Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.

Our study utilizes a longitudinal isotopic metabolic labeling approach in vivo in combination with organelle fraction proteomics to address the role of parkin in mitochondrial protein turnover in mice. The use of metabolic labeling provides a method to quantitatively determine the global changes in protein half-lives whilst simultaneously assessing protein expression. Studying two diverse mitochondrial populations, we demonstrated the median half-life of brain striatal synaptic mitochondrial proteins is significantly greater than that of hepatic mitochondrial proteins (25.7 vs. 3.5 days). Furthermore, loss of parkin resulted in an overall, albeit modest, increase in both mitochondrial protein abundance and half-life. Pathway and functional analysis of our proteomics data identified both known and novel pathways affected by loss of parkin that are consistent with its role in both mitochondrial quality control and neurodegeneration. Our study therefore adds to a growing body of evidence suggesting dependence on parkin is low for basal mitophagy in vivo and provides a foundation for the investigation of novel parkin targets.

Sorafenib treatment of advanced renal cell carcinoma patients in daily practice: the large international PREDICT study.

BACKGROUND: Patients with advanced renal cell carcinoma in routine clinical practice can differ considerably from those in phase III studies. PATIENTS AND METHODS: PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with sorafenib) was a prospective, noninterventional study of open-label sorafenib for the treatment of advanced RCC conducted in 18 countries. Patient characteristics, therapy duration, tumor status, and tolerability were assessed at baseline and during routine follow-up. RESULTS: Overall, 2599 patients were evaluable for safety and 2311 for efficacy. The diverse population included patients with brain metastases (5%), non-clear-cell histologies (17%), high Memorial Sloan-Kettering Cancer Center risk score (11%), poor Eastern Cooperative Oncology Group performance status (PS ≥ 2, 29%), and patients with no previous nephrectomy (16%) or no previous systemic therapy (37%). The median duration of sorafenib therapy was 7.3 months and was similar in clinically relevant subgroups (eg, patients with PS 2, brain metastases, or concomitant hypertension or diabetes [range, 6.7-7.0 months]). The median duration of therapy was shorter for patients with PS 3 or non-clear-cell histologies (4.6 and 4.8 months, respectively). The most common drug-related adverse events were hand-foot skin reaction (20%), diarrhea (17%), and rash (8%). CONCLUSION: Sorafenib was generally well tolerated and provided clinical benefit in a large, diverse population of patients with advanced RCC treated in routine clinical practice.

Intravenous or sequential ciprofloxacin therapy in hospitalised patients with a broad spectrum of infections: a post-marketing surveillance study.

OBJECTIVE: This study set out to obtain up-to-date information on the efficacy, safety and tolerability of ciprofloxacin as well as the time to improvement and recovery, and to explore data on drug utilisation in hospitalised patients with a special focus on intravenous therapy with ciprofloxacin. METHODS, DESIGN AND PATIENTS: Hospitalised patients with a broad spectrum of infections were included in this non-interventional multicentre study. In order to be included, the patients had to be treated with intravenous ciprofloxacin for a minimum of 2 days. Physicians were advised to pay attention to the contraindications mentioned in the summary of product characteristics. They documented demographic and anamnestic data, the type and severity of the infection, concomitant diseases and medications, the course of clinical and laboratory symptoms, and the treatment. In addition, they rated the overall efficacy of intravenous ciprofloxacin and recorded the time to improvement and recovery. All adverse events were reported. RESULTS: 1012 hospitalised patients with mild to severe clinical infections were included. Their mean age was 61.5 years (SD 16.7), and 57.4% were males. Intravenous ciprofloxacin was given to 28.7% of patients exclusively and 69.6% started with intravenous ciprofloxacin and were switched later to oral treatment. The majority of patients presented with one defined source of infection (77.9%), mainly located in the respiratory tract (40.2%), the abdomen (21.4%), the urinary tract (14.9%) or the kidney (13.4%). Other infections involved the bones and joints (4.5%) or were classified as sepsis (8.0%); 39.6% of infections were classified as severe. Infection symptoms improved in 86.2% of the patients within 5 days. The overall improvement and recovery rates were 91.9% and 85.8%, respectively. Efficacy of ciprofloxacin was judged as 'very good' or 'good' in 86.5% of patients. Tolerability was judged as 'very good' or 'good' in 98.2% of patients. Adverse events occurred rarely and were reported in 2.17% of patients. Seventeen (1.68%) fulfilled the criteria of serious adverse events. In only 0.4% of patients was a relationship between the adverse event and ciprofloxacin treatment suspected. CONCLUSIONS: Intravenous ciprofloxacin is an effective and well tolerated antibacterial treatment in hospitalised patients experiencing a broad spectrum of mild to severe infections.

