Comment and reply on: The cost-effectiveness of palivizumab for respiratory syncytial virus prophylaxis in premature infants with a gestational age of 32–35 weeks: a Canadian-based analysis

Summary

Correspondence on: The cost-effectiveness of palivizumab for respiratory syncytial virus prophylaxis in premature infants with a gestational age of 32–35 weeks: a Canadian-based analysis [Lanctôt KL et al., Curr Med Res Opin 2009; 24: 3223-37; doi:10.1185/03007990802484234]     

Association of interleukin-12p40 gene polymorphisms with respiratory syncytial virus inflection in infancy

AIM: To explore the relationship between the TaqI restriction fragment length polymorphism (RFLP) in the 3'-untranslated region (UTR) of IL-12p40 gene or the length polymorphism in the promoter of IL-12p40 gene and the clinical phenotype of infantile RSV infection. METHODS: One hundred and fifty-seven infants with RSV lower respiratory infection (106 bronchiolitis and 51 pneumonia, of them 53 were severe) and 48 healthy children as control were enrolled in the study. Direct immunofl…     

Trends in respiratory syncytial virus bronchiolitis hospitalizations in children less than 1 year: 2004–2012

Objective To analyze trends in health outcomes and the influence of risk factors in children under 1 year with acute bronchiolitis due to respiratory syncytial virus (RSV bronchiolitis). A risk-adjustment model for RSV bronchiolitis in-hospital mortality was also developed.

Research design and methods Retrospective study of hospitalizations for RSV bronchiolitis in children aged?<1 year from 2004 to 2012. We used nationally representative data from the Spanish National Health Service records.

Results Over the study period, the annual hospital discharges for RSV bronchiolitis ranged between 6390 and 8637. The annual in-hospital mortality rate ranged from 120 (2004) to 69 (2012) per 100,000 hospitalizations and the mean length of stay decreased steadily from 6.5 to 5.2 days (p?<?0.001); 98.3% of hospitalizations for RSV bronchiolitis were children without risk factors. The in-hospital mortality rate due to RSV bronchiolitis in children with risk factors was 18.8 times higher than non-high-risk children and, in adjusted analyses, the OR of in-hospital mortality due to RSV bronchiolitis was higher than that due to other causes.

Limitations This study is a retrospective analysis, based on administrative data. It does not include data about pre- or in-hospital treatments, and has the limitations inherent in procedures for determining risk-adjusted mortality rates. Socioeconomic and environmental factors have not been considered in this study.

Conclusions RSV bronchiolitis is a leading cause of hospitalizations for infants under 1 year and has not shown incidence reduction over a 9 year period. Risk factors increase the in-hospital mortality risk and it is higher if the hospitalization cause is RSV bronchiolitis than any other reason.     

The pharmacokinetics of ampicillin–sulbactam in anuric patients: dosing optimization for prophylaxis during cardiovascular surgery

Background The administration of antibiotic prophylaxis during cardiothoracic surgery can reduce the rate of surgical site infections. Trials of cardiothoracic antibiotic prophylaxis have found it to be beneficial in preventing postoperative wound infections. Objective To determine the more appropriate timing of repeated doses of ampicillin–sulbactam to maintain adequate antibiotic concentrations during cardiovascular surgery in anuric patients. Method Five adult anuric dialysis patients who received ampicillin–sulbactam during cardiovascular surgery at Kagoshima University Hospital, the total plasma concentrations of ampicillin and sulbactam were monitored after ampicillin (1 g)–sulbactam (0.5 g) administration. Pharmacokinetic parameters were estimated and used to predict the free plasma concentrations of ampicillin and sulbactam. Results The mean values for the volume of distribution, total clearance, elimination rate constant and the elimination half-life for ampicillin were 8.9 ± 2.4 L, 1.69 ± 0.93 L/h, 0.180 ± 0.059 h^?1 and 4.23 ± 1.48 h, respectively. The pharmacokinetic parameters were similar to those of sulbactam. When ampicillin (1 g)–sulbactam (0.5 g) was intravenously administered at 8, 12 and 24 h intervals, the predicted free trough plasma concentrations of ampicillin were 28.72, 12.06 and 1.25 μg/mL, respectively. Conclusion We suggest that ampicillin (1 g)–sulbactam (0.5 g) should be intravenously administered every 12 h in order to maintain a free ampicillin concentration of more than 12 μg/mL in anuric patients during cardiovascular surgery.     

