REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES

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GANCICLOVIR 

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1.) Oral ganciclovir for the prevention of cytomegalovirus disease inpersons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. 

2.) Oral ganciclovir as maintenance treatment for cytomegalovirus retinitisin patients with AIDS. Syntex Cooperative Oral Ganciclovir 

3.) Absence of teratogenicity of oral ganciclovir used during earlypregnancy in a liver transplant recipient. 

4.) Clinical course of cytomegalovirus (CMV) viremia with and withoutganciclovir treatment in CMV-seropositive kidney transplant recipients.Longitudinal follow-up of CMV pp65 antigenemia assay. 

5.) A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation. 

6.) Foscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after allogeneic hematopoietic stem cell transplantation (HSCT): a randomised study. 

7.) Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. 

8.) Superior cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D- arabinofuranosil thymine in herpes simplex virus-thymidine kinase-expressing cells: a novel paradigm for cell killing. 

9.) High-dose (2000-microgram) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis. 

10.) Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis. 

11.) The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS. 

12.) Metabolism of ganciclovir and cidofovir in cells infected with drug-resistant and wild-type strains of murine cytomegalovirus. 

13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis. 

14.) Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group. 

15.) Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. 

16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and AIDS treated with oral or intravenous ganciclovir. 

17.) The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients. 

18.) GANCICLOVIR (Systemic) The product 

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CIDOFOVIR 

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19.) Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis. 

20.) Bioavailability and metabolism of cidofovir following topical administration to rabbits. 

21.) Cidofovir: a new therapy for cytomegalovirus retinitis. 

22.) Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of Ocular complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. 

23.) Cidofovir and experimental herpetic stromal disease. 

24.) Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. 

25.) Cidofovir in the treatment of cytomegaloviral disease. 

26.) Antitumor potential of acyclic nucleoside phosphonates. 

27.) Clinical uses of cidofovir. 

28.) Characterization of the DNA polymerase and thymidine kinase genesof herpes 

simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed. 

29.) A case study: the use of cidofovir for the management of progressive multifocal leukoencephalopathy. 

30.) Antiinfectives update: focus on treatment and prevention of viral and associated infections. 

31.) Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents. 

32.)Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa) xenografts in athymic nude mice. 

33.) Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines. 

34.) Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. 

35.) Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. 

36.) Topical and intralesional cidofovir: a review of pharmacology and therapeutic effects. 

37.) Treatment of classical Kaposi's sarcoma with intralesional injections of cidofovir: report of a case. 

38.) Selective inhibition of human papillomavirus-induced cell proliferation by (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine. 

39.) Resistance of human cytomegalovirus to antiviral drugs. 

40.) Comparative antiviral efficacies of cidofovir, trifluridine, and acyclovir in the HSV-1 rabbit keratitis model. 

41.) [Human herpesvirus 8 (HHV8). II. Pathogenic role and sensitivity toantiviral drugs]. 

42.) Inhibitory effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus replication. 

43.) Comparison of antiviral compounds against human herpesvirus 6 and 7. 

44.) [Advances in the diagnosis and treatment of infections caused by herpesvirus and JC virus]. 

45.) A multicenter phase I/II dose escalation study of single-dose cidofovir gel for treatment of recurrent genital herpes. 

46.) Cidofovir use in acyclovir-resistant herpes infection. 

47.) A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. 

48.) Isolation of human adenovirus type 5 variants resistant to the antiviral cidofovir. 

49.) Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options. 

50.) Topical cidofovir for severe molluscum contagiosum. 

51.) Abatement of cutaneous Kaposi's sarcoma associated with cidofovir treatment. 

52.) Treatment of verruca vulgaris with topical cidofovir. 

53.) Topical cidofovir for severe molluscum contagiosum. 

54.) CIDOFOVIR, The product 

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GANCICLOVIR 

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1.) Oral ganciclovir for the prevention of cytomegalovirus disease in 

persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. 

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Journal: N Engl J Med 334:1491-7, 1996 

Publication Date: 1996 June 6 

Author(s): Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk R, Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W, Wong R, Stempien M 

Abstract: 

BACKGROUND. In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. 

METHODS. We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo. 

RESULTS. The study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent). 

CONCLUSIONS. In persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease. 

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2.) Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis  in patients with AIDS. Syntex Cooperative Oral Ganciclovir 

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Study Group (see comments) 

Journal: N Engl J Med 333:615-20, 1995 

Publication Date: 1995 September 7 

Author(s): Drew WL, Ives D, Lalezari JP, Crumpacker C, Follansbee SE, 

Spector SA, Benson CA, Friedberg DN, Hubbard L, Stempien MJ, et al 

Abstract: 

BACKGROUND. Cytomegalovirus retinitis, a sight-threatening infection  associated with the acquired immunodeficiency syndrome (AIDS), currently  requires lifelong intravenous treatment. An effective oral treatment would  be an important advance. 

METHODS. We compared oral with intravenous ganciclovir in an open-label, randomized study in patients with AIDS and newly diagnosed, stable cytomegalovirus retinitis (the disease was stabilized by three weeks of treatment with intravenous ganciclovir). Sixty subjects were randomly assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 mg per kilogram of body weight daily, and 63 to maintenance therapy with oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for up to 20 weeks, with photography of the fundi conducted every other week. The photographs were evaluated at the completion of the study by an experienced grader who was unaware of the subjects' treatment assignments. 

RESULTS. Efficacy could be evaluated in 117 subjects; photographs were ungradable for 2 of the 117. On the basis of the masked assessment of photographs from 115 subjects, the mean time to the progression of retinitis was 62 days in those given intravenous ganciclovir and 57 days in those given oral ganciclovir (P = 0.63; relative risk (oral vs. intravenous), 1.08; 95 percent confidence interval for the difference in means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who were aware of the subjects' treatment assignments, the mean time to progression was 96 days in subjects given intravenous ganciclovir and 68 days in subjects given oral ganciclovir (P = 0.03; relative risk (oral vs. intravenous), 1.68; 95 percent confidence interval for the difference in means, -45 to -11 days). Survival, changes in visual acuity, the incidence of viral shedding, and the incidence of adverse gastrointestinal events were similar in the two groups. Neutropenia, anemia,  intravenous-catheter-related adverse events, and sepsis were more common in  the group given intravenous ganciclovir. 

CONCLUSIONS. Oral ganciclovir is safe and effective as maintenance therapy for cytomegalovirus retinitis and is more convenient for patients to take  than intravenous ganciclovir. 

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3.) Absence of teratogenicity of oral ganciclovir used during early  pregnancy in a liver transplant recipient. 

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Transplantation 1999 Mar 15;67(5):758-9 

Pescovitz MD 

Department of Surgery, Indiana University, Indianapolis 46202-5253, USA. 

BACKGROUND: Ganciclovir (GCV) is effective for prevention of  cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity.  There is little information on the effect of GCV on a human fetus.

METHODS:  The chart of a liver transplant recipient who received oral GCV during the  first trimester was reviewed as was the published literature.

RESULTS:  There was no evidence of teratogenicity in the baby or in a case reported 

elsewhere.

CONCLUSIONS: GCV has been used in a few female transplant  recipients without untoward effects. The still uncertain risk of short term  and long term teratogenicity, however, must be weighed against the risk of  CMV disease in the recipient and the development of congenital CMV in the  baby. 

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4.) Clinical course of cytomegalovirus (CMV) viremia with and without  ganciclovir treatment in CMV-seropositive kidney transplant recipients.  Longitudinal follow-up of CMV pp65 antigenemia assay. 

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Author 

Yang CW; Kim YO; Kim YS; Kim SY; Moon IS; Ahn HJ; Koh YB; Bang BK 

Address 

Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's Hospital, Catholic University Medical College, Seoul, South Korea. 

Source 

Am J Nephrol, 18(5):373-8 1998 

Abstract 

This study was designed to evaluate the longitudinal history of  cytomegalovirus (CMV) infection and to test the capacity of ganciclovir as  effective therapy in CMV-seropositive renal transplant recipients. The CMV  viremia was detected with CMV pp65 antigenemia assay in 153 renal  transplants. The recipients were classified as having low-grade and  high-grade CMV infections according to the severity of CMV infection. The  recipients with low-grade CMV infections were observed without ganciclovir  treatment, and the recipients with high-grade CMV infection were randomly  assigned to ganciclovir-treated and untreated groups.

The clinical course  between low-grade and high-grade CMV infections was evaluated. All  recipients with low-grade CMV infection (n = 62) showed spontaneous  remission regardless of immunosuppresants. In high-grade CMV infection (n =  31), the ciclosporin A treated group (n = 11) showed no evidence of CMV  disease, and the methylprednisolone-treated group (n = 8) showed CMV  disease in 1 (25%) of 4 ganciclovir-untreated recipients. In the OKT3 group  (n = 12), symptomatic CMV infection was observed in 6 (100%)  ganciclovir-untreated recipients contrary to no CMV disease in the  ganciclovir-treated group (p < 0.05). In conclusion, the CMV antigenemia  assay is effective in monitoring CMV viremia, and ganciclovir treatment  should be done during early CMV viremia in OKT3-treated recipients. 

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5.) A study of the pharmacokinetics, antiviral activity, and tolerability of  oral ganciclovir for CMV prophylaxis in marrow transplantation. 

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Author 

Boeckh M; Zaia JA; Jung D; Skettino S; Chauncey TR; Bowden RA 

Address 

Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. 

Source 

Biol Blood Marrow Transplant, 4(1):13-9 1998 

Abstract 

Oral ganciclovir is effective in preventing cytomegalovirus (CMV) disease in HIV-infected patients despite a bioavailability of only 6-9%. To determine safety, pharmacokinetics, and the influence of acute  gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability  and antiviral effect of oral ganciclovir after marrow transplantation, CMV  seropositive patients received oral ganciclovir (1000 mg 3 times per day)  from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose  (intravenous and oral) and steady-state oral pharmacokinetic profiles and  weekly trough levels were performed.

Twenty-one patients received oral  ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state  pharmacokinetic profiles and seven had single-dose profiles. The absolute  bioavailability was similar in patients with or without acute GI-GVHD (7.2  vs. 6.9%). At steady state, the extent and rate of absorption of oral  ganciclovir were comparable in these same patient subgroups (area under the  curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum  ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough  CMV antigenemia, viremia, or plasma polymerase chain reaction positivity  occurred in eight of 21 (38%) patients (four of seven with GVHD and four of  14 without). Drug discontinuation because of GI adverse effects was  required in six of 21 (29%) patients.

Neutropenia occurred in two of 15  (13%) patients who had received oral ganciclovir for more than 10 days. In  conclusion, the bioavailability of oral ganciclovir seems similar to that  reported in other settings. The presence of acute GVHD of the GI tract did  not appear to adversely affect absorption of oral ganciclovir. The use of  oral ganciclovir was limited by the presence of GI intolerance in the early  posttransplant period. The efficacy of oral ganciclovir in preventing CMV  infection in marrow transplant recipients is being assessed in a separate  randomized controlled trial. 

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6.) Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after  allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study. 

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Author 

Moretti S; Zikos P; Van Lint MT; Tedone E; Occhini D; Gualandi F; 

Lamparelli T; Mordini N; Berisso G; Bregante S; Bruno B; Bacigalupo A 

Address 

Divisione Ematologia II, Ospedale San Martino, Genova, Italy. 

Source 

Bone Marrow Transplant, 22(2):175-80 1998 Jul 

Abstract 

This trial was designed to compare foscarnet with ganciclovir as pre-emptive therapy for CMV infection in patients undergoing allogeneic hemopoietic stem cell transplant (HSCT).

Thirty-nine patients were randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 5 mg/kg every 12 h (n = 19) for 15 days at the time of development of CMVAg-emia. Primary-end points of the study were

(1) outcome of CMVAg-emia; 

(2) progression to CMV disease; and (3) side-effects of treatment. The secondary end-point was transplant-related mortality (TRM). The two groups were comparable for diagnosis, status of disease, donor type, acute graft-versus-host (aGVHD) prophylaxis, interval between HSCT and CMVAg-emia and number of CMVAg positive cells; the donor and recipient age were borderline older in the foscarnet group.

Increments of serum creatinine in the foscarnet group, and cytopenia in the ganciclovir group were controlled by reducing the administered dose: in the first 15 days of therapy 9/20  foscarnet and 10/19 ganciclovir patients had a dose reduction greater than  20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group  although with borderline statistical significance. Failures of treatment  occurred in 3/20 patients in foscarnet group vs 8/19 patients in  ganciclovir group (P= 0.06): causes of failure were the need for  combination therapy to control antigenemia (1/20 vs 5/19), and reactivation  during treatment for 2 vs 3 patients, respectively. CMV disease was  diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial  1-year TRM was 25 vs 12%, respectively (P = 0.3).

This study suggests that  foscarnet and ganciclovir are both effective for pre-emptive therapy of  CMVAg-emia, although the number of failures would seem to be slightly  higher in the ganciclovir patients. Side-effects are seen in both groups  and can be managed with appropriate dose reduction. 

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7.) Ganciclovir. An update of its use in the prevention of cytomegalovirus  infection and disease in transplant recipients. 

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Author 

Noble S; Faulds D 

Address 

Adis International Limited, Auckland, New Zealand. 

Source 

Drugs, 56(1):115-46 1998 Jul 

Abstract 

Ganciclovir is a nucleoside analogue which is used to treat and prevent cytomegalovirus (CMV) infection. Most recent clinical studies of ganciclovir in transplant recipients have focused on preventive approaches. When ganciclovir was last reviewed in Drugs in 1994, substantial data on post-transplantation CMV prophylaxis with this drug were available only for patients undergoing allogeneic bone marrow transplantation (BMT). Two strategies had emerged: prophylaxis for all patients or early treatment started after detection of asymptomatic CMV infection. Subsequently, a large double-blind study has shown that ganciclovir prophylaxis is more effective than early treatment in preventing early CMV disease after allogeneic BMT and is not associated with an increased incidence of neutropenia. However, mortality for the 2 strategies was similar.

The efficacy of prophylactic intravenous ganciclovir in liver transplant recipients [including high risk donor seropositive/recipient seronegative (D+/R-) or antilymphocyte-treated patients] is now well established. Prophylaxis with oral ganciclovir was effective both overall and in D+/R-patients in a large placebo controlled study, and prolonged intravenous ganciclovir was significantly more effective than high dose aciclovir (acyclovir) in seropositive liver recipients.

