Archives of Drug Information

Current scientific publishing uses a selective, slow, and adversarial editorial process to publish a minority of papers submitted, and thus maximize a journal's impact factor, a major measure of success. However, the results of many pharmaceutical industry studies are deemed low priority and are therefore difficult or impossible to publish in scientific journals. Society is poorly served because access to the results of these studies is in the public interest. Archives of Drug Information is an independent, online only journal that will publish papers that are free of bias and that provide new information about a drug. Articles that would not usually be published by traditional journals, for example articles reporting negative studies, studies reporting animal toxicity or Phase I human studies, or routine pharmacokinetic or drug interaction studies are welcome. The editorial process will be rapid and user friendly. The contents of the journal will be available freely to all. Archives of Drug Information will allow the pharmaceutical industry to publish the results of studies and make freely accessible to the public the results of research studies that would otherwise remain unavailable "on-file." Making the results of studies available to the public is not only ethical and good scientific citizenship, but ultimately, also good business.

C. Michael Stein

Archives of Drug Information—A New Approach to Publishing the Results of Drug Studies

药物信息档案——药物研究成果出版的新方法

OBJECTIVES: Cardiovascular risk is increased in patients with systemic lupus erythematosus (SLE). Drugs used to treat SLE can modify traditional cardiovascular risk factors. We examined the effect of selected drugs used in the treatment of SLE on cardiovascular risk factors. METHODS: We compared systolic and diastolic blood pressure, serum lipid concentrations, glucose, homocysteine, and urinary F(2)-isoprostane concentrations in 99 patients with lupus who were either current users or non-users of systemic corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, azathioprine, and methotrexate. Multivariable adjustment was done with linear regression modeling using sex, age and disease activity (SLEDAI) as controlling variables. RESULTS: Serum triglyceride concentrations were higher (135.1 +/- 61.4 vs. 95.3 +/- 47.5 mg/dL, adjusted P = 0.003) in patients receiving corticosteroids. Homocysteine concentrations were marginally higher in patients receiving methotrexate (adjusted P = 0.08). Current use of either NSAIDs or COX-2 inhibitors was not associated with increased cardiovascular risk factors. Current hydroxychloroquine use was not associated with significant alterations in lipid profiles. CONCLUSIONS: In a non-random sample of patients with SLE, current corticosteroid use was associated with increased triglyceride concentrations, but other drugs had little effect on traditional cardiovascular risk factors.

Young Hee Rho

Annette Oeser

Cecilia P. Chung

Jason D. Morrow

Drugs to Treat Systemic Lupus Erythematosus: Relationship between Current Use and Cardiovascular Risk Factors

治疗系统性红斑狼疮的药物：当前使用与心血管风险因素之间的关系

OBJECTIVE: C-reactive protein (CRP) and homocysteine are markers of cardiovascular risk that may have inflammatory effects. HMG coenzyme A reductase inhibitors (statins) have anti-inflammatory effects in vitro, but it is not clear if such responses in vivo are secondary to lipid lowering. We examined the hypothesis that CRP and homocysteine would stimulate cytokine release in human whole blood and that short-term treatment with a statin would inhibit it. METHODS: The time course of IL-6 and MCP-1 production was determined in whole blood incubated with saline, 1 microg/mL lipopolysaccaride (LPS), 50 and 100 microM/L DL-homocysteine, and 5 microg/mL human recombinant CRP for 24 hours at 37 degrees C under 5% CO(2) atmosphere. Cytokine responses were determined in blood drawn from 15 healthy volunteers before and after administration of pravastatin 40 mg daily for 2 days. RESULTS: Both human recombinant CRP and LPS significantly increased the production of IL-6 and MCP-1 in whole blood samples more than 4-fold (P < 0.001) but homocysteine did not. Oral administration of pravastatin, 40mg daily for 2 days, decreased CRP-stimulated IL-6 production by approximately 20% (P = 0.02) 6 hours after incubation, but did not affect MCP-1 production (P = 0.69). Pravastatin treatment did not affect LPS-stimulated MCP-1 but increased IL-6 modestly. CONCLUSIONS: CRP stimulated the production of the proatherogenic mediators MCP-1 and IL-6 in human whole blood, but homocysteine did not. CRP-stimulated production of IL-6, but not MCP-1, was modestly attenuated by short-term treatment with pravastatin.

