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Antithrombotic efficacy of thrombin inhibitor L-374,087: Intravenous activity in a primate model of venous thrombus extension and oral activity in a canine model of primary venous and coronary artery thrombosis

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 503-510页

作者： Cook, JJ Gardell, SJ Holahan, MA Sitko, GR Stump, GL Wallace, AA Gilberto, DB Hare, TR Krueger, JA Dyer, DL Sanderson, PEJ Vacca, JP Shafer, JA Lynch, JJ Merck Res Labs Dept Pharmacol W Point PA 19486 USA Merck Res Labs Dept Biol Chem W Point PA 19486 USA Merck Res Labs Dept Lab Anim Resources W Point PA 19486 USA Merck Res Labs Dept Med Chem W Point PA 19486 USA

The small molecule direct thrombin inhibitor L-374,087 was characterized across species in an in vitro activated partial thromboplastin clotting time (aPTT) assay and in vivo in rhesus monkey and dog thrombosis models. In vitro in rhesus, dog, and human plasma, L-374,087 concentrations eliciting 2-fold increases in aPTT were 0.25, 1.9, and 0.28 mu M, respectively. In anesthetized rhesus monkeys, 300 mu g/kg bolus plus 12 mu g/kg/ min and 300 mu g/kg bolus plus 30 mu g/kg/min L-374,087 i.v. infusions significantly reduced jugular vein thrombus extension, with both regimens limiting venous thrombus extension to 2-fold that of baseline thrombus mass compared with a 5-fold extension observed in the vehicle control group. Antithrombotic efficacy in the rhesus with the-lower-dose regimen was achieved with 2.3- to 2.4-fold increases in aPTT and prothrombin time. In a conscious instrumented dog model of electrolytic vessel injury, the oral administration of two 10 mg/kg L-374,087 doses 12 h apart significantly reduced jugular vein thrombus mass, reduced the incidence of and delayed time to occlusive coronary artery thrombosis, and significantly reduced coronary artery thrombus mass and ensuing posterolateral myocardial infarct size. Antithrombotic efficacy in the dog was achieved with 1.6- to 2.0-fold increases in aPTT at 1 to 6 h after oral dosing with L-374,087. These results indicate significant antithrombotic efficacy against both venous and coronary arterial thrombosis with L-374,087 with only moderate elevations in aPTT or prothrombin time. The oral efficacy of L-374,087 characterizes this compound as a prototype for the further development of orally active direct thrombin inhibitors.

关键词：投药口服麻醉出血时间血液凝固/药物作用冠状动脉血栓形成/血液冠状动脉血栓形成/药物疗法纤维蛋白溶解药/投药和剂量纤维蛋白溶解药/药代动力学纤维蛋白溶解药/药理学血细胞比容血红蛋白类/代谢注射静脉内颈静脉/病理学恒河猴部分促凝血酶原时间血小板计数/药物作用吡啶酮类/投药和剂量吡啶酮类/药代动力学吡啶酮类/药理学磺胺类/投药和剂量磺胺类/药代动力学磺胺类/药理学凝血酶/拮抗剂和抑制剂静脉血栓形成/血液静脉血栓形成/药物疗法动物狗女(雌)性人类男(雄)性

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PHARMACOLOGY & TOXICOLOGY 2000年第1期87卷 33-38页

作者： Esparza, JL Gómez, M Domingo, JL del Castillo, D Hernández, M Univ Rovira & Virgili Sch Med Lab Toxicol & Environm Hlth E-43201 Reus Spain Univ Rovira & Virgili Sch Med Surg Unit E-43201 Reus Spain

