Safety,tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine,in healthy subjects: A randomized study

Background

GS-4774 is a recombinant, heat-killed, yeast-based immunotherapy engineered to express hepatitis B virus (HBV)-specific antigens. GS-4774 is being developed as a therapeutic vaccine for chronic HBV infection. The aim of this study was to assess the safety, tolerability and immunogenicity of GS-4774 in healthy subjects.

Design

This was a randomized, open-label, dose-ascending study. Subjects were allocated to one of three dose groups (n = 20 per group) to receive 10, 40 or 80 yeast units (YU; 1 YU = 10⁷ yeast) of GS-4774 in two immunization regimens (five subcutaneous injections at weekly intervals with one monthly booster or three subcutaneous injections at monthly intervals). T-cell-mediated responses were determined by interferon (IFN)-γ enzyme-linked immunospot (ELISpot) assay and lymphocyte-proliferation assay (LPA).

Results

Adverse events were reported by 39 of 60 (65%) subjects; all were mild or moderate and none was serious. Adverse events occurred most frequently in the highest dose group, 80 YU, and the number of individual events was higher after weekly immunization than monthly. The most common adverse events were injection-site reactions. Most (88%) subjects responded to GS-4774 by at least one of the T-cell assays. Following immunization with GS-4774, IFN-γ-producing T-cells specific for HBV antigens were detectable in 30 (51%) subjects. The ELISpot response was observed at all doses, with the highest frequency of responders occurring at the highest dose (10 YU: 45%; 40 YU: 35%; 80 YU: 74%). Proliferative responses to HBV recombinant antigens were observed in 90% subjects; responses were mainly independent of GS-4774 dose and immunization regimen.

Conclusions

GS-4774 was safe and well-tolerated in healthy subjects with injection-site reactions being the most frequently reported adverse events. With both weekly and monthly regimens, GS-4774 provided HBV-specific immune responses at all doses evaluated. Further evaluation of GS-4774 is ongoing in patients with chronic HBV infection.Clinical trial registry: Clinicaltrials.gov (NCT01779505)     

Cellular mechanisms of cadmium-induced toxicity: a review

Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20–30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in significant quantities from cigarette smoke, food, water and air contamination and is known to have numerous undesirable effects in both humans and animals. Cadmium has a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenicity and endocrine and reproductive toxicities. At the cellular level, cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Most important seems to be cadmium interaction with DNA repair mechanism, generation of reactive oxygen species and induction of apoptosis. In this article, we have reviewed recent developments and findings on cadmium toxicology.     

Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Society for Blood and Marrow Transplantation

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.     

Prophylactic dexamethasone for postoperative nausea and vomiting in pediatric strabismus surgery: a dose ranging and safety evaluation study

In this double-blind, randomized, placebo-controlled study, we evaluated the efficacy and safety of different doses of prophylactic IV dexamethasone for postoperative nausea and vomiting (PONV) in 168 children (aged 2-15 yr) scheduled for strabismus surgery. Patients received IV dexamethasone 0.25 mg/kg (D 0.25), 0.5 mg/kg (D 0.5), 1.0 mg/kg (D 1), or saline (S) immediately after induction of general anesthesia. Patients were discharged 24 h after surgery. Nausea and vomiting were assessed at 0-2, 2-6, and 6-24 h after surgery. Blood glucose was measured preoperatively and at 4 h after study drug administration. Wound healing and infection were assessed after 1 wk. More patients in group S had vomiting at 0-2, 2-6, and 6-24 h (P = 0.001, P = 0.003, and P = 0.04, respectively) and required larger doses of rescue antiemetics compared with the dexamethasone groups. Fewer patients in the dexamethasone groups (6, 3, and 6 in D 0.25, D 0.5, and D 1, respectively) had severe PONV compared with group S (P = 0.001). No significant increase in postoperative blood glucose levels was observed and wound healing was satisfactory in all four groups. The results suggest that dexamethasone 0.25 mg/kg is more effective than saline and equally effective compared with larger doses for preventing PONV for pediatric strabismus surgery.     

