Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis.

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor.

PURPOSE: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi. EXPERIMENTAL DESIGN: The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi. RESULTS: Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples. CONCLUSIONS: The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.

Vismodegib (ERIVEDGE) pregnancy prevention programme: assessment of risk awareness.

INTRODUCTION: Vismodegib (Erivedge; Roche), a Hedgehog pathway inhibitor (HPI), is indicated for the treatment of symptomatic metastatic basal cell carcinoma (BCC) and locally advanced BCC inappropriate for surgery or radiotherapy. Due to the known risk of HPI teratogenicity, the Erivedge Pregnancy Prevention Program (PPP) was introduced at approval (2013) as part of the EU Risk Management Plan. METHODS: Structured, quantitative Web-based surveys were conducted in 2015 (Wave 1), 2016 (Wave 2), and 2017/2018 (Wave 3) among prescribing oncologists and dermato-oncologists in Austria, France, Germany, Hungary, and the United Kingdom to assess the effectiveness of the Erivedge PPP. RESULTS: Overall, 95%, 87%, and 91% of respondents in Waves 3 (N = 181), 2 (N = 214), and 1 (N = 207), respectively, were vismodegib prescribers. The surveys consistently showed a high awareness about the risk of teratogenicity associated with vismodegib (98%, Wave 3; 95%, Wave 2) and that a high proportion of prescribing physicians took appropriate precautions to minimize this risk (95%, Wave 3; 92%, Wave 2; 88%, Wave 1). Physicians were also highly aware of the Erivedge PPP (70%, Wave 3; 67%, Wave 2; 71%, Wave 1). CONCLUSION: Survey data suggest that the risk of teratogenicity with vismodegib has been effectively communicated to the prescribing community.

Model-based approach for methoxy polyethylene glycol-epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease.

AIMS: Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. METHODS: Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data. RESULTS: Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL-1 ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] µg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL-1 and median C.E.R.A. dose was 100 µg). CONCLUSIONS: These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.

Evolution to a Competency-Based Training Curriculum for Pharmaceutical Medicine Physicians in Switzerland.

In Switzerland, Pharmaceutical Medicine has existed as one of 46 physician specialties accredited by the Federal Office of Public Health for more than 20 years. As a medical-scientific discipline, our goal is to enable best possible therapeutic coverage for the benefit of patients and society through a medical need-based development and optimal use of medicinal products. The role of the specialist in Pharmaceutical Medicine is to closely collaborate with various stakeholders of the healthcare system in the context of the discovery, research, development and approval of new medicinal products, as well as safe and effective use of new and established medicinal products in daily clinical practice. The post-graduate training consists of 2 years of patient-related clinical work, followed by 3 years of vocational training at certified training centers in Pharmaceutical Medicine. This also includes completion of an academic post-graduate diploma in Pharmaceutical Medicine (30 ECTS) according to the IFAPP/PharmaTrain syllabus and a 1 day board exam. As part of an ongoing revision of the training curriculum, we are developing a Swiss Catalog of Core Competencies in Pharmaceutical Medicine (SC3-PM), based on the IFAPP competency framework for drug development specialists in industry. In this article we discuss how we adapt the scope of the IFAPP competency framework to better reflect such roles in academic institutions or regulatory bodies in Switzerland.

Validation of a treatment satisfaction questionnaire in non-Hodgkin lymphoma: assessing the change from intravenous to subcutaneous administration of rituximab.

