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1.
Pediatr Ann ; 49(3): e140-e146, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32155280

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin condition in pediatric patients. AD has long been associated with comorbidities including food allergies, asthma, and allergic rhinitis, but recent literature has expanded this list to include attention-deficit/hyperactivity disorder and depression. AD has tremendous impact on quality of life for both affected children and their families. Improved understanding of AD pathogenesis, particularly regarding skin barrier dysfunction, the role of the cutaneous microbiome, and immune dysregulation, has spawned exciting new therapeutic directions. Although good skin care and appropriate use of topical corticosteroids remain first-line treatment, more precisely targeted treatments hold great promise. A recently approved topical phosphodiesterase inhibitor, crisaborole, and a subcutaneously administered interleukin-4/interleukin-13 blocker, dupilumab, are the first of what will likely be many new treatment options for patients with AD. [Pediatr Ann. 2020;49(3):e140-e146.].


Assuntos
Dermatite Atópica , Inibidores de Fosfodiesterase , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/complicações , Criança , Comorbidade , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Hipersensibilidade Alimentar/complicações , Humanos , Inibidores de Fosfodiesterase/uso terapêutico , Qualidade de Vida , Rinite Alérgica/tratamento farmacológico
2.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(9. Vyp. 2): 51-55, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31825390

RESUMO

Erectile dysfunction (ED) significantly deteriorates the quality of life of patients with Parkinson's disease (PD). Until recently, treatment of ED received insufficient attention. Management of ED in patients with PD requires an integrated and multidisciplinary approach. Pharmacotherapy with apomorphine or sildenafil (or other inhibitors of phosphodiesterase-5) has shown encouraging results in most patients with PD and ED. This review of literature addresses problems of ED in patients with PD.


Assuntos
Disfunção Erétil , Doença de Parkinson , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Humanos , Masculino , Doença de Parkinson/complicações , Inibidores de Fosfodiesterase/uso terapêutico , Piperazinas , Purinas , Qualidade de Vida , Sulfonas
4.
Food Chem Toxicol ; 134: 110822, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31536753

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Animais , Humanos , Inibidores de Fosfodiesterase/uso terapêutico
5.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374894

RESUMO

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis.


Assuntos
Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Relação Estrutura-Atividade , Humanos , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/efeitos dos fármacos , Água/química
6.
Nat Rev Drug Discov ; 18(10): 770-796, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31388135

RESUMO

Phosphodiesterases (PDEs), enzymes that degrade 3',5'-cyclic nucleotides, are being pursued as therapeutic targets for several diseases, including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Clinical development programmes have focused exclusively on catalytic inhibition, which continues to be a strong focus of ongoing drug discovery efforts. However, emerging evidence supports novel strategies to therapeutically target PDE function, including enhancing catalytic activity, normalizing altered compartmentalization and modulating post-translational modifications, as well as the potential use of PDEs as disease biomarkers. Importantly, a more refined appreciation of the intramolecular mechanisms regulating PDE function and trafficking is emerging, making these pioneering drug discovery efforts tractable.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Terapia de Alvo Molecular , Inibidores de Fosfodiesterase/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos
7.
Ital J Pediatr ; 45(1): 108, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439016

RESUMO

INTRODUCTION: Pentoxifylline may be an important approach to treat neonatal sepsis. However, its use has not been well established. We conduct a systematic review and meta-analysis to evaluate the efficacy of pentoxifylline treatment for neonatal sepsis. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials are searched. Randomized controlled trials (RCTs) assessing the influence of pentoxifylline treatment on neonatal sepsis are included. Two investigators independently have searched articles, extracted data, and assessed the quality of included studies. This meta-analysis is performed using the random-effect model. RESULTS: Seven RCTs involving 439 patients are included in the meta-analysis. Compared with control intervention for neonatal sepsis, pentoxifylline treatment is associated with reduced hospital stay (Std. MD = -0.61; 95% CI = -0.93 to - 0.29; P = 0.0002) and metabolic acidosis (RR = 0.38; 95% CI = 0.22 to 0.66; P = 0.0006), but has no remarkable impact on mortality (RR = 0.59; 95% CI = 0.30 to 1.16; P = 0.13), serum TNF-α (Std. MD = -0.38; 95% CI = -1.29 to 0.52; P = 0.41), serum CRP (Std. MD = -0.25; 95% CI = -0.92 to 0.42; P = 0.47), plasma IL-6 (Std. MD = -0.13; 95% CI = -0.41 to 0.15; P = 0.37), disseminated intravascular coagulopathy (RR = 0.55; 95% CI = 0.25 to 1.21; P = 0.14), and oliguria/anuria (RR = 0.77; 95% CI = 0.28 to 2.16; P = 0.62). In addition, pentoxifylline treatment can significantly reduce mortality (RR = 0.50; 95% CI = 0.29 to 0.88; P = 0.02) after excluding the study conducted by Akdag during the sensivity analysis. CONCLUSIONS: Pentoxifylline treatment may be associated with reduced mortality and hospital stay in neonatal sepsis.


