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Basis for dosing time-dependent changes in the antiviral activity of interferon-α in mice

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 488-493页

作者： Ohdo, S Wang, DS Koyanagi, S Takane, H Inoue, K Aramaki, H Yukawa, E Higuchi, S Kyushu Univ Grad Sch Dept Clin Pharmacokinet Div Pharmaceut SciHigashi Ku Fukuoka 8128582 Japan Daiichi Coll Pharmaceut Sci Dept Mol Biol Fukuoka 815 Japan

The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7: 00 AM to 7: 00 PM). 2'-5' Oligoadenylate synthetase activity in plasma at 24 h after IFN-alpha (10 MI. U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P<.05). The uptake of [H-3] thymidine by lymphocytes after 24-h incubation with IFN-alpha, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9: 00 AM than in the cells obtained at 9:00 PM (P<.01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P<.05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-alpha, which showed higher clearance for injections given at 9: 00 PM than for those at 9:00 AM (P<.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9: 00 PM than at 9: 00 AM (P<.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.

关键词： 2' 5'-寡腺苷酸合成酶/血液抗病毒药/投药和剂量抗病毒药/药代动力学抗病毒药/药理学时间生物学昼夜节律/生理学 DNA结合蛋白质类/生物合成 DNA结合蛋白质类/血液用药计划表干扰素调节因子1 干扰素α/投药和剂量干扰素α/药代动力学干扰素α/药理学碘放射性同位素肾/解剖学和组织学肾/代谢淋巴细胞活化/药物作用淋巴细胞/药物作用淋巴细胞/免疫学淋巴细胞/代谢小鼠近交ICR 磷蛋白类/生物合成磷蛋白类/血液受体干扰素αβ 受体干扰素/代谢受体干扰素/生理学时间因素动物男(雄)性小鼠

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The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The ganciclovir cidofovir cytomegalovirus retinitis trial

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AMERICAN JOURNAL OF OPHTHALMOLOGY 2001年第4期131卷 457-467页

作者： Jabs, DA Johns Hopkins Univ Sch Med Baltimore MD 21205 USA

PURPOSE: To compare the regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis. METHODS: Sixty-one patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis were randomized either to the regimen of the ganciclovir implant plus oral ganciclovir, 1 gm three times daily, or intravenous cidofovir, 5 mg/kg once weekly for two doses, followed by 5 mg/kg every other week. RESULTS: Mortality was similar between the two treatment groups. Mortality rates were 0.41 per person-year in patients assigned to the ganciclovir regimen and 0.49 per person-year in patients assigned to cidofovir (P = .59). Ocular outcomes were similar between the two groups. Retinitis progression occurred at a rate of 0.67 per person-year in the ganciclovir group and 0.71 per person-year in the cidofovir group (P = .72), A loss of visual acuity of 15 letters or more occurred at a rate of 0.78 per person-year in the ganciclovir group and 0.47 per person-year in the cidofovir group (P = .28). The rate of loss of visual field was 7 degrees per month in the ganciclovir group and 2 degrees per month in the cidofovir group (P = .048). Vitreous hemorrhage was more common in the ganciclovir implant group (0.13 per person year) than in the cidofovir group (no cases, P = .014), whereas uveitis appeared to be more common in the cidofovir group (0.35 per person-year) than in the ganciclovir group (0.09 per person-year, P = .066). Nephrotoxicity (serum creatinine 1.6 mg/dL or greater) occurred at a rate of 0.18 per person-year in the ganciclovir group and 0.48 per person-year in the cidofovir group (P = .10). CONCLUSIONS: Although the small number of patients in this study limits definitive interpretation, these data suggest that in the era of highly active antiretroviral therapy, the regimens of the ganciclovir implant plus oral ganciclovir and of intravenous cidofovir are similar for controlling cytomegalovirus re

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A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS

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AMERICAN JOURNAL OF GASTROENTEROLOGY 1999年第11期94卷 3267-3273页

