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An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

Purpose: 5 alpha-Reductase inhibitors reduced the risk of prostate cancer in 25% in 2 randomized trials but increased the risk of Gleason 8-10 at biopsy. One explanation is that 5 alpha-reductase inhibitors induce morphological changes in prostate cancer cells similar to higher Gleason grades but without its adverse biology. We compared risk of prostate cancer death between men on 5 alpha-reductase inhibitors and men not on 5 alpha-reductase inhibitors before prostate cancer diagnosis in each Gleason Grade Group. Materials and Methods: Prostate Cancer data Base Sweden consists of linkages between the National Prostate Cancer Register, the Prescribed Drug Registry and the Cause of Death Registry. Of 89,227 men diagnosed with prostate cancer between July 2007 and December 2016, 5,816 had been on 5 alpha-reductase inhibitors for more than 180 days before the date of diagnosis. Followup ended in December 2018. A Cox proportional hazard model was used to assess hazard ratio for prostate cancer death. Adjustments for age, comorbidity, education and curative treatment were made. Men with high risk cancer were stratified according to Gleason Grade Group. Results: In men with high risk cancer the risk of prostate cancer death was similar among 5 alpha-reductase inhibitor users and nonusers, with Gleason Grade Group 1 HR 1.02 (95% CI 0.53-1.95), Gleason Grade Group 2 HR 1.04 (95% CI 0.65-1.69), Gleason Grade Group 3 HR 1.27 (95% CI 0.89-1.80), Gleason Grade Group 4 HR 0.95 (95% CI 0.76-1.18) and Gleason Grade Group 5 HR 0.99 (95% CI 0.83-1.19), for 5 alpha-reductase inhibitor users vs nonusers. Conclusions: We found no evidence that 5 alpha-reductase inhibitors affect Gleason grading as no difference in mortality was observed among 5 alpha-reductase inhibitor users and nonusers in each Gleason group.

Context: Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective: To study whether epigenetic modifications occur in PFS patients. Methods: Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results: SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions: For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

Hidradenitis suppurativa is a severe and debilitating dermatologic disease. Clinical management is challenging and consists of both medical and surgical approaches, which must often be combined for best outcomes. Therapeutic approaches have evolved rapidly in the last decade and include the use of topical therapies, systemic antibiotics, hormonal therapies, and a wide range of immunomodulating medications. An evidence-based guideline is presented to support health care practitioners as they select optimal medical management strategies and is reviewed in this second part of the management guidelines. A therapeutic algorithm informed by the evidence available at the time of the review is provided.

Hidradenitis suppurativa is a chronic inflammatory disorder affecting hair follicles, with profoundly negative impact on patient quality of life. Evidence informing ideal evaluation and management of patients with hidradenitis suppurativa is still sparse in many areas, but it has grown substantially in the last decade. Part I of this evidence-based guideline is presented to support health care practitioners as they select optimal management strategies, including diagnostic testing, comorbidity screening, and both complementary and procedural treatment options. Recommendations and evidence grading based on the evidence available at the time of the review are provided.

Context: Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective: To study whether epigenetic modifications occur in PFS patients. Methods: Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results: SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions: For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

Over 36,000 units of blood are transfused every day in the US. With nearly 40% of the population eligible to donate, we may frequently treat potential blood donors. We reviewed the American Red Cross and World Health Organization’s restrictions on blood donation. Multiple drugs used, and diseases treated in dermatology, are associated with blood donation restrictions. Understanding these restrictions may help us better educate our patients.

Over 36,000 units of blood are transfused every day in the US. With nearly 40% of the population eligible to donate, we may frequently treat potential blood donors. We reviewed the American Red Cross and World Health Organization’s restrictions on blood donation. Multiple drugs used, and diseases treated in dermatology, are associated with blood donation restrictions. Understanding these restrictions may help us better educate our patients.

Over 36,000 units of blood are transfused every day in the US. With nearly 40% of the population eligible to donate, we may frequently treat potential blood donors. We reviewed the American Red Cross and World Health Organization’s restrictions on blood donation. Multiple drugs used, and diseases treated in dermatology, are associated with blood donation restrictions. Understanding these restrictions may help us better educate our patients.

Este trabajo consiste en una revisión actual sobre la alopecia y sus posibles tratamientos. La alopecia es un problema hoy en día entre la población, que se define como la disminución o pérdida del cabello, tanto de una manera específica como generalizada. Hay una serie de factores que pueden producir alopecia: Falta de oligoelementos, estrés, hormonas, embarazo y parto, medicamentos, humedad, oxidantes y reductores, radiación solar y determinadas patología autoinmunes. Existen diferentes tipos de alopecia, siendo las principales la androgénica y la areata. La primera es de origen hormonal y la segunda de etiología desconocida aunque parecen tener gran influencia factores genéticos y autoinmunes. Para evitar la caída del cabello hay tratamientos farmacológicos, siendo los más efectivos el minoxidil (se usa en los dos tipos más importantes), el finasteride (principalmente en la alopecia androgénica) y los corticoides (fundamentales en el tratamiento de la alopecia areata). Sin embargo, la terapia farmacológica tiene el inconveniente de que presenta reacciones adversas en la mayoría de los casos. Por ello, hemos realizado una recopilación bibliográfica de los tratamientos naturales que existen para evitar la caída del cabello, encontrándose entre ellos vitaminas, minerales, aminoácidos y plantas medicinales. Estas terapias pueden utilizarse como una alternativa a la farmacología, o en muchos casos como coadyuvantes, evitando así muchos de sus efectos secundarios.

