceptive effect was found between intrathecal (IT) clonidine (10 micrograms) and physostigmine (15 micrograms, IT). The effect of clonidine was attenuated by atropine (15 micrograms, IT). Physostigmine (15 micrograms, IT) antinociception, which was of short duration was abolished by atropine (15 micrograms, IT) and attenuated by phentolamine (20 micrograms, IT). Neostigmine (5 micrograms, IT) produced a prolonged antinociceptive response. In animals pretreated with 6-hydroxydopamine IT, leading to a selective depletion of spinal cord noradrenaline, physostigmine (15 micrograms, IT) was ineffective in altering the nociceptive test response. Neither clonidine, nor physostigmine produced changes in latency times in the hot plate test (58 degrees C) in the doses employed. In conclusion, a clear-cut interaction exists between spinal noradrenergic and cholinergic systems for antinociception. To explain the interactions, several possible mechanisms may be considered, including cholinomimetic effects produced by clonidine, and the presence of muscarinic receptors in the dorsal horn of the spinal cord.

Adrenergic alpha-Agonists↗
PubMed1989

Distribution of 11C-labelled morphine and pethidine after spinal administration to Rhesus monkey.

The kinetics of 11C-labelled morphine and pethidine were studied by positron emission tomography (PET) at different levels of the spinal canal (C4, T4, T5, T6, L1 and L6). Studies were performed in the Rhesus monkey after intrathecal and extradural administration of the drugs at the lumbar level (L3-L4 or L4-L5, seven experiments). Radioactivity 100-300 times higher than with even distribution in the body was measured initially near the site of injection for both morphine and pethidine, irrespective of the route of administration. After injection of pethidine, high activity was observed at the L6 and L1 levels, whilst the radioactive uptake was lower at T6 (10-20% of those at lumbar level). Morphine-derived 11C-radioactivity showed more constant levels along the spinal canal, except at C4 where radioactivity was low. In CSF taken from the cervical level the peaks of radioactivity of the two drugs appeared 80-170 min after injection. The importance of different distribution routes was quantified in a pharmacokinetic compartment model, using the above results. The systemic distribution was extensive, irrespective of drug or route of administration. From the site of injection the systemic distribution was at least 60 times larger than the rostral distribution within the spinal canal.

Animals↗
PubMed1989

Reversal of postoperative somnolence using a two-rate infusion of physostigmine.

In order to antagonize immediate postoperative somnolence, 24 surgical patients were given a two-rate infusion of physostigmine, aiming at a constant plasma concentration in the range of 1 to 10 ng/ml. Plasma concentrations of physostigmine were determined during infusion and after infusion and the effects of physostigmine on analgesia and postoperative sedation, and its side effects were monitored throughout. On the 1st postoperative day some of the patients (n = 8) were given 5 mg physostigmine orally, after which plasma concentrations as well as effects were measured. Steady-state concentrations were generally lower than predicted. Clearance varied between 10 and 85 ml/min x kg with a mean of 40.8 +/- 21.0 ml/min x kg. Oral bioavailability was 25.3 +/- 11.1%. Physostigmine administered as an intravenous infusion antagonized immediate postoperative somnolence in 21 out of 24 patients. Effects were poorly correlated with the established steady-state concentration of physostigmine. The patients' experience of postoperative pain relief was mostly satisfactory and the side effects of physostigmine infusion were generally limited. The effects of physostigmine in the immediate postoperative period seemed dependent on the dose as well as on the time which had elapsed since administration of anticholinergic drugs. After oral physostigmine administration the following morning, the majority of patients experienced side effects such as nausea and abdominal pain. In conclusion, physostigmine given as infusion antagonizes postoperative somnolence. However, the arousal effect was considered not better than that resulting from a bolus dose of the drug, although the infusion regimen allowed a prolonged clinical effect duration.

Administration, Oral↗
PubMed1989

Characterization of the antinociception induced by intrathecally administered carbachol.

