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Biomedical subjects

M C Michel

Publications and source records attributed to M C Michel.

At least 19 recordsLinked to original sources
PubMed2007

Effect of short-term outlet obstruction on rat bladder nerve density and contractility.

1 The present study was designed to investigate the relationship between innervation density and contractile responses to field stimulation and exogenous agonists at early time points after induction of bladder outlet obstruction (BOO) in rats. 2 When compared with sham-operated animals, 1, 3 and 7 days of BOO were associated with a 75%, 80% and 90% increase of bladder weight. Field stimulation caused a frequency-dependent increase in force of contraction. The force of contraction was reduced at each frequency in BOO rats with the greatest decrease after 1 day and a gradual but incomplete recovery thereafter. In contrast, contractile responses to ATP, carbachol and KCl were markedly reduced after 1 day of BOO and fully recovered after 7 days. The neurofilament staining was not altered by 1 day of BOO, but gradually decreased with increasing duration of BOO reaching the lowest levels after 7 days. 3 We conclude that impaired cellular contractility seems to underlie the early reductions of field stimulation-induced contraction, possibly reflecting surgical trauma of the tissue. However, at later time points a reduced nerve density, possibly reflecting a partial denervation, appears to be the main reason for impaired contractile response to field stimulation.

Adenosine Triphosphate↗
PubMed2006

BML-241 fails to display selective antagonism at the sphingosine-1-phosphate receptor, S1P(3).

BACKGROUND AND PURPOSE: The thiazolidine carboxylic acid, BML-241, has been proposed as a lead compound in development of selective antagonists at the sphingosine-1-phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML-241 for the S1P(3) receptor in more detail. EXPERIMENTAL APPROACH: Chinese hamster ovary (CHO) cells stably transfected with the S1P3, S1P2 or alpha(1A)-adrenoceptors were used to investigate the effect of BML-241 on increases in [Ca2+]i mediated via different receptors. CHO-K1 cells were used to study ATP-induced [Ca2+]i elevations. Effects on S1P3 -mediated inhibition of forskolin-induced cAMP accumulation and on binding to alpha(1A)-adrenoceptors were also investigated. In addition, the effect of BML-241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. KEY RESULTS: High concentrations of BML-241 (10 microM) inhibited the rise in [Ca2+]i induced by S1P3 and S1P2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML-241 also inhibited [Ca2+]i increases via P2 (nucleotide) receptor or alpha(1A)-adrenoceptor stimulation. Moreover, BML-241 (10 microM) inhibited alpha(1)-adrenoceptor-mediated contraction of rat mesenteric artery but did not displace [3H]-prazosin from alpha(1A)-adrenoceptors in concentrations up to 100 microM. BML-241 (10 microM) did not affect the S1P3 -mediated decrease of forskolin-induced cAMP accumulation. CONCLUSIONS AND IMPLICATIONS: We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor.

Animals↗
PubMed2006

[Anticholinergics for overactive bladder: does subtype selectivity play a role?].

Anticholinergics act in the treatment of overactive bladder by blocking muscarinic receptors of which five subtypes exist. Their desired effects occur via M(3) receptors, but a role for M(2) receptors is being discussed. Adverse effects such as dry mouth and constipation occur also via M(3) receptors, but M(2) and M(1) receptors can mediate side effects in the heart or on cognitive function, respectively. Therefore, an M(3)-selective drug such as darifenacin could theoretically be less effective but also have fewer cardiac or central nervous side effects. However, the limited available clinical data do not support a smaller efficacy or better general tolerability. The lack of adverse effects on cognitive function is well documented for darifenacin, but it cannot yet be determined definitively whether this discriminates it from other modern anticholinergics.

Benzofurans↗
PubMed2006

Safety and tolerability of duloxetine in women with stress urinary incontinence.

BACKGROUND: The serotonin/noradrenaline uptake inhibitor duloxetine has been shown to be effective in the medical treatment of stress urinary incontinence (SUI) in women. AIM: To review the safety and tolerability of duloxetine with SUI. METHODS: A systematic Medline search for the key word "duloxetine" was performed, and abstracts from recent international gynaecological and urological meetings were also considered. RESULTS: Various unpleasant adverse effects exist, among which nausea is the most frequent, but is mild to moderate and transient in most cases. Dose escalation upon initiation of treatment improves the tolerability of duloxetine. The use of duloxetine appears safe as it lacks the cardiovascular adverse effects of older amine reuptake inhibitors. CONCLUSIONS: Duloxetine has an acceptable safety profile. Dose escalation combined with patient counselling on the intensity and transient nature of adverse effects may help to further improve the benefit/tolerability ratio of duloxetine in the treatment of SUI.

Adrenergic Uptake Inhibitors↗
PubMed2005

[Pharmacotherapy of stress incontinence].