Early treatment with ganciclovir has proved useful in this setting. More limited data indicate that CMV prophylaxis with intravenous ganciclovir may be useful after heart or lung transplantation but its value in D+/-patients remains unclear. Combined chemoimmunotherapy may be valuable in these high risk patients but controlled data are lacking. Targeted prophylaxis with intravenous ganciclovir is effective in renal transplant recipients receiving antilymphocyte therapy; the role of oral ganciclovir in this setting is less clear. The value of ganciclovir in D+/- renal transplant recipients and its efficacy compared with high dose aciclovir have not been  determined.

Conclusions: Ganciclovir is the only antiviral chemotherapy  which reduces the risk of CMV infection or disease after most types of  major transplantation. Unresolved issues include the best (and most  cost-effective) use of ganciclovir and aciclovir after allogeneic BMT, the  efficacy of oral ganciclovir compared with other anti-CMV regiments, the  potential clinical effect of viral resistance during prolonged ganciclovir  exposure and the value of ganciclovir in certain high risk transplant  populations. In the meantime, ganciclovir has an important role in the  prevention of CMV infection and disease after bone marrow and liver  transplantation and is likely to gain wider clinical use in heart, lung and  kidney transplant recipients. 

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8.) Superior cytotoxicity with ganciclovir compared with acyclovir and  1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine  kinase-expressing cells: a novel paradigm for cell killing. 

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Author 

Rubsam LZ; Davidson BL; Shewach DS 

Address 

Department of Pharmacology, University of Michigan Medical Center, Ann 

Arbor 48109-0504, USA. 

Source 

Cancer Res, 58(17):3873-82 1998 Sep 1 

Abstract 

Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine kinase (HSV-TK) has demonstrated excellent antitumor activity in many different types of malignant cells.

Previously, we noted that ganciclovir was substantially more cytotoxic than other HSV-TK substrates. Therefore, we embarked on a study to determine the basis for the superior cytotoxicity of ganciclovir. In U251tk human glioblastoma cells that stably express HSV-TK, ganciclovir elicited a >4 log cell kill instead of the < or =1.5 log cell kill mediated by two other HSV-TK substrates, 1-beta-D-arabinofuranosylthymine (araT) and acyclovir.

Study of the metabolism of these drugs demonstrated that acyclovir was poorly phosphorylated to its active triphosphate with DNA incorporation below the limit of detection, which may explain the < 1 log cell kill in these cells. Lower levels of ganciclovir triphosphate accumulated compared with araT triphosphate (araTTP) under conditions that induced < or =1 log cell kill (67 versus 1235 pmol/10(7) cells, respectively), and the half-life for the triphosphate of ganciclovir was shorter than that of araT (terminal half-lives of 15 and 41 h, respectively).

Incorporation of ganciclovir monophosphate into DNA was less than that of araT monophosphate, and both analogues were retained in DNA for > or =48 h. Thus, the superior cytotoxicity of ganciclovir was not due to enhanced metabolism to active forms. Highly cytotoxic concentrations of ganciclovir produced only weak inhibition of DNA synthesis.

This allowed cells to proceed through S and G2-M phases during and after drug exposure, resulting in a doubling of cell number by 48 h after drug washout. As they attempted to progress through the cell cycle a second time, ganciclovir-treated cells accumulated in early S-phase and remained there until cell death, suggesting that ganciclovir incorporation in the DNA template was important for cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP prevented cells from traversing the cell cycle for at least 12 h after drug washout, when the active metabolite was largely degraded araT-treated cells were unable to divide for at least 72 h after drug exposure, at which point  the surviving cells displayed a normal cell cycle distribution pattern. 

Based on the results presented here, we propose a novel paradigm in which  the ability of ganciclovir to incorporate into DNA without inhibiting  progression through S-phase, combined with high cytotoxicity for  incorporated ganciclovir monophosphate, produces multilog cytotoxicity. 

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9.) High-dose (2000-microgram) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis. 

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Author 

Young S; Morlet N; Besen G; Wiley CA; Jones P; Gold J; Li Y; Freeman WR; 

Coroneo MT 

Address 

Department of Ophthalmology, University of New South Wales, Sydney, 

Australia. 

Source 

Ophthalmology, 105(8):1404-10 1998 Aug 

Abstract 

OBJECTIVE: The authors prospectively studied visual outcome, relapse, complications, and survival of patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus (CMV) treated with high-dose  intravitreous ganciclovir (2 mg/0.1 ml) injections. The outcomes were  compared with those of patients treated with standard doses of intravenous  ganciclovir in the same institution. The histopathologic and  electrophysiologic effects of high-dose intravitreous ganciclovir  injections in rabbits also were studied.

DESIGN: A nonrandomized case  series.

PARTICIPANTS: A total of 42 patients (74 eyes) were treated with  intravitreous injections and 18 patients (27 eyes) were treated with  intravenous ganciclovir. Five eyes of three New Zealand white rabbits were  injected with ganciclovir, and the sixth eye was a control specimen.  INTERVENTION: Patients treated with intravitreous injections received  twice-weekly doses of 2 mg/0.1 ml ganciclovir for 3 weeks, then weekly  injections. Patients treated with intravenous ganciclovir received standard  doses. Patients were monitored with regular examinations. Rabbit eyes were  given intravitreous injections of 1 mg/0.1 ml of ganciclovir weekly for 4  weeks.

MAIN OUTCOME MEASURES: Assessments of vision, retinal inflammation,  and survival were made. Electroretinograms were performed on the rabbit  eyes, and they were processed for light and electron microscopy. RESULTS:  In the intravitreous group, visual acuity (VA) was stable in 64 of 74 eyes,  5 improved, and 5 deteriorated. Sixty-three (85%) of 74 eyes had final VA  of 20/20 to 20/40. Relapse occurred in five eyes (7%; median time, 42  weeks). There were three cases of endophthalmitis. Median survival after  diagnosis of CMV retinitis was 36 weeks. In the intravenous group, VA was  stable in 18 eyes, 0 improved, and 9 deteriorated. Sixteen (59%) of 27 eyes  had final VA of 20/20 to 20/40. Relapse occurred in 15 eyes (56%) at a  median time of 21 weeks. Median survival was 21 weeks. The rabbit studies  showed no evidence of toxicity.

CONCLUSION: High-dose intravitreous  ganciclovir effectively suppressed CMV retinitis, preserved vision, and  prevented relapse without deterioration in survival. 

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10.) Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis. 

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Author 

Bowen EF; Emery VC; Wilson P; Johnson MA; Davey CC; Sabin CA; Farmer D; 

Griffiths PD 

Address 

Department of Virology, Royal Free Hospital and School of Medicine, London, UK. 

Source 

AIDS, 12(6):605-11 1998 Apr 16 

Abstract 

OBJECTIVES: To determine whether recurrence of polymerase chain reaction (PCR) viraemia during maintenance ganciclovir for cytomegalovirus (CMV) retinitis correlates with (i) CMV disease at a new anatomical site, (ii) progression of the presenting retinitis, or (iii) acquisition of genetic changes in gene UL97 associated with resistance to ganciclovir.

DESIGN: A previously described cohort of 45 patients presenting with first episode retinitis was followed clinically using ophthalmoscopy and serial tests for PCR viraemia for a median of 7 months. CMV viral load and genetic markers of ganciclovir resistance were measured in PCR-positive samples. METHODS:  PCR amplification of the glycoprotein B region of CMV and quantitative  competitive PCR assays were employed. Genetic changes in UL97 were  identified by sequencing/point mutation assay.

RESULTS: PCR viraemia  correlated significantly with new episodes of CMV disease (P=0.011) and a  trend was seen for the association with progression of retinitis (P=0.07).  Amongst the 14 patients PCR-positive during maintenance ganciclovir, 10  (71%) had genetic markers of resistance. None of these patients became  PCR-negative in blood after reinduction ganciclovir therapy compared with  three out of four without markers of resistance (P=0.022).

CONCLUSIONS: CMV  PCR viraemia correlated strongly with the development of new episodes of  CMV disease. Most patients with progression of retinitis remained  PCR-negative in blood, consistent with therapeutic failure due to poor  intraocular penetration of ganciclovir. However, the minority who were  PCR-positive in blood may have reinfected their eye, and frequently had  markers of ganciclovir resistance. The implications of these findings for  the management of patients with CMV disease are discussed. 

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11.) The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS. 

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Author 

Ward-Able C; Phillips P; Tsoukas CM 

Address 

BioMed Business Unit of Hoffmann-La Roche (Canada), Mississauga, Ont. 

Source 

CMAJ, 154(3):363-8 1996 Feb 1 

Abstract 

OBJECTIVE: To recommend the appropriate use of oral ganciclovir as an alternative to intravenous (i.v.) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS.

OPTIONS: i.v. infusion of ganciclovir and foscarnet have been the only approved choices for maintenance therapy until the introduction of oral ganciclovir.

OUTCOMES: Ease of administering maintenance therapy and improved quality of life for patients with AIDS. VALUES: The medical advisory group comprised physicians treating patients with AIDS therapy. Ease of administration of maintenance  therapy and quality of patients' lives were considered important. BENEFITS,  HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to  i.v. maintenance therapy for patients with CMV retinitis. However, its low  bio-availability precludes its use for induction therapy and necessitates  careful monitoring for compliance. Compared with i.v. administration of  ganciclovir, oral maintenance therapy is cost effective.

EVIDENCE: Evidence  for the guidelines was gathered from data presented at a symposium on CMV  retinitis and oral ganciclovir, clinical trials of oral ganciclovir and  input from a visiting expert. It was presented at a meeting of the advisory  board whose members are involved in the care of patients with AIDS and the  management of CMV retinitis. The guidelines were approved by each member of  the advisory board.

RECOMMENDATIONS: Diagnosis, treatment and follow-up of  CMV retinitis should always be in consultation with an ophthalmologist who  is experienced in treating this disease. The patient should be fully  informed about the limitations of the oral form of ganciclovir; he or she  should be involved in decision making and carefully monitored. Oral  ganciclovir should not be used for induction therapy or for maintenance  therapy in high-risk patients.

VALIDATION: Similar guidelines have been  produced in England where the drug has been available since January 1995.  SPONSOR: The deliberations of the advisory board and the preparation of  this report were funded through an educational grant from Hoffmann-La Roche  (Canada). 

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12.) Metabolism of ganciclovir and cidofovir in cells infected with  drug-resistant and wild-type strains of murine cytomegalovirus. 

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Author 

Okleberry KM; Warren RP; Smee DF 

Address 

Institute for Antiviral Research, Utah State University, Logan, USA. 

Source 

Antiviral Res, 35(2):83-90 1997 Jul 

Abstract 

Murine cytomegalovirus (MCMV) has been used extensively as an animal model for human cytomegalovirus (HCMV).

Understanding drug resistance and its treatment in MCMV may lead to more effective treatments of HCMV disease. Most ganciclovir-resistant HCMV clinical isolates exhibit a decreased  capacity to induce ganciclovir phosphorylation (to its biologically active  form) in infected cells. Using an MCMV strain resistant to both ganciclovir  and cidofovir, the intracellular metabolism of these drugs was studied to  determine if MCMV resistance correlates with decreases in drug  phosphorylation.

The wild-type (WT) MCMV used for comparison was inhibited  in plaque reduction assays, by ganciclovir and cidofovir by 50% at 5.1 and  0.24 microM, respectively; the resistant strain was inhibited at 72 and 2.7  microM, respectively. In uninfected, WT, or resistant virus-infected cells,  the extent of metabolism of 10 microM ganciclovir or 1 microM cidofovir to  intracellular triphosphorylated species was similar. Phosphorylation and  catabolism (following drug removal) rates over time were also similar.  Intracellular levels of ganciclovir triphosphate and cidofovir diphosphate  increased less than two-fold with increasing multiplicity of virus  infection.

Because few differences in drug phosphorylation between WT and  resistant virus-infected cells were found, virus resistance to ganciclovir  and cidofovir apparently is not linked to altered drug phosphorylation.  Since the viral DNA polymerase is the antiviral target for these compounds,  the resistant MCMV is most likely a DNA polymerase mutant. 

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13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis. 

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Author 

Carroll NM; Chase M; Chiocca EA; Tanabe KK 

Address 

Department of Surgery, Massachusetts General Hospital, Boston 02114, USA. 

Source 

J Surg Res, 69(2):413-7 1997 May 

Abstract 

Entry of herpes simplex virus (HSV) into tumor cells results in viral gene expression followed by cellular lysis.

Attenuated HSVs selectively destroy tumors with sparing of surrounding normal tissue. HSV encodes a thymidine  kinase (TK) that converts ganciclovir to a toxic metabolite. This  metabolite may be transferred between cells and lead to the death of  neighboring uninfected cells, termed bystanders. We sought to determine if  HSV-mediated oncolysis is enhanced by ganciclovir treatment.

In addition,  we examined bystander killing in cocultures of TK transfectants and  parental cells. hrR3, an attenuated HSV, expresses TK. The 50% lethal dose  of hrR3 for a rat gliosarcoma (9L) and three human colorectal carcinomas  (HT29, KM12C6, and KM12L4) was determined. Cells were infected with a 50%  lethal dose of hrR3, followed by treatment with ganciclovir, and then cell  survival was quantitated.

In separate experiments 9L and HT29 cells were  transfected with TK. Parental cells and TK transfectants were cocultured in  various ratios, in the presence of ganciclovir, and cell survival was  quantitated. hrR3-mediated oncolysis was enhanced by ganciclovir in the  gliosarcoma but not in the three colorectal carcinomas. Cocultures of both  9L and HT29 parental cells with their corresponding TK transfectants  demonstrated bystander killing.

The mortality of 9L cocultures was 54%  greater than that predicted for exclusive killing of transfectants. HT29  mortality was 8% greater than predicted. The ability of ganciclovir to  augment hrR3-mediated oncolysis varies significantly between tumor cells  lines. The extent of ganciclovir-mediated killing of neighboring  nontransduced parental cells similarly varies. Consideration should be  given to these factors in the design of gene therapy strategies using HSV  vectors as oncolytic agents. 

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14.) Treatment of cytomegalovirus retinitis with a sustained-release  ganciclovir implant. The Ganciclovir Implant Study Group. 

