Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men.

The objective of this review was to summarize the literature on the risk factors, comorbidities, and consequences of male hypogonadism, which is defined as a syndrome complex that includes biochemical confirmation of low testosterone (T) and the consistent symptoms and signs associated with low T. A systematic literature search was performed in PubMed/MEDLINE, EMBASE, Cochrane Library for articles published in the last 10 years on risk factors, comorbidities, and consequences of male hypogonadism. Of the 53 relevant studies identified, nine examined potential risk factors, 14 examined potential comorbidities, and 30 examined potential consequences of male hypogonadism. Based on studies conducted in Asia, Australia, Europe, and North & South America, the important factors that predicted and correlated with hypogonadism were advanced age, obesity, a diagnosis of metabolic syndrome (MetS), and a poor general health status. Diabetes mellitus was correlated with hypogonadism in most studies, but was not established as a risk factor. Although diseases, such as coronary heart disease, hypertension, stroke, and peripheral arterial disease did not predict hypogonadism, they did correlate with incident low T. The data reviewed on potential consequences suggest that low T levels may be linked to earlier all-cause and cardiovascular related mortality among men. This literature review suggests that men with certain factors, such as advanced age, obesity, MetS, and poor general health, are more likely to have and develop hypogonadism. Low levels of T may have important long-term negative health consequences.

Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data.

OBJECTIVE: Assess and categorise the available prevalence data on coexistent LUTS and ED in the general population and among individuals consulting a healthcare provider for any reason or when seeking treatment for LUTS and/or ED. METHODS: Literature search of English-language articles published during the last 15 years. RESULTS: Of 23 relevant studies identified, 12 used both the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) as assessment tools and 11 used alternative approaches. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS/ED of any severity was not assessable for men in the general population, but rates ranged from 14-37% based on alternative assessments. In the general male population, 13-29% had moderate to severe LUTS and 8-35% had moderate to severe ED. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS and ED of any severity was 71-80% among men seeking treatment for LUTS, and 74% based on alternative assessments. Among men who sought treatment for either condition, 67-100% had moderate to severe LUTS and 43-59% had moderate to severe ED. Coexistence of LUTS and ED increased with age, ranging from 59-86% among men aged 40s to 60s in primary care to 79-100% in treatment-seeking men with LUTS aged 50s to 70s. Impact on QoL varied, but health-related QoL was generally worse in treatment-seeking men compared with men in the general population. CONCLUSIONS: Although less than one-third of middle-aged and older men in the general population have coexisting LUTS and ED, most men seeking treatment for either LUTS or ED have both conditions. Symptom severity and impact on QoL in each condition increase when LUTS and ED coexist.

A comprehensive review of predictive and prognostic composite factors implicated in the heterogeneity of treatment response and outcome across disease areas.

AIM: To assess and present the current body of evidence regarding composite measures associated with differential treatment response or outcome as a result of patient heterogeneity and to evaluate their consistency across disease areas. METHODS: A comprehensive review of the literature from the last 10 years was performed using three databases (PubMed, Embase and Cochrane). All articles that met the inclusion/exclusion criteria were selected, abstracted and assessed using the NICE level-of-evidence criteria. RESULTS: Forty-nine studies were identified in the data abstraction. Approximately one-third focused on existing composite measures, and the rest investigated emerging composite factors. The majority of studies targeted patients with cancer, cardiovascular disease or psychological disorders. As a whole, the composite measures were found to be disease-specific, but some composite elements, including age, gender, comorbidities and health status, showed consistency across disease areas. To complement these findings, common individual factors found in five previous independent disease-specific literature assessments were also summarised, including age, gender, treatment adherence and satisfaction, healthcare resource utilisation and health status. CONCLUSIONS: Composite measures can play an important role in characterising heterogeneity of treatment response and outcome in patients suffering from various medical conditions. These measures can help clinicians to better distinguish between patients with high likelihood to respond well to treatment and patients with minimal chances of positive therapeutic outcomes. Herein, the individual factors identified can be used to develop novel predictive or prognostic composite measures that can be applicable across disease areas. Reflecting these cross-disease measures in clinical and public health decisions has the distinctive appeal to enable targeted treatment for patients suffering from multiple medical conditions, which may ultimately yield significant gains in individual outcomes, population health and cost-effective resource allocation.

A review of treatment response in type 2 diabetes: assessing the role of patient heterogeneity.

The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes.