作者： Holodniy, M Koch, J Mistal, M Schmidt, JM Khandwala, A Pennington, JE Porter, SB AIDS Res Ctr FACP VA Palo Alto Hlth Care Syst Palo Alto CA 94304 USA Stanford Univ Palo Alto CA 94304 USA Univ Calif San Francisco San Francisco CA 94143 USA

OBJECTIVE: The aim of this study was to investigate the safety and effectiveness of orally administered SP-303 in patients with AIDS and diarrhea. METHODS: This is a multicenter, phase II, randomized, double blind, placebo-controlled study. HIV-positive subjects with a history of a CD4 count <200 or an AIDS-defining illness were admitted to an inpatient study unit and screened for diarrhea defined as at least three abnormal (i.e., soft or watery) stools and >200 g of abnormal stool weight over a 24-h period. Subjects discontinued all antidiarrheal agents >24 h before enrollment. Stool samples were studied for routine pathogens. Subjects received 500 mg y.o. of SP-303 or placebo every 6 h for 96 h (4 days). Stool frequency and weights were recorded. Subjects were monitored for symptoms and side effects and were seen 1 wk later in follow-up. RESULTS: A total of 26 subjects received SP-303, and 25 received placebo. There were no significant demographic differences between treatment arms. A total of 41 subjects (80%) were receiving antiretroviral therapy and 39 subjects (77%) were receiving at least one protease inhibitor. Stool studies revealed no pathogens in 38 of 51 patients (94%). There were no serious adverse events or laboratory abnormalities. The SP-303 treatment group demonstrated a mean reduction from baseline stool weight of 451 g/24 h vel-sw 150 g/24 h with placebo on day 4 of treatment (p = 0.14), and a mean reduction in abnormal stool frequency of three abnormal stools in 24 h versus two in 24 h in the placebo group (p = 0.30). Daily measures analysis over 4 days of treatment demonstrated that SP-303 subjects had a significant reduction in stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) when compared to placebo-treated subjects. CONCLUSIONS: SP-303 is safe and well tolerated. These results suggest that SP-303 may be effective in reducing stool weight and frequency in patients with AIDS and (C) 1999 by Am. Cell. of Gastroenterology.

关键词：获得性免疫缺陷综合征/并发症投药口服抗HIV药/治疗应用止泻药/投药和剂量止泻药/治疗应用抗病毒药/投药和剂量抗病毒药/治疗应用生物聚合物/治疗应用儿茶素/类似物和衍生物儿茶素/治疗应用腹泻/药物疗法腹泻/病毒学双盲法粪便随访研究 HIV蛋白酶抑制药/治疗应用安慰剂安全成年人女(雌)性人类男(雄)性中年人

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AEROSOL THERAPY OF INFLUENZA INFECTIONS OF MICE AND PRIMATES WITH RIMANTADINE, RIBAVIRIN, AND RELATED COMPOUNDS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1977年第MAR4期284卷 264-271页

作者： STEPHEN, EL WALKER, JS DOMINIK, JW YOUNG, HW BERENDT, RF USA MED RES INST INFECT DISDIV ANIM ASSESSMENTFREDERICKMD 21701

Ribavirin administered as small-article aerosols had significant therapeutic effect in the treatment of viral respiratory infections induced by influenza virus. The preliminary experiment using ribavirin to treat influenza infection in the squirrel monkey is encouraging. We expect to extend these experiments by initiating therapy at a later time to investigate the potential value of ribavirin in a clinical situation. Several derivatives of ribavirin are effective antiviral compounds. The tri-O-acetyl derivative appears to offer a potential advantage over ribavirin, although this cannot be stated with certainty since the data were obtained from separate experiments. Radiolabeling has been used as a means of measuring tissue concentration and clearance rates of various drugs. It is hoped that the use of labeled ribavirin and the tri-O-acetyl derivative will assist us in determining whether a depot of antiviral drug is created in pulmonary tissues after administration as a small-particle aerosol. These experiments are now in progress.