The antinociceptive effect of intrathecally administered carbachol at the L1/L2 level in the rat was evaluated using the tail immersion test. A dose dependent increase in the nociceptive reaction times was evident following intrathecal carbachol in the dose range of 2.5-15 micrograms. At doses of 20 micrograms and above, although still effective in the test, motor impairment was pronounced. The antinociception was antagonized with atropine, and with either pirenzepine (PZ) or AFDX 116, which are selective M1 and M2 muscarinic receptor blocking drugs, respectively. Spinal cholinergic pain modulation was also studied in rats pretreated with DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine), which causes a selective depletion of the noradrenergic nerve fibres in the CNS. The increased latency times after spinal carbachol were attenuated in animals depleted of spinal noradrenaline by DSP4. In conclusion, spinal analgesia by carbachol in the rat may therefore be mediated through both M1 and M2 muscarinic receptor stimulation in the spinal cord. It is also concluded that this spinal cholinergic pain modulation is interacting with spinal noradrenergic nerve terminals, but that the mechanism of the interaction remains to be established.

Analgesics↗
PubMed1989

Brain and plasma kinetics of the opioid 11C-hydromorphone in two macaque species.

The regional brain kinetics of the opioid receptor agonist, hydromorphone, labelled with 11C, were studied with positron emission tomography in two Macaque species. Rhesus and Cynomolgus monkeys. The plasma kinetics of 11C-hydromorphone was simultaneously determined. Rapid plasma elimination was obvious in both monkey species. Brain radioactivity was generally low in both, but 1.4 times higher in the Rhesus than in the Cynomolgus monkey brain. This observation might explain the more rapid development of tolerance in the Rhesus monkey.

Animals↗
PubMed1989

The diabetic heart: a porcine model evaluated with positron emission tomography using 1-11C-palmitate and 3-11C-pyruvate.

The potential value of positron emission tomography (PET) in evaluating the myocardial energy metabolism was studied in two previously healthy mini-pigs before, during and after the induction of non-insulin dependent diabetes with alloxan. The distribution and kinetics of radioactivity derived from trace amounts of 11C-pyruvate and 1-11C-palmitate were followed in different sections of the myocardium. The early distribution of both tracers was similar even after the development of diabetes. The elimination of 11C-pyruvate derived radioactivity was slower in the diabetic heart. The rate of beta-oxidation was also decreased as suggested by the elimination curve of 11C-palmitate and the incorporation of 11C-palmitate into the triglyceride and phospholipid pool of the myocardium was increased in the diabetic animals. The results are consistent with previous observations using other techniques. Positron emission tomography offers the opportunity to characterize regional tissue metabolism quantitatively in vivo. This method may become a powerful tool in studying myocardial metabolism and the metabolic basis for the cardiac dysfunction in diabetes mellitus.

Animals↗
PubMed1989

Cholinergic mechanisms in pain and analgesia.

There is now substantial evidence that acetylcholinesterase inhibitors and muscarinic receptor agonists increase the pain threshold after both systemic and spinal administration. In rats, physostigmine gave a significant dose-dependent increase in latency times in the tail immersion test following intrathecal administration. The effect was antagonized with atropine. Neostigmine gave more prolonged latencies as did the muscarinic receptor agonist carbachol. Spinal cholinergic pathways for antinociception interacted with the spinal opioid and adrenergic nerve tracts. No cross-tolerance to the selective alpha 2-adrenoreceptor agonist guanfacine or to morphine was seen in rats tolerant of spinal carbachol antinociception. The mechanism of spinal cholinergic antinociception is not known but a muscarinic interneuron may explain the interactions with other neurotransmitters. Clinically, the centrally active cholinesterase inhibitor physostigmine has been shown to give postoperative pain relief although of short duration. Severe neurogenic pain has been successfully treated with physostigmine or distigmine.

Analgesia↗
PubMed1989

Positron emission tomography in studies on fetomaternal disposition of opioids.

The noninvasive radiotracer technique, positron emission tomography, has been applied in studies on the transfer of drugs from mother to fetus in Rhesus monkeys. 11C-labelled morphine or heroin was administered intravenously to pregnant monkey and the radioactivities with time were measured in the placenta, fetal liver and maternal blood. The information from the 11C-morphine experiment was supplemented with data from the simultaneous administration of 14C-morphine followed by the analysis of unchanged drug and metabolites in maternal blood and also in one sample from fetal blood. In placenta, 11C-morphine and 11C-heroin rapidly reached high radioactivities already within the first few minutes after administration. The transfer of 11C-morphine-derived radioactivity to the fetus was also rapid, although there was a lag-time in relation to the placental uptake. The elimination rate of the radioactivity was fast from the blood, placenta and the fetal liver and in plasma there was a rapid appearance of conjugated morphine metabolites. The fetal plasma concentration of morphine was twice that in maternal plasma 100 min after injection. The transfer of 11C-heroin-derived radioactivity to the fetus was even faster than was the elimination of radioactivity. The plasma kinetics of morphine in the mother and fetus was simulated in a compartment flow model and simulated concentrations agreed well with measured values.

