Principles and practice of HIV-protease inhibitor pharmacoenhancement

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (C_trough or C_min) plasma concentrations, which are close to, or below, the plasma protein binding‐corrected inhibitory concentration (IC₅₀ or IC₉₅) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug–drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher C_min levels, and in most cases prolonged elimination half‐lives. The long‐term clinical benefits of PK enhancing are unknown as are the long‐term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low‐dose RTV in HIV‐infected patients. Head‐to‐head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.     

NKT cells play critical roles in the induction of oral tolerance by inducing regulatory T cells producing IL-10 and transforming growth factor beta, and by clonally deleting antigen-specific T cells

Oral tolerance is the systemic unresponsiveness induced by orally administered proteins. To explore the roles of natural killer T (NKT) cells in oral tolerance, we induced oral tolerance to ovalbumin (OVA) in NKT cell-deficient mice. In CD1d-/- mice, the induction of tolerance to orally administered high- or low-dose OVA was impaired. Dendritic cells (DCs) in the Peyer's patches (PPs) of CD1d-/- mice fed OVA showed high expression of major histocompatibility complex (MHC) class II and B7 molecules, whereas DCs of control mice fed OVA expressed low levels of these molecules. The adoptive transfer of NKT cells restored oral tolerance and induction of tolerogenic DCs in the PPs and spleens of CD1d-/- mice. Moreover, interleukin (IL)-10 and transforming growth factor (TGF)-beta1 production in vitro were reduced in cells from the spleen and PPs of CD1d-/- mice compared with those of control mice fed OVA. The numbers of OVA-specific CD4+ KJ1-26+ T cells were significantly reduced in the PPs and spleens of DO11.10 mice fed OVA. In contrast, OVA-specific CD4+ KJ1-26+ T cells were not deleted in the PPs or spleens of DO11.10 CD1d-/- mice. In conclusion, NKT cells were found to play an indispensable role in oral tolerance by inducing regulatory T cells, and clonally deleting antigen-specific CD4+ T cells.     

Induction of long-term immunity against respiratory syncytial virus glycoprotein by an osmotic polymeric nanocarrier

Respiratory syncytial virus (RSV) is one of the most common causes of viral deaths in infants worldwide, yet no effective vaccines are available. Here, we report an osmotically active polysaccharide-based polysorbitol transporter (PST) prepared from sorbitol diacrylate and low-molecular-weight polyethylenimine (PEI) showing a potent, yet safe, adjuvant activity and acting as an effective delivery tool for RSV glycoprotein (RGp) antigen. PST showed no toxicity in vitro or in vivo, unlike PEI and the well-known experimental mucosal adjuvant cholera toxin (CT). PST formed nano-sized complexes with RGp by simple mixing, without affecting antigenic stability. The complexes exhibited negative surface charges that made them highly efficient in the selective activation of phagocytic cells and enhancement of phagocytic uptake. This resulted in an improved cytokine production and in the significant augmentation of RGp-specific antibody production, which persisted for over 200 days. Interestingly, PST/RGp enhanced phagocytic uptake owing to the osmotic property of PST and its negative zeta potential, suggesting that PST could selectively stimulate phagocytic cells, thereby facilitating a long-lived antigen-specific immune response, which was presumably further enhanced by the polysaccharide properties of PST.     

Reference Values and Determinants of Fractional Concentration of Exhaled Nitric Oxide in Healthy Children

Purpose

Measurement of the fractional concentration of exhaled nitric oxide (FeNO) is a quantitative, noninvasive, simple, safe method of assessing airway inflammation. While FeNO measurement has been standardized, reference values for elementary school children are scarce. The aim of this study was to establish reference values for FeNO in children.

Methods

FeNO was measured in elementary school children at 6-12 years of age in Seoul, Korea, following American Thoracic Society guidelines and using a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden). A total of 1,252 children completed a modified International Study of Asthma and Allergy in Children (ISAAC) questionnaire; FeNO was measured in 1,063 children according to the protocol and in 808 children defined as healthy controls.

Results

Mean FeNO were 10.32 ppb, 16.58 ppb, and 12.36 ppb in non-atopic, atopic, and all 808 healthy controls, respectively. FeNO was not associated with age and gender. The FeNO reference equations were determined by multiple linear regression analysis, taking into account the variables of age, height, weight, total IgE, eosinophil percent, and bronchial hyper-responsiveness (methacholine PC20). FeNO=0.776+0.003×total IgE+0.340×eosinophil percent; coefficient of determination (R2)=0.084 in the 501 healthy non-atopic controls. FeNO=-18.365+1.536×eosinophil percent, R2=0.183 in the 307 healthy atopic controls; and FeNO=-7.888+0.130×Height+0.004×total IgE+1.233×eosinophil percent, R2=0.209 in the 808 all healthy controls. Eosinophil percent was correlated with FeNO in all healthy controls. FeNO was not associated with BMI.

