Improved adherence and growth outcomes with jet-delivered growth hormone.

Background We previously reported improved persistence and adherence to daily recombinant growth hormone (rGH) in children using jet transjection delivery compared to using needle-based devices. This study examines the relationship between improved adherence and medium-term growth outcomes in children receiving jet-delivered rGH (JrGH) at a single centre. Methods This was a retrospective longitudinal follow-up study of children (<16 years) treated with daily JrGH (somatropin; Ferring Pharmaceuticals) in the form of Zomacton® with the Zomajet® device. Delivery schedules of home distribution services were utilised to calculate adherence, quantified as the proportion of days covered (PDC) index (PDC > 0.8 adherent, PDC ≤ 0.8 less adherent). Demography, patient history, height standard deviation scores (HTSDS) and difference from mid-parental height SDS (MPHSDS - HTSDS) were extracted from hospital records for up to 3 years of treatment. Results Of 75 patients eligible for JrGH, 52 had PDC treatment and height data for at least 1 year and 22 for 3 years. A greater proportion of patients were classified as adherent in both 1- and 3-year treated cohorts (adherent 30 [57.7%] and 14 [63.6%], less adherent 22 [42.3%] and 8 [36.4%]). After 1 year of JrGH treatment, HTSDS was not significantly different in either adherence group. After 3 years, only adherent patients demonstrated sustained year-on-year increments in HTSDS and significant improvement in target HTSDS positions (by 1.32 SDS) compared to baseline (p = 0.0008). MPHSDS - HTSDS showed a similar significant improvement at 3 years in adherent patients only (p = 0.0043). Conclusions Patients adherent to JrGH demonstrate significant growth improvement compared to baseline over 3 years.

Norbuprenorphine and respiratory depression: Exploratory analyses with new lyophilized buprenorphine and sublingual buprenorphine
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OBJECTIVES: To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression. MATERIALS AND METHODS: Opioid-dependent subjects were randomized 2 : 1 to novel lyophilized rapid-disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels. RESULTS: Respiratory depression (cumulative duration of SpO2 < 90% over 30-minute periods) increased with corresponding exposure levels (AUC30 min) of buprenorphine and particularly with norbuprenorphine. A lower buprenorphine/norbuprenorphine ratio was predictive of respiratory depression. The mean (SD) observed ratio was significantly higher for "bup-lyo" (3.4 (2.8)) compared to "bup-SL" (1.7 (0.77)), p < 0.0001. CONCLUSION: Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.
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Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study.

AIMS: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL"). DESIGN: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. SETTINGS: Specialised clinical trials facility and addictions treatment facility. PARTICIPANTS: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). MEASUREMENTS: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). FINDINGS: Oral lyophilised buprenorphine ("bup-lyo") completely dissolved within 2 min for 58 vs. 5% for "bup-SL." Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of "hold," respiratory function. No serious adverse events (AEs), nor "severe" AEs, although more AEs and Treatment-Emergent AEs with "bup-lyo" (mostly "mild"). PK found greater bioavailability of buprenorphine with "bup-lyo" (but not norbuprenorphine). CONCLUSIONS: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with "bup-lyo" relative to "bup-SL." In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.

Bioavailability, safety and immunogenicity of biosimilar infliximab (BOW015) compared to reference infliximab.