Assuntos
Sepse Neonatal/tratamento farmacológico , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Humanos , Lactente , Recém-Nascido , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Drugs ; 79(12): 1321-1335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317509

RESUMO

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indanos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Mesalamina/uso terapêutico , Oxidiazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Triazóis/uso terapêutico
10.
Rev. patol. respir ; 22(supl.2): S202-S210, jul. 2019. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-188013

RESUMO

La piedra angular del tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC) es la broncodilatación, y en los últimos años se ha desarrollado un importante número de moléculas que han ido cambiando paulatinamente la práctica clínica habitual en estos pacientes. Los fármacos multivalentes con más de un mecanismo de acción broncodilatador representan el próximo paso en materia de relajación del músculo liso bronquial, pero dada la creciente evidencia sobre el estrés oxidativo y estado inflamatorio generalizado de la EPOC, existe una clara tendencia a demostrar el beneficio de formulaciones antiinflamatorias respecto a un potencial control sintomático, y secundariamente la reducción de la importante carga económica que supone el consumo de recursos sanitarios. En este capítulo se pretende dar un resumen esquemático y actualizado sobre los fármacos en investigación en EPOC en las fases previas de su desarrollo clínico


Bronchodilators are the cornerstone of Chronic obstructive pulmonary disease (COPD) treatment, and in the last years an important number of new molecules have changed gradually the clinical practice in these patients. Multivalent drugs with more than one mechanism of action represent the next step in terms of bronchial smooth muscle relaxation, although, giving the growing evidence of oxidative stress and generalized inflammation in COPD, there is a clear tendency to test the potential benefit of new anti-inflammatory drugs for symptoms control in the first place and consequently the reduction of the high economic burden of this disease. This chapter aims to give a schematical and updated review of new drugs for COPD in the preclinical phases of their clinical development


Assuntos
Humanos , Drogas em Investigação/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Relaxamento Muscular/efeitos dos fármacos , Broncodilatadores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Interleucina-1/antagonistas & inibidores , Interleucina-13/antagonistas & inibidores , Interleucinas/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Fosfodiesterase/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos
11.
J Clin Psychopharmacol ; 39(4): 318-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205187

RESUMO

BACKGROUND: Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study. METHODS: The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points. RESULTS: Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed. CONCLUSIONS: Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.


Assuntos
Inibidores de Fosfodiesterase/uso terapêutico , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica
12.
Med J Aust ; 210(10): 469-476, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31099420

RESUMO

Erectile dysfunction (ED) is a common male sexual dysfunction associated with a reduced quality of life for patients and their partners. ED is associated with increasing age, depression, obesity, lack of exercise, diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and lower urinary tract symptoms related to benign prostatic hyperplasia. The evaluation of men with ED requires a full medical and personally and culturally sensitive sexual history, a focused clinical examination, fasting glucose levels, a fasting lipid profile and, in select cases, a total testosterone level and a prostate-specific antigen test. Treatment of ED requires lifestyle modification, reduction of comorbid vascular risk factors, and treatment of organic or psychosexual dysfunction with either pharmacotherapy alone or in combination with psychosexual therapy. Between 60% and 65% of men with ED, including those with hypertension, diabetes mellitus, spinal cord injury and other comorbid medical conditions, can successfully complete intercourse in response to the phosphodiesterase type 5 inhibitors (PDE5i) sildenafil, tadalafil, vardenafil and avanafil. Patient-administered intracorporal injection therapy using vasodilator drugs such as alprostadil is an effective treatment and is useful in men who fail to respond to oral pharmacological agents. Surgical treatment of ED with multicomponent inflatable penile implants is associated with high satisfaction rates. Penile arterial revascularisation and venous ligation surgery are associated with relatively poor outcome results in men with penile atherosclerotic disease or corporal veno-occlusive dysfunction.


