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M Leuwer

Publications and source records attributed to M Leuwer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives.

We have studied the effects of four different phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to find structural determinants of blocking potency. All compounds blocked skeletal muscle sodium channels in a concentration-dependent manner. The methylated phenol 3-methylphenol and the halogenated phenol 4-chlorophenol blocked sodium currents on depolarization from -100 mV to 0 mV with IC(50) values of 2161 and 666 microM respectively. Methylation of the halogenated compound further increased potency, reducing the IC(50) to 268 microM in 2-methyl-4-chlorophenol and to 150 microM in 3,5-dimethyl-4-chlorophenol. Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from -70 mV or when a 2.5 s prepulse was introduced before the test pulse inducing slow inactivation, the IC(50) was reduced more than 3 fold in all compounds. The values of K(D) for the fast-inactivated state derived from drug-induced shifts in steady-state availability curves were 14 microM for 3,5-dimethyl-4-chlorophenol, 19 microM for 2-methyl-4-chlorophenol, 26 microM for 4-chlorophenol and 115 microM for 3-methylphenol. All compounds accelerated the current decay during depolarization and slowed recovery from fast inactivation. No relevant frequency-dependent block after depolarizing pulses applied at 10, 50 and 100 Hz was detected for any of the compounds. All the phenol derivatives that we examined are effective blockers of skeletal muscle sodium channels, especially in conditions that are associated with membrane depolarization. Blocking potency is increased by halogenation and by methylation with increasing numbers of methyl groups.

Cell Line↗
PubMed2001

Propofol blocks human skeletal muscle sodium channels in a voltage-dependent manner.

UNLABELLED: Propofol decreases muscle tone in the absence of neuromuscular blocking drugs. This effect probably cannot be attributed solely to central nervous depression. We studied the effects of propofol on heterologously expressed skeletal muscle sodium channels. Our hypothesis was that the decrease in muscle tone may partly be attributed to an interaction of propofol with sarcolemmal sodium channels. Cells were voltage clamped and whole-cell sodium inward currents were recorded in the absence and presence of propofol. When depolarizing pulses to 0 mV were started from a holding potential close to the normal resting potential of muscle (-70 mV), or when a 2.5-s prepulse inducing slow inactivation was applied before the test pulse at -100 mV, a significant reduction in the peak current amplitude was achieved by 10 and 5 microM propofol, respectively (P < 0.001). Half-maximum blocking concentrations with these protocols were 23 and 22 microM. Blocking potency increased at depolarized membrane potentials with the fraction of inactivated channels; the estimated dissociation constant K(d) from the inactivated state was 4.6 microM. These results suggest that propofol significantly blocks sarcolemmal sodium channels at clinically relevant concentrations while maintaining potentials close to the physiological resting potential. IMPLICATIONS: Voltage-gated sodium channels mediate the initiation and propagation of action potentials along the sarcolemma. Results from our study show that those channels are targeted and blocked in a concentration- and voltage-dependent manner by propofol. This mechanism may contribute to the reduction in muscle excitability.

Action Potentials↗
PubMed2001

Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging.

OBJECTIVE: Up to 37% of patients undergoing MR imaging examinations experience moderate to severe levels of anxiety that necessitate the termination of the procedure in 5-10% of patients. Although the clinical use of MR imaging has increased, effective procedures to handle claustrophobia are lacking. We evaluated the effectiveness of intranasally administered midazolam spray in preventing claustrophobic responses of patients undergoing MR imaging. SUBJECTS AND METHODS: Fifty-four patients scheduled for MR imaging were included in this prospective study. Anxiety and sedation of patients were evaluated before drug administration, immediately before MR imaging, and at the end of the procedure. The Spielberger State-Trait Anxiety Inventory, the visual analogue scale of anxiety, and a five-point sedation scale were used. Half the patients received intranasal spray applications of 4 mg midazolam, whereas the other patients received a placebo, in a randomized, double-blind study design (six sprayings of 0.5% midazolam solution or NaCl 0.9%, respectively). The intensity of the sensation of burning of the nasal mucosa was rated by patients using a three-point scale (no, slight, or strong burning). The quality of scan images was evaluated by a radiologist using a five-point scale (0 = extremely poor, 5 = excellent). RESULTS: No cancellations occurred with patients who received midazolam, whereas four of 27 patients receiving placebo panicked and terminated the scanning procedure. The initial anxiety and sedation scores did not differ between the groups. Patients who received midazolam spray were more sedated and less anxious immediately before entering the MR scanner and reported a more intense slight transient burning of the nasal mucosa than those in the placebo group. The quality of the MR image was higher in the midazolam group. CONCLUSION: A sizeable reduction in MR imaging-related anxiety and improved MR image quality were seen with patients who received intranasal midazolam spray. With the exception of transient burning of the nasal mucosa, no adverse effects were reported. This simple and safe method is useful in sedating patients for MR imaging and other minor procedures.