关键词：金刚烷/投药和剂量金刚烷/类似物和衍生物金刚烷/治疗应用气雾剂抗病毒药/投药和剂量抗病毒药/治疗应用直鼻猴亚目正黏病毒科感染/药物疗法利巴韦林/投药和剂量利巴韦林/类似物和衍生物利巴韦林/治疗应用核糖核苷类/治疗应用松鼠猴属动物女(雌)性小鼠

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Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 2000年第4期45卷 511-516页

作者： Snell, GI Kotsimbos, TC Levvey, BJ Skiba, M Rutherford, DM Kong, DCM Williams, TJ Krum, H Alfred Hosp Lung & Heart Transplant Serv Prahran Vic 3181 Australia Alfred Hosp Dept Clin Pharmacol Prahran Vic 3181 Australia Alfred Hosp Dept Pharm Prahran Vic 3181 Australia Alfred Hosp Dept Clin Biochem Prahran Vic 3181 Australia

Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ganciclovir but has a relatively low bioavailability and this may be problematic in at-risk patients with malabsorption. The bioavailability and therefore therapeutic potential of oral ganciclovir in cystic fibrosis (CF) patients post-lung transplant (LT) might be expected to be inadequate given the high incidence of malabsorption in these patients. An 8 h pharmacokinetic study was performed in 12 CF patients 160 +/- 122 days post-transplant who had been taking 1 g oral ganciclovir tds for 3 days with food (plus normal enzyme supplements). Mean (range) serum creatinine was 150 mu mol/L (70-280). Blood was sampled at 0.5, 1, 2, 3, 4, 6 and 8 h post-final dose. Plasma was stored at -20 degrees C and later analysed by highperformance liquid chromatography. Mean peak concentration (C-min) was 4.8 mg/L (0.96-12.8), mean minimum concentration (C-min) was 3.6 mg/L (0.78-11.7) and mean area under the curve (AUC) was 35.4 mg.8 h/L (8-99). C-max, C-min and AUC correlated significantly with one another (P < 0.001) as well as with serum creatinine and creatinine clearance(P < 0.01). When corrected for alterations in renal function, plasma oral ganciclovir levels are as predicted for other transplant populations. Three days of oral ganciclovir results in therapeutically useful plasma drug levels in the CF LT population, despite a background of general malabsorption. C-max, C-min and AUC are highly correlated, allowing for the possibility of steady-state drug monitoring to confirm that the recommended dosing algorithm produces appropriate plasma levels.

关键词：抗病毒药/投药和剂量抗病毒药/血液抗病毒药/药代动力学曲线下面积肌酸酐/血液囊性纤维化/代谢囊性纤维化/外科学更昔洛韦/投药和剂量更昔洛韦/血液更昔洛韦/药代动力学肺移植/生理学成年人女(雌)性人类男(雄)性

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Influence of the treatment protocol upon the in vivo efficacy of cidofovir (HPMPC) and of acyclovir (ACV) formulations in topical treatment of cutaneous HSV-1 infection in hairless mice

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第5期88卷 530-534页

作者： Afouna, MI Mehta, SC Ghanem, AH Higuchi, WI Kern, ER DeClercq, E El-Shattaway, HH Univ Alabama Dept Pediat Birmingham AL 35294 USA Univ Utah Dept Pharmaceut Salt Lake City UT 84112 USA Univ Utah Dept Pharmaceut Chem Salt Lake City UT 84112 USA Glaxo Wellcome Inc Res Triangle Pk NC 27709 USA Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Al Azhar Univ Dept Pharmaceut Nasr City Cairo Egypt

In recent studies we found that the topical effectiveness of acyclovir (ACV) formulations was a single-valued function of C*-the target site free drug concentration. The topical efficacy was the same when the therapy was initiated 0, 1, or 2 days after intracutaneous herpes simplex virus type-1 (HSV-1) inoculation in hairless mice. The purpose of the present study was to examine the hypothesis that the topical effectiveness of cidofovir (HPMPC) would not be a single valued function of C* and that it would be dependent upon when the therapy was initiated relative to the time of viral infection. Formulations of HPMPC and AGV in 95% DMSO as a vehicle were used. Hairless mice intracutaneously infected with HSV-1 were used, and 20 mu L of the test formulation was topically applied twice a day. In protocol A, the treatment was continued until the fourth day after virus inoculation, whereas in protocol B the treatment was terminated on the day of virus inoculation. Treatment was initiated on various days ranging from day -6 to day 4, and the lesions were scored on day 5. Treatment of ACV according to protocol A proved efficacious whether started as early as 6 days before virus inoculation or later, whereas the efficacy of ACV was annihilated if applied following protocol B. For HPMPC, on the other hand, the in vivo efficacies were found to be strongly dependent on how early the therapy was initiated, and significant efficacy was observed even when the treatment was terminated on the day of virus inoculation. This difference was attributed to the virus-independent intracellular phosphorylation of HPMPC and slow clearance of its metabolites from the cell. It was also noted that, similar to ACV, for HPMPC the topical efficacy is likely to be a function of C* for a fixed protocol. However, unlike for ACV, for HPMPC the efficacy was not a single-valued function of C*.

关键词：阿昔洛韦/投药和剂量投药局部抗病毒药/投药和剂量胞嘧啶/投药和剂量胞嘧啶/类似物和衍生物疱疹单纯/药物疗法有机磷化合物/投药和剂量皮肤疾病病毒性/药物疗法动物女(雌)性小鼠

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Efficacy of topical acyclovir monophosphate, acyclovir, or penciclovir in orofacial HSV-1 infections of mice and genital HSV-2 infections of guinea pigs

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NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2000年第1-2期19卷 501-513页

作者： Kern, ER Palmer, J Szczech, G Painter, G Hostetler, KY Univ Alabama Sch Med Birmingham AL 35294 USA Triangle Pharmaceut Inc Durham NC 27707 USA Univ Calif San Diego La Jolla CA 92093 USA VA Med Ctr La Jolla CA 92093 USA

The purpose of these studies was to compare the efficacy of acyclovir monophosphate (ACVMP), acyclovir (ACV), or penciclovir (PCV) against HSV-I in an orofacial infection of mice and against ACV sensitive and resistant genital HSV-2 infections of guinea pigs. Treatment was initiated 24, 48, or 72 hours post inoculation with 5% ACVMP, 5% ACV (Zovirax) or 1% PCV (Denavir). In all experiments, similar efficacy was obtained for ACVMP and ACV, whereas PCV was considerably less effective.

关键词：阿昔洛韦/投药和剂量阿昔洛韦/类似物和衍生物阿昔洛韦/治疗应用投药局部抗病毒药/投药和剂量抗病毒药/治疗应用疱疹生殖器/药物疗法疱疹生殖器/病理学疱疹唇/药物疗法疱疹唇/病理学疱疹病毒1型人/药物作用疱疹病毒2型人/药物作用小鼠近交HRS 动物女(雌)性豚鼠小鼠

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Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection

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ANTIVIRAL THERAPY 1999年第3期4卷 143-149页

作者： Calfee, DP Peng, AW Hussey, EK Lobo, M Hayden, FG Univ Virginia Hlth Sci Ctr Dept Internal Med Charlottesville VA 22908 USA Glaxo Wellcome Inc Res Triangle Pk NC 27709 USA

Zanamivir, a potent inhibitor of influenza A and B virus neuraminidases, is protective against experimental human influenza when given intranasally twice daily. We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir, In the first study, 36 uninfected volunteers received a single dose of zanamivir by intranasal spray (6.4 mg), intranasal drops (16 mg) or dry powder oral inhalation (10 mg). At 4 h, median nasal wash concentrations were 50-fold higher after intranasal dosing than after inhalation. Substantial levels (spray group, median 4596 ng/ml;drop group, 1239 ng/ml) were detected in nasal wash 48 h after intranasal dosing. In the double-blinded efficacy study, 47 sere-susceptible volunteers were randomized to receive either placebo or zanamivir intranasal spray (6.4 mg). Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge. In the group given three daily doses, reductions were seen in viral shedding and infection. In the two regimens providing zanamivir 4 h prior to inoculation, significant reductions in nasal mucus weight were observed, Decreases in total symptom scores and the incidence of upper respiratory illness also occurred, but they did not reach statistical significance. The efficacy of a single dose of zanamivir given 4 h prior to inoculation supports the hypothesis that influenza virus neuraminidase is essential for initial virus spread through respiratory secretions. These findings indicate that once daily dosing of zanamivir is protective against experimental influenza A infection.