IntroductionCurrently, only topical minoxidil (MNX) and oral finasteride (FNS) are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of androgenetic alopecia. Although FNS is efficacious for hair regrowth, its systemic use is associated with side effects limiting long-term utilization. Exploring topical FNS as an alternative treatment regimen may prove promising.MethodsA search was conducted to identify studies regarding human in vivo topical FNS treatment efficacy including clinically relevant case reports, randomized controlled trials (RCTs), and prospective studies.ResultsSeven articles were included in this systematic review. In all studies, there was significant decrease in the rate of hair loss, increase in total and terminal hair counts, and positive hair growth assessment with topical FNS. Both scalp and plasma DHT significantly decreased with application of topical FNS; no changes in serum testosterone were noted.ConclusionPreliminary results on the use of topical FNS are limited, but safe and promising. Continued research into drug-delivery, ideal topical concentration and application frequency, side effects, and use for other alopecias will help to elucidate the full extent of topical FNS' use. J Drugs Dermatol. 2018;17(4):457-463..

Benigna hiperplazija prostate je jedno od najčešćih oboljenja kod muškaraca starijih od 50 godina. Postoji više strategija u terapiji benigne hiperplazije koje se razlikuju po mogućnosti primjene i ekonomskoj isplativosti u zavisnosti od socio- ekonomskih uslova svake pojedinačne zemlje. Cilj ove studije je da pokaže koje su terapijske opcije sa aspekta odnosa troškova i efikasnosti najopravdanije za korišćenje u Crnoj Gori. ID Metod: U izradi studije su primjenjene tri različite metode istraživanja (triangulacioni pristup): farmakoekonomsko modeliranje, studija troškova i kvalitativna studija metodom intervjua. Modeliranje je sprovedeno kroz izradu farmakoekonomskog Markovljevog modela, kojim je upore odnos troškova i efikasnosti dutasterida i finasterida. Markovljev model je razvijen na osnovu podataka iz literature o efektivnosti i na osnovu troškova liječenja u Crnoj Gori. Trajanje jednog ciklusa u modelu je jedna godina a vremenski horizont praćenja 20 godina. Za troškove i ishode korišćena je perspektiva društva i oni su diskontovani po stopi od 3% godišnje. Urađena je Monte Karlo mikrosimulacija modela sa 1.000 virtuelnih pacijenata. Studija troškova je sprovedena tzv. “microcosting” pristupom, kroz analizu istorija bolesti pacijenata liječenih u Opštoj bolnici Nikšić. Metoda intervjua je primjenjena na osobama koje su ključne za donošenje odluka u zdravstvenom sistemu Crne Gore. Ova studija je pokazala da dutasterid ima bolji odnos troškova i kliničke efikasnosti u odnosu na finasterid, pa je finansiranje dutasterida od strane Fonda za zdravstveno osiguranje Crne Gore farmakoekonomski opravdano. Ova studija će doprinijeti da Fond za zdravstveno osiguranje Crne Gore izabere farmakoekonomski najpovoljniju strategiju liječenja benigne hiperplazije prostate što će omogućiti bolju terapiju ovog oboljenja za pacijente u Crnoj Gori., Benign prostatic hyperplasia is one of the most common diseases in men older than 50 years. There are several strategies for the treatment of benign prostatic hyperplasia which differ in their application possibilities and economic profitability depending on the socioeconomic conditions of each country. The aim of this study is to demonstrate that the therapeutic options in terms of cost and efficiency most apt to use in Montenegro. Method: In the preparation of the study were applied three different methods of research (triangulation access): pharmacoeconomic modeling, costs study and a qualitative study through interviews. Modeling was carried out through the creation of Mark model, which is comparing the cost-effectiveness of dutasteride and finasteride. A Mark model was developed using data from the literature on the effectiveness of and on the basis of the cost of treatment in Montenegro. The duration of one cycle in the model is the one year, time horizon and follow-up for 20 years. For costs and outcomes societal perspective was used and they are discounted at a rate of 3% per annum. We performed Monte Carlo microsimulation with 1000 virtual patients. The study was carried out socalled costs. "Microcosting" approach, through the analysis of medical histories of patients treated at the General Hospital Niksic. Interview method was applied to the persons who are the key decision-making in the health system of Montenegro. This study demonstrated that dutasteride has a better ratio of cost and clinical effectiveness compared to finasteride so financing of dutasteride by the Fund for health insurance Montenegro pharmacoeconomically justified. This study will contribute to the Health Insurance Fund of Montenegro chooses the most favorable pharmacoeconomic strategy of treating benign prostatic hyperplasia which will enable better therapy of this disease for patients in Montenegro.

BackgroundA previous analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) reported 82% overall prevalence of intraprostatic inflammation and identified a link between inflammation and higher-grade prostate cancer and serum PSA. Here, we studied these associations in the PCPT finasteride arm.MethodsProstate cancer cases (N = 197) detected either on a clinically indicated biopsy or on protocol-directed end-of-study biopsy, and frequency-matched controls (N = 248) with no cancer on an end-of-study biopsy were sampled from the finasteride arm. Inflammation in benign prostate tissue was visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used for statistical analysis.ResultsIn the finasteride arm, 91.6% of prostate cancer cases and 92.4% of controls had at least one biopsy core with inflammation in benign areas (P < 0.001 for difference compared with placebo arm). Overall, the odds of prostate cancer did not differ by prevalence [OR, 0.90; 95% confidence interval (CI), 0.44-1.84] or extent (P trend = 0.68) of inflammation. Inflammation was not associated with higher-grade disease (prevalence: OR, 1.07; 95% CI, 0.43-2.69). Furthermore, mean PSA concentration did not differ by the prevalence or extent of inflammation in either cases or controls.ConclusionThe prevalence of intraprostatic inflammation was higher in the finasteride than placebo arm of the PCPT, with no association with higher-grade prostate cancer.ImpactFinasteride may attenuate the association between inflammation and higher-grade prostate cancer. Moreover, the missing link between intraprostatic inflammation and PSA suggests that finasteride may reduce inflammation-associated PSA elevation.