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Author 

Musch DC; Martin DF; Gordon JF; Davis MD; Kuppermann BD 

Address 

Department of Ophthalmology, University of Michigan, Ann Arbor, USA. 

Source 

N Engl J Med, 337(2):83-90 1997 Jul 10 

Abstract 

BACKGROUND: Sustained-release, intraocular implants that deliver  ganciclovir are an alternative method for the treatment of cytomegalovirus  retinitis in patients with the acquired immunodeficiency syndrome (AIDS). 

METHODS: We conducted a randomized study of 188 patients with AIDS and  newly diagnosed cytomegalovirus retinitis. The patients were randomly  assigned to treatment with an implant delivering 1 microg of ganciclovir  per hour, an implant delivering 2 microg of ganciclovir per hour, or  intravenous ganciclovir.

The primary outcome we studied was progression of  cytomegalovirus retinitis.

RESULTS: The median time to progression of  retinitis was 221 days with the 1-microg-per-hour implant (75 eyes), 191  days with the 2-microg-per-hour implant (71 eyes), and 71 days with  ganciclovir administered intravenously (76 eyes; P<0.001). The risk of  progression of retinitis was almost three times as great among patients  treated with intravenous ganciclovir as among those treated with a  ganciclovir implant (risk ratio, 2.8; P<0.001). However, the risk of  disease in the initially uninvolved eye was lower with intravenous  ganciclovir than with a ganciclovir implant (risk ratio, 0.5; P=0.19).  Patients treated with intravenous ganciclovir were also less likely to have  extraocular cytomegalovirus infections (0, vs. 10.3 percent in the two  implant groups; P=0.04).

CONCLUSIONS: For the treatment of cytomegalovirus  retinitis, the sustained-release ganciclovir implant is more effective than  intravenous ganciclovir, but patients treated with a ganciclovir implant  alone remain at greater risk for the development of cytomegalovirus disease  outside of the treated eye. 

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15.) Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. 

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Author 

Griffy KG 

Address 

Roche Bioscience, Palo Alto, California, USA. 

Source 

AIDS, 10 Suppl 4():S3-6 1996 Dec 

Abstract 

OBJECTIVES: To delineate the pharmacokinetic profile of the oral capsule formulation of ganciclovir, and determine whether oral ganciclovir has any pharmacokinetics interactions with zidovudine, didanosine or probenecid. 

MEASUREMENTS: Serum and urine concentrations of ganciclovir, zidovudine and didanosine were measured. From these concentrations, standard pharmacokinetic parameters such as peak concentration, area under the curve (AUC), elimination half-life and renal clearance were determined.

RESULTS: The bioavailability of oral ganciclovir averages 6-9%. Inter- and intrasubject variability of AUC is low (coefficient of variation 21.8 and 12.6%, respectively). The steady-state AUCs achieved with oral ganciclovir (1000 mg three times daily or 500 mg six times daily) are approximately 70% of the AUC achieved with the daily maintenance dose of intravenous ganciclovir (5 mg/kg). Serum concentrations of ganciclovir are 20% higher when the oral formulation is administered with a high fat meal than when taken following an overnight fast. Serum concentrations of didanosine (200 mg every 12 h) are approximately doubled when taken in combination with  oral ganciclovir (1000 mg every 8 h).

CONCLUSIONS: Although bioavailability  of the oral formulation of ganciclovir is low, the serum concentrations are  predictable, with low inter- and intrasubject variability in peak  concentrations and AUC.

The two oral regimens studied (500 mg six times  daily or 1000 mg three times daily) have comparable bioavailability. Food  has a beneficial effect of increasing serum concentrations. There is a  potentially important pharmacokinetic interaction between oral ganciclovir  and didanosine. 

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16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and AIDS treated with oral or intravenous ganciclovir. 

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Author 

Drew WL; Stempien MJ; Andrews J; Shadman A; Tan SJ; Miner R; Buhles W 

Address 

Clinical Microbiology and Infectious Diseases, University of California at San Francisco-Mt. Zion Medical Center, San Francisco, CA, USA. drew@pangloss.ucsf.edu 

Source 

J Infect Dis, 179(6):1352-5 1999 Jun 

Abstract 

Treatment of cytomegalovirus (CMV) retinitis with oral ganciclovir results in relatively low plasma concentrations of drug, which theoretically could cause more frequent viral resistance compared with intravenous (iv) ganciclovir.

By use of a plaque-reduction assay to quantify phenotypic sensitivity to ganciclovir, virus isolates were studied from patients with CMV retinitis participating in four clinical trials of oral ganciclovir.  Before treatment, 69% of patients were culture-positive but just 1.1% of  patients yielded a resistant CMV, defined as a median inhibitory  concentration (IC50) >6 microM.

On treatment, the first resistant isolate  was recovered at 50 days. Overall, 3.1% of patients receiving iv  ganciclovir and 6. 5% of those taking oral ganciclovir shed resistant CMV  (median ganciclovir exposures of 75 and 165 days, respectively). Since  IC50s for clinical isolates increased proportionately with treatment  duration, it is likely that viral resistance would be more frequent with  longer treatment. 

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17.) The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients. 

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Author 

Jung D; AbdelHameed MH; Teitelbaum P; Dorr A; Griffy K 

Address 

Roche Global Development, Palo Alto, California, USA. 

Source 

J Clin Pharmacol, 39(5):505-12 1999 May 

Abstract 

Two open-label, randomized, multiple-dose, three-way crossover studies were  performed to assess the pharmacokinetics and safety of oral ganciclovir  1000 mg q8h in asymptomatic patients seropositive for human  immunodeficiency virus and cytomegalovirus. Ganciclovir was administered  alone and in combination with zalcitabine 0.75 mg q8h (study 1) or  stavudine 40 mg q12h (study 2).

In the presence of zalcitabine, the only  statistically significant change in the pharmacokinetic parameters of  ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no  significant change in the renal clearance of ganciclovir when  coadministered with zalcitabine, suggesting that the increase in serum  ganciclovir concentration cannot be attributed to competition for active  renal tubular secretion.

No change in zalcitabine pharmacokinetics was  observed in combination with ganciclovir. There were no significant changes  in the pharmacokinetics of ganciclovir or stavudine when coadministered.  Ganciclovir was well tolerated when given alone and in combination with  either zalcitabine or stavudine. 

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18.) GANCICLOVIR (Systemic) The product 

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Revised: 08/08/95 

VA CLASSIFICATION (Primary/Secondary);AM800 

Commonly used brand name(s): 

Cytovene; 

Cytovene-IV. 

Another commonly used name is DHPG 

Note: For a listing of dosage forms and brand names by country 

availability, see Dosage Forms section(s). 

Category 

Antiviral (systemic). 

Indications 

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling. 

Accepted 

Cytomegalovirus retinitis (treatment);Parenteral ganciclovir is indicated for induction and maintenance in the treatment of cytomegalovirus (CMV)  retinitis in immunocompromised patients, including patients with acquired  immunodeficiency syndrome (AIDS). Oral ganciclovir is indicated only for  the maintenance of CMV retinitis in patients who have had a complete  resolution of active retinitis after an induction course of parenteral  ganciclovir1,61; however, oral ganciclovir has been associated with a  shorter time to CMV retinitis progression.1,2,15,60,62 [Intravitreal  administration of ganciclovir has also been used in patients who have been  unresponsive to intravenous ganciclovir, or in whom serious  myelosuppression has precluded the continuation of intravenous  therapy.]29,31,34 

Cytomegalovirus disease (prophylaxis)*;Parenteral ganciclovir is indicated for the prophylaxis of CMV disease in transplant patients who are at risk for the disease.1,49,50,51,52,53,54 

[Cytomegalovirus disease (treatment)]*;Parenteral ganciclovir is used in the treatment of severe CMV disease, including CMV pneumonia, CMV gastrointestinal disease, and disseminated CMV infections, in immunocompromised patients.3,6,11,15,20 

[Polyradiculopathy (treatment)]*;Parenteral ganciclovir is used in the treatment of polyradiculopathy caused by CMV in patients with AIDS.38,39,40 

Resistance to ganciclovir has been reported. One paper described CMV  disease refractory to ganciclovir therapy due to infections with a  resistant virus, a susceptible virus that became resistant, and an  infection first by a susceptible strain, and later by a genetically  distinct, resistant one.26 The primary mechanism of resistance to  ganciclovir is the decreased ability to form the active triphosphate  moiety.1 Recurrence may be more frequent in patients treated with  ganciclovir for prolonged periods, (> 3 to 6 months).33,43 

*Not included in Canadian product labeling. 

Pharmacology/Pharmacokinetics 

Physicochemical characteristics: 

High pH (11).1 

Molecular weight;; 

Ganciclovir: 255.234 

Ganciclovir sodium: 277.224 

Mechanism of action/Effect: 

Ganciclovir is a prodrug6 that is structurally similar to acyclovir.8 Its antiviral activity results from its intracellular conversion to the  triphosphate form. In cytomegalovirus (CMV)-infected cells, ganciclovir is  thought to be rapidly phosphorylated to the monophosphate form by a  CMV-encoded enzyme63, then subsequently converted to the diphosphate and  triphosphate forms by cellular kinases. Ganciclovir is phosphorylated much  more rapidly in infected cells7; however, uninfected cells can also produce  low levels of ganciclovir-triphosphate.3Ganciclovir-triphosphate  competitively inhibits DNA polymerase by acting as a substrate and becoming  incorporated into the DNA.5 This inhibits DNA synthesis by suppressing DNA  chain elongation.5The drug inhibits viral DNA polymerases more effectively  than it does cellular polymerase.24 Chain elongation resumes when  ganciclovir is removed.5 

Absorption: 

Ganciclovir is poorly absorbed after oral administration; 

bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9%.1,15,59 

Distribution: 

Ganciclovir is widely distributed to all tissues and crosses the placenta15,58; however, there is no marked accumulation in any one type of tissue. Penetration into the cerebral spinal fluid averaged 38% in one study9, and ranged from 7 to 67% in others.10,22 Ganciclovir also appears to have good intraocular penetration.3 In one patient, the subretinal fluid ganciclovir concentration was 7.2 micromoles per L with a corresponding plasma concentration of 8.2 micromoles per L 5.5 hours after a dose of 5 mg per kg of body weight (mg/kg), and 2.58 micromoles per L with a  corresponding plasma concentration of 1.3 micromoles per L 8 hours after a  subsequent dose of 5 mg/kg.28 

VolD(steady state) ;Adults and neonates: Approximately 0.74 L per kg.1,57 

Protein binding: 

Low (1 to 2%).1 

Biotransformation: 

Little to no metabolism.3,6 

Half-life: 

Serum; 

Intravenous 

Adults;Normal renal function: 2.5 to 3.6 hours (average, 2.9 hours).1,3,6,7 

Adults;Renal function impairment: 9 to 30 hours (creatinine clearance of 20 to 50 mL per minute [0.33 to 0.83 mL per second]).15 

Neonates;Approximately 2.4 hours.1,57 

Oral: 

Normal renal function;3.1 to 5.5 hours.59 

Renal function impairment;15.7 to 18.2 hours (creatinine clearance of 10 to 50 mL per minute [0.17 to 0.83 mL per second]).1 

Vitreous fluid; Approximately 13 hours.34 

Time to peak concentration: 

Intravenous; 

End of infusion (approximately 1 hour).13 

Oral; 

Fasting: Approximately 1.8 hours.1 

With food: Approximately 3 hours.1 

Peak concentrations 

Intravenous; 

Adults: 5 mg/kg over 1 hour;8.3 to 9 mcg/mL.1 

Neonates: 4 and 6 mg/kg over 1 hour;Approximately 5.5 and 7 mcg/mL, 

respectively.1,57 

Oral; 

3 grams per day: 1 to 1.2 mcg/mL.1 

Intravitreal injection; 1000 mcg administered in 5 divided doses over 15 days: 16.2 mcg/mL; ganciclovir was not detected in plasma.15 

Elimination: 

Renal; almost 100% excreted unchanged in the urine by glomerular filtration and tubular secretion.1,9,11,15 

In dialysis;Plasma ganciclovir concentrations are reduced by approximately 50% after a single, 4-hour hemodialysis.1,12 

Precautions to Consider 

Cross-sensitivity and/or related problems 

Patients hypersensitive to acyclovir may also be hypersensitive to  ganciclovir because of the chemical similarity of the 2 medications.1,2 

Carcinogenicity/Tumorigenicity 

Ganciclovir is carcinogenic in animals and should be considered a potential carcinogen in humans. Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg per day (approximately 0.1 and 1.4 times, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on the area under the concentration-time curve [AUC]) comparisons. Mice given oral doses of 20 mg per kg of body weight (mg/kg) per day showed a slightly increased incidence of tumors in the preputial and harderian glands in males, forestomach in males and  females, and liver in females.

Studies in mice given oral doses of 1000  mg/kg per day showed an increased incidence of tumors of the forestomach in  males and females, preputial gland in males, and reproductive tissues and  liver in females. All ganciclovir-induced tumors were of epithelial or  vascular origin, except for histiocytic sarcoma of the liver. No  carcinogenic effect occurred at a dose of 1 mg/kg per day.1  Mutagenicity Ganciclovir was mutagenic in mouse lymphoma cells at concentrations between 50 and 500 mcg/mL, and caused chromosomal damage in vitro in human lymphocytes at concentrations between 250 and 2000 mcg/mL.