BACKGROUND: A subcutaneous (SC) formulation of rituximab (MabThera®/Rituxan®) has been developed that could reduce administration time and improve patient satisfaction with treatment. The Rituximab Administration Satisfaction Questionnaire (RASQ) was created to assess patients' perceptions and satisfaction with rituximab SC (RASQ-SC) or rituximab intravenous (RASQ-IV). We assessed the content validity and psychometric properties of RASQ in patients with non-Hodgkin lymphoma. METHODS: Face and content validity of RASQ-SC and RASQ-IV were qualitatively assessed using 60-minute combined concept elicitation and cognitive debriefing interviews. Psychometric validation of RASQ (item performance and reliability) was assessed quantitatively against the established Cancer Therapy Satisfaction Questionnaire (CTSQ), using questionnaire data from the PrefMab (NCT01724021) and MabCute (NCT01461928) clinical studies. RESULTS: RASQ-IV demonstrated excellent coverage of concepts relevant to patients' (n=10) own treatment experiences and no new concepts were identified. Patients' expectations of rituximab SC were conceptually consistent with items included in the RASQ-SC, suggesting that the tool is also conceptually adequate. In 1,051 patients from PrefMab and MabCute, correlations with domains such as "RASQ: Physical Impacts" and "CTSQ: Feelings About Side Effects", "RASQ: Physical Impacts" and "CTSQ: Satisfaction With Therapy", and "RASQ: Satisfaction" and "CTSQ: Satisfaction With Therapy", achieved moderate-to-high correlations (>0.4) for convergent domains and <0.3 for divergent domains. CONCLUSION: This study supports the qualitative face and content validity and psychometric validity of RASQ-IV and RASQ-SC. Minor revisions were made to the questionnaires to enhance clarity and aid consistent reporting.

Pharmaceutical quality of eight generics of ceftriaxone preparation for injection in Eastern Asia.

OBJECTIVES: To compare the pharmaceutical quality of original and generic ceftriaxone sodium preparations for injection produced in Eastern Asia. METHODS: Standard physical and chemical laboratory tests were performed. Participants/material: Ceftriaxone (Rocephin®, Roche, Switzerland) was the reference material. Generics produced in China, India, and Indonesia were sampled in China and Myanmar within their expiration dates. RESULTS: Eight generics obtained from Eastern Asia markets in January 2013 were analysed. All eight generics failed the specifications in three or more tests. Residues of solvents and metals were detected in all generics, four were not particle free, and two were not sterile. CONCLUSIONS: All tested generic ceftriaxone products failed to meet the pharmaceutical quality standards of the branded original. The high levels of impurities and the identified contamination of particles and residues are of clinical concern, as they could impact tolerability and safety in patients in need of an effective parenteral antibiotic.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

BACKGROUND: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. METHODS: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. RESULTS: The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. CONCLUSIONS: The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.

Malaria chemoprophylaxis regimens: a descriptive drug utilization study.

BACKGROUND: Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. METHODS: We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. RESULTS: Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%-13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%-0.1% among other antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%-15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%-1.4% among users of other antimalarials). CONCLUSIONS: The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women.

The ability of the general male public to assess their suitability to take 50-mg sildenafil: an assessment of the comprehension of patient information materials via internet survey.

INTRODUCTION: Erectile dysfunction (ED) is the most common male sexual dysfunction and has a negative impact on masculinity and self-esteem. Phosphodiesterase type 5 inhibitors, including sildenafil, are the first-line treatment option for ED. Providing appropriate information regarding suitability for using sildenafil is important. AIM: The purpose of this study was to assess whether a broad spectrum of men could appropriately evaluate their suitability for 50-mg sildenafil after reviewing patient information materials. MAIN OUTCOME MEASURES: Patient information (Pack) on appropriate use of 50-mg sildenafil and patient information leaflet (PIL), a Web survey including demographics, self-assessed suitability for sildenafil use, and suitability screener. METHODS: A randomly selected, population-representative Web-based panel of males in the UK was recruited for this study. Eligible men answered a brief sociodemographic questionnaire and then were presented with the Pack. If a participant desired additional information, he could also review the PIL. The participants then rated the Pack and PIL (if reviewed), self-assessed their suitability for sildenafil use, and completed a previously validated screener for suitability. RESULTS: A total of 1,275 men aged 40 and above were included in these analyses; the mean age was 57.8 ± 9.9 years. A total of 1,054 men reported ED; 517 men (40.5%) deemed themselves suitable for sildenafil; 504 men (39.6%) deemed themselves unsuitable; and 254 (19.9%) were unsure. The concordance rate between screener-assessed suitability and self-assessed suitability was 70.9% (95% confidence interval [CI] = 68.1-73.7%). When accounting for men who would not take sildenafil even though they were suitable or would seek additional information from a healthcare professional prior to using sildenafil, the concordance rate was 84.2% (95% CI = 82.2-86.2%). CONCLUSION: The results of this study suggest that men in the general population are capable of using written sildenafil patient education materials to accurately assess their suitability for treatment with 50-mg sildenafil.

