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We propose the hypothesis that small high‐density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Background: The association of periodontitis and Porphyromonas gingivalis (Pg) with rheumatoid arthritis (RA) is incompletely understood. To gain further insights, we evaluated periodontal status, oral, serum and joint inflammatory profiles, and Pg biomarkers in RA patients.Methods: In this cross-sectional study, we evaluated 33 patients with predominantly untreated new-onset RA, 20 healthy individuals (HIs), and 20 non-RA chronic periodontitis patients. Thirteen mediators (IFN-γ, IL-10, IL-17A, IL-6, IL-8, CXCL10, TNF-α, CXCL13, IL-23, MMP-1, MMP-3, MMP-8, MMP-9) were measured in serum, synovial fluid, saliva and gingival crevicular fluid (GCF) by multiplex immunoassay. Serum Pg IgG antibodies and subgingival Pg DNA were determined.Results: Most RA patients (91%) received routine dental care; only one currently smoked. Ten (30.3%) had periodontal health, 13 (39.4%) had gingivitis, and 10 (30.3%) had periodontitis. Th1 and innate immune responses predominated in serum. Many mediators were concentrated in joints, particularly IL-6, IL-8, and CXCL10. However, salivary and GCF profiles were more restricted, emphasizing neutrophilic inflammation (IL-8, MMP-8) and MMP-9. Compared with HI, most RA patients, regardless of periodontal status, had significantly elevated oral fluid levels of these mediators, with suppression of GCF IL-10, a pattern similar to non-RA periodontitis patients. Pg antibodies or DNA however were primarily associated with clinical periodontitis.Conclusions: Despite routine dental care, RA patients often had inflammation in oral fluids, but inflammatory profiles differed from serum and joints. Neutrophilic inflammatory profiles in oral fluids, regardless of periodontal status, suggests that gingival tissues are a common, and often unrecognized, site of extra-articular inflammation in RA. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There is increasing concern about the use of those medicines in children which have not been fully studied and licensed for childhood use. Such use is not uncommon, due in large part to a lack of availability of fully licensed products and formulations that are suitable for children. • There is little published information on the views of the public on this important area of paediatric care. WHAT THIS STUDY ADDS • A survey of 1000 members of the public in Northern Ireland indicated that such use of medicines in children is not well known. • However, when informed about this practice, the majority believed that it would compromise safety and increase the likelihood of adverse effects. They also believed that parents/guardians should be told if their child was prescribed a medicine that had not been fully tested in children. • Participants in the survey indicated that they would be reluctant to involve their child in a clinical trial to help with the licensing process unless the child was suffering from a life-threatening illness. AIMS To explore awareness and views of the general public on unlicensed use of medicines in children and on the participation of children in clinical trials. METHODS Members of the public completed a questionnaire survey administered by face-to-face interview in public areas in N. Ireland. The main outcome measures were the views on unlicensed use of medicines in children and on clinical trials in children. RESULTS One thousand participants (59.2% female) took part; 610 were parents. Most participants (86%) had no previous knowledge about unlicensed use of medicines in children. Being a parent did not influence this nor did being a parent of a child who suffered from a health problem ( P > 0.05). Most participants (92%) felt that parents should be told about unlicensed use of medicines, with the doctor most frequently selected as the person who should inform parents. At the outset, only 1.8% of participants felt that the use of medicines in children was unsafe. However, having been informed about unlicensed use of medicines, this proportion increased dramatically (62.4%; P < 0.001). Views on whether participants would enter a child of their own into a clinical trial varied according to the health status of the child ( P < 0.05) i.e. a child in good health (3.9%) vs a child with a life-threatening condition (41.9%). CONCLUSIONS There is limited public knowledge of unlicensed use of medicines in children and a general reluctance to involve children in clinical trials unless the child to be involved has a life-threatening condition. [ABSTRACT FROM AUTHOR]

To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment. Data were collected from 35 infants (gestational age 25–34 weeks; postnatal age 1–77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1–0.2 mg kg−1) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared. The concentration-time course of indometacin was best described by a one-compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h−1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l−1. Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l−1 24 h after the last dose. Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l−1. Although the pharmacokinetic estimates will be affected by both interindividual and within-individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome. [ABSTRACT FROM AUTHOR]

1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml-1 h to 1066 ng ml-1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0-1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml-1 h) vs 397 ng ml-1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy.

In a randomised crossover study in volunteers plasma midazolam levels were estimated for 24 h following 15 mg by mouth, either preceded by no medication or following 24 h therapy with ranitidine. Administration of the H2-receptor blocker significantly increased bioavailability of the benzodiazepine and resulted in higher plasma levels for the first 6 h after taking midazolam. This was accompanied by a greater soporific effect.

The pharmacokinetics of a fixed dose of midazolam (0.3 mg kg-1 i.v.) were studied in detail in 115 healthy patients or volunteers and nine were found with a prolonged elimination half-life. A further 102 patients had an abbreviated pharmacokinetic study, of whom five showed a similar abnormality. Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug.

1 The bioavailabilty of phenytoin sodium (Epanutin both alone and in combination with activated dimethicone and Asilone (a proprietary antacid preparation containing activated dimethicone) was examined in six healthy male volunteers. 2 The bioavailability of phenytoin when given concomitantly with Asilone was decreased in five of six volunteer subjects (by greater than 30% in three subjects) although this decrease was not shown to be statistically significant. 3 Dimethicone, which has been shown to decrease phenytoin absorption in vitro did not affect phenytoin bioavailability in vivo. 4 It is recommended that when treating patients stabilised on phenytoin one should exercise caution with concomitant phenytoin and antacid therapy to guard against possible changed drug absorption.