Biomedical subjects

R Dirksen

Publications and source records attributed to R Dirksen.

At least 19 recordsLinked to original sources

PubMed1997

Responses to propofol in relation to GABA functionality of discrete parts of the brain of rats.

Genetically-determined regional differences in the GABA-ergic make-up of the brain exist in two lines of Wistar rats viz apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) Wistar rats, Propofol is a GABA-mimetic general anesthetic. This study compared the responses to propofol in APO-SUS and APO-UNSUS rats. Propofol induced a higher incidence of involuntary muscular contractions and oral movements, but a lower incidence of grooming, in APO-SUS rats than in APO-UNSUS rats. Reflex inhibition and narcosis, being defined as the behavior marked by both full absence of purposeful movements and by complete loss of righting reflexes, after propofol did not differ between the two lines. APO-SUS rats had less variation of the heart rates and greater variations of diastolic arterial pressures in response to electrical stimulation than the APO-UNSUS rats, and these variations were reduced by increasing doses of propofol. Arterial pressures in APO-SUS rats were higher than in APO-UNSUS rats. Propofol caused a biphasic change in intra-arterial pressures and had the greatest effect in APO-SUS rats. Differences in cerebral GABA transmission, especially in the striato-nigro-collicular pathway, did not give rise to differences in the effect of propofol on narcosis and hindlimb withdrawal reflex. In contrast, these differences in GABA transmission were accompanied by line-specific differences in effect of propofol on certain behavioral and cardiovascular parameters.

Anesthesia, Intravenous↗

PubMed1997

Pain characteristics help to predict the analgesic efficacy of radiotherapy for the treatment of cancer pain.

It is recognised that radiotherapy provides relief for intractable pain in approximately 50% of patients with cancer pain. Unfortunately, traditional explanatory variables, such as age, gender, histology or radiation dose, do not help to predict which individuals will benefit from palliative radiotherapy. A non-randomised prospective clinical trial was conducted on 51 patients to evaluate the value of pain characteristics as new explanatory variables for predicting the efficacy of palliative radiotherapy for providing cancer pain relief. Two new explanatory variables were identified: the presence of radiating pain and the pain score before radiotherapy.

Female↗

PubMed1997

A method for long duration anaesthesia for a new hindlimb ischaemia-reperfusion model in mice.

To study the relationship between ischaemia-reperfusion and multiple organ dysfunction syndrome (MODS), a new anaesthesia method was required to be applied to C57BL/6 mice. These mice are also used in a well accepted, standardized model for MODS using intraperitoneally administered zymosan (zymosan induced general inflammation, ZIGI). The aim was to develop a new model for ischaemia-reperfusion with 6 h of anaesthesia. This and further specific requirements for the combination of ischaemia-reperfusion and the ZIGI method, made us select inhalational anaesthesia using isoflurane in oxygen. This study evaluates whether long-term anaesthesia confounds the results of ischaemia-reperfusion and the ZIGI model. In addition the benefits of using the analgesic buprenorphine were evaluated. Ischaemia was induced with a tourniquet around the hindlimb. Ischaemia and reperfusion were verified by imaging a radioactive tracer with a gamma-camera. It was established that anaesthesia with isoflurane in oxygen caused little perturbation of body temperature and respiratory rate. A survival rate of 89% without noteworthy influence on organs was obtained. Buprenorphine proved to provide adequate analgesia and had no influence on measured parameters. In our experimental setting, this model with long duration anaesthesia allowed us to induce ischaemia and reperfusion of the hindlimb without perturbation of measurements. It also allowed good exposure of the abdomen and facilitated combination with the ZIGI model.

Analgesics, Opioid↗

PubMed1996

Effects of acute and chronic cocaine administration on EEG and behaviour in intact and castrated male and intact and ovariectomized female rats.

