Committee For Proprietary Medicinal Products Research Articles

Effect of processed aloe vera gel on immunogenicity in inactivated quadrivalent influenza vaccine and upper respiratory tract infection in healthy adults: A randomized double-blind placebo-controlled trial

BackgroundAloe vera is a functional food with various pharmacological functions, including an immune-modulating effect. Until now, A. vera has never been studied as an adjuvant in influenza vaccine, and its effects on upper respiratory tract infection (URI) are unknown. PurposeThe objective of our study was to investigate the effect of processed A. vera gel (PAG) on immunogenicity of quadrivalent inactivated influenza vaccine and URI in healthy adults. Study designA randomized, double-blind, placebo-controlled clinical trial was performed. MethodsThis study was conducted in 100 healthy adults at a single center from September 2017 to May 2018. Subjects were randomly divided into a PAG group (n = 50) and a placebo group (n = 50). The enrolled subjects were instructed to ingest the study drug for 8 weeks. The participants received a single dose of quadrivalent inactivated influenza vaccine after taking the study drug for the first 4 weeks of the study. The primary endpoint was seroprotection rate against at least one viral strain at 4 weeks post-vaccination. Other outcomes were seroprotection rate at 24 weeks post-vaccination, seroconversion rate, geometric mean fold increase (GMFI) at 4 and 24 weeks post-vaccination, seroprotection rate ratio and geometric mean titer ratio (GMTR) at 4 weeks post-vaccination between PAG and placebo groups, and incidence, severity, and duration of URI. ResultsThe European Committee for proprietary medicinal products (CPMP) evaluation criteria were met at least one in the PAG and placebo groups for all strains. However, there was no significant difference in the seroprotection rate at 4 weeks post-vaccination against all strains in both PAG and placebo groups. Among secondary endpoints, the GMFI at 4 weeks post-vaccination for the A/H3N2 was significantly higher in the PAG than in placebo group. The GMTR as adjuvant effect was 1.382 (95% CI, 1.014-1.1883). Kaplan–Meier curve analysis showed a reduction in incidence of URI (p = 0.035), and a generalized estimating equation model identified a decrease in repeated URI events (odds ratio 0.57; 95% CI, 0.39-0.83; p = 0.003) in the PAG group. ConclusionsOral intake of PAG did not show a significant increase in seroprotection rate from an immunogenicity perspective. However, it reduced the number of URI episodes. A well-designed further study is needed on the effect of PAG's antibody response against A/H3N2 in the future.

Comparison of immunogenicity between intradermal and intramuscular injections of repeated annual identical influenza virus strains post-pandemic (2011-2012) in COPD patients

ABSTRACT We compared the antibody responses and persistence of the reduced-dose, 9 µg hemagglutinin (HA)/strain intradermal (ID) injection via the Mantoux technique and the 15 μg HA/strain intramuscular (IM) injection of the repeated annual identical trivalent, inactivated, split-virion vaccine 2011–2012 in chronic obstructive pulmonary disease (COPD) patients. Eighty patients were randomized to ID (n = 41) and IM (n = 39) groups. Four weeks post-vaccination, the antibody responses of the two groups were similar; those for influenza A(H1N1)pdm09 and influenza A(H3N2)–but not influenza B–met the criteria of the Committee for Proprietary Medicinal Products (CPMP). The antibody responses for influenza A(H1N1)pdm09 rapidly declined in both groups, especially with the ID injection, whereas those for influenza A(H3N2) maintained above the CPMP criteria throughout 12 months post-vaccination. The geometric mean titres for influenza A(H1N1)pdm09 persisted above the protective threshold (≥ 40) until 6 months post-vaccination in both the ID and IM groups. The seroprotection rates of the ID and IM groups were above 60% until 3 months and 6 months post-vaccination, respectively. In conclusion, the 9 μg HA/strain ID injection of vaccine 2011–2012 elicited antibody responses similar to the standard dose of 15 μg of the HA/strain IM injection at 4 weeks post-vaccination. However, the antibody responses for influenza A(H1N1)pdm09 rapidly declined, especially in the case of the ID injection, whereas they were comparable for influenza A(H3N2). Additional strategies for increasing vaccine durability should be considered, especially for new pandemic strains affecting elderly COPD patients.