The efficacy of deferoxamine, deferiprone, and a combination of these chelating agents in the mobilization and promotion of aluminium (Al) excretion was compared in two age groups of uraemic rats which had previously received Al nitrate nonahydrate intraperitoneally in a daily dose of 45 mg/kg for 5 weeks. At the end of the period of Al exposure, Al-loaded rats of each age (young and adult) group were given one of the following treatments for 5 days: 0.90 mmol/kg/day of deferoxamine (subcutaneously), 0.90 mmol/kg/day of deferiprone (orally), and 0.45 mmol/kg/day of deferoxamine (subcutaneously) plus 0.45 mmol/kg/day of deferiprone (orally). Control rats were given 0.9% saline (subcutaneously) and deionized water (orally). Total urines were collected 24 hr after each chelator administration. Although young rats treated with deferoxamine, deferiprone, or deferoxamine plus deferiprone showed significant increases in the total amount of Al excreted into urine during 5 consecutive days, the effect of combined administration of deferoxamine and deferiprone was lower than that caused by deferoxamine or deferiprone only. On the other hand, after administration of deferoxamine and deferiprone, a significant reduction of Al was noted only in the liver of young rats, while no significant effects of the chelators were seen in any of the examined tissues of adult animals. The results of the current study show that a combined therapy with deferoxamine and deferiprone (at half-doses of each drug) can also be effective in mobilizing Al from the body of Al-loaded uraemic rats.

关键词：投药口服衰老/代谢铝/尿铝化合物/毒性抗蠕虫药/毒性螯合剂/投药和剂量螯合剂/治疗应用去铁胺/投药和剂量去铁胺/治疗应用药物疗法联合注射皮下硝酸盐类/毒性吡啶酮类/投药和剂量吡啶酮类/治疗应用大鼠 Sprague-Dawley 尿毒症/药物疗法尿毒症/代谢动物男(雄)性大鼠

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Diuretic effect of phosphodiesterase inhibitors depends on baseline renal function in patients with congestive heart failure

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第8期83卷 1274-+页

作者： Kanda, M Yasuda, S Goto, Y Sumida, H Baba, T Noguchi, T Nonogi, H Natl Cardiovasc Ctr Dept Internal Med Div Cardiol Osaka 5658565 Japan

We examined the diuretic effects of phosphodiesterase inhibitors in heart failure patients with and without renal failure. We found that, despite the improvement in central hemodynamics, phosphodiesterase inhibitors d... 详细信息

关键词：氨力农/投药和剂量氨力农/治疗应用肌酸酐/血液利尿/药物作用随访研究咪唑类/投药和剂量咪唑类/治疗应用输注静脉内肾/药物作用肾/病理生理学肾功能试验米力农/投药和剂量米力农/治疗应用磷酸二酯酶抑制剂/投药和剂量磷酸二酯酶抑制剂/治疗应用吡啶酮类/投药和剂量吡啶酮类/治疗应用治疗结果老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Anti-inflammatory effect of pirfenidone in the bleomycin-hamster model of lung inflammation

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INFLAMMATION 2000年第5期24卷 477-491页

作者： Iyer, SN Hyde, DM Giri, SN Univ Calif Davis Sch Vet Med Dept Mol Biosci Davis CA 95616 USA Univ Calif Davis Sch Vet Med Dept Anat Physiol & Cell Biol Davis CA 95616 USA

We have previously reported the antifibrotic effects of pirfenidone (PD) in the bleomycin (BL)-hamster model of lung fibrosis. Since the development of fibrosis is generally preceded by acute lung inflammation, the present study was conducted to find out if dietary intake of PD (0.5%) has any effects on BL-induced lung inflammation. In this regard, we evaluated the effects of PD on BL-induced increased pulmonary vascular permeability, increased influx of inflammatory cells and increased levels of TGF-beta in the bronchoalveolar lavage fluid (BALF). Hamsters were intratracheally (IT) instilled with saline (SA) or BL (5.5 units/kg/5 mi). The animals were fed the control diet (CD) or the same diet containing 0.5% PD 2 days prior to IT instillation and throughout the study. The bronchoalveolar lavage was carried out at different times after IT instillation. Lavage fluid was used for total and differential cell counts and BALF-supernatant for measurement of total protein and TGF-beta. IT instillation of BL caused significant increases in total cells, neutrophils, macrophages and lymphocytes and in the levels of total protein and TGF-beta in BALF from hamsters in the BL + CD groups as compared to the corresponding SA + CD control groups. In contrast, treatment with pirfenidone in general, suppressed the BL-induced increases in the levels of proteins and TGF-beta and in the influx of neutrophils, macrophages and lymphocytes in BALF at the early time points in BL + PD groups. Based on the data reported in this study, we conclude that the anti-inflammatory effects of pirfenidone as evident by suppressions of BL-induced increased pulmonary vascular permeability and increased influx of inflammatory cells in the lung contribute additionally to its inherent anti-fibrotic effect.

