Angiotensin II analogues encompassing 5,9- and 5,10-fused thiazabicycloalkane tripeptide mimetics

A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT(1) receptor affinity (K(i) = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT(1) receptor.     

Aggregation inhibitory activity of minor acetophenones from Paeonia species

Two minor acetophenones, 2,5-dihydroxy-4-methoxy-acetophenone (2) and 2,5-dihydroxy-4-methylacetophenone (7) from Paeonia species were found to selectively inhibit the aggregation of rabbit platelets induced by arachidonic acid. They were more potent than the major compound, paeonol (1), and 7 also inhibited the formation of TXA2 and PGD2 from arachidonic acid.     

中药川芎中无机阴离子和有机酸成分的研究

目的：研究中药川芎中有机酸和无机阴离子的同时分析方法。方法：采用非抑制型阴离子交换色谱法,色谱柱为ＳｈｉｍｐａｃｋＩＣＡ１,流动相为０８ｍｍｏｌ·Ｌ－１邻苯二甲酸氢钾。结果：川芎提取液中３种有机酸和３种无机阴离子得到了较好的分离。结论：该方法分析速度快,准确,灵敏度高。     

口服Ⅱ号避孕药对血小板功能及血液凝固的影响

为了解口服Ⅱ号避孕药对血小板功能及血液凝固性的影响,本文对65名连续服药妇女进行了研究。她们的年龄为27～45(平均36.5)岁。服药期限1～17(平均6.7)年。测定项目有纤维蛋白原,血小板粘附率,血小板聚集率,Ⅷ因子相关抗原,抗凝血酶活力等。20例未服药妇女作对照。测定结果服药组血小板粘附率、聚集率及纤维蛋白原比对照组明显增高(P<0.001)。Ⅷ因子相关抗原略增高,但无统计学意义。抗凝血酶活力显著降低(P<0.001)。本文就急性心肌梗塞及血栓栓塞的潜在可能性等问题进行了讨论,并对预防此类并发症提出了建议。     

Syntheses and in vitro evaluation of water-soluble "cationic metalloporphyrin-ellipticine" molecules having a high affinity for DNA

The synthesis of hybrid "cationic metalloporphyrin-intercalator" molecules is reported. These molecules are based on 9-methoxyellipticine as intercalator and tris-(4-N-methylpyridiniumyl)metalloporphyrins having a 4-aminophenyl or a 4-hydroxyphenyl group for the attachment of the linker. The effect of the length of linker (7-13 bonds), the chemical nature of the linking group (with a carboxamido or an ether function), the position of amino group between the two parts of hybrid molecules, the number of intercalator moieties (ellipticinium) covalently attached to the metalloporphyrin, and the nature of the central metal atom (Mn, Fe, Zn) on the biological activity of these hybrid molecules were studied. In addition, these molecules have a high affinity for double-stranded DNA (affinity constant of hybrid molecule 9Mn,Me = 2.3 x 10(9) M-1 for poly[d(A-T)] and 2.8 x 10(8) M-1 for poly[d(G-C)] and are cytotoxic against murine leukemia cells L1210 in vitro (IC50 of 9Mn,Me = 0.8 microM). Their cytotoxicities are dependent on the nature of central atom. Iron derivatives are less active than manganese analogues and the corresponding zinc derivatives are nearly inactive despite their same affinity for nucleic acids. These highly water-soluble hybrid molecules could be considered as efficient bleomycin models based on a cationic metalloporphyrin.     

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.     

Cervene (Nalmefene) in acute ischemic stroke : final results of a phase III efficacy study. The Cervene Stroke Study Investigators

BACKGROUND AND PURPOSE: The goals of the present study were to assess the efficacy and safety of nalmefene (Cervene) in patients with acute (< or =6 hours) ischemic stroke and to investigate the safety of combined recombinant tissue plasminogen activator and nalmefene in a separate subset of patients. Nalmefene, an opioid antagonist with relative kappa receptor selectivity, has shown neuroprotective effects in multiple experimental central nervous system injury and ischemic models. Results from an earlier phase II study in patients with acute ischemic stroke suggested that nalmefene was safe and tolerable and may be effective for patients <70 years old. METHODS: This investigation was a phase III, placebo-controlled, double-blind, randomized study of a 24-hour infusion of nalmefene. Patients with acute ischemic stroke who had an onset of symptoms within 6 hours and a baseline score of > or =4 on the NIH Stroke Scale were randomized to receive either 60 mg nalmefene administered as a 10-mg bolus over 15 minutes and then a 50-mg infusion over 23.75 hours or placebo. The primary efficacy outcome was the proportion of patients achieving a score of > or =60 on the Barthel Index and a rating of "moderate disability" or better on the Glasgow Outcome Scale at 12 weeks. Assessments were performed at baseline (predose), hours 12 and 24, days 2 and 7, and week 12. RESULTS: A total of 368 patients were randomized at 42 centers, including 32 patients treated with recombinant tissue plasminogen activator and study drug. Nalmefene was well tolerated. Overall, there was no significant difference in 3-month functional outcome for nalmefene treatment compared with placebo on any of the planned analyses. A prospective secondary analysis also failed to find a treatment effect in patients <70 years old. CONCLUSIONS: Although nalmefene appears to be safe and well tolerated, this study failed to find any treatment benefit in stroke patients treated within 6 hours.