A Review of Regulatory Guidelines on Stability Studies

Stability could be an essential quality attribute; so, the stability program plays a very important role while manufacturing fresh pharmaceutical products. Particularly, this is in regard with the pharmaceutical preparations or formulations, which are to be distributed in various strengths and various types of packages for the purpose of marketing. It involves many samples to be tested at a given cost, and also involves testing large number of samples of various strengths, package types, many batches of different storage conditions, testing parameters and testing intervals. To design a successful stability-testing program, there are many regulatory guidance documents that should be consulted. These guidance documents provide information on how to conduct a stability program to ensure that appropriate data are generated in support of a new drug substance or product. This paper discusses the various guidelines governing the stability studies, particularly the FDA (Food and Drug Administration), ICH (The International Conference on Harmonization), CPMP (Committee for Proprietary Medicinal Products), & WHO (Word Health Organization)-their rules, regulations, and recommendations regarding stability studies. In this paper, details regarding the formation of International Conference on Harmonization, the regions involving it, the suggestions made by them, and the various guidelines issued by it, relating not only to stability studies but many other aspects relating to it, and an overview of various ICH stability guidelines, their names and the codifications, have been described briefly.

Offline: Medicines leadership—Britain's loss, Europe's gain

The shadow of Brexit continues to darken. One consequence is the loss of the European Medicines Agency (EMA) from London to continental Europe. The EMA, together with the European Banking Authority (EBA), is one of the prized institutions of the European Union. It is responsible for evaluating medicines use across 28 member states. It provides a single route for the authorisation of new medicines, avoiding the duplication of separate member-state approvals. Since its inception in 1995, the EMA has authorised over 1000 products. It employs 900 staff, and attracts 36 000 experts each year, including 4000 non-EU visitors. It holds more than 500 meetings annually. The concentration of medicines expertise in the UK brings many additional benefits. The EMA enhances Britain's reputation as a scientific centre for drug discovery. It expands the nation's capacity in medicines research—from the epidemiology of drug safety to randomised trials to assess the efficacy of new medicines. And it strengthens the country's global leadership role in medicines regulation. All that will now be lost to Britain. The deadline for applications to host the EMA is July 31, 2017. An early leader was Milan. Italy has a distinguished reputation in basic science (consider, for example, the international standing of the Mario Negri Institute for Pharmacological Research). It has built formidable clinical trial networks (eg, the GISSI studies into survival after myocardial infarction). And Italy has produced some of the most creative life scientists of modern times, from Rita Levi-Montalcini (who discovered nerve growth factor; Nobel laureate, 1986) to Mario Capecchi (who pioneered the use of knockout mice; Nobel laureate, 2007). Italian clinical scientists have made important contributions to medicines regulation. Silvio Garattini, who co-founded the Mario Negri Institute, was one of the most radically engaged members of the EMA's Committee for Proprietary Medicinal Products. But the prospect of attracting such a jewel in the European crown has inevitably led to a rush of competitors. 16 countries have declared an interest in hosting the EMA. The slew of cities in the running is a compendium of European urban chic—Amsterdam, Barcelona, Copenhagen, Dublin, Lille, Lisbon, and Stockholm. But there is a contender that could beat all of these candidates: Bratislava, the capital of Slovakia. In February, Slovakia's Minister of Foreign and European Affairs indicated that his country had “ambitions to host the EMA”. In April, Prime Minister Fico wrote to the Presidents of the European Council (Donald Tusk) and European Commission (Jean-Claude Juncker) to notify them formally of Bratislava's application. Slovakia is the only country from central Europe not to host a European institution. But how will this decision be made? The new EMA has to be up and running by April 1, 2019. On June 22, the EU published its “Procedure leading up to a decision on the relocation of the European Medicines Agency and the European Banking Authority.” It set out six criteria. First, “The assurance that the agency can be set up on site and take up its functions at the date of the United Kingdom's withdrawal from the Union”. Second, “The accessibility of the location”. Third, “The existence of adequate education facilities for the children of agency staff”. Fourth, “Appropriate access to the labour market, social security, and medical care for both children and spouses”. Fifth, “Business continuity”. And finally, “Geographical spread”. The European Commission will publish an analysis of candidate cities in September. A debate will follow in October, with a vote in November. But the decision will not be technical. It will be political. There is already strong suspicion that a deal has been struck. Could it be true, for example, that Angela Merkel has agreed to support Bratislava in return for the EBA being housed in Frankfurt? There is, perhaps, one further consideration. Italy has been on the front-line of humanitarian efforts to help the tens of thousands of refugees flowing into Europe. It has done so with compassion and commitment, while many EU nations have refused to offer comparable assistance. Prime Minister Fico has said that, “Islam has no place in Slovakia”. The Slovakian Government has taken legal action to block the EU's refugee quotas for the country. It would be scandalous for the EU to reward Slovakia with the EMA given its racist immigration policies. Italy deserves more serious consideration, on moral as well as medical grounds.

