口服抗病毒新药——缬更昔洛韦

缬更昔洛韦 (valganciclovir)是抗病毒药更昔洛韦的前体药物 ,用于治疗AIDS病人发生的巨细胞病毒 (CMV)视网膜炎。缬更昔洛韦口服后迅速吸收 ,并水解为更昔洛韦 ,其口服给药的生物利用度较高 (60 % )。试验表明 ,口服缬更昔洛韦 (90 0mg)与静脉注射更昔洛韦 (5mg·kg-1) ,bid,3wk后改为 qd ,治疗 1 60例AIDS病人发生的CMV视网膜炎有相同疗效 ,且耐受性相似。缬更昔洛韦维持治疗中最常见的不良反应为中性粒细胞减少症、贫血、胃肠道反应 (腹泻、恶心、呕吐 )、发热、头痛和失眠等     

抗巨细胞病毒新药──西多福韦

巨细胞病毒（CMV）是严重危害人体健康的病原体，所有年龄段的人群都可能感染CMV，尤其是新生儿、器官移植者和免疫功能缺损者如HIV感染者和AIDS患者等。感染CMV后，一般呈无症状隐性感染，一旦免疫功能缺损时将导致发生严重疾病，其临床表现为发热、昏睡、白细胞减少、血小板减少、肝炎、肺炎、脑炎、胃炎及其它全身感染症状；有45％的AIDS患者发展为致盲率极高的急性视网膜炎。用于治疗CMV感染的药物有更昔洛韦和磷甲酸。更昔洛韦是目前治疗CMV感染的首选药物，由于可出现耐药性和严重的不良反应，其临床应用有一定的局限性。…     

缬更昔洛韦

缬更昔洛韦 (ｖａｌｇａｎｃｉｃｌｏｖｉｒ)是更昔洛韦的前药 ,更昔洛韦用来治疗艾滋病患者的由巨细胞病毒(ＣＭＶ)引起的视网膜炎。口服缬更昔洛韦后迅速吸收和水解为更昔洛韦。口服缬更昔洛韦比口服更昔洛韦能提高其生物利用度。缬更昔洛韦为ＤＮＡ聚合酶抑制剂 ,适应证为艾滋病患者中的ＣＭＶ视网膜炎。临床试验常用剂量为 180 0ｍｇ·ｄ- 1(ｂｉｄ) ,共 3周 ,用于诱导治疗 ;然后90 0ｍｇ·ｄ- 1(ｂｉｄ)用于维持治疗。缬更昔洛韦 (875ｍｇ·ｄ- 1,与食物同服 3ｄ ,用于ＣＭＶ和ＨＩＶ阳性患者 )的血药浓度峰值为 6 .1ｍｇ·Ｌ- 1,达峰…     

治疗巨细胞病毒视网膜炎的第一种口服药物戊更昔洛韦

最新研究结果表明 ,罗氏公司的戊更昔洛韦(valganciclovir,更昔洛韦的口服前体药物 )在治疗HIV病毒感染的病人巨细胞病毒 (CMV)视网膜炎方面与静脉给药一样有效。戊更昔洛韦成为第一种有此疗效的口服制剂。经 1 60例病人进行研究 ,结果静脉给药组 77%有效 ,口服给药组 72 %有效 ,没有显著差别。1 989年 ,更昔洛韦静脉给药在美国获得批准 ,用于治疗 CMV视网膜炎且被作为标准疗法 ,罗氏把戊更昔洛韦发展为口服药物 ,且正争取于今年年底前使戊更昔洛韦作为治疗 CMV视网膜炎药物在美国获得批准。罗氏公司的 Martin博士认为 ,戊更昔洛韦疗…     

