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PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.
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Autofagia , Progresión de la Enfermedad , Regulación hacia Abajo , Fibroblastos , Sistema de Señalización de MAP Quinasas , Inhibidores de Fosfodiesterasa 5 , Hiperplasia Prostática , Masculino , Humanos , Autofagia/fisiología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Fibroblastos/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Persona de Mediana Edad , GMP Cíclico/metabolismo , Anciano , Transducción de SeñalRESUMEN
BACKGROUND: Major depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. AIM: To investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. METHODS: ACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. RESULTS: Sub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. CONCLUSION: This study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.
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Trastorno Depresivo Mayor , Imipramina , Masculino , Ratas , Animales , Escitalopram , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/uso terapéutico , Hormona Adrenocorticotrópica , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Roedores , Trastorno Depresivo Mayor/tratamiento farmacológico , Ratas Sprague-Dawley , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Conducta AnimalRESUMEN
Background: Avanafil is a second-generation phosphodiesterase type 5 (PDE5) inhibitor, and offers a rapid onset of action (15 minutes). Its real-world data, including treatment satisfaction, are still lacking. Aim: The study sought to investigate the treatment outcomes of avanafil and the factors impacting treatment satisfaction in a real-world setting. Methods: Between November 2021 and February 2023, erectile dysfunction (ED) patients prescribed avanafil were consecutively enrolled in this phase 4, open-label, cross-sectional, observational study. At each follow-up visit (4-week intervals), participants completed a questionnaire for assessing the use and treatment-emergent adverse events of avanafil, ED severity, and treatment satisfaction. Outcomes: The outcome measures included the Sexual Health Inventory for Men (SHIM), and Erectile Dysfunction Inventory of Treatment Satisfaction. Results: Among 234 patients enrolled, 112 (47.9%) patients had follow-up visits and answered the questionnaire. Treatment with avanafil significantly improved the mean SHIM total score from 10.2 ± 5.6 at baseline to 17.5 ± 6.2 (P < .001). Of the patients treated with avanafil, 71.4% (n = 80 of 112) reported a >4-point improvement in the SHIM total score, and 33.1% (n = 37 of 112) reported normal erectile function. The proportion of patients satisfied with avanafil treatment (defined as Erectile Dysfunction Inventory of Treatment Satisfaction index score ≥60) was 87.5%. Several physical factors (younger age, lower waist circumference, and lower level of low-density lipoprotein), and sexual function factors (shorter duration of ED, higher SHIM total score at baseline, PDE5 inhibitor treatment naive, and acquired premature ejaculation) tended to contribute to satisfaction with avanafil treatment. Treatment-emergent adverse events occurred in 41.1% of patients, and all were mild in severity. Clinical Implications: This study identifies the factors associated with treatment satisfaction of avanafil, which may ultimately lead to better treatment outcomes. Strengths and Limitations: This is the first study to provide real-world evidence of avanafil for ED treatment, and validated questionnaires were used to assess erectile function and treatment satisfaction. However, the limitations of this study include single-center observational study design, small sample size, and short-term follow-up. Conclusion: Avanafil is an effective treatment for ED, and satisfaction rate is high in an outpatient setting. The awareness of identified factors related to patient satisfaction may improve treatment outcomes.
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AIMS: In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with 'classical PAH' and 'PAH with co-morbidities'. METHODS: Fifty patients (median age 57 [42-71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC-S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow-up. RESULTS: At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; -25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; -52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P < 0.05). Haemodynamic improvements correlated with improved clinical parameters including 6-min walking distance (336 ± 315 to 389 ± 120 m), NTproBNP levels (1.712 ± 2.024 to 506 ± 550 ng/L, both P < 0.05) and WHO-FC at 12 months, resulting in improved risk status, and were found in patients with few (n = 37) or multiple cardiovascular co-morbidities (BMI > 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co-morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co-morbidities (-42.7% vs. -54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4-strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co-morbidities. CONCLUSIONS: Rapid sequential combination therapy with PDE5i/sGC-S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow-up in patients without, and to a lesser extent, with cardiovascular co-morbidities. This occurs in line with improvements of clinical parameters and risk status.
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Quimioterapia Combinada , Hemodinámica , Inhibidores de Fosfodiesterasa 5 , Humanos , Femenino , Masculino , Persona de Mediana Edad , Hemodinámica/fisiología , Hemodinámica/efectos de los fármacos , Anciano , Adulto , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/diagnóstico , Estudios de Seguimiento , Resultado del Tratamiento , Cateterismo Cardíaco/métodos , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Resistencia Vascular , Factores de Tiempo , Antagonistas de los Receptores de Endotelina/administración & dosificaciónRESUMEN
AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.