The enzyme 5 alpha-reductase (5 alpha R) catalyzes the conversion of progesterone and testosterone into neuroactive steroids implicated in a wide array of behavioral functions. The prototypical 5 alpha R inhibitor, finasteride (FIN), is clinically approved for the treatment of androgenic alopecia and benign prostatic hyperplasia. Recent evidence has shown that FIN, albeit generally well tolerated, can induce untoward psychological effects in a subset of patients; furthermore, this drug may have therapeutic efficacy for a number of different neuropsychiatric conditions, ranging from Tourette syndrome to schizophrenia. In rat models of these conditions, FIN has been shown to block the effects of dopamine receptors in the nucleus accumbens (NAcc), a key terminal of the dopamine mesolimbic system. The biological underpinnings of these effects, however, remain mostly elusive. To elucidate the neurochemical networks that may be responsible for the behavioral effects of FIN, we evaluated the proteomic profile of the NAcc following acute (100 mg/kg, IP) and subchronic (7 days; 100 mg/kg/day, IP) treatment with this drug, in comparison with vehicle treatment (n=5/group). Two-dimensional electrophoresis (2-DE) analysis coupled to mass spectrometry revealed significant changes in the expression of nine proteins (CRMP2, PSMD1, STX18, KCNO, CYP255, GABRP, GABT, PRPS1, CYP2B3), which were further analyzed by ontological classification (PANTHER). These results point to a number of novel potential chemical targets of FIN, and may help elucidate the underpinnings of FIN's behavioral effects and therapeutic potential for neuropsychiatric disorders. (C) 2016 Elsevier Ltd. All rights reserved.

BackgroundTelomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy.MethodsTelomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer.ResultsMen with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86-5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47-2.80; P = 0.77) cells.ConclusionsThese findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essenti

Hepatiĉna encefalopatija (HE) predstavlja neuropsihijatrijski sindrom, koji se razvija kao posledica akutne ili hroniĉne insuficijencije jetre. Za ispitivanje patogeneze HE koriste se razliĉiti eksperimentalni modeli, ukljuĉujući model izazvan portno-kavnim šantom, stenozom portne vene, modele izazvane hepatotoksiĉnim agensima (tioacetamid, D-galaktozamin, paracetamol, azoksimetan, ugljen-tetrahlorid) i modele ciroze jetre. U razvoju HE kljuĉnu ulogu ima hiperamonijemija, a mehanizmi ukljuĉeni u patogenezu HE ukljuĉuju: citotoksiĉni edem mozga, poremećaje neurotransmisije (preteţno glutamatergiĉke i GABA-ergiĉke), energetske poremećaje, oksidacijski stres, mitohondrijsku disfunkciju i neuroinflamaciju. U HE povećava se sinteza neurosteroida, koji pozitivnom alosternom modulacijom receptora za gama-aminobuternu kiselinu (GABAA receptora) pojaĉavaju efekte GABA u centralnom nervnom sistemu. Finasterid, inhibitor 5α-reduktaze i sinteze neurosteroida, potencijalno moţe menjati tok HE. Ciljevi ove disertacije su bili: da se ispitaju bihejvioralne i elektroencefalografske (EEG) promene u HE izazvanoj tioacetamidom kod pacova; da se odrede parametri oksidacijskog stresa i antioksidacijske zaštite, aktivnost acetilholinesteraze (AchE) i ekspresiju ćelijskih markera u razliĉitim moţdanim regionima u intoksikaciji tioacetamidom; da se ispita uticaj finasterida na bihejvioralne, EEG i ćelijske promene u HE izazvanoj tioacetamidom kod pacova. U cilju ispitivanja efekata tioacetamida (TAA) na ponašanje, EEG i ćelijske promene muţjaci Wistar pacova su podeljeni u sledeće grupe: 1. kontrolna grupa (n=8); 2. eksperimentalna grupa tretirana TAA na dozno zavisan naĉin: TAA300 (300 mg/kg, n=8), TAA600 (600 mg/kg, n=10) i TAA900 (900 mg/kg, n=18). Dnevne doze TAA (300 mg/kg) su primenjene tokom jednog (TAA300), dva (TAA600) ili tri uzastopna dana (TAA900). U cilju ispitivanja uticaja finasterida na HE izazvanu TAA-om, ţivotinje su podeljene u sledeće grupe: 1. kontrolna grupa (n=8); 2., Hepatic encephalopathy (HE) represents a neuropsychiatric syndrome, that appears as a consequence of acute or chronic liver failure. Various experimental models are used for the investigation of the pathogenesis of HE, including porto-caval shunt, portal vein stricture, models induced by hepatotoxic agents (thioacetamide, D-galactosamine, acetaminophen, azoxymethane, carbon tetrachloride) and models of liver cirrhosis. Hyperammonemia has a pivotal role in the development of HE, and mechanisms involved in the pathogenesis of HE include: cytotoxic brain edema, alterations in neurotransmission (especially glutamatergic and GABAergic), energy disturbances, oxidative stress, mitochondrial dysfunction and neuroinflammation. The synthesis of neurosteroids is increased in HE and by positive allosteric modulation of gamma-aminobutyric acid (GABAA) receptors they potentiate the effects og GABA in the central nervous system. Finasteride, 5α-reductase and neurosteroid synthesis inhibitor, may potentially modulate the course of HE. The aims of this dissertation were: to investigate the behavioral and electroencephalographic (EEG) changes in thioacetamide-induced HE in rats; to determine the parameters of oxidative stress and antioxidative protection, the activity of acetylcholinesterase (AchE) and cellular marker expression in various brain regions; to investigate the effects of finasteride on behavioral, EEG and cellular changes in thioacetamide-induced HE in rats. In order to investigate the effects of thioacetamide (TAA) on the behavior, EEG and cellular changes male Wistar rats were divided into the following groups: 1. control; 2. experimental group treated with TAA in a dose-dependent manner: TAA300 (300 mg/kg; n=8), TAA600 (600 mg/kg; n=10) and TAA900 (900 mg/kg; n=18). Daily doses of TAA (300 mg/kg) were administered once (TAA300), twice (TAA600) or three times (TAA900) in subsequent days. In order to investigate the effects of finasteride on TAA-induced HE, the animals