Intact and gonadectomized male and female WAG/ Rij rats were used to study the effects of gender and gonadal hormones on the development of sensitization and tolerance to cocaine-induced changes in EEG and behaviour. The four groups of WAG/Rij rats differed in the number of spontaneously occurring spike-wave discharges: ovariectomy decreased and castration increased the number of spike-wave discharges. This confirms that testosterone has antiabsence effects and that female gonadal hormones may promote the occurrence of spike-wave discharges. Cocaine [10 and 20 mg/kg, intraperitoneally (IP)] was administered before and after chronic cocaine administration (9 days, one daily injection with 10 mg/kg) and EEG and behaviour were monitored. Cocaine strongly suppressed the occurrence of spike-wave discharges before and after chronic administration in all four groups, although the decrease was less in the intact males. Sensitization or tolerance induced by cocaine on EEG could not be established. Acute cocaine administration eliminated explorative, automatic, and passive behaviour, whereas various stereotypical activities such as uncoordinated head and body movements and head swaying emerged. Differences between groups were observed as intact males were less likely than subjects in the three other groups to engage in intense stereotyped behaviour. These data suggest that testosterone inhibits EEG and behavioural effects of acute cocaine administration. All four groups displayed less head swaying and more uncoordinated head and body movements after chronic cocaine administration, suggesting that behavioural sensitization had occurred. Differences between the four groups had faded away. Although pharmacokinetic differences in levels of cocaine and benzoylecgonine between the four groups were found, they could not easily be related to the behavioural differences between groups.

Animals↗

PubMed1996

Advanced age alone does not suppress anastomotic healing in the intestine.

BACKGROUND: Because retrospective clinical studies yield conflicting results and experimental data are completely absent, this study was performed to determine whether anastomotic repair in the intestine deteriorates with age. METHODS: Ileal and colonic anastomoses were constructed in two groups of healthy rats, ages 2 to 3 months and 27 to 30 months, respectively. Healing was assessed, both 3 and 7 days after operation, by measuring anastomotic bursting pressure, breaking strength, and collagen content, the latter both biochemically (hydroxyproline) and morphometrically. In addition, the ex vivo collagen synthetic capacities were compared. RESULTS: The development of anastomotic strength was similar in young and old rats; average strength increased from 3 to 7 days and was never lower in the older animals. This was true for both bursting pressure and breaking strength. The collagen production capacity was suppressed in the old rats, particularly in the ileum (p < 0.05), whereas the synthesis of noncollagenous protein remained unaltered. However, this did not result in a reduced accumulation of collagen in the anastomotic area--both anastomotic hydroxyproline content and the volume percentage of collagen in the actual wound area were unchanged. CONCLUSIONS: Advanced age per se does not affect development of strength or deposition of collagen during early repair of intestinal anastomoses.

Age Factors↗

PubMed1995

Pancuronium masks the prejunctional muscarinic autoreceptor in guinea pig tracheal smooth muscle.

The effect of pancuronium pretreatment on the function of the prejunctional muscarinic receptor in guinea-pig trachea was studied by using electrical field stimulation (EFS). The effects of cumulative doses of the muscarinic M2 receptor antagonist gallamine were investigated in tracheal smooth muscle strips from guinea-pigs after addition of pancuronium in vitro and in strips from guinea-pigs which had been pretreated with doses of pancuronium that caused 100% neuromuscular blockade. The results of both types of experiments were compared to those of control groups of the same size. In all strips a dose response curve with cumulative doses of methacholine was made before EFS was switched on. No differences were found between the mean pD2 value and slope of the concentration-response curves of untreated guinea-pigs and animals treated with anaesthetics and pancuronium. The animals showed variable responses to pancuronium. The bath concentration of pancuronium which decreased the EFS-induced contraction to half the original value varied between 14-61 microM. The intravenous dose necessary to paralyze the muscles, varied among the different guinea-pigs from 0.017-0.085 mg.kg-1. The EFS-induced contraction for the concentration range of gallamine 0.32 microM-0.32 mM was found to differ significantly between the strips treated with pancuronium in the organ bath and their control group. For the guinea-pigs anaesthetized and pretreated with pancuronium a significant difference with control was observed at gallamine concentrations ranging from 0.032-0.32 mM. These results show that pancuronium, added to the organ bath as well as administered intravenously to the guinea-pig, masked the inhibitory muscarinic receptor.

Animals↗

PubMed1995

A system model for halothane closed-circuit anesthesia. Structure considerations and performance evaluation.

