THE PHARMACOLOGICAL ROLE OF P-GLYCOPROTEIN IN THE INTESTINAL EPITHELIUM

P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises thein vivodata on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption.     

埋入5—氟尿嘧啶植入剂后家兔血清及肌肉组织中药物浓度的测定

埋入5-氟尿嘧啶（5-Fu)植入剂后，用高效液相色谱法测定家兔血清中及埋植处肌肉组织的药物浓度，结果表明：埋入植入剂后，5-Fu在体内能缓慢、恒定、长时间地释放，使埋植处局部维持较高浓度，而血药浓度长期稳定在较低范围，因此，该剂型的研制对于提高5-Fu的抗肿瘤疗效，降低其毒性具有积极的意义。     

国产卡莫氟在犬体内的药动学及片剂绝对生物利用度研究

按随机交叉实验设计法,用反相高效液相色谱法测定血清药物浓度。对5只犬po和iv卡莫氟(10mg/kg)的药动学及其片剂绝对生物利用度进行了研究。结果表明,静注给药的药时曲线符合二室开放模型,T_(1/2α)=1.67min,T_(1/2β)=34.55min,Vc=0.2525 L/kg,Cl=0.3205 L/kg·h~(-1),AUC_(iv)=1.9375 mmol·min/L;口服卡莫氟片的药时曲线符合一室开放模型,T_(1/2ka)=12.13min,T_(1/2ke)=38.51min,T_(mix)=28.46min,C_(max)=8.1396×10~(-3)mmol/L,AUC_(po)=1.5856 mmol·min/L;由AUC_(iv)和AUC_(po)算得绝对生物利用度F=82.14%。     

1,2∶5,6-二去水卫矛醇与美登新联合用药的实验研究

去水卫矛醇(DAG)和美登新(MAY)同时或间隔24小时给药(无论先后顺序如何),对EAC小鼠的生命延长和杀瘤细胞均有协同作用;不同先后顺序给药对L1210得到同样结果,但同时给药则无协同作用。给DAG后24小时再给MAY,对接种21天的B16黑色素瘤瘤重抑制率超过了“相加作用”,但不能延长生命。联合用药对HepA及S180无协同疗效。联合使用DAG及MAY,对正常小鼠骨髓干细胞的杀灭低千“相加作用”。本实验表明,DAG及MAY间隔24小时给药较同时给药为佳。     

用~2H-标记物和GC-MS分离鉴定联苯双酯在大鼠尿中的一个代谢产物

联苯双酯(BDD)是人工合成的五味子丙素类似物,其化学结构为4,4′-二甲氧基-5,6,5′,6′-二次甲二氧基-2.2′-二甲氧羰基联苯,已用于迁、慢性肝炎的治疗。临床证明,该药降血清谷丙转氨酶的作用很强。为阐明其在体内的转化过程,并进一步研究其构效关系,我所曾用放射性同位素结合薄层层析对联苯双酯的代谢途径进行过研究,并分     

A Phase II Trial of Etoposide, Leucovorin, 5-FU, and Interferon Alpha 2b (ELFI) + G-CSF for Patients with Pancreatic Adenocarcinoma: a Southwest Oncology Group Study (SWOG 9413)

Background. Chemotherapeutic treatments using combinationsof etoposide, leucovorin and 5-FU (ELF) have shown activity inthe treatment of gastrointestinal malignancies. Interferon alpha2b is known to have antiproliferative effects on several celllines and has well documented in vitro evidence ofsynergism with 5-FU. It was postulated that the combination ofELF and interferon alpha 2b would improve response rates andsurvival in patients with pancreas cancer. Methods. Fifty-five eligible patients with locally-advancedor metastatic pancreatic adenocarcinoma received a regimenconsisting of: IV leucovorin at 300 mg/m²/day on Days 1-3(of 28-day cycle), IV etoposide at 80 mg/m²/day on Days 1-3, IV 5-FU at 500 mg/m²/day on Days 1-3, subcutaneousinterferon alpha 2b at 3 million units TIW, and subcutaneousG-CSF at 5 g/kg/day on Days 4-14 (or until WBC exceeds10,000/l). Patients with no evidence of disease progressioncontinued on treatment for a total of 6 cycles. Results. Complete response was demonstrated in 1 patient,partial response in 5 patients (11% confirmed response rate).The median survival was 5 months, and the six-month survival ratewas 40%. Ten patients completed all 6 cycles of treatment.Toxicity-related dose delays and reductions were necessary formost patients. Conclusions. Although the combination of ELF and interferonalpha 2b (ELFI) has modest activity in pancreatic cancer, it isa toxic and complex regimen that is not superior to othercurrently available approaches for the chemotherapeuticmanagement of pancreatic cancer. ELFI cannot be recommended asa standard therapy.     

