O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯的合成

合成了18个O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯类化合物(Ⅰ_1～18)。初步杀螺试验结果表明,其中5个化合物,即Ⅰ_2,3,7,11,12有明显的杀螺增效作用。     

Synergism between buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat

 Buprenorphine, a partial mu-opioid receptor agonist, has been proposed as a treatment for cocaine abuse. However, studies in animals have produced conflicting results on the nature of the interaction between buprenorphine and cocaine. In some studies, buprenorphine attenuated the effects of cocaine and in others it enhanced them. The purpose of the present study was to evaluate the interaction of buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat. Both buprenorphine (0.003–0.1 mg/kg) and cocaine (1.0– 30 mg/kg) alone produced dose-dependent increases in rotational behavior. Buprenorphine produced long-lasting turning with a peak at 60 min after administration, while cocaine produced turning that peaked immediately after administration and lasted for about 2 h. To distinguish simple additivity from other possible outcomes, we determined the relative potency of each drug alone, using a defined level of effect: 150 turns above the saline control in 4 h. This effect was produced by 10.0 mg/kg cocaine alone and by 0.0175 mg/kg buprenorphine alone. Based on these results, fixed ratio combinations were tested and the experimentally derived effects were compared to the theoretically additive values, using an isobolographic analysis. The fixed ratio combinations of the two drugs tested produced turning greater than predicted from simple additivity. This finding provides statistically-supported evidence for synergism between the actions of buprenorphine and cocaine. Received: 28 January 1997 / Final version: 7 June 1997     

CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first beta-strand of chemokine

In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first beta-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4(+) T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines.     

日本血吸虫与HBV合并感染对幽门螺杆菌感染的影响

目的 :探讨HBV与日本血吸虫合并感染对幽门螺杆菌 (Hp)感染的影响。 方法 :利用Hp全菌抗原检测HBV、日本血吸虫单独或合并感染者血清抗HpIgG抗体。 结果 :HBV与血吸虫合并感染时 ,血清HpIgG抗体检出率 ( 85.7% )明显高于HBV或血吸虫单独感染 (阳性率分别为 4 5.5%和 72 .9% ) ,合并感染时血清抗体水平 ( 0 .87± 0 .1 0 )亦高于单独感染 ( 0 .77± 0 .2 0 ,0 .70± 0 .1 7) ,差异有显著性意义。HBV阳性者与HBV阴性者之间Hp 感染率和抗体水平相近。结论 :HBV和血吸虫合并感染对Hp感染具有协同作用     

Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis

It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guineapig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 M) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 M), GR-94,800 (0.3 M) and SR-48,968 (0.1 M) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5–20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only. CP-96,345 was without effect on peristalsis when it was applied in the presence of a threshold concentration of atropine. These findings indicate that transmission via tachykinin NK-2, but not NK-1, receptors synergizes with cholinergic transmission via muscarinic receptors in the relay of excitatory enteric pathways subserving intestinal peristalsis. Correspondence to: P. Holzer at the above address     

Antibiotic C3368-A,a fungus-derived nucleoside transport inhibitor,potentiates the activity of antitumor drugs

Antibiotic C3368-A (CA) is produced by a fungus strain from a soil sample collected in Antarctica. CA markedly inhibited radiolabeled thymidine and uridine transport in mouse Ehrlich carcinoma cells, its 50% inhibitory concentration (IC₅₀) being 4.6 and 7.7 M, respectively. In clonogenic assay, CA displayed a synergistic effect with methotrexate (MTX), mitomycin C (MMC), 5-fluorouracil (5FU), and Adriamycin (ADR) against human oral epidermoid carcinoma KB cells. CA also markedly enhanced the inhibitory effect of 5FU and ADR on the proliferation of human hepatoma BEL-7402 cells as determined by thep-nitrophenyl-N-acetyl--d-glucosaminide (NAG) enzyme-reaction assay. 5FU or ADR cytotoxicity was not augmented by CA in human fetal lung 2BS cells. In vivo, CA significantly potentiated the inhibitory effect of MMC against colon carcinoma 26 in mice. No significant augmentation of toxicity by the combination was found in treated mice. The results suggest that CA, the newly found nucleoside-tranport inhibitor, may be useful in potentiation of the effect of antitumor drugs.     

克拉霉素和环丙沙星合用对铜绿假单胞菌生物被膜的影响

目的：研究克拉霉素与环丙沙星联合应用对铜绿假单胞菌生物被膜的影响。方法：采用平板法培养细菌生物被膜，微量稀释法测定抗菌药物的最低抑菌浓度，银染法快速鉴定细菌生物被膜，噻唑蓝(MTT)比色法测定生物被膜中的活菌数。结果：1／16、1／4MIC克拉霉素可显著增加1／4、1／2MIC环丙沙星对铜绿假单胞菌生物被膜的抑菌活性。结论：克拉霉素与环丙沙星合用对铜绿假单胞菌生物被膜具有明显的协同抑制作用。     

Tapentadol – A representative of a new class of MOR-NRI analgesics

Tapentadol is a centrally acting analgesic with a dual mode of action as a μ-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor (NRI). It was initially approved by the US Food and Drug Administration in November 2008 for the treatment of moderate-to-severe acute pain in adult patients, and in August 2011, for chronic pain in an prolonged release form in the same population. Due to its limited protein binding capacity, the absence of active metabolites and significant microsomal enzyme induction or inhibition, tapentadol has a limited potential for drug–drug interactions. It appears to be well-tolerated and effective in the treatment of moderate-to severe acute and chronic pain. Owing to its dual mechanism of action, it is hypothesized to be good option in the treatment of both nociceptive and neuropathic pain.     

Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity

Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.