Assuntos
Disfunção Erétil/diagnóstico , Disfunção Erétil/terapia , Qualidade de Vida , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/uso terapêutico , Comportamento Sexual/psicologia , Vasodilatadores/uso terapêutico
13.
Life Sci ; 230: 150-161, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125564

RESUMO

Despite novel technologies, colon cancer remains undiagnosed and 25% of patients are diagnosed with metastatic colon cancer. Resistant to chemotherapeutic agents is one of the major problems associated with treating colon cancer which creates the need to develop novel agents targeting towards newer targets. A phosphodiesterase is a group of isoenzyme, which, hydrolyze cyclic nucleotides and thereby lowers intracellular levels of cAMP and cGMP leading to tumorigenic effects. Many in vitro and in vivo studies have confirmed increased PDE expression in different types of cancers including colon cancer. cAMP-specific PDE inhibitors increase intracellular cAMP that leads to activation of effector molecules-cAMP-dependent protein kinase A, exchange protein activated by cAMP and cAMP gated ion channels. These molecules regulate cellular responses and exert its anticancer role through different mechanisms including apoptosis, inhibition of angiogenesis, upregulating tumor suppressor genes and suppressing oncogenes. On the other hand, cGMP specific PDE inhibitors exhibit anticancer effects through cGMP dependent protein kinase and cGMP dependent cation channels. Elevation in cGMP works through activation of caspases, suppression of Wnt/b-catenin pathway and TCF transcription leading to inhibition of CDK and survivin. These studies point out towards the fact that PDE inhibition is associated with anti-proliferative, anti-apoptotic and anti-angiogenic pathways involved in its anticancer effects in colon cancer. Thus, inhibition of PDE enzymes can be used as a novel approach to treat colon cancer. This review will focus on cAMP and cGMP signaling pathways leading to tumorigenesis and the use of PDE inhibitors in colon cancer.


Assuntos
Neoplasias do Colo/terapia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Humanos , Diester Fosfórico Hidrolases/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Clin Perinatol ; 46(2): 291-310, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010561

RESUMO

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions. Many drugs remain inadequately tested and no new drugs have been approved in more than 25 years for BPD prevention or therapy. More progress is needed in defining appropriate end points based on the pathophysiology of BPD and postdischarge chronic pulmonary insufficiency of prematurity and to develop effective new drugs. In addition, much work is needed to better define perinatal factors, early postnatal findings, and physiologic phenotypes or endotypes.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/prevenção & controle , Administração por Inalação , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , Cafeína/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Fator de Crescimento Insulin-Like I/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Óxido Nítrico/uso terapêutico , Oxigenoterapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Gravidez , Cuidado Pré-Natal , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Vitamina A/uso terapêutico , Vitaminas/uso terapêutico
15.
Life Sci ; 222: 245-254, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30858122

RESUMO

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-ß1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Cirrose Hepática/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Masculino , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/uso terapêutico
17.
BJU Int ; 124(1): 27-34, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30681264

RESUMO

OBJECTIVES: To assess the effects of phosphodiesterase inhibitors (PDEI) compared to placebo and other standard of care drugs i.e alpha blockers (AB) and 5-alpha reductase inhibitors (5-ARI) in men with LUTS consistent with benign prostatic hyperplasia (BPH). METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). Citation tracking and hand-searching of abstracts and conference proceedings was done. We also attempted to contact the study authors in case additional information was needed. Randomised controlled trials (RCT) comparing PDEI versus placebo, AB, or 5-ARI used for at least four weeks in men with BPH-LUTS were included. Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AE). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. RESULTS: We included a total of 16 randomised trials in this review. Primary outcomes: PDEI versus placebo: PDEI may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI versus AB: PDEI and AB probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AE (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI and AB versus AB : The combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AE may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AE per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks. PDEI and AB versus PDEI alone: The combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AE. Study results were limited to a treatment duration of four weeks. PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AE. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AE (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AE per 1000 participants (95% CI 43 fewer to 98 more per 1000). We found no trials comparing other combinations of treatments or comparing different PDEI for BPH-LUTS. CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AE. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AE. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB or PDEI combined with 5-ARI compared to ARI with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.