The economics of upper gastrointestinal bleeding in a US managed-care setting: a retrospective, claims-based analysis.

OBJECTIVE: To assess 12-month healthcare resource utilization and costs associated with upper gastrointestinal (UGI) bleeding events. METHODS: Patients hospitalized with a UGI bleeding event were identified in US national health-plan claims data (1999-2003) and propensity matched to control patients without UGI bleeding in the same health plan. Matching criteria included age, gender, index date, Charlson Comorbidity Index score, geographic region, and prior medical utilization. RESULTS: A total of 9,033 UGI-bleed patients and 579,018 control patients met the inclusion criteria, yielding 4,651 matched pairs. After matching, differences between the UGI bleed and general population cohorts remained for office visits, ER visits, and ER costs during the 6-month baseline period prior to the index date. During the 12 months following the index date, both UGI-related healthcare utilization and total healthcare, medical, and pharmacy costs incurred by the UGI-bleed cohort were significantly greater (p< 0.0001) than those incurred by the general population cohort (mean of $20,405 vs. 3,652), even after excluding the initial hospitalization costs (mean of $11,228 vs. 3,652). Costs were primarily due to inpatient hospitalizations (mean of $13,059 for the UGI-bleed cohort vs. $729 for the general population cohort) and ambulatory services (mean of $4,037 for the UGI-bleed cohort vs. $1,537 for the general population cohort). Sixteen percent of the UGI-bleed cohort had a GI-related hospitalization, and about 40% of total costs occurred after the initial hospitalization. CONCLUSIONS: Patients with UGI bleeds experienced significantly higher (p< 0.0001) 12-month health-resource utilization and costs than patients without UGI bleeds. This study provides empirical evidence of the long-term economic burden associated with UGI bleeding. Interpretation of the results should take into account the lack of available information in claims data that could have an effect on study outcomes, such as particular clinical and disease-specific parameters that are not mitigated by propensity score and comorbidity index matching. In addition, this study is limited by the intensive demographic matching that was done between the two cohorts, which may have eliminated the sickest UGI patients and the healthiest general health-plan population patients.

Physician perception of patient adherence compared to patient adherence of osteoporosis medications from pharmacy claims.

OBJECTIVE: This study explored physicians' perceptions of patient adherence to medications compared with patient adherence derived by administrative data in the treatment of osteoporosis. RESEARCH DESIGN AND METHODS: A study involving written questionnaires from prescribers treating patients with postmenopausal osteoporosis (PMO) compared the questionnaire responses to pharmacy claims of these prescribers' patients' refill patterns. Approximately 2000 physicians from a large US health plan were faxed or mailed a survey. Data from the physician survey were merged with administrative claims data of the participating physicians' patients. RESULTS: A total of 412 physicians (21.8%) responded. Although a low response rate, there were no significant demographic differences between participating and non-participating physicians. Surveyed physicians reported that 66% of their patients had private/commercial coverage and over 60% reported seeing their PMO patients annually. Overall, physicians estimated that 69.2% of patients were adherent 80% of the time after 12 months of therapy. Yet, pharmacy claims data for those physicians' patients indicated 48.7% of patients were adherent (defined as having an MPR of >or=80%) after 12 months of therapy. Physicians overestimated their patients' adherence regardless of medication class and across physician specialties. Regression modeling revealed that physicians who have been in practice longer estimated fewer patients as adherent, whereas those who prescribe more PMO treatments estimate a greater number of patients as adherent. Providers cited side effects and affordability of medication as the most frequent reasons for non-adherence. CONCLUSIONS: Physicians overestimate patient adherence to PMO therapies. Improving physician awareness of medication non-adherence to PMO therapies may facilitate physician-patient dialogue, with the aim of identifying patient-centered reasons for non-adherence. These discussions are important because patients with poorer adherence have a higher risk of fracture. Future research should focus on reasons for patient non-adherence to osteoporosis regimens and intervention strategies that improve communication between the provider and patient. Findings must be considered within the limitations of this claims database analysis. Some degree of incomplete or incorrect coding may exist, and the presence of a claim for a filled prescription does not indicate that the medication was consumed or taken as prescribed. Patients included in the study are not necessarily representative of all patients being treated for osteoporosis.

Multiple-dose plasma pharmacokinetic and safety study of LY450108 and LY451395 (AMPA receptor potentiators) and their concentration in cerebrospinal fluid in healthy human subjects.

The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.