-
Current Urology Reports Dec 2004Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5)... (Review)
Review
Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies.
Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5) inhibitor therapy is the current cornerstone of erectile dysfunction (ED) therapy in this population. Although no head-to-head trials have been performed with sildenafil, vardenafil, and tadalafil in this population, there are numerous studies in the general ED population. The results of these studies demonstrate that neither of the new PDE-5 inhibitors met statistical noninferiority to sildenafil. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it effected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation. This effect appears to be mediated by properties unique to sildenafil that include improved endothelial function and neuronal regeneration and neuroprotection. In primary prevention, unlike ED therapy, one has only "one shot" by definition. Therefore, it is even more critical to apply evidence-based medicine.
Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Prostatectomy; Purines; Sildenafil Citrate; Sulfones
PubMed: 15541217
DOI: 10.1007/s11934-004-0072-0 -
Journal of Equine Veterinary Science Aug 2020Spontaneous nuclear maturation of mammalian oocytes can occur when physically removed from the ovarian follicle during in vitro oocyte maturation (IVM), largely because...
The Phosphodiesterase Inhibitor, Isobutyl-1-Methylxanthine Prevents the Sudden Drop in Cyclic Adenosine Monophosphate Concentration and Modulates Glucose Metabolism of Equine Cumulus-Oocyte Complexes Matured in Vitro.
Spontaneous nuclear maturation of mammalian oocytes can occur when physically removed from the ovarian follicle during in vitro oocyte maturation (IVM), largely because of a decrease in cyclic adenosine monophosphate (cAMP) concentration. Modulation of oocyte cAMP during IVM by using phosphodiesterase inhibitors has been shown to maintain elevated oocyte cAMP concentrations and control meiotic resumption of bovine and ovine oocytes. This study determined the effect of inclusion of isobutyl-1-methylxanthine (IBMX) during collection and the first 12 hours of incubation of equine oocytes on cAMP concentration and glucose metabolism of cumulus-oocyte complexes (COCs). Abattoir-derived COCs were collected in aspiration medium with (Asp-IBMX) or without (Asp) IBMX. Cumulus-oocyte complexes were then incubated for 12 hours in IVM medium with (Mat-IBMX) or without (Mat) IBMX, followed by additional 24 hours in Mat medium. The cAMP concentration, glucose consumption, lactate production, and metaphase II rates of the COCs were assessed. Cumulus-oocyte complexes aspirated into Asp-IBMX (62.2 ± 2.6 fmol per COC) medium had higher cAMP concentration than Asp (31.8 ± 2.8 fmol per COC) control group (P < .05). Likewise, at 12 hours of IVM, Mat-IBMX group (33.2 ± 2.1 fmol per COC) had higher cAMP concentration than the Mat group (7.68 ± 0.5 fmol per COC; P < .05). Glucose consumption and lactate production were lower during the first 12 hours of incubation in COCs cultured in Mat-IBMX (P < .05). Isobutyl-1-methylxanthine prevented the rapid drop in cAMP concentration and altered metabolism of glucose by the COC. Preventing the sudden drop in cAMP prevents the premature nuclear maturation of in vitro-matured oocytes causing poor developmental competence.
Topics: Adenosine Monophosphate; Animals; Cattle; Female; Glucose; Horses; Oocytes; Phosphodiesterase Inhibitors; Sheep; Xanthines
PubMed: 32684257
DOI: 10.1016/j.jevs.2020.103112 -
Food and Chemical Toxicology : An... Dec 2019Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic... (Review)
Review
Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy.