膦甲酸钠与更昔洛韦治疗获得性免疫缺陷综合征相关巨细胞病毒感染的安全性比较

目的比较膦甲酸钠与更昔洛韦治疗获得性免疫缺陷综合征(AIDS)合并巨细胞病毒(CMV)感染的安全性,为临床安全合理用药提供参考。方法将315例AIDS合并CMV感染患者分为膦甲酸钠组(155例)和更昔洛韦组(160例),治疗后比较其安全性。结果膦甲酸钠可引起局部麻木、抽搐及电解质异常,更昔洛韦常致骨髓抑制及胃肠道反应。膦甲酸钠组药品不良反应(ADR)发生率(45.15%)低于更昔洛韦组(72.50%),组间差异有统计学意义(P<0.05);膦甲酸钠组44.28%的患者因ADR停药,9.68%的患者更换为更昔洛韦继续治疗。更昔洛韦组64.66%的患者因ADR停药,24.38%的患者更换为膦甲酸钠继续治疗。两组间因ADR停药及更换治疗方案间差异有统计学意义(P<0.05)。ADR发生后,及时停药或对症处理,无严重后遗症或死亡病例发生。结论膦甲酸钠的安全性优于更昔洛韦。AIDS患者抗CMV感染选择药物时,可根据膦甲酸钠与更昔洛韦所致ADR的临床表现,避免选择与正在使用药物有相同ADR的药物,以减少ADR的叠加。膦甲酸钠的ADR发生率、ADR发生后的停药比例及更换治疗方案比例均小于更昔洛韦,患者不能耐受更昔洛韦时,可使用膦甲酸钠作为替代治疗。     

Valcyte预防肾移植患者巨细胞病毒感染获批

罗氏集团旗下基因泰克公司近日对外宣布，FDA已经批准其生产的Valcyte（盐酸缬更昔洛韦）用于有巨细胞病毒（CMV）感染风险的肾脏移植患者的长期治疗，这是Valcyte获批的又一新适应证。     

美国首次用植入法治疗巨细胞病毒性视网膜炎

美国FDA已经批准罗氏／奇诺公司的眼内更昔洛韦（ganciclovir）植入物，商品名Vit－rasert，用于治疗艾滋病（AIDS）病人的巨细胞病毒（CMV）性视网膜炎，美国是该植入物的第一个市场。Vitrasert是治疗CMV视网膜炎的第一个眼内装置。该装置由奇诺（Chiron）Vi－sion公司制造，将与罗氏公司共同上市和合作销售。CMV疾病是AIDS病人最常见的机会致病菌感染之一，且能影响全身器官，包括肺和胃肠道，引起致命的感染。CMV视网膜炎是该疾病的最常见的表现形式，AIDS病人中患此病的高达4O％，若不治疗可致盲。罗氏公司已经上市了Cyto…     

更昔洛韦的临床应用进展

更昔洛韦（ganciclovir）具有广谱抗疱疹病毒活性，是第一个治疗人体巨细胞病毒（CMV）感染的有效抗病毒药物。1988年首次在英国上市，至今已有静脉注射剂、胶囊、限内植入剂和0．15％眼膏等4种制剂被批准用于治疗CMV感染及疱疹性角膜炎。本文概述更昔洛韦的作用机理及其产生耐药性的机理，并论述静脉与口服给药的临床疗效。1作用机制更昔洛韦的化学结构与阿昔洛韦（aciclovir）相似。在体内可被转化为三磷酸更昔洛韦（GCV－TP），通过竞争性抑制三磷酸脱氧鸟苷嵌入延伸的病毒DNA，从而抑制单纯疱疾病毒（HSV）与CMV的DNA聚合酶；…     

02066 Roche申报valganciclovir

Roche公司已经向美国的FDA申报valganciclovir(I)的新药申请，希望能够获准上市。(Ⅰ)是该公司Cytovene(ganciclovir，更昔洛韦，口服或静脉注射)(Ⅱ)的前药，用于治疗艾滋病患者因巨细胞病毒(CMV)感染的视网膜炎。     

口服缬更昔洛韦治疗新生儿先天性巨细胞病毒感染1例

目的:探讨口服缬更昔洛韦治疗先天性巨细胞病毒感染新生儿的疗效。方法:口服缬更昔洛韦16 mg/kg,每日2次,治疗1例先天性巨细胞病毒感染新生儿6周,监测新生儿体质量、头围、中性粒细胞、血小板、直接胆红素、丙氨酸氨基转移酶及病毒载量,随访头颅超声、脑干听性诱发电位和头颅磁共振成像(MRI)。结果:缬更昔洛韦治疗后尿液中和血液中病毒载量转阴,听力和发育结果改善,患儿治疗期间出现粒细胞减少症,治疗结束后好转。结论:口服缬更昔洛韦治疗先天性巨细胞病毒感染疗效较显著,需进一步研究确定最佳剂量、疗程以达到更好的疗效和安全性。     

