Fluoroquinolones and tendon disorders

Since the 'thalidomide disaster' in 1961, there is extensive national and intemationallegisiation for the registration and monitoring of drugs. The current drug approval process in most developed countries includes pre-clinical animal testing followed by three phases of clinical testing during which the efficacy and safety of drugs are detennined. Despite this process, however, not all drug effects are known at the moment of marketing approval. For most indications less than 3,000 patients are exposed to a drug during the pre-registration phase. This implies that an adverse reaction can only be detected with 95% certainty if the occurrence is at least 1 per 1,000 patients and the background incidence is zero. After regulatory approval, however, millions of people will use the drug with the possibility that less common unknown adverse drug reactions can emerge. In order to enable continuous reassessment of the benefit/risk ratio of a specific drug in the post-marketing phase, it is necessary to continuously monitor utilisation and effects of drugs after their approval

Про деякі зв'язки та узагальнення пронормальних підгруп

Отримано нові результати щодо зв'язків та узагальнень пронормальних підгруп. Зокрема, розглянуто групи, кожна циклічна підгрупа яких є самоспряжено-переставною. Наведено повний опис таких груп в деяких дуже широких класах груп, які містять в собі всі скінченні групи.Получены новые результаты относительно связей и обобщений пронормальных подгрупп. В частности, рассмотрены группы, каждая циклическая подгруппа которых является самосопряженно-переставляемой. Приведено полное описание таких групп в некоторых очень широких классах групп, которые содержат в себе все конечные группы.New results concerning the connections and generalizations of pronormal subgroups are presented. In particular, we studied groups, in which every cyclic subgroup is self-conjugate-permutable. We obtained the full description of such groups in some very wide classes of groups which contain all finite groups

Changes in antibiotic use in Dutch hospitals over a six-year period: 1997 to 2002

OBJECTIVE: To analyse trends in antibiotic use in Dutch hospitals over the period 1997 to 2002. METHODS: Data on the use of antibiotics and hospital resource indicators were obtained by distributing a questionnaire to all Dutch hospital pharmacies. Antibiotic use was expressed as the number of defined daily doses (DDD) per 100 patient-days and as DDD per 100 admissions. RESULTS: Between 1997 and 2002, the mean length of stay decreased by 18%. The mean number of admissions remained almost constant. Total antibiotic use significantly increased by 24%, from 47.2 in 1997 to 58.5 DDD per 100 patient-days in 2002 (p<0.01), whereas expressed as DDD per admissions it remained constant. Antibiotic use varied greatly between the hospitals. Moreover, the mean number of DDD per hospital of amoxicillin with clavulanic acid, clarithromycin, cefazolin, clindamycin and ciprofloxacin increased by 16, 38, 39, 50 and 52%, respectively. Total antibiotic use was higher in university hospitals than in general hospitals. CONCLUSIONS: Between 1997 and 2002, patients hospitalised in the Netherlands did not receive more antibiotics but, since they remained in the hospital for fewer days, the number of DDD per 100 patient-days increased. For macrolides, lincosamides and fluoroquinolones increases in both DDD per 100 patient-days and in DDD per 100 admissions were observed. It is arguable whether these trends result in an increase in selection pressure towards resistance in the hospitals. Continuous surveillance of antibiotic use and resistance is warranted to maintain efficacy and safety of antibiotic treatment

Severe epistaxis related to intravitreal bevacizumab

Surgical oncolog

Ciprofloxacin pharmacokinetics after oral and intravenous administration in (morbidly) obese and non-obese individuals: a prospective clinical study

Background and Objective Ciprofloxacin is a fluoroquinolone used for empirical and targeted therapy of a wide range of infections. Despite the increase in obesity prevalence, only very limited guidance is available on whether the ciprofloxacin dose needs to be adjusted when administered orally or intravenously in (morbidly) obese individuals. Our aim was to evaluate the influence of (morbid) obesity on ciprofloxacin pharmacokinetics after both oral and intravenous administration, to ultimately guide dosing in this population. Methods (Morbidly) obese individuals undergoing bariatric surgery received ciprofloxacin either orally (500 mg; n = 10) or intravenously (400 mg; n = 10), while non-obese participants received semi-simultaneous oral dosing of 500 mg followed by intravenous dosing of 400 mg 3 h later (n = 8). All participants underwent rich sampling (11-17 samples) for 12 h after administration. Non-linear mixed-effects modelling and simulations were performed to evaluate ciprofloxacin exposure in plasma. Prior data from the literature were subsequently included in the model to explore exposure in soft tissue in obese and non-obese patients. Results Overall, 28 participants with body weights ranging from 57 to 212 kg were recruited. No significant influence of body weight on bioavailability, clearance or volume of distribution was identified (all p > 0.01). Soft tissue concentrations were predicted to be lower in obese individuals despite similar plasma concentrations compared with non-obese individuals. Conclusion Based on plasma pharmacokinetics, we found no evidence of the influence of obesity on ciprofloxacin pharmacokinetic parameters; therefore, ciprofloxacin dosages do not need to be increased routinely in obese individuals. In the treatment of infections in tissue where impaired ciprofloxacin penetration is anticipated, higher dosages may be required.Pharmacolog

Impact of mucositis on oral bioavailability and systemic exposure of ciprofloxacin Gram-negative infection prophylaxis in patients with haematological malignancies

Background Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. Objectives We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. Methods Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. Results In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 mu mol/L (12-23)]. The time to C-max was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively. Conclusions This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.Pharmacolog

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Antibiotic prescribing on admission to patients with pneumonia and prior outpatient antibiotic treatment: a cohort study on clinical outcome

Contains fulltext : 154344.pdf (publisher's version ) (Open Access)OBJECTIVE: Most pneumonia treatment guidelines recommend that prior outpatient antibiotic treatment should be considered when planning inpatient antibiotic regimen. Our purpose was to study in patients admitted for community-acquired pneumonia the mode of continuing antibiotic treatment at the outpatient to inpatient transition and the subsequent clinical course. DESIGN: Retrospective cohort study. SETTING: Dutch PHARMO Record Linkage System. PARTICIPANTS: 7323 patients aged >18 years and hospitalised with pneumonia in the Netherlands between 2004 and 2010. MAIN STUDY PARAMETER: We identified all prescribed antibiotics prior to, during and after hospitalisation. In case of prior outpatient treatment, the continuation of antibiotic treatment on admission was categorised as: no atypical coverage > no atypical coverage; atypical coverage > atypical coverage; no atypical coverage > atypical coverage; and atypical coverage > no atypical coverage. MAIN OUTCOME MEASURES: Length of hospital stay, in-hospital mortality and readmission within 30 days. Results : Twenty-two per cent of the patients had received prior outpatient treatment, of which 408 (25%) patients were switched on admission to antibiotics with atypical coverage. There were no differences in length of hospital stay, in-hospital mortality or readmission rate between the four categories of patients with prior outpatient treatment. The adjusted HR for adding atypical coverage versus no atypical coverage was 0.91 (95% CI 0.55 to 1.51) for time to discharge. For in-hospital mortality and readmission within 30 days, the adjusted ORs were 1.09 (95% CI 0.85 to 1.34) and 0.59 (95% CI 0.30 to 1.18), respectively. CONCLUSIONS: This study found no association between mode of continuing antibiotic treatment at the outpatient to inpatient transition and relevant clinical outcomes. In particular, adding atypical coverage in patients without prior atypical coverage did not influence the outcome