Yu Asanuma

Eran Stanley

David G. Bailey

Ayumi Shintani

Effects of C‐reactive Protein and Homocysteine on Cytokine Production: Modulation by Pravastatin

C反应蛋白和同型半胱氨酸对细胞因子产生的影响：普伐他汀的调节作用

ABSTRACT Objectives. Selective cyclooxygenase (COX)‐2 inhibitors are effective analgesic and anti‐inflammatory agents with improved gastrointestinal safety and tolerability compared with traditional NSAIDs. However, data from long‐term, placebo‐controlled studies have shown an increased risk of thrombotic cardiovascular (CV) events for COX‐2 inhibitors. Changes in levels of CV biomarkers are potentially useful surrogate measures of pathologic changes associated with CV risk. Methods. We randomized 433 patients with osteoarthritis to etoricoxib 90 mg once daily, celecoxib 200 mg twice daily, ibuprofen 800 mg three times daily, or placebo for 12 weeks. The hypothesis was that etoricoxib would be non‐inferior or superior to placebo in effect on C‐reactive protein (CRP), LDL‐cholesterol, homocysteine, and fibrinogen. Results. Relative to placebo, etoricoxib was noninferior for effect on CRP (decreased 7.8% vs. placebo; 97.5% CI of the difference: −30.5, 22.4), LDL‐C (−4.0% vs. placebo; 97.5% CI: −10.6, 3.2), homocysteine (−3.9% vs. placebo; 97.5% CI: −11.6, 4.6), and fibrinogen (−3.7% vs. placebo; 97.5% CI: −9.4, 2.3). Etoricoxib was not different from placebo, celecoxib, or ibuprofen for any biomarker. Conclusion. Etoricoxib was comparable to placebo, celecoxib, and ibuprofen for effects on the CV risk markers measured.

Christopher P. Cannon

Cong Chen

Sean P. Curtis

John Viscusi

Tuli Ahmed

Peter M. DiBattiste

A Comparison of Cardiovascular Biomarkers in Patients Treated for Three Months with Etoricoxib, Celecoxib, Ibuprofen, and Placebo

三种治疗三个月后患者心血管生物标志物的比较：依托考昔、塞来昔布、布洛芬与安慰剂

BACKGROUND: Hypertension in blacks imposes a greater left ventricular hypertrophy, and accelerated heart failure onset. We evaluated and compared the echocardiographically determined systolic and left ventricular diastolic functional indices in Nigerian hypertensive patients, associated with the chronic use of ACE inhibitors, Calcium channel blockers (CCB) or their combinations. METHODS: Ejection fraction -EF, intraventricular relaxation time (IVRT), E/A peak velocity ratio, E wave deceleration time] as well as the left ventricular mass index (LVMI) was undertaken among 41 Nigerian patients with essential hypertension only, on treatment for 4-6 months prior. The 41 patients (aged 59 +/- 10 years, 40% females) were divided into three groups; those receiving (i) ACE inhibitors; or (ii) CCB or (iii) combination of ACEI and CCB. All the three groups had a background of diuretic treatment for optimal blood pressure control. RESULTS: There were no statistically significant differences in the mean LVMI or sitting blood pressure between treatment groups. E/A ratio for ACEI treatment was 1.06 +/- 0.44, CCB 0.74 +/- 0.19, and for ACEI + CCB 0.87 +/- 0.26 (F = 3.29, P = 0.048 anova). The 95% confidence interval for the E/A ratio on ACEI was 0.8 to 1.33. The A wave duration time integral (AVVTi) were all abnormally large, but showed a significant between treatment group difference (P = 0.037, anova). The values were 21.9 +/- 4.7 for ACEI, 25.3 +/- 6.3 for CCB, and least at 20.1 +/- 3.6 cm for the ACE + CCB combination. Similarly, the IVRT was lowest and <100 ms with ACEI + CCB being 93 +/- 18 ms, ACEI 115 +/- 23 ms, and CCB being 117 +/- 22 ms (F = 4.92, P = 0.01, anova). The 95% CI for IVRT on ACEI + CCB was 82 to 104 ms. There were no between treatment group differences in systolic contractility, (fractional shortening or EF). CONCLUSIONS: The results indicate that use of an antihypertensive drug regime inclusive of an ACE inhibitor (+/-CCB) may be associated with greater salutary effect on indices of diastolic function, (E/A > 1, lower AVVTi, IVRT < 100 ms) even in the presence of an equivalent effect on systolic function and blood pressure.