Valganciclovir

Valganciclovir is a prodrug of ganciclovir which has been developed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Oral valganciclovir is rapidly absorbed and hydrolysed to ganciclovir. The oral bioavailability of ganciclovir after oral valganciclovir administration is high. Oral valganciclovir 900 mg provides a daily exposure of ganciclovir comparable to that of intravenous ganciclovir 5 mg/kg. A single, randomised, nonblind study indicated that oral valganciclovir (900mg twice daily for 3 weeks then 900 mg once daily) and intravenous ganciclovir (5 mg/kg twice daily for 3 weeks then 5 mg/kg once daily) were equally effective in the treatment of newly diagnosed CMV retinitis in 160 patients with AIDS. Valganciclovir appears to have a similar tolerability profile to intravenous ganciclovir during induction therapy in patients with AIDS and newly diagnosed CMV retinitis. During maintenance therapy with valganciclovir, the most commonly reported adverse events included neutropenia, anaemia, thrombocytopenia, gastrointestinal (including diarrhoea, nausea, vomiting and abdominal pain), fever, headache, insomnia, peripheral neuropathy, paraesthesia and retinal detachment.     

Valganciclovir: a review of its use in the management of CMV infection and disease in immunocompromised patients

Valganciclovir (Valcyte) is an orally administered prodrug of the standard anti-cytomegalovirus (CMV) drug ganciclovir. Valganciclovir is as effective as intravenous ganciclovir for the treatment of AIDS-related CMV retinitis, and oral ganciclovir for the prophylaxis of CMV infection and disease in high-risk solid organ transplant recipients. The drug is generally well tolerated and has a similar tolerability profile to that of oral or intravenous ganciclovir, but is devoid of adverse events related to intravenous or indwelling catheter access associated with the use of intravenous ganciclovir, cidofovir and foscarnet. The simple and convenient once-daily valganciclovir regimen offers potential for improved patient compliance. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients. Furthermore, the use of valganciclovir instead of intravenous ganciclovir may provide significant cost savings, based on data comparing oral versus intravenous regimens for the treatment of AIDS-related CMV retinitis. Overall, valganciclovir appears to have some advantages over ganciclovir. Therefore, when used as prophylaxis against CMV infection and disease in high-risk solid organ transplant recipients or as induction and maintenance therapy of CMV retinitis in patients with AIDS, oral valganciclovir is an attractive alternative to other available anti-CMV drugs.     

Valganciclovir: new preparation. CMV retinitis: a simpler,oral treatment

For AIDS patients with cytomegalovirus (CMV) retinitis, the standard initial treatment has so far been ganciclovir or foscarnet, both of which are infused intravenously. The choice between these two antiviral agents is based on their differing side effects. Maintenance treatment is based on ganciclovir or foscarnet, but both these drugs must be given as daily intravenous infusions. Oral ganciclovir is less effective. Intraocular maintenance treatment in appropriate only for patients with localised infections and a low risk of relapse. Valganciclovir can be taken orally for both initial and maintenance treatment of CMV retinitis. Valganciclovir has good bioavailability and is rapidly metabolised into ganciclovir. A comparative randomised trial in 160 patients showed that oral valganciclovir is as effective as intravenous ganciclovir when used as an initial treatment. There are no comparative trials of oral valganciclovir as a maintenance treatment, but non comparative data and pharmacokinetic studies suggest that oral valganciclovir is about as effective as intravenous ganciclovir. The adverse effects of oral valganciclovir are similar to those of intravenous ganciclovir, except that the oral route avoids the risk of local complications at the infusion site. Valganciclovir causes more frequent diarrhoea and oral candidosis than intravenous ganciclovir. In practice, for patients with CMV retinitis who require systemic treatment, oral valganciclovir is easier to use and, in our opinion, should now replace IV ganciclovir for both initial and maintenance treatment. The convenience of oral valganciclovir should also limit the use of purely intraocular treatment of CMV retinitis.     

