Surgery for transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction: European Congenital Heart Surgeons Association multicentre study

Objectives: Optimal surgical management for patients with transposition of the great arteries (TGA), ventricular septal defect (VSD) and left ventricular outflow obstruction (LVOTO) remains controversial. Although the Rastelli operation has been the most widely performed surgical procedure during the past decades, several studies have shown its suboptimal long-term prognosis. Other operations have been developed to improve results. This study was performed to compare the outcomes of the different surgical approaches for patients with TGA, VSD and LVOTO, as well as to determine risk factors for mortality and re-intervention. Methods: Records from 146 patients undergoing surgery from 1980 to 2008 from eight European hospitals were reviewed. Median age at operation was 21.5 months (range 0.2–165.1 months), and median weight was 10.0 kg (range 2.0–41.0 kg). Surgical procedures involved were the Rastelli procedure (82), arterial (24) and atrial (5) switch operation with relief of LVOTO, Réparation à l’Etage ventriculaire (REV) procedure (7) and the Metras modification (24), as well as the Nikaidoh procedure (4). Results: The overall survival was 88%, 88% and 58% at 1, 10 and 20 years, respectively. The overall event-free survival was 80%, 45% and 26% at 1, 10 and 20 years, respectively. The REV procedure and the Metras modification were found to have the best long-term results in both survival and event-free survival rates. Multivariate analysis revealed year of operation, non-commitment of the VSD and prolonged cardiopulmonary bypass (CPB) time as risk factors for mortality while age at surgery, year of operation and type of corrective surgery were risk factors for re-intervention. Conclusions: Different surgical approaches have been developed for patients with TGA, VSD and LVOTO. The REV procedure and the Metras modification were observed to have favourable long-term results in survival and event-free survival rates. Aortic translocation techniques such as the Nikaidoh procedure seem promising, but further studies will be needed to confirm this in the long term.     

Future development of global regulations of Chinese herbal products

Ethnopharmacological relevance

GP-TCM is the first EU-funded Coordination Action consortium dedicated to traditional Chinese medicine (TCM) research. One of the key deliverables of the Work Package 7 in GP-TCM was to investigate information of the existing requirements for registration of TCM products listed by global regulatory bodies. The paper aims to collate data and draw comparison of these regulations. Case studies are also presented to illustrate the problems involved in registering TCM products in different regions worldwide.

Materials and methods

A collaborative network task force was established during the early stage of the GP-TCM project and operated through exchanges, teleconferences and focused discussions at annual meetings. The task force involved coordinators, academics who are actively involved with R&;D of Chinese herbal medicines, experts on monographic standards of Chinese materia medica, representatives from regulatory agencies, experts from industries in marketing Chinese medicines/herbal medicines and natural products. The co-ordinators took turns to chair teleconferences, led discussions on specific issues at AGM discussion sessions, at joint workshops with other work-packages such as WP1 (quality issues), WP3 (toxicology issues) and WP6 (clinical trial issues). Collectively the authors were responsible for collating discussion outcomes and updating written information.

Results

A global overview of regulations on herbal registration has been compiled during the three years of the consortium. The regulatory requirements for registration of herbal products in the EU and China were compared, and this is extended to other regions/countries: Africa, Australia, Brazil, Canada, Japan, Russia, South Korea, Taiwan, and the United States. A wide variation of the regulations for the categories of herbal products exists: food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use, food supplement); cosmetic, traditional herbal medicine products; herbal medicines for human use and veterinary use.

Conclusion

The regulatory issues for registration of herbal products are complicated among the countries and regions worldwide. The information summarised in the text is for reference only. Some regulations which are presented in this review are still in legislation process and may change in due course. Before taking any regulatory action, readers are advised to consult current official legislation and guidance and/or to seek appropriate professional advice. The lessons learnt from global regulation of TCM will provide valuable insights for regulation of other traditional medicine such as Ayurveda and Unani medicine, as well as other forms of indigenous medicine. The WHO is well placed to co-ordinate a consultation process with the aim of putting forward suggestions for harmonisation to key regulatory agencies.     

碘硒缺乏地区甲状腺肿患者甲状腺自身抗体的观察

５９例地方性甲状腺肿患者分为碘硒双补组及单纯补碘组。采用放射免疫法于防治前、后分别测定两组患者血清ＴＧＡ、ＴＭＡ。防治前上述两组血清ＴＭＡ分别为２３．２８±２２．８％，１９．３７±１８．８４％，防治后两组血清ＴＧＡ、ＴＭＡ显著下降（Ｐ＜０．０１）。结果提示地方性甲状腺肿患者中可能存在着自身免疫性甲状腺疾病；在碘硒缺乏地区，碘硒双补对调节甲状腺的自身免疫有一定作用     

Six-Year Outcome after Valve Replacement and Resynchronization Therapy in TGA Patient

Patients with complete transposition of the great arteries (TGA) treated by the Senning procedure have a higher risk of developing heart failure due to: a) additional work load of the systemic (morphologic right) ventricle (sRV), b) arrhythmias, mainly caused by surgical implications at the atria as well as c) worsening of systemic tricuspid regurgitation. We present a unique case of a female patient who developed all these complications, who was successfully treated and was able to carry out a twin pregnancy. This breakthrough approach was based on: 1. detecting reversibility potential of myocardial systolic dysfunction in a severe valvular lesion combined with continuous systemic afterload settings and permanent tachyarrhythmia, and 2. prevention of subsequently iatrogenic worsening of systemic ventricular function due to permanent pacing. Surgical replacement of systemic tricuspid valve (sTV) and cardiac resynchronization device (CRT) implantation after nodal ablation resulted in recovering of the systolic function and a positive remodeling of the sRV. The reversal of a further decline in systolic function was achieved by permanent arrhythmia control, synchronous pacing with epicardial leads of CRT, sTV replacement as well as echocardiographic monitoring during pregnancy to determine the right time for delivery. Two years after delivery, the patient remains in NYHA Class I.     

Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII

Introduction

The preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII, was assessed in a series of animal studies.

Materials and Methods

In the tail-clip bleeding model, hemophilia A mice were injected with escalating doses (1–150 IU/kg) of rVIII-SingleChain, B-domain deleted (BDD) rFVIII (ReFacto AF^®), or full-length rFVIII products (Advate^®, Helixate^®). Total blood loss and the percentage of animals in which hemostasis occurred were assessed in this observer-blinded, randomized study. In a second non-randomized study in hemophilia A mice, thromboelastographic analysis, thrombin generation, and activated partial thromboplastin time assays were performed. General safety and toxicity were assessed in three animal species, including determination of the prothrombotic potential of rVIII-SingleChain in a rabbit venous thrombosis model.

Results

Under acute bleeding conditions, the effect of rVIII-SingleChain on total blood loss and hemostasis was indistinguishable from BDD and full-length rFVIII. rVIII-SingleChain and full-length rFVIII (both 20 IU/kg) corrected thromboelastographic parameters, activated partial thromboplastin time, and thrombin generation to a similar degree in hemophilia A mice. In a thrombosis model, the effect of rVIII-SingleChain on thrombus incidence was non-significant and comparable to BDD rFVIII at doses up to 500 IU/kg. Treatment with rVIII-SingleChain did not cause anaphylactic reaction or local intolerance in safety and toxicity studies, and demonstrated an excellent overall safety profile.

Conclusions

rVIII-SingleChain showed convincing hemostatic efficacy and excellent tolerability in animal studies, warranting continued investigation in human Phase I/III trials (AFFINITY).     

Solid-State Characterization of Spironolactone 1/3 Hydrate

Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate.