First Generic Teriparatide: Structural and Biological Sameness to Its Reference Medicinal Product.

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility-mass spectrometry (IM-MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP.

A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer.

PURPOSE: This clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. METHODS: A Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28-168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FINDINGS: All 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28-168 in 96.8% (95% CI, 92.5%-98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. IMPLICATIONS: Leuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

[INERTIA study: Clinical inertia in non-insulinized patients on oral hypoglycemic treatment. A study in Spanish primary and specialty care settings]. / Inercia clínica en pacientes con diabetes mellitus tipo 2 no insulinizados en tratamiento con hipoglucemiantes orales. Estudio INERCIA.

BACKGROUND AND OBJECTIVE: To study clinical inertia in the management of oral hypoglycemic agents (OHA) in non-insulin treated patients with type 2 diabetes mellitus (T2DM) in Spain. PATIENTS AND METHOD: Epidemiological, cross-sectional, retrospective (2 years), multicenter study. Clinical inertia was measured as the total number of patients without OHA treatment intensification divided by the total number of patients with inadequate HbA1c values (≥7%), multiplied by 100. Total clinical inertia (TCI) was the absence of OHA treatment intensification in all visits with a HbA1c≥7% values in the previous 2 years; partial clinical inertia (PCI) occurred when this absence only occurred in some of these visits. We assessed OHA treatment compliance with the Morisky-Green test. RESULTS: We included 2,971 patients, 1,416 adequately controlled (HbA1c<7%) and 1,555 inadequately controlled (HbA1c≥7%). PCI prevalence was 52.5%(95% confidence interval [95% CI] 52.4-52.6%) while TCI prevalence was 12.8% (95% CI 12.2-13.8%). PCI was lower in patients adequately controlled as compared with those inadequately controlled (31.4% vs. 71.8%; P<.001). PCI was associated with sedentary lifestyle, hypertension and higher prevalence of micro and macrovascular complications. Only 38.0% of patients were compliant with the OHA treatment, being this percentage even lower in subjects with ICP. Two variables were independently associated with ICP: female sex (odds ratio [OR] 1.43; 95% CI 1.09-1.86%) and a shorter duration of DM2 (OR 0.98; 95% CI 0.95-0.99). CONCLUSIONS: One out of 2 patients with T2DM and treated with OHA without insulin suffer from PCI. Only 4 out of 10 patients are compliant with OHA treatment. Female sex and a shorter duration of T2DM are independently associated with PCI.