Local antibiotics: panacea for long term skeletal traction

Long periods of skeletal traction are frequently needed in busy tertiary centres due to long waiting lists for surgery. A frequent complication is pin track infection, which leads to revision of pin insertion or switching over to skin traction. A prospective study was conducted on sixty patients with upper tibial pin insertion for various causes. Antibiotic (injection Cephazolin 0.5 g after sensitivity testing--250 mg on each side) was injected on thirty patients at the site of pin insertion and no antibiotic was injected in 30 controls. Only one stage one pin track infection was seen in the study group (3% cases), where as six cases had stage 1 infection, one case had stage 2 infection and two cases had stage 3 infections in the control group (30% cases). This study showed the usefulness of this modification in preventing morbidity in patients who are planned for long-term skeletal traction by temporarily suppressing the local flora.     

Cerebro-oculo-facio-skeletal (COFS) syndrome in siblings

The authors report two sibs with COFS syndrome and review the relevant literature in brief. They emphasize the importance of prenatal diagnosis in this syndrome that has many mimics.     

Effect of intraoperative magnesium infusion on perioperative analgesia in open cholecystectomy

STUDY OBJECTIVE: To study the role of magnesium sulphate (MgSO4) on analgesic requirement, pain, discomfort, and sleep during perioperative period. DESIGN: prospective, double-blinded, randomized study. SETTINGS: Operating room and recovery ward at a university teaching hospital. PATIENTS: 50 ASA physical status I and II patients scheduled for elective open cholecystectomy with general anesthesia. INTERVENTIONS: patients were randomly allocated to receive MgSO4 or saline intravenously (i.v.). Patients in the magnesium group received 50% MgSO4 (50 mg kg(-1)) in 100 mL saline and those in the control group received an equal volume of saline i.v. during the preoperative period followed by 50 mL hr(-1) infusion of either MgSO4 (15 mg kg(-1) hr(-1)) or saline until the end of surgery. MEASUREMENTS AND MAIN RESULTS: Morphine requirement, pain during rest and on coughing, discomfort, and insomnia were assessed during the postoperative period for 24 hours. Intravenous morphine 40 microg kg(-1) increments were given to all patients in the postoperative period for analgesia. Patients in the magnesium and control groups had similar morphine requirement during the first 24 hours postoperatively (p = 0.07). Patients in the magnesium group experienced less discomfort during the first hour after the operation. They also had better sleep quality during the first postoperative night than did the control group patients (p < 0.05). The frequency of side effects was similar in the two groups. CONCLUSION: Administration of intraoperative MgSO4 as an adjuvant analgesic in patients undergoing open cholecystectomy resulted in better pain relief and comfort in the first postoperative hour, but it did not significantly decrease the postoperative morphine requirement. Magnesium sulphate resulted in better sleep quality during the postoperative period, without any significant adverse effects. The role of MgSO4 as an adjuvant analgesic in open cholecystectomy needs to be studied further.     

A Physiologically-Based Pharmacokinetic Model of Drug Detoxification by Nanoparticles

Nanoparticles (NPs) may be capable of reversing the toxic effects of drug overdoses in humans by adsorbing/absorbing drug molecules. This paper develops a model to include the kinetic effects of treating drug overdoses by NPs. Depending on the size and the nature of the NPs, they may either pass through the capillary walls and enter the tissue space or remain only inside the capillaries and other blood vessels; models are developed for each case. Furthermore, the time scale for equilibration between the NP and the blood will vary with the specific type of NP. The NPs may sequester drug from within the capillaries depending on weather this time scale is larger or smaller than the residence time of blood within the capillary. Models are developed for each scenario. The results suggest that NPs are more effective at detoxification if they are confined to the blood vessels and do not enter the tissues. The results also show that the detoxification process is faster if drug uptake occurs within the capillaries. The trends shown by the model predictions can serve as useful guides in the design of the optimal NP for detoxification.