OBJECTIVES: To compare the single-dose pharmacokinetics (PK), safety, and immunogenicity of the biosimilar infliximab (BOW015) to reference infliximab (rIFX) in healthy volunteers and to establish bioequivalence. METHODS: In this randomized, double-blind, parallel-group, single-dose study, subjects received either BOW015 or rIFX. Both drugs were administered as a single IV 5 mg/kg dose over 2 hours on day 1. PK sampling occurred 10 times over 3 days and during safety and immunogenicity follow-up on day 4 and 1, 2, 3, 5, 7, 9, and 12 weeks after the infusion. RESULTS: Of the 84 healthy male Caucasian subjects randomized, 43 received BOW015 and 41 received rIFX. PK parameters (geometric mean) for BOW015 vs. rIFX were as follows; C(max) 142.47 vs. 126.74 µg/mL, AUC(0-t) 36,211 vs. 34,304 h×µg/mL, and AUC(0-inf) 36,775 vs. 34,801 h×µg/mL. The point estimates of the BOW015/rIFX geometric mean ratios (90% CI) were; C(max) 1.13 (1.07 - 1.18), AUC(0-t) 1.06 (0.98 - 1.14), and AUC(0-inf) 1.06 (0.98 - 1.15). Overall, anti-drug antibodies were detected in 18.6% of BOW015-treated subjects and 24.4% of rIFX-treated subjects. A total of 26 (60.5%) subjects in the BOW015 group reported 50 treatment-emergent adverse events (TEAEs) and 27 (65.9%) subjects in the rIFX group reported 54 TEAEs. CONCLUSIONS: Bioequivalence of BOW015 to rIFX is demonstrated as 90% CIs for the study drug mean ratios of C(max), AUC(0-t), and AUC(0-inf) were within the log-transformed ± 20% equivalence range of 0.80 - 1.25. Safety and immunogenicity were also comparable.

A systematic review of human norovirus survival reveals a greater persistence of human norovirus RT-qPCR signals compared to those of cultivable surrogate viruses.

Human noroviruses (hNoV) are the single largest cause of acute gastroenteritis in the western world. The efficacy of hNoV control measures remains largely unknown, partly owing to the inability to grow the virus in vitro and partly to the large number of surrogate studies of unknown relevance. A systematic review of the persistence and survival of hNoV in foods and the environment was undertaken based upon PRISMA (preferred reporting items for systematic reviews and meta analyses) guidelines to answer the questions: (1) "What are the natural hNoV persistence characteristics in food and the environment?" and (2) "How can these properties be altered by applying physical and/or chemical treatments to foods or food contact surfaces?" Over 10,000 citations were screened using defined inclusion and exclusion criteria. One hundred and twenty-six (126) citations were identified for further evaluation and data were extracted based upon the conditions of study and treatment (e.g., treatment parameters, pH, and temperature, time, infectivity, and RT-qPCR results). Since the only markers for hNoV persistence and survival were RT-qPCR data and human challenge studies, citations for further analysis were restricted to only those that included data on hNoV behavior (using RT-qPCR) as compared directly to surrogate virus behavior (using both RT-qPCR and infectivity) in the same study, and clinical studies. Based on these criteria, a total of 12 independent studies (5 for thermal inactivation and 7 for available chlorine) and 3 human challenge studies were identified. RT-qPCR always underestimated reductions in surrogate virus titre as a function of treatment when compared to infectivity. The corresponding reductions in RT-qPCR signals for hNoV under comparable conditions were nearly always less than those observed for the surrogates. These relationships were statistically significant for heat when comparing persistence of hNoV RT-qPCR signals with surrogate MNV-1 RT-qPCR signals (P equal persistence=<0.07); and for free chlorine when comparing persistence of hNoV RT-qPCR signals to those of FCV F-9 (p=<0.01). Overall the data suggest that hNoV are frequently more resistant to typical food and environmental control measures compared with cultivable surrogate viruses, when basing data on comparative RT-qPCR results.

Nationwide linkage analysis in Scotland-Has mortality following hospital admission for Crohn's disease changed in the early 21st century?