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Feto , Trabajo de Parto , Recién Nacido , Embarazo , Humanos , Femenino , Tadalafilo/efectos adversos , Factor de Crecimiento Placentario , Atención PrenatalRESUMEN
OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.
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Enfermedades del Tejido Conjuntivo , Hipertensión Pulmonar , Lupus Eritematoso Sistémico , Enfermedad Mixta del Tejido Conjuntivo , Hipertensión Arterial Pulmonar , Esclerodermia Sistémica , Humanos , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/complicaciones , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Enfermedad Mixta del Tejido Conjuntivo/tratamiento farmacológico , Enfermedades del Tejido Conjuntivo/complicaciones , Enfermedades del Tejido Conjuntivo/tratamiento farmacológico , Enfermedades del Tejido Conjuntivo/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar Primaria Familiar/complicaciones , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Esclerodermia Sistémica/complicacionesRESUMEN
PURPOSE: Erectile dysfunction (ED) is a worldwide health problem. Oral phosphodiesterase type 5 inhibitors (PDE5I) are used in its first-line treatment. This study aimed to compare the effects of hyperbaric oxygen (HBO) treatment with PDE5I treatment and determine the patient-dependent factors affecting the efficacy of the HBO treatment and duration of action of HBO treatment. METHODS: Adult male patients who presented to the HBO unit for HBO treatment with non-urological indications and had ED based on the International Index for Erectile Function (IIEF-5) constituted the target population of this study. Participants were given HBO treatment (Group 1), no treatment (Group 2), or daily oral tadalafil 5 mg treatment (Group 3). The treatment duration was 1 month. Patients were assessed by IIEF-5 both initially and after the completion of 1 month. RESULTS: There were significant increases in the mean IIEF-5 scores of the patients in Group 1 and Group 3 (p < 0.001, p < 0.001). However, there was no significant improvement in Group 2 (p = 0.496). Also, the post-treatment IIEF-5 scores of Group 1 and Group 3 were significantly higher than Group 2 (p < 0.001). There was no significant difference between the IIEF-5 scores and ∆IIEF-5 values of Group 1 and Group 3 (p = 0.166, p = 0.093). Evaluation regarding comorbidities revealed that patients with the peripheral vascular disease did not improve with HBO treatment (p = 0.285). CONCLUSION: HBO can improve erectile functions, and it can be a reasonable alternative for patients who cannot use PDE5Is due to comorbidities or treatment side effects.
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Disfunción Eréctil , Oxigenoterapia Hiperbárica , Adulto , Masculino , Humanos , Tadalafilo , Disfunción Eréctil/tratamiento farmacológico , Estudios Prospectivos , Carbolinas/uso terapéutico , Inhibidores de Fosfodiesterasa 5 , Método Doble Ciego , Resultado del TratamientoRESUMEN
INTRODUCTION: The drug classes of α1-adrenoceptor antagonists, 5α-reductase inhibitors, and phosphodiesterase type 5 inhibitors are guideline-recommended treatments of lower urinary tract symptoms suggestive of benign prostatic hyperplasia; muscarinic receptor antagonists and ß3-adrenoceptor agonists are also recommended if storage symptoms are insufficiently addressed with one of the other three drug classes. AREAS COVERED: We provide a narrative review (no formalized literature searches performed) of the tolerability of these drug classes with emphasis on the more recently introduced medications, on combination treatment, and on more lately emerging risks. EXPERT OPINION/COMMENTARY: The tolerability profiles are distinct between drug classes but, with few exceptions, similar within a drug class. Within a drug, formulations with longer duration of action tend to have better tolerability. Efficacy gains using combination treatment at least partly come at a cost of lesser tolerability. Greater susceptibility to experience adverse events based on age, comorbidities, and comedications appears conceptually important but remains under-investigated in this therapeutic area.