Parenteral ganciclovir was also clastogenic in the mouse micronucleus assay at doses of 150 and 500 mg/kg (2.8 to 10 times the human exposure based on area under the concentration-time curve [AUC] of a single intravenous dose of 5 mg/kg), but not at a dose of 50 mg/kg (exposure approximately comparable to the human dose based on AUC). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL.1 

Pregnancy/Reproduction 

Fertility;Although data in humans have not been obtained, temporary or permanent suppression of fertility in women and spermatogenesis in men may occur.1 

In female mice, ganciclovir caused decreased mating behavior, decreased fertility, and increased death in utero at doses approximately 1.7 times the recommended human dose (based on the AUC of a single intravenous dose of 5 mg/kg). Ganciclovir was also found to cause decreased fertility in male mice, and hypospermatogenesis in mice and dogs following daily oral or  intravenous administration of doses ranging from 0.2 to 10  mg/kg.1Inhibition of spermatogenesis and subsequent infertility was  reversible at lower doses and irreversible at higher doses in  animals.2Systemic drug exposure (as measured by AUC) at the lowest dose  showing toxicity in each species ranged from 0.03 to 0.1 times the AUC of  the recommended human intravenous dose.1 

Pregnancy;Adequate and well-controlled studies in humans have not been done. However, ganciclovir has been found to cross the placenta.15,58 Due to the high toxicity and mutagenic and teratogenic potential of ganciclovir, use during pregnancy should be avoided whenever possible. Women of childbearing age should use effective contraception. Men should use barrier contraception during, and for at least 90 days following,  treatment with ganciclovir.1 

Ganciclovir was found to be carcinogenic in animals and teratogenic in rabbits, causing cleft palate, anophthalmia/microphthalmia, aplastic organs (kidneys and pancreas), hydrocephaly, bradygnathia, and fetal growth retardation. It also was found to be embryotoxic in mice, and to cause death in utero and maternal toxicity in both rabbits and mice. Fetal resorptions occurred in at least 85% of rabbits and mice administered 60 mg/kg per day and 108 mg/kg per day (2 times the human exposure based on AUC comparisons), respectively. Daily intravenous doses of 90 mg/kg  administered to female mice prior to mating, during gestation, and during  lactation caused hypoplasia of the testes and seminal vesicles in the  month-old male offspring, as well as pathologic changes in the nonglandular  region of the stomach. The drug exposure in mice as estimated by the AUC  was approximately 1.7 times the human AUC.1 

FDA Pregnancy Category C. 

Breast-feeding 

It is not known whether ganciclovir is distributed into breast milk1; however, it is likely that some drug will accumulate because of its pharmacokinetic properties.35 Because of the potential for serious adverse effects in nursing infants, breast-feeding should be stopped during ganciclovir therapy.1 Ganciclovir has caused irreversible toxicity in nursing animal pups.14 

Pediatrics 

There is little information currently available on the use of ganciclovir in children, especially those up to the age of 12. At this time, the side effects seen in children appear to be similar to those seen in adults, especially granulocytopenia (17%) and thrombocytopenia (10%). However, the probability of long-term carcinogenicity and reproductive toxicity seen in animal studies should also be considered.1 Geriatrics 

No information is available on the relationship of age to the effects of ganciclovir in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage or dosing interval in patients receiving ganciclovir.1,2 

Dental 

The neutropenic and thrombocytopenic effects of ganciclovir may result in 

an increased incidence of microbial infection, delayed healing, and  gingival bleeding. Patients should be instructed in proper oral hygiene,  including caution in use of regular toothbrushes, dental floss, and  toothpicks. 

Drug interactions and/or related problems 

The following drug interactions and/or related problems have been selected  on the basis of their potential clinical significance (possible mechanism  in parentheses where appropriate);not necessarily inclusive (>> = major clinical significance): 

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. 

Blood dyscrasia-causing medications (See Appendix II) or >> Bone marrow depressants, other (See Appendix II) or Radiation therapy1;(concurrent use with ganciclovir may increase the bone marrow-depressant effects of these medications and radiation therapy) 

Didanosine;(concurrent and sequential [2 hours apart] administration of didanosine with ganciclovir results in a significant increase in the steady-state area under the concentration-time curve [AUC] of didanosine [range, 72 to 111%]1,19,21; when didanosine was administered 2 hours before oral ganciclovir, the steady-state AUC of ganciclovir was decreased by approximately 21%1; there was no significant change in renal clearance of either medication1) Imipenem and cilastatin combination1,2;(generalized seizures have been reported in patients receiving ganciclovir and imipenem and cilastatin combination concurrently)

 >> Nephrotoxic medications (See Appendix II)1;(concurrent use with ganciclovir may increase serum creatinine; concurrent use with nephrotoxic medications, such as cyclosporine or amphotericin B, may increase the chance of renal function impairment; this may also decrease elimination of ganciclovir and increase the risk of toxicity) 

Probenecid;(concurrent use with probenecid increases the AUC of ganciclovir by approximately 53%21 and decreases its renal clearance by approximately 22%1; concurrent use of ganciclovir with probenecid, or other medications that inhibit renal tubular secretion, may reduce the renal clearance of ganciclovir and lead to toxicity1,21) 

>> Zidovudine1,2,16,18;(concurrent use of ganciclovir with zidovudine has been associated with severe hematologic toxicity in some patients, even when the zidovudine dose was reduced to 300 mg per day37; concurrent use increases the AUC of zidovudine by approximately 14 to 19%1,21; in vitrostudies found concurrent use of these 2 drugs to be synergistically cytotoxic48; concurrent administration should be used with caution) 

Laboratory value alterations 

The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate);not necessarily inclusive (>> = major clinical significance): With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]), serum and Alkaline phosphatase, serum and Aspartate aminotransferase (AST [SGOT]), serum and Bilirubin, serum;(values may be increased1,2,3,13,17) Blood urea nitrogen (BUN) or Creatinine, serum;(values may be increased1,2)  Medical considerations/Contraindications 

The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in  parentheses where appropriate);not necessarily inclusive (>> = major  clinical significance). 

Risk-benefit should be considered when the following medical problems exist 

>> Absolute neutrophil count (ANC) <500 cells/mm3 or platelet count <25,000 cells/mm31; 

>> Hypersensitivity to acyclovir or ganciclovir1; 

>> Renal function impairment1,3,6;(because ganciclovir is excreted through  the kidneys, the dose of ganciclovir should be reduced or the dosing  interval increased in patients with renal function impairment) 

Patient monitoring 

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; >> = major clinical significance): 

>> Complete blood counts (CBCs) and >> Platelet counts1,2,3,11,13,45,46,47;(because ganciclovir may cause  granulocytopenia and thrombocytopenia, neutrophil and platelet counts  should be monitored prior to treatment, every 2 days during induction  therapy, then at least weekly thereafter. Neutrophil and platelet counts  should be performed daily in patients undergoing hemodialysis, patients  with neutrophil counts less than 1000 cells/mm3 at the beginning of  treatment, and those in whom use of ganciclovir or other nucleoside analogs  previously resulted in leukopenia. When severe neutropenia [absolute  neutrophil count < 500 cells/mm3] or severe thromboctyopenia [platelet  count < 25,000 cells/mm3] occurs, discontinuation of ganciclovir may be  necessary; however, a small number of patients have been successfully  treated with concurrent use of sargramostim [GM-CSF; granulocyte-macrophage  colony stimulating factor] or filgrastin [G-CSF; granulocyte colony  stimulating factor]61) 

Liver function tests15,17;(liver function tests, including serum ALT [SGPT] and AST [SGOT] values, and serum bilirubin concentration, should be monitored periodically since elevations, usually reversible, have occurred during ganciclovir therapy) 

>> Renal function determinations1;(blood urea nitrogen and serum creatinine determinations should be monitored at least every 2 weeks since patients with renal function impairment will require an adjustment in dosage or dosage interval) 

For treatment of cytomegalovirus [CMV] retinitis, in addition to the above 

>> Ophthalmologic examinations30,61,64;(ophthalmologic examinations should be performed weekly during induction and every 4 weeks during maintenance since ganciclovir is not a cure for cytomegalovirus [CMV] retinitis, and progression of retinitis may occur during or following ganciclovir treatment; however, the frequency of examinations may vary, depending on the extent of disease, activity, and proximity to the macula and optic disc) 

Side/Adverse Effects 

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate);not necessarily inclusive:  Those indicating need for medical attention 

Incidence more frequent 

For intravenous and oral administration  Granulocytopenia (sore throat and fever)1,3,6,24,59; thrombocytopenia  (unusual bleeding or bruising)1,3,6,7,24,32,59 

Note: Granulocytopenia is usually reversible, with an overall incidence of  approximately 40%1,2,3,6; the incidence of dose-limiting toxicity is <20%.24 

Thrombocytopenia is also usually reversible, with an overall incidence of approximately 20%1,2,3,6,7; the incidence of dose-limiting toxicity is 5 to 10%.24,32 

Incidence less frequent 

For intravenous and oral administration Anemia (unusual tiredness and weakness)1,2,59; central nervous system (CNS) effects (mood or other mental changes; nervousness; tremor)1,3,6,13,41; hypersensitivity (fever; skin rash)1,2,59phlebitis (pain at site of injection)1,3,6 

For intravitreal administration35 Bacterial endophthalmitis; conjunctival scarring, mild; foreign body sensation; retinal detachment; scleral induration; or subconjunctival hemorrhage (decreased vision or any change in vision) 

Those indicating need for medical attention only if they continue or are bothersome 

Incidence less frequent  Gastrointestinal disturbances (abdominal pain; loss of appetite; nausea  and vomiting)1,2,6,7,59 

Patient Consultation 

As an aid to patient consultation, refer to Advice for the Patient, Ganciclovir (Systemic). 

In providing consultation, consider emphasizing the following selected information (>> = major clinical significance): 

Before using this medication 

>> Conditions affecting use, especially: 

Hypersensitivity to acyclovir or ganciclovir 

Pregnancy; Use of ganciclovir during pregnancy should be avoided whenever possible. Ganciclovir crosses the placenta and has been found to be carcinogenic and teratogenic in animals. Use of effective contraception by men and women who are undergoing treatment and in men for 90 days following treatment is recommended 

Breast-feeding; Because of ganciclovir's potential for severe toxicity, breast-feeding should be stopped during therapy 

Use in children;There is little information currently available on the use  of ganciclovir in children, especially those up to the age of 12; long-term  carcinogenicity and reproductive toxicity due to ganciclovir use in  children is unknown 

Dental;The neutropenic and thrombocytopenic effects of ganciclovir may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding 

Other medications, especially other bone marrow depressants, nephrotoxic medications, or zidovudine 

Other medical problems, especially renal function impairment, an absolute  neutrophil count (ANC) <500 cells/mm3, or platelet count <25,000 cells/mm3 

Proper use of this medication 

>> Taking ganciclovir capsules with food 

>> Importance of receiving medication for full course of therapy and on a regular schedule 

>> Proper dosing 

Precautions while using this medication 

To reduce the risk of bleeding during periods of low blood counts: >> Checking with physician immediately if getting an infection or fever or chills 

>> Checking with physician immediately if unusual bleeding or bruising;  black, tarry stools; blood in urine or stools; or pinpoint red spots on  skin occur 

Using caution in use of regular toothbrushes, dental floss, and toothpicks; physician, dentist, or nurse may suggest alternative methods for cleaning teeth and gums; checking with physician before having dental work done 

Using caution to avoid accidental cuts with use of sharp objects such as a safety razor or fingernail or toenail cutters 

>> Using contraception since ganciclovir has mutagenic and teratogenic potential; women should use effective contraception during treatment, and men should use barrier contraception during and for at least 90 days following treatment1 

>> Regular visits to physician to check blood counts 

>> For CMV retinitis;Regular visits to ophthalmologist to examine eyes since progression of retinitis and visual loss may occur during ganciclovir  therapy 

Side/adverse effects 

Signs of potential side effects, especially granulocytopenia, thrombocytopenia, anemia, CNS effects, hypersensitivity, and phlebitis when ganciclovir is administered intravenously or orally; and bacterial endophthalmitis, mild conjunctival scarring, foreign body sensation, retinal detachment, scleral induration, and subconjunctival hemorrhage when it is administered intravitreally 

General Dosing Information 

Ganciclovir is not a cure for cytomegalovirus infections. Maintenance  therapy is almost always necessary in AIDS patients to prevent relapse,  which is very common once the medication has been withdrawn.1 

Monitoring of serum ganciclovir concentrations has not been shown to be  useful for ensuring efficacy or avoiding toxicity.24 

Ganciclovir sodium should be administered by intravenous infusion only.  Intramuscular or subcutaneous injection will result in severe tissue  irritation due to ganciclovir's high pH (11).1,2 

Intravenous infusions of ganciclovir should be administered at a constant rate over at least a 1-hour period, and patients must be adequately hydrated, to avoid increased toxicity. The recommended dosage, frequency, and infusion rate should not be exceeded.1 

Severe neutropenia or thrombocytopenia (absolute neutrophil count [ANC] <500 cells/mm3 or platelet count <25,000 cells/mm3) requires an interruption in therapy until there is evidence of bone marrow recovery (ANC &sup3;750 cells/mm3); however, a small number of patients have been successfully treated with concurrent use of sargramostim (GM-CSF;  granulocyte-macrophage colony stimulating factor).45,46,47 

Ganciclovir capsules should be taken with food for maximum absorption.1 

The dose of ganciclovir must be decreased in patients with renal function impairment. 

Patients undergoing hemodialysis should not receive a dose in excess of 1.25 mg per kg of body weight (mg/kg) every 24 hours. On dialysis days, the dose of ganciclovir should be administered after hemodialysis has been performed since dialysis will reduce plasma ganciclovir concentrations by approximately 50%.1,2 

Ganciclovir capsules are indicated as an alternative to intravenous  ganciclovir for maintenance therapy of CMV retinitis in immunocompromised  patients, including those with AIDS. Oral ganciclovir should be used in  patients in whom retinitis is stable and quiescent following appropriate  induction therapy and for whom the risk of more rapid progression is  balanced by the benefit associated with avoiding long-term daily intravenous infusions, usually requiring indwelling intravenous catheters.1 

Intravitreal administration of ganciclovir has been used in patients who have been unresponsive to intravenous ganciclovir, or in whom serious myelosuppression has precluded the continuation of intravenous therapy. Intravitreal doses of 200 micrograms have resulted in improvement or stabilization of retinitis, and have been well tolerated. In one report describing a patient who received 28 intravitreal injections, plasma concentrations after intravitreal injections showed no significant systemic absorption. The elimination half-life of ganciclovir from the vitreous fluid was estimated to be 13.3 hours, and the intravitreal concentration remained above the ID 50 of cytomegalovirus for approximately 62 hours after a single injection.29,31,34 

Safety considerations for handling this medication 

Caution should be exercised in the handling and preparation of ganciclovir. Because ganciclovir shares some properties of anti-tumor agents (i.e., carcinogenicity and mutagenicity), it should be handled and disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct contact of ganciclovir with the skin or mucous membranes. If contact does occur, wash area thoroughly with soap and water; rinse eyes thoroughly with plain water.42 Ganciclovir capsules should not be opened or crushed.1 

Oral Dosage Forms 

GANCICLOVIR CAPSULES 

Usual adult and adolescent dose 

Cytomegalovirus retinitis; 

Induction: Ganciclovir capsules should not be used for induction therapy. See Sterile Ganciclovir Sodium1 

Maintenance: Oral, 1000 mg three times a day with food, or 500 mg six times a day every three hours with food, during waking hours.1 

Note: For maintenance, patients with impaired renal function may require a  reduction in dose as follows:1,3,12 

Creatinine Clearance (mL/min)/(mL/sec) Dose 

sup3;70/1.17 See Usual adult and  adolescent dose 50-69/0.83-1.15 1500 mg once a day, or 500 mg three times a day 25-49/0.42-0.82 1000 mg once a day, or 500 mg twice a day 10-24/0.17-0.40 500 mg once a day <10/0.17 500 mg three times a week, following hemodialysis 

Usual pediatric dose 

Dosage has not been established.1 

Strength(s) usually available 

U.S.; 250 mg (Rx)[Cytovene]. 