INVOLVEMENT OF NITRIC OXIDE IN CORONARY VASCULAR RESPONSES TO 5-HYDROXYTRYPTAMINE IN THE ANAESTHETIZED GREYHOUND

1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1–1.0 μFg/ kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-l-arginine (NOLA; 5 mg/ kg i.c.) in nine anaesthetized greyhounds. Before administration of NOLA, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of NOLA significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of NOLA, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before NOLA treatment. 3. The response to NOLA suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.     

SUBSTANCE USE IN THE CONSTRUCTION INDUSTRY: A COMPARISON OF ASSESSMENT METHODS

Most users of illicit drugs are employed adults, with substance use rates especially high in the construction industry. In an effort to shed light on the nature and extent of drug use among construction industry workers, and to compare drug use assessment methods, substance use among construction workers, 60% of whom were apprentices, across six sites was assessed by questionnaire, urinalysis, and hair analysis. Nearly 17% of the participants reported current drug use, although drug use differed dramatically by site. Drug use rates also differed by respondent characteristics, participation rates, and assessment method. The strengths and weaknesses of each assessment method are discussed, along with the rationale for combining methods.     

用2H-标记物和GC-MS分离鉴定联苯双酯在大鼠尿中的一个代谢产物

Dimethyl-4, 4′-dimethoxy-5, 6, 5′, 6′-dimethylenedioxybiphenyl-2, 2′-dicarboxylate (biphenyldimethyldicarboxylate; BDD), a synthetic compound, has been used in the treatment of chronic hepatitis with good results in reducing s-GPT. Previous work in our laboratory studied its metabolites using ³H-labeled compound in combination with TLC and found that its main methabolic pathway is demethylation followed by conjugation with glucuronic acid. This paper reports the isolation and identification of a metabolite of BDD from rat urine using ²H-labeled compound and GC-MS. Rats fasted for 12h were intragastrically given a mixture of ²H-labeled (consisting of monodeutero-and dideutero-BDD in the ratio about 1:1.3)and non-labeled BDD 150mg/kg and placed in metabolism cages for urine collection. The 24h urine was filtered and extracted three times each with 5ml of methylenedichloride. The extracts were pooled and evaporated to dryness under reduced pressure at 35℃. The residue was redissolved in chloroform and subjected to GC-MS analysis. The mass spectrum (m/z: 404, 405, 406; 373, 374, 375; 345, 346, 347; 330, 331, 332; etc)indicates that the molecular ionic and fragment peaks of the metabolite all have 14 amu less than those of BDD. This means that the metabolite isolated is mono-O-demethylated BDD. The result confirmed our findings reported previously.     

A DOUBLE-BLIND CONTROLLED CLINICAL TRIAL OF MASTIC AND PLACEBO IN THE TREATMENT OF DUODENAL ULCER

A double-blind clinical trial was carried out on thirty-eight patients with symptomatic and endoscopically proven duodenal ulcer to compare the therapeutic responses to mastic (1 g daily, twenty patients) and placebo (lactose, 1 g daily, eighteen patients) given orally over a period of 2 weeks. Symptomatic relief was obtained in sixteen (80%) patients on mastic and in nine (50%) patients on placebo, while endoscopically proven healing occurred in fourteen (70%) patients on mastic and four (22%) patients on placebo. The differences between treatments were highly significant (P less than 0.01). Mastic was well tolerated and did not produce side effects. It is concluded that mastic has an ulcer healing effect, but further studies are needed to establish its role in treating peptic ulcer.     

