Newborn Screening for Severe Combined Immunodeficiency.

The T-cell receptor excision circle (TREC) assay is an effective screening tool for severe combined immunodeficiency (SCID). The TREC assay was designed to detect typical SCID and leaky SCID, but any condition causing low naïve T-cell counts will also be detected. Newborn screening for SCID using the TREC assay has proven itself to be highly sensitive and cost-efficient. This review covers the history of SCID newborn screening, elaborates on the SCID subtypes and TREC assay limitations, and discusses diagnostic and management considerations for infants with a positive screen.

Newborn Screening for Severe Combined Immunodeficiency.

The T-cell receptor excision circle (TREC) assay is an effective screening tool for severe combined immunodeficiency (SCID). The TREC assay was designed to detect typical SCID and leaky SCID, but any condition causing low naïve T-cell counts will also be detected. Newborn screening for SCID using the TREC assay has proven itself to be highly sensitive and cost-efficient. This review covers the history of SCID newborn screening, elaborates on the SCID subtypes and TREC assay limitations, and discusses diagnostic and management considerations for infants with a positive screen.

The 'stage-by-stage' deposition of drugs from commercial single-active and combination dry powder inhaler formulations.

Inhalation of salmeterol xinafoate (SX) and fluticasone propionate (FP) from a combination product is reported to produce superior clinical outcomes in comparison to the concurrent administration of 'similar' doses via separate single-active inhalers. For bioequivalence determination across different products, emphasis is currently placed on the assessment of drug deposition within inertial impactors on a 'stage-by-stage' basis as stipulated in a recent European Medicines Agency guidance. The aim of this study was to compare the stage-by-stage deposition of drugs aerosolised from the single-active Accuhaler® products Serevent® (SX) and Flixotide® (FP) with the SX-FP combination product Seretide® Accuhaler® in vitro. Drug deposition on a stage-by-stage basis was assessed using the next generation impactor (NGI). Significant differences in drug deposition profiles were obtained following aerosolisation from the single-active versus combination products. The concurrent administration of the two single-active products: Serevent® and Flixotide® Accuhaler® may not be bioequivalent to inhalation of the combination product Seretide® Accuhaler®. The observed differences may have resulted from different characteristics of the active pharmaceutical ingredient (APIs) and the carrier alpha-lactose monohydrate between the single-active and combination inhalers and/or a change in the drug-carrier inter-particulate interaction as a consequence of the presence of a second active.

The production of 'aerodynamically equivalent' drug and excipient inhalable powders using a novel fractionation technique.

Inhalation particles can be produced by various techniques such as milling, controlled crystallisation and spray-drying, but current methods cannot, to-date, precisely control the aerodynamic size distribution of produced powders. The aim of this study was to develop and validate a novel preparative technique whereby the efficient and reproducible aerodynamic fractionation of drug and excipient powders could be achieved. Salmeterol xinafoate (SX), fluticasone propionate (FP) and fine α-lactose monohydrate (FL) were chosen as model compounds. Powders were aerosolised using a dry powder feeder into a Next Generation Impactor operated at 60 L min(-1). Powders deposited on NGI stages were then collected and analysed. The fractionation process was successful for all powders producing significant linear correlations between the pre-set aerodynamic cut-off limits and geometric size measurements. For each of SX, FP and FL, sufficient powder quantities were recovered from NGI stages 1-6 producing six fractions with sequential aerodynamic and geometric particle size distributions. The fractionation technique was efficient and reproducible for all powders studied. The method can be equally applied to various drugs and excipients regardless of their previous production/processing history. Therefore, the aerodynamic fractionation technique may be used to compare and contrast samples produced by different processes.

Aerodynamic deposition of combination dry powder inhaler formulations in vitro: a comparison of three impactors.

Inertial impaction is generally regarded as the 'gold standard' for the in vitro assessment of aerodynamic deposition of inhaled formulations. Despite the availability of several impactors, few studies have compared measurements of aerodynamic deposition using multiple impactors and none employed a combination formulation. The aerodynamic deposition of the combination dry powder inhaler (DPI) Seretide Accuhaler, which contains salmeterol xinafoate (SX) and fluticasone propionate (FP), was assessed using the Andersen cascade impactor (ACI), multi-stage liquid impinger (MSLI) and next generation impactor (NGI) and the results were compared. Two Seretide products were tested at flow rates of 30 and QLmin(-1), the latter corresponding to a pressure drop of 4kPa across the device. Significant differences in the particle size distributions were observed when the same formulation was tested using various impactors. The ACI was found to be less suitable for DPI testing at flow rates considerably higher than 28.3Lmin(-1) due to the significant overlap in the cut-off curves of the pre-separator and stage 0. This was not the case with the MSLI but the data derived were limited by the relatively small number of stages. Deposition data determined by the three impactors were significantly different. The NGI produced good resolution and minimal inter-stage overlap and was regarded as the impactor of choice for DPI testing.