Canada; Not commercially available. 

Packaging and storage: 

Store below 40 &deg;C (104 &deg;F), preferably between 15 and 30 &deg;C (59 and 86 &deg;F), unless otherwise specified by manufacturer. 

Auxiliary labeling: 

middot; Continue medicine for full time of treatment. 

Note: Ganciclovir capsules should not be opened or crushed. 

Parenteral Dosage Forms 

GANCICLOVIR SODIUM STERILE 

Usual adult and adolescent dose 

Cytomegalovirus retinitis (treatment); 

Induction; Intravenous infusion, 5 mg per kg of body weight, administered over at least one hour, every twelve hours for fourteen to twenty-one days.1,2,3,6,8,20 Note: Doses of 7.5 to 15 mg per kg of body weight per day divided into two or three doses have been used, and treatment has been continued for longer than twenty-one days; if retinitis does not show significant improvement, the possibility of viral resistance should be considered.32 

Intravitreal injection, 200 mcg two times a week for three weeks.35,44 

Note: For induction, patients with impaired renal function may require a reduction in dose as follows1: 

Creatinine Clearance (mL/min)/(mL/sec) Dose 

sup3;70/1.17 See Usual adult and adolescent dose  50-69/0.83-1.15 2.5 mg per kg every twelve hours 25-49/0.42-0.82 2.5 mg per kg every twenty-four hours 10-24/0.17-0.40 1.25 mg per kg every twenty-four hours <10 1.25 mg per kg three times a week, following hemodialysis 

Maintenance; 

Intravenous infusion, 5 mg per kg of body weight a day, administered over  at least one hour, once a day for seven days per week; or 6 mg per kg of  body weight, administered over at least one hour, once a day for five days  of the week.1,2,3,6 

Note: If CMV retinitis progresses during maintenance therapy, patients should be retreated with the twice-a-day induction regimen. 

Intravitreal injection, 200 mcg once a week.35,36 

Note: For maintenance, patients with impaired renal function may require a reduction in dose as follows1: 

Creatinine Clearance (mL/min)/(mL/sec) Dose &sup3;70/1.17 See Usual adult and adolescent dose 

50-69/0.83-1.15 2.5 mg per kg every twelve hours 25-49/0.42-0.82 1.25 mg per kg every twenty-four hours 10-24/0.17-0.40 0.625 mg per kg every twenty-four hours  <10 0.625 mg per kg three times a week, following hemodialysis 

Cytomegalovirus disease (prophylaxis); Intravenous infusion, 5 mg per kg of body weight, administered over at least one hour, every twelve hours for seven to fourteen days; then 5 mg per kg of body weight, administered over at least one hour, once a day for seven days of the week, or 6 mg per kg of body weight, administered over at  least one hour, once a day for five days of the week.49 

Usual pediatric dose 

Dosage has not been established. However, induction doses of 7.5 to 10 mg per kg of body weight divided into two or three doses, and maintenance doses of 2.5 to 5 mg per kg of body weight a day have been used in children.25,27,28,32 

Strength(s) usually available U.S.; 500 mg (Rx)[Cytovene-IV (sodium 46 mg)]. 

Canada; 500 mg (Rx)[Cytovene]. 

Packaging and storage: 

Store below 40 deg;C (104 deg;F), preferably between 15 and 30 deg;C (59 and 86 deg;F), unless otherwise specified by manufacturer. 

Preparation of dosage form: 

To prepare initial dilution for intravenous infusion, 10 mL of sterile water for injection (without parabens) should be added to each 500-mg vial to provide 50 mg per mL. To ensure complete dissolution, the vial should be shaken until solution is clear. The resulting solution should be further diluted, usually with 100 mL of 0.9% sodium chloride injection, 5% dextrose  injection, Ringer's injection, or lactated Ringer's injection. Final  concentrations of 10 mg per mL or less are recommended.2,23 

Note: Caution should be exercised in the handling and preparation of  ganciclovir. Because ganciclovir shares some properties of anti-tumor  agents (i.e., carcinogenicity and mutagenicity), it should be handled and  disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir  solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct  contact of ganciclovir with the skin or mucous membranes. If contact does  occur, wash area thoroughly with soap and water; rinse eyes thoroughly with  plain water.2,42 

Stability: 

The manufacturer states that after reconstitution, solutions at concentrations of 50 mg per mL retain their potency for 12 hours at room temperature. Refrigeration is not recommended. After further dilution for intravenous infusion, it is recommended that solutions be used within 24 hours since nonbacteriostatic infusion solutions must be used; refrigerate the diluted solution; do not freeze.2,23 

However, studies have found that ganciclovir, when diluted to concentrations of 1, 5, and 10 mg per mL in 5% dextrose injection and 0.9% sodium chloride injection, was stable when assayed at 28 and 35 days.55,56 These solutions were refrigerated in polyvinyl chloride (PVC) bags and syringes. Ganciclovir was also stable when 5 and 10 mg per mL solutions were frozen in PVC bags for 28 days.56 

Incompatibilities: 

Parabens are incompatible with ganciclovir sodium and may cause precipitation.1,2 

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CIDOFOVIR 

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Source: HARRISON'S 14 

Cidofovir is a phosphonomethylether derivative of cytosine that is highly active against CMV, including some ganciclovir- and foscarnet-resistant strains. This agent is administered intravenously and is cleared largely by the kidney, with a serum half-life of 2.6 h. Concomitant administration with probenecid markedly prolongs the half-life of cidofovir and protects recipients against the major form of toxicity elicited by the drug (nephrotoxicity). The intracellular half-life of cidofovir diphosphate;17 to 30 h;is the basis for its infrequent administration (once a week or once every other week). Cidofovir is currently being evaluated for the treatment of CMV retinitis in patients with AIDS. 

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19.) Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis. 

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Author 

Kaufman HE; Varnell ED; Thompson HW 

Address 

LSU Eye Center, Louisiana State University Medical Center School of Medicine, New Orleans 70112-2234, USA. 

Source 

Arch Ophthalmol, 116(6):777-80 1998 Jun 

Abstract 

OBJECTIVE: To compare trifluridine eyedrops, cidofovir eyedrops, and penciclovir ophthalmic ointment for the treatment of herpes simplex virus type 1 keratitis.

METHODS: New Zealand white rabbits were infected with the McKrae strain of herpes simplex virus type 1. Three days after viral inoculation, the rabbits were randomly assigned to treatment with 1% trifluridine, 0.2% cidofovir, 3% penciclovir ointment, or phosphate-buffered saline (for control) on various schedules. The severity of keratitis was graded in a masked manner.

RESULTS: Treatment with any of the antiviral drugs resulted in significantly less severe keratitis than treatment with phosphate-buffered saline. There was no statistically significant difference between eyes given trifluridine 2, 4, or 7 times a day and eyes given cidofovir 2 times a day (P=.06, P=.43, and P=.19,  respectively, using the F test of the analysis of variance). Cidofovir  given twice a day was significantly more effective than penciclovir given  either 2 or 4 times a day (P<.001 and P=.002, respectively).

Even with  once-a-day dosage, all 3 drugs were significantly more effective than  phosphate-buffered saline (P<.001 for all). There was no significant  difference between once-a-day trifluridine and cidofovir treatments  (P=.17). Trifluridine administered 5 times a day was as effective as 1%  cidofovir. A similar degree of punctate keratitis was seen after 4 to 5  days in eyes treated with trifluridine at the highest frequency, 1%  cidofovir, or penciclovir ointment.

CONCLUSION: Trifluridine treatment was  highly effective in this rabbit model, even when given only once a day.  Treatment with cidofovir was as effective as that with trifluridine.  CLINICAL RELEVANCE: Cidofovir and penciclovir treatments may prove to be  effective against epithelial keratitis. Clinical trials of trifluridine,  cidofovir, and penciclovir with lower treatment frequencies appear to be  warranted. 

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20.) Bioavailability and metabolism of cidofovir following topical  administration to rabbits. 

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Author 

Cundy KC; Lynch G; Lee WA 

Address 

Gilead Sciences, Foster City, CA 94404, USA. 

Source 

Antiviral Res, 35(2):113-22 1997 Jul 

Abstract 

The bioavailability and metabolism of the antiviral nucleotide analog cidofovir (HPMPC) were examined in New Zealand white rabbits following topical administration to normal and abraded skin. Male rabbits (four per group) received 14C-cidofovir (100 microCi/kg) intravenously (1 mg/kg) as a solution or topically (2 mg/animal) as a 1% w/w gel containing hydroxyethylcellulose (HEC) with or without propylene glycol (PG).

The same PG/HEC formulation was applied topically to an abraded skin site in a fourth group of animals. All radioactivity detected in plasma and skin was accounted for by cidofovir. Plasma concentrations of radioactivity declined multiexponentially following intravenous administration, with a terminal half-life of 5.4 h. For intact skin, the absolute bioavailabilities of the HEC and PG/HEC formulations were 0.2 and 2.1%, respectively. For abraded skin, the bioavailability for the PG/HEC gel was 41%.

Radioactivity in kidneys was attributed to cidofovir ( > 95%) and cyclic HPMPC. Concentrations in kidney following topical administration of cidofovir to normal skin were < 4% of those following intravenous dosing. Topical application of cidofovir to intact skin led to negligible systemic exposure to the drug. The topical bioavailability and hence the flux of cidofovir  through intact skin was enhanced by the presence of PG in the formulation.  Abrasion of the skin removed the principal barrier to absorption and led to  significant systemic exposure to cidofovir. 

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21.) Cidofovir: a new therapy for cytomegalovirus retinitis. 

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Author 

Lalezari JP 

Address 

Department of Medicine, University of California, San Francisco 94115, U.S.A. 

Source 

J Acquir Immune Defic Syndr Hum Retrovirol, 14 Suppl 1():S22-6 1997 

Abstract 

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly known as HPMPC, is the first antiviral nucleotide analogue available for the treatment of cytomegalovirus (CMV) retinitis. Because cidofovir does not require viral activation, it has two advantages over nucleoside  analogues such as ganciclovir and acyclovir. Cidofovir is active in  uninfected cells and may act preemptively, and it may retain activity  against ganciclovir-resistant strains.

Preclinical studies showed the major  toxicity of cidofovir to be dose-, schedule-, and species-dependent  nephrotoxicity.

These studies also showed that concomitant administration  of probenecid protects animal models against cidofovir-induced  nephrotoxicity. Two phase I-II studies were undertaken in HIV-positive  patients with asymptomatic CMV excretion to evaluate several  dose-escalation regimens. Data from both phase I-II studies showed that in  patients receiving cidofovir at > or =3 mg/kg, the virologic response rate  (> or =2 log reduction in CMV titer) was 93% for urine and 74% for semen.  In addition, four treatment modifications were indicated to reduce the  incidence of cidofovir-related nephrotoxicity:

(a) dose reduction or  interruption for changes in renal function;

(b) concomitant administration  of probenecid;

(c) administration of 1 L of normal saline 1 h before  infusion of cidofovir; and

(d) extension of the dosing interval. 

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22.) Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of Ocular complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. 

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Source 

Ann Intern Med, 126(4):264-74 1997 Feb 15 

Abstract 

BACKGROUND: Cytomegalovirus (CMV) retinitis is a common infection and a  major cause of visual loss in patients with the acquired immunodeficiency  syndrome (AIDS).

OBJECTIVE: To evaluate intravenous cidofovir as a  treatment for CMV retinitis. DESIGN: Two-stage, multicenter, phase II/III,  randomized, controlled clinical trial.

SETTING: Ophthalmology and AIDS  services at tertiary care medical centers.

PATIENTS: 64 patients with AIDS  and previously untreated, small, peripheral CMV retinitis lesions (that is,  patients at low risk for loss of visual acuity).

INTERVENTION: Patients  were randomly assigned to one of three groups: the deferral group, in which  treatment was deferred until retinitis progressed; the low-dose cidofovir  group, which received cidofovir, 5 mg/kg of body weight once weekly for 2  weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks;  or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once  weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once  every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with  hydration and probenecid.

MEASUREMENTS: Progression of retinitis, evaluated  in a masked manner by a fundus photograph reading center; the amount of  retinal area involved by CMV; the loss of visual acuity; and morbidity.  RESULTS: Median time to progression was 64 days in the low-dose cidofovir  group and 21 days in the deferral group (P = 0.052, log-rank test). The  median time to progression was not reached in the high-dose cidofovir group  but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis  of the rates of increase in the retinal area affected by CMV confirmed the  data on time to progression.

The three groups had similar rates of visual  loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in  the deferral group, 2.8 per person-year in the low-dose cidofovir group (P  > 0.02), and 6.8 per person-year in the high-dose cidofovir group (P =  0.135). No patient developed 4+ proteinuria, but two cidofovir recipients  developed persistent elevations of serum creatinine levels at more than 177  mumol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per  person-year.

CONCLUSIONS: Intravenous cidofovir, high- or low-dose,  effectively slowed the progression of CMV retinitis. Concomitant probenecid  and hydration therapy, intermittent dosing, and monitoring for proteinuria  seemed to minimize but not eliminate the risk for nephrotoxicity. 

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23.) Cidofovir and experimental herpetic stromal disease. 

==================================================================== 

Author 

Kaufman HE; Varnell ED; Thompson HW 

Address 

LSU Eye Center, Louisiana State University Medical Center School of Medicine, New Orleans 70112-2234, USA. 