Administration, Intranasal↗
PubMed2000

Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease.

BACKGROUND: If intravenous access cannot be attained during resuscitation of adult patients, endotracheal application of at least 2 mg of adrenaline is recommended. However, the effects of this intervention have not yet been demonstrated in adults. OBJECTIVE: To demonstrate the effects of adrenaline administered through the airways. DESIGN: Prospective clinical trial. SETTING: Operating theater at university hospital. PATIENTS: 34 patients receiving implantable cardioverter defibrillators under general anesthesia. INTERVENTION: When mean arterial pressure decreased below 80 mm Hg, 100 times the effective central intravenous dose of adrenaline (mean +/- SD, 1.3+/-0.6 mg [range, 0.7 to 3 mg]) was administered over 5 seconds into the endotracheal tube or through a bronchial catheter. Ten forced ventilations followed. MEASUREMENTS: Hemodynamic variables were recorded with a polygraph recorder. Adrenaline levels were measured in 13 patients. RESULTS: Plasma levels and arterial pressure increased in all patients (P < 0.002). Higher plasma levels (P < 0.039) and greater arterial pressure (P < 0.001) were achieved with this method than with intravenous injection. The effects of adrenaline did not differ between the two airway routes. Sustained ventricular arrhythmia did not occur. CONCLUSION: These substantial effects support the standard recommendation to consider the airways as an alternate route for at least 2 mg of adrenaline during resuscitation.

Absorption↗
PubMed2000

Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients.

OBJECTIVE: Capillary leakage syndrome (CLS) is a frequent complication in sepsis, characterized by loss of intravasal fluids leading to generalized edema and hemodynamic instability despite massive fluid therapy. In spite of its importance no standardized diagnostic criteria are available for CLS. DESIGN: Prospective clinical study. SETTING: 1,800-bed university hospital PATIENTS: Six septic shock patients with CLS were compared to six control patients. MEASUREMENTS AND RESULTS: CLS was clinically determined by generalized edema, positive fluid balance, and weight gain. Plasma volume was measured by indocyanine green, red blood cell volume by chromium-51 labeled erythrocytes, and colloid osmotic pressure before and 90 min after the administration of 300 ml 20% albumin. Extracellular water (ECW) was measured using the inulin distribution volume and bioelectrical impedance analysis. Red blood cells averaged 20.2 +/- 1.0 ml/ kg body weight in CLS patients and 23.3 +/- 4.1 in controls. ECW was higher in CLS patients than in controls (40.0 +/- 6.9 vs. 21.7 +/- 3.71; p< 0.05). ECW of inulin was correlated with that measured by bioelectrical impedance analysis (r = 0.74, p< 0.01). The increase in colloid osmotic pressure over the 90 min was less in CLS patients than in controls (1.1 +/- 0.3 vs. 2.8 +/- 1.3 mmHg;p< 0.05). CONCLUSION: These results suggest that measurements of an increased ECW using bioelectrical impedance analysis combined with a different response of colloid osmotic pressure to administration of albumin can discriminate noninvasively between patients with and those without CLS.

Adult↗
PubMed2000

Endoluminal grafting of abdominal aortic aneurysms: experience with the Talent endoluminal stent graft.

