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Introduction: Phytotherapeutics, particularly extracts from Sabal serrulata (saw palmetto) fruit or Urtica dioica (stinging nettle) root, are popular for the treatment of male lower urinary symptoms in many countries, but their mechanism of action is poorly understood. We performed in vivo and in vitro studies to obtain deeper insight into the mechanism of action of WS® 1541, a proprietary combination of a Sabal serrulata fruit and an Urtica dioica root extract (WS® 1473 and WS® 1031, respectively) and its components. Methods: We used the sulpiride model of benign prostatic hyperplasia in rats and tested three doses of WS® 1541 in comparison to finasteride, evaluating weight of prostate and its individual lobes as well as aspects of inflammation, oxidative stress, growth and hyperplasia. In human BPH-1 cells, we studied the effect of WS® 1473, WS® 1031, WS® 1541 and finasteride on apoptosis, cell cycle progression and migrative capacity of the cells. Results: WS® 1541 did not reduce prostate size in sulpiride treated rats but attenuated the sulpiride-induced changes in expression of most analyzed genes and of oxidized proteins and abrogated the epithelial thickening. In vitro, WS® 1473 and WS® 1031 showed distinct profiles of favorable effects in BPH-1 cells including anti-oxidative, anti-proliferative and pro-apoptotic effects, as well as inhibiting epithelial-mesenchymal-transition. Conclusion: This data supports a beneficial effect of the clinically used WS® 1541 for the treatment of lower urinary tract symptoms associated with mild to moderate benign prostate syndrome and provides a scientific rationale for the combination of its components WS® 1473 and WS® 1031.
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The popularity of natural products for the treatment of lower urinary tract symptoms (LUTS) differs considerably between countries. Here we discuss the clinical evidence for efficacy in two indications, male LUTS suggestive of benign prostatic hyperplasia and urinary tract infections, and the mechanistic evidence from experimental studies. Most evidence for male LUTS is based on extracts from saw palmetto berries, stinging nettle roots, and pumpkin seeds, whereas most evidence for urinary tract infection is available for European golden rod and combined preparations although this field appears more fragmented with regard to extract sources. Based on differences in sample collection and extraction, extracts from the same plants are likely to exhibit at least quantitative differences in potential active ingredients, which makes extrapolation of findings with one extract to those of others potentially difficult. While only limited information is available for most individual extracts, some extracts have been compared to placebo and/or active controls in adequately powered trials.
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BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH, in German guidelines: benign prostatic syndrome [BPS]) is considered the most common disease of the lower urinary tract in men and can have a tremendous impact on the quality-of-life of affected patients. Conservative and pharmacological therapy of this disease are of great importance, both in improving LUTS and reducing progression-related complications. OBJECTIVES: Presentation of the conservative and pharmacological treatment options according to the current German S2e guideline on BPS. MATERIALS AND METHODS: Summary and overview of chapters 9 and 10 of the current German S2e guideline on BPS. RESULTS: In addition to a controlled watchful waiting for BPS patients without an absolute indication for prostate surgery, a variety of phytopharmacological formulations and synthetic drugs according to the symptomatology and clinical progress are available. Phytotherapy should, due to inconsistent study data, only be considered for mild to moderate symptoms. Synthetic drugs include alpha-blockers, 5α-reductase inhibitors, phosphodiesterase inhibitors, antimuscarinics and, more recently, the ß3-agonist mirabegron in the current guideline. In addition, various combination therapies are listed and evaluated according to their indications, effects and side effects. CONCLUSIONS: The current German S2e guideline on the diagnosis and treatment of BPS provides an evidence-based foundation for finding the best possible and most effective medication.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Drogas Sintéticas , Masculino , Humanos , Hiperplasia Prostática/diagnóstico , Resultado del Tratamiento , Próstata , Antagonistas Adrenérgicos alfa/uso terapéutico , Síntomas del Sistema Urinario Inferior/diagnóstico , Drogas Sintéticas/uso terapéuticoRESUMEN
Functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS), are frequently handled by self-management with over-the-counter (OTC) products such as hyoscine butylbromide (HBB), alone or in combination with paracetamol, and natural products such as peppermint oil. To obtain real-world information, we have performed an anonymous pharmacy-based patient survey among 1686 users of HBB, HBB + paracetamol, and peppermint oil. Based on the distinct but overlapping indications for the three OTC products, multiple logistic regression was applied to compare them in users reporting gastrointestinal cramps and pain, bloating, flatulence, or IBS as cardinal symptoms. All three treatments reduced symptoms and associated impairments of work/daily chores, leisure activities, and sleep by approximately 50%. Based on the four cardinal symptoms and the four dependent continuous variables of interest (change in intensity of symptoms and of the three impairment domains) a total of 16 logistic regression models were applied. HBB, HBB + paracetamol, and peppermint oil had similar reported overall effectiveness in those models. Gender, age, baseline symptom severity, and impairment in one of three domains had small and inconsistent effects on perceived treatment success. We provide evidence that HBB, HBB + paracetamol, and peppermint oil have comparable effectiveness in their approved indications under real-world conditions in an OTC setting.