Real-life treatment of acute exacerbations of chronic bronchitis with moxifloxacin or macrolides: a comparative post-marketing surveillance study in general practice.

OBJECTIVE: To compare the real-life treatment of acute exacerbations of chronic bronchitis (AECBs) using moxifloxacin tablets or one of the oral macrolides azithromycin, clarithromycin or roxithromycin in terms of symptom relief, time until improvement and cure, overall efficacy and tolerability. METHODS: This prospective, non-interventional, multicentre study included out-patients with AECB whose last exacerbation was treated with a macrolide. The current AECB was treated either with moxifloxacin or with one of the macrolides azithromycin, clarithromycin or roxithromycin. Data were obtained on the patient's characteristics, disease and treatment history, the course of the current AECB including time to improvement and cure, and the final assessments of efficacy and tolerability. All adverse events were recorded in patients treated with moxifloxacin; for patients receiving macrolides, only drug-related adverse events were reported. RESULTS: 464 physicians treated 904 patients with moxifloxacin and 846 patients with one of the macrolides. Age, sex and body mass index were well matched between the two treatment groups. However, more moxifloxacin than macrolide patients presented with a generally bad condition (62.8% vs 48.6%). About 42% of patients in both groups had had chronic bronchitis for 1-5 years, and about 27% for 5-10 years. The mean number of AECBs in the previous 12 months was 2.7 and 2.6, respectively. Moxifloxacin was administered to most patients for 5 (43.8%) or 7 days (42.4%). Patients in the macrolide group were treated in most cases with clarithromycin 500 mg for 4-7 days, roxithromycin 300 mg for 6-7 days or azithromycin 500 mg for 3 days. Physicians assessed overall efficacy and tolerability as 'very good' or 'good' in 96.1% and 98.1%, respectively, of moxifloxacin-treated patients and in 67.5% and 91.7%, respectively, of macrolide-treated patients. The mean duration until improvement and cure of AECB was 3.2 days (+/- SD 1.5) and 6.2 days (+/- 2.6) in moxifloxacin-treated patients compared with 4.5 days (+/- 1.8) and 7.5 days (+/- 3.0) in macrolide-treated patients (p < 0.0001). CONCLUSION: The results of this study conducted under real-life treatment conditions in patients with AECBs who were previously treated with a macrolide showed faster symptom relief and higher recovery rates with moxifloxacin compared with macrolides. The two treatment groups had comparably good safety and tolerability profiles.

The real-life safety and efficacy of vardenafil: an international post-marketing surveillance study--results from 29 358 German patients.

We assessed the safety, efficacy and patient acceptability of vardenafil (Levitra, Bayer HealthCare, Leverkusen, Germany) under real-life conditions in patients with erectile dysfunction (ED) in a multinational post-marketing surveillance study. An initial and up to two follow-up visits were documented for 29 358 German ED patients receiving vardenafil. Patients were interviewed about overall treatment success, and individual sexual attempts were evaluated in a patient questionnaire. Overall erectile improvement was reported by 93.9% of physicians, and similar improvement rates were reported for both 10 mg and 20 mg vardenafil dosages. Most patients experienced improved erections after the first (73.6%) or second (88.5%) tablet. Sexual attempts were successful with respect to partner penetration in 94.9% of patients and with respect to maintenance of erection during intercourse in 87.7% of patients. Adverse drug reactions were very rare (1.3% of patients). Vardenafil was highly effective, reliable and well tolerated in ED patients treated under real-life conditions.

Efficacy and tolerability of sequential intravenous/oral moxifloxacin therapy in pneumonia: results of the first post-marketing surveillance study with intravenous moxifloxacin in hospital practice.