A feasibility study comparing pharmacist and physician recommendations for sildenafil treatment.

INTRODUCTION: In Europe, pharmacists may be an important first point of contact for men with erectile dysfunction (ED) asking for advice and treatment. AIM: To determine if European community pharmacists could appropriately recommend suitability for supply of sildenafil 50 mg for the treatment of ED. METHODS: For this cross-sectional, observational study, the current Summary of Product Characteristics was adapted to create a study drug information sheet for use in a pharmacy setting in which, for certain patients, supply is not suitable and referral to a physician is recommended. After training and with use of a guidance questionnaire, pharmacists assessed the suitability of supply of sildenafil 50 mg for men presenting to their pharmacy. Men with self-reported ED who were not currently using a phosphodiesterase type 5 inhibitor were recruited. Within 7 days of the pharmacist-patient interaction, a physician with experience in the management of ED telephoned the subject to assess suitability. If there was discordance between the pharmacist and physician recommendations, the case was independently reassessed by a physician specialist in sexual medicine. MAIN OUTCOME MEASURES: The primary end point was the concordance rate (with 95% confidence intervals) between pharmacist and physician recommendations. Rates were weighted by country sample sizes. RESULTS: Concordance (95% confidence interval) was 0.70 (0.66-0.74) between pharmacist and physician recommendation, indicating agreement in 70% of cases, and was 0.90 (0.86-0.94) between pharmacist and physician specialist in sexual medicine. Furthermore, if the cases in which the pharmacist did not put subjects at risk (i.e., gave an acceptable recommendation) are assessed, the success rate is 83.5% (79.6-87.4%) and 92.8% (90.1-95.5%), respectively. CONCLUSION: Pharmacists were accurate in providing suitable treatment recommendation, generally not recommending sildenafil for men without ED and recommending physician assessment when there was any question about cardiovascular health, other comorbidity, or co-medication.

Interrelationship of sildenafil treatment effects on the physiological and psychosocial aspects of erectile dysfunction of mixed or organic etiology.

INTRODUCTION: In a previous paper using mediation modeling, the direct and indirect effects of sildenafil on erection maintenance were demonstrated. OBJECTIVE: In an extension of this previous work, the historical psychosocial paradigm of ED, which focuses on performance anxiety, is tested by using mediation modeling to define the relationship of the physiological aspects (hardness and maintenance) and the associated psychosocial aspects (confidence, sexual relationship satisfaction, and performance anxiety) of ED. METHODS: Statistical mediation analysis using the following outcomes from a double-blind placebo-controlled trial of fixed-dose sildenafil 100 mg or 50 mg: Erection Hardness Score; the 15-item International Index of Erectile Function (IIEF), including item 4 (frequency of erection maintenance after penetration) and item 5 (difficulty of erection maintenance to intercourse completion); the Self-Esteem And Relationship questionnaire; and the question, "Do you feel anxious about your next attempt at sexual intercourse?" MAIN OUTCOME MEASURES: Estimated percentages of direct and indirect effects of sildenafil on psychosocial aspects of ED (95% confidence intervals). RESULTS: The model estimated that erection hardness mediated 43.7% (29.3%, 62.4%) of the effect of treatment onto confidence and 45.9% (32.2%, 61.8%) of the effect of treatment onto sexual relationship satisfaction, and that erection maintenance (using IIEF item 4 as a proxy) mediated 23.0% (10.1%, 39.1%) and 22.4% (10.1%, 36.5%), respectively. Similar results were obtained when IIEF item 5 was used as the proxy for measurement of maintenance. Of all possible paths to performance anxiety, only that from treatment via confidence was statistically significant, mediating an estimated 88.6% (55.5%, 146.2%; item 4 model) or 74.9% (47.0%, 121.0%; item 5 model) of the effect of treatment onto anxiety. The direct path to anxiety from treatment was not statistically significant. CONCLUSIONS: In men treated with sildenafil for ED, performance anxiety might be ameliorated by improved confidence. Improved confidence might be mainly mediated via increased erection hardness.

The EPIFARM study: an observational study in 574 community pharmacies in Spain characterizing patient profiles of men asking for erectile dysfunction medication.

