Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy.

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.

Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston area community health survey.

PURPOSE: In this study we investigated the relationship between lower urinary tract symptoms as defined by the American Urological Association symptom index and the metabolic syndrome, and determined the relationship between individual symptoms comprising the American Urological Association symptom index and the metabolic syndrome. MATERIALS AND METHODS: The Boston Area Community Health Survey used a 2-stage cluster design to recruit a random sample of 2,301 men 30 to 79 years old. Analyses were conducted on 1,899 men who provided blood samples. Urological symptoms comprising the American Urological Association symptom index were included in the analysis. The metabolic syndrome was defined using a modification of the Adult Treatment Panel III guidelines. The association between lower urinary tract symptoms and the metabolic syndrome was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. RESULTS: Increased odds of the metabolic syndrome were observed in men with mild to severe symptoms (American Urological Association symptom index 2 to 35) compared to those with an American Urological Association symptom index score of 0 or 1 (multivariate OR 1.68, 95% CI 1.21-2.35). A statistically significant association was observed between the metabolic syndrome and a voiding symptom score of 5 or greater (multivariate adjusted OR 1.73, 95% CI 1.06-2.80) but not for a storage symptom score of 4 or greater (multivariate adjusted OR 0.94, 95% CI 0.66-1.33). Increased odds of the metabolic syndrome were observed even with mild symptoms, primarily for incomplete emptying, intermittency and nocturia. These associations were observed primarily in younger men (younger than 60 years) and were null in older men (60 years old or older). CONCLUSIONS: The observed association between urological symptoms and the metabolic syndrome provides further evidence of common underlying factors between lower urinary tract symptoms and chronic conditions outside the urinary tract.

Modified-release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis.

OBJECTIVE: To examine the effect of sildenafil in patients with Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis (lcSSc). METHODS: In this double-blind, placebo-controlled study, 57 patients with RP secondary to lcSSc were randomized to receive modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo. The primary assessment was the percentage change in the number of RP attacks per week in the per-protocol population. Secondary end points included Raynaud's Condition Score, duration of attacks, RP pain score, endothelial dysfunction assessed by a peripheral arterial tonometric (PAT) device, and serum biomarker levels. RESULTS: The mean percentage reduction from baseline to day 28 in attacks per week was greater for modified-release sildenafil than for placebo (-44.0% versus -18.1%, P = 0.034); the mean number of attacks per week improved from 25.0 at baseline to 19.3 after placebo treatment and from 30.5 to 18.7 after modified-release sildenafil treatment (P = 0.244). Decreases from baseline in Raynaud's Condition Score, duration of attacks, and RP pain score were not significantly different between groups. Mean values and changes from baseline in PAT responses and serum biomarker levels were similar between groups. The most frequent adverse events were headache and dyspepsia; the majority of adverse events were mild or moderate. CONCLUSION: Our findings indicate that modified-release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and was well tolerated. Modified-release sildenafil may be a treatment option in this patient population.

A Retrospective Study of Clinical and Economic Burden of Focal Segmental Glomerulosclerosis (FSGS) in the United States.