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The American Society for Pharmacology and Experimental Therapeutics has revised the Instructions to Authors for Drug Metabolism and Disposition, Journal of Pharmacology and Experimental Therapeutics, and Molecular Pharmacology These revisions relate to data analysis (including statistical analysis) and reporting but do not tell investigators how to design and perform their experiments. Their overall focus is on greater granularity in the description of what has been done and found. Key recommendations include the need to differentiate between preplanned, hypothesis-testing, and exploratory experiments or studies; explanations of whether key elements of study design, such as sample size and choice of specific statistical tests, had been specified before any data were obtained or adapted thereafter; and explanations of whether any outliers (data points or entire experiments) were eliminated and when the rules for doing so had been defined. Variability should be described by S.D. or interquartile range, and precision should be described by confidence intervals; S.E. should not be used. P values should be used sparingly; in most cases, reporting differences or ratios (effect sizes) with their confidence intervals will be preferred. Depiction of data in figures should provide as much granularity as possible, e.g., by replacing bar graphs with scatter plots wherever feasible and violin or box-and-whisker plots when not. This editorial explains the revisions and the underlying scientific rationale. We believe that these revised guidelines will lead to a less biased and more transparent reporting of research findings.
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Guías como Asunto , Farmacología/normas , Edición/normas , Proyectos de Investigación , Sociedades Científicas/normas , Análisis de Datos , Interpretación Estadística de Datos , Evaluación Preclínica de Medicamentos/normas , Humanos , Estados UnidosRESUMEN
Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.
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Aprobación de Drogas , Evaluación Preclínica de Medicamentos/tendencias , Publicaciones Periódicas como Asunto/tendencias , Proyectos de Investigación/tendencias , United States Food and Drug Administration , Alternativas a las Pruebas en Animales/tendencias , Animales , Bibliometría , Bioensayo/tendencias , Humanos , Estudios Longitudinales , Farmacocinética , Factores de Tiempo , Pruebas de Toxicidad/tendencias , Estados UnidosRESUMEN
The present study aimed to explore early publication patterns (i.e. up to 1 year after obtaining regulatory approval) for newly registered drugs. From the website of the US Food and Drug Administration, all newly approved drugs for 6 calendar years between 1991 and 2011 were identified. Non-clinical original publications for these compounds were retrieved from PubMed and their abstracts analysed for type of study and reported data. This yielded 170 compounds for which 1954 original non-clinical publications were identified, i.e. a median/mean of 5/11.5 publications per compound; however, number of publications per compound varied widely (0-90) and this variation exhibited a non-Gaussian distribution. The earliest non-clinical publication typically was published less than 5 years before regulatory approval and more than 5 years after filing of the primary patent, but some compounds exhibited notable deviations from this pattern. Publications most often reported on efficacy related to the target indication and on potential future indications, with fewer studies addressing mechanisms of action, potency, selectivity, pharmacokinetics and toxic effects. For most compounds, data at the cellular and in vivo level were published, with fewer reports on effects on isolated tissues and even fewer at the molecular level. The preferred species for cellular studies was human, whereas for in vivo studies, it was rats and mice. In 75 % of cases, the lead author of the publication came from an academic institution, and most studies were published in classic pharmacology journals. We conclude that number, timing and scope of early non-clinical publications on newly approved drugs exhibit major variance. Factors potentially associated with such variance are explored in a companion paper.