Olufemi E. Ajayi

Anthony O. Akintomide

Adegboyega Q. Adigun

Adesuyi A. L. Ajayi

Left Ventricular Diastolic Function in Nigerian Patients with Essential Hypertension: A Retrospective Study to Compare Angiotensin Converting Enzyme Inhibitors, Calcium Channel Blockade or Their Combination

尼日利亚原发性高血压患者左心室舒张功能：一项回顾性研究，比较血管紧张素转换酶抑制剂、钙通道阻滞剂或其联合应用的效果

INTRODUCTION: Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio®), was investigated and compared to placebo in a randomised, double-blind clinical trial in adult cancer patients receiving nonplatinum-based chemotherapy. The primary efficacy endpoint was the responder rate (complete haemoglobin (Hb) response, i.e., Hb increase ≥2 g/dl) without the benefit of a transfusion within the previous 4 weeks. RESEARCH DESIGN AND METHODS: 186 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (N = 95) or placebo (N = 91). The starting dose was 20,000 IU once weekly Epoetin theta or placebo. RESULTS: The incidence of complete Hb responders was significantly higher in the Epoetin theta group than in the placebo group (72.6 vs. 25.3%, P < 0.0001). More patients in the placebo group than in the Epoetin theta group received blood transfusions after randomisation (23 patients, 25.3% vs. 13 patients, 13.7%, P = 0.0277). The majority of patients with a complete Hb response had 20,000 IU/week as their maximum dose prior to response, indicating that a dose of 20,000 IU is an appropriate starting dose. The overall frequencies of adverse events (AEs) were similar in both treatment groups. Hypertension was the only AE that was more frequent in the Epoetin theta group compared to the placebo group (8.4 vs. 1.1%). CONCLUSIONS: Epoetin theta showed a superior efficacy to placebo in terms of complete Hb response without blood transfusion within the previous 4 weeks. Treatment with Epoetin theta resulted in a statistically significant increase in mean haemoglobin levels compared to placebo. The overall frequencies of adverse events were similar in both treatment groups.

Sergei A. Tjulandin

Peter Bias

Reiner Elsässer

Beate Gertz

Erich Kohler

Anton Buchner

Epoetin Theta with a New Dosing Schedule in Anaemic Cancer Patients Receiving Nonplatinum-Based Chemotherapy: A Randomised Controlled Trial

新剂量方案的依泊汀θ在非铂类化疗的贫血癌症患者中的随机对照试验

Introduction. AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. Methods. In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. Results. Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. Conclusion. AZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

Taito Esaki

Takashi Seto

Hiroshi Ariyama

Shuji Arita

Chinatsu Fujimoto

Koichiro Tsukasa

Takuro Kometani

Kaname Nosaki

Fumihiko Hirai

Katsuro Yagawa

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors

AZD4877在日本实体瘤患者中的安全性、耐受性和药代动力学I期研究

OBJECTIVES: The penetration of hydrocortisone (HC) from six topical over-the-counter products along with one prescription cream through cultured normal human-derived epidermal keratinocytes (Epiderm™), mouse skin and synthetic nylon membrane was performed as well as the effect hydrating the skin by pre-washing was explored using the Upright Franz Cell. METHOD AND RESULTS: Permeation of HC through EpiDerm™, mouse skin and synthetic membrane was highest with the topical HC gel formulation with prewash treatment of the membranes among seven products evaluated, 198 ± 32 µg/cm(2), 746.32 ± 12.43 µg/cm(2), and 1882 ± 395.18 µg/cm(2), respectively. Pre-washing to hydrate the skin enhanced HC penetration through EpiDerm™ and mouse skin. The 24-hour HC released from topical gel with prewash treatment was 198.495 ± 32 µg/cm(2) and 746.32 ± 12.43 µg/cm(2) while without prewash, the 24-h HC released from topical gel was 67.2 ± 7.41 µg/cm(2) and 653.43 ± 85.62 µg/cm(2) though EpiDerm™ and mouse skin, respectively. HC penetration through synthetic membrane was ten times greater than through mouse skin and EpiDerm™. Generally, the shape, pattern, and rank order of HC diffusion from each commercial product was similar through each membrane.