Several classes of medicines are available to treat male lower urinary tract symptoms that are believed to result from an enlarged prostate. These include α1-adrenoceptor antagonists (α-blockers), 5α-reductase inhibitors (ARI), and phosphodiesterase type 5 inhibitors (PDEI); muscarinic receptor antagonists and ß3-adrenoceptor agonists are additionally used in men that have persisting storage symptoms upon treatment with the former three drug classes. Each drug class has a distinct tolerability profile. Within a drug class, medicines with a longer duration of action, either intrinsically or due to specific drug formulations, tend to have better tolerability. Men with greater age, comorbidities, and comedications may be at greater risk of experiencing side effects when medically treating their lower urinary tract symptoms. While combination of members of multiple drug classes may increase efficacy, this often comes at the price of experiencing more side effects. The relative benefit/risk ratio needs to be individually analyzed in each patient.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Humanos , Masculino , Hiperplasia Prostática/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5 , Quimioterapia Combinada , Receptores Adrenérgicos/uso terapéuticoRESUMEN
An evidence-based consensus meeting was held with urologists, a pharmacist and a cardiologist to perform a structured benefit-risk analysis of reclassifying tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor for treatment of erectile dysfunction (ED), to be available without prescription in Germany. As per the Brass process endorsed by regulatory authorities, an evidence-based Brass value tree was developed, which identified the incremental benefits and risks that should be considered above the safety and efficacy evidence required for prescription medicines. During the Group Delphi consensus meeting, the expert panel rated the likelihood and clinical impact of each benefit and risk on a scale of 0 (none) to 3 (high). Overall attribute scores were calculated from the product of the mean likelihood and mean clinical impact scores giving a possible score of 0-9. The overall benefit attribute scores ranged from 2.8 to 5.4. The overall risk attribute scores ranged from 0.2 to 2.2 though most were 1.0 or less (3 or more is generally considered to be of concern). On balance, the independent meeting scored the benefits of reclassification of tadalafil higher than the risks and considered the risk mitigation strategies of the packaging label and patient information leaflet (PIL) sufficient.
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PURPOSE OF REVIEW: This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. RECENT FINDINGS: This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.
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Isquemia Miocárdica , Inhibidores de Fosfodiesterasa 5 , Humanos , Masculino , Inhibidores de Fosfodiesterasa 5/efectos adversos , Nitratos/uso terapéutico , Nitratos/efectos adversos , Isquemia Miocárdica/tratamiento farmacológico , Interacciones Farmacológicas , Medición de RiesgoAsunto(s)
Hipertensión Pulmonar , Enfermedades Pulmonares Intersticiales , Humanos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Purinas/uso terapéutico , Purinas/farmacología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas , Citrato de Sildenafil/uso terapéutico , Tadalafilo/uso terapéutico , Tadalafilo/farmacología , Carbolinas/farmacologíaRESUMEN
Background: The aim of this study is to evaluate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, plus mirabegron, a ß3-adrenoreceptor agonist, in patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Methods: The registration of this study started in August 2016 and ended in July 2019. The inclusion criteria included patients aged ≥ 50 years who were diagnosed with benign prostatic hyperplasia and who presented with overactive bladder symptoms. Patients were treated with oral tadalafil 5 mg once daily for 4 weeks. Then, its efficacy was evaluated. Patients who responded to the treatment received oral tadalafil 5 mg once daily for 4 more weeks (monotreatment group). Meanwhile, those who did not respond received oral tadalafil 5 mg and mirabegron 50 mg, which is an add-on treatment, once daily for 4 more weeks (combination therapy group). Results: After 8 weeks, the monotreatment group (n = 19) and the combination group (n = 56) had significantly better total Overactive Bladder Symptom Score and International Prostate Symptom Score and International Prostate Symptom Score voiding and storage subscale scores. Moreover, the two groups experienced significant improvements in the total Overactive Bladder Questionnaire and Nocturia Quality of Life Questionnaire scores, and Nocturia Quality of Life Questionnaire Bother/Concern subscale score after 8 weeks. However, there were no cases of urinary retention or serious adverse events. Conclusion: Combination treatment with tadalafil and mirabegron is effective and safe for patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Hence, tadalafil plus mirabegron is a promising therapeutic option, and it can improve overactive bladder related-quality of life.
