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M C Michel

Publications and source records attributed to M C Michel.

At least 37 records · Page 2Linked to original sources
PubMed2002

[Combination of plate and external fixator for biological osteosynthesis of comminuted fractures].

In a comminuted fracture, a unilateral plate doesn't always give enough stability because the contralateral cortex cannot be used as a buttress. New plate systems as the Locking Compression Plate (LCP) may solve this problem. Another method to stabilize the contralateral cortex is by using an External Fixator (EF) in addition to a conventional platte either on the opposite side of the plate or on the ipsilateral side over the plate. By doing so, a half frame of an EF acts as a substitute for the damaged cortex. This method is easily available and may also be considered when a conventional plate osteosynthesis must be mechanically improved after the conventional plate is already put in place. With this combination of a plate with a EF we treated twelve patients with comminuted fractures of the tibia, the humerus and the femur. Eleven fractures healed without further operations or complications. In one case, there was a superficial wound infection with Staph. epidermidis that lead to an early metal removal, but healing of the fracture was not impaired. We also tested this set-up in a model and found, that the additional EF increased the stiffness of the plate by 73% for axial load. The combination of a plate and a contralateral EP is a useful way to treat comminuted fractures biologically achieving enough stability to allow early motion of the adjacent joints and fast healing of the fracture. Especially for fractures adjacent to a joint, this method is an alternative to an intramedullary nail.

Adult↗
PubMed2001

Do saw palmetto extracts block human alpha1-adrenoceptor subtypes in vivo?

BACKGROUND: To test whether saw palmetto extracts, which act as alpha1-adrenoceptor antagonists in vitro, also do so in vivo in man. METHODS: In a placebo-controlled, double-blind, four-way cross-over study 12 healthy young men were treated with three different saw palmetto extract preparations (320 mg o.d.) for 8 days each. On the last day, before and 2, 4 and 6 hr after drug intake blood pressure and heart rate were determined and blood samples obtained, which were used in an ex vivo radioreceptor assay with cloned human alpha1-adrenoceptor subtypes. RESULTS: Saw palmetto extract treatment did not result in alpha1-adrenoceptor subtype occupancy in the radioreceptor assay. Although the saw palmetto extracts caused minor reductions of supine blood pressure, they did not affect blood pressure during orthostatic stress testing and did not alter heart rate under either condition. Moreover, plasma catecholamines remained largely unaltered. CONCLUSIONS: Despite their alpha1-adrenoceptor antagonist effects in vitro, therapeutically used doses of saw palmetto extracts do not cause alpha1-adrenoceptor antagonism in man in vivo.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2001

Chronic mu-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity.

BACKGROUND: Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by mu-opioid receptor blockade during antagonist-supported detoxification under general anesthesia. METHODS AND RESULTS: Fifteen young patients (30+/-1 years old, mean+/-SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65+/-10 mg/d for 21+/-6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of mu-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4+/-2 versus 22+/-2 bursts/min, P<0.0001) and antecubital venous norepinephrine plasma concentration (100+/-64 versus 256+/-48 pg/mL, P=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5+/-2 to 24+/-3 bursts/min) and norepinephrine (49+/-12 to 305+/-48 pg/mL) and epinephrine (13+/-2 to 482+/-67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82+/-4 to 108+/-3 mm Hg) and heart rate (70+/-3 to 86+/-4 beats/min). CONCLUSIONS: Chronic mu-opioid receptor stimulation by methadone decreases resting MSA in humans.

Adult↗
PubMed2001

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2001

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors.

We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

In vitro and in vivo uroselectivity of B8805-033, an antagonist with high affinity at prostatic alpha1A- vs. alpha1B- and alpha1D-adrenoceptors.

