An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.     

Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy

Graefe's Archive for Clinical and Experimental Ophthalmology -     

Nervous reactivity changes in patients with late post-traumatic mental disturbances

Summary A polygraphic study of 105 patients with late-post-traumatic psychiatric disturbances and 158 matched subjects in two control groups has shown marked differences in nervous reactivity. The differences, estimated by testing the electrographic components of the orienting reaction elicited by a repetitive auditory stimulus and its habituation were expressed by changes in the intensity, resistance to habituation, and sequence of habituation of the somatic, autonomic, and EEG components. The character and severity of alterations depended on the site of the traumatic impact, lesional aspect of the craniocerebral trauma, clinical picture of mental disturbances, and features of the EEG tracings.     

A comparative demographicand socioeconomic study of spasmus nutans and infantile nystagmus.

PURPOSE: To compare the demographic and socioeconomic background of patients with spasmus nutans (SN) and patients with idiopathic infantile nystagmus (IIN). METHODS: This study was performed according to an observational case-control design. Parents or guardians of 23 patients with SN and 24 patients with IIN completed a 28-point questionnaire on demographic, socioeconomic, behavioral, personal, and family history. Mann-Whitney U tests were used to compare continuous dependents and chi(2) analyses for categorical variables. Correlation between variables was calculated by Spearman rho tests and odds ratios for SN by Mantel-Haenszel estimates. RESULTS: Comparing SN and IIN, Afro-American, and Hispanic ethnicity was significantly more common in SN (14 patients, 61%) than in IIN (1 patient, 4%). Significant differences between the groups were also found for gestational age (mean SN: 37.7 weeks, IIN: 40.3 weeks), home luminance at birth was reported to be brighter in more IIN patients (22 patients, 96%) as compared with the SN patients (15 patients, 71%). Factors reflecting a lower socioeconomic status were more prevalent in SN patients (annual household income, individual financially responsible for the household, source of income, availability of private medical insurance). In the SN group there were fewer married parents living together (9 families, 39%) than in the IIN group (21 families, 88%). Psychiatric disorders, including alcohol and drug abuse, were more frequent among parents of SN (10 parents, 47%) than of IIN (none). Annual household income and ethnicity correlated significantly with number of rooms/household. CONCLUSION: This study demonstrated differences between SN and IIN patients and their families with regard to socioeconomic status, ethnicity, gestational age, psychiatric diseases of parents, and parental estimation of light exposure early in life. We conclude that low socioeconomic status represents a risk factor for the development of SN.     

Polyéthers aromatiques à motifs azoïques, 2. Note sur I'hétéropolycondensation en milieu basique du azobenzène-4,4′-diol avec le 1,4-bis(chlorométhyl)-2,5-diméthylbenzène

The influence of the concentration of the reactants (bis(chloromethyl) derivative, NaOH) and of the reaction time upon the intrinsic viscosity and the yield of the polymers synthesized by the heteropolycondensation of sodium azobenzene-4,4′-diolate with 1,4-bis(chloromethyl)-2,5-dimethylbenzene is presented. The optimum conditions of polymer synthesis are established.     

Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.

OBJECTIVE: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. SUMMARY BACKGROUND DATA: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. METHODS: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. RESULTS: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. CONCLUSIONS: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.     

Plasma prostacyclin and thromboxane concentration in healthy children and in offspring of parents suffering from myocardial infarct

6-keto-prostaglandin F1a and thromboxane B2 were determined by radioimmunoassay in 135 healthy children, as a control group, and in 125 offsprings of parents suffering from premature coronary artery disease. Plasma prostacyclin concentration had decreased in children with a positive family history of coronary artery disease. It was demonstrated a strong reduction of thromboxane level in boys from age 11 in endangered group while the thromboxane/prostacyclin ratio did not differ from the control. It was supposed that in adolescent sons of parents who have had an acute myocardial infarction before the age of 45, a compensatory mechanism exists to protect them from disturbances in regulation of the balance between prostacyclin and thromboxane.