Dose sparing and the lack of a dose-response relationship with an influenza vaccine in adult and elderly patients - a randomized, double-blind clinical trial.

The currently licensed seasonal trivalent influenza vaccines contain 15μg haemagglutinin per strain for adult, and up to 60μg for elderly patients. However, due to recent shortages, dose sparing to increase production capacity would be highly desirable. In the present study, we attempted to find a dose-response relationship for immunogenicity and, thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients. A total of 256 subjects, including adult (aged 18-60years) and elderly (aged over 60years) individuals, were enrolled. Subjects were randomly assigned in a 1:1:1:1 ratio to receive a whole-virion, aluminium-adjuvanted trivalent influenza vaccine containing 3.5, 6, 9 or 15μg haemagglutinin of seasonal A/H1N1, A/H3N2 and B influenza antigens manufactured by Omninvest Ltd., Hungary. Serum antibody titres against the vaccine virus strains were measured by haemagglutination inhibition. All vaccines were well tolerated. All four vaccines fulfilled all three immunogenicity licensing criteria, as determined by the European Committee for Proprietary Medicinal Products (CPMP)/Biotechnology Working Party (BWP)/214/96 guideline for all three virus strains and both age groups. The 3.5μg vaccine showed 28% less seroconversion compared to the 15μg dose in terms of influenza AH3N2 in the adult group (95% confidence interval -51, -3; P < 0.05). All other doses showed no significant difference in immunogenicity compared with the licensed vaccine containing 15μg haemagglutinin. Our data suggested that significant dose sparing is possible with the use of whole-virion vaccines and aluminium adjuvants, without compromising safety. This could have significant economic and public health impacts.

Clinical Study of Safety and Efficacy of a Polymer-Subunit Adjuvant Influenza Vaccine Applied in Combination with an Immune Modulator in People Aged 60 and Over

Relevance. In Russia, acute respiratory viral infections (ARVI) account for 93% of all infectious diseases. Flu is more serious disease than many ARVI. Flu especially dangerous for people aged 60 years or older, for the reason that they have a weakened immune system, and as a rule there are a chronic diseases. Vaccination is the most effective way to prevent flu. In the Sverdlovsk region of long-term epidemiological monitoring has shown that vaccines can provide protection for up to 92% of persons from some social and age groups. Vaccination of elderly has features because of decline of cellular and humoral immune response to foreign antigens. There is evidence that the addition to the inactivated influenza vaccine immunomodulators immunogenicity of vaccines increased significantly. Goal. To evaluate the effectiveness of the vaccine Grippol® plus with immunomodulator Polyoxidonium® for elderly people aged 60 and older Materials and method. Medical immunobiological drug Grippol® plus -three valency inactivated polymer-subunit influenza vaccine produced by LLC «Scientifically Production Association Petrovax Farm»: 5 microgram hemagglutinin current strains of flu virus subtypes A(H1N1) and A(H3N2) and type B, 500 microgram immunoadjuvant Polioksidonium® in phosphate-salt buffer. The vaccine does not contain a preservative. Polioksidonium® - immunomodulator produced by LLC «Scientifically Production Association Petrovax Farm», which contains as active substance 12 mg Polyoxidonium (azoximer bromide) in a mixture with excipients: mannitol, povidone, betakarotene - up to 18 mg; lactose, potato starch, stearic acid to produce tablets weighing 0.25 g. Placebo - tablet in appearance and packaging are not different from Polioksidonium® produced by LLC «Scientifically Production Association Petrovax Farm» without the active substance and containing potato starch, stearic acid, polyvinylpyrrolidone, lactose monohydrate, betakarotene to obtain tablets with a weight of 0.25 g. Study Design: A prospective open «case - control» randomized placebo-controlled study. Results. Clinical study demonstrated a high safety and areactogenicity profile and immunologic, clinical and epidemiologic efficacy of the Grippol® plus vaccine in people aged 60 and over treated previously with Polyoxidonium® or placebo. Immunogenicity of the vaccine met all the criteria of the Committee for Proprietary Medicinal Products for all three flu virus stains in 21 - 28 days and 6 months after vaccination in both study cohorts. We found no statistically significant differences in the frequency of general and local reactions and immune response rate between the cohorts vaccinated with Grippol® plus with the prior use of Polyoxidonium® or placebo. The incidence rate of acute respiratory viral infections in the age group 60+ immunized with the Grippol® plus vaccine was twice as low as that among the non-vaccinated, p < 0.05.

