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Biomedical subjects

P Hartvig

Publications and source records attributed to P Hartvig.

At least 145 records · Page 8Linked to original sources
PubMed1988

Cerebrospinal fluid concentrations of substance P and (met)enkephalin-Arg6-Phe7 during surgery and patient-controlled analgesia.

The possible role of two neuropeptides (substance P and (Met)enkephalin-Arg6-Phe7) in nociception were studied in 14 surgical patients. Lumbar cerebrospinal fluid (CSF) concentrations of the putative excitatory afferent transmitter substance P and the mu and delta receptor agonist (Met)enkephalin-Arg6-Phe7 were measured during general anesthesia for abdominal surgery and during the postoperative period when patient-controlled analgesia (PCA) was used for control of pain. The CSF was sampled through an intrathecal catheter. Seven of the patients were randomly assigned to receive neurolept anesthesia; the rest were given isoflurane anesthesia without narcotics. No statistically significant changes occurred in substance P concentrations in CSF during surgery or postoperative PCA, nor were there significant differences between the two groups. There was, however, a significant correlation between CSF substance P concentrations before the start of PCA and pain assessment on a visual analogue scale. The individual changes in substance P concentrations during PCA was also inversely correlated to the consumption of meperidine. The CSF (Met)enkephalin-Arg6-Phe7 concentrations were below the level of detection in seven of the patients before anesthesia. A large interindividual variability in both substance P and (Met)enkephalin-Arg6-Phe7 concentrations was evident. The absence of major changes in CSF neuropeptide concentrations was unexpected. Apparently inter-individual variations in neuropeptide output are considerable.

Adult↗
PubMed1988

Effects of flumazenil on post-operative recovery after total intravenous anesthesia with midazolam and alfentanil.

Midazolam and alfentanil were infused in a totally i.v. anesthetic technique (TIVA) to patients undergoing hysterectomy. Correlations of midazolam plasma concentrations and effects were made during recovery. Due to the high doses of midazolam administered during TIVA, metabolism and not redistribution mainly governed the duration of effects post-infusion. The concomitant administration of alfentanil contributed to the sedative effect, as illustrated by a shift of the concentration-response curve to the left. As a result of these effects, recovery was prolonged and extended over 2-6 h. The effect of the benzodiazepine antagonist flumazenil on post-operative performance after total i.v. anaesthesia with midazolam and alfentanil was studied. A bolus dose of flumazenil, 1.0 mg i.v., significantly improved recovery during the first post-operative hour but was followed later by resedation. The reduction in sedation followed by improvement in ventilation, without reduction of analgesia, demonstrated that antagonism of hypnosis is the primary factor in enhancing recovery from total i.v. anaesthesia.

Alfentanil↗
PubMed1987

Pharmacokinetics of midazolam in total i.v. anaesthesia.

The pharmacokinetics of midazolam during total i.v. anaesthesia were determined in 15 female patients undergoing major surgery. Midazolam was administered together with an analgesic drug and a neuromuscular blocking drug. The dose regimen of midazolam, based on simulations, included two consecutive infusions following a bolus injection at the induction of anaesthesia. Multiple blood samples were drawn and a two-compartment open model was fitted to the measured plasma concentrations. Plasma clearance (483 ml min-1), apparent volume of distribution (1.94 litre kg-1) and terminal half-life (3.1 h) were in agreement with other reports. Thus, there was no obvious evidence that the surgical procedure or the concomitant use of other drugs, or both, influenced the pharmacokinetics of midazolam. The relatively rapid elimination makes midazolam suitable for use by infusion in a total i.v. technique.

Adult↗
PubMed1987

Pharmacokinetics of epidural morphine and meperidine in humans.