BACKGROUND: Previously, the authors described a physiologic model for closed-circuit inhalational anesthesia. The basic version of this system model was clinically validated for isoflurane. An extended version adopted nonpulmonary elimination causing a constant fraction of anesthetic to be irreversibly lost. This version improved the accuracy of the model for enflurane. The model's performance for other inhalational anesthetics that are not biochemically inert, such as halothane, remained to be evaluated. METHODS: The current study quantified the predictive performance of four versions of the model by comparison of the predicted and measured alveolar halothane concentration-time profiles in 53 patients. Version A did not incorporate nonpulmonary elimination, whereas version D adopted a nonlinear hepatic nonpulmonary elimination following Michaelis-Menten kinetics. A and D used fixed partition coefficients. Their counterparts, A' and D', were formulated to examine the impact of age-adjusted partition coefficients on the accuracy of our model. Each concentration measured by mass spectrometry was compared to four predicted concentrations calculated by four computer simulations (one per version). For each patient, the authors calculated the root mean squared error (rmse; typical error size), bias (systematic component), and scatter of the prediction errors. RESULTS: Fifty-three patients were anesthetized with 330 ml of liquid halothane via 426 bolus injections during more than 61 h; 21,890 alveolar concentrations (average 0.6 vol%) were measured. Version D' showed the best overall performance with an rmse of 19.6 +/- 7.2%, a bias of 0.5 +/- 15.9%, and a scatter of 13.2 +/- 3.5% (mean +/- SD). CONCLUSIONS: The model incorporating nonpulmonary elimination and age-adjusted partition coefficients (D') is sufficiently reliable and accurate to represent halothane closed-circuit anesthesia. This system model, with its various versions, is a valuable tool to predict the dynamics of isoflurane, enflurane, and halothane for clinical, educational, and research purposes.

Adult↗

PubMed1995

Diazepam biphasically modulates [3H]TBOB binding to the convulsant site of the GABAA receptor complex.

Interactions of GABA, bicuculline methochloride and diazepam with [3H]TBOB binding to rat brain membranes were evaluated in vitro. GABA displaced [3H]TBOB binding with and IC50 of 4 microM and a slope factor near unity. The competitive GABA antagonist bicuculline methochloride shifted the displacement curve of GABA parallelly to the right, indicating that the interaction of GABA with [3H]TBOB binding is of an allosteric nature. In the presence of GABA, diazepam displaced the binding of [3H]TBOB according to a two-site model: a high affinity site with an IC50 of about 50 nM and a lower affinity site with an IC50 of about 30 microM. Bicuculline methochloride abolished the nanomolar displacement by diazepam and increased the micromolar IC50 value. These results indicate that the interaction of the high affinity diazepam site with the [3H]TBOB binding site is totally GABA dependent and that the low affinity effect of diazepam on [3H]TBOB binding is at least partially GABA dependent. It is likely that the low affinity potency of diazepam to displace [3H]TBOB binding has physiological relevance.

Animals↗

PubMed1995

The bioavailability of intramuscularly administered nicomorphine (Vilan) with its metabolites and their glucuronide conjugates in surgical patients.

The kinetics of 20 mg nicomorphine intramuscularly were described in 8 patients under combined general and epidural anesthesia. The half-life of nicomorphine was 0.32 +/- 0.20 h (mean +/- SD) and is governed by the absorption-rather than the elimination rate. The half-life of 6-mononicotinoylmorphine (0.39 +/- 0.09 h) was identical to that of the parent compound (p = 0.29), suggesting it is directly related to the absorption rate of nicomorphine. Morphine had a half-life of 1.38 +/- 0.31 h. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The half-life of these 2 glucuronide conjugates was about 2.6 h (p = 0.07). A glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In urine only morphine and its glucuronides are found, with renal clearance values of 214 ml.min-1 for morphine and 132 ml.min-1 for the glucuronides. The bioavailability of this pharmaceutical formulation after intramuscular administration equals that of intravenous administration in surgical patients (at the same dose).

Adult↗

PubMed1994

Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates.

The pharmacokinetics of 30 mg nicomorphine after rectal administration with a suppository are described in 8 patients under combined general and epidural anaesthesia. No nicomorphine or 6-mononicotinoylmorphine could be detected in the serum. Morphine appeared almost instantaneously with a lag-time of 8 min and had a final elimination half-life of 1.48 +/- 0.48 h. Morphine was metabolized to morphine-3-glucuronide and morphine-6-glucuronide. These glucuronide conjugates appeared after a lag-time of 12 min and the half-life of these two glucuronide conjugates was similar: about 2.8 h (P > 0.8). The glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In the urine only morphine and its glucuronides were found. The renal clearance value for morphine was 162 ml.min-1 and for the glucuronides 81 ml.min-1. This study shows that administration of a suppository with 30 mg nicomorphine gives an excellent absolute bioavailability of morphine and its metabolites of 88%. The lipid-soluble prodrug nicomorphine is quickly absorbed and immediately hydrolysed to morphine.