BACKGROUND: National Scottish data were used to compare 3-year mortality in patients hospitalized for Crohn's disease (CD) between 1998-2000 and 2007-2009. METHODS: The linked Scottish Morbidity Records database was used to identify patients admitted with CD during two periods: Period 1 (1998-2000) and Period 2 (2007-2009). 3-year mortality and standardized mortality ratio (SMR) were determined and multivariable logistic regression analysis of associated factors was performed. Mortality was determined following four admission types: surgery-elective, surgery-emergency, medical-elective and medical-emergency. 3-year mortality was compared between study periods using age-standardized rates. RESULTS: The number of patients per 100,000 population hospitalized with CD per year was unchanged (15.7 [Period 1]; 14.4 [Period 2]). Overall crude and adjusted 3-year mortality rates were also unchanged (crude mortality 9.0%-9.1%, adjusted mortality odds ratio [OR]=0.87, 95% confidence interval [CI] 0.65-1.17; p=0.36). The adjusted 3-year mortality increased following elective surgery (Period 1: 1/303 [0.3%]; Period 2: 9/261 [3.4%]); OR=13.5 [CI 1.66-109.99]) and decreased following emergency medical admission (Period 1: 99/779 [12.7%]; Period 2:86/802 [10.7%]; OR=0.68 [CI 0.47-0.97]). Directly age-standardized mortality rates were similar (Period 1:338/10,000 person years [CI 282-394]; Period 2:333/10,000 person years [CI 276-390], p=0.2). On multivariable regression, age, deprivation status, comorbidity and the length of hospital stay were associated with mortality in both periods. High 3-year mortality was observed during both periods in patients between 50 and 64years (Period 1: 33/298 [11.1%, SMR=4.8 [CI 3.44-6.63], Period 2: 33/296 [11.1%, SMR=5.9 [4.14-8.22]) and over 65years(Period 1: 94/275 [34.2%, SMR=2.78 [CI 2.42-3.62], Period 2: 78/251 [31.1%, SMR=3.31 [2.64-4.11]). CONCLUSION: Nationwide linkage data demonstrate that overall 3-year mortality after hospitalization for CD is high, especially in patients over 50years, and has not altered between the time periods 1998-2000 and 2007-2009.

Relationship between onset of pain relief and patient satisfaction with fentanyl pectin nasal spray for breakthrough pain in cancer.

BACKGROUND: Satisfaction with pain relief in patients with breakthrough pain in cancer (BTPc) has typically been assessed by overall efficacy without consideration of the rapidity of that response. OBJECTIVE: To determine the relationship between speed of onset of pain relief and patient satisfaction for treated BTPc episodes overall and for individual treatments. DESIGN: Pooled data from two randomized, double-blinded crossover studies. SETTING/SUBJECTS: Patients having 1-4 BTPc episodes per day on ≥60 mg/day oral morphine or equivalent. Episodes treated with fentanyl pectin nasal spray (FPNS; 100-800 µg), immediate-release morphine sulfate (IRMS), or placebo. MEASUREMENTS: Pain intensity was measured on an 11-point scale (5-60 minutes posttreatment); satisfaction was measured on a 4-point scale (30 and 60 minutes). The primary analysis assessed the overall relationship of time to onset of pain relief (pain intensity difference [PID]≥1) or time to clinically meaningfully reduction in pain (PID≥2) versus patient satisfaction and overall pain intensity (summed pain intensity difference at 30 [SPID30] and 60 minutes [SPID60]) assessed by analysis of variance (ANOVA). A secondary analysis assessed whether satisfaction was different between treatments using a within-patient comparison. RESULTS: Eight hundred thirty-one FPNS-treated, 368 IRMS-treated, and 200 placebo-treated episodes were analyzed. Overall, within the pool there was a statistically significant relationship between time to onset of pain relief (PID≥1 and PID≥2) and patient satisfaction (both speed of relief and overall) at 30 and 60 minutes (p<0.001); this relationship was also true within individual treatment groups (p<0.01). Similar results were found for overall pain intensity reduction. When treatment groups were compared using within-patient data, FPNS provided earlier onset of pain relief than IRMS or placebo (p<0.05), which translated into better satisfaction at 60 minutes (p<0.01). CONCLUSIONS: Earlier onset of pain relief resulted in greater patient satisfaction and overall relief of pain; between-treatment comparisons showed that FPNS provided earlier pain relief and greater satisfaction than IRMS or placebo.

An analysis of the variability of breakthrough pain intensity in patients with cancer.