Animals↗
PubMed1988

Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers.

We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Inter- and intraindividual differences in oral chlorambucil pharmacokinetics.

Inter- and intraindividual variation in the pharmacokinetics of oral chlorambucil was investigated in patients with chronic lymphocytic leukaemia. Five patients were given in randomized order 15, 40, 60 and 70 mg chlorambucil p.o. and plasma was analyzed for chlorambucil and its cytotoxic metabolite phenyl acetic acid mustard. The area under the plasma concentration-time curve of chlorambucil varied two- to fourfold between patients at each dose level. The AUC of the metabolite was higher and showed twofold interindividual variation. The intraindividual dose-corrected AUCcs also varied twofold. No dose dependency of the dose corrected AUC was seen either for chlorambucil or the metabolite. Elimination of both compounds form plasma was rapid, with half-lives of 1.01 and 1.94, respectively.

Administration, Oral↗
PubMed1988

Relation of sedation and amnesia to plasma concentrations of midazolam in surgical patients.

The kinetics and dynamics of midazolam were investigated in 20 female patients undergoing lower abdominal surgery. The relation between the plasma concentrations of midazolam and pharmacokinetic end points was evaluated after an intravenous infusion regimen in 10 patients given an epidural anesthetic. The remaining 10 patients were anesthetized with a totally intravenous anesthetic technique with midazolam and alfentanil. The effect was assessed by means of a rating scale divided into degree of sedation and amnesia. A good correlation was found between plasma level of midazolam and pharmacodynamic response. The relation between the quantal response data and the plasma concentration was represented by an s-shaped concentration-effect curve. Despite similar kinetics of midazolam in the two groups, the postoperative drowsiness was more pronounced in the group receiving total intravenous anesthesia. The concomitant administration of alfentanil shifted the concentration-effect curve regarding sedation to the left.

Adult↗
PubMed1988

Pharmacokinetics of alfentanil in total i.v. anaesthesia.

Alfentanil was administered, together with midazolam, as part of a total i.v. anaesthetic technique. The pharmacokinetics of alfentanil were determined in 10 female patients undergoing lower abdominal surgery. The dose regimen of alfentanil, based on simulation studies, consisted of a two-stage infusion following an initial bolus dose. The kinetics of alfentanil were described by a linear two-compartment open model. The total plasma clearance ranged between 93 and 431 ml min-1 (mean 249 ml min-1). The apparent volume of distribution at steady-state ranged between 0.27 and 0.64 litre kg-1 (mean 0.44 litre kg-1). The apparent volume of distribution (Vd beta) was 0.58 litre kg-1, resulting in a terminal half-life of 112 min. Alfentanil concentrations at the time of extubation and postoperative analgesic requirements were also monitored. Good correlation between respiratory depression and plasma alfentanil concentration was found. Neither lower abdominal surgery nor the simultaneous administration of midazolam seemed to affect the kinetics of alfentanil as compared with results from studies in healthy volunteers. The short half-life of alfentanil, resulting from a small volume of distribution, makes it suitable as part of a total i.v. technique. Consideration must be paid, however, to interindividual differences in the pharmacodynamic response and in plasma clearance.

Adult↗
PubMed1988

Pulmonary disposition of pethidine in postoperative patients.

1. Two methods of pethidine administration, namely constant-rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2. Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3. The mean total plasma clearance was 810 ml min-1 and the volume of distribution was 3.11 kg-1. 4. A flow model was used to describe the disposition of pethidine in man. The concentration-time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5. Constant-rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.

Aged↗
PubMed1988

Effect of total intravenous anaesthesia with midazolam/alfentanil on the adrenocortical and hyperglycaemic response to abdominal surgery.