1. The metabolite profile of the 5 alpha-reductase type II inhibitor finasteride has been studied in pig plasma, urine and bile using high-resolution mass spectrometry. The porcine biotransformation products were compared to those formed by human liver microsomes and to literature data of recently identified human in vivo metabolites. The objective of this study was to gain further evidence for the validity of using pigs for advanced, invasive drug-drug interaction studies that are not possible to perform in humans. 2. The use of high-resolution mass spectrometry with accurate mass measurements enabled identification of the metabolites by calculation of their elemental compositions as well as their fragmentation patterns. 3. There was an excellent match between the porcine and human metabolic profiles, corroborating the pig as a model of human drug metabolism. The glucuronides of the two recently described human hydroxylated metabolites MX and MY and the carboxylated metabolite M3 were identified as the major biotransformation products of finasteride in pig urine and bile. 4. Furthermore, the CYP enzymes involved in the formation of the hydroxylated metabolites were characterized. Human recombinant CYP3A4 could produce the two major hydroxylated metabolites MX and MY, whereas human recombinant CYP2D6 formed MY only.

BackgroundThe Prostate Cancer Prevention Trial (PCPT)-a randomized placebo-controlled study of the efficacy of finasteride in preventing prostate cancer-offered the opportunity to prospectively study effects of finasteride and other covariates on the health-related quality of life of participants in a multiyear trial.MethodsWe assessed three health-related quality-of-life domains (measured with the Health Survey Short Form-36: Physical Functioning, Mental Health, and Vitality scales) via questionnaires completed by PCPT participants at enrollment (3 months before randomization), at 6 months after randomization, and annually for 7 years. Covariate data obtained at enrollment from patient-completed questionnaires were included in our model. Mixed-effects model analyses and a cross-sectional presentation at three time points began at 6 months after randomization. All statistical tests were two-sided.ResultsFor the physical function outcome (n = 16 077), neither the finasteride main effect nor the finasteride interaction with time were statistically significant. The effects of finasteride on physical function were minor and accounted for less than a 1-point difference over time in Physical Functioning scores (mixed-effect estimate = 0.07, 95% confidence interval [CI] = -0.28 to 0.42, P = .71). Comorbidities such as congestive heart failure (estimate = -5.64, 95% CI = -7.96 to -3.32, P < .001), leg pain (estimate = -2.57, 95% CI = -3.04 to -2.10, P < .001), and diabetes (estimate = -1.31, 95% CI = -2.04 to -0.57, P < .001) had statistically significant negative effects on physical function, as did current smoking (estimate = -2.34, 95% CI = -2.97 to -1.71, P < .001) and time on study (estimate = -1.20, 95% CI = -1.36 to -1.03, P < .001). Finasteride did not have a statistically significant effect on the other two dependent variables, mental health and vitality, either in the mixed-effects analyses or in the cross-sectional analysis at any of the three time

The neurosteroid allopregnanolone (AP) is a GABAergic agonist that suppresses central nervous system (CNS) activity in the adult brain, and by reducing excitotoxicity is considered to be neuroprotective. A role for neurosteroids in the developing brain, particularly in late gestation, is still debated. The aim of this study was to investigate effects on proliferation and cell death in the brain of late gestation fetal sheep after inhibition of AP synthesis using finasteride, a 5alpha-reductase type 2 (5alpha-R2) inhibitor. Catheters were implanted in fetal sheep at ~125 days of gestation. At 3-4 days postsurgery, fetuses received infusions of either finasteride (20 mg/kg/h; n=5), the AP analogue alfaxalone (5 mg/kg/h; n=5), or finasteride and alfaxalone together (n=5). Brains were obtained at 24 h after infusion to determine cell death (apoptotic or necrotic) and cell proliferation in the hippocampus and cerebellum, areas known to be susceptible to excitotoxic damage. Finasteride treatment significantly increased apoptosis (activated caspase-3 expression) in hippocampal CA3 and CA1, and cerebellar molecular and granular layers, an effect abolished by co-infusion of alfaxalone and finasteride. Double-label immunohistochemistry showed that both neurons and astrocytes were caspase-3 positive. Finasteride treatment also increased the number of dead (pyknotic) cells in the hippocampus and cerebellum (Purkinje cells), but not when finasteride+alfaxalone was infused. Cell proliferation (Ki-67-immunoreactivity) increased after finasteride treatment; double-labeling showed the majority of Ki-67-positive cells were astrocytes. Thus, steroids such as AP appear to influence the constitutive rate of apoptosis and proliferation in the hippocampus and cerebellum of the fetal brain, and suggest an important role for neurosteroids in the development of the brain. © 2009 IBRO.