THE BIOAVAILABILITY OF ORAL DOSAGE FORMS OF A NEW HIV-1 PROTEASE INHIBITOR,KNI-272, IN BEAGLE DOGS

The bioavailability (BA) of a tripeptide protease inhibitor, KNI-272, which has a strong pharmacological potential for treating human immunodeficiency virus type 1 (HIV-1), has been studied in beagle dogs by administering several oral dosage forms. The tested dosage forms were form 1, plain gelatin capsules; forms 2 and 3, gelatin capsules of which the inner and outer surfaces were coated with 7G ethylcellulose (EC, 30 μm thickness) and an enteric coating material, hydroxypropyl methylcellulose phthalate (HP-55), respectively; and form 4, gelatin capsules of which the inner surface is coated with 10G EC (60 μm thickness). The difference between forms 2 and 3 was the amount of citric acid contained in the capsule, namely 100 mg in form 2 and 200 mg in form 3. One hundred milligrams of KNI-272 was placed in each capsule after being dissolved with propylene glycol (PG). These capsules were used to deliver KNI-272 to the stomach for form 1, to the upper part of the small intestine for forms 2 and 3, and to the middle part of the small intestine for form 4. As a reference, 50.0 mg of KNI-272 was administered to the same dogs by intravenous (IV) infusion for 15 min. By measuring the plasma drug levels with the HPLC method, BAs were estimated for each test dosage form. Form 1 showed the highest BA of 26·2±7·0% (mean±SE), though the other capsules showed BAs of approximately 10%, namely 6·6±0·4% for form 2, 10·3±1·1% for form 3 and 14·2±1·0% for form 4. Therefore, as the site where KNI-272 is released from the capsule becomes higher, the BA increases. In addition, as the amount of citric acid contained in a capsule increases, the BA value tends to increase. These results suggest that KNI-272 is stable and not extensively hydrolysed in the gut after oral administration, that the dissolution process into GI fluids is important for the BA of KNI-272, and that the most appropriate absorption site of KNI-272 in dogs is the duodenum. The potential of this new tripeptide compound as an orally active anti—AIDS drug has been confirmed.     

“金牡蛎”治疗高脂血症的临床观察

“金牡蛎”胶囊,是纯天然海洋生物制品,可用于治疗多种疾病。本文就金牡蛎胶囊治疗高脂血症进行了临床观察。结果表明,有明显的降血脂作用。     

THE HEPATIC TRANSPORT OF TAUROCHOLIC ACID IN THE RAT: DEVELOPMENT OF A MATHEMATICAL MODEL

1. The transport of taurocholic acid from portal blood to bile was studied in the anaesthetized rat by injecting a radiolabeled pulse of bile acid. 2. The transport process was very rapid, 50% of the dose being secreted within 5 min, and the total dose within 15 min. 3. The transport process had a large capacity. The secretory profile was little modified by a 500-fold increase in the injected dose. 4. The transport process was modelled with both analogue and digital computers. The simplest model which fitted the data comprised rapid uptake from portal blood, slow transport across the cell and rapid secretion into bile. The digital computer simulation suggested that this model is not unique, but will require further testing.     

EFFECT OF REGULAR ALCOHOL USE ON BLOOD PRESSURE CONTROL IN TREATED HYPERTENSIVE SUBJECTS: A CONTROLLED STUDY

Forty-four males with treated essential hypertension and a moderate-to-heavy alcohol intake participated in a randomized controlled crossover trial of the effects of varying alcohol intake on blood pressure control. Usual antihypertensive therapy was maintained unchanged throughout. Self-reported alcohol consumption fell from 452 ml ethanol/week (s.e.m. = 29) during normal drinking habits to 64 ml/week (s.e.m. = 8) while drinking low alcohol content beer. Mean systolic and diastolic blood pressures were significantly lower during the last 2 weeks of reduced alcohol (supine 5.0 mmHg, s.e.m. = 1.4, and 3.0 mmHg, s.e.m. = 0.9, respectively; erect 5.9 mmHg, s.e.m. = 1.6, and 2.9 mmHg, s.e.m. = 1.0, respectively). Body weight was also lower (0.94 kg, s.e.m. = 0.25) at the conclusion of the low alcohol intake period. Regression analysis suggested that reduction in alcohol intake contributed independently to the fall in both systolic and diastolic blood pressure, while weight change contributed independently to the fall in systolic blood pressure alone. It was concluded that curtailing moderate to heavy alcohol intake leads to improved blood pressure control in treated essential hypertensive males.     

THE EFFECT OF SMOKING ON CAFFEINE ELIMINATION: IMPLICATIONS FOR ITS USE AS A SEMIQUANTITATIVE TEST OF LIVER FUNCTION

1. The effects of caffeine ingestion and cigarette smoking on caffeine and antipyrine pharmacokinetics were studied using normal subjects as their own controls before and after cessation of smoking in an attempt to minimize genetic and other environmental influences. 2. Moderate caffeine ingestion had no inducing effect on caffeine or antipyrine clearance. 3. Cessation of cigarette smoking significantly reduced clearance of caffeine and antipyrine. 4. These results demonstrate that cigarette smoking significantly affects caffeine pharmacokinetics and this may contribute to the variable results for caffeine kinetics found in patients with liver disease.     

EVIDENCE FOR THE INHIBITORY EFFECT OF 5-HYDROXYTRYPTAMINE AT CENTRAL AND PERIPHERAL SITES ON OVULATION IN RABBITS

1. The effect of 5-hydroxytryptamine (5-HT) has been investigated on ovulation per se as well as on induced ovulation in rabbits. 2. 5-HT administered intracerebroventricularly (i.c.v.) did not induce ovulation per se. 3. The ovulation was induced by coitus, subcutaneous administration of progesterone and intravenous administration of cupric acetate. 4. Postcoital and progesterone induced ovulation was found to be blocked by i.c.v. administered 5-HT. 5. Cupric acetate induced ovulation was, however, not found to be blocked by i.c.v. administered 5-HT. 6. Intraperitoneal administration of 5-HT was found to block cupric acetate induced ovulation. 7. It is concluded that 5-HT exerts an inhibitory control over ovulation by acting at central as well as at peripheral sites in rabbits.     

5-HT_(1A)受体激动剂乌拉地尔对吗啡依赖大鼠前列腺组织的病理学影响

目的··:观察5-HT1A 受体激动剂乌拉地尔对吗啡依赖大鼠前列腺的组织学影响。方法··:皮下注射(sc)5d吗啡 ,建立吗啡依赖大鼠模型 ;实验组分别进行侧脑室注射 (icv)乌拉地尔和继续sc吗啡。实验后将前列腺组织作HE染色后在光镜下观察。结果··:吗啡依赖大鼠的前列腺组织有轻度萎缩 ,吗啡依赖大鼠自然戒断后前列腺有明显增生 ,icv乌拉地尔可抑制吗啡戒断大鼠的前列腺组织增生。结论··:乌拉地尔可抑制吗啡戒断大鼠前列腺组织的增生     

石杉碱甲全合成中关键中间体2-甲氧基-6-羟基-7,8-二氢-5-喹啉羧酸甲酯的合成

2-甲氧基-6-羟基-7,8-二氢-5-喹啉羧酸甲酯(1)是石杉碱甲全合成中的关键中间体。本文报道从易得到的原料4-氧-1,7-庚二酸二甲酯(6)经四步反应合成(1)的新方法,总收率为39％。     

SEROTONIN (5HT) AND ITS ANTAGONISTS: INVOLVEMENT IN THE CARDIOV ASCULAR SYSTEM

The cardiovascular actions of serotonin and its antagonists are reviewed with a view to clarifying whether serotonin has a role in blood pressure control through actions on the peripheral vasculature. Serotonin has complex actions in the heart and vasculature but none of these actions is completely understood. There is no doubt, however, that serotonin has extensive interactions with the sympathetic nervous system. The nature of the serotonin receptor is also discussed. There is extensive evidence that more than one type of serotonin receptor exists. Biochemical studies in brain homogenates have delineated two sub-populations of serotonin receptors, named 5HT1 and 5HT2. It is not clear whether the same receptor types exist in the vasculature but various actions of serotonin on the vasculature have tentatively been ascribed to actions on 5HT1- and 5HT2-type receptors. It is clear that there is some functional overlap between serotonin-receptors and alpha-adrenoceptors. The mechanism by which this overlap could occur is unknown although we suggest it may result from a physical overlap of serotonin receptors and alpha-adrenoceptors. Compounds which antagonize serotonin have provided the means for investigating serotonin receptors but have not clarified the role of serotonin in blood pressure control; certainly they have comparatively little effect on blood pressure and this may simply reflect the lack of free circulating serotonin. In animal studies the new serotonin antagonist ketanserin appears to lower blood pressure via alpha-adrenoceptor blockade.