We have investigated the pharmacological properties of B8805-033 [(+/-)- 1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl] amino]-2,4(1H,3H)-pyrimidinedione], a new alpha1A-adrenoceptor (AR) selective antagonist. In radioligand binding studies, B8805-033 was 150- to 1200-fold selective for alpha1A-ARs (pKi rat cerebral cortex 8.70, cloned human receptor 7.71) relative to alpha1B-ARs (pKi rat cerebral cortex 5.60, rat liver 5.39, cloned human receptor 5.16) and alpha1D-ARs (pKi cloned human receptor 5.49). B8805-033 inhibited noradrenaline (NA) induced contractions mediated by alpha1A-ARs in rat vas deferens and rabbit and human prostate (pA2 7.62-8.40) much more potently than those mediated by alpha1B-ARs in guinea pig and mouse spleen or by alpha1D-ARs in rat aorta and pulmonary artery (pA2 5.21-5.52). With the exception of a high agonist affinity at 5-HT1A receptors (pKi 9.74 in pig cortex, pD2 6.82 for contraction of rabbit basilar artery) and a moderate to low affinity at histamine H1-receptors (pA2 6.74) and beta1-ARs (pA2 5.75), B8805-033 did not interact with a number of other neurotransmitter receptors (pKi or pA2<5.0). From the i.v. doses of B8805-033 to either inhibit the urethral pressure response to NA by 50% (29 nmol/kg) or to evoke a fall in diastolic blood pressure by 25% (1.54 micromol/kg) in anaesthetized dogs, an urethral/ vascular selectivity ratio of 52 was obtained, far exceeding that found for the nearly unselective prazosin (ratio 1.8). We conclude that B8805-033 is a highly alpha1A-AR selective antagonist, which may potentially be useful as pharmacological tool to investigate alpha1-AR heterogeneity and in the treatment of benign prostatic hyperplasia.

Adrenergic alpha-Antagonists↗
PubMed2001

Nifedipine inhibits sphinogosine-1-phosphate-induced renovascular contraction in vitro and in vivo.

Sphingosine-1-phosphate (SPP) can constrict isolated intrarenal blood vessels in vitro and reduce renal blood flow in vivo. The present study has investigated the role of extracellular Ca2+ and dihydropyridine-sensitive Ca2+ channels in SPP-induced renovascular contraction. In isolated intrarenal microvessels, cumulative addition of SPP (0.1-100 microM) caused concentration-dependent vasoconstriction (maximum effect 5.0 +/- 1.1 mN). In the presence of nifedipine (300 nM, added 30 min before SPP) or EGTA (5 mM, added 1 min before SPP), SPP-induced vasoconstriction was almost completely abolished. In thiobutabarbitone-anaesthetized rats, i.v. bolus injections of SPP (1-100 microg/kg) dose-dependently lowered renal blood flow from basal values of approximately 4.8 ml/min by up to 2.2 +/- 0.2 ml/min but had only little effect on mean arterial pressure. Pretreatment with nifedipine (10-100 microg/kg per min, i.v.) dose-dependently attenuated SPP-induced renal blood flow reductions. We conclude that SPP-induced renovascular contraction requires the influx of extracellular Ca2+ which may occur largely via nifedipine-sensitive L-type Ca2+ channels.

Animals↗
PubMed2001

Platelet adenylyl cyclase signaling remains unaltered in children undergoing hemodialysis treatment.

Patients with chronic renal failure exhibit multiple endocrine, gastrointestinal and cardiovascular abnormalities, many of which may be explained by alterations of adenylyl cyclase (AC) responsiveness and/or G-protein expression. Since such alterations were previously reported, e.g., for platelets of adult chronic renal failure patients undergoing hemodialysis treatment (HD), we have investigated whether children with chronic renal failure undergoing HD exhibit similar alterations. Eleven uremic children undergoing HD were compared with 11 age-matched healthy controls. Platelet AC activity was determined in the absence (basal) and presence of a receptor agonist, direct G-protein activators and direct AC stimulators. G-protein alpha-subunits were measured by quantitative immunoblotting. Basal and stimulated platelet AC and immunoreactivity for platelet G-protein alpha-subunits did not significantly differ between HD and control children. We conclude that HD in children is associated with much smaller, if any, abnormalities of blood cell signal transduction than in adult patients. We speculate that quality of dialysis, age, and underlying disease might differentially influence blood cell signal transduction cascades.

Adenylyl Cyclases↗
PubMed2001

Loads acting in an intramedullary nail during fracture healing in the human femur.

The form and function of the musculo-skeletal system is closely related to the forces acting in its components. Significant forces are present in the long bones, but their magnitudes have so far only been estimated from mathematical models. Fracture fixation by means of metal implants provides an opportunity to measure the implant-born forces and to estimate the long bone forces before healing occurs. The load changes during fracture healing may provide additional information. Therefore, a telemetrized, interlocking femoral nail for wireless transmission of forces and moments acting across the fracture site was developed. The design was based on the geometry and material of a 16 mm AO nail with a circular, closed cross-section allowing full protection of the electronic circuits from the body fluids. After careful testing, it was implanted in a 33-year-old patient who had sustained a multifragmentary fracture of the left femur. Measurements at a rate of approx. 0.4 Hz were performed in different patient postures between the 2nd and 26th postoperative week. Significant axial forces and bending moments were measured during several activities such as sitting, unsupported leg elevation and partial weight bearing in a standing position. Forces orthogonal to the nail axis remained small. The reductions of the implant loads due to fracture consolidation were in the order of 50%. Dynamization of the nail did not change the forces. Even though the telemetry system did not allow for dynamic measurements and the results presented here provide data from one subject only, the new information will be useful with respect to implant design, biomechanics of fracture fixation and evaluation of healing progression.