Topics: Alzheimer Disease; Animals; Humans; Phosphodiesterase Inhibitors
PubMed: 31536753
DOI: 10.1016/j.fct.2019.110822 -
Recent Patents on Cardiovascular Drug... Jan 2009Systemic vascular disease is the greatest cause of mortality in the western world. Treatment options have been preventative with medical therapy or curative with... (Review)
Review
Systemic vascular disease is the greatest cause of mortality in the western world. Treatment options have been preventative with medical therapy or curative with surgical bypass. Recently, there has been an increase in the use and popularity of minimally invasive endovascular techniques, particularly angioplasty and stent insertions. The short-term results of these techniques have been demonstrated to be superior in a number of studies when compared with conventional surgery, which itself carries high mortality and morbidity. The long-term outcomes of endovascular treatments have not been as impressive, due to vascular restenosis caused mainly by intimal hyperplasia. There have been a large number of studies and therapeutic trials to discover a solution to restenosis, but to date success has not been reached. Cilostazol is a phosphodiesterase inhibitor licensed for treating patients suffering from intermittent claudication. Recent clinical trials have shown the effects of cilostazol in also preventing coronary artery restenosis post-endovascular treatments. These results have recently been repeated for peripheral vascular stents. This review discusses the pharmacology of cilostazol, peripheral vascular disease, mechanisms of intimal hyperplasia causing vascular restenosis. We also discuss the use of cilostazol and other current patents of novel targets and therapeutics, for preventing restenosis of both coronary and peripheral arterial disease following endovascular therapies.
Topics: Angioplasty; Arterial Occlusive Diseases; Cilostazol; Clinical Trials as Topic; Coronary Restenosis; Humans; Leg; Patents as Topic; Peripheral Vascular Diseases; Phosphodiesterase Inhibitors; Stents; Tetrazoles
PubMed: 19149700
DOI: 10.2174/157489009787260025 -
British Journal of Anaesthesia Nov 1998
Topics: Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cardiotonic Agents; Humans; Intraoperative Care; Phosphodiesterase Inhibitors
PubMed: 10193272
DOI: 10.1093/bja/81.5.663 -
World Journal of Urology Feb 2001Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly... (Review)
Review
Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly personal well-being, family and social interrelationships. Research into ED has focused primarily on the physiologic mechanisms of corpus cavernosum smooth muscle relaxation, and penile erection as the end result of smooth muscle relaxation. These processes are mediated by cholinergic, nonadrenergic, noncholinergic (NANC, e.g., nitric oxide), vasoactive intestinal peptide (VIP), and potentially calcitonin gene-related peptide (CGRP) containing nerves. Release of nitric oxide following sexual stimulation from non-adrenergic, non cholinergic nerves and vascular endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis. In turn, cGMP results in lowering intracellular concentrations, inhibits contractility of the penile smooth muscle, and induces an erectile response. Phosphodiesterase type 5 (PDE 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, and subsequent penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively. FDA approval of sildenafil citrate as the first oral agent for ED in males has resulted in significant interest. We discuss the clinical and pharmacologic properties of sildenafil citrate as well as the urologic and cardiac implications.
Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cardiovascular Physiological Phenomena; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones
PubMed: 11289569
DOI: 10.1007/pl00007091 -
Expert Opinion on Therapeutic Patents Sep 2011Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA... (Review)
Review
Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA repair inhibitors can potentially improve response to these widely used chemotherapeutics. One line of inquiry focuses on inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), a repair enzyme for Top1cc. Tdp1 catalyzes the hydrolysis of DNA adducts covalently linked to the 3'-phosphate of DNA, including Top1-derived peptides and also 3'-phosphoglycolates. Tdp1 inhibitors should synergize not only with Top1-targeting drugs (camptothecins, indenoisoquinolines), but also with bleomycin, topoisomerase II (Top2) inhibitors (etoposide, doxorubicin) and DNA alkylating agents. Here, we summarize the structure-activity relationship obtained from the reported Tdp1 inhibitors. Better understanding of Top1cc repair in vivo coupled with detailed structural studies on Tdp1-inhibitor interaction will be crucial in guiding the rational design of Tdp1 inhibitors.
Topics: Animals; Benzamidines; Biomimetics; DNA Adducts; Humans; Models, Molecular; Patents as Topic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Ribosomes; Tetracyclines; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors
PubMed: 21843105
DOI: 10.1517/13543776.2011.604314 -
Bioorganic & Medicinal Chemistry Letters Sep 2017Mass-guided isolation of the dichloromethane/methanol extracts from a specimen of teleomorphic fungus of the family Cortinariaceae resulted in the identification of a...
