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.     

Lung function after acute and repeated exposures to extremely cold air (-110 degrees C) during whole-body cryotherapy

Whole-body cryotherapy (WBC) is one mode of cold therapy, during which rheumatic patients are exposed to very cold air (-110 degrees C) in minimal clothing. It is also proposed to have a bronchodilatory effect. The aim was to examine the effects of WBC on lung function in healthy humans after acute and repeated exposures. Twenty-five healthy, non-smoking subjects participated in the study. They were exposed to WBC for 2 min three times per week for 12 weeks. The peak expiratory flow rate (PEF) and forced expiratory volume in 1 s (FEV1) were measured before and after (at 2 and 30 min) the first WBC, and then similarly at 4, 8 and 12 weeks. At all time points, after 30 min of the WBC the PEF values were slightly lower compared with values before the WBC, and the reductions reached statistical significance at 1 month (5.1 +/- 1.2%), and at 3 months (3.2 +/- 1.7%). After 30 min of the first WBC, the FEV1 was significantly reduced by 2.3 +/- 0.8%, but no other changes were observed during the study. In conclusion, the WBC induced minor bronchoconstriction in healthy humans instead of proposed bronchodilatation. The WBC seems not to be harmful for lung function, but should be used with caution in susceptible individuals.     

Fast transmission of alterations in plasma phosphatidylcholine/sphingomyelin ratio and lyso phosphatidylcholine levels into changes of red blood cell membrane phospholipid composition after low density lipoprotein apheresis

Abstract. In order to evaluate whether changes in plasma phospholipid composition are rapidly transmitted to the red blood cell membrane (RBCM) under in vivo conditions, the levels of major phospholipids in plasma, low density and high density lipoproteins (LDL and HDL) as well as in RBCM were determined before (pre), directly after (post) and 2 days after (48 h post) LDL apheresis in six patients with severe hypercholesterolaemia. LDL apheresis induced a 30–70% decrease in plasma and LDL cholesterol and total phospholipid levels within 2–3 h. Concomitantly, the percentages of plasma phosphatidylcholine (PC) and the PC/sphingomyelin (SM) ratio were increased compared to initial values. The percentage of plasma lyso PC (LPC) determined before apheresis in the patients was 30% lower with respect to the mean level of LPC in a normolipidaemic control. For LPC of LDL no differences were observed between normolipidaemia and hypercholesterolaemia. LDL apheresis induced a rise by about one third in the percentage of plasma LPC. At 48 h post, plasma LPC levels reapproached pre-apher-esis levels, while the percentages of PC and the PC/SM ratio remained elevated. The pattern of changes induced by apheresis in plasma PC, SM and LPC levels was mimicked by changes in RBCM phospholipids. Strong positive relationships were noted for PC, SM and PC/SM as determined at pre, post and 48 h post between plasma and RBCM. In summary, changes in plasma PC, LPC, and PC/SM ratios as induced by LDL apheresis are rapidly transmitted to the RBCM under in vivo conditions, most probably as a result of phospholipid transfer between both compartments. In addition, the percentages of LPC in plasma and LDL particles of patients with severe hypercholesterolaemia are certainly below the levels of LPC reported to mediate biological effects of in vitro oxidized LDL.     

络合沉淀-紫外分光光度法测定黄芩素脂肪乳中甲氧基苯胺值

目的：建立一种专属性好适用于主药有干扰的脂肪乳中甲氧基苯胺值的测定方法。方法：以醋酸铅为络合沉淀剂,采用络合沉淀法排除主药黄芩素对甲氧基苯胺值测定的影响,并对改进后的方法进行验证分析;结果：方法中选择加入沉淀剂的量为200μL,专属性良好,干扰试验结果为99.39%,RSD为1.73%(n=3),重复性结果RSD均小于5.0%(n=5)。结论：该方法专属性好,测定结果准确可靠,能有效排除药物对脂肪乳甲氧基苯胺值测定影响,扩大了甲氧基苯胺值紫外分光光度测定法的适用性,为载药脂肪乳中甲氧基苯胺值控制提供了新的思路和方法。     

Impact of Method of Preparation of Amorphous Solid Dispersions on Mechanical Properties: Comparison of Coprecipitation and Spray Drying

Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that the method of preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASDs) of 50% GDC-0810 with hydroxypropyl methylcellulose acetate succinate: (1) spray drying, (2) coprecipitation using overhead mixing, and (3) coprecipitation using resonant acoustic mixing. All 3 methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (overhead mixing and resonant acoustic mixing) demonstrated superior tabletability and flow properties when compared to the spray drying powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through coprecipitation.     

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.     

The impact of work on the night blood pressure dipping profile

Objective. The purpose of this study was to elucidate whether ambulatory blood pressure (ABPM) performed during a work day and a non-work day had any impact on the night dipping profile. Study design. A crossover randomized ABPM study in primary healthcare was retrospectively analysed for the occurrence of non-dipping (ND), dipping (D) or extreme (XD) nightly dipping. Non-dippers were defined as subjects with less than 10% and extreme dippers as subjects with more than 20% nightly blood pressure fall measured as mean arterial pressure (MAP). Subjects. Forty treated hypertensives and 40 normotensives (20 men and 20 women in each group), who had performed ABPM twice in a fortnight. They had been randomly allocated to perform a work day or a non-work day as the first period. Result. Only one of the 16 subjects who at any time was a non-dipper remained so during both monitoring periods. Extreme dipping was more often reproduced in nine persons out of 29. Of all 80 subjects, 43.8% (35 persons) remained dippers during both periods. No one changed from a non-dipper to an extreme dipper or the reverse. The odds of being an ND were 3.8 times more common on a non-work day, p = 0.010. XDs were slightly more common (1.7 times) on a work day than on a non-work day, p = 0.040. There was no correlation as to the degree of MAP and the dipping profile, p = 0.629. Conclusions. More subjects were non-dippers at the end than at the beginning of the work week. It is essential to consider this when attempting to identify a non-dipper by ABPM.     

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。