INTRODUCTION: Community pharmacists may be an important first point of contact for erectile dysfunction (ED) patients, but to date there are no reports of the characteristics of men approaching pharmacists for ED advice or treatment. AIM: To characterize the profiles of men with and without phosphodiesterase-5 inhibitors (PDE5i) prescription asking for ED treatment at the pharmacy. METHODS: A multicenter, observational, cross-sectional study was conducted in Spanish community pharmacies September-November 2008. Of men asking for ED advice or treatment, each investigator recruited one with and one without PDE5i prescription. Study pharmacists completed a questionnaire of patient demographic, clinical, and behavioural data including the Sexual Health Inventory for Men. MAIN OUTCOME MEASURES: Demographic characteristics and responses to questionnaires. RESULTS: Five hundred and seventy-four pharmacists recruited 1,147 patients; 1,113 were included for analysis. There were no statistical differences between the groups regarding weight, hypertension, diabetes mellitus, hypercholesterolemia, dyslipidemia, depression, or stress. There were no statistical differences in severity of ED (P=0.7892) or proportion of men without ED in each group (P=0.5755). ED symptoms had been present for a mean of 26 months in both groups before first consultation with a healthcare professional. The visit to the pharmacy was the first discussion about ED for 60.2% of the nonprescription group, and 50% of those who had previously discussed ED had done so with a pharmacist in the first instance. In the nonprescription group, 85.1% of men asked for a PDE5i. CONCLUSIONS: Many men approached a community pharmacist for ED treatment and those with and without a PDE5i prescription had an equivalent ED severity and comorbidity profile. Community pharmacists should be trained in current concepts underlying the diagnosis and management of ED to enable them to educate men and encourage them to seek further medical care, increasing the chance of early detection of undiagnosed comorbidities such as cardiovascular disease.

Understanding the effects of sildenafil treatment on erection maintenance and erection hardness.

INTRODUCTION: Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. Although intuitively related, the link between erection hardness and erection maintenance has not been formally established and quantified. AIM: To understand the components of erection maintenance through statistical modeling. METHODS: Data from a double-blind placebo-controlled trial of fixed-dose sildenafil (100 or 50 mg, 8 weeks) with open-label extension of flexible-dose sildenafil (100 and 50 mg, 4 weeks) were analyzed. Erection maintenance was assessed with item 4 (how often erection was maintained) or item 5 (difficulty in maintaining erection) of the International Index of Erectile Function (IIEF). Erection hardness was assessed with the Erection Hardness Score. MAIN OUTCOME MEASURES: Longitudinal modeling estimated mean treatment differences averaged over the double-blind phase for sildenafil 100 mg vs. placebo and 50 mg vs. placebo. Statistical mediation analysis was applied to partition the effect of sildenafil (pooled into one treatment group) on erection maintenance directly and indirectly through erection hardness. RESULTS: Longitudinal mean differences for sildenafil 100 and 50 mg vs. placebo were high (P < 0.0001 for each), with large standardized effect sizes (>0.8). Mediation modeling showed that sildenafil treatment affected maintenance directly as well as indirectly via erection hardness, when measured by IIEF item 4 (direct effect, 44.6%; indirect effect, 55.4%) or IIEF item 5 (direct effect, 56.9%; indirect effect, 43.1%). CONCLUSIONS: Sildenafil treatment significantly improved erection maintenance, a physiologic requirement for satisfactory sexual performance. According to our model, only approximately half of the effect of sildenafil on erection maintenance was estimated to be driven through direct effects. Rather, the effect of sildenafil on erection maintenance seems to be substantially driven by erection hardness. Therefore, achievement of optimal initial erection hardness appears to be an important treatment goal for enhancing erection maintenance and achieving successful ED treatment.

The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials.