Administration, Rectal↗

PubMed1994

Irradiation and responsiveness to pain stimuli in rats.

This study evaluates whether irradiation inhibits responses to pain in an animal model. We found that irradiation with doses of 10 Gy, 15 Gy and 17.5 Gy of the lumbar enlargement of the spinal cord inhibits the behavioural responses to the stimulus of the hot-plate. These doses were otherwise without effects. This data is discussed in view of the effects of irradiation of living cells, and we propose that a modification of pain signal processing is accomplished. Similar considerations apply to the human condition.

Animals↗

PubMed1994

Site- and test-dependent antinociceptive efficacy of amitriptyline in rats.

The antinociceptive efficacy of systemic- (IV), spinal- (IT), and global supraspinal (ICV)-administered amitriptyline (AMIT) was compared in three different tests for nociception: the hot-plate test, the tail-flick test, and the withdrawal reflex test. Systemic AMIT inhibited the responses in each of the three tests, with distinct dose-effect relationships. Spinal AMIT reduced in a dose-dependent fashion the force of withdrawal to noxious electrical stimulation but was ineffective in the hot-plate test and facilitated the responses in the tail-flick test. Supraspinal AMIT inhibited in dose-dependent fashion the response to the stimulus of the hot plate, reduced the force of withdrawal after a dose that was effective by the IV route, and again facilitated the responses in the tail-flick test. The results suggest that spinal sites mediate the inhibition of the withdrawal reflex and the supraspinal site the inhibition of the hot-plate test. Two conclusion are drawn: First, AMIT's site of action varies among the pain modalities; and, second, augmentation of the reactions can occur. The complex interaction accords with the clinical experience that the benefits of AMIT in pain treatment are hard to predict.

Amitriptyline↗

PubMed1993

The predictive performance of a system model for enflurane closed-circuit inhalational anesthesia.

BACKGROUND: Previously, the authors described a system model for closed-circuit inhalational anesthesia, and demonstrated close agreement between end-tidal isoflurane concentrations measured in their clinical study and those predicted by the model. The predictive performance of their model has not, however, been tested for anesthetics featuring nonpulmonary elimination (NPE). METHODS: The authors quantified the predictive performance of two versions (A and C) of the model in 50 patients by comparing the predicted and the measured alveolar concentration-time profiles after bolus injections of liquid enflurane into the expiratory limb of the closed system. Version A did not incorporate NPE, but version C emulated NPE by adopting the irreversible loss of a fraction of the enflurane present in the arterial hepatic blood flow (0.131, derived from a mass balance study performed by others). For each concentration measured by mass spectrometry, the authors used computer simulations of version A and C to calculate a predicted concentration for both versions. For each patient, the authors calculated the bias (indicating systematic over- or underprediction) and the scatter of the prediction errors (indicating typical error size). RESULTS: The authors administered a total of 379 ml of liquid enflurane via 466 injections. A total of 18,432 alveolar concentrations (one per 10-s period; average concentration = 0.96 vol%) were measured. The bias and the scatter, both given as mean (and SD), were 10.0 (13.1)% and 11.8 (3.9)% for version A and -0.8 (11.4)% and 11.4 (2.8)% for C. The bias for version C was closer to zero; the scatters were similar. CONCLUSIONS: Version C incorporating NPE performs better than version A. The accuracy that was obtained should encourage the use of version C for clinical, teaching, research, economic, and ecologic purposes.

Adult↗

PubMed1993

Pharmacokinetics of intravenously administered nicomorphine and its metabolites in man.

Intravenous doses of 30, 20 and 10 mg nicomorphine (Vilan) are extremely quickly metabolized into the metabolites 6-nicotinoylmorphine and morphine. The half-lives of elimination are respectively 3 min for nicomorphine, 3 and 15 min for 6-nicotinoylmorphine, and 135-190 min for morphine. The kinetics of the 30 and 20 mg dose are comparable, the 10 mg dose shows patient dependent variations in metabolism. The AUC of the parent drug and its metabolites is linearly related to the dose.

Adult↗

PubMed1992

The GABAA receptor complex in relation to epilepsy. Reversal of [3H]TBOB inhibition: a prediction of proconvulsive properties?