Adult↗
PubMed2001

Limited signal transduction repertoire of human Y(5) neuropeptide Y receptors expressed in HEC-1B cells.

In HEC-1B cells transfected with human Y(5) neuropeptide Y (NPY) receptors (but not in non-transfected cells) NPY inhibited forskolin-stimulated cAMP accumulation in a pertussis toxin-sensitive manner (-log EC(50) 8.88 +/- 0.25). Elevations of intracellular Ca(2+) were largely restricted to very high NPY concentrations and similar in transfected and nontransfected cells. NPY did not increase inositol phosphate accumulation and did not activate a variety of isoforms of protein kinase C or mitogen-activated protein kinases. We conclude that at least upon expression in HEC-1B cells the signal transduction of Y(5) NPY receptors is limited to inhibition of cAMP accumulation.

Analysis of Variance↗
PubMed2001

An in vivo rat model to study calcitonin gene related peptide release following activation of the trigeminal vascular system.

Calcitonin gene related peptide (CGRP) released from the C-fibers projecting from the trigeminal ganglion to the meninges has been suggested to play a crucial role in the pathophysiology of headache, particularly migraine. In humans it has been shown that CGRP is released during migraine-attacks, and this is attenuated by the administration of typical anti-migraine drugs such as dihydroergotamine or sumatriptan. We describe a new rat model which allows the study of CGRP release from the meninges into venous blood following activation of the trigeminal vascular system. The effects of classical and new anti-migraine drugs such as acetylsalicylic acid (ASA), sumatriptan and the new high efficacy 5-HT1B/1D agonist donitriptan (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl]benzonitrile) were evaluated in comparison with the established model of neurogenic inflammation in the meninges. Sumatriptan and donitriptan inhibited CGRP release as well as neurogenic inflammation. ASA, however, attenuated neurogenic inflammation, but not CGRP release, confirming the concept of prejunctional inhibition of CGRP release by 5-HT1B/1D receptors. This new model allows the further study of prejunctional pharmacology and mechanisms of neuropeptide release in the trigeminal vascular system, which might be crucial for the further development of potent, more effective anti-migraine drugs.

Animals↗
PubMed2001

Lysosphingolipid receptor-mediated diuresis and natriuresis in anaesthetized rats.

Lysosphingolipids such as sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) can act on specific G-protein-coupled receptors. Since SPP and SPPC cause renal vasoconstriction, we have investigated their effects on urine and electrolyte excretion in anaesthetized rats. Infusion of SPP (1 - 30 microg kg(-1) min(-1)) for up to 120 min dose-dependently but transiently (peak after 15 min, disappearance after 60 min) reduced renal blood flow without altering endogenous creatinine clearance. Nevertheless, infusion of SPP increased diuresis, natriuresis and calciuresis and, to a lesser extent, kaliuresis. These tubular lysosphingolipid effects developed more slowly (maximum after 60 - 90 min) and also abated more slowly upon lysosphingolipid washout than the renovascular effects. Infusion of SPPC, sphingosine and glucopsychosine (3 - 30 microg kg(-1) min(-1) each) caused little if any alterations in renal blood flow but also increased diuresis, natriuresis and calciuresis and, to a lesser extent, kaliuresis. Pretreatment with pertussis toxin (10 microg kg(-1) 3 days before the acute experiment) abolished the renovascular and tubular effects of 30 microg kg(-1) min(-1) SPP. These findings suggest that lysosphingolipids are a hitherto unrecognized class of endogenous modulators of renal function. SPP affects renovascular tone and tubular function via receptors coupled to G(i)-type G-proteins. SPPC, sphingosine and glucopsychosine mimic only the tubular effects of SPP, and hence may act on distinct sites.

Anesthesia↗
PubMed2001

A 6-month large-scale study into the safety of tamsulosin.