The aim of this study was to evaluate the Talent endoluminal stent graft (TESG) in treating abdominal aortic aneurysms (AAA). The TESG is a polyester-covered nitinol endograft (proximal diameters 20-38 mm and iliac limb diameters 8-22 mm). Twenty-two men were treated with the TESG via bilateral femoral arteriotomies. Pre-implantation, coil embolization of various vessels arising from the aneurysm was performed in 6 patients. Plain radiographs and spiral CT angiograms (CTA) were carried out at 7 days, 3, 6, and 12 months following TESG implantation or re-intervention. Median aortic and iliac diameters were 27 mm (range 20-34 mm) and 14 mm (range 10-19 mm). The corresponding graft diameters were 30 mm (range 24-38 mm) and 14 mm (range 12-20 mm). No patient was rejected purely on the basis of too large aortic or iliac diameters. Eight patients required custom-made grafts. Graft implantation was successful in all patients. There were no blood transfusions, distal embolic episodes, or conversions to open surgery. Re-intervention was necessary in 1 patient. Complications included one fatal myocardial infarction, one inguinal hematoma, and two superficial wound infections. The aneurysm thrombosed completely following implantation in 14 patients and at 3 or 6 months in 4 other patients. One patient with endoleak is awaiting his 3-month control and 2 patients show tiny endoleaks but reduction of aneurysm size. The mean aneurysm size decreased significantly from 58 +/- 10 to 53 +/- 13 mm (p < 0.0005). Due to the large sizes available and the option of custom-made grafts, the TESG helps widen the spectrum of patients who can be treated with endoluminal grafting. The treatment is associated with a significant reduction in aneurysm size.

Aged↗
PubMed2000

Acute vascular rejection is associated with systemic complement activation in a pig-to-primate kidney xenograft model.

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-to-primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life-supporting model of pig-to-primate kidney transplantation, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low-dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h-DAF transgenic group. Stable initial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti-porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short-term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig-to-primate combination.

Acute Disease↗
PubMed2000

Low-dose dopexamine in patients undergoing hemihepatectomy: an evaluation of effects on reduction of hepatic dysfunction and ischaemic liver injury.

BACKGROUND: Hepatic dysfunction is a common problem in patients after hemihepatectomy. Treatment with low-dose dopamine has been shown to be beneficial in hemihepatectomy patients. We hypothesized that dopexamine, a synthetic vasoactive catecholamine, due to its specific pharmocodynamic profile may be more effective in reducing hidden ischaemic episodes in the hepato-splanchnic region during and after temporary total cross-clamping of hepatic inflow in these patients. METHODS: The effects of low-dose dopexamine on hepatic venous haemoglobin oxygen saturation (ShvO2), hepatic venous lactate level, monoethylglycinxylid (MEGX) formation, hepatic synthetic function and indicators for hepatic cell damage were studied during hemihepatectomy and for 16 h postoperatively in hemihepatectomy patients and compared to those of low-dose dopamine. In a prospective, double-blind clinical study 20 patients received randomly either dopexamine (DPX) 0.5 microg kg(-1) min(-1) (n=10) or dopamine (DO) 2.5 microg kg(-1) min(-1) (n= 10). Infusions were started after induction of anaesthesia and continued 16 h postoperatively. Hepatic vein, radial and pulmonary artery were catheterized. Measurements were carried out after induction of anaesthesia, after total cross-clamping of hepatic inflow, and at 2 h and 16 h postoperatively. RESULTS: There were no differences in systemic haemodynamics, oxygenation, ShvO2, serum aminotransferases or MEGX levels between the groups. At 16 h postoperatively prothrombin and antithrombin III levels were significantly lower while hepatic venous lactate was significantly higher in the DPX group compared to the DO group. CONCLUSION: In patients undergoing hemihepatectomy, we could not reveal superior hepatoprotective effects of low-dose dopexamine compared to low-dose dopamine.

Adult↗
PubMed2000

Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol.

1. We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant alpha-subunits of human skeletal muscle sodium channels. 2. Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR(50) of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at -100 mV, the ECR(50) was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM). 3. Membrane depolarization before the test depolarization significantly promoted benzylalcohol-induced sodium channel blockade. The values of K(D) for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI(50) for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4. Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5. Benzylalcohol induced significant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6. Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.

Amino Acid Substitution↗
PubMed2000

Anaesthesia with midazolam and S-(+)-ketamine in spontaneously breathing paediatric patients during magnetic resonance imaging.