关键词：投药鼻内抗病毒药/投药和剂量双盲法胍类流感病毒A型/药物作用流感人/预防和控制吡喃类唾液酸类/投药和剂量唾液酸类/药代动力学扎那米韦青少年成年人女(雌)性人类男(雄)性

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Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a Phase I/II study

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ANTIVIRAL THERAPY 1999年第2期4卷 101-107页

作者： Kamp, W Schokker, J Cambridge, E De Jong, S Schuurman, R De Groot, T Boucher, CAB Fight Life Fdn Amsterdam Netherlands Univ Utrecht Hosp Eijkman Winkler Inst Dept Virol Utrecht Netherlands

The compound 9-(2-phosphonylmethoxyethyl)adenine (adefovir;PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus (HIV) type 1 and 2, herpes simplex virus (HSV) type 1 and 2, human papillomavirus virus (HBV) and Epstein-Barr virus (EBV). Adefovir also proved to be effective in vivo against feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in rhesus monkeys. In an open, non-placebo-controlled trial the antiviral activity of weekly doses of adefovir in nine patients with AIDS or AIDS-related complex was studied for a period of 11 weeks. CD4 cell counts at baseline were between 10 and 450 cells/mm(3), HIV-1 RNA levels at baseline were between 24210 copies/ml and 406197 copies/ml. The drug was administered intravenously at a dose of 1000 mg every week and plasma viral load was assessed at multiple points during the study. Administration of adefovir was tolerated well and no severe side effects were seen. The response to adefovir treatment differed widely between patients. The increase in CD4 cell count at end point ranged from -40 to 120 cell/mm(3). The lowest HIV RNA levels were measured after 3-5 days, showing an increase thereafter. The nadir in viral load was achieved after 2 weeks, with a mean viral load decline of 0.7 from baseline. The decrease of the HIV RNA level at end point ranged from -0.3 log(10) to 1.8 log(10), with a mean decrease of 0.4 log(10). Our results indicate that adefovir given intravenously once weekly has a short-lasting initial antiviral effect. The effect of more frequent dosing requires further evaluation. If adefovir is to be useful clinically, it needs to be combined with other antiviral agents.

关键词：获得性免疫缺陷综合征/药物疗法获得性免疫缺陷综合征/病毒学腺嘌呤/投药和剂量腺嘌呤/类似物和衍生物抗病毒药/投药和剂量 CD4淋巴细胞计数 HIV-1/遗传学 HIV-1/分离和提纯 RNA 病毒/血液成年人人类男(雄)性中年人

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Retreatment of hepatitis C patients who do not respond to interferon: The search continues

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AMERICAN JOURNAL OF GASTROENTEROLOGY 2000年第5期95卷 1122-1124页

作者： Pianko, S McHutchison, J Scripps Res Inst Div Gastroenterol Hepatol La Jolla CA 92037 USA

Hepatitis C may represent one of the 21st century's largest public health challenges, affecting 100-300 million individuals worldwide (1). Interferon based regimens have been the mainstay of therapy for hepatitis C since α-interferon was shown to have beneficial effects in the late 1980s (2, 3). The addition of ribavirin to interferon in 1998 has led to a major therapeutic advance in the treatment of naive and interferon relapse patients (4, 5, 6). Combined therapy has increased the sustained virological response (SVR) of naive patients from 10%, with interferon alone, to 40%, when given in combination with ribavirin. Despite this improvement, the majority of treated patients fail to achieve the benefits of sustained virological eradication (7).

关键词：金刚烷胺/投药和剂量抗病毒药/投药和剂量抗病毒药/治疗应用药物疗法联合肝炎丙型/药物疗法干扰素α/投药和剂量干扰素α/治疗应用利巴韦林/投药和剂量治疗失败人类

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