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Background: Erectile Dysfunction (ED) is the most common sexual dysfunction worldwide. This study is the first reported from Somalia to the best of our knowledge. Objective: The current study aimed to assess knowledge, attitude, and practice (KAP) regarding erectile dysfunction disease and its medications among community pharmacy technicians in Mogadishu, Somalia. Method: The current is a cross-sectional descriptive study conducted among pharmacy technicians in Mogadishu to assess their KAP regarding erectile dysfunction disease and its medications. A convenient sampling technique was used. A structured questionnaire contained 45 questions, including; demographic characteristics (4 items), the knowledge of erectile dysfunction disease and its medications (18 items), attitudes (5 items), and practice (15 items) were assessed among technicians. A total of 200 respondents participated in the study. Results: Knowledge. 79 and 72.5% of technicians comprehended the condition of ED and whom it affects; however, about half did not know the underlying risk factors and complications associated with PDE5 inhibitors. Attitude: 77-85% of technicians believe medication requires prescriptions, medications may have complications, and quality medications are essential. Practice: 64% of technicians give ED medication with prescriptions, and 85% do not consult a physician. 64.5% of technicians always provide the same type of medication, and 63% do not give the same dose to each client. About half of the technicians also vend herbal medicines to clients, such as honey, fish, and sea urchins. Conclusion: The findings of this study suggest pharmacy technicians have some knowledge, although not sufficient for understanding the risks and complications of medications. Technicians did not engage in good standard practices despite this knowledge and attitudes. These findings highlight the need for regulations to support good practice among pharmacy technicians and the quality, safety, and efficacy of medicines in Mogadishu by establishing the National Medicine Regulatory Authority.
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OBJECTIVE: To evaluate the efficacy and safety of add-on therapy with the phosphodiesterase type 5 inhibitor tadalafil in Japanese men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with dutasteride. RESULTS: Twenty-four patients were enrolled. The participants had a median age of 71.0 (64.8-73.0) years and a median prostate volume of 37.3 (29.7-41.8) mL as measured using transabdominal sonography. The efficacy indicators, such as International Prostate Symptom Score (IPSS), quality of life (QOL) score, night-time urinary frequency, and night-time maximum voided volume, improved significantly at 4 weeks, and the effects lasted until 24 weeks (IPSS: 9.5 vs. 17.0, QOL: 2.0 vs. 4.0, nocturia: 2.0 vs. 2.0, night-time maximum voided volume: 290.0 vs. 240.0 mL). Overactive bladder symptom score (OABSS) and sexual health inventory for men (SHIM) significantly improved at 12 weeks, and the effects lasted until 24 weeks (OABSS: 3.0 vs. 5.0, SHIM: 11.0 vs. 7.5). However, maximum urine flow and residual urine volume showed no improvement at any point. Adverse events occurred in two cases. Taken together, add-on therapy with tadalafil was effective for patients with LUTS/BPH resistant to dutasteride monotherapy. In addition, this therapy was not associated with severe adverse events.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Vejiga Urinaria Hiperactiva , Anciano , Dutasterida/efectos adversos , Humanos , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Tadalafilo/uso terapéutico , Vejiga Urinaria Hiperactiva/complicacionesRESUMEN
BACKGROUND: C-reactive protein (CRP), as a marker of inflammation, may be closely related to erectile dysfunction (ED), however, there is no meta-analysis exists for it. OBJECTIVES: We aimed to verify the relationship between CRP and erectile dysfunction and to explore the changes of CRP levels in ED patients after first-line treatment. MATERIALS AND METHODS: We searched databases including the Cochrane Library, PubMed, and MEDLINE to identify studies up to January 1, 2022. We performed a comprehensive analysis of the included studies by STATA software and calculated standardized mean differences (SMDs) and their corresponding 95% confidence intervals. RESULTS: A total of 12 studies were included and the analysis showed that CRP levels were higher significantly in patients with erectile dysfunction than the healthy controls (p < 0.001) and decreased by a mean of 0.38 mg/L after first-line PDE5i drug treatment (p = 0.001). DISCUSSION AND CONCLUSION: This novel meta-analysis suggests that CRP is statistically significantly associated with erectile dysfunction and may be a predictor or risk factor for the assessment of ED. However, further original studies with large sample sizes are needed to validate this.
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Disfunción Eréctil , Biomarcadores , Proteína C-Reactiva , Humanos , Masculino , Factores de RiesgoRESUMEN
Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration-time curve values. The mean accumulation ratio in area under the plasma concentration-time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once-daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single-dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.
