Succinobucol: review of the metabolic,antiplatelet and cardiovascular effects

Background: Succinobucol (AGI-1067) was developed as a probucol derivative with anti-inflammatory and antioxidant properties. It has undergone Phase III clinical trials to determine its place in the treatment of atherosclerotic disease. Objective: This paper reviews the available history, pharmacology and preclinical and clinical trial data of succinobucol. Methods: Data were compiled following review of publications indexed in Medline and International Pharmaceutical Abstracts, industry media releases and relevant bibliographies. Results/conclusion: In preclinical studies, succinobucol exhibited antioxidant, anti-inflammatory, antihyperglycemic and antiplatelet properties; however, these effects have not resulted in a reduction in cardiovascular clinical end points in clinical trials. Although proposed antihyperglycemic effects are being investigated, safety concerns and lack of clear cardiovascular benefit may limit its clinical use as an antihyperglycemic agent.     

C-reactive protein levels and survival in patients with moderate to very severe COPD

BACKGROUND: Serum levels of C-reactive protein (CRP) are increased in patients with COPD and correlate modestly with variables predictive of outcomes. In epidemiologic studies, CRP level is associated with all-cause mortality in patients with mild-to-moderate disease. OBJECTIVE: To determine if CRP levels are associated with survival in patients with moderate to very severe COPD in comparison with other well-known prognostic parameters of the disease. METHODS: In 218 stable patients with COPD, we measured baseline serum CRP level, BODE (body mass index, obstruction, dyspnea, and exercise capacity) index and its components, arterial oxygenation (Pao(2)), inspiratory capacity (IC) to total lung capacity (TLC) ratio, and Charlson comorbidity score. We followed up the patients over time and evaluated the strength of the association between the variables and all-cause mortality. RESULTS: During the follow-up time (median, 36 months; 25th to 75th percentiles, 24 to 50 months), 54 patients (25%) died. CRP levels were similar between survivors and the deceased (median, 3.8 mg/L; 95% confidence interval, 1.9 to 8.1; vs median, 4.5 mg/L; 95% confidence interval, 2.1 to 11.5; p = 0.22) and was not significantly associated with survival. CONCLUSIONS: In this population of patients with clinically moderate to very severe COPD, the level of CRP level was not associated with survival compared with other prognostic clinical tools such as the BODE index, modified Medical Research Council scale, 6-min walk distance, percentage of predicted FEV(1), IC/TLC ratio < 0.25, and Pao(2). Other long-term studies of well-characterized patients with COPD could help determine the exact role of CRP levels as a biomarker in patients with clinical COPD.     

Reevaluation of the lingual split-bone technique for removal of impacted mandibular third molars

In 1970 the author published an article on the results of use of the split-bone technique for removal of impacted mandibular third molar teeth. By this method, first described by Ward, a thin segment of distolingual bone is removed and the tooth delivered lingually. This clinical update reviews the previous paper, adds additional cases and findings, and gives the author's current views of the value of the technique, indications for its use, and possible complications.     

软癥散结合剂对食管癌移植瘤BAT-26及D3S1067微卫星不稳定性的影响

[目的]观察软瘸散结合剂对裸鼠人食管癌移植瘤的抑制作用,及其对瘤体BAT-26及D3S1067微卫星不稳定性（MSI）的影响。[方法]建立裸鼠皮下食管癌移植瘤模型,模型建成后随机分为5组：正常组、生理盐水组、软瘸散结合剂低、中、高剂量组。实验15d后剥取肿瘤并称重,计算抑瘤率。荧光PCR法检测移植瘤组织中BAT-26及D3S1067MSI的表达。[结果]低、中、高剂量软瘾散结合剂对裸鼠的移植瘤抑制率分别为27．11％、47．69％和35．56％。软瘾散结合剂中剂量组D3S1067 MSI发生率显著性低于生理盐水组（P〈0．05）。各组BAT-26位点MSI表达均很低,且无统计学差异。[结论]软瘕散结合剂能抑制人食管癌细胞移植瘤生长,这一作用可能与其下调肿瘤细胞D3S1067位点的微卫星不稳定性相关。     

Selective thromboxane inhibition after vascular protectant AGI-1067: results of assessment of lipoprotein profiles (ALPS) biomarkers in vitro and in vivo substudy

Background Oxidative stress play an important role triggering platelet/endothelial activation. AGI-1067 is a novel, phenolic antioxidant, and vascular protectant which dose-dependently inhibits PEA biomarkers in vitro. Whether treatment with AGI-1067 alters platelets in vivo is not known. We serially assessed release of established PEA biomarkers in subjects treated with AGI-1067 versus placebo in the frame of Assessment of Lipoprotein Profiles Randomized Trial (ALPS). Methods Healthy subjects (18–65 years) with multiple risk factors for coronary artery disease were randomized 1:1 to receive 300 mg AGI-1067 (n = 112) or matching placebo (n = 117) daily for 12 weeks. Anticoagulants, aspirin, NSAIDS, and COX inhibitors were not permitted in this study. Plasma samples were collected at baseline, and at week 12 after randomization. Platelet factor 4 (PF4), β-thromboglobulin (βTG), P-selectin, thromboxane (TxB₂), and prostacyclin (6-keto-PGF_1a) were measured by ELISA. Results Treatment with AGI-1067 was associated with a highly significant reduction of TxB₂ release (P < 0.0001) when compared to the placebo. There were no differences in PF4, βTG, P-selectin, and 6-keto-PGF_1a between and within groups. AGI-1067 also inhibits TxB₂ release from calcium ionophore (A23187)-stimulated human platelets with the IC50 equals 1 μM; but does not interfere with 6-keto-PGF1α release in either A23187-, or TXA₂-stimulated human aortic endothelial cells. Conclusion AGI-1067 selectively reduces TxB₂ production from stimulated platelets, and diminishes plasma TxB₂ levels in ALPS participants. These data support earlier in vitro, and pilot ex vivo experiments suggesting antiplatelet properties of AGI-1067. Lack of 6-keto-PGF1a down regulation may represent an attractive advantage of AGI-1067 over currently available antiplatelet regimens.     