The immunogenicity of the intradermal injection of seasonal trivalent influenza vaccine containing influenza A(H1N1)pdm09 in COPD patients soon after a pandemic

ABSTRACTThe antibody responses of a reduced-dose intradermal seasonal influenza vaccination have never been studied in COPD patients soon after a pandemic. A total of 149 COPD patients (60 y of age or older) were randomized to receive trivalent influenza vaccine (Sanofi-Pasteur, France) either 9 µg of hemagglutinin (HA) per strain split into 2-site intradermal (ID) injections via the Mantoux technique or one intramuscular (IM) injection of 15 µg of HA per strain. The geometric mean titers, seroconversion factors, seroconversion rates and seroprotection rates for influenza A(H3N2) and B administered through the ID injection (n = 75) were similar to those obtained with the IM injection (n = 74) 4 weeks post-vaccination. The antibody responses for influenza A(H1N1)pdm09 administered through the ID injection were lower than those obtained with the IM injection, but all of these responses met the 3 criteria proposed by the Committee for Proprietary Medicinal Products (CPMP) for annual re-licensure. The seroprotection rates 4 weeks post-vaccination for influenza A(H1N1)pdm09 were 64.0% (95%CI 52.7-74.0%) in the ID group vs. 78.4% (95% CI 67.6-86.3%) in the IM group (p = 0.053). Influenza-related acute respiratory illness (ARI), diagnosed as a 4-fold rise in HI titers with a convalescent titer > 1:40, and/or the RT-PCR between the ID group (5.3%) and the IM group (8.1%) were not significantly different. The reduced-dose intradermal influenza vaccine may expand vaccine coverage in cases of vaccine shortage.

Immunogenicity and Safety of Influenza Vaccination in Systemic Lupus Erythematosus Patients Compared with Healthy Controls: A Meta-Analysis.

ObjectiveTo assess the immunogenicity and safety of influenza vaccine in patients with systemic lupus erythematosus (SLE).MethodsRelevant articles were retrieved from electronic databases. Seroprotection rate, seroconversion rate and factors that increase antibody geometric mean titer (GMT) were used as indices to measure the immunogenicity. The safety of vaccine was assessed through monitoring adverse events, which included side effects and SLE exacerbations. We performed a meta-analysis of influenza vaccine seroprotection, seroconversion and adverse effects. SLE exacerbation after vaccination was comprehensively described. We used the Committee for Proprietary Medicinal Products (CPMP) guidelines to determine whether influenza can induce adequate immunogenicity in patients with SLE.ResultsEighteen studies with 1966 subjects met the inclusion criteria. At least 565 of the subjects were patients with low-to-moderate SLE Disease Activity Index (SLEDAI) score or stable SLE disease. Compared with the general population, seroprotection rate in SLE patients was significantly decreased in patients with H1N1 [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.27–0.50] and H3N2 vaccination (OR = 0.48, 95% CI: 0.24–0.93), but not influenza B vaccination (OR = 0.55, 95% CI: 0.24–1.25). Seroconversion rate also significantly decreased in patients with H1N1 (OR = 0.39, 95% CI: 0.27–0.57) and influenza B (OR = 0.47, 95% CI: 0.29–0.76) vaccination, but not H3N2 vaccination (OR = 0.62, 95% CI: 0.21–1.79). However, the immunogenicity of influenza vaccine in SLE patients almost reached that of the CPMP guidelines. The OR for side effects (patients versus healthy controls) was 3.24 (95% CI: 0.62–16.76). Among 1966 patients with SLE, 32 experienced mild exacerbation of SLE and five had serious side effects for other reasons.ConclusionInfluenza vaccine has moderate effect on protecting patients with SLE. The side effects of influenza vaccine are not serious and are manageable. With consideration of a higher risk of SLE exacerbation and a more severe course of infection among SLE patients, influenza vaccination should be promoted among SLE patients with a low-to-moderate SLEDAI score or stable disease.

