A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg^-1. This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg^-1) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.     

Sound vibration,a non-invasive stress: antagonism by diazepam

Rats, subjected to sound-vibration stress, showed an abrupt increase in plasma corticosterone (CS). This stimulation was reliably produced using a Burgess brand vibro-graver, a standard tool used for engraving. With the tool set at 8 or coarse, the barrel of the tool was placed on the animal's flank and the point held against the side of the metal cage for 15 s. Plasma CS increased to 29.3±4.7 µg/dl at 15 min and 15.7±1.8 µg/dl at 30 min. These levels were significantly higher than animals pretreated with diazepam, 5 mg/kg IV, 2 h prior to stimulation (9.2±2.0 and 7.4±1.5 µg/dl, respectively). Animals which were pretreated with CGS-8216 (a mixed agonist/antagonist at the benzodiazepine receptor), 2 mg/kg IV, 30 min prior to diazepam had the protective effects of diazepam abolished. Sound/vibration produced a significant elevation in plasma CS in animals given CGS-8216 alone; but, this elevation was significantly lower than in vehicle-treated controls. This comparatively lower plasma CS level suggests a partial-agonist, diazepam-like effect by CGS-8216. Experiments were done in conscious unrestrained male Sprague-Dawley rats with chronic IV catheters. Except for 15 s stimulation exposure, all animals remained isolated in sound-attenuated one-way vision boxes for the duration of the serial blood sampling. Control stimulation exposure involved similar handling without turning on the engraving tool. These results demonstrate: 1) the usefulness of this tool to provide a repeatable stress stimulus; 2) the ability of diazepam to abolish the stress response; 3) that CGS-8216 can antagonize the action of diazepam; and 4) a demonstration of the partial agonist effects of CGS-8216.     

Edrophonium antagonism of vecuronium at varying degrees of fourth twitch recovery

The purpose of this study was to determine the optimal dose of edrophonium needed for successful antagonism (train-of-four ratio, or T₄/T₁ > 0.7) of vecuronium-induced blockade when all four twitches were visible in response to indirect train-offour (TOF) stimulation. Forty patients, scheduled for elective surgical procedures not exceeding 120 min, received vecuronium, 0.08 mg · kg^?1, during thiopentone-N₂O-isoflurane anaesthesia. Train-of-four stimulation was applied every 20 sec and the force of contraction of the adductor pollicis muscle was recorded. Increments of vecuronium, 0.015 mg · kg^?1, were given as required. At the end of surgery, and provided that neuro-muscular activity had recovered to four visible twitches, edrophonium, 0.1 mg · kg^?1, was given. Two minutes later, edrophonium, 0.1 mg · kg^?1, was given if T₄/T₁ did not reach 0.7. After another two minutes, edrophonium, 0.2 mg · kg^?1, was given if T₄/T₁ did not reach 0.7 or more. Finally, if T₄/ T₁ was still < 0.7, a dose of 0.4 mg · kg^?1 was given. Seventeen patients (42.5%) required 0.1 mg · kg^?1 of edrophonium for successful reversal, sixteen patients (40%) needed a cumulative dose of 0.2 mg · kg^?1 and six patients (15%) required 0.4 mg · kg^?1. Only one patient received 0.8 mg · kg^?1. There was a good correlation between T₄/ T₁ two minutes after the first dose of edrophonium and pre-reversal T₄/T₁ (r = 0.6; P = 0.00014). All patients with pre-reversal T₄/ T₁ > 0.23 required at most 0.2 mg · kg^?1 of edrophonium for successful reversal. We conclude that when all four twitches are clearly visible following train-of-four stimulation, small doses of edrophonium (0.1-0.2 mg · kg^?1) might be sufficient to antagonize vecuronium neuromuscular blockade.     

“In vitro” and “ex vivo” effects of picotamide,a combined thromboxane A2-synthase inhibitor and -receptor antagonist,on human platelets

Summary Picotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies.When whole blood was activated with collagen in the presence of picotamide 5×10^–4 M, thromboxane B₂ production was decreased, and 6-keto-PGF₁ generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A₂-receptor antagonism, possibly of competitive nature.A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B₂ were also reduced.Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of -thromboglobulin.The results indicate that picotamide is a combined thromboxane B₂-synthetase inhibitor and thromboxane A₂-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent.     