The repeated administration of rhIL-12 for 14 weeks in rhesus monkeys: A toxicity assessment

Interleukin-12 (IL-12) is known to exert antitumor immune effects by promoting the activation and proliferation of T cells and NK cells within the immune system. However, clinical trials have observed systemic toxicity associated with the administration of IL-12. This has shelved development plans for its use as a cancer therapeutic drug. Therefore, it is critical that we perform a systematic evaluation of the toxicity and safety of repeated IL-12 administration. In this study, we conducted a comprehensive evaluation of the toxicity and safety of repeated rhIL-12 (recombinant human interleukin-12) administration in rhesus monkeys by assessing its effects on the immune system, organ function, and vital signs. Rhesus monkeys were subcutaneously injected with 0.5, 2.5, and 12.5 μg/kg of rhIL-12 for up to for 14 consecutive weeks. The low dose exhibited no signs of toxicity, whereas animals receiving higher doses displayed symptoms such as loose stools, reduced activity, anemia, and elevated liver function indicators (AST and TBIL). Following three administrations of 12.5 μg/kg, high dosing was adjusted to 7.5 μg/kg due to manifestations of symptoms like loose stools, decreased activity, and huddling in the cage. Furthermore, rhesus monkeys exhibited marked immunogenic responses to recombinant human interleukin-12 (rhIL-12). However, based on overall study findings, the No Observed Adverse Effect Level (NOAEL) for the subcutaneous injection of rhIL-12, when repeatedly administered for 3 months in rhesus monkeys, was considered to be 0.5 μg/kg. The Highest Non-Severely Toxic Dose (HNSTD) was considered to be 7.5 μg/kg.     

OnabotulinumtoxinA (BOTOX®): a review of its use in the prophylaxis of headaches in adults with chronic migraine

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of intramuscularly injected onabotulinumtoxinA (onaBoNTA; BOTOX?) for headache prophylaxis in adults with chronic migraine, with a focus on UK labelling for the drug. The pharmacological actions of onaBoNTA include a direct antinociceptive (analgesic) effect; while not fully understood, the mechanism of action underlying its headache prophylaxis effect in chronic migraine is presumed to involve inhibition of peripheral and central sensitization in trigeminovascular neurones. Pooled findings from two large phase III studies of virtually identical design (PREEMPT [Phase III REsearch Evaluating Migraine Prophylaxis Therapy] 1 and 2) showed that treatment with up to five cycles of onaBoNTA (155-195 units/cycle) at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life (HR-QOL) in patients with chronic migraine, approximately two-thirds of whom were overusing acute headache medications at baseline. During the double-blind phase of both trials, significantly more patients treated with onaBoNTA (two cycles) than placebo experienced clinically meaningful improvements in the monthly frequencies of headache days, moderate to severe headache days and migraine days, and in the cumulative hours of headache on headache days/month. OnaBoNTA therapy also resulted in statistically significant and clinically meaningful improvements in functioning and HR-QOL compared with placebo. Notably, improvements in headache symptoms, functioning and HR-QOL favouring onaBoNTA over placebo were seen regardless of whether or not patients were medication overusers and irrespective of whether or not they were naive to (oral) prophylactic therapy. Further improvements relative to baseline in headache symptoms, functioning and HR-QOL were observed during the open-label extension phase of both trials (all patients received three cycles of onaBoNTA). Treatment with up to five cycles of onaBoNTA was generally well tolerated in the PREEMPT trials. Treatment-related adverse events reported by onaBoNTA recipients (e.g. neck pain, facial paresis and eyelid ptosis) were consistent with the well established tolerability profile of the neurotoxin when injected into head and neck muscles; no new safety events were observed. Debate surrounding the PREEMPT studies has centred on the small treatment effect of onaBoNTA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population. Nonetheless, the totality of the data showed that onaBoNTA therapy produced clinically meaningful improvements in headache symptoms, functioning and HR-QOL; on the basis of these trials, it has become the first (and so far only) headache prophylactic therapy to be specifically approved for chronic migraine in the UK and US. Overall, onaBoNTA offers a beneficial, acceptably tolerated and potentially convenient option for the management of this highly disabling condition, for example in patients who are refractory to oral medications used for prophylaxis.     