Source 

Arch Ophthalmol, 117(7):925-8 1999 Jul 

Abstract 

OBJECTIVE: To compare topical cidofovir with topical trifluridine for the prevention and treatment of herpes simplex type 1 stromal keratitis in rabbits.

METHODS: The RE strain of herpes simplex virus 1 was injected into the central stroma of both eyes of New Zealand white rabbits. Two to 3 days after virus inoculation, the rabbits were randomized to treatment groups of 10 each and treated with 1% trifluridine administered 5 or 7 times a day, 1%, 0.5%, or 0.2% cidofovir administered twice a day, fluorometholone administered twice a day, or balanced salt solution (BSS) administered twice a day (control) until day 21 after injection. The treated corneas were examined 3 times a week and the severity of stromal keratitis was graded in a masked fashion. To evaluate the ability of cidofovir to treat established stromal disease, groups of 10 rabbits each were inoculated with herpes simplex virus and treated with 1% cidofovir twice a day, 1% trifluridine 5 times a day, fluorometholone twice a day, or BSS twice a day beginning on day 7 after virus inoculation through day 21.

RESULTS: Treatment with 0.2% cidofovir twice a day was not effective in preventing the appearance of stromal disease (P = .89), whereas treatment with 0.5%  (P<.001) or 1% (P<.001) cidofovir twice a day or 1% trifluridine 5 times a  day (P<.001) or 7 times a day (P = .006) significantly reduced the  appearance of stromal keratitis on the 8 evaluation days, compared with BSS  treatment (F test analysis of variance). There was no difference between  the eyes treated with 0.5% cidofovir twice a day and those treated with 1%  trifluridine 5 times a day. Treatment with 1% cidofovir was not effective  in treating established stromal disease.

CONCLUSIONS: Cidofovir and  trifluridine are highly effective in preventing the appearance of herpetic  stromal disease. Cidofovir is as effective as, but no more effective than,  trifluridine in this model. Neither cidofovir nor trifluridine benefits  established stromal disease, however.

CLINICAL RELEVANCE: Cidofovir is a  new, potent antiviral that seems similar in efficacy to trifluridine and is  effective in the prevention of the development of stromal herpes, but is  not effective in the treatment of established stromal disease in which  hypersensitivity predominates. 

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24.) Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. 

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Author 

Cundy KC 

Address 

Gilead Sciences Inc., Foster City, California, USA. ken_cundy@gilead.com 

Source 

Clin Pharmacokinet, 36(2):127-43 1999 Feb 

Abstract 

Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases.

Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS.

Cidofovir and adefovir are dianionic at  physiological pH and have low oral bioavailability in animals and humans.  After intravenous administration to HIV-infected patients, the  pharmacokinetics of both drugs are independent of dose and are consistent  with preclinical data. Systemic exposure is proportional to the intravenous  dose and both drugs are cleared by the kidney and excreted extensively as  unchanged drug in the urine.

Intracellular activation of a small fraction  (< 10%) of the dose by cellular kinases leads to prolonged antiviral  effects that are not easily predicted from conventional pharmacokinetic  studies. The observed rate of elimination of cidofovir and adefovir from  serum may not reflect the true duration of action of these drugs, since the  antiviral effect is dependent on concentrations of the active  phosphorylated metabolites that are present within cells. For both drugs, >  90% of an intravenous dose is recovered unchanged in the urine over 24  hours. Metabolism does not contribute significantly to the total clearance  of either drug.

Concomitant oral probenecid decreases both the renal  clearance of cidofovir and the incidence of nephrotoxicity, presumably by  blocking its active tubular secretion. This is the basis of the clinical  use of concomitant probenecid as a nephroprotectant during cidofovir  therapy. Subcutaneous administration produces exposure equivalent to that  following intravenous administration. Drug interaction studies with  cidofovir are ongoing, but there is no evidence of an interaction between  zidovudine and either cidofovir or adefovir.

Clearance of cidofovir in  patients with renal impairment showed a linear relationship to creatinine  clearance. The low oral bioavailability of adefovir has led to the  development of an oral prodrug, adefovir dipivoxil, currently in  development for the treatment of HIV and hepatitis B infections. 

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25.) Cidofovir in the treatment of cytomegaloviral disease. 

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Author 

Kendle JB; Fan-Havard P 

Address 

Division of Pharmacy Practice and Administration, College of Pharmacy, Ohio State University, Columbus 43210, USA. 

Source 

Ann Pharmacother, 32(11):1181-92 1998 Nov 

Abstract 

OBJECTIVE: To review the clinical pharmacology and microbiology of cidofovir in the therapy of cytomegalovirus (CMV) disease. DATA SOURCES: Pertinent literature was identified via a MEDLINE search (October 1986-February 1997), and data from abstracts presented at recent scientific meetings were also included; unpublished information was provided by the manufacturer.

STUDY SELECTION: Antiviral activity data were included if widely accepted methodology was used. All clinical data currently available from human studies were also included.

DATA SYNTHESIS: Cidofovir is similar to ganciclovir in mechanism of action; however, cidofovir does not require viral enzymes for activation. Although the half-life of cidofovir in plasma is only 2.6 hours, the intracellular half-life may be much longer, allowing efficacy with biweekly maintenance dosing. In vitro, cidofovir appears to be equally or more effective than the other agents currently available for  the treatment of CMV. In vivo, cidofovir appears to be effective in  delaying the progression of CMV retinitis, although no clinical trials to  date have directly compared cidofovir with either ganciclovir or foscarnet.  Current intravenous dose recommendations are 5 mg/kg once weekly for two  doses (induction), and then 5 mg/kg once every other week (maintenance). 

Since cidofovir is cleared almost entirely by the kidneys, dosage  adjustments must be made in patients with impaired renal function.  Disadvantages of cidofovir primarily include its risks of adverse drug  reactions, such as nephrotoxicity, which is likely to occur in up to 50% of  patients if appropriate preventative measures are not taken. Neutropenia  and constitutional reactions to probenecid are also commonly encountered  during the course of cidofovir therapy.

CONCLUSIONS: Cidofovir is the first  acyclic phosphonate nucleoside antiviral agent to be approved for general  use in the US. In addition to delaying the progression of CMV retinitis,  cidofovir may provide some protective benefits to patients at risk for  developing the disease and may be active against certain strains of virus  resistant to other currently available therapies.

Another advantage of  cidofovir is its infrequent dosage schedule, which may prove beneficial in  patients who are not compliant with daily intravenous dosing regimens. When  determining the appropriate treatment for a patient with CMV retinitis, the  benefits of using cidofovir must be weighed carefully against the risk of  potentially serious adverse effects. 

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26.) Antitumor potential of acyclic nucleoside phosphonates. 

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Nucleosides Nucleotides 1999 Apr-May;18(4-5):759-71 

De Clercq E, Andrei G, Balzarini J, Hatse S, Liekens S, Naesens L, Neyts J, Snoeck R 

Rega Institute for Medical Research, K.U. Leuven, Belgium. 

Acyclic nucleoside phosphonates such as HPMPC (cidofovir) and PMEA (adefovir) have been identified as broad-spectrum antiviral agents that are  effective against herpes-, retro- and hepadnavirus infections (PMEA) and  herpes-, pox-, adeno-, polyoma-, and papillomavirus infections (HPMPC).  Here we show that HPMPC and PMEA also offer great potential as antitumor  agents, through the induction of tumor cell differentiation (PMEA),  inhibition of angiogenesis (HPMPC) and induction of apoptosis (HPMPC). In  vivo tumor regressions have been noted for choriocarcinoma (PMEA) in rats,  hemangioma (HPMPC) in rats and papillomatous lesions (HPMPC) in humans.  Acyclic nucleoside phosphonates can be considered as a new dimension to the  discipline of chemotherapy.

They have a unique mode of action that is  targeted at (viral or tumoral) DNA synthesis. They exhibit a pronounced and  prolonged anti-viral and/or tumoral activity that can persist for days or  weeks after a single administration.

Most importantly, they have a uniquely  broad spectrum of indications for clinical use, encompassing both DNA- and  retrovirus infections, as well as various forms of cancer of both viral and  non-viral origin. 

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27.) Clinical uses of cidofovir. 

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Rev Med Virol 1997 Sep;7(3):145-156 

Safrin S, Cherrington J, Jaffe HS 

Gilead Sciences, Foster City, CA, USA. 

Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients.

Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross-resistance to cidofovir in ganciclovir-resistant clinical DNA polymerase mutants has been identified. Cross-resistance of cidofovir and foscarnet has not been identified to date.

A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications.

Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposi's sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum  contagiosum, anogenital condyloma acuminata, and recurrent genital herpes,  and ophthalmic instillation for treatment of viral keratoconjunctivitis. 

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28.) Characterization of the DNA polymerase and thymidine kinase genesof  herpes simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed. 

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J Infect Dis 1999 Aug;180(2):487-90 

Schmit I, Boivin G 

Infectious Disease Research Center, Centre Hospitalier de l'Universite Laval, Quebec, Canada, G1V 4G2. isabelle_schmit@hotmail.com. 

Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir (prefoscarnet) HSV isolates were resistant to acyclovir and susceptible to foscarnet. Of the 9 postfoscarnet isolates, 8 were  foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both  drugs.

Acyclovir- or foscarnet-resistant isolates retained susceptibility  to cidofovir. The acyclovir-resistant isolates contained single-base  substitutions or frameshift mutations in G or C homopolymer nucleotide  repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant  strains contained single-base substitutions in conserved (II, III, or VI)  or, more rarely, nonconserved (between I and VII) regions of the DNA  polymerase (pol) gene.

The single isolate exhibiting resistance to  acyclovir and foscarnet contained mutations in both genes. In this study of  clinical HSV isolates, DNA pol mutations conferring foscarnet resistance  were not associated with decreased acyclovir or cidofovir susceptibility. 

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29.) A case study: the use of cidofovir for the management of progressive  multifocal leukoencephalopathy. 

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J Assoc Nurses AIDS Care 1999 Jul-Aug;10(4):70-4 

Dodge RT 

Max Robinson Center, Whitman-Walker Clinic, Inc. 

Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection of the brain in advanced stages of AIDS. PML is caused by the JC virus, which leads to a decline in mental acuity and motor functions over a period of weeks or months.

Currently, there is no treatment or cure for PML. Cidofovir, an antiviral agent, at the standard dosages for the treatment of cytomegalovirus (CMV) was implemented in the treatment and management of a 35-year-old, newly diagnosed AIDS, White male with PML. The patient presented with impaired motor functions of the left upper and lower  extremities, which resulted in hemiparalysis and hemiparesis. The use of  cidofovir infusions at standard recommendations for treatment and  management of CMV has resulted in improvement and some resolution of the  patient's paralysis and paresthesia.

The patient has remained on the  cidofovir for more than a year, with no signs of advancement of his PML or  AIDS. Further investigation and extensive clinical trials are needed in the  treatment and management of PML with the use of cidofovir. 

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30.) Antiinfectives update: focus on treatment and prevention of viral and  associated infections. 

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Ann Pharmacother 1999 May;33(5):607-14 

McNicholl IR, Palmer SM, Ziska DS, Cleary JD 

Division of Pharmacy Practice, St. Louis College of Pharmacy, MO, USA. 

OBJECTIVE: To review the clinically significant antiinfectives approved by the Food and Drug Administration (FDA) since 1996, with an emphasis on agents used for treatment, prevention, or suppression of infection in immunocompromised individuals.

DATA SOURCES: A MEDLINE search covering November 1994 to March 1998 was conducted to identify all antiinfectives (new medications and old medications with new indications) and the pertinent literature for review. The search was updated in August 1998 and supplemented with an FDA listing of approved drugs to enhance completeness. 

STUDY SELECTION: Clinically relevant studies were selected to highlight specific points about each medication. Preclinical publications were used when sufficient information was not available from clinical trials and this information was needed for clinical practice.

CONCLUSIONS: Several new and promising antiretroviral agents (stavudine, lamivudine, saquinavir soft-gel  capsules, nelfinavir, efavirenz) have been approved, which may allow more  options to control HIV viremia.

New options for treatment, prevention, and  suppression of infections in immunocompromised individuals include  azithromycin, cidofovir, famciclovir, valacyclovir, and itraconazole  suspension. Liposomal-based amphotericin products may be associated with  less toxicity than conventional amphotericin B; however, superior efficacy  has not been proven. 

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31.) Identification and rapid quantification of early- and late-lytic human  herpesvirus 8 infection in single cells by flow cytometric analysis:  characterization of antiherpesvirus agents. 

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J Virol 1999 Jul;73(7):5894-902 

Zoeteweij JP, Eyes ST, Orenstein JM, Kawamura T, Wu L, Chandran B, Forghani B, Blauvelt A 

Dermatology Branch, National Cancer Institute,National Institutes of Health, Bethesda, Maryland 20892, USA. 

Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease.

In this study, we used monoclonal antibodies (MAbs) directed against HHV-8 lytic cycle-associated proteins encoded by open reading frame (ORF) 59 (nuclear PF-8 protein) and ORF K8.1 (viral envelope glycoprotein K8.1 [gpK8.1]) to investigate HHV-8 lytic infection in single cells. Lytically infected cells were labeled with MAbs, stained with fluorescently conjugated secondary Abs, and analyzed by flow cytometry.

A 3-day stimulation of HHV-8-positive PEL cell lines (BCBL-1 and BC-3) with 12-O-tetradecanoylphorbol-13-acetate (30 nM) or n-butyric acid (0.3 mM) maximized the expression of lytic-phase viral proteins and minimized cell toxicity. The absolute number of expressing cells was inducer and cell line dependent. Expression of PF-8 occurred earlier and more frequently (in up to 20% of cells) than did expression of gpK8.1. A subset of PF-8 positive cells (25%) co-expressed gpK8.1, representing the majority of gpK8.1  expressing cells.

Acyclovir, foscarnet, cidofovir, and PMEA reduced the  number of cells expressing gpK8.1, but not the number expressing the  nonstructural early lytic gene product PF-8. By contrast, alpha interferon  (IFN-alpha) and IFN-beta reduced expression of both PF-8 and gpK8.1,  implying an overall inhibitory effect on viral gene transcription or  translation. In summary, we have characterized and quantified HHV-8 lytic  infection in single cells by dual measurement of early- and  late-lytic-cycle HHV-8 protein expression. This technique should prove  useful for screening of possible antiherpesvirus agents and for detailed  phenotypic characterization of HHV-8-infected cells in vitro and in  patients with HHV-8-associated diseases. 

