Catamenial Acute Intermittent Porphyria Managed with GnRH Analogues and Estrogen and Progesterone Add-back Therapy

BackgroundCatamenial precipitation of attacks of acute intermittent porphyria (AIP) is commonly treated with gonadotropin-releasing hormone analogues (GnRHas). However, this leads to various adverse effects that might necessitate “add-back” therapy with estrogen. The literature on the efficacy and safety of such therapy is scarce.CaseA 15-year-old girl presented to us with recurrent catamenial attacks of AIP. GnRHa therapy led to near-complete amelioration of the episodes but her bone density worsened as an adverse effect. To circumvent this, low-dose estrogen was added to her regimen as an “add-back” therapy, which was later coupled with cyclical progesterone. She continues to do well using this regimen, with no new episodes.Summary and ConclusionGnRHa therapy with estrogen “add-back” is an attractive option for treating catamenial AIP episodes.     

Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin

Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid–buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid–buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids–buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid–buffered formulation.     

Correction: Hood,M.A., et al. Synthetic Strategies in the Preparation of Polymer/Inorganic Hybrid Nanoparticles. Materials 2014, 7, 4057–4087

This article reviews the recent advances and challenges in the preparation of polymer/inorganic hybrid nanoparticles. We mainly focus on synthetic strategies, basing our classification on whether the inorganic and the polymer components have been formed in situ or ex situ, of the hybrid material. Accordingly, four types of strategies are identified and described, referring to recent examples: (i) ex situ formation of the components and subsequent attachment or integration, either by covalent or noncovalent bonding; (ii) in situ polymerization in the presence of ex situ formed inorganic nanoparticles; (iii) in situ precipitation of the inorganic components on or in polymer structures; and (iv) strategies in which both polymer and inorganic component are simultaneously formed in situ.     

Preparation of clinical‐scale 177Lu‐Rituximab: Optimization of protocols for conjugation,radiolabeling, and freeze‐dried kit formulation

Rituximab is a monoclonal chimeric antibody, which has been approved by the US Food and Drug Administration for immunotherapy of non–Hodgkin lymphoma. Bexxar and Zevalin are the two other approved radiolabeled antibodies for radioimmunotherapy of non–Hodgkin lymphoma; however, they are of murine origin that reduces their treatment efficacy. So as to circumvent this, efforts have been made to radiolabel Rituximab with various therapeutic radioisotopes. In the present study, an effort has been made to optimize the conjugation (bifunctional chelating agent and antibody) and radiolabeling procedures for the preparation of clinical‐scale ¹⁷⁷Lu‐labeled Rituximab. An attempt was also made to prepare the freeze‐dried Rituximab kit for the easy and convenient clinical translation of the agent. Clinical‐scale ¹⁷⁷Lu‐Rituximab (40 mCi, 1.48 GBq) was prepared with >95% radiochemical purity using the kit. Biological evaluation of ¹⁷⁷Lu‐Rituximab was performed by in vitro cell binding studies in Raji cell lines, which showed satisfactory binding at 4°C and 37°C. Pharmacokinetic behavior of the agent, evaluated by biodistribution studies in normal Swiss mice, revealed high blood and liver uptake at the initial time points, although it exhibited slow and gradual clearance with time. The study indicates that clinical‐scale ¹⁷⁷Lu‐Rituximab could be conveniently formulated using the methodology described in the present article.     

Identification of Physical-Chemical Variables Affecting Particle Size Following Precipitation Using a Supercritical Fluid

The physical-chemical processing variables affecting particle size following precipitation using the supercritical antisolvent (SAS) method were investigated by varying both the composition of the feed solvent and the structure of the solute, using a series of steroids. The key factor influencing particle size in these studies appears to be the solubility of the drug in the organic solvent/supercritical fluid mixture, where relatively high solubility causes a lower degree of supersaturation in the precipitation vessel, resulting in a relatively large particle size. Higher operating pressures result in larger particle sizes, probably through the effect of pressure on solubility. Physical properties of the carrier solvent, such as vapor pressure and dielectric constant, were not effective predictors of relative particle size of the precipitated powder, nor was solubility of the model drug in the carrier solvent. In limited studies of the physical state of the precipitated solid, higher apparent crystallinity was observed for powders with larger particle size. A precipitate of a different crystal form was observed when starting with hydrocortisone hemisuccinate monohydrate and may represent the loss of water of hydration. An amorphous solid was precipitated when starting with yttrium acetate dihydrate. Broad guidelines for effective particle size reduction using this technique are presented.     

