Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70 years of age. In the first major trial of sildenafil in ED, at 24 weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100 mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardenafil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildenafil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100 mg) by men with ED, possibly because of its longer duration of action. of the phosphodiesterase inhibitors, tadalafil may displace sildenafil as the drug of choice among men with ED.

Drug combination: pharmaceutical technologies applied to the manufacturing of combined dosage forms for oral administration

Lo scopo di questa ricerca di dottorato è stato lo studio di una forma di dosaggio flessibile e personalizzabile, indirizzata alle necessità individuali di ogni paziente, per il trattamento dell’iperplasia prostatica benigna. La terapia proposta prevede l’utilizzo di due farmaci, un alfa bloccante (farmaco A) e un inibitore delle 5- fosfodiesterasi (farmaco B) e, somministrati in una singola forma di dosaggio contenenti differenti dosi e combinazioni dei due farmaci. Lo sviluppo di un sistema di rilascio per la somministrazione orale di farmaco A e farmaco B è stato realizzato grazie alla tecnologia Dome Matrix. La tecnologia si basa sull’assemblaggio di moduli utilizzati come elementi di controllo del rilascio. L’assemblaggio dei moduli può essere ottenuto attraverso diverse configurazioni. Sono stati quindi realizzati sistemi assemblati in grado di galleggiare sul contenuto gastrico; la prolungata permanenza della forma farmaceutica nello stomaco favorisce la solubilizzazione dei due principi attivi che quindi potrebbero raggiungere il sito di assorbimento nel primo tratto intestinale già in dispersione molecolare, condizione ideale per essere assorbiti. La prima parte della ricerca è stata focalizzata sulla realizzazione di un sistema assemblato a rilascio modificato di farmaco A. Moduli contenenti diversi dosaggi di farmaco sono stati assemblati in varie configurazioni e dosi differenti per ottenere una forma di dosaggio flessibile, adattabile alle esigenze terapeutiche del paziente. La seconda parte del lavoro di tesi ha riguardato la realizzazione di un sistema assemblato, contenente entrambi i farmaci in associazione. L’ultima parte della ricerca è stata svolta presso la “University of Texas at Austin” sotto la supervisione del Professor Nicholas Peppas. Il lavoro svolto è stato focalizzato sullo studio delle caratteristiche di rigonfiamento dei singoli moduli di farmaco e dei loro sistemi assemblati; il comportamento di tali sistemi è stato investigato anche grazie all’utilizzo della tecnica di tomografia computerizzata a raggi X.

The commercial bark harvest of the African cherry (Prunus africana) on Mount Oku, Cameroon: Effects on traditional uses and population dynamics

Bark extracts of the African cherry (Prunus africana) are used to treat benign prostatic hyperplasia. This study examined the effects of commercial bark harvest on population dynamics in the Kilum-Ijim Forest Preserve on Mount Oku, Cameroon and on traditional uses. P. africana is valued for its timber and as fuel although its greatest value is as a traditional medicine for human and animal ailments. Harvest has depleted the resource and has eroded traditional forest protection practices. I constructed matrix models to examine the effects of bark harvest on population structure and on population dynamics in harvested and unharvested populations. Harvesting simulations examined the effect on the population growth rate (λ) with differing levels of mortality of harvest-sized and large trees and differing harvest frequencies. Size class frequencies for the entire forest decreased in a reverse j-shaped curve, indicating adequate recruitment in the absence of harvest. Individual plots showed differences from the overall forest data, suggesting effects of natural and man-made perturbations, particularly due to bark harvest. One plot (harvested in the 1980s) showed a temporal difference in λ and fluctuated around one, due to alternating high and low fruiting years; other unharvested plots showed smaller temporal differences. Harvested plots (harvested illegally in 1997) had values of λ less than one and showed small temporal differences. The control plot also showed λ less than one, due to poor recruitment in the closed canopy forest. The value of λ for the combined data was 0.9931 suggesting a slightly declining population. The elasticity matrix for the combined data indicated the population growth rate was most sensitive to the survival of the large reproductive trees (42.5% of the elasticity). In perturbation analyses, reducing the survival of the large trees caused the largest reductions in λ. Simulations involving harvesting frequency indicated λ returns to pre-harvest conditions if trees are re-harvested after 10–15 years, but only if the large trees are left unharvested. Management scenarios suggest harvest can be sustainable if seedlings and small saplings are planted in the forest and actively managed, although large-scale plantations may be the only feasible option to meet market demand. ^

Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer

Background: Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including cancers of the prostate. Over the past several years, our group has been studying how mycoplasmas could possibly initiate and propagate cancers of the prostate. Specifically, Mycoplasma hyorhinis encoded protein p37 was found to promote invasion of prostate cancer cells and cause changes in growth, morphology and gene expression of these cells to a more aggressive phenotype. Moreover, we found that chronic exposure of benign human prostate cells to M. hyorhinis resulted in significant phenotypic and karyotypic changes that ultimately resulted in the malignant transformation of the benign cells. In this study, we set out to investigate another potential link between mycoplasma and human prostate cancer. Methods: We report the incidence of men with prostate cancer and benign prostatic hyperplasia (BPH) being seropositive for M. hyorhinis. Antibodies to M. hyorhinis were surveyed by a novel indirect enzyme-linked immunosorbent assay (ELISA) in serum samples collected from men presenting to an outpatient Urology clinic for BPH (N = 105) or prostate cancer (N = 114) from 2006-2009. Results: A seropositive rate of 36% in men with BPH and 52% in men with prostate cancer was reported, thus leading us to speculate a possible connection between M. hyorhinis exposure with prostate cancer. Conclusions: These results further support a potential exacerbating role for mycoplasma in the development of prostate cancer.

Factors Affecting De Novo Urinary Retention after Holmium Laser Enucleation of the Prostate

Objective Patients can experience urinary retention (UR) after Holmium laser enucleation of the prostate (HoLEP) that requires bladder distension during the procedure. The aim of this retrospective study is to identify factors affecting the UR after HoLEP. Materials and Methods 336 patients, which underwent HoLEP for a symptomatic benign prostatic hyperplasia between July 2008 and March 2012, were included in this study. Urethral catheters were routinely removed one or two days after surgery. UR was defined as the need for an indwelling catheter placement following a failure to void after catheter removal. Demographic and clinical parameters were compared between the UR (n = 37) and the non-urinary retention (non-UR; n = 299) groups. Results The mean age of patients was 68.3 (±6.5) years and the mean operative time was 75.3 (±37.4) min. Thirty seven patients (11.0%) experienced a postoperative UR. UR patients voided catheter free an average of 1.9 (±1.7) days after UR. With regard to the causes of UR, 24 (7.1%) and 13 (3.9%) patients experienced a blood clot-related UR and a non-clot related UR respectively. Using multivariate analysis (p<0.05), we found significant differences between the UR and the non-UR groups with regard to a morcellation efficiency (OR 0.701, 95% CI 0.498–0.988) and a bleeding-related complication, such as, a reoperation for bleeding (OR 0.039, 95% CI 0.004–0.383) or a transfusion (OR 0.144, 95% CI 0.027–0.877). Age, history of diabetes, prostate volume, pre-operative post-void residual, bladder contractility index, learning curve, and operative time were not significantly associated with the UR (p>0.05). Conclusions De novo UR after HoLEP was found to be self-limited and it was not related to learning curve, patient age, diabetes, or operative time. Efficient morcellation and careful control of bleeding, which reduces clot formation, decrease the risk of UR after HoLEP.

BPH and sexuality

Quality of life has become a very important parameter in benign prostatic hyperplasia (BPH) and one of the major concepts identified by the patients to be important is related to sexuality after BPH therapy. The impact on sexuality resulting from the various treatment modalities of BPH, either medical, surgical or instrumental has been too often neglected in the past and poorly investigated. The present article reviews the influence on sexual function of current therapies for symptomatic BPH.

Beers versus STOPP criteria in polyharmacy community-dwelling older patients

Objective: To assess potentially inappropriate prescribing (PIP) using Beers (2012 version) and STOPP (2008 version) criteria in polypharmacy, community-dwelling, older patients. Methods: From the information collected in the invoicing data of the prescriptions and the electronic medical records, a sample was selected of 223 ≥ 65-year-old patients who were taking simultaneously 10 or more drugs per day. Beers and STOPP criteria were separately applied, and the results obtained with the two methods were compared. Results: A total of 141 (63.2%) patients presented at least one Beers criterion. The two most frequently observed Beers criteria independent of diagnosis were the use of benzodiazepines and the use of non-COX-2-selective non-steroidal anti-inflammatory drugs. With regard to Beers criteria considering diagnosis, the most frequent were the use of anticholinergic drugs in patients with lower urinary tract symptoms or benign prostatic hyperplasia, and the use of benzodiazepines, antipsychotics, Zolpidem or H2-antihistamines, in patients with dementia or cognitive impairment. A total of 165 (73.9%) patients had at least one PIP according to the STOPP criteria. Duplicate drug classes and long-term use of long-acting benzodiazepines were the two most frequent STOPP criteria. Discussion: Our study identified a high frequency of PIP in poly-medicated community-dwelling older patients. Simultaneous application of Beers and STOPP criteria represents a useful tool to improve prescribing in this population group.