Efficacy of a paracetamol–pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection

ABSTRACT

Objective: This study compared the efficacy of 1000?mg of paracetamol combined with 60?mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.

Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm³ s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4?h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.

Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.

Results: A single dose of the combination was superior to paracetamol and placebo for NAC (?p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief (?p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion (?p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction (?p ≤ 0.0057). All treatments were well tolerated.

Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.     

The effect of fibrate–statin combination therapy on cardiovascular events: a retrospective cohort analysis

Abstract

Objective:

To investigate the long-term efficacy of fibrate–statin combination therapy on cardiovascular events as opposed to lipid levels.     

Mode of action and dose–response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose–response behavior of key events, alteration of the dose–response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.     

The future of pharmacotherapy for obsessive–compulsive disorder may lie in a better understanding of its heterogeneity

Pharmacological treatments currently available to treat obsessive–compulsive disorder (OCD) rarely produce remission. This Editorial aims to encourage more targeted research based on the specific OCD symptoms patients primarily present with. Specific OCD symptoms have been associated with distinct clinical characteristics, aetiological hypotheses and treatment responses. Treatment studies should use these findings to develop more targeted pharmacotherapy for patients with OCD.     

Cost–effectiveness analysis of sacral neuromodulation (SNM) with Interstim for fecal incontinence patients in Spain

ABSTRACT

Introduction: Fecal incontinence (FI) is a condition with a high impact on the psychological and social life of healthy people. Interstim, the sacral neuromodulation (SNM) therapy, has shown higher effectiveness and safety rates than surgical procedures like dynamic graciloplasty or artificial anal sphincter in patients with intact anal sphincter (IAS) and after sphincteroplasty in patients with structurally deficient anal sphincter (SDAS).

Objective: To assess the cost-effectiveness of FI management in two scenarios – with and without SNM – and to estimate the potential budget impact of its progressive introduction in the Spanish setting.

Methods: Two decision analytical models were developed (IAS and SDAS patients) representing the possible clinical paths for each of the scenarios (with and without SNM), as well as its clinical and economic consequences in the mid-to long term with a Markov model. Clinical and resource use data were retrieved from the literature and validated by a clinician expert panel. Effectiveness was measured with both QALYs and symptom-free years (SFY). A 3% discount rate was used for future costs and benefits (time horizon = 5 years). Prevalence figures were combined with Interstim sales forecasts to estimate the total number of patients to receive therapy over the next 5 years and the associated budget impact.

Results: The introduction of Interstim in the therapeutic management of FI has an associated cost-effectiveness of €16?181 (IAS patients) and €22?195 (SDAS patients) per QALY gained. The progressive introduction of Interstim in 75 to 100 patients/year will have an estimated budget impact of 0.1% of incremental costs in patients with FI.

Conclusions: Introducing Interstim in the management of FI in IAS and SDAS patients in the Spanish setting has shown to be an efficient measure with an incremental cost–effectiveness ratio below the accepted Spanish threshold (around €35?000/QALY), and with a relatively low additional cost for the Spanish NHS.     

Metabolic fate analysis of Huang–Lian–Jie–Du Decoction in rat urine and feces by LC–IT-MS combining with LC–FT-ICR-MS: a feasible strategy for the metabolism study of Chinese medical formula

1.?Huang–Lian–Jie–Du Decoction (HLJDD) is widely used for the treatment of hypertension, diabetes, inflammation and neural system diseases in clinic. In the present study, the comprehensive metabolic profile of HLJDD was demonstrated reliably and rapidly followed by the metabolic pathway analysis of six typical pure compounds (four alkaloids, one flavonoid and one iridoid) in HLJDD using LC–IT-MS combined with high resolution LC–FT-ICR-MS.

2.?Totally, 85 compounds, including 32 prototype components and 53 biotransformed metabolites were detected and characterized in the urine and feces after oral administration of HLJDD and six pure compounds to rats, respectively. Among them, 17 prototypes were identified definitely with standard references.

3.?Hydroxylation, demethylation and glucuronidation reactions of alkaloids, as well as glucuronidation and sulfonation reactions of iridoids and flavonoids, were observed as the major metabolic pathways of HLJDD. Flavonoids, iridoids and their metabolites were mainly excreted from urine. However, amount of alkaloids were detected in feces.

