Exercise during Hemodialysis in Patients with Chronic Kidney Failure.

BACKGROUND: Patients with kidney failure undergoing hemodialysis experience physical deconditioning and multimorbidity. Exercise interventions may mitigate this outcome, but their clinical role is unclear. METHODS: This multicenter, cluster randomized controlled trial evaluated combined endurance and resistance exercise training during hemodialysis versus usual care in chronic kidney failure. It assessed physical functioning, quality of life, hospitalizations, and overall survival. The primary outcome was the change in the 60-second sit-to-stand test (STS60) between baseline and 12 months. RESULTS: A total of 1211 patients underwent randomization, 917 (65.9±14.4 years; 38.9% female) of whom were included in the full analysis (exercise intervention, n=446; usual care, n=471). At 12 months, the STS60 repetitions improved from 16.2±7.6 to 19.2±9.1 in the exercise group but declined from 16.2±7.1 to 14.7±7.9 in the usual care group (group difference, 3.85 repetitions; 95% confidence interval [CI], 2.22 to 5.48; P<0.0001). The timed up-and-go test (−1.1 seconds; 95% CI, −1.9 to −0.3) and the 6-minute walk test (37.5 m; 95% CI, 14.7 to 60.4) also differed in the exercise group versus usual care group. The physical summary score and vitality subscale of the quality of life questionnaire (i.e., the 36-item Short Form Health Survey) differed in the exercise group versus usual care group, but the other subscales did not change. Adverse events during dialysis sessions were similar in both groups. Median days spent in the hospital annually were 2 in the exercise group and 5 in the usual care group. Mortality and dialysis-specific adverse events were not affected. CONCLUSIONS: Twelve months of intradialytic exercise in patients with kidney failure significantly improved the STS60 compared with usual care. (Funded by the Innovation Fund, Federal Joint Committee; ClinicalTrials.gov number, NCT03885102.)

Development of the Commercial Manufacturing Process for Ipatasertib.

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

A structured exercise programme during haemodialysis for patients with chronic kidney disease: clinical benefit and long-term adherence.

OBJECTIVE: Long-term studies regarding the effect of a structured physical exercise programme (SPEP) during haemodialysis (HD) assessing compliance and clinical benefit are scarce. STUDY DESIGN: A single-centre clinical trial, non-randomised, investigating 46 patients with HD (63.2 ± 16.3 years, male/female 24/22, dialysis vintage 4.4 years) performing an SPEP over 5 years. The SPEP (twice/week for 60 min during haemodialysis) consisted of a combined resistance (8 muscle groups) and endurance (supine bicycle ergometry) training. Exercise intensity was continuously adjusted to improvements of performance testing. Changes in endurance and resistance capacity, physical functioning and quality of life (QoL) were analysed over 1 year in addition to long-term adherence and economics of the programme over 5 years. Average power per training session, maximal strength tests (maximal exercise repetitions/min), three performance-based tests for physical function, SF36 for QoL were assessed in the beginning and every 6 months thereafter. RESULTS: 78% of the patients completed the programme after 1 year and 43% after 5 years. Participants were divided--according to adherence to the programme--into three groups: (1) high adherence group (HA, >80% of 104 training sessions within 12 months), (2) moderate adherence (MA, 60-80%), and 3. Low adherence group (LA, <60%)) with HA and MA evaluated quantitatively. One-year follow-up data revealed significant (p<0.05) improvement for both groups in all measured parameters: exercise capacity (HA: 55%, MA: 45%), strength (HA: >120%, MA: 40-50%), QoL in three scores of SF36 subscales and physical function in the three tests taken between 11% and 31%. Moreover, a quantitative correlation analysis revealed a close association (r=0.8) between large improvement of endurance capacity and weak physical condition (HA). CONCLUSIONS: The exercise programme described improves physical function significantly and can be integrated into a HD routine with a high long-term adherence.

Occupational functioning, sickness absence and medication utilization before and after cognitive-behaviour therapy for generalized anxiety disorders.

