The influence of repeated injections on pharmacokinetics and biodistribution of different types of sterically stabilized immunoliposomes

AbstractSterically stabilized immunoliposomes (IL) with diameters of about 135 nm carrying mouse IgG, either coupled directly to the liposome surface, or linked to the terminal ends of grafted poly(ethylene glycol) (PEG) chains by a recently described conjugation procedure (Cyanur-PEG-PE), were intravenously injected into rats and the elimination kinetics and biodistribution were determined and compared with control liposomes. The amounts of conjugated antibodies were about 30 μg/μmol total lipid for all IL. In naive rats, plain pegylated liposomes displayed the longest blood circulation time, whereas the terminal-coupled IL exhibited the fastest elimination. Liposomes containing the underivatized anchor molecules circulate nearly as long as plain pegylated liposomes, indicating that the fast elimination of the IL can be attributed to the presence of antibodies.A second injection of identical liposomes 14 days after the first injection had a considerable influence on the pharmacokinetic parameters of the liposomes. The circulation time of plain pegylated liposomes drastically dropped by half and their uptake by the liver increased concomitantly, indicating that the PEG, upon repeated injection, ceases to function as an efficient barrier reducing opsonization and/or immune reactions. The circulation time of conventional IL was moderately reduced upon a second injection, whereas that of the terminally coupled IL was nearly unaffected. These differences among the IL demonstrate that the pharmacokinetic behavior of IL is strongly dependent on the antibody conjugation site on the liposome. The observed effects of repeated injections were similar for liposomes of 90-nm diameter. The phenomena described may have important implications for the repeated application of IL as drug carriers

Preoperative CSF Melatonin Concentrations and the Occurrence of Delirium in Older Hip Fracture Patients:A Preliminary Study

BACKGROUND: Delirium is characterized by disturbances in circadian rhythm. Melatonin regulates our circadian rhythm. Our aim was to compare preoperative cerebrospinal fluid (CSF) melatonin levels in patients with and without postoperative delirium. METHODS: Prospective cohort study with hip fracture patients ≥ 65 years who were acutely admitted to the hospital for surgical treatment and received spinal anaesthesia. CSF was collected after cannulation, before administering anaesthetics. Melatonin was measured by radioimmunoassay (RIA). Data on delirium was obtained from medical and nursing records. Nurses screened every shift for delirium using the Delirium Observation Screening Scale (DOSS). If the DOSS was ≥3, a psychiatrist was consulted to diagnose possible delirium using the DSM-IV criteria. At admission, demographic data, medical history, and information on functional and cognitive status was obtained. RESULTS: Seventy-six patients met the inclusion criteria. Sixty patients were included in the analysis. Main reasons for exclusion were technical difficulties, insufficient CSF or exogenous melatonin use. Thirteen patients (21.7%) experienced delirium during hospitalisation. Baseline characteristics did not differ between patients with and without postoperative delirium. In patients with and without postoperative delirium melatonin levels were 12.88 pg/ml (SD 6.3) and 11.72 pg/ml (SD 4.5) respectively, p-value 0.47. No differences between patients with and without delirium were found in mean melatonin levels in analyses stratified for cognitive impairment or age. CONCLUSION: Preoperative CSF melatonin levels did not differ between patients with and without postoperative delirium. This suggests that, if disturbances in melatonin secretion occur, these might occur after surgery due to postoperative inflammation

Unraveling the Relationship Between Delirium, Brain Damage, and Subsequent Cognitive Decline in a Cohort of Individuals Undergoing Surgery for Hip Fracture

ObjectivesTo assess the association between serum S100B levels (a marker of brain damage), delirium, and subsequent cognitive decline. DesignSubstudy of a multicenter randomized controlled trial. SettingSurgical, orthopedic, and trauma surgery wards of two teaching hospitals. ParticipantsIndividuals aged 65 and older (range 65-102) admitted for hip fracture surgery (N = 385). MeasurementsDuring hospitalization, presence of delirium was assessed daily. S100B was assayed in repeated serum samples. Twelve months after discharge, cognitive decline and mortality were evaluated. Cognitive decline was defined as an increase in Informant Questionnaire on Cognitive Decline Short Form score of 1 standard deviation or more or a decrease in Mini Mental State Examination score of 3 points or more between admission and 12 months after discharge. ResultsPremorbid cognitive impairment was present in 226 (58.7%) participants, and 127 (33.0%) experienced perioperative delirium. Multivariable analysis showed that older age and presence of infection, but not of delirium, were associated with higher S100B levels. Levels were also higher after surgery than before. Of participants with perioperative delirium, 58.6% experienced cognitive decline or death, and only age was a risk factor; 36.5% of participants without perioperative delirium experienced cognitive decline or death in the following year, and higher S100B, premorbid cognitive impairment, and older age were risk factors. ConclusionIn a cohort of older adults with hip fracture, no association was found between serum S100B levels and occurrence of delirium. S100B was associated with cognitive decline or death in the first year after hip fracture only in participants without perioperative delirium. S100B seems to be of limited value as a biomarker of brain damage associated with delirium