Five groups of surgical patients, each comprising six individuals, received epidural doses of morphine or meperidine, and the plasma and CSF kinetics were studied. Three groups received epidural doses of morphine 3 mg in 1 or 10 ml or meperidine 30 mg in 1 ml. Cerebrospinal fluid (CSF) and central venous blood opioid concentrations were measured intermittently for 6 h after injection. Two groups received epidural doses of morphine 3 mg in 1 ml or meperidine 30 mg in 1 ml, and opioid CSF concentrations were determined over a 24-h period. Morphine appeared rapidly in plasma, and maximum plasma concentrations were usually detected 5 min after injection and averaged 33 ng.ml-1 in the 1-ml volume group and 40 ng.ml-1 in the 10-ml volume group. The terminal plasma half-life averaged 91 +/- 34 min and 87 +/- 27 min, respectively (mean +/- SEM). Maximal plasma concentrations of meperidine were usually detected 10 or 15 min post-injection and averaged 196 +/- 29 ng.ml-1. The terminal plasma half-life averaged 124 +/- 26 min. Morphine crossed the dura relatively slowly, and the absorption half-life across the dura averaged 22 min. Maximal CSF concentrations were usually seen 60-90 min post-injection. In contrast, meperidine crossed the dura quickly, with an absorption half-life averaging 7.6 +/- 2.0 min. Maximal CSF concentrations were seen 15 or 30 min post-injection. Morphine and meperidine concentrations remained several times higher in the CSF than in the plasma. The fraction of the opioid dose crossing the dura was calculated to be 3.6% for morphine and 3.7% for meperidine. There were no significant differences in the kinetics of morphine administered in 1 or in 10 ml when CSF was sampled close to the site of lumbar epidural injection. The CSF concentration-time curves of both drugs decreased biexponentially after the initial rise due to diffusion across the dura. The early half-life in CSF averaged 73.3 +/- 11.5 min for morphine and 71.3 +/- 3.1 min for meperidine, and the late half-life averaged 369 +/- 113 min for morphine and 982 +/- 449 min for meperidine. Dose-normalized morphine and meperidine CSF concentrations after epidural administration showed that meperidine concentrations were down to one-fourth the corresponding morphine concentrations from the 2nd to the 15th h after administration, which may partly explain the longer duration of analgesia from morphine.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Pharmacokinetics of intrathecal morphine and meperidine in humans.

Two groups of surgical patients each comprising six individuals received an intrathecal injection of morphine 0.3 mg or meperidine 10 mg. Cerebrospinal fluid (CSF) and plasma were sampled frequently during a 6-h period and analyzed for morphine or meperidine. Maximum plasma morphine concentrations were found 5-10 min after injection, and averaged 4.5 +/- 1.1 ng.ml-1 (mean +/- SEM). Maximum CSF morphine concentrations were considerably higher than maximum plasma concentrations, 6410 +/- 1290 ng.ml-1. Maximum plasma concentrations of meperidine were also measured 5 or 10 min after injection and were low (36 +/- 9 ng.ml-1) compared with the maximum CSF concentrations (364 +/- 105 micrograms.ml-1). After a rapid initial decline for about 15 min after injection, the CSF concentrations decreased with a half-life of 89.8 +/- 16.1 min for morphine and 68.0 +/- 5.1 min for meperidine during the rest of the study period. The initial volume of distribution in CSF was similar for both drugs, or 22 +/- 8 ml for morphine and 18 +/- 5 ml for meperidine. After 6 h, 1.6 +/- 0.9% of the injected morphine dose and 0.41 +/- 0.09% of the meperidine dose remained in the initial volume of distribution. Large inter-individual differences in morphine and meperidine CSF kinetics existed, which may explain some of the reported individual differences in duration of effects. The disappearance of meperidine from CSF tended to be faster than that of morphine, which may be explained, in part, by the differences in lipid solubilities of the drugs.

Adult↗
PubMed1987

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography.

In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C-nomifensine was administered i.v. in trace amounts (10-50 micrograms) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the time-course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

Aged↗
PubMed1987

Dopamine receptor properties in Parkinson's disease and Huntington's chorea evaluated by positron emission tomography using 11C-N-methyl-spiperone.