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32.)Inhibiting effects of cidofovir (HPMPC) on the growth of the human  cervical carcinoma (SiHa) xenografts in athymic nude mice. 

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Oncol Res 1998;10(10):533-9 

Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E 

Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium. graciela.andrei@rega.kuleuven.ac.be 

At present more than 70 human papillomaviruses (HPV) genotypes have been described and each shows a predilection for a cutaneous or mucosal surface. 

There is a strong association between infection with specific genital viruses (i.e., types 16 and 18) and the development of cervical cancer. Thus, intervention with the natural history of HPV infection in the genital tract may form the basis for an effective anticancer strategy. We have shown that treatment of cell lines derived from human cervical carcinomas [i.e., SiHa and CaSki (HPV-16-positive)] and HeLa (HPV-18-positive)] with HPMPC (cidofovir) results in a concentration- and time-dependent inhibition of cell proliferation. We report here the effects of HPMPC on the growth of cervical carcinoma (SiHa) xenografts in athymic nude mice. Athymic mice between the age of 6 and 8 weeks were injected SC with 5 to 10x10(6) cells.

 Once tumors were established, the mice were injected with PBS (placebo), HPMPC, or cytarabine (AraC) at the tumor site. Animals that were injected intratumorally with HPMPC at a dose of 5 mg/ml (0.25 mg/injection) or 10 mg/ml (0.5 mg/injection) three or five times per week, once daily, during 4 weeks showed a statistically significant reduction in tumor size compared to the placebo group or AraC group.

However, when HMPC was administered  topically (as a cream) or systemically (intraperitoneally), no reduction of  tumor growth was observed at nontoxic concentrations, suggesting that a  high local concentration of HPMPC is required to achieve a significant  decrease of tumor growth. 

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33.) Antiproliferative effects of acyclic nucleoside phosphonates on human  papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell  lines. 

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Oncol Res 1998;10(10):523-31 

Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E 

Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium. Graciela.Andrei@rega.kuleuven.ac.be 

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV),  ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents  cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant  mycophenolic acid (MPA) on the proliferation of human cervical  keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical  carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). 

In vitro incubation of these cell lines with ANPs resulted in a  concentration- and time-dependent inhibition of cell proliferation. This  inhibitory effect was most striking for HPMPC. The 50% inhibitory  concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to  0.6-2 microg/ml at day 7.

When the IC50 values of the ANPs for the various  HPV-harboring cells were compared with those for primary human  keratinocytes isolated from normal cervix, HPMPC emerged as the most  selective ANP, with a selectivity index (SI) in the range of 15-42. When  IC50 values as a function of time were determined for several tumor cell  lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs  again showed an antiproliferative effect as a function of time, although of  a lower extent (5- to 25-fold decrease in the IC50 values between days 3  and 7) than for the HPV-positive cells.

Treatment of SV40- and  adenovirus-transformed cells with ANPs resulted in the inhibition of cell  proliferation as a function of time, similar to that observed with  HPV-positive cells, HPMPC and cHPMPC being the most potent  antiproliferative agents.

These results suggest that the antiproliferative  activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may  be explained, at least in part, by a specific inhibitory effect on rapidly  proliferating cells, and the presence of the HPV genome might enhance the  sensitivity of cells to HPMPC due to interactions of the viral-transforming  proteins with products of the tumor suppressor genes. 

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34.) Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. 

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Arch Dermatol 1997 Aug;133(8):987-90 

Meadows KP, Tyring SK, Pavia AT, Rallis TM 

Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, USA. 

BACKGROUND: Molluscum contagiosum virus (MCV) causes cutaneous skin growths that mainly affect children, sexually active adults, and immunocompromised individuals. Lesions of MCV in patients infected with human immunodeficiency virus can be large and numerous, and response to available treatments is often unsatisfactory.

OBSERVATIONS: We describe 3 men infected with human immunodeficiency virus who presented with extensive MCV lesions that were not responsive to various treatments. Patient 1 demonstrated dramatic clearing of his MCV lesions when intravenous cidofovir therapy was started for his treatment-resistant bilateral CMV retinitis and because of cidofovir's possible activity against MCV.

In case 2, cidofovir was compounded as a 3% cream in a combination vehicle  (Dermovan) for extensive facial involvement, and complete resolution of MCV  was seen after 1 month of therapy. In case 3, intravenous cidofovir therapy  was started both for CMV retinitis and in an attempt to clear 90% facial  MCV involvement; after 1 month of treatment, all clinical evidence of MCV  had resolved. All 3 patients remain clear of recurrence.

CONCLUSIONS:  Cidofovir, a nucleotide analog of deoxycytidine monophosphate, appears to  have contributed to clearing of advanced MCV lesions in these 3 patients,  thus providing suggestive evidence of clinical activity against MCV.  Controlled trials of cidofovir therapy for MCV in persons infected with  human immunodeficiency virus are warranted. 

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35.) Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. 

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Verh K Acad Geneeskd Belg 1996;58(1):19-47; discussion 47-9 

De Clercq E 

Rega Institute for Medical Research, Katholieke Universiteit, Leuven. 

(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, Cidofovir, Vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity against a wide variety of DNA viruses including herpesviruses [Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and equine and bovine herpesviruses], papovaviruses [human polyoma virus and human papilloma virus (HPV)], adeno-, irido-, hepadna-, and poxviruses. HPMPC has proved effective against these viruses in different cell culture systems and/or animal models.

The mechanism of action of HPMPC is based upon the interaction of its active intracellular metabolite, the diphosphorylated HPMPC derivative HPMPCpp, with the viral DNA polymerase. HPMPCpp has been shown to block CMV DNA synthesis by DNA chain termination following incorporation of two consecutive HPMPC molecules at the 3'-end of the DNA chain. HPMPC confers a prolonged antiviral action, which lasts for several days or weeks, thus allowing infrequent dosing (i.e. every week or every two weeks).

This prolonged antiviral action is probably due to the very long intracellular half-life of the HPMPC metabolites, particularly the HPMPCp-choline adduct. In clinical studies, HPMPC has proved efficacious in the treatment of CMV retinitis, following both intravenous injection (3 or 5 mg/kg, every other week) and intravitreal injection (single dose of 20 micrograms per eye). 

Initial clinical trials also point to the efficacy of both systemic (intravenous) and topical HPMPC (1% ointment) in the treatment of acyclovir-resistant HSV infections, and of topical HPMPC (ointment or injection) in the treatment of pharyngeal, laryngeal and anogenital HPV infections. HPMPC is now being pursued in the topical and/or systemic (intravenous) treatment of various infections due to CMV, HSV, VZV, EBV, HPV, polyoma-, adeno- and poxviruses. 

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36.) Topical and intralesional cidofovir: a review of pharmacology and  therapeutic effects. 

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J Am Acad Dermatol 1998 Nov;39(5 Pt 1):741-5 

Zabawski EJ Jr, Cockerell CJ 

University of Texas Southwestern Medical Center, Dallas, USA. 

BACKGROUND: Cidofovir is a potent nucleoside analog antiviral drug approved for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It is currently available only for intravenous infusion. Several small studies and case reports describe the successful use of cidofovir applied either topically or intralesionally in several virally induced cutaneous diseases.

OBJECTIVE: Our purpose was to review the usefulness of topical and intralesional cidofovir for the treatment of viral infections caused by human papillomavirus, herpesviruses (including acyclovir-resistant strains), Kaposi's sarcoma-associated herpesvirus, and molluscum contagiosum. METHODS: We performed a review of recent literature.

RESULTS: Cidofovir is a potent topical intralesional antiviral agent with activity against several DNA viruses that cause cutaneous disease. No significant systemic side effects have been noted, although application site reactions are common and can occasionally be severe.

CONCLUSION: The effective use of topical and intralesional cidofovir for the treatment of diseases of the skin caused by DNA viruses has been demonstrated in a limited number of patients including those infected with HIV. Although larger studies will be  necessary to determine the specific function that topical cidofovir will  have in the treatment of cutaneous diseases caused by DNA viruses, the drug  offers significant promise. 

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37.) Treatment of classical Kaposi's sarcoma with intralesional injections of cidofovir: report of a case. 

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J Med Virol 1998 Jul;55(3):215-8 

Simonart T, Noel JC, De Dobbeleer G, Parent D, Van Vooren JP, De Clercq E, Snoeck R 

Department of Dermatology, Erasme University Hospital, Brussels, Belgium. 

The effect of intralesional injections of cidofovir, a nucleotide analog  with potent in vitro activity against human herpesvirus 8 (HHV-8), was  studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma  (KS).

After five weekly injections of the drug, no clinical, histological,  immunohistological, or virological changes could be detected in comparison  with saline-injected lesions. These findings suggest that, once the KS  tumor has developed, active viral replication is no longer involved in the  pathogenesis of the disease. Alternative hypotheses are that HHV-8  replication in blood-borne cells may foster growth of spindle cells in the  skin, or that blocking HHV-8 may not affect existing lesions but may  prevent new lesions from developing. 

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38.) Selective inhibition of human papillomavirus-induced cell  proliferation by (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. 

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Antimicrob Agents Chemother 1999 May;43(5):1198-205 

Johnson JA, Gangemi JD 

Department of Microbiology and Molecular Medicine and the Greenville

 Hospital System Biomedical Cooperative, Clemson University, Clemson, South Carolina 29634, USA. 

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a  nucleoside phosphonate analog which in its active diphosphorylated form is  known to inhibit herpesvirus DNA polymerase. In this study, we have  demonstrated that, in a dose-dependent manner, this compound irreversibly  suppressed proliferation of cells infected with human papillomavirus (HPV),  which does not possess a viral DNA polymerase.

To elucidate the mechanism  of cell growth inhibition, cell cycle indicator-regulator expression,  thymidine incorporation, transcript levels of apoptosis factors, and  anabolic products of HPMPC following drug treatment were evaluated. HPMPC  treatment reduced WAF1 (p21) levels independent of those of p53, while  proliferating cell nuclear antigen increased. However, in comparison to  controls, HPMPC-treated cells displayed a decrease in thymidine  incorporation, indicating an inhibition of host DNA polymerase activity. In  normal primary keratinocytes, HPMPC predominantly accumulated in the form  of the choline adduct HPMPCp-choline.

However, in HPV type 16-transformed  keratinocytes, HPMPCpp was the most abundant anabolic product, with little  HPMPCp-choline having formed. The data imply that an unrecognized viral  factor is modulating the conversion of nucleotides, including HPMPC, to the  triphosphorylated form. 

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39.) Resistance of human cytomegalovirus to antiviral drugs. 

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Clin Microbiol Rev 1999 Apr;12(2):286-97 

Erice A 

Department of Laboratory Medicine & Pathology and Department of Medicine, 

University of Minnesota Medical School, Minneapolis, Minnesota 55455, 

USA.erice001@tc.umn.edu 

Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting.

Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease.

Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of  CMV to ganciclovir is related to mutations in the UL97 region of the viral  genome and/or mutations in the viral DNA polymerase. Resistance to  foscarnet and cidofovir is associated with mutations in the viral DNA  polymerase. Antiviral susceptibility of CMV strains containing DNA  polymerase mutations is dependent on the region of the DNA polymerase where  the mutations are located.

Some DNA polymerase mutant viruses are  cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition  that specific UL97 and UL54 mutations are associated with resistance to  antiviral agents has led to the development of molecular methods for  detection of mutant viruses.

This article reviews the mechanisms of  resistance of CMV to antiviral agents, the laboratory methods for detection  of resistant CMV, and the clinical aspects of infections caused by  antiviral-resistant CMV. 

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40.) Comparative antiviral efficacies of cidofovir, trifluridine, and  acyclovir in the HSV-1 rabbit keratitis model. 

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Invest Ophthalmol Vis Sci 1999 Feb;40(2):378-84 

Romanowski EG, Bartels SP, Gordon YJ 

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pennsylvania, USA. 

PURPOSE: To determine the relative antiviral inhibitory activity of topical 1% and 0.5% cidofovir, topical trifluridine (Viroptic; Burroughs-Wellcome,  Research Triangle Park, NC), and topical acyclovir (Zovirax; The Wellcome  Foundation, London, UK) during a 7-day period for the treatment of herpes  simplex virus type 1 (HSV-1) keratitis and HSV-1 replication in the New  Zealand rabbit ocular model.

METHODS: In a series of four experiments using  a two-eye design, a total of 80 New Zealand rabbits were inoculated in both  eyes with HSV-1 McKrae after epithelial scarification. Forty-eight hours  after inoculation, the rabbits were randomly assigned to a treatment group.  Five treatment groups (16 rabbits/group) were evaluated: I, 1% cidofovir,  twice daily for 7 days; II, 0.5% cidofovir, twice daily for 7 days; III, 3%  acyclovir ointment, five times daily for 7 days; IV, 1% trifluridine, nine  times daily for 3 days, then 4 times daily for 4 days; and V, control  vehicle twice daily for 7 days. HSV-1 dendritic keratitis was graded in a  masked fashion by slit-lamp examination on days 2, 3, 5, 7, 9, 11, and 14.  Ocular viral cultures were obtained after slit-lamp examination on days 1,  3, 5, 7, 9, 11, and 14.

RESULTS: Compared with the control group, all four  treatment groups demonstrated significantly lower viral titers, fewer  HSV-1-positive eyes/total during the treatment period, lower keratitis  scores, fewer eyes with keratitis/total, and a shorter time to resolution  of keratitis. Within the treatment groups, the 1% and 0.5% cidofovir  treatments were significantly more effective than acyclovir and  trifluridine as measured by the previous viral and keratitis parameters. 

CONCLUSIONS: Topical 1% and 0.5% cidofovir both appeared to be  significantly more efficacious than topical trifluridine and acyclovir,  during a 7-day course, in the treatment of experimental HSV-1 ocular  disease in the New Zealand rabbit keratitis model. 

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41.) [Human herpesvirus 8 (HHV8). II. Pathogenic role and sensitivity to  antiviral drugs]. 

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Ann Biol Clin (Paris) 1999 Jan-Feb;57(1):19-28 

Boulanger E 

Service d'hematologie clinique, hopital Saint-Louis, Paris. 