The effect of anaesthesia on the hyperglycaemic and adrenocortical response induced by surgery was studied in patients undergoing abdominal hysterectomy. The study group was anaesthetized with midazolam and alfentanil using a totally intravenous anaesthetic technique. A reference group received anaesthesia with thiopentone, alfentanil and nitrous oxide. Midazolam 0.42 mg.kg-1 was given as a loading infusion followed by a maintenance infusion of 0.125 mg.kg-1.h-1. Alfentanil was given as a bolus dose of 0.075 mg.kg-1 in both groups, followed by a loading infusion of 0.3 mg.kg-1.h-1 for 15 min and a maintenance infusion of 0.065 mg.kg-1.h-1. Increments of alfentanil were given whenever heart rate or systolic blood pressure exceeded pre-induction values by more than 10%. During anaesthesia mean arterial pressure and heart rate were similar in both groups and there was no difference in alfentanil requirement. An immediate increase in blood glucose concentrations was seen following incision, but maximum concentrations were measured in the early postoperative period. Serum cortisol concentrations decreased after induction of anaesthesia. During surgery they returned to pre-induction values, and in the postoperative period they increased to about twice the pre-induction values. It is concluded that midazolam/alfentanil anaesthesia is as effective as anaesthesia induced by thiopentone, alfentanil and nitrous oxide in suppressing the stress-response to surgery until the postoperative period. No signs of prolonged adrenocortical depression were observed.

Alfentanil↗
PubMed1988

Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil.

Postoperative performance following total intravenous anaesthesia (TIVA) using midazolam and alfentanil was studied with and without the administration of a single dose of a benzodiazepine antagonist, flumazenil (Ro 15-1788). Performance was compared with a reference group anaesthetized with thiopentone, alfentanil and nitrous oxide. All patients were assessed by use of a rating scale which took into account the degree of sedation, amnesia, comprehension and cooperation as well as temporal and spatial orientation. There was a slow recovery following TIVA with somnolence and amnesia lasting several hours. Administration of flumazenil 1.0 mg i.v. at extubation caused a significant reduction of sedation (P less than 0.001) during the first postoperative hour, with patients fully awake or only lightly sedated, but was later followed by resedation. The patients of the reference group were moderately sedated during the observation period. Five and six hours postoperatively there was no difference between the groups. Amnesia was more profound in the groups that received midazolam; the effect of the antagonist could only be seen for 15 min after its administration. Comprehension and cooperation, as well as orientation, were equally good in the antagonist and in the reference group during the immediate postoperative period, whereas in the TIVA group a gradual improvement over the first hours was seen. In the antagonist group there was no increase in the number of analgesic requirements, no anxiety attacks or other adverse effects. It is concluded that flumazenil offers an improvement in postoperative performance following TIVA induced by midazolam and alfentanil, but the effects are of short duration.

Alfentanil↗
PubMed1988

Monoamine re-uptake sites in the human brain evaluated in vivo by means of 11C-nomifensine and positron emission tomography: the effects of age and Parkinson's disease.

Six patients with Parkinson's disease, selected to cover a range of clinical features, and 7 healthy volunteers aged 24-81 years, were examined by positron emission tomography after i.v. injection of racemic 11C-nomifensine, a catecholamine re-uptake blocking drug. After injection the radiotracer, radioactivity was rapidly distributed to the brain. The highest accumulation of radioactivity was found in areas rich in dopaminergic and noradrenergic innervation, such as the striatum and the thalamus. In regions with negligible dopaminergic and noradrenergic innervation, such as the cerebellum, radioactivity was lower and evenly distributed. In all investigated brain regions a marked age-related decline in 11C-nomifensine-derived radioactivity relative to the cerebellum was observed in the group of healthy volunteers. Parkinsonian patients did not show such a decline with age. In the group of parkinsonian patients with mainly unilateral involvement, the contralateral putamen exhibited the most pronounced decrease. Only the 3 parkinsonian patients aged 63 and younger showed markedly lower 11C-nomifensine binding in striatal areas than age-matched healthy volunteers. 11C-nomifensine seems to be a valuable tool for investigating noradrenergic and dopaminergic re-uptake sites in vivo. Further achievements will most likely be made when the active enantiomer becomes available.

Adult↗
PubMed1988

Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of rhesus monkeys studied with positron emission tomography.

The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D2-dopamine receptors in the striatal area. Raclopride was selectively bound to the D2-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02-0.07 min-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.

Animals↗