SUMMARYWhat is known and objective: The prevailing theory regarding Alzheimer disease (AD) is that insoluble amyloid b-peptide (Ab) plays a critical role in the cortical plaques characteristic of the disease. Because Ab is formed from the sequential splicing of amyloid precursor protein (APP) catalysed by 'secretase' enzymes (a, b and c), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of Ab in AD. With recent clinical trial failures, is the Ab theory wrong? Methods: Literature searches were conducted on the topics of secretases and clinical trials, including PubMed searches, United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected and evaluated for relevance and quality. Results and discussion: Several direct-acting (e.g. CTS-21166, LY2811376) and indirect-acting (e.g. ACI-91) b-secretase inhibitors and several c-secretase inhibitors (e.g. avagacestat, JNJ-40418677 and semagacestat) have not fared well in early clinical trials due to the lack of efficacy or concerns over possible serious side effects.
BackgroundFluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Elevated drug concentrations of fluoroquinolones in the urine and therapy with high-dose levofloxacin are believed to overcome resistance and effectively treat infections caused by resistant bacteria. The ASPECT-cUTI phase 3 clinical trial (ClinicalTrials.gov, NCT01345929 and NCT01345955, both registered April 28, 2011) provided an opportunity to test this hypothesis by examining the clinical and microbiological outcomes of high-dose levofloxacin treatment by levofloxacin minimum inhibitory concentration.MethodsPatients were randomly assigned 1:1 to ceftolozane/tazobactam (1.5 g intravenous every 8 h) or levofloxacin (750 mg intravenous once daily) for 7 days of therapy. The ASPECT-cUTI study provided data on 370 patients with at least one isolate of Enterobacteriaceae at baseline who were treated with levofloxacin. Outcomes were assessed at the test-of-cure (5–9 days after treatment) and late follow-up (21–42 days after treatment) visits in the microbiologically evaluable population (N = 327).ResultsTest-of-cure clinical cure rates above 90% were observed at minimum inhibitory concentrations ≤4 μg/mL. Microbiological eradication rates were consistently >90% at levofloxacin minimum inhibitory concentrations ≤0.06 μg/mL. Lack of eradication of causative pathogens at the test-of-cure visit increased the likelihood of relapse by the late follow-up visit.ConclusionsResults from this study do not support levofloxacin therapy for complicated urinary tract infections caused by organisms with levofloxacin minimum inhibitory concentrations ≥4 μg/mL.Trial registrationClinicalTrials.gov, NCT01345929 and NCT01345955 Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-2057-2) contains supplementary material, which is available to authorized users.
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