INTRODUCTION: Information on the economic burden of focal segmental glomerulosclerosis (FSGS) is sparse. This study characterized health care resource utilization (HCRU) and costs in patients with FSGS, and evaluated the impact of nephrotic range proteinuria on these outcomes. METHODS: This retrospective, observational cohort study used administrative claims data from the Optum Clinformatics Data Mart Database from October 2015 to December 2019. Patients with FSGS (n = 844; first claim = index event) between April 2016 and December 2018 were matched on index date, age, sex, and race to non-FSGS controls (n = 1688). FSGS nephrotic range (urine protein/creatinine ratio >3000 mg/g or albumin/creatinine ratio >2000 mg/g) and non-nephrotic subpopulations were identified. Baseline comorbidities, 12-month post-index all-cause HCRU and costs (per patient per year [PPPY]), and immunosuppressant prescriptions were compared between matched cohorts and between FSGS subpopulations. RESULTS: Comorbidity burden was higher in FSGS. Of 308 patients with available urine protein/creatinine ratio/albumin/creatinine ratio results, 36.4% were in nephrotic range. All-cause HCRU was higher in FSGS across resource categories (all P < 0.0001); 50.6% of FSGS and 23.3% of controls were prescribed glucocorticoids (P < 0.0001). Mean total medical costs were higher in FSGS ($59,753 vs. $8431 PPPY; P < 0.0001), driven by outpatient costs. Nephrotic range proteinuria was associated with higher all-cause inpatient, outpatient, and prescription costs versus nonnephrotic patients (all P < 0.0001), resulting in higher total costs ($70,481 vs. $36,099 PPPY; P < 0.0001). CONCLUSIONS: FSGS is associated with significant clinical and economic burdens; the presence of nephrotic range proteinuria increased the economic burden. New treatment modalities are needed to reduce proteinuria, help improve patient outcomes, and reduce HCRU and associated costs.

A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia.

OBJECTIVES: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men with and without erectile dysfunction (ED). PATIENTS AND METHODS: This was a multicentre, double-blind, placebo- and active-controlled, parallel-group study conducted across 45 centres in North and South America, Europe, and Australia. In all, 418 men aged ≥ 40 years with a clinical diagnosis of BPH, an International Prostate Symptom Score (IPSS) of ≥ 13, and maximum urinary flow rate (Q(max) ) of 5-15 mL/s for a voided volume of > 150 mL were stratified into two groups (with and without ED) and randomized to one of seven treatment groups, i.e. UK-369,003 at 10, 25, 50 or 100 mg modified release (MR), UK-369,003 40 mg immediate release (IR), tamsulosin 0.4 mg prolonged release, or placebo, for 12 weeks. The primary study endpoint was the change in total IPSS after 12 weeks of treatment. Secondary efficacy measures were IPSS storage and voiding subscores, Q(max) , International Index of Erectile Function-Erectile Function domain, questions 5 and 6 of the Quality of Erection Questionnaire, the International Consultation on Incontinence Questionnaire-Male LUTS, the patient-reported treatment-impact questionnaire, and a bladder diary in which patients recorded the number of voluntary urinary voids, volume of urine voided per micturition, leaks, and urgency episodes. RESULTS: The mean change in the IPSS from baseline at week 12 for UK-369,003 100 mg MR and 40 mg IR was -2.91 and -2.50 better than placebo, respectively. There was increasing efficacy with increasing dose of the MR formulation. For UK-369,003 100 mg MR, Q(max) improved by 2.10 mL/s compared with 0.84 mL/s in the placebo group. CONCLUSIONS: UK-369,003 had clinically meaningful efficacy and was well tolerated in men with LUTS associated with BPH. The Bayesian statistical analysis gave high posterior probabilities for true differences between UK-369,003 100 mg MR and placebo. There was greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo.

A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder.

OBJECTIVES: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED). PATIENTS AND METHODS: This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥ 18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥ 8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72-h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function-Erectile Function domain (IIEF-EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire-Male LUTS, and the patient-reported treatment impact questionnaire. RESULTS: Overall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK-369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF-EF and QEQ scores in all UK-369,003 treatment groups compared with placebo. CONCLUSIONS: These data provide no evidence of efficacy for UK-369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo.

Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston Area Community Health Survey.

