Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region.

Safety assessment and immunogenicity of a cell-culture-derived influenza vaccine in adults and elderly subjects over three successive influenza seasons.

BACKGROUND: Adult and elderly subjects previously immunized with cell culture-derived (CCIV; Optaflu(®)) or egg-derived (TIV; Agrippal(®)) trivalent influenza vaccines were enrolled in two extension studies (E1 and E2) to evaluate safety and immunogenicity after revaccination with CCIV/TIV alone or in combination with concomitant pneumococcal vaccine (PV). METHODS: Adults and elderly subjects (n = 2609) were randomized 1:1 in E1 and allocated 3:1 in E2 to receive CCIV/TIV. In E2, a subset of elderly subjects was randomized to receive CCIV/TIV, with or without PV. Adverse reactions were monitored for six months and immunogenicity was assessed by hemagglutination inhibition (HI) assay using CHMP criteria. RESULTS: Overall, the safety profile of both vaccines was similar, no serious adverse events related to either vaccine occurred. Mild or moderate pain was the most commonly reported reaction. Reactogenicity was slightly higher in elderly subjects receiving CCIV/TIV concomitantly with PV [46% vs. 37%; p = non-significant (NS)]. Both vaccines met CHMP licensure criteria for adults and elderly subjects. With concomitant CCIV and PV, all three CHMP criteria were met for A/H1N1 and A/H3N2, whereas the B strain only met seroprotection and GMR criteria. CONCLUSIONS: Safety and immunogenicity of CCIV was not influenced by the type of vaccine received previously or by concomitant PV administration.

Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function.

AIM: To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODS All subjects received a single transdermal 10 cm² patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h⁻¹). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. RESULTS: Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,t(last) ) and C(max) for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for C(max) for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. CONCLUSIONS: The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis.

Clinical efficacy of cell culture­derived and egg­derived inactivated subunit influenza vaccines in healthy adults.

BACKGROUND: More efficient methods are needed to manufacture influenza vaccines. This trial compared the efficacy of cell culture-derived influenza vaccine (CCIV) and egg-derived trivalent inactivated vaccine (TIV) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States, Finland, and Poland during the 2007-2008 influenza season. METHODS: A total of 11,404 study participants aged 18-49 years were randomized equally to receive CCIV (Optaflu; n = 3828), TIV (Agrippal; n = 3676), or placebo (n = 3900). Each participant was observed during a 6-month study surveillance period. Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness. Vaccine immunogenicity was evaluated in a subset of 1045 participants. RESULTS: Efficacy of CCIV and TIV against vaccine-like (83.8% [1-sided 97.5% confidence interval [CI] lower limit, 61.0%] and 78.4% [1-sided 97.5% CI lower limit, 52.1%], respectively) and all circulating influenza virus strains (69.5% [1-sided 97.5% CI lower limit, 55.0%] and 63.0% [1-sided 97.5% lower limit, 46.7%], respectively) exceeded the Center for Biologics Evaluation and Research efficacy criteria. Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria. Both vaccines were well tolerated, with similar safety profiles. Most solicited reactions were mild to moderate in severity and transient. No vaccination-related serious adverse events were reported; no withdrawals resulted from vaccine-related adverse events. CONCLUSIONS: Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains, were well tolerated, and had good safety profiles. Both vaccines can be considered for annual influenza vaccination campaigns. CLINICAL TRIALS REGISTRATION: NCT00630331.

Safety and immunogenicity of a novel influenza subunit vaccine produced in mammalian cell culture.

BACKGROUND: Immunization remains the best prevention strategy for influenza, but production constraints for egg-based influenza vaccines have prompted the development of innovative cell culture manufacturing processes. Here, we describe a novel cell culture-derived influenza vaccine (CCIV) produced in Madin-Darby canine kidney cells. METHODS: This phase 3, observer-blind, randomized, multicenter study in Poland compared the immunogenicity of a CCIV and a conventional egg-based vaccine. Participants, stratified by age (adults 18-60 years, n = 1300; elderly persons > or = 61 years, n = 1354), received a single intramuscular vaccination. Immunogenicity was assessed 21 days later by hemagglutination inhibition assay. Reactogenicity was assessed using self-completed diary cards. RESULTS: The immunogenicity of CCIV was noninferior to that of the conventional vaccine for all 3 vaccine strains in both age groups, regardless of underlying health status. Both vaccines fulfilled European Union registration criteria and were well tolerated, with similar incidences of solicited local and systemic reactions in both age groups; the only significant difference was an increased frequency of mild or moderate pain with CCIV than the conventional vaccine among adult (22% vs 17%; P < .05) and elderly (9% vs 5%; P < .001) vaccinees. CONCLUSIONS: CCIV was well tolerated and highly immunogenic in adults 18 years of age or older. Cell culture may offer greater flexibility of supply during periods of high demand for both seasonal and pandemic vaccines.

Acute renal failure in patients with rhabdomyolysis.

BACKGROUND: Rhabdomyolysis is a relatively rare, not always diagnosed cause of acute renal failure (ARF). This fact motivated us to present the results of ARF treatment in the course of this polyetiological clinical syndrome. MATERIAL/METHODS: The analysis was performed on 84 patients (6 F, 78 M) ranging in age from 18 to 82 years (mean 46.5), in whom rhabdomyolysis was diagnosed based on clinical manifestation and laboratory test results (CPK, GTP, GOT, LDH). RESULTS: The most frequent cause of rhabdomyolysis was alcoholic intoxication (41 patients), often accompanied by hypothermia (15 patients) or trauma (30 patients). Isolated trauma was found in 30 patients, epileptic seizure in 5, and physical exercise in 1 case. In 17 patients, besides alcohol consumption, trauma or epileptic seizure, the use of tranquilizers, anticonvulsants, or narcotic drugs was additionally noted. 78 patients developed ARF requiring dialysis therapy; 49 patients recovered, 5 required maintenance dialysis, and 30 died. CONCLUSIONS: During the initial phase of ARF in the course of rhabdomyolysis dynamic increases in serum urea and creatinine were observed, as well as a tendency to hyperkalemia. The treatment results and mortality rate in our study group were primarily influenced by the patients' general condition at admission, as well as the extent of organ damage caused by the primary etiological factor. Favorable treatment results were obtained especially in those patients who were hospitalized in a nephrological center, while the worst outcomes were noted in those patients dialyzed in intensive care units, most with multiple trauma.