Glafenine-associated anaphylaxis as a cause of hospital admission in the Netherlands

Summary In 1981 generalized anaphylaxis was registered on 166 occasions in Dutch general and academic hospitals. Clinical details of 120 of those patients revealed that in 107 anaphylaxis was either probable (n=90) or possible (n=17), whereas in 13 cases some other reaction than anaphylaxis had occurred. The series of confirmed cases contained 46 men and 61 women, with mean ages of 47 y and 48 y, respectively.There was a complete recovery in 102 patients and two patients died. Hypotension was present in 79 cases (74%), dyspnoea in 34 cases (32%) and a skin reaction, mainly urticaria, erythema or angioedema, was mentioned in 62 cases (58%). Most cases of anaphylaxis were drug-induced (76%), the main causes being the analgesic glafenine and contrast media. Glafenine was mentioned as the cause in 36% of all admissions for drug-induced anaphylaxis. Only 3.7% of cases had been reported to the voluntary reporting scheme of the Netherlands Centre for Monitoring of Adverse Reactions to Drugs.On the basis of reimbursement data, the risk of developing severe anaphylaxis to glafenine was estimated at 11.7–19.3-fold relative to indomethacin, and 13.4–20.2-fold relative to oral penicillins.     

Effect of etodolac on the prostaglandin concentrations in the kidney of the normal rat

The effect of acute and subchronic dosing with etodolac on the renal PGE₂ and 6-keto-PGF_1α concentrations in the normal rat were studied. Etodolac and other nonsteroidal antiinflammatory drugs (NSAIDs) were administered orally, at equieffective antiinflammatory doses, to normal rats either as a single dose or as seven daily doses. Whole kidney prostaglandin (PG) concentrations were measured. In the acute study, etodolac (3 mg/kg) did not significantly lower the PGE₂ levels for up to 4 hr postdosing. In contrast, naproxen (3 mg/kg) and piroxicam (0.5 mg/kg) significantly decreased the PGE₂ levels to about 20% and 60% of control, respectively. Similar reductions in 6-keto-PGF_1α concentrations were observed. In the subchronic study, etodolac (3 mg/kg/day) did not lower either PGF₂ or 6-keto-PGF_1α concentrations whereas naproxen (3 mg/kg/day), piroxicam (0.5 mg/kg/day), indomethacin (1 mg/kg/day), and aspirin (300 mg/kg/day) significantlydecreased both PGs. In both studies, the effect of etodolac was significantly different from that of the NSAIDs. It is concluded that etodolac possesses only a very weak capacity to lower renal PGs, and therefore is unlikely to cause any renal complications related to PG biosynthesis inhibition.     

家兔实验性减压病时血浆中血拴素A_2及前列环素含量的变化

实验观察了“安全”减压和不适当减压条件下家兔减压病(DCS)的发病情况、Doppler超声以及血浆中TxB_2和6-keto-PGF_(1a)的变化;还观察了消炎痛对DCS的预防怍用。结果显示:减压愈不当,DCS发病愈重,Doppler超声气泡探测仪检测到的级别愈高。血浆TxB_2、6-keto-PGF_(1α)值在濒死动物中明显升高(P<0.01);存活动物中,TxB_2经历了下降、再恢复的过程(P<0.01),而6-keto-PGF_(1α)值未见明显变化。消炎痛在抑制血浆TxB_2升高的同时,有效地降低了DCS发病率。此结果表明:TxA_2、PGI_2参与了重型DCS的发病过程,消炎痛的顶防作用与抑制花生四烯酸代谢物的生成有关。     

经颅多普勒观察消炎痛治疗兔急性脑外伤的实验研究

为探讨消炎痛（ＩＤＴ）对急性实验性颅脑损伤后脑血流速度的早期影响，采用直接打击法建立具有临床闭合性颅脑损伤特点的兔急性实验性颅脑损伤模型。在该模型的基础上，静脉注射ＩＤＴ（４ｍｇ／ｋｇ），应用经颅多普勒超声（ＴＣＤ），观察其对大脑中动脉（ＭＣＡ）血流速度的影响，并结合颅内压（ＩＣＰ）监护，综合评定消炎痛在脑外伤治疗中的作用。结果表明：ＩＤＴ对脑外伤后脑血流速度有明显影响（Ｐ＜０．０５）。具体表现为ＭＣＡ收缩期血流速度（Ｖｓ）和血流速度时间平均值（ＴＡＭ）降低，而舒张末期血流速度（Ｖｄ）保持相对恒定。随着脑血流速度的下降，动物ＩＣＰ升高的速度及幅度也明显低于对照组。结果提示：ＩＤＴ在不影响脑氧代谢的基础上，可以减少脑血流量，从而有效地控制ＩＣＰ升高，改善脑外伤的预后。     