OBJECTIVE: This study aimed to investigate the efficacy, safety and tolerability of sequential intravenous (IV)/oral therapy with moxifloxacin in pneumonia under general hospital treatment conditions. PATIENTS AND METHODS: Patients with pneumonia were documented in this non-interventional multicentre study. The patients were treated with IV moxifloxacin or moxifloxacin sequential therapy (IV and oral) in hospitals throughout Germany. Exclusion criteria were limited to the contraindications mentioned in the summary of product characteristics. The participating hospital-based physicians documented the patients' demography, anamnesis, antibiotic pretreatment, concomitant diseases and medications. Moxifloxacin therapy and symptom status were recorded daily up to the ninth day and on the last day of treatment. The physicians assessed the efficacy and tolerability of IV moxifloxacin therapy and reported all adverse events observed within the treatment period. RESULTS: The 1749 documented patients had a mean age of 66.2 (SD 15.5) years; 56.4% were males and 43.5% females. The majority (99.3%) were treated with moxifloxacin 400mg once daily. On average, moxifloxacin was given for 7.6 days (SD 3.2). In cases of sequential therapy (78.9% of patients), IV moxifloxacin was switched to oral moxifloxacin after a mean of 4.1 days (SD 1.8). Moxifloxacin produced a significant clinical improvement in 58.2% of patients by day 3 of therapy, in 84.2% by day 5 and in 89.4% by day 7. Recovery occurred in 27.0% of patients by day 5, in 54.0% by day 7 and in 87.0% by day 14. It took a mean of 3.4 days (SD 1.9) until improvement and 7.2 days (SD 3.0) until cure. Overall efficacy of IV moxifloxacin therapy was rated by the physicians as 'very good' or 'good' in 82.9% of patients. Tolerability was rated in 94.3% of patients as 'very good' or 'good'. Adverse events were recorded for 92 (5.3%) patients, but events were considered by the attending physician to be related to moxifloxacin therapy for only 45 patients (2.6%). CONCLUSIONS: IV moxifloxacin shows high efficacy in the treatment of pneumonia under routine clinical treatment conditions. IV moxifloxacin relieves pneumonia-associated symptoms rapidly and allows an early switch to oral administration. Because of its high efficacy and very good safety and tolerability profile, moxifloxacin delivers excellent benefits as first-line therapy for pneumonia.

Efficacy and tolerability of moxifloxacin in patients with sinusitis treated in general practice : results of a post-marketing surveillance study.

OBJECTIVE: To assess the efficacy, safety and tolerability of moxifloxacin, an 8-methoxy fluoroquinolone, in patients with respiratory tract infections (RTIs) treated in general practice in Germany. Different RTIs were analysed separately, and this paper focuses on patients with acute sinusitis. METHODS, DESIGN AND PATIENTS: This was an open-label, prospective, uncontrolled, post-marketing surveillance study undertaken between October 2001 and June 2002. Symptoms of sinusitis (fever, cough, nasal obstruction, nasal secretion and headache) were assessed at baseline and at follow-up visits, and classified as 'absent', 'mild' or 'severe' by the attending physician. RESULTS: Altogether 9036 patients were treated with moxifloxacin, of whom 2405 adult men and women had sinusitis. Sinusitis symptoms were improved or cured in at least 92% of patients. Moxifloxacin produced significant improvements after only 3 days (71.6% of patients); 96.2% of patients were improved after 5 days. Most patients (89.5%) had recovered by day 8 and 97.3% by day 10. Physicians rated moxifloxacin therapy as 'good' or 'very good' in 96.6% of patients and almost all favoured prescribing moxifloxacin in the future. Very few adverse events were reported with moxifloxacin (<0.4%), and were mostly gastrointestinal disturbances. CONCLUSIONS: Moxifloxacin is a very effective and safe treatment for patients with acute sinusitis in general practice and is highly regarded by both physicians and patients because of rapid symptom improvement and good tolerability.

Once-daily moxifloxacin therapy for community-acquired pneumonia in general practice : evidence from a post-marketing surveillance study of 1467 patients.