PURPOSE: In this study we investigated the relationship between lower urinary tract symptoms as defined by the American Urological Association symptom index and the metabolic syndrome, and determined the relationship between individual symptoms comprising the American Urological Association symptom index and the metabolic syndrome. MATERIALS AND METHODS: The Boston Area Community Health Survey used a 2-stage cluster design to recruit a random sample of 2,301 men 30 to 79 years old. Analyses were conducted on 1,899 men who provided blood samples. Urological symptoms comprising the American Urological Association symptom index were included in the analysis. The metabolic syndrome was defined using a modification of the Adult Treatment Panel III guidelines. The association between lower urinary tract symptoms and the metabolic syndrome was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. RESULTS: Increased odds of the metabolic syndrome were observed in men with mild to severe symptoms (American Urological Association symptom index 2 to 35) compared to those with an American Urological Association symptom index score of 0 or 1 (multivariate OR 1.68, 95% CI 1.21-2.35). A statistically significant association was observed between the metabolic syndrome and a voiding symptom score of 5 or greater (multivariate adjusted OR 1.73, 95% CI 1.06-2.80) but not for a storage symptom score of 4 or greater (multivariate adjusted OR 0.94, 95% CI 0.66-1.33). Increased odds of the metabolic syndrome were observed even with mild symptoms, primarily for incomplete emptying, intermittency and nocturia. These associations were observed primarily in younger men (younger than 60 years) and were null in older men (60 years old or older). CONCLUSIONS: The observed association between urological symptoms and the metabolic syndrome provides further evidence of common underlying factors between lower urinary tract symptoms and chronic conditions outside the urinary tract.

Drug development: from concept to marketing!

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events.

A review of the most common patient-reported outcomes in COPD--revisiting current knowledge and estimating future challenges.

Patient-reported outcome (PRO) measures that quantify disease impact have become important measures of outcome in COPD research and treatment. The objective of this literature review was to comprehensively evaluate psychometric properties of available PRO instruments and the ability of each of them to characterize pharmaceutical treatment effects from published clinical trial evidence. Identified in this study were several PRO measures, both those that have been used extensively in COPD clinical trials (St George's Respiratory Questionnaire and Chronic Respiratory Questionnaire) and new instruments whose full value is still to be determined. This suggests a great need for more information about the patient experience of treatment benefit, but this also may pose challenges to researchers, clinicians, and other important stakeholders (eg, regulatory agencies, pharmaceutical companies) who develop new treatment entities and payers (including but not limited to health technology assessment agencies such as the National Institute for Health and Care Excellence and the Canadian Agency for Drugs and Technologies in Health). The purpose of this review is to enable researchers and clinicians to gain a broad overview of PRO measures in COPD by summarizing the value and purpose of these measures and by providing sufficient detail for interested audiences to determine which instrument may be the most suitable for evaluating a particular research purpose.

Cardiovascular co-morbidity in chronic kidney disease: Current knowledge and future research needs.

Chronic kidney disease (CKD) is recognised as a health concern globally and leads to high rates of morbidity, mortality and healthcare expenditure. CKD is itself an independent risk factor for unfavorable health outcomes that include cardiovascular disease (CVD). Coronary artery disease is the primary type of CVD in CKD patients and a significant cause of death among renal transplant patients. Traditional and non-traditional risk factors for CVD exist in patients with CKD. Traditional factors include smoking, hypertension, dyslipidemia and diabetes which are highly prevalent in CKD patients. Non-traditional risk factors of CKD are mainly uraemia-specific and increase in prevalence as kidney function declines. Some examples of uraemia-specific risk factors that have been well documented include low levels of haemoglobin, albuminuria, and abnormal bone and mineral metabolism. Therapeutic interventions targeted at more traditional risk factors which contribute to CVD, have not had the desired effect on lowering CVD events and mortality in those suffering with CKD. Future research is warranted to delineate clear evidence to the benefit of modifying non-traditional risk factors.

Resistant hypertension: a methodological approach to diagnosis and treatment.

Resistant hypertension affects approximately 10% of the hypertensive patient population. It should be differentiated from white-coat hypertension and pseudo-resistant hypertension. Non-compliance to anti-hypertensive therapy remains the most common cause of resistant hypertension. Primary hyperaldosteronism is not as uncommon as previously thought, but its prevalence depends on the selected population. Low-renin resistant hypertension responds to aldosterone blockade when other drugs are apparently inadequately effective. Sleep apnea syndrome can also contribute to the development of resistant hypertension by stimulating aldosterone secretion, which leads to vascular damage and may promote scarring through more direct actions. Normal blood levels of potassium in resistant hypertension do not exclude the possible presence of hyperaldosteronism.