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Aprobación de Drogas , Evaluación Preclínica de Medicamentos/tendencias , Publicaciones Periódicas como Asunto/tendencias , Proyectos de Investigación/tendencias , United States Food and Drug Administration , Animales , Bibliometría , Humanos , Farmacocinética , Factores de Tiempo , Pruebas de Toxicidad/tendencias , Estados UnidosRESUMEN
As the prostate abundantly expresses muscarinic receptors and antagonists for such receptors are increasingly used in the treatment of men with voiding function and large prostates, we have explored an association of the mRNA expression of human M1, M2, M3, M4, and M5 receptors in human prostate with patient age, prostate size, prostate-specific antigen level, pathological diagnosis, and concomitant medication. mRNA was isolated from prostate chips of 110 consecutive patients undergoing transurethral resection of the prostate for the treatment of benign prostatic hyperplasia or prostate cancer. Expression of each of the five muscarinic receptor subtype transcripts was assessed by real-time PCR and association with patient age, prostate size, prostate-specific antigen level, pathological diagnosis, and concomitant medication were explored. M1 and M4 receptors were the most and least prevalently expressed subtypes in the human prostate, respectively. M1 receptor mRNA expression was weakly but significantly associated with prostate size (r = 0.2494, p = 0.0451), but mRNA expression of none of the five subtypes was significantly associated with age, prostate-specific antigen level, pathological diagnosis (benign prostatic hyperplasia vs. prostate cancer), or concomitant medication (5α-reductase inhibitors, α1- or ß-adrenoceptor antagonists). We conclude that human prostate muscarinic receptor subtype transcripts apparently undergo only a very limited regulation by a variety of physiological, pathophysiological, or treatment factors. In light of the growing use of muscarinic receptor antagonists in men with voiding dysfunction including those with large prostates, the functional role of the weak association between M1 receptor mRNA expression and prostate size merits further investigation.
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Próstata/metabolismo , Hiperplasia Prostática/genética , Neoplasias de la Próstata/genética , ARN Mensajero/metabolismo , Receptores Muscarínicos/genética , Factores de Edad , Anciano , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Próstata/patología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Resección Transuretral de la PróstataRESUMEN
OBJECTIVE: To present a summary of the 2013 version of the European Association of Urology guidelines on the treatment and follow-up of male lower urinary tract symptoms (LUTS). EVIDENCE ACQUISITION: We conducted a literature search in computer databases for relevant articles published between 1966 and 31 October 2012. The Oxford classification system (2001) was used to determine the level of evidence for each article and to assign the grade of recommendation for each treatment modality. EVIDENCE SYNTHESIS: Men with mild symptoms are suitable for watchful waiting. All men with bothersome LUTS should be offered lifestyle advice prior to or concurrent with any treatment. Men with bothersome moderate-to-severe LUTS quickly benefit from α1-blockers. Men with enlarged prostates, especially those >40ml, profit from 5α-reductase inhibitors (5-ARIs) that slowly reduce LUTS and the probability of urinary retention or the need for surgery. Antimuscarinics might be considered for patients who have predominant bladder storage symptoms. The phosphodiesterase type 5 inhibitor tadalafil can quickly reduce LUTS to a similar extent as α1-blockers, and it also improves erectile dysfunction. Desmopressin can be used in men with nocturia due to nocturnal polyuria. Treatment with an α1-blocker and 5-ARI (in men with enlarged prostates) or antimuscarinics (with persistent storage symptoms) combines the positive effects of either drug class to achieve greater efficacy. Prostate surgery is indicated in men with absolute indications or drug treatment-resistant LUTS due to benign prostatic obstruction. Transurethral resection of the prostate (TURP) is the current standard operation for men with prostates 30-80ml, whereas open surgery or transurethral holmium laser enucleation is appropriate for men with prostates >80ml. Alternatives for monopolar TURP include bipolar TURP and transurethral incision of the prostate (for glands <30ml) and laser treatments. Transurethral microwave therapy and transurethral needle ablation are effective minimally invasive treatments with higher retreatment rates compared with TURP. Prostate stents are an alternative to catheterisation for men unfit for surgery. Ethanol or botulinum toxin injections into the prostate are still experimental. CONCLUSIONS: These symptom-oriented guidelines provide practical guidance for the management of men experiencing LUTS. The full version is available online (www.uroweb.org/gls/pdf/12_Male_LUTS.pdf).
