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M Goepel

Publications and source records attributed to M Goepel.

At least 19 recordsLinked to original sources
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

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

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

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↗
PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction--what's the long-term effectiveness of medical therapies?

The primary treatment goal in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) is symptom relief. However, it is also important to assess the effects of medical treatments on disease progression because this can lead to complications such as acute urinary retention or can ultimately require surgical treatment. In a placebo-controlled study finasteride was shown to reduce the incidence of acute urinary retention and the need for surgery in patients with LUTS suggestive of BPO. While alpha(1)-adrenoceptor antagonists are superior to finasteride with regard to LUTS relief, systematic studies on their effects on BPO complications and progression to surgery are not available. However, we reviewed a number of smaller studies which consistently indicate that alpha(1)-adrenoceptor antagonists may be at least as effective as finasteride in the prevention of acute urinary retention or the need for surgery in patients with LUTS suggestive of BPO. While this needs to be confirmed in adequately designed and powered studies, such evidence should be taken into consideration when choosing between alpha(1)-adrenoceptor antagonists and finasteride treatment.

Acute Disease↗
PubMed2000

Comparison of [3H]tamsulosin and [3H]prazosin binding to wild-type and constitutively active alpha1B-adrenoceptors.

We have tested the hypothesis that smaller alpha1B-adrenoceptor labeling by [3H]tamsulosin compared to [3H]prazosin is related to differential recognition of agonist low affinity states. Paired saturation binding experiments with [3H]prazosin and [3H]tamsulosin were performed in membrane preparations from rat liver and Rat- fibroblasts stably transfected with wild-type hamster alpha1B-adrenoceptors or a constitutively active mutant thereof. In all three settings [3H]tamsulosin labeled significantly fewer alpha1B-adrenoceptors than [3H]prazosin. In noradrenaline competition binding experiments, the percentage of agonist low affinity sites was smallest for the constitutively active alpha1B-adrenoceptor but the percentage of agonist low affinity sites recognized by [3H]tamsulosin and [3H]prazosin did not differ significantly. We conclude that [3H]tamsulosin labels fewer alpha1B-adrenoceptors than [3H]prazosin but this is not fully explained by a poorer labeling of agonist low affinity sites.

Adrenergic alpha-Antagonists↗
PubMed2000

alpha(1)-adrenoceptor subtypes differentially couple to growth promotion and inhibition in Chinese hamster ovary cells.

We have compared the coupling of human alpha(1A)-, alpha(1B)-, and alpha(1D)-adrenoceptors (expressed at approximately 2000 fmol/mg protein in Chinese hamster ovary cells) to cellular growth promotion (as assessed by [(3)H]thymidine incorporation) and related signaling mechanisms. Maximum elevation of intracellular Ca(2+) by the three subtypes occurred with the rank order alpha(1A) (1691 nM) > alpha(1D) (1215 nM) > alpha(1B) (360 nM). In contrast, activation of the ERK, JNK, and p38 forms of mitogen-activated protein kinases occurred with the rank order alpha(1D) > alpha(1A) > alpha(1B). alpha(1A)-Adrenoceptor stimulation inhibited basal and growth factor-stimulated [(3)H]thymidine incorporation by 74%, and this was mitigated by p38 inhibition. In contrast, alpha(1D)-adrenoceptor stimulation enhanced cellular growth by 136%, and this was blocked by two distinct inhibitors of ERK activation. We conclude that within a given cell type alpha(1)-adrenoceptor subtypes can have opposite effects on cellular growth, although their proximal signal transduction displays only quantitative differences.

Animals↗
PubMed2000

Lack of neuropeptide Y receptor detection in human bladder and prostate.

OBJECTIVE: To investigate the presence of functional neuropeptide Y (NPY) receptors in human bladder and prostate (both richly endowed with NPY-containing nerve fibers) using peptide YY (PYY) as the agonist. Materials and methods Binding studies were conducted using [125I]PYY as the radioligand. Organ-bath studies were performed on isolated tissue strips for direct (postjunctional) contractile effects and for (prejunctional) inhibition of field stimulation effects. Any possible degradation of PYY was determined using high-performance liquid chromatography (HPLC). RESULTS: In the radioligand binding studies no quantifiable specific [125I]PYY binding was detected in human bladder or prostate, while specific high-affinity binding was readily seen in rat cerebral cortex. In organ-bath experiments, PYY (up to 1 micromol/L) caused no contraction of human prostate or bladder, whereas noradrenaline and carbachol, respectively, were effective; the potency or efficacy of noradrenaline and carbachol were not altered by PYY. Field stimulation-induced contraction was not affected by PYY in either human bladder or prostate, but was readily inhibited in rat vas deferens. HPLC detected no relevant PYY degradation by human bladder or prostate homogenates. CONCLUSION: Human bladder and prostate express only very few if any functional NPY receptors.

Animals↗
PubMed2000

Affinity of trazodone for human penile alpha1- andalpha2-adrenoceptors.