Dopaminergic receptor properties in the striatum of patients with Parkinson's disease (PD) and Huntington's chorea (HD) were studied by positron emission tomography (PET), using 11C-N-methyl-spiperone as a dopamine D2 receptor ligand. The time-dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3-compartment pharmacokinetic model. The rate constant k3 for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex . k3, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k3 values calculated from the 6 PD patients is discussed in relation to any side-to-side differences in dopamine receptor densities in hemiparkinsonism and to possible "hypersensitivity" of dopamine receptors in the early stage of the disease and down-regulation in more advanced disease.

Aged↗
PubMed1987

Positron emission tomography (PET) in the study of dopamine receptors in the primate brain: evaluation of a kinetic model using 11C-N-methyl-spiperone.

The regional kinetics of 11C-N-methyl-spiperone (11C-NMSP) are described in the monkey brain under tracer conditions and after displacement and protection experiments. The primary aim of the study was to investigate different methodological problems associated with use of 11C-NMSP in the quantitation of receptor properties before applying the method in clinical research. Special emphasis was placed on the evaluation of different mathematical approximations of a general compartment model. Different mathematical procedures are described and the results indicate that the approximations performed are reasonable. The simplest method for obtaining a reliable measurement of the rate constant k3 (which is approximately equal to proportional to the number of receptors) and k4 (the receptor dissociation rate constant) uses the radioactivity in the cerebellum as a measure of the tissue concentration of ligand equilibrating with the receptor compartment.

Animals↗
PubMed1987

Positron emission tomography: an animal model of spinal distribution of drugs after intrathecal administration.

An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transport of drugs by external detectors i.e. positron emission tomography. The model compromises the cannulation of the subarachnoid space (with a spinal needle), and has been used without any damage to the monkey. With the method it was shown that injection rate had a major influence on the transport rate of 68GaCl3 in the CSF. Injection of 0.5 ml over 60 sec gave the highest radioactivity near the injection site, whereas an injection rate of this volume over 10 sec resulted in high radioactivity more rostrally shortly after injection. This method have been of value for the determination of drug kinetics after spinal administration.

Animals↗
PubMed1986

Kinetics of four 11C-labelled enkephalin peptides in the brain, pituitary and plasma of rhesus monkeys.

The kinetics of four 11C-labelled enkephalin peptides: Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2 [D-Met2,Pro5)-enkephalinamide), Tyr-D-Ala-Gly-Phe-Met-NH2 (DALA) and Tyr-D-Ala-D-Ala-Phe-Met-NH2 (TAAFM) all labelled at the methyl group of methionine was studied in the Rhesus monkey. After intravenous administration, the regional kinetics in the head, lungs, liver and kidneys were followed by means of positron emission tomography (PET). The total radioactivity in blood and urine was measured and the composition of 11C-labelled peptide fragments in plasma in vivo and in vitro was analysed by liquid chromatography. With PET, an increased radioactivity was observed in the brain and pituitary over the 60-90 min investigation period after i.v. injection of the peptides. The highest radioactivities were noted for Met-enkephalin, followed by DALA and D-Met2, Pro5-enkephalinamide, while very low radioactivities were found for TAAFM. The uptake of Met-enkephalin- and DALA-derived radioactivity was of the same order as has previously been shown for morphine in the brain and considerably higher than that of D-Met2,Pro5-enkephalinamide and TAAFM, respectively. A large fraction of the brain radioactivity derived from Met-enkephalin and DALA probably emanated from [11C]methionine as indicated by plasma and urine analysis. Met-Enkephalin was rapidly eliminated from plasma in vitro with an half-life of less than two minutes, whereas DALA was stable suggesting clearance by other tissues than plasma. In conclusion, both Met-enkephalin and DALA, were rapidly hydrolyzed in vivo to [11C]methionine. [11C]Methionine was probably taken up in the brain, as the radioactivity increased with time in different brain regions as measured with PET.D-Met2,Pro5-Enkephalinamide and TAAFM were virtually stable in vivo and at least part of the radioactivity observed in the brain may have represented the intact peptide.

