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Member
Join Date: Jan 2008
Location: Maryland outside WASH DC
Posts: 258
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Vinpocetine abstracts
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Phosphodiesterase inhibitors cause relaxation of the internal a-n-a-l sphincter in vitro.
Jones OM, Brading AF, McC Mortensen NJ.
SourceUniversity Department of Pharmacology, John Radcliffe Hospital, Oxford, United Kingdom.
Abstract
PURPOSE: Pharmacologic treatments are gaining widespread acceptance as first-line therapy for a-n-a-l fissure. However, existing treatments have limited clinical usefulness because of side effects and incomplete healing rates.
METHODS: Fresh human surgical resection specimens containing internal a-n-a-l sphincter and rectal circular muscle were collected. Strips of smooth muscle were cut from each muscle group and mounted in a superfusion organ bath. The effects of increasing concentrations of phosphodiesterase inhibitors were evaluated.
RESULTS: All phosphodiesterase inhibitors tested caused a dose-dependent reduction in the tone of the internal a-n-a-l sphincter, with potencies as follows: vinpocentine (phosphodiesterase-1 inhibitor; 50 percent maximum inhibition concentration = 0.87 +/- 0.10 microM), erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (phosphodiesterase-2 inhibitor; 32 +/- 4.8 microM), trequinsin (phosphodiesterase-3 inhibitor; 0.28 +/- 0.041 microM), rolipram (phosphodiesterase-4 inhibitor; 63 +/- 9 microM), zaprinast (phosphodiesterase-1,5,6,9,11 inhibitor; 3 +/- 0.69 microM), and dipyridamole (phosphodiesterase-5,6,8,10,11 inhibitor; 5.5 +/- 2 microM). Although all inhibitors were also effective on rectal circular muscle strips, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, trequinsin, and rolipram were at least an order of magnitude more potent in this tissue than in the internal a-n-a-l sphincter.
CONCLUSIONS: There are several functionally important phosphodiesterases in the internal a-n-a-l sphincter and rectal circular muscle. Both adenosine 3', 5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate appear to be important in the myogenic tone of the internal a-n-a-l sphincter, and this study provides further evidence of the sphincteric specialization of this tissue. Phosphodiesterase inhibitors might represent a new therapy for the treatment of a-n-a-l fissure.
World J Urol. 2001 Nov;19(5):344-50.
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Quote:
Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside.
Phosphodiesterase inhibitors cause relaxation of the internal a-n-a-l sphincter in vitro.
Jones OM, Brading AF, McC Mortensen NJ.
SourceUniversity Department of Pharmacology, John Radcliffe Hospital, Oxford, United Kingdom.
Abstract
PURPOSE: Pharmacologic treatments are gaining widespread acceptance as first-line therapy for a-n-a-l fissure. However, existing treatments have limited clinical usefulness because of side effects and incomplete healing rates.
METHODS: Fresh human surgical resection specimens containing internal a-n-a-l sphincter and rectal circular muscle were collected. Strips of smooth muscle were cut from each muscle group and mounted in a superfusion organ bath. The effects of increasing concentrations of phosphodiesterase inhibitors were evaluated.
RESULTS: All phosphodiesterase inhibitors tested caused a dose-dependent reduction in the tone of the internal a-n-a-l sphincter, with potencies as follows: vinpocentine (phosphodiesterase-1 inhibitor; 50 percent maximum inhibition concentration = 0.87 +/- 0.10 microM), erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (phosphodiesterase-2 inhibitor; 32 +/- 4.8 microM), trequinsin (phosphodiesterase-3 inhibitor; 0.28 +/- 0.041 microM), rolipram (phosphodiesterase-4 inhibitor; 63 +/- 9 microM), zaprinast (phosphodiesterase-1,5,6,9,11 inhibitor; 3 +/- 0.69 microM), and dipyridamole (phosphodiesterase-5,6,8,10,11 inhibitor; 5.5 +/- 2 microM). Although all inhibitors were also effective on rectal circular muscle strips, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, trequinsin, and rolipram were at least an order of magnitude more potent in this tissue than in the internal a-n-a-l sphincter.
CONCLUSIONS: There are several functionally important phosphodiesterases in the internal a-n-a-l sphincter and rectal circular muscle. Both adenosine 3', 5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate appear to be important in the myogenic tone of the internal a-n-a-l sphincter, and this study provides further evidence of the sphincteric specialization of this tissue. Phosphodiesterase inhibitors might represent a new therapy for the treatment of a-n-a-l fissure.
PMID: 12006938 [PubMed - indexed for MEDLINE]
Truss MC, Stief CG, Uckert S, Becker AJ, Wefer J, Schultheiss D, Jonas U.