Evaluation of rationality of fixed-dose combinations prescribed in psychiatric patients

Background: There is a growing concern about the increasing number of irrational fixed-dose combinations (FDCs), which impose unnecessary financial burden, increase the occurrence of adverse drug reactions, and ultimately reduce the quality of life. Aims and Objective: To study the prescribing frequency of FDCs and to evaluate the rationality of FDCs prescribed in psychiatric patients. Materials and Methods: This prospective study was carried out in Pharmacology and Psychiatry Department of a tertiary care teaching hospital in Rajasthan, India. The data were collected in a case record form from patients of all ages and from either sex, who visited the outpatient department of psychiatry. Data were analyzed with the help of well-known comprehensive seven-point criteria by Panda et al, which were developed by carefully studying the guidelines of the World Health Organization and Committee for Proprietary Medicinal Products, Europe. Result: Total 383 drug formulations were prescribed in 200 patients of which 107 (27.93%) were in the form of FDCs. Most frequently prescribed FDC was escitalopram + clonazepam (22.44%), followed by amitriptyline + chlordiazepoxide (13.08%). The maximum score for the seven-point criteria for assessing the rationality of FDCs was 14, with each criterion carrying a score of 2. Scores obtained in this study ranged between 5 and 14 with an average of 8.79. Conclusion: Most of the FDCs were irrational according to the criteria used and only 28.57% of the FDCs were found to be rational considering safety and efficacy as the most important criteria for rationality. So, drug regulatory bodies should take urgent action to stop the free flow of irrational FDCs.

Pharmacokinetic studies for proving bioequivalence of orally inhaled drug products-critical issues and concepts.

OPINION article Front. Pharmacol., 03 June 2015Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2015.00117

Safety and immunogenicity of influenza whole inactivated virus vaccines: A phase I randomized clinical trial

BACKGROUND: Influenza vaccine production capacity is still insufficient to meet global demand in case of a pandemic. To expand worldwide influenza vaccine production capacity, a solid and transferable egg-based influenza vaccine production process was established that is suitable for upscaling and technology transfer to vaccine manufacturers in low- and middle-income countries. As a proof-of-concept, the safety and immunogenicity of a pandemic whole inactivated virus (WIV) vaccine (H5N1) and a monovalent seasonal WIV vaccine (H3N2) were evaluated in a phase I clinical trial in adults. METHODS: Subjects were vaccinated with 2 doses of pandemic WIV vaccine (pWIV), or one dose of either seasonal WIV vaccine (sWIV) or a commercially available trivalent comparator vaccine followed by a placebo dose. Haemagglutination inhibiting antibody titres against the influenza strains were determined before and 21 d after each vaccination. RESULTS: The frequency and severity of adverse reactions were comparable between groups. No serious adverse events were reported. After a single dose of sWIV the seroconversion rate was 91% (Committee for Proprietary Medicinal Products (CPMP) criterion >40%), the seroprotection rate was 100% (CPMP criterion >70%), and the mean geometric mean titre (GMT) increase was 24.9 (CPMP criterion >2.5). After two doses of pWIV, seroconversion rate and seroprotection rate were both 71%, and the mean GMT increase was 7.8. CONCLUSIONS: Both pWIV and sWIV were equally well-tolerated as the comparator vaccine, and both vaccines complied with all 3 CPMP criteria. EudraCT 2011-000159-17. Netherlands National Trial Register 2695.

Anti-Influenza Antibody Level in Mother-Infant Pairs Depending on Trimester of Vaccination of Pregnant Women Using Immunoadjuvant Vaccine

Introduction: Anti-influenza vaccination of pregnant women using a subunit vaccine is an effective method to prevent pregnancy complications and fetal disorders. The efficacy of immunoadjuvant vaccines, as well as the production of IgG antibodies depending on the vaccination trimester requires further investigation. Materials and Methods: 48 mothers were vaccinated against influenza in the II and III trimesters. Grippol plus vaccine was used. Each dose of the vaccine contains antigens of A and B strains and adjuvant Polyoxidonium 500 µg. Hemagluttinine-inhibiting antibodies level (HIAb) were evaluated in sera of mothers and babies at different time points after vaccination using a standard reaction of hemagglutination inhibition, in accordance with criteria developed by the committee for proprietary medicinal products (CPMP). Results: Within 1 month after vaccination, the seroprotection rate against all influenza strains was above the threshold level of 140 in more than 70% of pregnant women. After delivery, the seroprotection level in the group vaccinated in the III trimester was similar for A/California/7/2009/H1N1/v and А/H3N2 strains, and differed for B strain. The percentage of infants with seroprotection was 55.5%-59.3%, while in their mothers, the respective value was 74.1%-81.5% (p<0.05). Within 3 months, the number of infants with seroprotection against influenza strains in mother-infant pairs was decreased: A/California/7/2009/H1N1/v, А/H3N2, B. In infants and the seroprotection level disappeared completely by 6 months. The time of vaccination of pregnant women had no effect on these parameters. In mothers, the protective levels against vaccine strains were found in 46.2%-65.4% of cases after delivery. Conclusion: Vaccination of pregnant women in the II and III trimesters using Grippol plus results in production of antibodies at levels complying with CPMP criteria. No difference in production and transplacental transfer of IgG antibodies against influenza was found in mother-infant pairs vaccinated in different trimesters of pregnancy.