OBJECTIVE: To determine the affinities of human penile alpha-adrenoceptors and cloned human alpha-adrenoceptor subtypes for trazodone, an antidepressant with reported beneficial effects in erectile dysfunction. Materials and methods Competition radioligand binding studies were performed with trazodone in human penile tissue and in cell lines stably expressing all cloned human alpha-adrenoceptor subtypes. RESULTS: Trazodone had higher affinity for human alpha1-adrenoceptors (10-130 nmol/L) than for alpha2-adrenoceptors (300-700 nmol/L), but did not discriminate between subtypes of human alpha1- or alpha2-adrenoceptors. CONCLUSION: Trazodone has high and moderate affinity for human alpha1- and alpha2-adrenoceptors, respectively; this might contribute to its reported beneficial effects in erectile dysfunction.

Antidepressive Agents, Second-Generation↗
PubMed2000

Treatment satisfaction of patients with lower urinary tract symptoms: randomised controlled trials vs. real life practice.

Randomised controlled trials (RCTs) are an important scientific tool to determine the efficacy and tolerability of a given treatment relative to placebo or other treatment forms. However, due to strict inclusion and exclusion criteria the patient populations in RCTs may not be fully representative for those routinely consulting the physician. Moreover, participation in a formal study puts physician and patient in a situation where they may react different than in real life. In contrast real life practice (RLP) studies cannot determine treatment efficacy or tolerability in absolute terms since they typically do not include a control group and are purely observational. On the other hand, they tend to be more representative for real treatment outcomes. Thus, RCTs have high internal but less external validity whereas RLP studies have less internal and greater external validity. Hence, RCTs and RLP studies should not be considered as mutually exclusive but rather as complementing each other. Specific advantages and disadvantages of RCTs and RLP studies will be discussed using published evidence for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction with alpha1-adrenoceptor antagonists and other treatments.

Humans↗
PubMed2000

Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia.

PURPOSE: Several studies have suggested a specific association between the presence and/or symptom intensity of benign prostatic hyperplasia (BPH) and diabetes but to our knowledge no definitive conclusion has been reached. Therefore, we examined the intensity of lower urinary tract symptoms in a large cohort of men with BPH with and without diabetes. We then determined whether the alpha1-adrenoceptor antagonist tamsulosin similarly improved lower urinary tract symptoms in patients with BPH with or without diabetes. MATERIALS AND METHODS: The International Prostate Symptom Score (I-PSS), maximum flow rate and post-void residual were determined in 9,856 men with clinically diagnosed BPH, of whom 1,290 also had diabetes, at baseline and after a 12 week, open label course of 0.4 mg. tamsulosin daily. RESULTS: Logistic regression of the baseline data indicated that older age and I-PSS were independently associated with a statistically significant increase in the odds ratio of having diabetes. Accordingly, diabetics had a significantly greater baseline I-PSS and smaller maximum flow rate than non-diabetic patients on age-adjusted analysis, while residual urine was not significantly altered. Tamsulosin markedly improved lower urinary tract symptoms. The extent of improvement was similar in diabetic and nondiabetic patients, although some slight differences reached statistical significance due to large patient numbers. CONCLUSIONS: The severity of lower urinary tract symptoms in patients with BPH and the likelihood of having diabetes are significantly associated. Within the limitations of an open label, observational study tamsulosin appears to reduce lower urinary tract symptoms similarly in patients with BPH with or without diabetes.

Adrenergic alpha-Antagonists↗
PubMed1999

Differential regulation of 46 and 54 kDa jun N-terminal kinases and p38 mitogen-activated protein kinase by human alpha(1A)-adrenoceptors expressed in Rat-1 cells.

We have investigated the alpha(1A)-adrenoceptor-mediated activation of 46 and 54 kDa isoforms of c-jun N-terminal kinase (JNK) and of p38 mitogen-activated protein kinase. The alpha(1)-adrenoceptor agonist phenylephrine activated all three kinases but with different time courses and maximal effects. Activation of all three kinases was insensitive to the phosphatidylinositol-3-kinase inhibitor wortmannin but was enhanced by the protein kinase C inhibitor bisindolylmaleimide I; a protein kinase C-activating phorbol ester inhibited JNK but not p38 activation. Activation of 54 kDa JNK, but not of the other two kinases, was inhibited by pertussis toxin and the phospholipase C inhibitor U 73,122. We conclude that alpha(1)-adrenoceptor stimulation activates 46 kDa JNK, 54 kDa JNK and p38 but uses at least partly different pathways to do so.

Adrenergic alpha-Agonists↗
PubMed1999

Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro.

BACKGROUND: We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro. METHODS: Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated. RESULTS: Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists. CONCLUSIONS: Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

[Urological diagnosis in children with myelomeningocele].

Neurogenic bladder dysfunction in childhood is mostly caused by spinal dysraphism. The urologic diagnostic procedure tries to evaluate the underlying form of neurogenic bladder, dysfunction the associated disturbances at the upper tract and the development of changes by body growth. Therapeutic main aim is the conservation and protection of the kidney function and, secondly, the development of social dryness and a form of bladder emptying, that is related to the individual situation and associated disabilities. We report here about the diagnostic procedure and result of a group of 190 patients, that have been seen in our department since birth and for more than ten years continuously. Developmental changes of neurogenic bladder dysfunction has been found in more than 25% of the children. This figure shows the need of life-long close urodynamic follow-up.

Child↗