Animals↗
PubMed1986

Distribution of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in experimental animals studied by postiron emission tomography and whole body autoradiography.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective potent neurotoxin which has induced a syndrome similar to parkinsonism both in man and in monkeys. At autopsy degeneration of pigmented nerve cells in the pars compacta of the substantia nigra has been confirmed. The regional distribution of intravenously administered 1-(11C-methyl)-4-phenyl-1,2,3,6-tetrahydropyridine (11C-MPTP) in the brain of Rhesus monkeys was studied by positron emission tomography and the whole body distribution in mice was documented by autoradiography and by impulse counting of selected tissues. A very rapid and high uptake of 11C-MPTP derived radioactivity was seen in areas corresponding to striatum and midbrain, including the substantia nigra area. No elimination from these regions was seen during the study period of 2 h. The uptake was in the order of 7-8 times the homogenous distribution of the radioactivity in the monkey. The uptake was generally high also in other regions of the brain, but there some elimination could be distinguished. Pretreatment of the monkey with spiperone, a selective dopamine receptor antagonist, did not alter uptake nor the kinetics of the 11C-MPTP derived radioactivity. Thus 11C-MPTP does not have a high affinity for postsynaptic dopamine receptors. A remarkably high uptake of 11C-MPTP derived radioactivity was seen in the eye of the monkey. The selective uptake of radioactivity in the eye was also confirmed in pigmented but not in albino mice. The melanin affinity of MPTP may cause high intracellular concentrations of the compound or its metabolites in the melanin containing nerve cells in substantia nigra, which may explain the serious vulnerability of these neurons to MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET).

By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.

Animals↗
PubMed1986

Potential pulmonary uptake and clearance of morphine in postoperative patients.

The influence of lung uptake and lung clearance on the disposition of morphine was studied in surgical patients. In the postoperative period morphine was given intravenously by a two-rate infusion regimen. Under steady-state conditions samples of mixed central venous blood (pulmonary artery) and peripheral arterial blood (radial artery) were taken simultaneously and at the same time cardiac output was measured. The concentration differences between venous and arterial blood were used to calculate the extraction ratio of morphine across the lung. In all patients there was marked pulmonary uptake, but the concentration differences in most of them were small under steady-state conditions. The extraction ratio (mean +/- SD) across the lung was 0.06 +/- 0.10, implying insignificant lung clearance. However, in two patients, both with diabetes mellitus, there was a significant concentration gradient, indicating that the lung could contribute to the total body elimination of morphine. On the other hand, the total clearance was similar in diabetic and nondiabetic patients (1190 and 1150 ml/min, respectively), implying that pulmonary clearance would have no significant influence on the kinetics of morphine. A physiologically based pharmacokinetic model was used to describe the disposition of morphine in post-operative patients. The model allowed simulation of pulmonary diffusion, uptake and elimination and supported conclusions based on model-independent experimental data.

Adult↗
PubMed1986

Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients.

The pharmacokinetics of azathioprine (AZA) and 6-mercaptopurine (6-MP) was studied in uremic patients after 100 mg AZA intravenously (fifteen patients) and orally (eight patients). 6-MP was analysed with gas chromatography mass spectrometry following extractive alkylation. AZA was determined indirectly assuming quantitative conversion to 6-MP in whole blood. The plasma concentration of AZA fell rapidly after i.v. administration. The mean half-time of elimination for the first rapid phase (t1/2 alpha) was 6.1 min (S.D. +/- 4.1) and for the terminal phase (t1/2 beta) 50 min (+/- 31). The total plasma clearance (Cl) was 6.9 1./min (+/- 3.0). AZA was rapidly converted to 6-MP in vivo, and maximal plasma concentrations of 6-MP were found as early as 5 min after i.v. injection of AZA. The mean t1/2 alpha was 4.6 min (+/- 2.2), t1/2 beta 74 min (+/- 58) and Cl 8.0 1./min (+/- 5.8). The plasma levels of both AZA and 6-MP were either low or undetectable 4-6 h after dose. In erythrocytes AZA levels were low or undetectable indicating rapid conversion to 6-MP in these cells. 6-MP concentration - time curve in erythrocytes was similar to that in plasma, except for a somewhat slower terminal phase of elimination. Oral administration of AZA generated flat plasma curves for AZA and 6-MP. The area under the concentration - time curve (AUC) was considerably smaller than after i.v. administration, 18 and 41% for AZA and 6-MP, respectively. There seems to be little danger of accumulation of AZA/6-MP in uremia. We also studied inhibition of Leucoagglutin (LA) stimulated lymphocyte proliferation by patient plasma at different times in six of the patients following AZA i.v. Sera drawn at 5, 10 and 30 min significantly inhibited the LA-induced proliferation, with an estimated minimum effective concentration of 6-MP in the cultures of about 0.02-0.04 microM. This suggests the possibility of a therapeutic effect even of the low plasma levels of 6-MP obtained after AZA orally. The combined use of sensitive pharmacokinetic and immunological assays as described should be useful in studying the relationship between plasma levels of AZA/6-MP and their immunosuppressive effect and toxicity.