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Síntomas del Sistema Urinario Inferior/terapia , Hiperplasia Prostática/terapia , Resección Transuretral de la Próstata/normas , Agentes Urológicos/uso terapéutico , Urología/normas , Espera Vigilante/normas , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Humanos , Síntomas del Sistema Urinario Inferior/diagnóstico , Síntomas del Sistema Urinario Inferior/fisiopatología , Masculino , Antagonistas Muscarínicos/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/fisiopatología , Conducta de Reducción del Riesgo , Índice de Severidad de la Enfermedad , Stents/normas , Resección Transuretral de la Próstata/efectos adversos , Resultado del Tratamiento , Cateterismo Urinario/normas , Agentes Urológicos/efectos adversosRESUMEN
OBJECTIVES: To determine the role of treatment-associated improvement in nocturia in health-related quality of life (HRQL) in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia, and secondarily to confirm the role of nocturia in HRQL at baseline and to compare the effects of watchful waiting, transurethral microwave treatment (TUMT) and transurethral resection of the prostate (TURP) to those of α1-adrenoceptor antagonists (α-blockers) on nocturia. PATIENTS AND METHODS: We retrospectively analysed using multiple regression a large single-centre database of patients receiving routine care for treatment-associated alterations of symptoms and HRQL (assessed at baseline, 2611 men) and 6-12 months after initiation of treatment (1258 men). RESULTS: Among the symptoms assessed using the International Prostate Symptom Score, nocturia (together with urgency and weak stream) had the strongest correlation with HRQL at baseline and after treatment. Watchful waiting, α-blockers, TUMT and TURP reduced nocturia episodes by a mean (sd) of 7 (53)%, 17 (40)%, 32 (47)% and 75 (23)%, respectively. The treatment-associated improvements in nocturia (together with those of weak stream) had the strongest association with those of HRQL. CONCLUSIONS: We conclude that among all LUTS assessed in the IPSS, nocturia has one of the strongest associations with HRQL, and that treatment-associated improvements in nocturia contribute considerably to overall improvements in HRQL.
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Síntomas del Sistema Urinario Inferior/terapia , Nocturia/terapia , Hiperplasia Prostática/terapia , Calidad de Vida , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Anciano , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Resección Transuretral de la Próstata , Espera VigilanteRESUMEN
Since extracts from the plants Rhois aromatica and Solidaginis virgaurea are being used in the phytotherapy of bladder dysfunction including the overactive bladder syndrome, and since muscarinic receptors are the main pharmacological target in the treatment of bladder dysfunction, we have investigated whether these extracts can inhibit carbachol-induced, muscarinic receptor-mediated contraction of rat and human bladder. In vitro contraction experiments were performed with rat and human bladder strips. Radioligand binding and inositol phosphate accumulation studies were done with cells transfected with human M(2) or M(3) muscarinic receptors. Both extracts concentration-dependently (final concentrations 0.01-0.1%) inhibited carbachol-induced contraction of rat and human bladder with insurmountable antagonism. Radioligand binding experiments and inositol phosphate accumulation studies with cloned receptors demonstrated direct but non-competitive effects on muscarinic receptors. Reductions of KCl-induced bladder contraction demonstrated that inhibition by the higher extract concentrations also involved receptor-independent effects. We conclude that extracts from Rhois aromatica and Solidaginis virgaurea inhibit muscarinic receptor-mediated contraction of rat and human bladder. While this could contribute to the beneficial effects of these extracts in patients with bladder dysfunction, such therapeutic effects remain to be demonstrated in controlled clinical studies.