两类胃酸分泌抑制剂治疗急性消化性溃疡出血的比较研究

目的　比较抑酸药 H2 受体拮抗剂 (H2 A)与质子泵抑制剂 (PPI)对消化性溃疡出血的疗效 .方法　 130只 SD大鼠随机分成 6组 ,制备急性胃溃疡出血模型 ,以不同 p H值的缓冲液冲洗胃溃疡部位后记录其胃粘膜出血时间 (GMBT) .2 2 4例消化性溃疡急性出血患者 ,随机分 2组 ,2 4h内洛赛克组静滴 40 mg洛赛克 ,法莫替丁组静滴 40 mg法莫替丁 ,动态测定给药前 1h及给药后 2 4h胃内 p H值 . 3回顾性分析2 72例应用洛赛克 (4 0 m g静滴 ,1次· d- 1 )与 2 70例应用法莫替丁 (4 0 mg静滴 ,2次· d- 1 )的消化性溃疡出血患者手术率与死亡率 .结果　当 p H≥ 6 .0时大鼠 GMBT明显缩短 (P<0 .0 5 ) .胃内 p H值监测结果 ,用药后各组 p H>4.0 ,p H>6 .0的时间 ,洛赛克组比法莫替丁组显著延长 (P<0 .0 1) .洛赛克治疗组手术率比法莫替丁治疗组明显减低 (P<0 .0 5 ) ,而死亡率无显著差异 .结论　对急性消化性溃疡出血 ,质子泵抑制剂的抑酸止血效果明显高于 H2 受体拮抗剂     

1—（9H—卟唑—4—氧）—3—取代氨基—2—丙醇类化合物的合成及生物活性（Ⅰ）

目的：寻找有-β－受体阻滞活性,且高效低毒的化合物。方法：以β－受体阻滞剂咔唑洛尔为先导化合物,根据药物设计中的结构拼合原理,对其内醇胺侧链进行结构修饰,设计并合成了10个1－（9H－卟唑－4－氧）－3－取代氨基－2－丙醇类化合物V1－V10。结果和结论：所合成的目的物均未见文献报道,结构经红外光谱、核磁共振氢谱、质谱、元素分析或高分辨质谱确证。初步药理筛选结果显示,10个化合物均能够不同程度地拮抗异丙肾上腺素引起的心支过速,其中化合物V1、V3、V4的活性与先导化合物相似。     

钙通道拮抗剂与微生态活菌制剂联合治疗肠易激综合征

为研究选择性胃肠道钙通道拮抗剂与肠道菌群调节剂对肠易激综合征（IBS）的疗效,从1998年1月至1999年10月对84例IBS患者分两组进行了观察。联合治疗组（联合组）采用钙通道拮抗剂匹维溴铵与微生态活菌制剂米雅-BM联合治疗,对照组单用匹维溴铵。联合组的腹痛及腹泻有效率分别为95.9%（47/49）和93.3%（28/30）,明显高于对照组的81.2%（26/32）和69.6%（16/23）并均有显著性差异（P<0.05）,但便秘及便秘腹泻交替等症状的疗效两组无明显差异。提示IBS腹泻型的部分患者可能确有肠道菌群失调,对这部分患者采用匹维溴铵加调节肠道群菌的药物治疗可取得更好的疗效。     

应用动态血压观察氯沙坦钾治疗难治性高血压的临床疗效

目的 :观察氯沙坦钾治疗高血压的临床疗效。方法 :选择 3 2例其他降压药物疗效不佳的高血压患者 ,年龄 4 1～ 67( 55.6± 6.5)岁 ,服用氯沙坦钾 50 mg～ 1 0 0 mg/d,总疗程为 6w。全部病人在服用氯沙坦钾前和服用氯沙坦钾 6w后均行动态血压监测 ( ABPM)、偶测血压及肝肾功能、血脂和血糖检查。结果 :1 .用药后 2 4 h平均血压、日昼和夜间平均血压比用药前下降 ( P<0 .0 1 ) ,用药后收缩压及舒张压负荷均较用药前明显下降 ( P<0 .0 1 )。 2 .偶测血压疗效　服氯沙坦钾降压有效率为 1 0 0 % ,其中 2例需 1 0 0 mg/d,1例加用了双氢克尿噻 1 2 .5mg/d。 3 .降压作用的谷 /峰比值　氯沙坦钾降低收缩压和舒张压的谷 /峰比值分别为 71 .6%和 68.1 %。结论 :Ang II受体拮抗剂是继 ACEI之后的新一类抗高血压药物 ,与 ACEI相比 ,此类药物直接作用于AT1受体 ,降压作用安全可靠 ,副作用少 ,对于其他降压药物疗效不佳的高压患者也有良好效果     