We evaluated safety and efficacy of a sedation technique based on rectal and intravenous S-(+)-ketamine and midazolam to achieve immobilization during Magnetic Resonance Imaging (MRI). Thirty-four paediatric patients were randomly assigned to undergo either the sedation protocol (study group) or general anaesthesia (control group). Imaging was successfully completed in all children. Children in the study group received a rectal bolus (0.5 mg x kg(-1) midazolam and 5 mg x kg(-1) S-(+)-ketamine) and required additional i.v. supplementation (20+/-10 microg x kg(-1) x min(-1) S-(+)-ketamine and 4+/-2 microg x kg(-1) x min(-1) midazolam), spontaneous ventilation was maintained. Transient desaturation occurred once during sedation and four times in the control group (P=0.34). PECO2 was 5.3+/-0.5 kPa (40+/-4 mm Hg) in the study group and 4.1+/-0.6 kPa (31+/-5 mm Hg) in the control group (P<0.001). Induction and discharge times were shorter in the study group (P<0.001), recovery times did not differ significantly between the groups. Our study confirms that a combination of rectal and supplemental intravenous S-(+)-ketamine plus midazolam is a safe and useful alternative to general anaesthesia for MRI in selected paediatric patients.

Administration, Rectal↗
PubMed2000

Anaesthesiological and criterial care aspects regarding the treatment of patients with arteriovenous malformations in interventional neuroradiology.

In recent years, the neuroradiological treatment of cerebral and spinal arteriovenous malformations (AVMs) has undergone significant evolution and improvement. Endovascular embolisation procedures of AVMs are mainly performed under general anaesthesia. Different pathophysiological characteristics of patients with AMVs must be considered for the choice of the anaesthetic procedures. Anaesthesiological management must aim at maintaining stable intracranial haemodynamics; thus, the drugs used must be evaluated according to their effects on brain perfusion, brain metabolism, and intracranial pressure. Rapid recovery to normal central nervous functions should be obtained postoperatively. Close-meshed neurological surveillance should be exercised in order to detect immediately any alteration of neurological state. In summary, anaesthesiological management of interventional neuroradiology is based on the same well-established principles as anaesthesia in neurosurgery.

Anesthesia, General↗
PubMed2000

Anaesthesia with propofol decreases FMLP-induced neutrophil respiratory burst but not phagocytosis compared with isoflurane.

Propofol has been reported to produce a dose-dependent inhibition of phagocytosis and superoxide anion production during the respiratory burst (RB) of polymorphonuclear cells (PMNs) in vitro. In this randomized, blinded study, these two parameters were compared during propofol or isoflurane anaesthesia in patients undergoing elective interventional embolization of cerebral arterio-venous malformations. Anaesthesia was performed with continuous intravenous propofol 6-8 mg kg-1 h-1 (n = 15) or isoflurane 0.8-1.0% end tidal (n = 15). Heparinized blood was drawn before, and 2 and 4 h after induction of anaesthesia. The RB in isolated leucocytes was measured with the fluorescent dye rhodamine after ex vivo induction by Escherichia coli or tumour necrosis factor alpha/N-formyl-methionyl-leucylphenylalanine (TNF-alpha/FMLP). Phagocytosis was carried out in whole blood after incubation with fluorescein isothiocyanate (FITC)-labelled, opsonized E. coli and also measured with a flow cytometer. The two groups were similar in terms of biometric data and haemodynamic responsiveness. After 4 h of propofol or isoflurane anesthesia, the mean (SD) phagocytosis of E. coli was 93.2% (7.0%) and 94.3% (9.2%), respectively, of that before anaesthesia. The percentage of PMN with RB activity following TNF-alpha/FMLP stimulation was significantly reduced after 2 h (80.9% (24.2%); P < 0.05) and 4 h (53.7% (27.3); P < 0.05) of anaesthesia with propofol compared with the values before induction. This effect of propofol anaesthesia was significantly different from the effect of isoflurane anaesthesia. In contrast to published in vitro results, 4 h of anaesthesia with propofol did not reduce the phagocytotic capacity of human blood PMN more than isoflurane anaesthesia.

Adolescent↗
PubMed2000

No implicit memory for stories played during isoflurane/alfentanil/nitrous oxide anesthesia: a reading speed measurement.

