Public health impact and cost-effectiveness of intranasal live attenuated influenza vaccination of children in Germany.

In 2011, intranasally administered live attenuated influenza vaccine (LAIV) was approved in the EU for prophylaxis of seasonal influenza in 2-17-year-old children. Our objective was to estimate the potential epidemiological impact and cost-effectiveness of an LAIV-based extension of the influenza vaccination programme to healthy children in Germany. An age-structured dynamic model of influenza transmission was developed and combined with a decision-tree to evaluate different vaccination strategies in the German health care system. Model inputs were based on published literature or were derived by expert consulting using the Delphi technique. Unit costs were drawn from German sources. Under base-case assumptions, annual routine vaccination of children aged 2-17 years with LAIV assuming an uptake of 50% would prevent, across all ages, 16 million cases of symptomatic influenza, over 600,000 cases of acute otitis media, nearly 130,000 cases of community-acquired pneumonia, nearly 1.7 million prescriptions of antibiotics and over 165,000 hospitalisations over 10 years. The discounted incremental cost-effectiveness ratio was 1,228 per quality-adjusted life year gained from a broad third-party payer perspective (including reimbursed direct costs and specific transfer payments), when compared with the current strategy of vaccinating primarily risk groups with the conventional trivalent inactivated vaccine. Inclusion of patient co-payments and indirect costs in terms of productivity losses resulted in discounted 10-year cost savings of 3.4 billion. In conclusion, adopting universal influenza immunisation of healthy children and adolescents would lead to a substantial reduction in influenza-associated disease at a reasonable cost to the German statutory health insurance system. On the basis of the epidemiological and health economic simulation results, a recommendation of introducing annual routine influenza vaccination of children 2-17 years of age might be taken into consideration.

The epidemiological impact of childhood influenza vaccination using live-attenuated influenza vaccine (LAIV) in Germany: predictions of a simulation study.

BACKGROUND: Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. METHODS: A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. RESULTS: In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. CONCLUSIONS: Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.

Subjective well-being in schizophrenia: a randomised controlled open-label 12-month non-inferiority study comparing quetiapine XR with risperidone (RECOVER).

UNLABELLED: This randomised 12-month open study analysed the effectiveness of quetiapine XR (400-800 mg) versus risperidone (2-6 mg) on subjective well-being in schizophrenia (NCT00600756). Primary objective was to demonstrate non-inferiority of quetiapine XR to risperidone in 6-month responder rate using the Subjective Well-Being under Neuroleptics scale (SWN-K) (per-protocol at Month 6 [PP 6] population). Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) greater than -9.7% for the adjusted difference between quetiapine XR and risperidone. Secondary objectives included non-inferiority of quetiapine XR versus risperidone (lower limit of 95% CI greater than -7.5 points) for SWN-K change from baseline to Month 12 (PP 12). 798 patients were randomised (quetiapine XR, n=395; risperidone, n=403); at Month 12, 212 (54%) and 227 (56%) patients, respectively, completed the study. At Month 6, SWN-K responder rate in the PP 6 population was 65% (136/210) with quetiapine XR and 68% (158/232) with risperidone (adjusted treatment difference: -5.7%; 95% CI: -15.1, 3.7); thus, non-inferiority could not be established. SWN-K change from baseline to Month 12 was 23.2 points for quetiapine XR and 21.1 points for the risperidone group; treatment difference was 2.1 (95% CI: -0.8; 5.0); non-inferiority was established (PP 12). CONCLUSION: SWN-K response at 6 months was comparable between the two antipsychotics. However, with a lower than expected responder rate and a lower than expected number of evaluable patients in the PP 6 population, non-inferiority was not demonstrated. A secondary objective (SWN-K total score) established non-inferiority of quetiapine XR to risperidone at Month 12.

Assessment of tinnitus-related impairments and disabilities using the German THI-12: sensitivity and stability of the scale over time.

OBJECTIVE: To evaluate the reliability, dimensionality, predictive validity, construct validity, and sensitivity to change of the THI-12 total and sub-scales as diagnostic aids to describe and quantify tinnitus-evoked reactions and evaluate treatment efficacy. DESIGN: Explorative analysis of the German tinnitus handicap inventory (THI-12) to assess potential sensitivity to tinnitus therapy in placebo-controlled randomized studies. Correlation analysis, including Cronbach's coefficient α and explorative common factor analysis (EFA), was conducted within and between assessments to demonstrate the construct validity, dimensionality, and factorial structure of the THI-12. STUDY SAMPLE: N = 618 patients suffering from subjective tinnitus who were to be screened to participate in a randomized, placebo-controlled, 16-week, longitudinal study. RESULTS: The THI-12 can reliably diagnose tinnitus-related impairments and disabilities and assess changes over time. The test-retest coefficient for neighboured visits was r > 0.69, the internal consistency of the THI-12 total score was α ≤ 0.79 and α ≤ 0.89 at subsequent visits. Predictability of THI-12 total score and overall variance increased with successive measurements. The three-factorial structure allowed for evaluation of factors that affect aspects of patients' health-related quality of life. CONCLUSIONS: The THI-12, with its three-factorial structure, is a simple, reliable, and valid instrument for the diagnosis and assessment of tinnitus and associated impairment over time.

MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients.

This retrospective study investigated the impact of MDR1 haplotypes derived from the single-nucleotide polymorphisms (SNPs) 2677G>T (exon 21) and 3435C>T (exon 26) on the pharmacokinetics of cyclosporine in 98 renal transplant patients. Based on SNPs 2677 and 3435, four different haplotypes and nine different genotypes were identified in the study sample. Frequencies of SNPs, genotypes, and haplotypes were in agreement with previously reported values. Cyclosporine pharmacokinetics were characterized using a 2-hour AUC (AUC0-12), trough concentrations (C0), and blood concentrations 2 hours after cyclosporine administration (C2). No significant differences in dose-corrected AUC0-12, C0, or C2 values were observed between carriers of different SNP variants and genotypes (Kruskal-Wallis test), as well as between carriers and noncarriers of each haplotype (Mann-Whitney U test). Carriers of haplotype 12 (2677G and 3435T), which has previously been associated with increased digoxin AUC values, had a median AUC0-12 of 18.9 micro g*h*L-1 (range: 9.0-35.2) compared to 17.5 micro g*h*L-1 (range: 7.5-37.1) in the noncarrier group. It was concluded that MDR1 haplotypes derived from the SNPs 2677G>T (exon 21) and 3435C>T (exon 26) are not associated with cyclosporine pharmacokinetics in renal transplant patients.

Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients.

BACKGROUND: This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA). METHODS: Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil. RESULTS: Dose-corrected AUC((0-12)) of TAC decreased significantly from 180 ng/ml/h at baseline to 75.9 ng/ml/h after 2 weeks of SJW treatment. To maintain therapeutic TAC concentrations, dose adjustments from a median 4.5 mg/day at baseline to 8.0 mg/day under SJW treatment were required. Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 6.5 mg/day. MPA pharmacokinetics remained unaffected by comedication with hypericum extract. CONCLUSIONS: Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection.

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients.

AIM: This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). METHODS: In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. RESULTS: After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. CONCLUSION: Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.

Enhanced visualisation of the normal prostate blood flow in young healthy volunteers using a new ultrasound contrast agent.

PURPOSE: To evaluate the sonographic appearance of normal prostate vascularity before and after injection of a new ultrasound contrast agent, Sonazoid (NC100100, Nycomed Amersham). MATERIAL AND METHODS: Five healthy male volunteers were given three injections of Sonazoid each. Transrectal B-mode, colour Doppler and colour Doppler energy (i.e. power Doppler) imaging was performed. The visibility of the vascular pattern and the vascular architecture of the prostate, including dynamics of contrast inflow and blood flow symmetry, were evaluated. RESULTS: The depiction of the vascularity was improved in all subjects after injection of Sonazoid for both Doppler modes. No improvement was seen for B-mode. Contrast dynamics within the prostate vessels were demonstrated with a mean time from injection of the ultrasound contrast agent to enhancement of the Doppler signals in the subcapsular arteries of 14+/-1 s (11--17 s), and the ultrasound contrast agent reached the central periurethral veins 4--7 s later. A symmetric, radial, spoke-like intraprostatic vascular pattern could be identified in all subjects using power Doppler imaging and ultrasound contrast agent. CONCLUSION: Sonazoid improved the detection of normal human prostate vascular anatomy for both colour and power Doppler imaging. Contrast dynamic studies revealed a radial spoke-like intraprostatic vascular pattern. This information might be useful in examination of patients with suspicion of prostate cancer, and needs to be further investigated.

Clinical trial program for iopentol. A new nonionic ratio 3.0 contrast medium with emphasis on clinical phases I and II.

Iopentol is a new nonionic, water-soluble ratio 3.0 roentgen contrast medium (CM) for vascular use. The aim is to present the vascular clinical trial program for iopentol and to report the findings from the clinical phases I and II. The clinical program started with an intravenous (IV) safety and pharmacokinetic phase I trial (24 volunteers) and continued with six open, noncomparative phase II trials (61 patients) for studying cardiovascular and arterial tolerance (two trials in cardioangiography), venous tolerance (two trials in IV computed tomography [CT] enhancement), and cerebral and arterial tolerance (2 trials in cerebral arteriography). One volunteer in the phase I trial was excluded because of a vasovagal reaction following saline injection, and four patients were protocol deviators in cardioangiography. Mainly renal glomerular filtration of unmetabolized iopentol, close to 100% recovered after 24 hours in the urine, was found in the phase I study. No unexpected or severe contrast-induced reactions were encountered in phases I and II. Good diagnostic efficiency was obtained in phase II. As also expected, iopentol seemed to be well-tolerated. However, its relative efficiency and tolerance profile can only be documented from the ongoing comparative phase III trials.