The neurosteroid allopregnanolone (AP) is a GABAergic agonist that suppresses central nervous system (CNS) activity in the adult brain, and by reducing excitotoxicity is considered to be neuroprotective. A role for neurosteroids in the developing brain, particularly in late gestation, is still debated. The aim of this study was to investigate effects on proliferation and cell death in the brain of late gestation fetal sheep after inhibition of AP synthesis using finasteride, a 5alpha-reductase type 2 (5alpha-R2) inhibitor. Catheters were implanted in fetal sheep at ~125 days of gestation. At 3-4 days postsurgery, fetuses received infusions of either finasteride (20 mg/kg/h; n=5), the AP analogue alfaxalone (5 mg/kg/h; n=5), or finasteride and alfaxalone together (n=5). Brains were obtained at 24 h after infusion to determine cell death (apoptotic or necrotic) and cell proliferation in the hippocampus and cerebellum, areas known to be susceptible to excitotoxic damage. Finasteride treatment significantly increased apoptosis (activated caspase-3 expression) in hippocampal CA3 and CA1, and cerebellar molecular and granular layers, an effect abolished by co-infusion of alfaxalone and finasteride. Double-label immunohistochemistry showed that both neurons and astrocytes were caspase-3 positive. Finasteride treatment also increased the number of dead (pyknotic) cells in the hippocampus and cerebellum (Purkinje cells), but not when finasteride+alfaxalone was infused. Cell proliferation (Ki-67-immunoreactivity) increased after finasteride treatment; double-labeling showed the majority of Ki-67-positive cells were astrocytes. Thus, steroids such as AP appear to influence the constitutive rate of apoptosis and proliferation in the hippocampus and cerebellum of the fetal brain, and suggest an important role for neurosteroids in the development of the brain. © 2009 IBRO.

BackgroundThe Prostate Cancer Prevention Trial (PCPT)-a randomized placebo-controlled study of the efficacy of finasteride in preventing prostate cancer-offered the opportunity to prospectively study effects of finasteride and other covariates on the health-related quality of life of participants in a multiyear trial.MethodsWe assessed three health-related quality-of-life domains (measured with the Health Survey Short Form-36: Physical Functioning, Mental Health, and Vitality scales) via questionnaires completed by PCPT participants at enrollment (3 months before randomization), at 6 months after randomization, and annually for 7 years. Covariate data obtained at enrollment from patient-completed questionnaires were included in our model. Mixed-effects model analyses and a cross-sectional presentation at three time points began at 6 months after randomization. All statistical tests were two-sided.ResultsFor the physical function outcome (n = 16 077), neither the finasteride main effect nor the finasteride interaction with time were statistically significant. The effects of finasteride on physical function were minor and accounted for less than a 1-point difference over time in Physical Functioning scores (mixed-effect estimate = 0.07, 95% confidence interval [CI] = -0.28 to 0.42, P = .71). Comorbidities such as congestive heart failure (estimate = -5.64, 95% CI = -7.96 to -3.32, P < .001), leg pain (estimate = -2.57, 95% CI = -3.04 to -2.10, P < .001), and diabetes (estimate = -1.31, 95% CI = -2.04 to -0.57, P < .001) had statistically significant negative effects on physical function, as did current smoking (estimate = -2.34, 95% CI = -2.97 to -1.71, P < .001) and time on study (estimate = -1.20, 95% CI = -1.36 to -1.03, P < .001). Finasteride did not have a statistically significant effect on the other two dependent variables, mental health and vitality, either in the mixed-effects analyses or in the cross-sectional analysis at any of the three time

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

In this project, we investigated the potential of targeting the androgen receptor and the 5(alpha)-reductase simultaneously in prostate cancer prevention. We report that this combined androgen receptor blockade approach produced a synergistic effect on tumor growth inhibition by in vitro and in vivo. We have also identified that methylseleninic acid (MSA) activates FOXO1 and FOXO1 activation plays an important role in mediating apoptosis induction and androgen receptor suppression by MSA. In summary, the research support by this grant suggests a novel and effective approach for managing early stage prostate cancer and contributes to a better understanding of the anticancer effects of MSA., The original document contains color images.

The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and

The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and

The aim of this study was to investigate what the consequences of induced drug metabolism, caused by St. John's wort (SJW, Hypericum perforatum) treatment, would have on the plasma, biliary and urinary pharmacokinetics of finasteride and its two previously identified phase I metabolites (hydroxy-finasteride and carboxy-finasteride). Twelve healthy men were administered 5mg finasteride directly to the intestine via a catheter with a multi-channel tubing system, Loc-I-Gut, before and after 14 days SJW (300mg b.i.d, hyperforin 4%) treatment. Bile samples were withdrawn via the Loc-I-Gut device from the proximal jejunum. LC-ESI-MS/MS was used to analyze finasteride and its metabolites in plasma, bile and urine. HPLC-UV was used to analyze hyperforin in plasma. The herbal treatment significantly reduced the peak plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC(0-24h)) and the elimination half-life (t(1/2)) of finasteride. The geometric mean ratios (90% CI) were 0.42 (0.36-0.49), 0.66 (0.56-0.79) and 0.54 (0.48-0.61), respectively. Finasteride was excreted unchanged to a minor extent into bile and urine. Hydroxy-finasteride was not detected in plasma, bile or urine. Carboxy-finasteride was quantified in all three compartments and its plasma pharmacokinetics was significantly affected by SJW treatment. Hyperforin concentration in plasma was 21+/-7ng/ml approximately 12h after the last dose of the 14 days SJW treatment. In conclusion, SJW treatment for 2 weeks induced the metabolism of finasteride and caused a reduced plasma exposure of the drug. New knowledge was gained about the biliary and urinary excretion or the drug and its metabolites.

In many tumors, the actively dividing cells account for only a small proportion of the total, with the remainder of the cells being in a quiescent state or G0. Indeed, tumor cell population in G0 ranges from 70-95% and the quiescent cell population of tumors poses a barrier to the success of many cancer therapies. Numerous studies demonstrate that non-steroidal antiinflammatory drugs (NSAIDs) hold significant promise as anti-cancer therapeutics. We started identifying now the best of NSAIDs therapy for apoptosis induction of quiescent ovarian cancer cells. In this report we show that structurally unrelated NSAIDS induces apoptosis in quiescent ovarian cancer cells. Strong inducers of apoptosis included flufenamic acid, flurbiprofen, celebrex and finasteride, whereas treatment with ibuprofen in low levels of apoptosis. Additionally, the spectrum of NSAIDs obtained in this analysis differs from the spectrum of NSAIDs obtained by our group for induction of apoptosis in proliferative ovarian cancer cells. Our results offer a multitude of novel entry points for drug development and will provide opportunities for a rational design of new combination treatment modalities for ovarian cancer.

Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5α-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism – such as decreased muscle and bone mass and decreased cognition and libido – has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited.

Early stage prostate cancer depends heavily on androgen signaling for growth and clonal expansion. In the previous report, we have demonstrated the combination of selenium, which down-regulates androgen receptor, and finasteride, a 5alpha-reductase inhibitor, has a synerigistic effect in inhibiting the growth of prostate cancer cells, suggesting this novel combination is a promising strategy for preventing prostate cancer. We have also demonstrated that FOXOlA plays a critical role in mediating apoptosis induction by selenium. In the second grant period, we have focused our effort on the following areas: (1) studying the impact of the selenium and finasteride combination on androgen signaling; (2) Identifying the pro-apoptotic target genes of FOXO1 that are induced by selenium; (3) studying the potential AR antagonistic effect of finasteride. The last was not proposed in the original application. But we strongly believe this is a topic worthwhile pursuing since a thorough understanding of the activities of finasteride is important for its use in clinical practices., The original document contains color images.

Objectives: Sexual function is one of the aspects in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) that has gained increasing attention. We compared the influence on men's sexuality of Permixon, a lipido-sterolic extract of Serenoa Repens, with Tamsulosin and Finasteride using a specific validated questionnaire exploring patient's sexual functions. Methods: A database was created comprising patients from 3 main double-blind, randomized studies - Permixon vs. Finasteride, Permixon vs. Tamsulosin and Permixon 160 mg vs. 320 mg including a total of 2511 patients. Three hundred fifty four were on Tamsulosin, 545 on Finasteride and 1612 patients on Permixon. LUTS were assessed using the I-PSS questionnaire. Peak flow rates and prostate volume were recorded. The MSF-4 questionnaire, including 4 items that explore the patient's interest in sex, quality of erection, achievement of orgasm and ejaculation, was used across the studies. This questionnaire was demonstrated as highly reproducible and both psychometrically and clinically valid across different cultures. Correlation coefficients were given to assess the linear relationship between continuous variables. Results: At 3 months, there were no statistically significant differences between the three treatment groups in terms of I-PSS or Qmax evolutions (all p values > 0.05). At 6 months, as compared to pretreatment data, there was a slight increase in sexual disorders in Tamsulosin (+0.3) and Finasteride (+0.8) treated patients while it slightly improved with Permixon therapy (-0.2). Ejaculation disorders were the most frequently reported side effects after Tamsulosin or Finasteride (both +0.2 on the specific MSF-4 question 4). There was no correlation between the evolution of the MSF-4 scores and the evolution in I-PSS neither in patients treated with Permixon, Finasteride or Tamsulosin. However, there was a slight correlation between the MSF-4 score at baseline a, SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: Sexual function is one of the aspects in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) that has gained increasing attention. We compared the influence on men's sexuality of Permixon, a lipido-sterolic extract of Serenoa Repens, with Tamsulosin and Finasteride using a specific validated questionnaire exploring patient's sexual functions. Methods: A database was created comprising patients from 3 main double-blind, randomized studies - Permixon vs. Finasteride, Permixon vs. Tamsulosin and Permixon 160 mg vs. 320 mg including a total of 2511 patients. Three hundred fifty four were on Tamsulosin, 545 on Finasteride and 1612 patients on Permixon. LUTS were assessed using the I-PSS questionnaire. Peak flow rates and prostate volume were recorded. The MSF-4 questionnaire, including 4 items that explore the patient's interest in sex, quality of erection, achievement of orgasm and ejaculation, was used across the studies. This questionnaire was demonstrated as highly reproducible and both psychometrically and clinically valid across different cultures. Correlation coefficients were given to assess the linear relationship between continuous variables. Results: At 3 months, there were no statistically significant differences between the three treatment groups in terms of I-PSS or Qmax evolutions (all p values > 0.05). At 6 months, as compared to pretreatment data, there was a slight increase in sexual disorders in Tamsulosin (+0.3) and Finasteride (+0.8) treated patients while it slightly improved with Permixon therapy (-0.2). Ejaculation disorders were the most frequently reported side effects after Tamsulosin or Finasteride (both +0.2 on the specific MSF-4 question 4). There was no correlation between the evolution of the MSF-4 scores and the evolution in I-PSS neither in patients treated with Permixon, Finasteride or Tamsulosin. However, there was a slight correlation between the MSF-4 score at baseline a, SCOPUS: ar.j, info:eu-repo/semantics/published

5-α-reductase inhibitors are now in widespread use for the treatment of benignprostatic hyperplasia (BHP) and these molecules have recently come under the spotlight in prostate cancer. Their peripheral "hormonal" action inducing reduced intraprostatic DHT synthesis seems to involve them in this hormone-dependant disorder. Finasteride evaluated in the treatment of BPH (PLESS study) was found to have a preventive effect on the incidence of cancer and this activity was assessed in a specific trial (PCPT study). Nevertheless, in the latter randomized study with a 7-year follow-up period, a reduction in the global incidence of the number of cases of cancers was associated with an increase in the number of high-grade cancers. A slight reduction in prostate cancer was also noted in the studies with dutasteride in BPH (ARIA3001, ARIA3002 and ARIB3003). An international mutticenter study (REDUCE) is currently being conducted to confirm the preventive value of this molecule which has a more complete activity than finasteride with its inhibitory action on the two 5-α-reductase iso-enzymes, and may therefore have a clearer efficiency and rule out the risk of onset of high-grade cancer. © 2004 Elsevier SAS. Tous droits réservés., SCOPUS: ar.j, info:eu-repo/semantics/published

To analyse the expression of the epidermal growth factor (EGF) system in prostate tissue and secretions obtained from patients with benign prostatic hyperplasia (BPH) treated with or without finasteride (which primarily targets the androgen-sensitive secretory epithelial cells in the prostate, with little effect on basal epithelial and stromal cells).