BACKGROUND: The management of breakthrough pain in patients with cancer (BTPc) generally includes an initial titration of breakthrough pain medication to an effective dose, followed by the use of that dose in all subsequent episodes. This strategy presumes that an individual patient has a degree of consistency of pain during repeat episodes; however, that presumption has not been formally assessed. OBJECTIVE: To examine the variation in pain intensity of BTPc episodes within individual patients and across patients. METHODS: Data were pooled from 2 randomized, double-blind, crossover studies that used fentanyl pectin nasal spray (FPNS) vs comparator to relieve BTPc. Eligible patients were adults with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and adequately controlled background pain. The FPNS dose was titrated prior to a double-blind treatment consisting of 10 episodes. Pain intensity was reported on an 11-point numeric scale in which 0 = no pain and 10 = worst possible pain. Inter- and intrapatient variabilities of baseline pain intensity scores per episode were analyzed by analysis of covariance via a mixed-effect model. The influences of demographics and ECOG grade at study entry were assessed. RESULTS: Mean baseline pain intensity score was 7.3 (standard deviation, 1.76; range, 2-10) across 1,399 BTPc episodes in 152 patients. The interpatient variability of baseline pain intensity scores was 75.96%; intrapatient variability was 20.64%. Fixed terms for demographics and ECOG grade did not significantly influence baseline pain intensity score (≤ 5% level). LIMITATIONS: This was a post hoc analysis. CONCLUSIONS: Baseline pain intensity scores during episodes of BTPc vary widely between patients, but vary little within individual patients; this supports the use of a consistent maintenance dosage of analgesia for BTPc, once it has been titrated to an effective dose. FUNDING/SUPPORT: The study was funded by Archimedes Development Ltd.

Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge.

We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus.

A pharmacokinetic assessment of an alternate titration strategy for fentanyl pectin nasal spray.

OBJECTIVE: Fentanyl pectin nasal spray (FPNS) is approved for management of breakthrough pain in cancer. It is available in 100 and 400 µg strength products which allow for doses of 100 - 800 µg (1 or 2 sprays). Existing titration strategies require a transition from the 100 µg product to the 400 µg product when increasing the dose from 200 to 400 µg. This study assessed the pharmacokinetic (PK) profile of FPNS administered as 4 sprays of 100 µg as an alternate titration strategy. METHODS: In this 3-way, crossover study, healthy subjects aged 18 - 65 years were randomized to receive each of 3 dosages of FPNS (4 × 100 µg, 2 × 100 µg, and 1 × 400 µg). PK samples were collected over 24 hours. RESULTS: Of 22 subjects randomized, 20 were included in the PK analysis. Administration of both 400 µg regimens (4 × 100 µg and 1 × 400 µg) provided greater systemic fentanyl exposure compared with the 200 µg dose (C(max): 1,748 and 1,485 pg/ml vs. 1,051 pg/ml; AUC(0-1h): 1,012 and 944 pg×h/ml vs. 665 pg×h/ml; and tmax: 0.25 hours and 0.50 hours vs. 0.25 hours); fentanyl exposure after 4 × 100 µg and 1 × 400 µg regimens was similar. Adverse events (AEs) were all mild or moderate in intensity; most common AEs were nausea (50%) and headache (23%). AE frequency was similar across treatments without reports of nasal effects. CONCLUSIONS: Given that systemic fentanyl exposure from FPNS administered as 4 × 100 µg is similar to that from FPNS as 1 × 400 µg, the 4 × 100 µg regimen provides an alternate titration strategy for patients needing more than 200 µg. This alternate strategy will facilitate a patient's ability to achieve an optimized FPNS regimen and reduce opioid wastage.

Impact of allergic rhinitis and its treatment on the pharmacokinetics of nasally administered fentanyl.