BACKGROUND: Cognitive-behaviour therapy (CBT) is efficacious in reducing symptoms of generalized anxiety disorders (GAD). The question is whether it is also efficient, i.e., whether there are also enduring effects with respect to improving utilization of medication and psychotherapy, or occupational functioning and sick leave after the end of treatment. METHOD: The study was based on 44 outpatients (age 18-65 years; HAM-A score ≥18; GAD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria as assessed by standardized interview) who were treated with 25 sessions of CBT (treatment by 12 state-licensed behaviour therapists in office-based practice; no psychotropic treatment for the duration of the therapy). The rate of medication treatment, occupational functioning and sick leave was assessed for 8 months before and after the end of treatment. RESULTS: In the comparison of the pre-treatment and post-treatment periods, 46.5% versus 7.2% of patients used psychotropic medication for at least 4 weeks and had been 3.1 versus 1.1 days on sickness absence per month, respectively. About 70% of patients showed impairment in occupational role performance during the pre-treatment phase compared with 5% to 20%, depending on the dimension, in the follow-up period. CONCLUSIONS: The data suggest that CBT is not only efficacious in terms of symptom reduction but also efficient in terms of reducing inappropriate medication intake and improving occupational functioning.

[4-(imidazol-1-yl)thiazol-2-yl]phenylamines. A novel class of highly potent colchicine site binding tubulin inhibitors: synthesis and cytotoxic activity on selected human cancer cell lines.

Synthesis and cytotoxic activity in the submicromolar range of a series of [4-(imidazol-1-yl)thiazol-2-yl]phenylamines are described. Cell cycle dependent cytotoxicity on RKO human colon carcinoma cells with inducible expression of p27(kip1) and the influence on microtubule formation were investigated. Considering the significant correlation between the IC(50) values of tubulin polymerization inhibition, [(3)H]colchicine competition, and cytotoxicity of the investigated compounds, tubulin is the main cellular target. The inhibition of microtubule formation was shown to be mediated by interference with the colchicine binding site of tubulin. In depth analysis of the investigated compounds allowed the identification of modifications that altered the pharmacological profile of the compounds from a mitosis-inducing phenotype to a G1 cell cycle arresting phenotype.

Prevalence and appropriateness of psychotropic drug use in old age: results from the Berlin Aging Study (BASE).

BACKGROUND: The aim of this epidemiological study is to examine the prevalence and correlates of psychotropic drug use in the very old and to evaluate the appropriateness of psychotropic drug use in very old age. METHODS: Data from the Berlin Aging Study (BASE), a multidisciplinary study of an age- and gender-stratified, randomly selected sample of elderly people living in Berlin are presented. Over-sampling, especially very old men, allows for powerful analyses of this population. All participants went through extensive psychiatric and somatic examinations. Medication intake was assessed by different data sources (interviewing patients and their family physicians, drug inspection at home). Results were brought together in a consensus-conference and research physicians gave operationalized ratings of medication appropriateness. RESULTS: The prevalence of elderly people who were taking at least one psychotropic medication within the 14 days immediately preceding investigation was 29.8%. Of these medications, 68.4% had been taken for longer than one year. There was no effect of age or gender on the scope of psychotropic drug use. Benzodiazepines were taken by 19.8% of the elderly. Antidepressants, neuroleptics and anti-dementia drugs were taken by about 3-4% each. People taking psychotropic drugs had significantly higher levels of psychiatric morbidity, as measured by syndromes and specified diagnoses. Psychotropic drugs were significantly less often judged to be indicated than somatic medications. This is mostly due to benzodiazepines. CONCLUSIONS: Psychotropic drug use is common in old age, but there is no additional increase in usage beyond the age of 70. Intake of psychotropics is mostly oriented at symptoms or syndromes, which explains why benzodiazepines are still the most commonly prescribed psychotropics.

Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder.

BACKGROUND: Current pathophysiological concepts of generalized anxiety disorder (GAD) assume a disturbed exteroceptive sensory system. Furthermore, central serotonergic neurotransmission has been shown to play an important role in anxiety disorder. Cortical signal processing as measured by auditory evoked potentials (AEPs) may reflect the integrity of the exteroceptive sensory system. Because a special aspect of AEP, the loudness dependence of the N1/P2-component (LD), has been related to central serotonergic activity, the LD may be useful for investigating serotonergic dysfunctions in GAD. METHODS: The LD was recorded in 31 medication-free patients with GAD without any psychiatric co-morbidity and in 31 matched control subjects. Dipole source analysis was performed to separate the LD of regions including the primary (LD-tangential dipole) and regions including the secondary auditory cortex (LD-radial dipole). RESULTS: A shallower LD-tangential was observed in patients with GAD as compared to healthy control subjects [F(1,60) = 6.727, p =.012; one-way analysis of variance]. The LD-radial showed no differences between groups. Severity of the anxiety symptoms was not related to the LDs. CONCLUSIONS: The results indicate an altered exteroceptive sensory system in GAD occurring at the level of the primary but not secondary auditory cortex. Because a shallow LD of the primary auditory cortex was related to a high firing rate of neurons in the dorsal raphe nucleus, the results may support evidence for an enhanced serotonergic activity in GAD.