OBJECTIVE: To assess the efficacy, safety and tolerability of oral moxifloxacin in outpatients with respiratory tract infections treated in general practices in Germany with the focus on community-acquired pneumonia (CAP). METHODS, DESIGN AND PATIENTS: This was an open-label, prospective, uncontrolled, post-marketing surveillance study undertaken between October 2001 and June 2002. Symptoms associated with pneumonia were documented at baseline and at follow-up visits. A general assessment was given and the number of days until improvement/cure were recorded by the attending physician at the end of therapy. RESULTS: A total of 9036 patients were treated with moxifloxacin, of which 1467 had CAP. The recommended dosage of moxifloxacin (400mg once daily) was used in 97.8% of all CAP patients. Between the initial and final follow-up visits, symptoms of CAP were either improved or cured in 90-99% of patients. More than half of the patients showed improvement after 3 days (54.2%); 89.2% of patients were improved after 5 days. The mean time for patients to recover was 8.0 +/- 2.7 days, with 88.7% of patients recovered by day 10 of treatment. Physicians rated moxifloxacin therapy as 'very good' or 'good' in 96.6% of patients and virtually all favoured prescribing moxifloxacin again. Ten patients (0.7%) reported adverse events during moxifloxacin therapy, mostly gastrointestinal disturbances. CONCLUSIONS: Moxifloxacin is a very effective and safe treatment for patients with CAP and is highly accepted by physicians and patients because of rapid symptom improvement and good tolerability.

Daily-practice treatment of acute exacerbations of chronic bronchitis with moxifloxacin in a large cohort in Germany.

OBJECTIVE: To monitor the efficacy and safety of moxifloxacin in respiratory tract infections (RTIs) focussing on acute exacerbations of chronic bronchitis (AECB). METHODS: Patients with RTIs could be enrolled in this open-label, prospective, non-controlled post-marketing surveillance study from October 2001 until June 2002 unless moxifloxacin was contraindicated. At the initial visit, data were recorded on patient demographics, diagnosis and clinical symptoms. Two follow-up examinations could be performed to determine cure or improvement based on clinical symptoms, and to record adverse events. Clinical symptoms including fever, cough and purulent sputum were assessed individually. Efficacy, tolerability and patient acceptance were assessed globally at the final visit. RESULTS: Of 9036 enrolled patients, 4328 had AECB, most of whom were treated with moxifloxacin at a daily dose of 400mg. Mean +/- SD time to clinical improvement was 3.4 +/- 1.5 days, and mean +/- SD time to clinical cure was 6.6 +/- 2.4 days. Cure rates were 39.4% at day 5 and 94.3% at day 10. By day 6, the proportion of patients with severe cough decreased from 85.4% at the initial visit to 6.9%, and those with severe dyspnoea from 22.5% to 1.2%. Purulent sputum was absent within 4 days in the majority of cases. Physicians rated efficacy, tolerability and patient acceptance as 'very good' or 'good' in approximately 95% of patients. There were 59 adverse events in 44 (1.0%) patients, most frequently gastrointestinal and nervous system disorders. CONCLUSIONS: This study further confirms that AECB patients treated with moxifloxacin benefit from more rapid symptom relief and that this therapy option is well accepted in general practice.

Effect of add-on acarbose to insulin therapy in routine clinical practice.

OBJECTIVE AND DESIGN: This post-marketing surveillance study collected data on the efficacy and tolerability of acarbose in patients with insulin-treated type 2 diabetes mellitus and, in particular, on its effect on postprandial blood glucose under normal daily practice conditions. PATIENTS AND METHODS: A total of 1142 patients were included in this observational study in which the treating physicians had sole responsibility for determining acarbose doses and other therapeutic measures. Efficacy parameters consisted of fasting and postprandial blood glucose and glycosylated haemoglobin (HbA(1c)). Additionally, cholesterol, triglycerides and weight were analysed. All patient data had to be recorded by the attending physician on a case report form. Patients were asked to self-monitor blood glucose daily after breakfast (1h) and to keep a diary. RESULTS: Mean HbA(1c) improved by 0.9%, fasting blood glucose by 32.4 mg/dL, and postprandial hyperglycaemia by 49.7 mg/dL during the observation period compared with baseline. Comparable results were obtained in combination with conventional, functional or intensive insulin therapy. Mean weight was reduced by 0.7kg. The incidence of acarbose-related side effects was low (6.9%) and consisted mostly of gastrointestinal complaints. The majority of patients assessed acarbose treatment positively. CONCLUSION: The addition of acarbose to different insulin regimens provided an efficacious and safe treatment for better glycaemic and weight control.