Urologische Klinik, Medizinische Hochschule, Hannover, Germany. truss.michael@mh-hannover.de
Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence. However, muscarinergic receptor blockers with adequate selectivity for detrusor smooth muscle are not available. Also, in contrast to the normal detrusor, the unstable detrusor neurotransmission seems to be at least partially regulated by non-cholinergic (NANC) pathways. These factors may explain the common side effects and the limited clinical efficacy of these compounds. Specific modulation of intracellular second messenger pathways offers the possibility of organ selective manipulation of tissue function, specifically contraction and relaxation of smooth musculature. Because of their central role in the intracellular regulation of smooth muscle tone phosphodiesterases (PDEs) are an attractive pharmacological targets. The PDE 5 specific inhibitor sildenafil (Viagra) has revolutionized the treatment of patients with erectile dysfunction. Numerous other PDE inhibitors are currently under investigation for the treatment of various disorders.
We investigated the role of PDEs in human detrusor smooth muscle. Our data demonstrate the presence of five PDE isoenzymes in human detrusor and suggest, for the first time, that the cAMP pathway and the calcium/calmodulin-stimulated PDE (PDE 1) are of functional importance in the intracellular regulation in this tissue in vitro. In addition. initial clinical data with the PDE 1 inhibitor vinpocetine in patients not responding to standard anticholinergic therapy indicate a possible role for vinpocetine in the treatment of urgency, urge incontinence and, possibly, low compliance bladder and interstitial cystitis.
The results of a larger randomized, double-blind, placebo-controlled, multicenter trial with vinpocetine show a tendency in favor of vinpocetine over placebo; however, statistically significant results were documented for one parameter only. This might be due to the rather low dosage chosen and the small sample size.
Further studies are necessary and currently underway to delineate the optimal dosage, indications and patient population. Modulation of intracellular key enzymes effecting second messenger metabolism, i.e. isoenzyme-selective PDE inhibition is a novel approach which possibly avoids the limitations of anticholinergic therapy in patients with lower urinary tract dysfunction.
PMID: 11760783 [PubMed - indexed for MEDLINE]
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World J Urol. 2000 Dec;18(6):439-43.
Quote:
Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder.
Truss MC, Stief CG, Uckert S, Becker AJ, Schultheiss D, Machtens S, Jonas U.
Department of Urology, Medizinische Hochschule Hannover, Germany. truss.michael@mh-hannover.de
Current pharmacological treatment modalities for urge incontinence and low compliance bladder are limited by a low clinical efficacy and the significant side effects of the standard drugs available. Previous in vitro studies indicated a possible functional relevance of the intracellular phosphodiesterase (PDE)-1 isoenzyme in the regulation of human detrusor smooth muscle contractility.
We therefore investigated the effect of the PDE-1 inhibitor vinpocetine in nonresponders to standard pharmacological therapy. In 11/19 patients (57.9%) clinical symptoms and/or urodynamic parameters were improved. Although these initial data are preliminary, they represent the first evidence that isoenzyme-selective PDE inhibition may be a novel approach to the treatment of lower urinary tract disorders.
PMID: 11204266 [PubMed - indexed for MEDLINE]
Eur J Drug Metab Pharmacokinet. 1984 Apr-Jun;9(2):169-75.
Pharmacokinetics of vinpocetine and apovincaminic acid in patients with impaired renal function.
Miskolczi P, Vereczkey L, Szalay L, Göndöcs CS.
Effects of renal insufficiency on the pharmacokinetics of vinpocetine and its main metabolite, apovincaminic acid (AVA) were investigated in the present study. The elimination rate constant, half-life, clearance, area under the curve and volume of distribution were measured and compared with reported values for subjects with normal renal function. Previous investigations have shown that the elimination half life of vinpocetine was 2.54 +/- 0.48 hours and half-life of AVA was 3.66 +/- 1.56 hours in healthy volunteers after i.v. administration of 10 mg vinpocetine.
PMID: 6745306 [PubMed - indexed for MEDLINE]
Mult Scler. 2000 Feb;6(1):56-8.
Drop in relapse rate of MS by combination therapy of three different phosphodiesterase inhibitors.
Suzumura A, Nakamuro T, Tamaru T, Takayanagi T.
Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-0813, Japan.
Phosphodiesterase inhibitors (PDEIs), when used in combination, synergistically suppress TNFalpha production by various cells and also suppress experimental demyelination at very low concentrations. We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses. Of the 12 relapsing remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+/-3.32 to 0.92+/-1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+/-142 days). The combination of three PDEIs can be safe and useful strategy for the future treatment of MS. - 58
PMID: 10694847 [PubMed - indexed for MEDLINE
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Mult Scler. 1999 Apr;5(2):126-33.
Quote:
Effects of phosphodiesterase inhibitors on cytokine production by microglia.
Yoshikawa M, Suzumura A, Tamaru T, Takayanagi T, Sawada M.
Department of Neurology, Nara Medical University, Kashihara, Japan.
Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-alpha in several types of cells. In the present study, we have shown that all the types of PDEIs, from type I- to V-specific and non-specific, suppress the production of TNF-alpha by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-alpha production by microglia at a very low concentration (1 microM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-alpha may play a critical role. Some PDEIs also suppressed interleukin-I (IL-I) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-alpha and induction of IL-10 were confirmed at the mRNA level by RT-PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).
PMID: 10335522 [PubMed - indexed for MEDLINE]
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Last edited by jackD; 07-06-2011 at 10:17 PM.
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