John Mark Christensen

Monica Chang Chuong

Hang Le

Loan Pham

Ehab Bendas

Hydrocortisone Diffusion Through Synthetic Membrane, Mouse Skin, and Epiderm™ Cultured Skin

氢化可的松通过合成膜、小鼠皮肤和Epiderm™培养皮肤的扩散

INTRODUCTION: Studies using MDCKII and LLC-PK1 cells transfected with MDR1 cDNA indicate that ciprofloxacin is not a substrate of P-glycoprotein. However, our data has shown that transport studies done using different P-gp overexpressing cell lines (MDCKI-MDR1, MDCKII-MDR1 and L-MDR1), could lead to contradictory conclusion on whether a compound is a substrate of P-gp. The aim of our study was to determine if ciprofloxacin is indeed not a P-glycoprotein substrate using MDCKI cells transfected with human MDR1 cDNA. METHODS: Semi-quantitative RT-PCR was used to determine the mRNA level of MDR1 while Western blot was performed to determine the protein expression level of P-gp, MRP1 and MRP2 in various cells. Ciprofloxacin bidirectional transport studies were performed in MDCKI, MDCKI-MDR1, MDCKII, MDCKII-MDR1, MDCKII-MRP2, LLC-PK1, L-MRP1 and L-MDR1 cells. RESULTS: Ciprofloxacin showed net secretion in MDCKI-MDR1 but net absorption in MDCKI cells. Various P-gp inhibitors decreased the B to A and increased the A to B transport of ciprofloxacin in MDCKI-MDR1 cells while having no effect in MDCKI cells. The B to A transport of ciprofloxacin in MDCKI-MDR1 cells was not affected by non-P-gp inhibitors. In the presence of indomethacin, ciprofloxacin showed net secretion instead of net absorption in MDCKI cells while in the presence of probenecid and sulfinpyrazone, there was no net secretion and absorption. There was no difference in ciprofloxacin transport between MDCKII and MDCKII-MDR1, LLC-PK1 and L-MDR1, LLC-PK1 and L-MRP1 and MDCKII and MDCKII-MRP2. CONCLUSIONS: Transport data in MDCKI and MDCKI-MDR1 cells indicate that ciprofloxacin is a substrate of P-gp but data from MDCKII, MDCKII-MDR1, LLC-PK1 and L-MDR1 cells indicate that ciprofloxacin is not a substrate of P-gp. Vinblastine, a well-known P-gp substrate, also did not show differences between LLC-PK1 and L-MDR1 cells. Further studies need to be performed to characterize these P-gp overexpressing cell lines and the transport of ciprofloxacin.

Miki Susanto Park

Hideaki Okochi

Leslie Z Benet

Is Ciprofloxacin a Substrate of P‐glycoprotein?

环丙沙星是P-糖蛋白的底物吗？

ABSTRACT Introduction. Telcagepant (MK‐0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. Methods. Healthy adult subjects were enrolled in two separate open‐label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. Results. Telcagepant was rapidly absorbed with a T max of approximately 1 to 2 hours after oral administration. The terminal half‐life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. Conclusions. Telcagepant was generally well tolerated. Oral telcagepant exhibits non‐linear pharmacokinetics.

Tae H. Han

Rebecca L. Blanchard

John Palcza

Ashley Martucci

Cynthia M. Miller‐Stein

Maria Gutierrez

Deborah Panebianco

Ronda K. Rippley

Christopher Lines

M. Gail Murphy

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects

健康成年受试者单次口服和静脉注射后Telcagepant的剂量比例性

Publication Information	Publisher: John Wiley & Sons Inc.，Publishing cycle: ，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2008，Proportion of original research papers: ，Self Citation Rate:， Gold OA Rate:

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