UNLABELLED: Implicit memory of intraoperatively presented stories was recently detected by using the reading speed paradigm during propofol-alfentanil-nitrous oxide anesthesia. Our main goal was to evaluate the reading speed test procedure under another anesthetic regimen, i.e., isoflurane combined with nitrous oxide and alfentanil-infusion. In both experiments, patients were premedicated with oral midazolam. In a previous experiment, patients postoperatively read "old" stories that had been presented during anesthesia quicker compared with "new," unpresented stories. The same study design and test material as in the previous experiment were used. One of two audio tapes with two short stories was played randomly to patients during lumbar disk surgery and to awake controls. Approximately 7 h later, a structured interview and the reading speed test were used to determine whether the participants had any explicit or implicit memories of the presented stories. The results of 30 patients and 30 controls were calculated. Whereas the control participants showed an intact explicit and implicit memory of the previously presented material, no such effect was found in the anesthetized patients. The present experiment shows that changing the main anesthetic in otherwise equal study conditions, i. e., propofol to isoflurane (end-expiratory 0.7%), implicit memory is abolished in anesthetized patients. IMPLICATIONS: We showed that implicit memory during general anesthesia can be abolished by changing the hypnotic anesthetic. Increased postoperative reading speed for stories presented during propofol-alfentanil-nitrous oxide anesthesia was shown in a previous experiment, but not in our study using isoflurane for balanced anesthesia.

Adult↗
PubMed2000

Succinylcholine metabolite succinic acid alters steady state activation in muscle sodium channels.

BACKGROUND: Animal experiments revealed that succinylcholine produced masseter muscle rigidity and activated myotonic discharges despite neuromuscular blockade with a nondepolarizing blocker. These results suggest that either succinylcholine or its metabolites might interfere directly with voltage-operated ion channels of the sarcolemma. The aim of this study was to examine effects of one product of succinylcholine hydrolysis, succinic acid, on voltage-gated muscle sodium (Na+) channels. METHODS: Alpha subunits of human muscle sodium channels were heterologously expressed in HEK293 cells. Activation of Na+ currents was examined applying standard whole-cell voltage-clamp protocols in the absence (control and washout) and presence of succinic acid in different concentrations (0.05-10 mm). RESULTS: Succinic acid shifted the midpoints of steady state activation plots in the direction of more negative test potentials, indicating that channels open during smaller depolarizations in the presence of the drug. The maximum amount of the negative shift in 10 mm succinic acid was -6.3 +/- 1.7 mV; the EC50 for this effect was 0.39 mm. In addition, succinic acid (10 mm) significantly enhanced maximum currents after depolarizations with respect to a series of control experiments. CONCLUSION: Succinic acid facilitates voltage-dependent activation in muscle sodium channels in vitro. This might lead to muscle hyperexcitability in vivo.

Anti-Ulcer Agents↗
PubMed2000

Do we need muscular blockers in ambulatory anaesthesia?

Since the introduction of the laryngeal mask airway, the majority of day case patients can safely be anaesthetized without the administration of muscle relaxants. If muscle relaxation is required, the modern non-depolarizing agents, vecuronium, rocuronium, atracurium, cisatracurium and mivacurium, provide an excellent choice. Succinylcholine should be regarded mainly as an option in the event of an emergency intubation, especially in paediatric patients.

Journal Article↗
PubMed1999

Effect of magnetic resonance imaging on human respiratory burst of neutrophils.

It is known that low intensity magnetic fields increase superoxide anion production during the respiratory burst of rat peritoneal neutrophils in vitro. We investigated whether the high intensity magnetic fields (1.5 T) during magnetic resonance imaging can influence the human neutrophil function under in vivo conditions. Blood samples were obtained from 12 patients immediately before and after magnetic resonance imaging (mean time 27.6(+/-11.4 min)). The induced respiratory burst was investigated by the intracellular oxidative transformation of dihydrorhodamine 123 to the fluorescent dye rhodamine 123 via flow cytometry. The respiratory burst was induced either with phorbol 12-myristate 13-acetate, Escherichia coli, N-formyl-methionyl-leucylphenylalanine or priming with tumor necrosis factor followed by FMLP stimulation. There was no significant difference between the respiratory burst before and after magnetic resonance imaging, irrespective of the stimulating agent. Short time exposure to a high intensity magnetic field during magnetic resonance imaging seems not to influence the production of radical species in living neutrophils.

Adult↗