Effects of fluvastatin extended-release (80 mg) alone and in combination with ezetimibe (10 mg) on low-density lipoprotein cholesterol and inflammatory parameters in patients with primary hypercholesterolemia: a 12-week, multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Combining lipid-lowering agents with complementary mechanisms of action can provide greater cholesterol reductions than using either agent alone, improving achievement of target low-density lipoprotein cholesterol (LDL-C) levels. OBJECTIVES: The aim of this study was to assess the effects of fluvastatin extended-release (XL) 80 mg/d administered alone or combined with ezetimibe 10 mg/d on plasma lipid levels and inflammatory parameters in patients with primary hypercholesterolemia. The tolerability of both regimens was also evaluated. METHODS: In this multicenter, randomized, open-label, parallel-group study, patients with hypercholesterolemia were randomized in a 1:1 ratio to receive fluvastatin XL 80 mg/d alone or in combination with ezetimibe 10 mg/d for 12 weeks. The primary end point was the percentage change from baseline to week 12 in LDL-C level with fluvastatin XL + ezetimibe combination therapy compared with fluvastatin XL alone. Plasma concentrations of inflammatory biomarkers were measured at baseline and week 12. Proportions of patients who achieved National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goals were calculated. Tolerability was assessed by the monitoring and recording of all adverse events (AEs) and laboratory values. RESULTS: A total of 82 patients were enrolled (mean [SD] age, 50.0 [12.0] years; 44% male; 100% white; mean [SD] weight, 73.5 [14.9] kg; combination group, 38 patients; monotherapy group, 44). Fluvastatin XL + ezetimibe and fluvastatin XL monotherapy were associated with significant decreases from baseline in mean LDL-C level (by 49.9% and 35.2%, respectively; between-group difference, P < 0.001). Fluvastatin XL + ezetimibe was associated with significantly greater reductions from baseline than fluvastatin XL monotherapy in total cholesterol (38.2% vs 27.5% P < 0.001), triglycerides (21% vs 3.8% P = 0.02) and apolipoprotein B (34.8% vs 22.5% P < 0.001). NCEP ATP III LDL-C goals were achieved by 87% of patients receiving fluvastatin XL + ezetimibe and 67% of patients receiving fluvastatin XL monotherapy (between-group difference, P = 0.042). The combination was associated with significantly lowered high-sensitivity C-reactive protein (hs-CRP) levels in patients with high baseline hs-CRP (>2 mg/L; P < 0.02), >1 cardiovascular risk factor (P < 0.05), or hypertension (P = 0.015); both regimens were associated with significantly reduced plasma levels of interleukin-1B. No significant between-group differences in the incidences of AEs were found. Most AEs were mild or moderate in intensity. Headache was the most common AE, occurring in 5/44 (11.4%) patients in the fluvastatin XL group and 2/38 (5.3%) patients in the fluvastatin XL + ezetimibe group. One serious AE (convulsive crisis) occurred in a patient receiving fluvastatin XL + ezetimibe, but was not suspected to be related to study medication. CONCLUSION: Fluvastatin XL in combination with ezetimibe was found to be well-tolerated and effective, allowing the majority (87%) of these patients with primary hypercholesterolemia to achieve current treatment goals, and reduced hs-CRP levels in patients at higher cardiovascular risk.

Risk factors for human Herpesvirus 8 infection and AIDS-associated Kaposi's sarcoma among men who have sex with men in a European multicentre study.

We aimed to identify risk factors for Kaposi's sarcoma (KS) among HIV-positive patients and behaviors associated with human Herpesvirus 8 (HHV-8) infection, as well as to assess KS incidence and mortality rates longitudinally. To fulfill the first objective, a European case-control study was designed in the early 1990s (each KS case was matched to 2 controls with another AIDS indicative disease). After the discovery of HHV-8, serology testing enabled us to assess risk factors for KS development among HHV-8 and HIV-1 coinfected men who have sex with men (MSM), as well as risk factors for HHV-8 infection. HHV-8 seroprevalence was determined using a latent immunofluorescence assay. Relevant information was obtained by means of a questionnaire and medical charts review. Assessment of risk factors for KS development and HHV-8 infection was performed using conditional and unconditional logistic regression models, respectively. A low CD4 count was the only significant risk factor for KS. HHV-8 infection was most strongly linked to the number of life-time sex partners, and multiple body fluids such as saliva and semen are quite likely involved in sexual transmission. Longitudinal follow up showed a significant protective role for highly-active antiretroviral therapy (HAART) both on KS development and mortality of KS patients. Although more conclusive data from cohort studies are needed to better define specific transmission mechanisms for HHV-8, our results contribute to explain why KS incidence is higher among MSM, and the decreasing KS incidence trend observed in countries with universal access to HAART.

[Diagnosis of allergic asthma in allergy and pneumology outpatient clinics]. / Diagnóstico de asma alérgica en consultas de alergología y neumología.