Administration, Oral↗
PubMed1986

Pharmacokinetics of physostigmine after intravenous, intramuscular and subcutaneous administration in surgical patients.

The pharmacokinetics of physostigmine after intravenous, intramuscular or subcutaneous administration as well as its arousal effect after anaesthesia have been studied in surgical patients in the early postoperative period. After intravenous administration physostigmine had a very rapid plasma elimination with a plasma clearance ranging from 47 to 163 l/h with a mean +/- s.d. of 92.5 +/- 37.7 l/h. The volume of distribution was 46.5 +/- 19.2 l, while distribution and plasma elimination half-lives were 2.3 and 22 min, respectively. A fraction of the dose was probably hydrolyzed in blood since its blood elimination half-life in vitro was approximately 190 min. After both intramuscular and subcutaneous administration the systemic availability was almost complete, the plasma terminal half-lives only being somewhat longer than after intravenous administration. Plasma clearance, volume of distribution and elimination half-life of physostigmine were not correlated to age or body weight of the patients. The rapid plasma clearance of physostigmine resulted in a short duration of antisedative effect. After administration of 1 mg physostigmine salicylate i.v., drug-induced sedation was rapidly reversed with a duration of 30-60 min. The duration of action was similar after intramuscular injection but onset was delayed by 20-30 min. It was concluded that a plasma concentration of 3-5 ng/ml of physostigmine should be exceeded if an adequate analeptic effect is to be achieved, meaning that 2 mg of physostigmine had to be administered subcutaneously in order to achieve a satisfactory reversal of sedation. The short duration of action may hamper the use of physostigmine as an agent for reversal of drug-induced sedation and anticholinergic effects after surgery.

Adult↗
PubMed1986

A double-blind trial of the analgesic properties of physostigmine in postoperative patients.

A double-blind clinical trial of the analgesic and antisedative effects of physostigmine was carried out on surgical patients (n = 60) during the first hours postoperatively. Pethidine and placebo were included for comparison in the double-blind study. The degree of pain and sedation was estimated when the patient demanded analgesics and immediately before the administration of the test drug. The dosage administered i.v. was: physostigmine salicylate 2 mg, placebo = saline, or pethidine chloride 50 mg. After this, the same parameters were recorded at regular intervals. In addition, ventilatory rate, pulse rate, systolic blood pressure and side effects, if any, were noted. The results showed that physostigmine caused analgesia that was of the same magnitude as pethidine during the first 15 min, after which it decreased to the level of the placebo at 30 min. An antisedative or arousal effect was recorded over a somewhat longer time period; after this, there was no difference between placebo and physostigmine. In contrast to pethidine, physostigmine caused no decrease in the ventilatory rate. The pulse rate and systolic blood pressure did not change in any of the groups. Although the durations of the analgesic and antisedative effects of physostigmine were short, the use of this drug may well be preferable to the use of e.g. naloxone when immediate alertness of the patient is wanted without causing an increase in postoperative pain.

Adult↗