关键词：投药口服动物饲料消炎药非甾类/投药和剂量消炎药非甾类/药理学消炎药非甾类/治疗应用博来霉素/毒性支气管肺泡灌洗液/化学毛细血管通透性/药物作用仓鼠亚科炎症巨噬细胞肺泡/药物作用金仓鼠中性白细胞浸润/药物作用肺纤维化/药物疗法肺纤维化/病理学吡啶酮类/投药和剂量吡啶酮类/药理学吡啶酮类/治疗应用转化生长因子β/分析动物男(雄)性

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Marked hemosiderosis in the myelodysplastic syndrome

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DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT 1999年第4期124卷 79-82页

作者： Klinz, C Bundeswehrkrankenhaus Innere Med Abt D-22049 Hamburg Germany

History and admission findings:A 68-year-old man was admitted because of symptoms of lumbar pain. He was known to have chronic anemia with ring sideroblasts and diabetes melitus and to be in heart failure. Three months before he had been given 7 units of red cell concentrate. On admission the outstanding features were brown discoloration of the skin, absent body hair, tachycardia, hepatomegaly and small testicles. Investigations: He had a normocytic anemia, hyperglycemia and raised transaminases, hypogonadism and vitamin D-3 deficiency. The serum levels of iron, transferrin saturation and ferritin were markedly elevated. Liver iron content/g dried liver was 4,2 g (by biomagnetometer). Radiology of the lumbar vertebrae showed osteoporosis and sonography confirmed hepatomegaly. Diagnosis, treatment and course: The known myelodysplastic syndrome (MDS) had led to secondary hemosiderosis with heart failure, liver involvement, diabetes mellitus, hypogonadism and osteoporosis. Symptomatic treatment was unsuccessfully complemented by desferoxamine (up to 4 g/12 h ) to release iron. But very good iron excretion was then achieved with deferiprone (3 x 1 g/d). The patient later died of the sequelae of hemosiderosis. Conclusion: Even when they have not required transfusions, patients with long-standing MDS should be examined regularly for the possible development of secondary hemosiderosis so that iron-chelating agents can be administered as needed.

关键词：糖尿病 2型/诊断红细胞输注心力衰竭/诊断含铁血黄素沉着症/诊断含铁血黄素沉着症/药物疗法性腺功能减退症/诊断铁螯合剂/投药和剂量腰椎骨髓增生异常综合征/诊断骨质疏松/诊断吡啶酮类/投药和剂量老年人人类男(雄)性

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Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis

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JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2000年第4期43卷 S57-S69页

作者： Bohn, M Kraemer, KT Aventis Pharma Deutschland GMBH Dermatol Div D528 D-65926 Frankfurt Germany