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Contracción Muscular/efectos de los fármacos , Rhus , Solidago , Vejiga Urinaria/efectos de los fármacos , Animales , Carbacol/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Técnicas In Vitro , Masculino , Contracción Muscular/fisiología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Hojas de la Planta , Raíces de Plantas , Ratas , Ratas Wistar , Receptores Muscarínicos/fisiología , Vejiga Urinaria/fisiologíaRESUMEN
The alpha(1)-adrenoceptor antagonist, tamsulosin, is selective for alpha(1A)- and alpha(1D)- over alpha(1B)-adrenoceptors. Both placebo-controlled and comparative studies with other agents have demonstrated tamsulosin to be an effective treatment for patients with lower urinary symptoms suggestive of benign prostatic hyperplasia. Its effectiveness appears to be maintained over many years. Tamsulosin may also effectively reduce lower urinary tract symptoms in other urological diseases. A dose of tamsulosin 0.4 mg/day has a tolerability close to that of placebo and has little, if any, blood pressure lowering effects. Tolerability and lack of blood pressure lowering are maintained even in high-risk patients such as those with cardiovascular comorbidity and/or comedication. Apart from adrenoceptor subtype-selectivity, a smooth pharmacokinetic profile of its modified-release formulation and a selective accumulation in target tissues may contribute to an excellent efficacy:tolerability ratio.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Hiperplasia Prostática/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Enfermedades Urológicas/tratamiento farmacológico , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Vigilancia de Productos Comercializados , Neoplasias de la Próstata/tratamiento farmacológico , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , TamsulosinaRESUMEN
PURPOSE: We determined whether an extract from the bark of the tree Aspidosperma quebracho blanco, which is used as a prescription drug to treat erectile dysfunction in some countries, can bind to human penile alpha1 and alpha2-adrenoceptors, and cloned human alpha-adrenoceptor subtypes. MATERIALS AND METHODS: Competition binding studies were performed with alpha1 and alpha2-adrenoceptors with the extract and 4 subfractions prepared from it using [3H]prazosin (New England Nuclear, Dreieich, Germany) and [3H]RX 821002 (2-methoxy-idazoxam) (Amersham, Braunschweig, Germany) as the radioligands, respectively. RESULTS: In a concentration dependent manner the extract inhibited 2-methoxy-idazoxam binding to human penile alpha2-adrenoceptors. Somewhat less potently it inhibited [3H] prazosin binding to penile alpha1-adrenoceptors. The extract also inhibited binding to cloned alpha2-adrenoceptors more potently than to alpha1-adrenoceptors but did not discriminate among subtypes. Subfraction B was more potent than the others for all cloned alpha1-adrenoceptor subtypes and much more potent at all penile and all cloned alpha2-adrenoceptor subtypes. This fraction largely contained yohimbine, whereas the other fractions were devoid of yohimbine. Based on yohimbine competition binding experiments with penile and cloned alpha1 and alpha2-adrenoceptors, it appears that the inhibitory effects of the abstract and its subfractions can largely be explained by its yohimbine content. CONCLUSIONS: An alpha-adrenoceptor mediated component of the pro-erectile effects of Aspidosperma quebracho blanco bark extract may predominantly be caused by its yohimbine content. The alpha-adrenoceptor independent, pro-erectile effects of the extract could not be determined from this study.