Valganciclovir: A new oral alternative for cytomegalovirus retinitis in human immunodeficiency virus-seropositive individuals

Oral valganciclovir recently was approved by the Food and Drug Administration for treatment of cytomegalovirus (CMV) retinitis. We performed MEDLINE (June 1998-May 2002) and AIDSLINE (June 1998-December 2000) searches of available information on valganciclovir, and the drug's prescribing information was used to identify relevant articles. Additional studies, case reports, reviews, and abstracts were identified from references in the reviewed literature. Most of the information was obtained from abstracts or product labeling, since few trials have been published in the medical literature. Valganciclovir is a prodrug of ganciclovir and has been shown to have significantly higher oral absorption than ganciclovir capsules. One short-term study found valganciclovir to be as effective as intravenous ganciclovir in treating CMV retinitis. Recommended dosages for patients with normal renal function are valganciclovir 900 mg twice/day for induction and 900 mg once/day for maintenance. Side effects are similar to those of intravenous ganciclovir and require periodic monitoring of complete blood count and renal function. Given the need for lifelong therapy for CMV retinitis in some human immunodeficiency virus-positive patients, valganciclovir is a welcome alternative to long-term administration of intravenous antivirals.     

Cytomegalovirus infection in patients with HIV infection

Cytomegalovirus (CMV) is responsible for the most common viral opportunistic infection in persons with acquired immunodeficiency virus syndrome (AIDS). Clinical disease due to CMV has been recognized in up to 40% of patients with advanced HIV disease. The most common presentation is retinitis, although colitis, esophagitis, pneumonitis and neurological disorders are also reported frequently. CMV retinitis is usually diagnosed clinically, and serological testing for CMV immunoglobulin is useful to support the diagnosis. Parts of the gastrointestinal tract (esophagus and colon) are the most common extraocular sites of CMV infection in AIDS patients. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. Ganciclovir is associated mainly with hematological toxicity, while foscarnet and cidofovir are nephrotoxic. Intravitreal injections with these antiviral agents are also effective, but inconvenient, and there is a need for repeated injections. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but the occurrence of contralateral ocular and extraocular disease is a serious concern. New agents, as for example an anti-sense agent against CMV, appear promising.     

Current and emerging antivirals for the treatment of cytomegalovirus (CMV) retinitis: an update on recent patents

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic complication and a serious cause of vision loss in immunocompromised patients. Even though, a rise in human immunodeficiency virus (HIV) infected individuals seems to be a major factor responsible for the prevalence of CMV retinitis, the introduction of highly active antiretroviral therapy (HAART) significantly reduced the incidence and severity of CMV retinitis. Thorough evaluation of the patient's immune status and an exact classification of the retinal lesions may provide better understanding of the disease etiology, which would be necessary for optimizing the treatment conditions. Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV, but prolonged therapy with these approved drugs is associated with dose-limiting toxicities thus limiting their utility. Moreover development of drug-resistant mutants has been observed particularly in patients with acquired immunodeficiency syndrome (AIDS). Continuous efforts by researchers in the industry and academia have led to the development of newer candidates with enhanced antiviral efficacy and apparently minimal side effects. These novel compounds can suppress viral replication and prevent reactivation in the target population. Though some of the novel therapeutics possess potent viral inhibitory activity, these compounds are still in stages of clinical development and yet to be approved. This review provides an overview of disease etiology, existing anti-CMV drugs, advances in emerging therapeutics in clinical development and related recent patents for the treatment of CMV retinitis.     

Management of cytomegalovirus infection in patients with acquired immunodeficiency syndrome

The clinical manifestations of cytomegalovirus (CMV) infection in persons with AIDS are described, and recent advances in the management of these syndromes with antiviral agents are reviewed. CMV infection is the most common serious opportunistic viral infection in AIDS patients. Clinical manifestations include chorioretinitis, gastroenteritis, hepatitis, pneumonia, CNS infection, adrenalitis, and a wasting syndrome. The diagnosis of CMV infection requires laboratory demonstration of a serologic response to the virus, detection of viral components or products, or isolation of the virus. Ganciclovir is an acyclic nucleoside analogue marketed for the treatment of CMV-related retinitis in immunocompromised hosts. After i.v. ganciclovir induction therapy, more than 80% of patients show improvement or stabilization of retinitis. Relapse is common in AIDS patients, however, and low-dose i.v. maintenance therapy is recommended. The most serious dose-limiting effect is neutropenia. Intravitreal injection of ganciclovir has been well tolerated and efficacious. Ganciclovir has shown some efficacy in the treatment of other life-threatening CMV infections, especially gastroenteritis, but data are limited. Ganciclovir-resistant strains have been reported. Foscarnet, a pyrophosphate analogue with activity against both human CMV and human immunodeficiency virus, is undergoing clinical trials. Foscarnet has shown promise in the therapy of CMV-related retinitis, but results for other CMV infections are disappointing. Nephrotoxicity is the major dose-limiting effect. AIDS patients with sight-threatening and rapidly progressive CMV-related retinitis should be treated with ganciclovir. Foscarnet may offer an alternative when it becomes available. More must be learned about the efficacy of these drugs in the treatment of CMV infection in patients with AIDS.     

Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers.

OBJECTIVE: Ganciclovir is commonly used in the treatment of cytomegalovirus (CMV) disease in patients who are immunocompromised and for the prevention of CMV disease in solid organ transplant recipients. Owing to limited bioavailability and saturable absorption, the use of oral ganciclovir in CMV retinitis is restricted to maintenance therapy only. As induction therapy must be given intravenously, an oral formulation which could be used for induction would offer significant benefits. A previous study of valganciclovir, a valyl ester prodrug of ganciclovir showed a 10-fold increase in plasma ganciclovir concentrations compared with the oral formulation. However, before studies can be conducted to confirm the utility of oral valganciclovir for the treatment and prevention of CMV disease, a dose must be selected for use in these studies. This study was designed to investigate the pharmacokinetics of ganciclovir and valganciclovir. DESIGN AND PARTICIPANTS: The study was an open-label, randomised, 4-way crossover, dose-ranging pharmacokinetic study, conducted in 39 patients who were HIV- and CMV-seropositive. The participants were randomised to one of 2 groups: fasted (n = 19) and fed (n = 20). In both groups, participants received 450, 875, 1750 and 2625 mg oral valganciclovir once daily for 3 days in a randomised order. RESULTS: In the 32 participants who completed the study, valganciclovir was rapidly absorbed and converted into ganciclovir (maximum ganciclovir concentrations occurred after 1.0 to 1.75 hours in the fasted group and 1.5 to 2.0 hours in the fed group). Systemic exposure to valganciclovir was low [with an area under the concentration-time curve to 24 hours (AUC24) of 1.3 to 2.5% that of ganciclovir]. The mean plasma concentrations of ganciclovir were dose-related. Peak concentrations of ganciclovir were achieved approximately 30 minutes after those for valganciclovir. In the fed state, the AUC24 of ganciclovir increased proportionally with dose. The mean AUC24 values for ganciclovir were slightly higher following food (24 to 56%) than in the fasted state. Based on linear regression of AUC24 values from the fed group, a dose of valganciclovir of 900 mg/day is expected to produce a daily exposure (AUC24) comparable with an intravenous dose of ganciclovir 5 mg/kg/day. CONCLUSIONS: These results show that once daily oral valganciclovir can produce exposures of ganciclovir (AUC24) exceeding those attained using intravenous ganciclovir 10 mg/kg. This suggests that oral valganciclovir may be suitable in many circumstances currently requiring intravenous ganciclovir, allowing for more convenience in the management of patients with CMV retinitis by utilising a 2 or 4 tablet daily regimen to cover all phases of treatment.     

Survival differences associated with treatment of cytomegalovirus retinitis in Maryland patients with AIDS, 1987-1994.

Differences in survival related to treatment of cytomegalovirus (CMV) retinitis in AIDS patients were studied. The medical records of adult AIDS patients who had been diagnosed with CMV retinitis in a Maryland inpatient facility between September 1987 and September 1994 were reviewed to assess determinants of survival, including treatment with ganciclovir and foscarnet, use of zidovudine, and demographic characteristics. The review was based on inpatient and outpatient medical records and computerized data from the Maryland HIV Information System. Of 212 AIDS patients with CMV retinitis, 123 (58.0%) were treated exclusively with ganciclovir, 55 (25.9%) received foscarnet only, and the remaining 34 (16.1%) received both ganciclovir and foscarnet at some point after their diagnosis for CMV retinitis. Patients who received both drugs survived significantly longer after the diagnosis than patients who received either drug by itself. The median time from diagnosis of CMV retinitis to death was 464 days for patients receiving both drugs, 225 days for ganciclovir recipients, and 202 days for foscarnet recipients. Other positive predictors of survival were male sex and use of zidovudine. Among Maryland adults with AIDS who were treated for CMV retinitis between September 1987 and September 1994, the most common treatment for the eye infection was ganciclovir. Patients receiving both ganciclovir and foscarnet survived longer than those treated with either drug alone.