Bioequivalence of Two Oral Tablet Formulations of Betahistine 24 Mg: Single-Dose, Open-Label, Randomized, Two-Period Crossover Comparison in Healthy Individuals

A bioequivalence study of betahisitine tablets was conducted. Thirty two healthy Mexican mestizo volunteers received each test (T) and reference (R) formulations of betahistine at a dose of 24 mg in a 2 × 2 cross-over study. There was a three-day washout period between the two formulations. Plasma concentrations of betahistine were monitored by an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) for over a period of 24 h after the administration. AUC0-t (the area under the plasma concentration–time curve from time 0 to last sampling time) and AUC 0-∞ (that from time 0 to infinity) were calculated by the linear-log trapezoidal rule method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration–time data. Analysis of variance was carried out using logarithmically transformed AUC and Cmax, and untransformed Tmax. The mean of AUC0-t was 7139.8 ng mL−1 h−1 (test medication) and 6714.4 ng mL−1 h−1 (reference medication) and that of AUC0-∞ were 7660.2 (test) and 6850.3 ng mL-1 h-1 (reference). Cmax values of 1716.2 and 1677.3 ng mL−1 were achieved for the test and the reference medication, respectively. Tmax were determined at 0.86 h for the test and 0.87 h for the reference formulations. The 90% confidence intervals for AUC0-t, AUC0-∞ and Cmax were 0.994-1.102, 0.994-1.131 and 0.969-1.069, respectively, satisfying the bioequivalence criteria of the Mexican Comision Federal Para la Proteccion Contra Riesgos Sanitarios, the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. These results indicate that the two medications of betahistine are bioequivalent and, thus, may be prescribed interchangeably.

PO-0558 Anti-influenza Igg Levels In Newborn Infants, Born From Mothers, Vaccinated From Influenza At Pregnancy: Abstract PO-0558 Table 1

Background and aims Influenza vaccination with inactivated vaccines is safe for pregnant women, as for fetus. But the levels of immunity protection against influenza in newborn infants, born from mothers, vaccinated by immunoadjuvant vaccines in pregnancy are not investigate yet. We study transplacental IgG levels in newborn infants, born from mothers, vaccinated in pregnancy by subunit influenza vaccines. Materials and methods We study 79 infants, born from mothers, vaccinated in second and third trimester of normal pregnancy. 42 of them (first group), who’s mothers were vaccinated by three-valent subunit vaccine (Grippol Plus by ‘Petrovax, Ltd company, Russia, contain 0,5 mcg influenza strains and 500 mcg of Polyoxidonium, 37 (second group) – were from mothers, vaccinated by three valent subunit vaccine (‘Agrippal S1’ by ‘Novartis Vaccines and Diagnostic’, Italy) see Table 1. Criteria of Committee for Proprietary Medicinal Products by CPMP/BWP/214/96 protocol be used as immunological criteria. IgG-antibody levels were measured in umbilical cord blood by hemagglutination-inhibition reaction. Results Comparative characteristic of laboratory data achieve that in newborn infants 53,1%, 67,6% and 62,5%, 57,7% were seroprotected against A/H1N1/v and A/H3N2/accordingly, and 59,4%, 80,8% - against influenza B strain (p). Conclusion When we vaccinate pregnant women against influenza – 53,1–80,8% infants were seroprotected against vaccine strains of influenza no matter of used vaccine type.