INTRODUCTION: Erectile dysfunction is a treatable condition that affects a large proportion of men. Most men do not seek medical help for their ED because of embarrassment or social stigma that may lead some men to self-treat. AIM: To evaluate men's ability to self-assess their suitability for 50 mg sildenafil use after reviewing patient information materials. MAIN OUTCOME MEASURES: Patient rating of patient information materials, self-assessment of suitability for sildenafil use, and clinician assessment of sildenafil suitability. METHODS: Men in the UK were recruited through newspaper, radio, and internet advertisements. Eligible men reviewed the 50 mg sildenafil patient information materials (packaging materials and patient information leaflet) at the in-person visit and then completed a survey to rate the materials and self-assess their suitability for sildenafil use. A clinician, blinded to the participant's ED status and self-assessed sildenafil suitability, then conducted a one-on-one interview to assess the participant's ED status and suitability for sildenafil treatment. The primary analysis was the concordance of self-assessed suitability versus clinician-assessed suitability. RESULTS: The initial study phase included 113 generally healthy men, mean age 40.2 ± 13.1 years. The second phase included 70 men with comorbid prostate or cardiac conditions, mean age 60.7 ± 7.8 years. The 183 men rated the patient information materials as easy to understand; few participants reported problems understanding the materials, and many participants learned new information. The concordance rate between clinician-assessed suitability and self-assessed suitability was 73.9% (95% confidence interval [CI] = 66.7-81.2%). When accounting for men who would not take sildenafil even though they were suitable or would seek additional information from a healthcare professional prior to using sildenafil, the concordance rate was 90.1% (95% CI = 85.8-94.4%). CONCLUSION: The results of this UK study suggest that men are capable of using written sildenafil patient education materials to accurately assess their suitability for treatment with 50 mg sildenafil.

Characteristics, behaviors, and attitudes of men bypassing the healthcare system when obtaining phosphodiesterase type 5 inhibitors.

INTRODUCTION: Men may choose to bypass the healthcare system to obtain a phosphodiesterase type 5 inhibitor (PDE5i). AIM: Evaluate the characteristics and purchasing patterns of men obtaining a PDE5i without prior healthcare professional (HCP) interaction. MAIN OUTCOME MEASURES: Prior HCP interaction, defined as having a prescription for any PDE5i, having a PDE5i sample from a physician, or buying the PDE5i in a retail pharmacy; and erectile dysfunction (ED, the Massachusetts Male Aging Study single-item question) were assessed. A multivariate regression analysis determined predictive factors for PDE5i purchase without prior HCP interaction. Methods. A Web-based observational study was conducted in the United Kingdom, Germany, and Italy. RESULTS: Of the 11,899 participants, 1,252 (10.5% [95% CI, 10.0-11.1%]) reported PDE5i use in the last 6 months. PDE5is were obtained without prior HCP interaction by 403 users (32.3% [95% CI, 29.6-34.8%]); 65.5% of them had ED. Overall prevalence of men using PDE5is without HCP interaction was 3.0% (95% CI, 2.6-3.5%), 4.1% (95% CI, 3.5-4.6%), and 2.8% (95% CI, 2.1-3.5%) for men aged 18-34, 35-50, and >50 years, respectively (P = 0.0045). Predictive factors for obtaining a PDE5i without prior HCP interaction were embarrassment to speak to a physician (P = 0.0009) and the perception that this would be the cheapest way to get the medicine (P = 0.03). CONCLUSIONS: Based on these findings, it can be estimated that approximately 6 million men in Europe might currently bypass the healthcare system to obtain a PDE5i. In addition to the risks associated with use of PDE5is from uncontrolled sources, because most of these men have ED, they also miss the opportunity for important health information or medical follow-up. HCPs should actively address ED and offer treatment to discourage men from seeking uncontrolled sources of ED medicines.

Emotional changes in men treated with sildenafil citrate for erectile dysfunction: a double-blind, placebo-controlled clinical trial.

INTRODUCTION: Erectile dysfunction (ED) has been associated with several comorbidities and can cause significant loss of quality of life and self-esteem. AIM: In men with ED, to use the validated Self-Esteem and Relationship (SEAR) questionnaire to evaluate changes in self-esteem associated with sildenafil treatment of ED and to assess changes dependent on concomitant comorbid conditions. METHODS: This was a 14-week, international, randomized, parallel-group, double-blind, flexible-dose (25, 50, or 100 mg), placebo-controlled study of sildenafil in men aged >or=18 years with a clinical diagnosis of ED (score

Scoring correspondence in outcomes related to erectile dysfunction treatment on a 4-point scale (SCORE-4).