Identificación de infección del tracto urinario mediante el examen elemental microscópico de orina en los habitantes de la Comuna Sunicorral Tambo-Cañar 2015

Antecedentes: La infección del tracto urinario es una de las patologías más comunes y forma parte de las principales causas de consulta médica y hospitalización. (1, 2) Es frecuente en mujeres, personas con vida sexual activa, mujeres embarazadas y diabéticos. El 10 al 20 % de mujeres entre los 18 y 40 años experimentan infección del tracto urinario, en hombres mayores a 50 años se asocia a problemas por hiperplasia prostática y en personas de la tercera edad la frecuencia es similar tanto en hombres como en mujeres. (1) Objetivo: Identificar infección de vías urinarias mediante el examen elemental y microscópico de orina en los habitantes de la comuna Sunicorral Tambo- Cañar 2015. Metodología: Estudio de tipo descriptivo transversal en habitantes la comuna Sunicorral, la muestra fue de 202 personas. Luego firmar del consentimiento y asentimiento informado, se llenó las encuesta con información relacionada a las variables de estudio, se recolectaron las muestras de orina y el análisis se realizó en el laboratorio del Centro de Diagnóstico de la Universidad de Cuenca, los datos obtenidos fueron analizado en el programa SPSS y Microsoft Excel y presentados en tablas y gráficos estadísticos. Resultados: De 202 muestras el 15% reportó infección del tracto urinario, el 87,1% fue mujer, el 25,8% correspondió a la edad de 10 a 19 años, el 64,6% realizó su higiene intima pasando uno o más días, el 62,0% tiene actividad sexual siendo un factor importante.

Mercadeo farmacéutico de productos bajo prescripción: efectos de las estrategias Direct-to-Consumer-Advertising en el comportamiento de los consumidores y de prescripción de los médicos

Este proyecto se origina en el interés de analizar las estrategias actuales de promoción de productos farmacéuticos, en el marco del debate sobre el efecto persuasivo o informativo que la publicidad directa tiene sobre los consumidores. El objetivo es determinar el efecto de las estrategias de promoción directa para consumidores (Direct to Consumer Advertising [DTCA]) sobre el comportamiento de compra de pacientes y las prescripciones que formulan los médicos en el mercado de productos bajo receta en Estados Unidos. Para tal fin se propuso realizar una monografía que incluyera una revisión de literatura de carácter argumentativo, consultando información de nivel secundario en bases de datos científicas cuyos contenidos obedecieran a criterios metodológicos determinados por la naturaleza argumentativa del estudio. Adicionalmente, se analizó el debate sobre estos anuncios a la luz de dos estudios realizados a pacientes con cáncer de seno, próstata y colon, liderados por el Pennsylvania Cancer Registry con los productos biofarmacéuticos Avodart® y Flomax®. Finalmente, la investigación se fundamentó en la relación del mercado farmacéutico en Estados Unidos con cada uno de los agentes que interactúan en él; consumidores, médicos prescriptores y empresas farmacéuticas, así como el valor que estos comparten través de dichas interacciones. Se concluye que el comportamiento de compra de los consumidores está determinado por la naturaleza de la patología que padecen y el comportamiento de los profesionales que prescriben a sus pacientes se ve influenciado por los anuncios DTCA.

Identificazione di un nuovo meccanismo microRNA-dipendente di resistenza all'inibizione della via di segnale PI3K/AKT nel carcinoma della prostata

Benché le alterazioni della via PI3K/AKT siano molto sudiate a causa del loro ruolo nella tumorigenesi, e rappresentino pertanto un importante bersaglio terapeutico, i risultati di numerosi studi clinici con inibitori di PI3K o AKT sono finora deludenti, in parte a causa dell’insorgenza di resistenza provocata dall'interruzione dei circuiti di feedback negativo. In questo studio, abbiamo scoperto che l’inattivazione farmacologica di AKT in cellule di carcinoma prostatico PC3 porta alla down-regolazione di un microRNA con funzione di oncosoppressore, il miR-145-5p, e ad un drammatico aumento di espressione di uno dei suoi geni target, cioè N/KRas. E’ interessante sottolineare che questo microRNA è considerato un marker di progressione metastatica nel carcinoma prostatico, il cui livello di espressione aiuta a discriminare tra pazienti con iperplasia prostatica benigna e cancro alla prostata. Inoltre, la bassa espressione di miR-145 aumenta il rischio di progressione della malattia da localizzata a metastatica. La conferma che l’aumento di Ras, osservato sia in termini di mRNA che di proteina, è dipendente dalla caduta del miR-145-5p, è stata poi ottenuta tramite un modello di PC3 ingegnerizzate per ottenere il silenziamento inducibile del miR-145-5p. Tramite un array di fosfoproteine siamo poi stati in grado di verificare che l’aumento di Ras provoca la riattivazione della cascata di PI3K/AKT e di ERK. Dal punto di vista meccanicistico, quindi, lo studio ha portato all’identificazione di un nuovo meccanismo di resistenza adattativa, in cui l’inattivazione di AKT provoca una caduta del miR-145-5p che, a sua volta, aumenta l’espressione di Ras e riattiva il signaling di PI3K, rendendo inefficace il trattamento farmacologico. Questi risultati sono particolarmente rilevanti alla luce di recenti studi (NCT04493853; NCT03072238; NCT02525068) e di trial clinici in corso (NCT04737109; NCT03673787), basati sulla somministrazione combinata di inibitori della sintesi degli androgeni con gli inibitori di AKT capitasertib o ipatasertib.

Identification of the glycosaminoglycan keratan sulfate in the prostatic secretory cell

BACKGROUND. Prostate secretory granules (PSG) represent the basic secretory unit of the prostate gland, containing many of its exocrine proteases. Recent analysis of intraluminal corpora amylacea, a proposed by-product of PSG secretion, detected sulfated glycosaminoglycans (GAG) possibly keratan sulfate (KS),indicating a secretory mechanism for GAG in the human prostate surface epithelial cell. METHODS. Immunostains using anti-KS and anti-prostate-specific antigen (PSA) were evaluated on 10 sequential radical prostatectomy specimens, three of which had received neoadjuvant antiandrogen therapy. Extracts of normal secretory tissue as well as a sample composed almost entirely of prostatic stroma were subjected to Western blot analysis, using the same antibody panel. RESULTS. Keratan sulfate secretion from the normal prostate epithelial cell has been confirmed and correlates, as does PSA, with the presence of cytoplasmic PSG. No such correlation exists in most adenocarcinomas or in benign epithelium after androgen ablation. Western blot analyses confirmed tissue immunostains and demonstrated a secretory proteoglycan of 70-95 kDa. CONCLUSIONS. Recognition of PSG heralds a novel secretory mechanism within the human prostate gland that is linked to the secretion of KS. The role of KS in normal prostate secretion remains unknown, although it appears downregulated in neoplastic and androgen-ablated cells. (C) 2000 Wiley-Liss, Inc.

Immunohistochemical Characterization of Canine Prostatic Intraepithelial Neoplasia

The development of prostate cancer is believed to be a multistep process, progressing sequentially from normal epithelium, to prostatic intraepithelial neoplasia (PIN) and, finally, to invasive neoplasia. Malignant stem cells within the basal cell layer of the prostatic epithelium are believed to play an important role in the failure of androgen-ablation therapy that occurs in the most advanced form of prostate cancer. The aim of the present study was to immunohistochemically characterize the lesions of canine PIN. Prostatic tissue from five dogs with PIN was compared with normal prostate tissue from nine further dogs. There was an increase in the number of basal epithelial cells in lesions consistent with PIN as defined by expression of the nuclear protein p63. These lesions had elevated expression of proliferating cell nuclear antigen (PCNA) and heterogeneous labelling for the nuclear androgen receptor (AR). These findings suggest that the basal cells present in PIN may play a role in canine prostate carcinogenesis and that the proliferation of these cells occurs despite the heterogeneous expression of the AR. (C) 2009 Elsevier Ltd. All rights reserved.

CYR61, a cellular proliferation marker in dogs with prostatic disease

The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted. (c) 2006 Elsevier B.V. All rights reserved.

Oral exposure to methylmercury modifies the prostatic microenvironment in adult rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Collagen type VI is a component of the extracellular matrix microfibril network of the prostatic stroma

Stroma-epithelium relationships are of great relevance in prostatic morphogenesis and physiology, However, little knowledge exists about either stromal cells or extracellular matrix composition and arrangement in this system, Ultrastructural analysis revealed the existence of a microfibrillar system which occupies large areas of the rat prostatic stroma, In this work, we have applied immunocytochemistry and an ATP treatment for the ultrastructural identification of collagen type VI microfibrils, aiming at examining its participation in the prostatic microfibrillar network. Immunocytochemistry was also extended to a human case of prostatic nodular hyperplasia, Both methods succeeded in identifying collagen type VI in the rat ventral prostate, Collagen type VI is evenly distributed throughout the stroma but mainly associated with the basal lamina, collagen fibrils, and around the stromal cells, the use of ATP treatment allowed for the discrimination between collagen type VI and elastin-associated microfibrils, and demonstrated that these two classes of microfibrils establish an extended, mixed, and open network. The same aspects of association with the basal lamina, with stromal cells (particularly with smooth muscle cells), and with fibrillar components of the stroma were observed in the human tissue, We suggest that the collagen type VI and elastin-associated microfibril system may be involved in the control of some aspects of cellular behavior and may also play a structural role, maintaining the organ integrity after the deformations occurring under smooth muscle contraction.