Assuntos
Sintomas do Trato Urinário Inferior/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Hiperplasia Prostática/complicações , Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
18.
Int J Impot Res ; 31(2): 85-91, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30287894

RESUMO

This cross-sectional comparative study aimed to compare serum L-carnitine and 25(OH)D levels between men with ED non-responding for oral sildenafil citrate and healthy volunteers. Overall, 192 men, recruited from two University Hospitals, were allocated into two equal groups of matched age; healthy potent men and men with ED non-responders for oral sildenafil citrate. Oral sildenafil citrate non-responders self-reported inadequate erectile responses after four attempts using 100 mg with the manufacturer's guidelines relative to meals, associated medications, and sexual stimulation/arousal. Exclusion criteria were: diabetes, cardiovascular disorders, beta blockers treatment, morbid obesity, thyroid disorders, post-radical prostatectomy, and hepatic/renal failure. All participants were subjected to; history taking, clinical examination, validated IIEF-5 questionnaire, estimation of serum L-carnitine by calorimetric method and serum 25(OH)D by ELISA method. Compared with potent controls, ED men non-responders for oral sildenafil citrate showed significant decreases in the mean serum L-carnitine level (16.8 ± 3.6 uM/L versus 66.3 ± 11.9 uM/L, P = 0.001), the mean serum 25(OH)D level (21.2 ± 7.1 ng/ml versus 54.6 ± 7.9 ng/mL, P = 0.001) and IIEF-5 score (7.8 ± 2.6 versus 23.9 ± 1.3). Serum L-carnitine showed significant positive correlation with IIEF-5 scores (r = 0.873, P = 001), serum 25(OH)D (r = 0.796, P = 0.001) and significant negative correlation with the age (r = -0.515, P = 0.001). Serum 25(OH)D showed significant positive correlation with IIEF-5 scores (r = 0.855, P = 0.001) and significant negative correlation with the age (r = -0.223, P = 0.005). It is concluded that normal homeostasis of serum L-carnitine and 25(OH)D play a role in male sexual health being significantly decreased in ED non-responding for oral sildenafil citrate.


Assuntos
25-Hidroxivitamina D 2/sangue , Carnitina/sangue , Disfunção Erétil/sangue , Inibidores de Fosfodiesterase/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Administração Oral , Adulto , Estudos de Casos e Controles , Estudos Transversais , Egito , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
19.
Curr Drug Targets ; 20(1): 122-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30091414

RESUMO

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Doenças do Sistema Nervoso Central/patologia , Transtornos Cognitivos/patologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Fosfodiesterase/uso terapêutico , Resultado do Tratamento
20.
Sex Med Rev ; 7(1): 115-128, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30301707

RESUMO

INTRODUCTION: The serendipitous discovery of sildenafil (Viagra [sildenafil citrate]) as a treatment for erectile dysfunction (ED) is one of the most fascinating drug development stories of our time. When sildenafil was approved by the U.S. Food and Drug Administration in 1998, it revolutionized the treatment protocol for men with ED, once considered a psychological issue or an inevitable part of aging. AIM: To review the discovery of sildenafil and its role in changing the field of sexual medicine in the context of the epidemiology and history of treatment for ED. METHODS: For this narrative review, a literature search was conducted to identify essential articles and was supplemented by author observations from a historical perspective. MAIN OUTCOME MEASURE: A broad overview of ED and its past, current, and future treatments. RESULTS: ED is a prevalent condition for which medical treatment had been limited to genitally localized interventions, including surgery, vacuum pumps, injectable therapies, and intraurethral suppositories. The discovery of sildenafil provided a safe, oral pharmacotherapy for the treatment of ED, sparking greater understanding of the science behind ED and its role in men's overall health. CONCLUSION: The approval of sildenafil initiated a global conversation about ED that had profound implications for patients, methods of clinical practice, and academic sexual medicine. These changes will catalyze continued advances in ED treatment. Goldstein I, Burnett AL, Rosen RC, et al. The serendipitous story of sildenafil: an unexpected oral therapy for erectile dysfunction. Sex Med Rev 2019;7:115-128.


Assuntos
Desenvolvimento de Medicamentos , Disfunção Erétil/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Coito/psicologia , Disfunção Erétil/fisiopatologia , Disfunção Erétil/psicologia , Humanos , Masculino , Inibidores de Fosfodiesterase/farmacologia , Qualidade de Vida , Citrato de Sildenafila/farmacologia , Resultado do Tratamento
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