To analyse the expression of the epidermal growth factor (EGF) system in prostate tissue and secretions obtained from patients with benign prostatic hyperplasia (BPH) treated with or without finasteride (which primarily targets the androgen-sensitive secretory epithelial cells in the prostate, with little effect on basal epithelial and stromal cells).

Benign prostatic hyperplasia (BPH) can have a profound affect on a patient's quality of life and sexual function and is considered by patients to be one of the most important aspects affected by the disease. Different treatments can produce a variable response in terms of the patient's quality of life, including sexual activity and satisfaction. Varying rates of erectile dysfunction (ED) and retrograde ejaculation following surgery for BPH have been reported. In general, the incidence of these side-effects is less after minimally invasive therapies, such as interstitial laser coagulation and transurethral microwave therapy, but the data available are limited. The lowest rates of sexual dysfunction are reported with medical therapies. The 5α-reductase inhibitor, finasteride, can result in ED in 5-9% of patients and ejaculation disorders in 0.8-2.0%. With the exception of tamsulosin, α1 blockers are associated with a low rate of sexual dysfunction. No cases of ED have been reported with alfuzosin and abnormal ejaculation with terazosin or alfuzosin is negligible. Indeed, early research suggests a beneficial effect of α1 blockers on sexual function. In addition to information on the efficacy of a particular therapy, patients should be informed of side effects, in particular those relating to sexual function, in order that they can make informed treatment decisions. © 2001 Nature Publishing Group All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

If one were to wait for the perfect set of experimental results before launching a multi-agent chemoprevention or large risk reduction study, the trial would never be launched. On the other hand, non-scientific considerations have led to the premature launching of at least three prominent studies (CARET, Carotene and Retinol Efficacy Trial; ATBC, Apha Tocopherol Beta Carotene; PCPT, Prostate Cancer Prevention Trial) and the much delayed start-up of another, BCPT, the Breast Cancer Prevention Trial. Strong epidemiologic data by itself should not be adequate to justify starting a large trial; experimental and/or clinical data should be developed. On the other hand fear of secondary adverse events that are of low incidence should not be enough to delay a trial if the overall health benefit could be high. The development of multiagent chemoprevention trials requires that each agent is active and additively or synergistically so in combination in preclinical models. Additionally, side effects of each agent should be non-overlapping and low to non-existent, preferably a feature determined in formal phase IIa and IIb trials. These principles will be discussed in the context of prior (CARET, ATBC) and ongoing (EUROSCAN, acetylcysteine/retinol), as well as proposed future trials (difluromethyl/sulindac).

If one were to wait for the perfect set of experimental results before launching a multi-agent chemoprevention or large risk reduction study, the trial would never be launched. On the other hand, non-scientific considerations have led to the premature launching of at least three prominent studies (CARET, Carotene and Retinol Efficacy Trial; ATBC, Apha Tocopherol Beta Carotene; PCPT, Prostate Cancer Prevention Trial) and the much delayed start-up of another, BCPT, the Breast Cancer Prevention Trial. Strong epidemiologic data by itself should not be adequate to justify starting a large trial; experimental and/or clinical data should be developed. On the other hand fear of secondary adverse events that are of low incidence should not be enough to delay a trial if the overall health benefit could be high. The development of multiagent chemoprevention trials requires that each agent is active and additively or synergistically so in combination in preclinical models. Additionally, side effects of each agent should be non-overlapping and low to non-existent, preferably a feature determined in formal phase IIa and IIb trials. These principles will be discussed in the context of prior (CARET, ATBC) and ongoing (EUROSCAN, acetylcysteine/retinol), as well as proposed future trials (difluromethyl/sulindac).

SCOPUS: ar.j, info:eu-repo/semantics/published

We evaluated the effect of long-term administration of finasteride (MK-906), a potent inhibitor of 5 alpha-reductase in patients with benign prostatic hyperplasia (BPH). The effect of an increase in dose was also assessed. Finasteride was administered to 61 patients with BPH at the dose of 1 mg/day for 48 weeks. Thirty three of these patients subsequently received finasteride at the dose of 5 mg/day for further 24 weeks in an open extension study. Urinary symptoms, urinary flow rate, residual urinary volume, prostatic volume and serum concentrations of dihydrotestosterone and prostate-specific antigen were examined periodically during the treatment. The size of the prostate and total urinary symptom scores decreased progressively during the first 16 weeks of treatment. The patients who received finasteride had a significant increase in the maximal urinary flow rate and a significant decrease in residual urinary volume. After 72 weeks of treatment, finasteride at an increased dose of 5 mg did not provide additional benefit to patients, although the effects of the drug at a dose of 1 mg were well maintained. Treatment with finasteride was well tolerated at both doses. In conclusion, the treatment of BPH with 1 mg of finasteride per day for 48 weeks results in a significant increase in maximal urinary flow rate, and a decrease in prostatic volume, symptoms of obstruction and residual urinary volume, with minimal toxicity.