Safety and immunogenicity of co-administered MF59-adjuvanted 2009 pandemic and plain 2009–10 seasonal influenza vaccines in rheumatoid arthritis patients on biologicals

Rheumatoid arthritis (RA) patients under immunosuppressive therapy are particularly susceptible to infections, mainly of the respiratory tract, thus vaccination may represent a strategy to reduce their incidence in this vulnerable population. In the 2009-10 influenza season, the safety and immunogenicity of co-administered non-adjuvanted seasonal and MF59-adjuvanted pandemic influenza vaccines were evaluated in this study in 30 RA patients under therapy with anti-tumour necrosis factor (TNF)-α agents or Abatacept and in 13 healthy controls (HC). Patients and HC underwent clinical and laboratory evaluation before (T0), 1 (T1) and 6 months (T2) after vaccinations. No severe adverse reactions, but a significant increase in total mild side effects in patients versus HC were observed. Both influenza vaccines fulfilled the three criteria of the Committee for Proprietary Medicinal Products (CPMP). Seroconversion rate for any viral strain in patients and HC was, respectively, 68 versus 45 for H1-A/Brisbane/59/07, 72 versus 81 for H3-A/Brisbane/10/07, 68 versus 54 for B/Brisbane/60/08 and 81 versus 54 for A/California/7/2009. A slight increase in activated interferon (IFN)-γ-, TNF-α- or interleukin (IL)-17A-secreting T cells at T1 compared to T0, followed by a reduction at T2 in both patients and HC, was registered. In conclusion, simultaneous administration of adjuvanted pandemic and non-adjuvanted seasonal influenza vaccines is safe and highly immunogenic. The largely overlapping results between patients and HC, in terms of antibody response and cytokine-producing T cells, may represent further evidence for vaccine safety and immunogenicity in RA patients on biologicals.

Frequency of electrocardiogram testing among HIV‐infected patients at risk for medication‐induced QTc prolongation

HIV-infected patients are commonly prescribed several medications and are thus at risk for drug interactions that may result in QTc prolongation. We sought (1) to identify the frequency of electrocardiogram (ECG) monitoring (2), to determine the prevalence of drug interactions involving QTc-prolonging medications, and (3) to quantify the prevalence of QTc prolongation. A cross-sectional study was conducted among HIV-infected adults. Demographics, medications, drug interactions and comorbidities were abstracted from patients' medical records. Abnormal QTc interval was defined per the UK Committee for Proprietary Medicinal Products. Clinical characteristics were compared among ECG recipients and nonrecipients. Among ECG recipients, the prevalence and predictors of QTc prolongation were assessed. Among the 454 patients included in the study, 80.8% were prescribed a medication associated with QTc prolongation and 39% had drug interactions expected to increase QTc prolongation risk. There were 138 patients (30.3%) who received ECG testing. Receipt of ECG monitoring was associated with increasing age, diabetes, increasing total number of medications and gastroesophageal reflux disease. Among ECG recipients, the prevalence of abnormal QTc interval was 27.5%. Chronic kidney disease [prevalence ratio (PR) 3.47; 95% confidence interval (CI) 1.37-8.83; P = 0.009], hepatitis C virus coinfection (PR 2.26; 95% CI 0.97-5.27; P = 0.06) and hypertension (PR 2.11; 95% CI 0.93-4.81; P = 0.07) were independently associated with an abnormal QTc interval. A low frequency of ECG testing was observed, despite a high use of medications associated with QTc prolongation. The risk of abnormal QTc interval was highest among patients with chronic kidney disease, hypertension and hepatitis C virus coinfection.

Kinetics of the Antibody Response to Seasonal Influenza Vaccination Among the Elderly

Influenza vaccination, which has been targeted to the elderly and those at serious risk of complications, is recommended. The purpose of this study was to determine antibody responses after influenza vaccination among Thai elderly persons living in the community. A total of 591 subjects consisting of 308 vaccinees and 283 non-vaccinees were enrolled in the study. Antibodies to H1N1, H3N2, and B viruses were detected by hemagglutination inhibition (HI) testing. The numbers of subjects who had protective antibody titers ≥40 and geometric mean titers (GMTs) of antibodies against A(H1N1), A(H3N2), and B viruses prior to vaccination were similar for the vaccine and placebo groups. The seroprotection rates and GMTs for influenza virus A(H1N1), A(H3N2), and B strains after influenza vaccination at 1, 5, and 12 mo in the vaccine group were significantly higher than those in the placebo group. The seroprotection rates for the A(H1N1) and A(H3N2) strains, but not the B strain, met Committee for Proprietary Medicinal Products (CPMP) criteria (>60%). GMTs and seroprotection rates against influenza B strain in the vaccinees at all time points were <40% and <60%, respectively, and significant differences between the vaccinees and the placebo controls were observed. The GMTs and seroprotection rates for influenza strains in those with pre-existing antibody titers ≥40 were significantly higher than those in the group with pre-existing antibody titers <40. These findings demonstrated that the elderly living in the community developed adequate antibody responses with sustainable titers throughout the 12-month study period after influenza vaccine immunization. Moreover, the presence of pre-existing antibody at a titer ≥40 prior to vaccination strongly affected the antibody response to influenza vaccination.