Ipsilateral cluster headache and chronic paroxysmal hemicrania: two case reports

We report two patients with ipsilateral attacks of cluster headache and chronic paroxysmal hemicrania. The first patient, a 33-year-old man, started having attacks of chronic cluster headache at the age of 27. At 33, they were replaced by typical attacks of ipsilateral chronic paroxysmal hemicrania which showed a dramatic improvement with indomethacin 150 mg daily. After two days of complete remission, cluster headache attacks reappeared and persisted until verapamil, 360 mg a day, was added to indomethacin. The second patient, a 45-year-old man, first developed attacks of episodic cluster headache at the age of 35. At 44, he experienced ipsilateral typical attacks of chronic paroxysmal hemicrania, and two months later attacks of cluster headache. Under verapamil 240 mg daily, attacks of cluster headache disappeared, but those of chronic paroxysmal hemicrania increased in frequency until indomethacin 150 mg daily was added. These observations suggest a close relationship but not a similarity between cluster headache and chronic paraoxysmal hemicrania, and show the practical therapeutic interest of maintaining this distinction.     

Short-term indomethacin administration does not impair excretion of acute potassium load in humans

Maintenance treatment with prostaglandin synthesis inhibitors often causes some degree of hyperkalemia, indicating impaired potassium (K) excretion. Hypoaldosteronism probably is a mediating factor, but it is unknown whether these drugs also impair renal K excretion directly. Indomethacin, for example, stimulates NaCl reabsorption in Henle's loop, and thus may impair K excretion by decreasing distal NaCl delivery. We therefore studied the effect of 1 day administration of indomethacin (50 mg tid) on the excretion of a single oral KCl (1 mmol kg-1 body weight) in six healthy volunteers taking a 40 mmol sodium diet. To allow analysis of renal sodium handling, clearance studies were performed during water loading. In this acute setting, indomethacin had no effect on plasma K, and did not decrease plasma aldosterone. However, indomethacin clearly reduced NaCl excretion. Nonetheless, the excretion of the K load was entirely normal. Excretion of the K load was accompanied by increased clearance of phosphate and uric acid, and natriuresis. Data derived from the maximal free water clearance were compatible with increased delivery to and decreased reabsorption from the diluting segment. Occurrence of these effects was not prevented by indomethacin, although overall NaCl excretion remained less than observed without indomethacin. Indomethacin reduced prostaglandin E2 excretion substantially. Apparently, in normal man indomethacin does not impair K excretion directly, even though it greatly reduces NaCl excretion. Moreover, the effects of K on renal NaCl handling, probably contributing to the excretion of a K load, are not dependent on renal prostaglandins.     

Inhibition by indomethacin of spontaneous mammary tumorigenesis in SHN mice

This experiment was designed to examine the effects of indomethacin, a potent prostaglandin synthesis inhibitor, on spontaneous mammary tumors in mice. The growth of established mammary tumors and the appearance of new tumors in multiparous SHN mice were significantly suppressed by the subcutaneous implantation of pellets of indomethacin diluted to 1/12 with cholesterol. Furthermore, the same treatment inhibited normal and preneoplastic mammary gland growth in virgin SHN mice. The pattern of estrous cycles, ovarian structure, and plasma prolactin levels were not affected significantly by the treatment. All results have demonstrated that indomethacin inhibits mammary tumorigenesis of mice primarily by route(s) other than the endocrine system under the present experimental conditions. Indomethacin would be the first agent that appears to inhibit the growth of spontaneous mammary tumors of palpable size in mice.     

吲哚美辛对人结肠癌HCT116和SW480细胞的影响

目的：探讨吲哚美辛对人结肠癌HCT116和SW480细胞的影响。方法：体外培养细胞，采用MTT法分别检测吲哚美辛作用后两系细胞的生长情况，计算半抑浓度（IC50）；体内建立裸鼠皮下移植瘤模型，喂服吲哚美辛3 mg/(kg·d)共4周，隔日测瘤结节体积及鼠重，评价吲哚美辛的抑瘤效果。结果：吲哚美辛作用于结肠癌HCT116和SW480细胞48 h后，细胞的生长均受到明显抑制，呈剂量依赖效应，IC50分别为 (318.2±12.7) μmol/L和 (701.4±29.5) μmol/L；吲哚美辛显著减慢裸鼠皮下移植瘤的生长，用药4周后抑瘤率达44.6%，未见明显毒性反应。结论：吲哚美辛能抑制不表达环氧合酶的人结肠癌细胞（HCT116和SW480）生长，间接说明其抗癌作用不完全依赖环氧合酶途径，还存在其它的可能机制。     

微囊化吲哚美辛片剂的研讨

以明胶-CAP 为囊材,经复凝聚法制备吲哚美辛微囊,再按所筛选的最佳处方制备微囊化片剂。该片与市售片相比,体外 T_(50)延长约5.6倍,家兔体内达峰时间滞后,能明显减轻对大鼠胃的刺激性。     

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.