4.?In general, the distinctive metabolic process of three kinds of representative components in HLJDD was clarified. The in vivo metabolic network of HLJDD was demonstrated. Meanwhile, the investigation of representative pure compounds in metabolic study provided a valuable strategy to elucidate the full-scale metabolic fate of HLJDD. This might be helpful to understand the in vivo mechanism of Traditional Chinese medicine (TCM).     

Isobolographic analysis of interaction between drugs with nonparallel dose–response relationship curves: a practical application

The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)—two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose–response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.     

The role of pain in quitting among human immunodeficiency virus (HIV)–positive smokers enrolled in a smoking cessation trial

Background: Smoking rates among people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS; PLWHA) are at least twice as high as rates in the general population. Consistent with the reciprocal model of pain and smoking, PLWHA with pain who smoke may use smoking as a means of coping with pain, thus presenting a potential barrier to quitting. The aim of this study is to better understand how pain relates to smoking cessation among 474 HIV-positive adults enrolled in a cell phone–delivered smoking cessation trial. Methods: Participants were randomly assigned to usual care (cessation advice and self-help materials) or 11 sessions of cell phone–delivered smoking cessation treatment. Pain, as assessed by the Medical Outcomes Study-HIV Health Survey (MOS-HIV), and point prevalence abstinence were collected at the 3-month treatment end and at 6- and 12-month follow-ups. Self-reported abstinence was biochemically verified by expired carbon monoxide (CO) level of <7 ppm. Results: Using multilevel modeling for binary outcome data, the authors examined the relationship between pain and abstinence, from treatment end through the 12-month follow-up. Consistent with the authors' hypothesis, less pain was associated with greater likelihood of 24-hour (β = .01, t(651) = 2.53, P = .01) and 7-day (β = .01, t(651) = 2.35, P = .02) point prevalence abstinence, controlling for age, gender, baseline pain, nicotine dependence, and treatment group. No pain × treatment group interaction was observed. Conclusions: These results can help us to better identify PLWHA at greater risk for relapse in smoking cessation treatment. Future research may examine the effectiveness of more comprehensive smoking cessation treatment that incorporates aspects of pain management for PLWHA who smoke and have high pain and symptom burden.     

Empiric antibiotic protocols for cancer patients with neutropenia: a single–center study of treatment efficacy and mortality in patients with bacteremia

Background

There are several empiric antibiotic treatment options for febrile neutropenia, yet there is no universally-accepted initial protocol. We aimed to assess the performance of a protocol (piperacillin, gentamicin and cefazolin) introduced over 40 years ago and compare its coverage against bacteria isolated from blood of neutropenic patients with that of various commonly used antibiotic treatment protocols.

The effects of berberine on inflammatory markers in Chinese patients with metabolic syndrome and related disorders: a meta‑analysis of randomized controlled trials

Inflammopharmacology - A meta-analysis of randomized controlled trials (RCTs) was conducted to systematically evaluate the effects of berberine on the inflammatory markers of metabolic syndrome...     

Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan

ABSTRACT

Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A_2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off phenomenon with levodopa (L-DOPA). The authors present an interim report from a post-marketing surveillance (PMS) evaluating the safety and effectiveness of long-term istradefylline in a real-world setting.

Research design and methods: Istradefylline safety was assessed by the incidence of adverse events (AE) and adverse drug reactions (ADRs). Effectiveness was assessed using the physician’s assessment of off-time, off-time symptoms and motor dysfunction, unified PD rating scale (UPDRS) Part III score, and the physician’s global assessment.

Results: This analysis evaluated 476 patients. Istradefylline was generally well tolerated, despite dyskinesia and hallucination being the most common ADRs. Reduction in off-time was observed in 38.2% of patients, off-time symptoms were improved or markedly improved in 44.7%, and motor dysfunction was improved or markedly improved in 48.5%. The mean UPDRS Part III score decreased from 33.7 to 30.3 at the end of the study. The physician’s global assessment rated the drug as effective in 61.3% of patients.

Conclusions: This PMS provides useful safety and effectiveness data for long-term treatment with istradefylline in a real-world setting for patients with PD exhibiting the wearing-off phenomenon with L-DOPA.