[3H]-t-Butylbicycloorthobenzoate ([3H]TBOB), a convulsant, is known to label a binding site on the GABAA receptor complex. Bicuculline methochloride (bicuculline MCl), folic acid, pentazocine, naloxone, ethyl-beta-carboline-3-carboxylate (beta CCE) and Ro 5-4864 have (pro)convulsive properties in vivo. In the present study, we determined the extent to which these compounds modify the binding of [3H]TBOB in the presence of IC50 amounts of GABA (5 microM) or diazepam (50 microM). We found that the GABA antagonist bicuculline MCl reversed the inhibitory effect of GABA on [3H]TBOB binding completely, as was expected. Folic acid, pentazocine and naloxone also reversed the inhibitory effect of GABA on [3H]TBOB binding. This finding is compatible with the view that the proconvulsive effects of these compounds can be credited to a reduction of GABAergic action at the GABAA receptor complex. We suggest that the reversal of GABA's inhibition of [3H]TBOB binding is a sufficient (but not a necessary) condition to predict proconvulsive (side) effects of drugs. beta CCE and Ro 5-4864 modified [3H]TBOB binding in the presence of GABA in a biphasic fashion. A unique relation between beta CCE, Ro 5-4864 and the GABAA complex might exist. Bicuculline MCl reversed the inhibitory effect of diazepam on [3H]TBOB binding only partly. beta CCE did not reverse the inhibitory effect of diazepam on [3H]TBOB binding, neither did Ro 5-4864. The presence of a GABA-independent interaction between a low affinity benzodiazepine recognition site and the TBOB site is proposed.

Animals↗

PubMed1992

The dose-response and time-effect relationships of intrathecal bupivacaine in rats. The influence of epinephrine and pH.

The present study defined the dose-response relationship of intrathecally injected bupivacaine in rats. The effect was a quantified drug-induced and graded reduction in the magnitude of the withdrawal reflexes elicited by transcutaneous electrical stimulation. Intrathecal epinephrine reduced the magnitude of the withdrawal reflexes. The combination of epinephrine and bupivacaine resulted in a dose-response relationship different from that of bupivacaine alone, and the combination was more effective than bupivacaine alone. The intrathecal combinations of bupivacaine and 25 micrograms of the alpha 2-adrenergic antagonist idazoxan had an effect not different from that of bupivacaine alone, but the duration of effect was shorter. The dose-response relationship of bupivacaine was not different whether the pH of the solution was 4.4 or 6.1. The results concerning the effect as a function of time confirm those of earlier studies: 1) the duration of effect depends on the dose of bupivacaine; 2) epinephrine protracts the duration of effect; 3) the pH is of no relevance. Thermal tests for nociception showed that antinociception outlasted motor symptoms. Epinephrine enhanced this effect of bupivacaine, but did not change the duration of motor impairment.

Animals↗

PubMed1991

Pharmacokinetics of intramuscular nicomorphine and its metabolites in man.

After i.m. injection nicomorphine is relatively slowly absorbed from the muscular depot and is found in the serum for approximately 1 h. The rate of absorption differs between patients and governs the overall pharmacokinetic profile of the compound. The relative AUCs were nicomorphine 18%, 6-nicotinoylmorphine 17%, and morphine 65%. Nicomorphine and 6-nicotinoylmorphine have significantly higher AUCs after i.m. injection than after i.v. injection, while the AUC of morphine and the total AUC show no difference between the two modes of administration.

Adult↗

PubMed1991

Naloxone enhances epileptogenic and behavioral effects of pentazocine in rats.

Eight groups of six rats were either injected with saline, pentazocine, naloxone, or a combination of pentazocine and naloxone. Studied were the effects on EEG and behavior. It was found that pentazocine induced epileptic seizures in a dose-dependent fashion. In addition, similar behavioral changes were present after all three doses of pentazocine. High doses of naloxone did not cause epilepsy and affected behavior only slightly. Seizures induced by pentazocine were not antagonized by the opiate antagonist naloxone, but were facilitated after the combination of a noneffective dose of pentazocine and a noneffective dose of naloxone. In addition, exploratory behavior was facilitated by the combination of pentazocine and naloxone. It seems that both an opiate and a nonopiate system are involved in this type of epilepsy and in this type of behavior.

Animals↗