SCN1A基因T1067A多态性与全面性癫痫伴热性惊厥附加症易感性的研究

目的：探讨SCN1A基因T1067A多态性与全面性癫痫伴热性惊厥附加症（GEFS＋）的相关性。方法：采用PCR、变性高效液相色谱法检测105例GEFS＋患者及127名正常人SCN1A基因的第16编码外显子T1067A多态性、基因型频率、等位基因频率,比较癫痫患者及正常人的差异。结果：105例患者中,AA、AG和 GG型分别为82例（78.1%）、20例（19.0%）、3例（2.9%）;127名正常人中AA、AG和 GG型分别为102例（80.3%）、23例（18.1%）、2例（1.6%）,两组间基因型比较差异无统计学意义（P〉0.05）。患者中A、G等位基因频率分别为87.6%（184/210）、12.4%（26/210）,而正常人中A、G等位基因频率分别为89.4%（227/254）、10.6%（27/254）,两组中A、G等位基因频率的分布差异也无统计学意义（P〉0.05）。结论：本研究未发现SCN1A 基因T1067A多态性与GEFS＋存在相关性。     

Bone marrow aplasia after high voltage electrical injury

This report describes a patient with severe high voltage electrical injury in whom bone marrow aplasia developed on post-burn day 3. In addition to bone marrow aplasia alterations suggesting disintegration of leucocytes and reduced nitro-blue tetrazolium reductase activity pointing to functional disorders have been observed. Beyond the effect of the extensive burns to depress the bone marrow the possibility of an additional similar action of the high voltage electrical injury is raised.     

Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

Fibrodysplasia Ossificans Progressiva (FOP) is a rare debilitating disorder characterized by congenital deformity of the great toes from infancy and postnatal heterotopic ossification. Activating mutations in the activin A receptor type 1 (ACVR1) gene are responsible for the disease. The most common allelic variant leading to FOP is c.617 G>A; p.R206H, however, other alleles have been reported with atypical phenotypes. We report 14 cases presenting to a referral institution in South India over a 3‐year period. The patients were clinically diagnosed based on foot abnormality or abnormal ectopic ossification and were screened for ACVR1. The genetic analysis of ACVR1 identified the recurrent allelic variant in 12 of 14 patients. One of the remaining patients had a previously reported allele c.1067G>A; p.G356D in the 9th exon and the second allele c.983G>A; p.G328E in the 8th exon of ACVR1. The most common recurrent allele c.617 G>A; p.R206H is also the most common in Indian patients with FOP.     

Experimental and clinical studies show that the probucol derivative AGI-1067 prevents vascular growth

AGI-1067 is a derivative of probucol that is a promising new development for the treatment of restenosis and possibly atherosclerosis. In monkeys fed a high-fat diet for 1 year, AGI-1067 prevented the development of atherosclerosis. In these monkeys, AGI-1067 lowered plasma levels of low-density lipoprotein (LDL)-cholesterol and, in contrast to probucol, was capable of increasing high-density lipoprotein (HDL)-cholesterol levels. Although AGI1067 did not have marked lipid-lowering effects in two transgenic mouse models (the LDL-receptor-deficient and apolipoprotein-E-deficient models) fed a high-fat chow, it decreased the atherosclerotic lesion area in the aorta. In a mouse model of acute inflammation, the mRNA for the pro-inflammatory vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 was upregulated and this was inhibited by AGI-1067. AGI-1067 inhibited the TNF-α induction of redox-sensitive inflammatory proteins, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 and Eselectin, in cell culture. In addition, AGI-1067 is an antioxidant. In the Canadian Antioxidant Restenosis Trial (CART-1) of AGI-1067 in percutaneous coronary interventions, AGI-1067 had no effect on LDL-cholesterol but lowered HDL-cholesterol. At 6 months follow up, the lumen area of the percutaneous coronary interventions segments was greater in patients treated with AGI1067 than in untreated patients. Restenosis rates were 37.5% in the placebo group and 26% in the AGI-1067 group. The lumen area of reference segments was reduced in the placebo group but increased with the higher doses of AGI1067. Unlike probucol, AGI-1067 did not alter QTc interval.     

Cerebral hemodynamic crisis: Physiology,pathophysiology, and approach to therapy

The physiology and pathophysiology of the cerebral circulation have been discussed in relation to treatment of the cerebral hemodynamic crisis. Data are presented to show how cerebral vascular resistance, the intracranial compartments, and brain metabolic demand may be manipulated to effect internal decompression and raise local perfusion pressures. It is quite apparent that irreversibility occurs rapidly in cases of complete ischemia and therapeutic success is often limited by this fact. Application of sound therapeutic principles will limit the extent of cellular destruction. Of particular importance to the general surgeon treating the multiply injured patient, is the effect of anesthesia on intracranial pressure in patients with compromised intracranial volume reserve.