by Yu Hon Ming., Thesis (M.Sc.)--Chinese University of Hong Kong, 1996., Includes bibliographical references (leaves 70-74)., p.ii, Acknowledgements --- p.v, Abbreviations --- p.vi, List of tables and figures --- p.viii, Chapter Chapter I. --- Introduction, Chapter 1. --- Background --- p.1, Chapter 2. --- Physiology of prostate --- p.3, Chapter 2.1. --- Prostate --- p.3, Chapter 2.2. --- Embryonic development of prostate --- p.3, Chapter 2.3. --- Anatomy of prostate --- p.5, Chapter 2.4. --- The role of steroids in the growth of prostate --- p.7, Chapter 2.4.1. --- T --- p.7, Chapter 2.4.2. --- DHT --- p.8, Chapter 2.5. --- 5α-reductase --- p.10, Chapter 3. --- Pathophysiology of BPH --- p.11, Chapter 3.1. --- Anatomic progression of BPH --- p.11, Chapter 3.2. --- Epidemiology of BPH --- p.11, Chapter 3.3. --- Pathogenesis of BPH --- p.12, Chapter 3.4. --- Clinical manifestations of BPH --- p.13, Chapter 3.5. --- Diagnosis of BPH --- p.14, Chapter 4. --- Treatment of BPH --- p.15, Chapter 4.1. --- a-adrenergic antagonist --- p.16, Chapter 4.2. --- DHT hypothesis --- p.16, Chapter 4.3. --- 5α-reductase inhibitor --- p.17, Chapter 5. --- Radioimmunoassay of DHT --- p.21, Chapter 6. --- Objectives --- p.22, Chapter Chapter II. --- Materials and methods --- p.23, Chapter 1. --- Materials and methods for development of specific RIA for serum DHT --- p.23, Chapter 1.1. --- Materials --- p.23, Chapter 1.2. --- Methods --- p.23, Chapter 1.2.1. --- Antiserum for DHT-RIA --- p.23, Chapter 1.2.1.1. --- Optimal antibody titre and dilution curve for DHT-RIA --- p.24, Chapter 1.2.1.2. --- Cross-reactivity with related steroids --- p.25, Chapter 1.2.2. --- KMnO4 treatment of T antiserum for DHT-RIA --- p.26, Chapter 1.2.2.1. --- Optimization of KMnO4 treatment --- p.26, Chapter 1.2.2.2. --- Upper limit of oxidizing power of 0.5% KMnO4 --- p.27, Chapter 1.2.2.3. --- Efficiency and background effect of 0.5% KMnO4 oxidation on DHT-RIA --- p.28, Chapter 1.2.3. --- Characteristic of DHT-RIA --- p.29, Chapter 1.2.3.1. --- Standard preparation --- p.29, Chapter 1.2.3.2. --- Blank preparation --- p.30, Chapter 1.2.3.3. --- Control preparation --- p.31, Chapter 1.2.3.4. --- Sample preparation --- p.31, Chapter 1.2.3.5. --- Dextran-coated charcoal --- p.31, Chapter 1.2.3.6. --- DHT-RIA procedure --- p.32, Chapter 1.2.3.7. --- Sensitivity test for DHT-RIA --- p.33, Chapter 1.2.3.8. --- Linearity test for DHT-RIA --- p.33, Chapter 1.2.3.9. --- Recovery test for DHT-RIA --- p.34, Chapter 1.2.3.10. --- Precision test for DHT-RIA --- p.34, Chapter 2. --- Materials and methods for establishing reference range of DHT in Chinese males and females --- p.35, Chapter 2.1. --- Samples --- p.35, Chapter 2.2. --- Methods --- p.35, Chapter 2.2.1. --- DHT determination --- p.35, Chapter 2.2.2. --- T determination --- p.36, Chapter 2.2.3. --- Cholesterol determination --- p.37, Chapter 3. --- Materials and methods for a small clinical trial on the usefulness of 5α-reductase inhibitor (finasteride) in the treatment of BPH --- p.38, Chapter 3.1. --- Samples --- p.38, Chapter 3.2. --- Methods --- p.38, Chapter 4. --- Statistical analysis --- p.39, Chapter Chapter III. --- Result --- p.40, Chapter 1. --- DHT-RIA --- p.40, Chapter 1.1. --- Antiserum for DHT-RIA, Chapter 1.1.1. --- Optimal antibody titre for DHT-RIA --- p.40, Chapter 1.1.2. --- Cross reactivity with related steroids --- p.42, Chapter 1.2. --- KMnO4 treatment of T antiserum for DHT-RIA --- p.43, Chapter 1.2.1. --- Optimization of KMnO4 treatment --- p.43, Chapter 1.2.2. --- Upper limit of oxidizing power of 0.5% KMnO4 --- p.44, Chapter 1.2.3. --- Efficiency and background effect of 0.5% KMnO4 treatment on DHT-RIA --- p.45, Chapter 1.3. --- Characterization of the DHT-RIA --- p.47, Chapter 2. --- Reference range for DHT in Chinese males and females --- p.51, Chapter 2.1. --- Reference range of DHT in three different study groups --- p.51, Chapter 2.2. --- Ratio of DHT/T in Chinese males and Caucasian males --- p.52, Chapter 2.3. --- Correlation studies --- p.53, Chapter 3. --- Results of small clinical trial --- p.54, Chapter 3.1. --- Mean serum analyte changes during the course --- p.54, Chapter 3.2. --- Changes in analyte concentrations during the course --- p.56, Chapter 3.3. --- Difference in mean serum analytes between BPH males predose level and normal males with and without age matching --- p.57, Chapter 3.4. --- "The response, percentage change of DHT and DHT/T ratio of individual patient during the course of study" --- p.58, Chapter Chapter IV. --- Discussion --- p.59, Chapter 1. --- Radioimmunoassay for DHT --- p.59, Chapter 2 . --- Establishment of DHT reference range in Chinese males and females --- p.62, Chapter 3. --- The usefulness of 5a reductase inhibitor in the treatment of BPH --- p.65, Chapter Chapter V. --- Conclusion --- p.69, References --- p.70, http://library.cuhk.edu.hk/record=b5895726, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)