Conclusion

This study provides reference values for FeNO that can be used to evaluate airway inflammation in elementary school children. Determinants that could most accurately predict FeNO in healthy school-age children were assessed.     

Cross-calibration of multi-frequency bioelectrical impedance analysis with eight-point tactile electrodes and dual-energy X-ray absorptiometry for assessment of body composition in healthy children aged 6–18 years

Background:  In diagnosis and treatment of obesity, body composition analysis including percent body fat (%BF) is useful in the clinical setting. Because bioelectrical impedance analysis (BIA) could be used quickly, easily and was non-invasive in clinical setting, the purpose of the present study was to evaluate the usefulness of multi-frequency BIA with eight-point tactile electrodes (MF-BIA8; InBody 720, Biospace) compared with dual-energy X-ray absorptiometry (DXA) in healthy children and adolescents.
Methods:  A total of 166 children and adolescents under 18 (male, n  = 86; female, n  = 80) were recruited. Height, weight, body mass index (BMI) and Tanner stage were measured for each subject. The body composition such as fat-free mass (FFM), fat mass (FM), and %BF was measured on BIA and DXA and compared.
Results:  On linear regression analysis, DXA FFM = 1.006(BIA FFM) + 0.554, R ² = 0.99 and the standard error of the estimate (SEE) was 1.16 kg; DXA FM = 0.971(BIA FM) – 0.596, R ² = 0.93; SEE, 1.34 kg; and DXA %BF = 0.940(BIA %BF) – 1.026, R ² = 0.858; SEE, 3.03%. Limit of agreement in FFM, FM, and %BF was 0.7 ± 2.3 kg, −0.9 ± 2.9 kg and –2.2 ± 6.1%, respectively.
Conclusions:  Although the %BF was not interchangeable with DXA, MF-BIA8 (InBody 720; Biospace) could be used to measure body composition of children and adolescents in the clinical field because of its high precision.     

Epidemiology of astrovirus infection in children

Human astrovirus (HAstV) is a major cause of acute diarrhea among children, resulting in outbreaks of diarrhea and occasionally hospitalization. Improved surveillance and application of sensitive molecular diagnostics have further defined the impact of HAstV infections in children. These studies have shown that HAstV infections are clinically milder (diarrhea, vomiting, fever) than infections with other enteric agents. Among the 8 serotypes of HAstV identified, serotype 1 is the predominant strain worldwide. In addition to serotype 1, the detection rate of HAstV types 2 to 8 has increased by using newly developed assays. HAstV is less common compared with other major gastroenteritis viruses, including norovirus and rotavirus; however, it is a potentially important viral etiological agent with a significant role in acute gastroenteritis. A better understanding of the molecular epidemiology and characteristics of HAstV strains may be valuable to develop specific prevention strategies.     

Comparison of an Intraoperative Infusion of Dexmedetomidine,Fentanyl, and Remifentanil on Perioperative Hemodynamics,Sedation Quality,and Postoperative Pain Control

We aimed to compare fentanyl, remifentanil and dexmedetomidine with respect to hemodynamic stability, postoperative pain control and achievement of sedation at the postanesthetic care unit (PACU). In this randomized double-blind study, 90 consecutive total laparoscopic hysterectomy patients scheduled for elective surgery were randomly assigned to receive fentanyl (1.0 µg/kg) over 1 minute followed by a 0.4 µg/kg/hr infusion (FK group, n = 30), or remifentanil (1.0 µg/kg) over 1 minute followed by a 0.08 µg/kg/min infusion (RK group, n = 30), or dexmedetomidine (1 µg/kg) over 10 minutes followed by a 0.5 µg/kg/hr infusion (DK group, n = 30) initiating at the end of main procedures of the operation to the time in the PACU. A single dose of intravenous ketorolac (30 mg) was given to all patients at the end of surgery. We respectively evaluated the pain VAS scores, the modified OAA/S scores, the BIS, the vital signs and the perioperative side effects to compare the efficacy of fentanyl, remifentanil and dexmedetomidine. Compared with other groups, the modified OAA/S scores were significantly lower in DK group at 0, 5 and 10 minutes after arrival at the PACU (P < 0.05), whereas the pain VAS and BIS were not significantly different from other groups. The blood pressure and heart rate in the DK group were significantly lower than those of other groups at the PACU (P < 0.05). DK group, at sedative doses, had the better postoperative hemodynamic stability than RK group or FK group and demonstrated a similar effect of pain control as RK group and FK group with patient awareness during sedation in the PACU. (World Health Organization registry, KCT0001524).