Female urinary incontinence is a medical and social problem with a large prevalence. Stress urinary incontinence (SUI) is the most common form of urinary incontinence and is responsible for 49 % of all incontinence, if mixed forms are included even for 78 %. As of yet, apart from "off-label" treatment, there is no pharmacological treatment available for stress urinary incontinence. For instance, estrogens are used in menopausal patients but a substantial effect in the treatment of SUI has not been demonstrated. a-Adrenergics, such as phenylpropanolamine and midodrine, and b-adrenergics, such as clenbuterol, are also used in "off-label" therapy. A recently conducted meta-analysis of 15 randomised studies with female patients who received a- und b-adrenergics as part of their therapy, failed to detect efficacy compared to placebo. Tricyclic antidepressives, such as imipramine and doxepine, which are used for the treatment of urge incontinence, are also used "off-label" in the treatment of SUI. However, no placebo-controlled studies have been conducted so far. The serotonin-norepinephrine reuptake inhibitor duloxetine represents a new therapeutic approach in the treatment of SUI. It has shown positive effects on bladder and urethra in animal experiments, most likely through an effect on the Onuf's nucleus in the spinal cord. In randomised, placebo-controlled studies (phase II and III) in women with SUI, a significant and clinically relevant reduction in urinary incontinence episodes as well as an improvement in the quality of life compared to placebo was shown.

Adrenergic Agents↗
PubMed2005

[Medical therapy of urinary incontinence].

Urinary incontinence has a high prevalence in both men and women. Women suffer predominantly from stress urinary incontinence and men from urge incontinence. Other types of incontinence are less frequent. Stress urinary incontinence is caused by an insufficient urethral closure mechanism and urge incontinence by uninhibited detrusor contractions. Medical treatment is beside other conservative options and operations only one part of the treatment strategy in incontinence. Duloxetine, a serotonine-norepinephrine reuptake inhibitor, is used to treat stress urinary incontinence, can increase activity of the external urethral sphincter and is able to reduce incontinence episodes in up to 64%. Antagonists of muscarinic receptors can reduce urgency, frequency and urge incontinence as well as increase bladder capacity significantly. In Germany, trospium chloride, tolterodine, solifenacin, oxybutynin and propiverine are available to treat urge incontinence. Efficacy of these agents are comparable. However, tolerability is different and side effects, especially dry mouth, often limit their use. None of the agents show ideal efficacy or tolerability in all patients and, therefore, new agents and formulations are currently under clinical investigation.

Cholinergic Antagonists↗
PubMed2005

Is cyclic AMP formation desensitized in patients with end-stage renal failure?

1 Cyclic AMP formation has consistently been reported to be desensitized in various tissues including heart of animal models of end-stage renal failure (ESRF). In contrast, reports on desensitization of cAMP formation in ESRF patients remain contradictory. Whether this discrepancy results from a difference between human ESRF and its animal models or from the use of circulating blood cells in the human and various solid tissues in the animal studies, remains unclear. Therefore, we performed three studies with heart and platelets of ESRF patients undergoing haemodialysis or continuous ambulatory peritoneal dialysis and age- and gender-matched controls with normal renal function (n = 11-13 each). 2 In platelets from haemodialysis patients adenylyl cyclase activity in response to receptor-dependent and -independent agonists was reduced by approximately 30%, and this could be explained by an alteration at the level of adenylyl cyclase itself. However, no such desensitization was seen in platelets from peritoneal dialysis patients. 3 In hearts from ESRF patients undergoing haemodialysis, beta-adrenoceptor density and subtype distribution, cAMP formation in response to the beta-adrenoceptor agonist isoprenaline or various receptor-independent stimuli, were very similar to those in control patients but activity of G-protein-coupled receptor kinase was increased by approximately 20%. 4 We conclude that conflicting reports on the desensitization of cAMP formation between ESRF patients and ESRF animal models are not explained by the use of solid tissues in animal studies vs. circulating blood cells in patient studies. Rather desensitization of cAMP formation seems to be a less consistent feature of human ESRF than of its animal models.

Adenylyl Cyclases↗
PubMed2004

Absorption of intravesically applied drugs: comparison of normal and ileal augmented rabbit bladder.