An inhibitor of complement-mediated prevention of immune precipitation in rheumatoid arthritis — relationship to disease activity and systemic manifestations

Summary In normal serum complement prevents precipitation of antigen-antibody complexes (PIP). However rheumatoid arthritis (RA) serum contains an inhibitor of this complement-mediated function. We have undertaken two prospective studies in order to look for any relationship between the presence and levels of inhibitory activity in sera and synovial fluids (SF) of patients with RA and disease activity (study A), and the presence of systemic manifestations (nodules and vasculitis) of RA (study B). In study A, levels of inhibitory activity were highest in the sera and synovial fluids of patients with seropositive RA. However there was no correlation between the inhibitory levels and indices of generalised disease activity (articular index, erythrocyte sedimentation rate (ESR), haemoglobin, white cell and platelet counts). Local joint tenderness score correlated weakly with the inhibitory level in SF (P<0.05). There was no correlation, however, with either the SF protein concentration or white cell count. In study B, PIP was shown to be lower in patients with the systemic manifestations of RA than in those with purely articular manifestations. PIP was particularly low in those patients with vasculitis compared to those with subcutaneous nodules. Serum levels of inhibitory activity were highest in patients with vasculitis and lowest in those with articular disease only, whereas patients with nodules had intermediate levels. Our conclusion is that inhibition of immune precipitation is not associated with disease activity, but is associated with the extra-articular manifestations of RA. The inhibitory factor may play a role in the pathogenesis of RA.     

弓形虫可溶性表膜糖蛋白抗原的分离及其分子特性

本文用免疫沉淀、亲和沉淀和放射性同位素表面标记等技术自弓形虫虫体可溶物和急性期受染小鼠腹水中分别分离检测出多种可溶性蛋白抗原、表膜抗原、精蛋白抗原和外泌性抗原．以ＳＤＳ—ＰＡＧＥ分析可溶性蛋白可见至少６２条区带，分子量９—１６９ｋＤａ，以刀豆素Ａ亲和沉淀法分离所得精蛋白有７条主区带；以多克隆抗体免疫沉淀法分离出１８种可溶性抗原，并经１２５Ｉ标记和免疫沉淀证实其中至少包括１１种表膜抗原，分子量７—１４ｇｋＤａ．进一步以免疫－亲和双沉淀法分离测出６条糖蛋白抗原带．从受染小鼠腹水中也分离出８条独特的糖蛋白带；其中１０２、７７、５４、３５ｋＤａ４条抗原区带与可溶性表膜糖蛋白抗原的相应区带具有分子特性同质性。     

C 反应蛋白快速定量检测试剂盒性能评价

目的：评价以胶乳免疫比浊法原理研制的C反应蛋白快速定量检测试剂盒的方法学性能。方法测定试剂盒的检测限、精密度、线性范围、回收率、贮存稳定性,将检测200份样本的结果与国外试剂盒比较。结果检测限为0．72 mg/L,精密度：高、低浓度水平的样本批内变异系数分别为3．09％、6．75％,批间变异系数分别为6．47％、6．84％;线性范围为1～215 mg/L,线性相关系数为0.99;平均回收率为112．5％,系统误差＜1/2TEa。贮存有效期：18个月。200份不同浓度样本测定结果与进口试剂盒比较差异无统计学意义。结论研制的C反应蛋白快速定量检测试剂盒符合临床检测要求。     

Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.     

MDR-TB诊断试剂盒鉴定广东结核分枝杆菌复合群及RIF和INH药敏效果分析

目的评价耐多药结核病(MDR-TB)快速诊断试剂盒对广东地区结核分枝杆菌复合群的鉴定效果及利福平(RIF)和异烟肼(INH)的药敏检测效果。方法选取151份痰标本和150份细菌培养物,采用MDR-TB快速诊断试剂盒对其进行菌群鉴定及RIF和INH药敏检测,结果分别与常规法进行比较。结果与常规生化菌种鉴定结果相比,两者鉴定结果一致率为96.7%(291/301);与常规比例法药敏试验结果相比,诊断试剂盒检测单耐RIF的灵敏度为94.1%(64/68),检测单耐INH的灵敏度为87.7%(57/65),检测RIF和INH皆耐药株的灵敏度为79.3%(46/58),检测RIF和INH皆敏感株的特异性为100%。结论该试剂盒能简单快速地鉴定结核分枝杆菌复合群,检测RIF和INF的敏感性高、特异性好,在广东地区应用前景较好。