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Inhibidores de Fosfodiesterasa 5 , Administración Oral , China , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Masculino , Inhibidores de Fosfodiesterasa 5/efectos adversosRESUMEN
Avanafil, a selective second-generation phosphodiesterase-5 inhibitor, was successfully labeled with iodine-125 via electrophilic and different factors affecting the labeling efficiency were studied. The labeled compound exhibited in-vitro stability of more than 24 h with a maximum labeling yield of up to 98.4 ± 1.9 %. Molecular modeling and in-vitro assessment of tracer inhibitory activity were performed to ensure that radiolabeling did not affect its binding ability to the target. Biodistribution studies were performed in normal rats and models of erectile dysfunction. The tracer specifically accumulated in the penis, and the clearance appeared to take place via the hepatobiliary route. Results suggested the usefulness of radiolabeled avanafil as a promising tracer for erectile dysfunction.
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Disfunción Eréctil/diagnóstico por imagen , Pirimidinas , Radiofármacos , Animales , Radioisótopos de Yodo , Masculino , Modelos Animales , Modelos Moleculares , Conformación Molecular , Inhibidores de Fosfodiesterasa 5 , Pirimidinas/química , Pirimidinas/farmacocinética , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas WistarRESUMEN
BACKGROUND: Topic modeling of patient medication reviews of erectile dysfunction (ED) drugs can help identify patient preferences regarding ED treatment options. The identification of a set of topics important to the patient from social network service drug reviews would inform the design of patient-centered medication counseling. OBJECTIVE: This study aimed to (1) identify the distinctive topics from patient medication reviews unique to tadalafil versus sildenafil; (2) determine if the primary topics are distributed differently for each drug and for each patient characteristic (age and time on ED drug therapy); and (3) test if the primary topics affect satisfaction with ED drug therapy controlling for patient characteristics. METHODS: Data were collected from the patient medication reviews of sildenafil and tadalafil posted on WebMD and Ask a Patient. The latent Dirichlet allocation method of natural language processing was used to identify 5 distinctive topics from the patient medication reviews on each drug. Analysis of variance and a 2-sample t test were conducted to compare the topic distribution and assess whether patient satisfaction varies with the primary topics, age, and time on medication for each ED drug. Statistical significance was tested at an alpha of .05. RESULTS: The patient medication reviews of sildenafil (N=463) had 2 topics on treatment benefit and 1 each on medication safety, marketing claim, and treatment comparison, while the patient medication reviews of tadalafil (N=919) had 2 topics on medication safety and 1 each on the remaining subjects. Sildenafil's reviewers quite frequently (94/463, 20.4%) mentioned erection sustainability as their primary topic, whereas tadalafil's reviewers were more concerned about severe medication safety. Those who mentioned erection sustainability as their primary topic were quite satisfied with their treatment as opposed to those who mentioned severe medication safety as their primary topic (score 3.85 vs 2.44). The discovered topics reflected the marketing claims of blue magic and amber romance for sildenafil and tadalafil, respectively. The topic of blue magic was preferred among younger patients, while the topic of amber romance was preferred among older patients. The topic alternative choices, which appeared for both the ED drugs, reflected patient interest in the comparative effectiveness and price outside the drug labeling information. CONCLUSIONS: The patient medication reviews of ED drugs reflect patient preferences regarding drug labeling information, marketing claims, and alternative treatment choices. The patient preferences concerning ED treatment attributes inform the design of patient-centered communication for improved ED drug therapy.
RESUMEN
The AMBITION study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH). Nevertheless, predictors of treatment response were not assessed.To identify predictors for response to initial combination therapy, we examined data from 302 patients with PAH (World Health Organization Functional Class II or III) who received initial combination therapy from the modified intention-to-treat population of the AMBITION study (n = 605). A responder was defined as not having undergone a clinical failure event. Univariate and multivariate analyses were performed. Multivariate logistic regression with interactive backward selection was used to assess the independent association of potential predictors with response.Treatment responders were younger, more often female, and less likely to have comorbidities or a requirement for oxygen therapy, compared with nonresponders. At multivariate analysis, female sex (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.29, 5.52; P = 0.0081), longer 6-minute walk distance (OR 1.01; 95% CI 1.00, 1.01; P = 0.0039), lower baseline log N-terminal-prohormone of brain natriuretic peptide (OR 0.70; 95% CI 0.52, 0.94; P = 0.0190), and aldosterone antagonist use (OR 2.54; 95% CI 1.03, 6.26; P = 0.0436) independently predicted response to initial combination therapy.Besides demographic factors, the absence of comorbidities and less severe disease state, and the use of aldosterone antagonist therapy identified patients with PAH most likely to respond to initial combination therapy with ambrisentan and tadalafil. Further study to evaluate the role of aldosterone antagonist therapy in PAH is warranted.