The induction of nitric oxide-mediated relaxation of human isolated pulmonary arteries by PACAP

1. The effects of pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) were analysed in human isolated circular segments of pulmonary arteries. Guinea-pig pulmonary arteries were used for comparison. The responses obtained were analysed in relation to the vascular endothelium and the nitric oxide (NO) synthase inhibitor N^G-monomethyl L-arginine (L-NMMA).
2. PACAP and VIP induced concentration-dependent relaxations of precontracted pulmonary arteries. The maximal dilator response (I_max,%) and the potency (pEC₅₀ value) were the same for both peptides, and there were no differences in the effects obtained on human and guinea-pig segments. PACAP and VIP were both more potent that acetylcholine (ACh).
3. Removal of the vascular endothelium abolished the PACAP induced dilator response in pulmonary arteries from both species. The VIP induced dilatation was unaffected, whereas the response to ACh was abolished. L-NMMA given before PACAP inhibited the dilatation. Furthermore, L-NMMA also reversed the dilatation already induced by PACAP and excess concentrations of L-arginine restored the dilator response of the L-NMMA treated arteries.
4. PACAP is a potent dilator of human pulmonary arteries. Although the dilator effect seems to be similar in amplitude to the one induced by VIP, the present results suggest differences in the underlying mechanisms of action (endothelium-dependency) between the two peptides.

     

Spatial heterogeneity of the effects of calcitonin gene-related peptide (CGRP) on the microvasculature of ligaments in the rabbit knee joint

1. Experiments were performed in anaesthetized rabbits to examine the effects of calcitonin gene-related peptide (CGRP) and the CGRP antagonist CGRP_8–37 on blood flow to the medial collateral ligament of the knee joint.
2. Topical application of CGRP (10⁻¹³ to 10⁻⁹  mol) to the exposed external surface of eight knee joints resulted in dose-dependent dilatation of vessels in both the ligament and the joint capsule. The magnitude of this response varied significantly in different regions of the medial collateral ligament, with the 10⁻⁹  mol dose of CGRP giving the maximum response (101.5±25.3% increase) at the femoral insertion site of the medial collateral ligament and lowest (23.1±8.8%) at the tibial insertion site.
3. Topical application of CGRP_8–37 (0.1, 1 and 10  nmol) produced dose-dependent constriction of vessels in the ligament and the joint capsule in five knees, with a trend towards the greatest effect occurring at the femoral insertion site (45.8±8.1% reduction in blood flow). With the 10  nmol dose, the vasoconstrictor response at the femoral insertion site differed significantly (P<0.05) from the responses obtained at the tibial insertion and joint capsule sites.
4. Topical application of CGRP_8–37 (0.1, 1 and 10  nmol) to four chronically denervated knees produced substantially smaller vasoconstrictor responses at all sites. At the femoral insertion site, where 10  nmol CGRP_8–37 normally produces a 45.8±8.1% reduction in blood flow (n=8), ten days following denervation this response was reduced to 6.5±6.1%, this difference being significant (P=0.01).
5. Adrenaline was applied topically to augment blood vessel tone, in order to establish how effectively co-administration of CGRP would offset this increase in tone. Adrenaline (10⁻¹⁰  mol) produced vasoconstriction at all sites (n=6). In the capsule this vasoconstriction was virtually abolished when CGRP (10⁻⁹  mol) was co-administered with adrenaline but in the ligament vasodilatation occurred at all sites. This vasodilatation was significantly greater at the femoral insertion site compared to the tibial insertion and mid ligament sites (P<0.05 for both) and the capsule (P<0.01).
6. Topical application of substance P (10⁻¹⁰ or 10⁻⁹  mol) failed to elicit dilatation of ligament blood vessels.
7. These results suggest that endogenous CGRP may play an important role in regulating blood flow to different structures in and around the knee joint.