OBJECTIVES: Fentanyl pectin nasal spray (FPNS, Lazanda® in the US and PecFent® in Europe and Australia) is a novel analgesic approved for the management of breakthrough pain in cancer patients. Given that the fentanyl is nasally administered, it is important to understand whether concomitant allergic rhinitis, or its treatment with a vasoconstrictor, would affect its absorption and, potentially, its efficacy or safety. METHODS AND SUBJECTS: Subjects with a history of allergic rhinitis were screened to identify subjects who developed at least moderate rhinitis symptoms on exposure to pollen allergen (either ragweed or tree) in an environmental exposure chamber (EEC). These were entered into a randomized, three-way crossover study in which each subject received 100 µg of FPNS under three exposure conditions; Control (no rhinitis), Rhinitis (symptomatic without decongestant), Treated (symptomatic with concomitant oxymetazoline). Blood samples for fentanyl were collected over a 24-hour period. RESULTS: A total of 132 subjects was screened to identify 54 for inclusion in the study; 31 were evaluable for pharmacokinetics. Measures of fentanyl absorption (mean or median) were similar between Control and Rhinitis conditions: Cmax 453.0 vs. 467.8 pg/ml; AUCt 1,292.3 vs. 1,325.4 pg×h/ml, AUC0-∞ 1,430.6 vs. 1,387 pg×h/ml and tmax 20 vs. 17 minutes. When oxymetazoline was co-administered, overall fentanyl absorption was slightly reduced (AUC0-∞ 1,362.4 pg×h/ml); but, more clinically relevant were the delayed rate of absorption (tmax 53 minutes) and reduced Cmax (235.3 pg/ml). CONCLUSIONS: Patients treated with FPNS will be unaffected by the development of allergic rhinitis; but, if oxymetazoline is prescribed, the patient would benefit from added supervision when oxymetazoline is started and stopped.

Adhesions after abdominal surgery in children.

PURPOSE: The objective of this study is to quantify the overall burden (operative and nonoperative) of small bowel obstruction caused by adhesions after laparotomy in children. METHODS: Data from the Scottish National Health Service Medical Record Linkage database were used to assess risk of an adhesion-related readmission in the 5 years after open abdominal surgery in children and adolescents younger than 16 years from April 1996 to March 1997. RESULTS: A total of 1581 children underwent abdominal surgery (ie, from duodenum downward). Patients undergoing surgery on the ileum had the highest risk of readmission because of adhesions in the subsequent 5 years after surgery (9.2%)--formation/closure of ileostomy had the greatest risk (25%); 6.5% of children were readmitted after general laparotomy, 4.7% after duodenal surgery, and 2.1% after colonic surgery. The incidence of readmissions was 0.3% after appendicectomy. The overall readmission rate was 5.3% (if appendicectomy was excluded) and 1.1% (if appendicectomy was included). CONCLUSION: This population-based study has demonstrated that children have a high incidence of readmissions owing to adhesions after lower abdominal surgery. The risks are related to the site and the type of the original surgery. The risk of further readmissions was highest in the first year but continued with time. The data enable surgeons to target antiadhesion strategies at procedures that lead to a high risk of adhesions.

Population-based analysis of the risk of adhesion-related readmissions after abdominal surgery in children.

PURPOSE: The aim of this study was to quantify the risk of adhesion-related readmissions after abdominal surgery in children. METHODS: This was a population-based study. One thousand five hundred eighty-one children younger than 16 years underwent laparotomy in 1996. Patients were identified from the Scottish Morbidity Records database and followed up for 4 years. RESULTS: In children younger than 5 years, 4.2% had a readmission "directly" owing to adhesions. In children younger than 16 years, 1.1% had a readmission directly owing to adhesions. The highest risk of readmission followed surgery on the small intestine (9.3%), followed by abdominal wall surgery (5.8%), duodenal surgery (2.6%), colonic surgery (2.1%), and appendicectomy (0.3%). 55% of all readmissions occurred in the first year. CONCLUSION: There was no difference in readmission rates between younger and older children when comparing the organ on which surgery was initially performed. The highest readmission rate followed small intestinal surgery and the lowest followed appendicectomy. The risk of readmission was highest in the first year.