AIMS: Tamsulosin is an alpha1-adrenoceptor antagonist for the treatment of symptomatic benign prostatic hyperplasia with a tolerability similar to that of placebo in short-term, placebo-controlled studies with limited patient numbers. The present study was designed to test the safety of tamsulosin treatment in a large cohort of men during a prolonged period of time, particularly with regard to comedications. METHODS: A multicentre, open-label phase IIIb study with 1784 patients receiving 0.4 mg o.d. tamsulosin for 6 months was performed according to good clinical practice guidelines. The analysis was performed on an intention-to-treat basis and powered to detect adverse events (AE) occurring in 0.15% of patients with 95% confidence. RESULTS: During a total drug exposure time of 811 patient years, 386 AE were recorded in 253 patients (14.2%; 95% confidence intervals [CI] 12.0-15.2%). Twenty-nine patients suffered 44 serious AE including five fatal events (CI 0.12-0.73%) due to myocardial infarction (n = 3) and to pneumonia and a car accident (one each), but all deaths were judged to be unlikely to be related to study medication. The frequency of AE in patients without any comedication (n = 1095) was 13.0% (CI 11.3-14.9%). In a logistic regression analysis beta-adrenoceptor blockers, converting enzyme inhibitors, antidiabetics and diuretics did not significantly affect the odds ratio for having AE. However, concomitant alpha-adrenoceptor antagonists (a protocol violation) and treatment with verapamil (which also has alpha-adrenoceptor antagonist activity) significantly enhanced the odds ratio for having AE to 3.87 (CI 1.52-9.85) and 3.17 (CI 1.52-6.58), respectively. Minor increases in the odds ratio, which did not reach statistical significance, were also observed for Ca2+ antagonists other than verapamil and for nitrates. CONCLUSIONS: We conclude that tamsulosin has a good safety profile relative to AE rates in the placebo arms of previous studies on tamsulosin even in the presence of most potentially complicating comedications. No major unexpected severe AE were recorded during our 6 months study.

Adrenergic alpha-Antagonists↗
PubMed2001

Endothelin-A receptor antagonist inhibits angiotensin II and noradrenaline in man.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear. METHODS: We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique. RESULTS: BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001). CONCLUSIONS: ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.

Adult↗
PubMed2001

The prevention of migraine: a critical review with special emphasis on beta-adrenoceptor blockers.

Migraine is one of the most frequent neurological disorders affecting up to 15% of the general population. Many patients require not only management of individual migraine episodes but also prophylactic treatment. beta-adrenoceptor blockers, flunarizine and valproic acid have been established as first-line agents for the prophylaxis of migraine attacks. Among the beta-adrenoceptor blockers propranolol and metoprolol are best documented and hence deserve preferential use. On the other hand, it appears that other beta-adrenoceptor blockers, perhaps with the exception of those with intrinsic sympathomimetic activity, can be equally effective. Uncertainties regarding the relative merits of various treatment modalities are largely caused by lack of adherence to specific requirements for clinical trials on migraine prophylaxis. Therefore, this article reviews internationally recommended conditions for reliable studies on migraine prophylaxis and appraises individual agents in the light of these criteria.

Adrenergic beta-Antagonists↗
PubMed2001

Does the time of administration (morning or evening) affect the tolerability or efficacy of tamsulosin?

OBJECTIVE: To determine whether the time of dosing (morning or evening) affects the tolerability or efficacy of tamsulosin in the treatment of lower urinary tract symptoms. PATIENTS AND METHODS: Data were analysed from an open-label, observational study in which patients were treated with 0.4 mg tamsulosin once daily for 12 weeks. Treatment effects were determined using the Benign Prostatic Hyperplasia Impact Index, the quality-of-life question of the International Prostate Symptom Score, a similarly phrased question about sexual satisfaction, the maximum urinary flow rate, the postvoid residual urine volume, and the overall efficacy and tolerability. The results were analysed statistically for differences between dosing times, using analysis of covariance for the quantitative variables and logistic regression for the qualitative variables. RESULTS: While no specific recommendation about the dosing time was given in the trial, the retrospective analysis showed that 4420 and 2087 patients received tamsulosin in the morning and evening, respectively. Both groups had similar values for all variables before treatment. The efficacy and tolerability of tamsulosin treatment was also similar in both groups; there were small advantages for morning dosing, which were statistically significant because there were many patients. CONCLUSION: In contrast to other alpha-blockers, night-time dosing is not necessary to improve the tolerability or efficacy of tamsulosin.

Adrenergic alpha-Antagonists↗