INTRODUCTION: The Erection Hardness Score (EHS), a validated single-item patient-reported outcome (PRO), may provide a simple method to capture erectile dysfunction (ED) symptoms and to monitor treatment outcome. AIM: To map the relationship between the EHS, which was used as the anchor, and other validated PROs: International Index of Erectile Function (IIEF), Quality of Erection Questionnaire (QEQ), Sexual Experience Questionnaire (SEX-Q), and Self-Esteem and Relationship questionnaire (SEAR). Methods. Data were from a trial of flexible-dose sildenafil (50 or 100 mg) in 209 men with ED. MAIN OUTCOME MEASURES: A mixed-effects repeated-measures model with EHS as a categorical explanatory variable and each of the other PROs, as a separate dependent variable, was applied to analyze the longitudinal data from randomization to the end of the 10-week, double-blind, placebo-controlled phase and the 6-week open-label phase. EHS data, which were generated at each sexual encounter (event), were averaged per patient over the same recall period that preceded administration of the other PRO questionnaires. RESULTS: Scores on all domains of the IIEF and SEX-Q, as well as the SEAR total score and SEAR Sexual Relationship domain, discriminated on all EHS categories. The QEQ total score discriminated on all EHS categories except EHS 1 and EHS 2. Although the model did not impose any functional relationship between PRO score and EHS, an approximately linear relationship existed between the EHS and all other PROs, which was especially pronounced for those PROs that were more directly related to erectile quality or function. CONCLUSIONS: The relationship between discrete EHS categories and PRO scores demonstrates the close correspondence of erectile hardness with erectile function (IIEF), erection quality (QEQ), overall sexual experience (SEX-Q), and ED-related psychosocial factors (SEAR) in men with ED.

Efficacy, tolerability and satisfaction with sildenafil citrate 100-mg titration compared with continued 50-mg dose treatment in men with erectile dysfunction.

OBJECTIVE: To evaluate the efficacy, tolerability, and treatment satisfaction after initiating treatment with sildenafil 50 mg and later titrating to 100 mg, compared with continuing treatment with sildenafil 50 mg, in men with erectile dysfunction (ED). PATIENTS AND METHODS: A multicentre, parallel-group trial was conducted in two 4-week periods. In period 1, patients received 50-mg doses of sildenafil single-blinded for 4 weeks. In period 2, patients were randomized to double-blind, placebo-controlled treatment with sildenafil 50 mg or sildenafil 100 mg for 4 weeks. All patients were aged >or=18 years with a documented clinical diagnosis of ED (score of

Invasive aspergillosis: is treatment with "inexpensive" amphotericin B cost saving if "expensive" voriconazole is only used on demand?

BACKGROUND: Voriconazole for the treatment of invasive aspergillosis (IA) shows superior clinical outcome and tolerability compared to conventional amphotericin B. However, the latter is often used as initial treatment due to lower drug acquisition costs. Therefore we performed a cost-effectiveness analysis. METHODS: A decision analytic model was designed to compare the cost-effectiveness of a regimen of voriconazole followed by conventional amphotericin B to a regimen of conventional amphotericin B followed by voriconazole. Patients initiated on treatment either completed initial therapy or switched to second line therapy due to toxicity or non-response. Probability of a switch was based on clinical trial data and local rates of renal toxicity. Resource use in the hospital was taken from the Global Comparative Aspergillosis (GCA) study. Costs were based on local drug acquisition costs, local cost estimates for hospitalisation and adjusted additional costs of amphotericin B-induced acute renal failure from the literature. Effectiveness was defined as survival at 12 weeks from the GCA study. An incremental cost-effectiveness ratio was estimated as the incremental cost per life saved comparing voriconazole to conventional amphotericin B. RESULTS: Based on this model, initial therapy of IA with voriconazole reduced total costs when compared to initial therapy with conventional amphotericin B (CHF 37 878/patient vs CHF 49 861/patient) and resulted in better survival at 12 weeks, making it the dominant treatment in terms of incremental cost-effectiveness. Results were most sensitive to alternative assumptions of the incidence of acute renal failure, but cost savings were sustained for voriconazole over a wide range of values. CONCLUSION: Considering that initial therapy with voriconazole is both cost-saving and results in better clinical outcomes, voriconazole is the dominant cost-effective option for initial therapy of IA, despite very low drug acquisition costs of conventional amphotericin B.