妊娠合并癫痫16例临床分析

目的探讨妊娠合并癫痫临床处理。方法回顾性分析16例妊娠合并癫痫孕妇服抗癫痫药情况、癫痫发作频率变化及妊娠结局。结果妊娠合并癫痫发生率0.078%,原发性4例,继发性12例。全身性癫痫发作13例（2例癫痫持续状态）,局部癫痫发作3例。孕期发作频率增加者5例,无变化者6例。孕期新发现单次发作5例。孕期未用抗癫痫药物（AEDs）3例,间断用药1例,连续用药7例,均为单一AEDs治疗。顺产4例,剖宫产10例,人工流产2例。新生儿出生无窒息,平均出生体重2852g,无新生儿出生缺陷,无新生儿死亡。母亲亦无产科并发症发生。2例人工流产孕妇癫痫持续状态、吸入性肺炎死亡,1例智力低下孕妇产后卡马西平中毒昏迷,抢救成功。结论妊娠可诱发并使癫痫发作频率增加。孕期用AEDs可控制癫痫发作。应采用单一AEDs治疗,且应按时监测血浆中AED及叶酸水平。     

基质金属蛋白酶-2在盐型高血压大鼠心脏中的表达及不同种类降压药物的影响

目的探讨基质金属蛋白酶-2/基质金属蛋白酶-2特异性组织抑制因子(MMP-2/TI MP-2)在脱氧皮质酮(DOCA)-盐型高血压大鼠(DHR)心脏微小血管重塑中的作用及其可能的调节机制。方法30只雄性SD大鼠,等分和制作为对照组、模型组、波生坦组、氨氯地平组和雷米普利组。5周末处死动物,检测心脏微小血管密度和MMP-2/TI MP-2蛋白与基因的表达。结果在DHR左心室心内膜下心肌中存在微小动脉密度增加和毛细血管密度减少,MMP-2的mRNA和MMP-2/TI MP-2的蛋白表达上调;波生坦和氨氯地平能明显减轻微小血管损害,下调MMP-2/TI MP-2的mRNA和蛋白表达;雷米普利不能减轻微小血管损害,也不影响MMP-2/TI MP-2的mRNA和蛋白表达;MMP-2的表达同微小血管密度间具有良好的相关性。结论在DHR心脏中存在微小血管病变,MMP-2/TI MP-2表达可能参与微小血管病变的病理机制,内皮素-1和血压可能是通过调节MMP-2/TI MP-2表达参与微小血管病变。     

Delayed pressure urticaria

Delayed pressure urticaria (DPU) is a poorly understood syndrome. We describe 17 patients with DPU. Chronic urticaria was present in 94%. All had negative challenges for immediate demographism and cold urticaria. DPU was induced with a pressure challenge on the shoulder of 15 pounds for 15 min. Average onset of pressure lesions after challenge was 6.5. Lesions were painful, not pruritic, peaked at 9 hr, and disappeared by 24 to 48 hr. Fever, chills, and/or arthralgias occurred in 78%. Positive laboratory abnormalities included leukocytosis in 20% and elevated erythrocyte sedimentation rate in 37.5%. Skin biopsies of lesions showed perivascular round cell infiltrates and negative immunofluorescence. Urticaria responded to antihistamines, but not aspirin, in 100% of patients, while pressure lesions improved with nonsteroidal anti-inflammatory drugs (NSAID), but not antihistamines, in 80% of patients. Both urticaria and DPU were controlled with prednisone, which was necessary in 87.5% of patients. A severe nonremitting course was noted in 7%, 40% had a moderate remitting course requiring intermittent prednisone, and 53% had a mild remitting disease requiring no medication or antihistamines and/or NSAID only. We conclude that DPU is more common than previously appreciated and likely involves mediators other than histamine, possibly the prostaglandin system.     

Ultrastructure of the Kidney in Acute Interstitial Nephritis

Fifteen percutaneous renal biopsies from patients with acute renal failure due to acute interstitial nephritis (AIN), in almost all cases due to drugs, were studied by electron microscopy. Differential counting of interstitial cells showed an average of 69% lymphocytes (small and large) and 11 % macrophages. Plasma cells and eosinophils were comparatively rare. The infiltrate resembled that of acute rejection, suggesting a cellular hypersensitivity reaction. Proximal and distal tubules were severely affected focally. Migration of lymphocytes through the tubular basement membrane of otherwise well-preserved tubules was considered to be the first phase. Other tubules showed extreme thinning of the tubular basement membrane, with still intact cellular walls. Rupture of the tubular basement membrane and necrotic disintegration of tubular epithelial cells are probably late phenomena. The non-necrotic tubules displayed severe reduction of proximal brush border and proximal as well as distal tubular basolateral infoldings. Focal tubular disintegration leading to tubular block and/or backleak as well as decrease of proximal tubular sodium resorption leading to a decreased glomerular filtration (a mechanism probably also acting in ischemic acute renal failure) may all be factors responsible for the acute renal failure in AIN.     

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984     

The legal mandate of drug registration authorities in theory and practice

In the course of this century all industrial nations witnessed a growth in the influence of the state over the individual. Usually, state intervention in private life is justified by the state's mandate to protect the health and security of its constituents, either through general, uniform precepts such as laws or decrees, or through individual arrangements such as licences or subsidies. The principle of state protection has also long been established in the pharmaceutical sector, and entails that regulatory agencies should only approve those drugs for market use, which--according to scientific knowledge--have benefits which outweigh their potential harmful effects. Although 'the state of scientific knowledge' seems to imply that safety decisions concerning drugs are predominantly based on medical, scientific criteria, it is argued in this paper, that regulatory agencies nevertheless have wide discretionary margins, which allow for a political dimension to such decisions. For this reason it is briefly examined how drug authorities react under political pressure, i.e. when a drug has become a public problem. Additionally, the issue is considered why especially so-called non-steroidal anti-inflammatory drugs (NSAID's) have recently been the focus of controversy in the media. This attention has led to a situation in which it seems that regulatory agencies only accept drugs for market use with zero risk. The paper concludes by recommending that safety decisions of health authorities should involve two expert levels: in order to make precise risk assessments on the scientific level all relevant information about risks and benefits of drugs should be collated, whereas safety decisions should be taken by experts knowledgeable in the field of societal proportions.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society