Ciclopirox is a synthetic hydroxypyridone antifungal agent. In contrast to the azoles, glucuronidation is the main metabolic pathway of ciclopirox;therefore interactions with drugs metabolized via the cytochrome P-450 system are unlikely Ciclopirox is also distinct from the common systemic agents, which interfere with sterol biosynthesis. In fact, ciclopirox chelates trivalent cations (such as Fe3+), inhibits metal-dependent enzymes that are responsible for degradation of toxic metabolites in the fungal cells, and targets diverse metabolic leg, respiratory) and energy producing processes in microbial cells. Ciclopirox is a broad spectrum antimicrobial with activity against all the usual dermatophytes as well as yeast and nondermatophyte molds. It has demonstrated activity against gram positive and negative bacteria, including resistant strains of Staphylococcus aureus. Ciclopirox exhibits fungal inhibitory activity (minimum inhibitory concentration < 4 mu g/mL for dermatophytes) as well as Fungicidal activity;to date resistance to the drug has not been identified. Ciclopirox has been formulated in a nail lacquer delivery system. After evaporation of volatile solvents in the lacquer, the concentration of ciclopirox in the remaining lacquer film reaches approximately 35%, providing a high concentration gradient for penetration into the nail. Radiolabel data demonstrate penetration into infected nails after only 1 application of the lacquer. Ciclopirox nail lacquer is a topical product that provides an active fungicidal agent in a delivery system capable of promoting nail penetration. With repeated applications, the antifungal agent is homogeneously distributed through all layers of the toenail achieving concentrations of ciclopirox in er;cess of inhibitory and fungicidal concentrations for most pathogens. Although ciclopirox readily penetrates nails, very low levels of ciclopirox are recoverable systemically even after chronic use. Ciclopirox nail lacquer 8% is a topi

关键词：投药局部抗真菌药/投药和剂量抗真菌药/药代动力学临床试验(主题) 疾病模型动物足皮肤病/药物疗法手皮肤病/药物疗法蹄和爪/代谢微生物敏感性试验指(趾)甲/代谢甲癣/药物疗法药用溶液/治疗应用吡啶酮类/投药和剂量吡啶酮类/药代动力学绵羊皮肤/代谢猪治疗结果动物牛人类

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Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis

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JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2000年第4期43卷 S70-S80页

作者： Gupta, AK Fleckman, P Baran, R Sunnybrook & Womens Coll Hlth Sci Ctr Div Dermatol Dept Med Toronto ON Canada Univ Toronto Toronto ON Canada Univ Washington Dept Med Div Dermatol Seattle WA USA Nail Res Ctr Cannes France

Background: Onychomycosis is a relatively common condition affecting toenails more than fingernails. It is caused predominantly by dermatophytes. Onychomycosis can cause pain and discomfort and has the potential to be a source of morbidity. Objective: We evaluated the efficacy and safely of ciclopirox nail lacquer solution 8% used to treat onychomycosis of the toe in the United States and in centers worldwide. Methods: Two identically designed, double-blind, vehicle controlled, parallel group multicenter studies were performed in the United States to evaluate the use of ciclopirox nail lacquer to treat mild to moderate toe onychomycosis caused by dermatophytes. In the first study 223 patients were randomized to treatment (ciclopirox group: 112, vehicle group: 111), and in the second study, 237 subjects were randomized (ciclopirox group: 119, vehicle group: 118). Before randomization, patients were to have clinical features of onychomycosis in at least one great toe with positive light microscopic examination and a positive dermatophyte culture. The test material was applied dairy For a period of 48 weeks to all toenails and affected fingernails, covering the entire nail plate and approximately 5 mm of surrounding skin. At baseline, subjects had between 20% to 65% area of target nail involved. Physician's assessments were carried out every 4 weeks, and mycologic evaluation and photographic planimetry using standardized photographs were performed every 12 weeks during the 48 weeks of treatment. In studies conducted outside the United States, patients were also to have clinical, microscopic, and culture evidence of onychomycosis. However, these studies included some patients infected with nondermatophyte organisms leg, Candida species), and the area of nail involvement was generally greater than observed in the US studies. Treatment regimens also varied in the non-US studies with lacquer applications that were sometimes less frequent than the once daily treatment used

关键词：投药局部方差分析抗真菌药/投药和剂量临床试验(主题) 双盲法随访研究足皮肤病/药物疗法多中心研究(主题) 甲癣/药物疗法药用溶液/投药和剂量吡啶酮类/投药和剂量参考值美国世界卫生组织成年人老年人女(雌)性人类男(雄)性中年人

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Topical treatment approved for fungal nail infection

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AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY 2000年第3期57卷 205-205页

作者： [Anonymous]

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