PURPOSE: Drug absorption within urinary diversions has been reported to cause prolonged and higher grade toxicity. Therefore, continuous urine drainage has been recommended during chemotherapy in patients with continent urinary diversion. We developed an animal model in which to examine the significance of drug absorption in normal rabbit bladders compared with ileal augmented bladders. MATERIALS AND METHODS: Ten rabbits with ileal bladder augmentation and 5 control animals were used for absorption studies with methotrexate and ofloxacin. One, 4 and 12 months after surgery the rabbits received an intravesical instillation of either drug. During 2 hours blood samples were drawn. To avoid overfilling the bladder by urine it was emptied after 30, 60, 90 and 120 minutes, and refilled with fresh solution to yield a relatively constant drug amount. After 12 months the animals were sacrificed. Area of the native bladder wall and of the intestinal segment was measured to allow the correction of absorbed drug amounts per surface area. Moreover, the median villous heights of native and augmented ileum were compared histologically. Serum levels of methotrexate and ofloxacin were determined by high performance liquid chromatography. RESULTS: The maximum serum concentration of the 2 drugs was typically seen after 60 to 120 minutes. During the 1-year period peak serum concentrations of ofloxacin remained consistently higher in ileal augmented than in control rabbits, although this did not achieve statistical significance at all instillation time points. For methotrexate a statistically significant difference was not shown for either time point. When absorption was corrected for total bladder surface area, the enhancement of ofloxacin absorption by ileal augmentation weakened and attained statistical significance only at the 1-month time point. Histological examinations after 12 months showed that augmented intestinal mucosa had a significantly smaller villous height than native ileum. CONCLUSIONS: Our data demonstrate that bladder surface is the most important factor for increased absorption but time dependent histological changes of the integrated intestinal mucosa also influence absorption. There is a broad interindividual discrepancy. Therefore, general rules in patients with urinary diversion may not be justified.

Absorption↗
PubMed2004

Comparison of noradrenaline and lysosphingolipid-induced vasoconstriction in mouse and rat small mesenteric arteries.

1 We have compared vasoconstriction responses in isolated mesenteric small arteries from mice and rats as elicited by KCl, noradrenaline and the lysosphingolipids sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). 2 Contractile responses to KCl and noradrenaline, but not those of S1P or SPC, were significantly related to vessel diameter in both species. 3 When comparing vessels of similar diameter, contractile responses for KCl and the three agonists were much smaller in mice than in rats, e.g. 8.3 +/- 0.4 vs. 14.7 +/- 0.7 mn for noradrenaline. 4 Based upon the antagonist rank order of potency of prazosin (pKB 8.80) > B8805-033 (pKB 7.89) > yohimbine (pKB 6.18) approximately BMY 7378 (pA2 6.03), noradrenaline responses in mice were mediated solely via alpha1A-adrenoceptors, similar to what repeatedly has been shown in rats. 5 The S1P3 receptor antagonist suramin (100 microM) significantly inhibited responses to S1P and SPC in rats but not in mice, and did not affect noradrenaline responses in either species. 6 We conclude that for any given diameter, mouse mesenteric arteries develop less contraction in response to various stimuli. Noradrenaline acts via alpha1A-adrenoceptors in both species. Responses to S1P and SPC differ between both species with regard to suramin-sensitivity indicating involvement of different receptor subtypes for lysosphingolipids in both species.

Adrenergic alpha-Antagonists↗
PubMed2003

[New pharmacological treatment concepts for overactive bladder].

Muscarinic receptor antagonists such as oxybutynin, propiverine, tolterodine, or trospium are the basis of medical treatment for overactive bladder. While they are moderately efficacious, their use can be limited by adverse effects such as dry mouth. This has sparked the search for new treatment options. Vanilloid receptor agonists, tachykinin receptor antagonists, potassium channel openers, and beta(3)-adrenoceptor agonists are currently under investigation, but are unlikely to become clinically available in the next few years. Therefore, current attempts to optimize treatment focus on improvement of existing drugs by new pharmaceutical formulations. Indeed, extended release formulations of oxybutynin (not available in Germany) or tolterodine have demonstrated an improved tolerability in clinical studies which was accompanied by an efficacy at least equal to that of their standard formulations.

Adrenergic beta-3 Receptor Agonists↗
PubMed2003

[The medication-induced dysfunction of the urinary bladder].

Bladder dysfunction can result from pathological changes in the bladder itself, of its central neurological regulation, (BPS), or of non-urological diseases such as diabetes or heart failure. Medication-induced bladder dysfunction can mostly be treated by simple changes in the pharmacological therapy. Bladder dysfunction can be induced pharmacologically by activating or inhibitory influences on adrenergic, sympathetic, beta-receptor-induced relaxation of the detrusor, alpha-receptor-induced contraction of the bladder neck, or cholinergic, parasympathetic, muscarinic receptor-induced contraction of the detrusor. Diuretics can increase urine production, thus possibly leading to incontinence. If incontinence occurs in patients, treatment should be stopped if possible and additional pharmacological therapy should not be started before medication-induced bladder dysfunction is excluded.

Diagnosis, Differential↗
PubMed2002

[alpha 1-receptor blockade in therapy of benign prostatic hyperplasia syndrome. Correct dosing for optimal effectiveness].

Four alpha 1-adrenoceptor antagonists are currently available for the medical treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction in Germany: alfuzosin, doxazosin, tamsulosin, and terazosin. Indirect comparison based on randomized, placebo-controlled trials as well as several direct comparative studies have shown equal efficacy of all four drugs on urinary flow and symptom relief if suggested dosing regimens are applied. A dosing regimen below this recommendation should be restricted to those patients who have a proven satisfactory response to a lower dose.

Adrenergic alpha-1 Receptor Antagonists↗