Comparative Pharmacokinetics and Bioequivalence of Two 50 mg Atenolol Tablet Formulations in Healthy Korean Male Volunteers

Atenolol is a selective β1 receptor antagonist that is available as a racemic mixture. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 50 mg atenolol test and reference formulations in 24 healthy Korean male volunteers.This study was a single-dose, randomized, open-label, 2 period crossover study. 24 healthy Korean male volunteers randomly received 50 mg of either test or reference atenolol formulations in a 2×2 crossover study. There was a 1 week washout period between doses. The area under the curve (AUC)0-24 h and Cmax of 50 mg atenolol were the primary criteria for evaluation of bioequivalence.The mean ± standard deviation (SD) values of the Cmax, Tmax, AUC0-24 h, AUC0-∞, ke, and t1/2 of the test and reference formulations were 268.4 (78.96) and 256.9 (79.34), 2.750 (0.9555) and 3.104 (1.053), 1 981 (729.2) and 1 872 (604.8), 2228 (697.1) and 2 187 (628.5), 0.1332 (0.02748) and 0.1421 (0.04223), 5.419 (1.110) and 5.442 (2.357), respectively. The 90% confidence intervals for AUC0-24 h and Cmax were 0.9037-1.166 and 0.9169-1.1987, respectively. These results were within the accepted bioequivalence range of 0.80-1.25, which satisfied the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. In conclusion, the findings of this study indicate that the 2 formulations of 50 mg atenolol that were tested are bioequivalent. Therefore, these formulations may be prescribed interchangeably.

Bioequivalence Evaluation of Two Different Tablet Formulations of Tinidazole in Healthy Volunteers

The bioequivalence of two different tablet formulations of tinidazole (CAS 19387-91-8) was determined in healthy volunteers after a single dose in a randomized crossover study, with a 1-week washout period between the doses. Reference and test products were administered to 24 volunteers with 240 mL water after overnight fasting. Plasma concentrations of tinidazole were monitored by a high-performance liquid chromatographic method (HPLC) over a period of 72 h after the administration. The pharmacokinetic parameters AUC(o-t), AUCo-infinity, C(max), T(max), T((1/2)el) and beta were determined from plasma concentration time profile of both formulations and found to be in good agreement with previously reported values. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals for the ratio of C(max) (93.9 -102.6%), AUC(o-t) (94.9-101.1%) and AUC(o-infinity) (94.6-100.8%) values for the test and reference products were within the 80-125% interval, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. These results Indicate that the test and the reference products of tinidazole are bioequivalent and, thus, may be prescribed interchangeably.

Comparative Bioavailability of Two Estazolam Tablet Formulations in Indonesian Healthy Volunteers

To compare the bioavailability of two estazolam (CAS 29975-16-4) tablet formulations (Estalin 2 mg tablets as test formulation and 2 mg tablets of the originator product as reference formulation). The study was conducted according to an open label, randomized two-way cross-over design with a two-week washout period. Twenty-four subjects received each of the two estazolam formulations. Blood samples for pharmacokinetic profiling were taken up to 72 h after drug administration in fasting condition. Plasma concentrations of estazolam were determined with a validated HPLC method with ultraviolet detection. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. The mean AUC(0-t), AUC(0-infinity) and Cmax were 2581.38 ng x h/mL, 2934.37 ng x h/mL and 95.25 ng/mL, respectively for the test formulation and 2835.75 ng x h/ mL, 3207.73 ng x h/mL and 99.32 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1 h. The point estimates and 90% confidence Intervals for AUC(0-t), AUC(0-infinity) and Cmax were 91.03% (87.48-94.72%), 91.48% (86.67-96.55%) and 95.90% (92.60-99.31%) respectively, satisfying the bloequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. These results indicate that two formulations of estazolam are bioequivalent and, thus, may be prescribed interchangeably.