OBJECTIVES: To estimate the prevalence of diagnosis of allergic asthma in patients with persistent asthma attending allergy or pneumology outpatient clinics and to describe the clinical management of asthma in these patients. METHODS: Systematic random sampling was used to retrospectively include 382 patients aged between 12 and 65 years old with a diagnosis of persistent asthma (according to GINA criteria) who had attended allergy or pneumology outpatient clinics during the previous year. Allergic asthma was defined as the presence of sensitization to any common allergen according to the results of specific IgE determinations and/or skin tests. Data on the treatment of asthma were gathered. RESULTS: Allergy studies were performed in 99.5% of the patients attending allergy centers and in 76.5% of those attending pneumology centers. A diagnosis of allergic asthma was made in 90.6% (95% CI: 86.5-94.7) and 46.1% (95% CI: 39.0-53.2), respectively. The prevalence of allergic asthma was highest in young male patients with less severe asthma. According to the GINA criteria, 14.1% of patients from allergy centres and 23.0% of those from pneumology centers were classified as having severe persistent asthma. Twenty-four percent of patients attending allergy clinics and 5.7% of those attending pneumology centers received bronchodilator treatment exclusively. CONCLUSIONS: Diagnosis of allergic asthma was much higher in allergy clinics than in pneumology centres. Although some of this difference may be due to more frequent performance of allergy studies in allergy clinics, the most probable explanation lies in the differences observed in the profiles of patients attending the two types of center.

[Management of type 2 diabetic patients in primary care in Spain]. / Tratamiento de los pacientes con diabetes mellitus tipo 2 en atención primaria en España.

BACKGROUND AND OBJECTIVE: We assess the metabolic control, complications, quality of life related to health (QLRH) and the type and amount of medical resource consumption (MRC) in type 2 diabetic patients (2DMp) followed by primary care physicians (PCP) in Spain. PATIENTS AND METHOD: We studied 628 2DMp divided in 4 cohorts: 1. Either newly diagnosed 2DMp who required pharmacological treatment or failed to non-pharmacological measures; 2. Patients pharmacologically treated for less than 1 year; 3. Patients with pharmacological treatment for more than 1 year; 4. Patients with impaired fasting glucose (control group). RESULTS: Eighty percent of the subjects were overweight. At baseline, 27.9, 23.5 and 36.9% of patients from cohorts 1, 2 and 3, respectively, had HbA1C < 8%. After 6 months of follow-up, 14.6, 21.3 and 22.8% of patients from cohorts 1, 2 and 3, respectively, still had "bad control". At baseline, 38.0%, 21.2% and 20.7% of patients from cohorts 1, 2, and 3, respectively, had "bad lipid profile". After 6 months, 57.4%, 54.2% and 45.3% of cohorts 1, 2 and 3, respectively, still had plasma cLDL levels > 130 mg/dl. Complications were more frequent in cohort 3. During the 6-month period, MRC was higher among 2DMp than controls (p < 0.05) and higher among patients from cohort 3 (p < 0.05) compared with all the other patients. More diabetic than control patients and more patients from cohort 3 than patients from cohort 1 and 2 reported that their expected quality of life would be better without diabetes. CONCLUSIONS: One out of four of diabetic patients studied had HbA1C and lipids higher than the limits suggested by guidelines. Type 2 diabetes is associated with higher MRC and worse QLRH. This situation is worse among long-term diabetic patients.

Risk Factors for AIDS Associated Kaposi's Sarcoma. An European Multicentre Case Control Study.

EURO-SHAKS, European study on HIV associated Kaposi's sarcoma, is a BIOMED 1 project financed by the European Union (DG XII). The Spanish side of the project has been financed by FISS (Fondo de Investigaciones Sanitarias). The aims of this study are to identify possible genetic, behavioural, biological and environmental risk factors for HIV associated Kaposi's sarcoma through a multicentre case-control study. An extensive personal questionnaire, a clinical data form and blood sample is required from all participants. In addition, a cutaneous biopsy is request from KS patients. The presence of several European groups in this project implies a large and diverse sample size and will allow to correlate the behaviour, clinical and biological data in different geographical areas, and therefore study the possible transmission routes as well as the natural history of the putative causal agent of KS. One of the main objectives of EURO-SHAKS is to create a European Bank of AIDS biological samples for possible future investigations.