Mass-guided isolation of the dichloromethane/methanol extracts from a specimen of teleomorphic fungus of the family Cortinariaceae resulted in the identification of a new dimeric cyclobutane metabolite, achyrodimer F (1), along with the monomers hispidin (2) and bisnoryangonin (3). Their structures were determined by NMR and MS data analyses. Density Function Theory (DFT) NMR calculations was employed to confirm the chemical structure of achyrodimer F. Compound 1 inhibited tyrosyl-DNA phosphodiesterase I with an IC value of 1μM.
Topics: Agaricales; Australia; Cyclobutanes; Dose-Response Relationship, Drug; Humans; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrones; Structure-Activity Relationship
PubMed: 28797798
DOI: 10.1016/j.bmcl.2017.07.062 -
Life Sciences Jun 2014This review focuses on the development of drugs targeting phosphodiesterase 9A (PDE9A). PDE9A normally regulates cGMP (cyclic guanosine monophosphate) levels, which in... (Review)
Review
This review focuses on the development of drugs targeting phosphodiesterase 9A (PDE9A). PDE9A normally regulates cGMP (cyclic guanosine monophosphate) levels, which in turn regulate signal transduction. However, in pathological conditions, PDE9A inhibition is required to treat diseases that lower the level of cGMP. Hence, there is a need for specific PDE9A inhibitors. Aligning the 3D structure of PDE9A with other phosphodiesterases reveals residues crucial to inhibitor selectivity. GLU406 is unique to PDE9A and stabilizes the side chain of an invariant glutamine (GLN453). TYR424 is another relevant residue, unique only to PDE9A and PDE8A. Therefore, TYR424 could discriminate between PDE9A and all other PDEs except PDE8A. TYR424 should also be considered in the design of selective inhibitors because PDE8A has low expression levels in the brain. Hence, GLU406 and TYR424 are important target residues in the design of PDE9A-selective inhibitors.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Brain Diseases; Humans; Membrane Proteins; Phosphodiesterase Inhibitors; Structure-Activity Relationship
PubMed: 24746902
DOI: 10.1016/j.lfs.2014.04.007 -
Handbook of Experimental Pharmacology 2011The first pharmacological investigations of phosphodiesterase (PDE) inhibitors were developed with the clinical efficacies of drugs isolated from coffee, cacao and tea... (Review)
Review
The first pharmacological investigations of phosphodiesterase (PDE) inhibitors were developed with the clinical efficacies of drugs isolated from coffee, cacao and tea but only later their relevant ingredients were identified as xanthines that act as PDE. With its diuretic, inotropic and bronchodilating clinical efficacy, use of theophylline anticipated the clinical goals, which were later approached with the first-generation of weakly selective PDE inhibitors in the period from 1980 to 1990. Pharmacological and clinical research with these early compounds provided a vast pool of information regarding desired and adverse actions - although most of these new drugs had to be discontinued due to severe adverse effects. The pharmacological models for cardiac, vascular and respiratory indications were analysed for their PDE isoenzyme profiles, and when biochemical and molecular biological approaches expanded our knowledge of the PDE superfamily, the purified isoenzymes that were now available opened the door for more systematic studies of inhibitors and for generation of highly selective isoenzyme-specific drugs. The development of simple screening models and clinically relevant indication models reflecting the growing knowledge about pathomechanisms of disease are summarised here for today's successful application of highly selective PDE3, PDE4 and PDE5 inhibitors. The interplay of serendipitous discoveries, the establishment of intelligent pharmacological models and the knowledge gain by research results with new substances is reviewed. The broad efficacies of new substances in vitro, the enormous biodiversity of the PDE isoenzyme family and the sophisticated biochemical pharmacology enabled Viagra to be the first success story in the field of PDE inhibitor drug development, but probably more success stories will follow.
Topics: Animals; Asthma; Bronchodilator Agents; Cardiovascular Diseases; Humans; Nitric Oxide; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Theophylline
PubMed: 21695634
DOI: 10.1007/978-3-642-17969-3_1