Physiological melatonin levels in healthy older people: A systematic review

Melatonin plays a major role in maintaining circadian rhythm. Previous studies showed that its secretion pattern and levels could be disturbed in persons with dementia, psychiatric disorders, sleep disorders or with cancer. Also ageing is a factor that could alter melatonin levels, although previous research provides contradicting results. As melatonin supplementation is increasingly applied in older persons as sleep medication, it is important to know if melatonin levels decrease in healthy ageing and/or secretion patterns change. The objective of this study is to determine physiological levels and secretion patterns of melatonin in healthy older people. We performed a systematic review and searched PubMed and Embase for studies published between January 1st 1980 and October 5th 2015 that measured melatonin in healthy persons aged ≥65years. Nineteen studies were retrieved. The number of participants ranged from 5 to 60 per study. Melatonin was mostly measured by radioimmunoassay (RIA) and the number of measurements per 24hours varied from 1 to 96. Sixteen studies showed a secretion pattern with a clear peak concentration, mostly at 0200h or 0300h. Maximum concentrations varied greatly from 11.2 to 91.3pgml(-1). Maximum melatonin level in studies with participants mean aged 65-70years was 49.3pgml(-1) and in studies with participants mean aged ≥75years 27.8pgml(-1), p-value <0.001. Total melatonin production in 24hours seems not to change in healthy ageing, but the maximal nocturnal peak concentration of melatonin might decline. It is important to take this into account when prescribing melatonin supplementation to older peopl

Variability of Delirium Motor Subtype Scale-Defined Delirium Motor Subtypes in Elderly Adults with Hip Fracture:A Longitudinal Study

OBJECTIVES: To examine changes in motor subtype profile in individuals with delirium. DESIGN: Observational, longitudinal study; substudy of a multicenter, randomized controlled trial. SETTING: Departments of surgery and orthopedics, Academic Medical Center and Tergooi Hospital, the Netherlands. PARTICIPANTS: Elderly adults acutely admitted for hip fracture surgery who developed delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for 2 days or longer (n = 76, aged 86.4 +/- 6.1, 68.4% female). MEASUREMENTS: Delirium Motor Subtype Scale (DMSS), Delirium Rating Scale R98 (DRS-R98), comorbidity, and function. RESULTS: Median delirium duration was 3 days (interquartile range 2.0 days). At first assessment, the hyperactive motor subtype was most common (44.7%), followed by hypoactive motor subtype (28.9%), mixed motor subtype (19.7%), and no motor subtype (6.6%). Participants with no motor subtype had lower DRS-R98 scores than those with the other subtypes (P CONCLUSION: Motor subtype profile was variable in the majority of participants, although changes that occurred were often related to changes from or to no motor subtype, suggesting evolving or resolving delirium. Changes appeared not be associated with demographic or clinical characteristics, suggesting that evidence from cross-sectional studies of motor subtypes could be applied to many individuals with delirium. Further longitudinal studies should be performed to clarify the stability of motor subtypes in different clinical populations

The Effects of Blood Transfusion on Delirium Incidence

Background: Both anemia and blood transfusion could be precipitating factors for delirium; hence in postoperative patients with anemia at high risk for delirium, it is controversial whether transfusion is the best option. The aim of this study is to investigate the association of anemia and delirium and the role of blood transfusion within the multicomponent prevention strategy of delirium. Methods: We conducted a substudy of a multicenter randomized controlled trial. Four hundred fifteen patients aged 65 to 102 years old admitted for hip fracture surgery were enrolled. Delirium was assessed daily using criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Data on hemoglobin values and transfusion were collected from the electronic medical records. Results: One hundred fifteen (32.5%) patients experienced delirium during hospitalization, 238 (57.5%) had a hemoglobin level Conclusion: Low hemoglobin level is associated with delirium, and receiving a blood transfusion is associated with a lower delirium incidence. It would be interesting to investigate the effect of blood transfusion as part of the multicomponent treatment of delirium in patients with anemia. (C) 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine

Plasma 5-HIAA activity indicative of serotonergic disturbances in cognitively impaired, elderly patients experiencing postoperative delirium

OBJECTIVES: Delirium frequently arises in older demented and non-demented patients in postoperative, clinical settings. To date, the underlying pathophysiological mechanisms remain poorly understood. Monoamine neurotransmitter alterations have been linked to delirium and cognitive impairment. Our aim was to investigate if this holds true in cognitively normal and impaired patients experiencing delirium following hip surgery. METHODS: Monoamines and metabolites were measured in plasma samples of 181 individuals by means of reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Delirium and delirium severity were scored with the Confusion Assessment Method and Delirium Rating Scale-Revised-1998. Cognitive function was assessed using the Informant Questionnaire on Cognitive Decline and the Mini-Mental State Examination, multimorbidity with the Charlson Comorbidity Index. RESULTS: Plasma 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT), was significantly higher in delirious and non-delirious cognitively impaired subjects as compared to control individuals without delirium and cognitive impairment (p < 0.001 and p = 0.007), which remained highly significant after excluding patients taking psychotropic medication (p < 0.0001 and p = 0.003). No significant differences were found for cognitively normal delirious patients, although serotonergic levels were numerically higher compared to control counterparts. CONCLUSIONS: Our findings indicate a general serotonergic disturbance in delirious and non-delirious postoperative patients suffering from cognitive impairment. We observed a similar, but less pronounced difference in delirious patients, which suggests serotonergic disturbances may be further aggravated by the co-occurrence of delirium and cognitive impairment