Human herpesvirus 8 (HHV8) has been found to be associated with three  different diseases observed in Aids patients: Kaposi's sarcoma, primary  effusion lymphoma, which is a rare type of non-Hodgkin lymphomas affecting  the body cavities, and multicentric Castleman's disease.

The role of this  new herpesvirus and other lymphoid proliferations, like angioimmunoblastic  lymphadenopathy or multiple myeloma, is much debatable. To date, there are  several evidences for a direct role of this virus in the occurrence of the  Kaposi's sarcoma, although the hypothesis of a passenger virus hypothesis  cannot be totally excluded. In vitro, HHV8 is sensitive to some  anti-herpesvirus drugs like foscarnet, cidofovir and adefovir, but the  indications of these therapies in the prevention or the treatment of the  Kaposi's sarcoma have not been documented so far. 

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42.) Inhibitory effects of novel nucleoside and nucleotide analogues on  Epstein-Barr virus replication. 

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Antivir Chem Chemother 1998 May;9(3):275-82 

Meerbach A, Holy A, Wutzler P, De Clercq E, Neyts J 

Institute for Antiviral Chemotherapy, Friedrich-Schiller-University Jena, Erfurt, Germany. 

The anti-Epstein-Barr virus (EBV) activity of different classes of compounds was assessed by means of an EBV DNA hybridization assay using a  digoxigenin-labelled probe specific for the BamHI W fragment of the EBV  genome, as well as by measuring viral capsid antigen (VCA) expression after  a 7 day incubation period of P3HR-1 producer cells with the test  substances.

Acyclovir, ganciclovir, cidofovir and zidovudine were included  as reference compounds. Several compounds proved to be potent and selective  inhibitors of EBV DNA synthesis and VCA expression.

Of the new compounds  that were evaluated for their anti-EBV activity, the highest efficacy  (lowest EC50) and highest selectivity index (SI) were shown by the purine  nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine  (S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate  analogues 9-(2-phosphono -methoxyethyl)-6-dimethylaminopurine (EC50 1.1  micrograms/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2-  amino-6-benzhydrylaminopurine (EC50 1.3 micrograms/ml; SI 29),  7-(2-phosphonomethoxyethyl)-6-dimethyl-aminopurine (EC50 0.8 microgram/ml;  SI 56), 9-(R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopur  ine (EC50 0.5 microgram/ml; SI 42), the 2',3'-dideoxythymidine derivative  3'-oximino-2',3'-dideoxythymidine (EC50 1.5 micrograms/ml; SI 65), and  1-(2,3- dideoxy-3-N-hydroxyamino-beta-D-threo-pentafuranyl)pentafuranos  yl)thymine (EC50 4.1 micrograms/ml; SI > 24). 

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43.) Comparison of antiviral compounds against human herpesvirus 6 and 7. 

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Antiviral Res 1998 Dec;40(1-2):73-84 

Yoshida M, Yamada M, Tsukazaki T, Chatterjee S, Lakeman FD, Nii S, Whitley RJ 

Department of Virology, Okayama University Medical School, Japan. 

mariko@med.okayama-u.ac.jp 

Four classes of antiviral compounds were evaluated for inhibitory activity against two variants of human herpesvirus 6 (HHV-6A and -6B) and human herpesvirus 7 (HHV-7). These included:

(1) a pyrophosphate analog, phosphonoformic acid (PFA);

(2) beta-guanine analogs,  9-(2-hydroxyethoxymethyl)guanine (acyclovir or ACV),  9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir or GCV) and  9-(4-hydroxy-3-hydroxy-3-hydroxymethylbutylyl)guanine (penciclovir or PCV); 

(3) acyclic nucleoside phosphonates,  (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine [cidofovir or  (S)-HPMPC] and its cyclic derivative (S)-cyclic-HPMPC (cHPMPC),  9-[[2-hydroxy-1-phosphonomethoxy)ethoxy]methyl]guanine (HPMEMG) and  9-[(2-phosphonylmethoxy)ethyl]-2,6-diaminopurine (PMEDAP), and the seven  other related compounds; and

(4) a series of benzimidazole ribonucleosides,  including 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole  (BDCRB). End-point inhibitory concentration (EPC) and 50% effective  inhibitory concentration (EC50) values were determined by a dot-blot  antigen detection method in cord blood mononuclear cells infected with  HHV-6A, HHV-6B or HHV-7 at a multiplicity of infection of 0.004  CCID50/cell. (S)-HPMPC and cHPMPC had an EC50 value of approximately 0.3  microg/ml for HHV-6A, 1.2 microg/ml for HHV-6B and 3.0 microg/ml for HHV-7. 

These compounds were the most active of those tested against each virus.  The EC50 value of GCV for HHV-6A was 0.65 microg/ml, 1.33 microg/ml for  HHV-6B, and >7 microg/ml for HHV-7. The EC50 values of ACV and PCV were  approximately 6-8 microg/ml for HHV-6A, 16-24 microg/ml for HHV-6B and  121-128 microg/ml for HHV-7. These drugs were the least active. The  sensitivity of HHV-7 to the guanine analogs was different from HHV-6,  suggesting a difference in selectivity of specific viral enzymes. 

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44.) [Advances in the diagnosis and treatment of infections caused by  herpesvirus and JC virus]. 

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Enferm Infecc Microbiol Clin 1998;16 Suppl 1:11-9 

Arribas JR, Arrizabalaga J, Mallolas J, Lopez-Cortes LF 

Hospital La Paz, Madrid. arrlopjo@hulp.es 

During the last two years important advances in the diagnosis and treatment of cytomegalovirus (CMV) disease have occurred. Several studies have suggested that biologic markers of CMV viremia (PCR, branched DNA and pp65 antigenemia) might be useful both to stratify the risk of developing CMV disease and to follow the response of CMV retinitis to therapy. It has been shown that patients who are plasma CMV PCR positive have a risk of developing CMV disease three times higher than patients who are plasma CMV PCR negative. In addition, for each log10 increase of the CMV viral load there is a 3-fold higher risk of developing CMV disease.

Currently, therapeutic options for induction treatment of CMV retinitis (CMVR) are: i.v. ganciclovir (GCV), i.v. foscarnet, i.v. cidofovir or GCV intraocular implant combined with oral GCV. For maintenance therapy options are: i.v. GCV (3, 5 or 7 days per week), oral GCV (only for peripheral retinitis), i.v. foscarnet (daily), i.v. cidofovir (biweekly) and GCV intraocular implant (replaced every 6-8 months) combined with oral GCV.

There is currently enough evidence to allow the diagnosis of progressive multifocal  leukoencephalopathy (PML) based on the finding of JC virus DNA in CSF by  PCR. There are still no drugs with proven clinical efficacy against JC  virus but the possibility that HAART treatments might improve the control  of this disease appear promising. 

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45.) A multicenter phase I/II dose escalation study of single-dose  cidofovir gel for treatment of recurrent genital herpes. 

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Antimicrob Agents Chemother 1998 Nov;42(11):2996-9 

Sacks SL, Shafran SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, Safrin S, Rudy J, McGuire B, Jaffe HS 

Viridae Clinical Sciences, Inc., and Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. sacks@viridae.com 

A randomized, double-blind, clinic-initiated, sequential dose-escalation pilot study was performed to compare the safety and efficacy of single applications of 1, 3, and 5% cidofovir gel with placebo in the treatment of early, lesional, recurrent genital herpes at five Canadian outpatient sites.

Ninety-six patients began treatment within 12 h of lesion appearance and were evaluated twice daily until healing of the lesion occurred. Cidofovir gel at all strengths significantly decreased the median time to negative virus culture in a dose-dependent fashion (3.0 days in the placebo group versus 2.2, 1.3, and 1.1 days in the 1, 3, and 5% cidofovir gel  treatment groups, respectively; P = 0.02, 0.0001, and 0.0003,  respectively). A trend toward a reduction in the median time to complete  healing in association with treatment was present, but the differences were  not statistically significant (5.0 days in the placebo group versus 4.3,  4.1, and 4.6 days in the 1, 3, and 5% cidofovir gel treatment groups,  respectively).

Application site reactions occurred in 3, 5, 19, and 22% of  the patients in these four groups, respectively. Treatment-associated  lesion recrudescence with delayed healing, which is suggestive of local  toxicity, was observed in three patients treated with 5% cidofovir gel and  one patient treated with 3% cidofovir gel. In summary, single-dose  application of cidofovir gel confers a significant antiviral effect on  lesions of recurrent genital herpes.

Additional studies are warranted to  further identify the optimal efficacious dose of cidofovir in association  with the maximum gel strength that can be tolerated. 

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46.) Cidofovir use in acyclovir-resistant herpes infection. 

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Ann Pharmacother 1997 Dec;31(12):1519-21 

Martinez CM, Luks-Golger DB 

Montefiore Medical Center, Bronx, NY, USA. 

Herpes infections continue to be prevalent, especially in immunocompromised patients. Some of these patients will develop resistant HSV infections. Therefore, it is important to explore new treatment options. Animal studies have shown cidofovir to be effective in the treatment and prevention of HSV  infections. Human data are limited, with only one randomized, double-blind,  placebo-controlled trial performed to date. The results from this study  look promising; however, due to the small sample size, a larger clinical  trial is warranted.

The human data available as case reports are suboptimal  in the quality of reporting time frames for resolution of lesions/symptoms  and outcomes of therapy. Another problem with the case report data is that  the TK status of the herpes simplex isolates was not reported. This would  have helped substantiate the acyclovir resistance seen in these patients. 

It was evident in these case reports that acyclovir resistance can be  overcome, as acyclovir-resistant strains became sensitive following  cidofovir therapy. This may be because TK(+) viruses have been shown to  establish latency more readily than do TK(-) viruses. This pattern suggests  that alternating between acyclovir and cidofovir therapies may provide a  strategy to manage the emergence of alternatively acyclovir-sensitive and  -resistant infections.

At present, only the intravenous formulation of  cidofovir is commercially available. Advantages of the intravenous  formulation include weekly dosing and efficacy. Disadvantages are the  complexity of administration and the adverse effect profile. The most  common adverse effects with this formulation include nephrotoxicity  manifested as proteinuria (12%), and increased creatinine (5%) and  neutropenia (15%).

Administration of probenecid and NaCl 0.9% hydration are  used to reduce the incidence and severity of nephrotoxicity in patients who  are receiving cidofovir. Probenecid also has toxicities, including nausea,  vomiting, headache, fever, and flushing. The topical formulation of  cidofovir looks promising for mucocutaneous HSV infection because it is  usually undetectable in the blood following topical administration.  Therefore, systemic adverse effects should be minimized.

A cidofovir gel  product (Forvade, Gilead Sciences) is currently being reviewed by the Food  and Drug Administration for the treatment of refractory HSV. Ultimately,  more controlled clinical studies are necessary to determine whether routine  cidofovir use can be justified in patients with acyclovir-resistant HSV  infection. 

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47.) A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. 

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J Infect Dis 1997 Oct;176(4):892-8 

Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Corey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S Mt.

Zion Medical Center and San Francisco General Hospital, University of California, USA. 

The safety and efficacy of cidofovir gel for treatment of  acyclovir-unresponsive herpes simplex virus infections in AIDS patients was  evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3%  or 1%) or placebo gel was applied once daily for 5 days.

Ten of 20  cidofovir-treated and none of 10 placebo-treated patients had complete  healing or >50% decreased area (P = .008); 30% of cidofovir-treated  patients versus 0 placebo recipients had complete healing (P = .031). Viral  shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9  placebo-treated patients (P = .00004). For cidofovir-treated patients,  median time to complete or good response was 21 days, and median time to  negative viral culture was 2 days (P = .025, P = .0001, respectively).  Median lesion area decreases were 58% for cidofovir-treated versus 0 for  placebo-treated patients (P = .005), and mean pain score changes were -1.84  versus -0.34 (P = .042).

Application site reactions occurred in 25% of  cidofovir-treated and 20% of placebo-treated patients; none was  dose-limiting. Cidofovir therapy provided significant benefits in lesion  healing, virologic effect, and pain reduction. 

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48.) Isolation of human adenovirus type 5 variants resistant to the antiviral cidofovir. 

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Invest Ophthalmol Vis Sci 1996 Dec;37(13):2774-8 

Gordon YJ, Araullo-Cruz TP, Johnson YF, Romanowski EG, Kinchington PR 

Department of Ophthalmology, Eye and Ear Institute, University of Pittsburgh Medical Center, Pennsylvania 15213, USA. 

PURPOSE: Cidofovir (S-HPMPC) is a potent broad-spectrum antiviral drug with potential clinical application against infections caused by human cytomegalovirus, herpes simplex virus, and adenovirus (AD). This study sought to determine whether variants of AD5 could be isolated in vitro that demonstrated increased resistance to this new antiviral drug.

METHODS: Homogenous stocks of wild-type AD5 (ATCC strain VR-5) were generated from isolated plaques grown in A549 cells. The stocks subsequently were serially passaged in cells containing increasing levels (from 5 to 75 micrograms/ml) of cidofovir. The recovered virus either was passaged, titrated, or assayed  for 50% inhibitory concentration (IC50) of cidofovir.

RESULTS: Three  independently isolated variants were obtained that demonstrated increased  resistance to cidofovir. Viral resistance to the drug increased on stepwise  passage in higher concentrations. Compared to the ATCC AD5 reference (IC50  = 6.2 micrograms/ml), stable cidofovir-resistant variants showed fivefold  to eightfold resistance (AD5 RI IC50 = 36.5 micrograms/ml; AD5 R2 IC50 =  36.7 micrograms/ml; and AD5 R3 IC50 = 32.6 micrograms/ml; analysis of  variance, P = 0.000001).

However, a variable number of passages (1 to 13)  at each concentration of cidofovir was performed to obtain robust  infectious virus suitable for testing at the next higher concentration. All  resistant virus isolates grew to levels of virus titer comparable to the  parental virus and showed no apparent phenotypic changes in growth rates,  plaque size, or efficiency of plaque formation.

CONCLUSIONS: The successful  isolation of AD5 variants in tissue culture resistant to cidofovir has  important clinical implications with respect to the anticipated use of this  antiviral drug in treating adenoviral ocular infections. 

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49.) Herpesvirus resistance to antiviral drugs: a review of the mechanisms,  clinical importance and therapeutic options. 

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J Hosp Infect 1996 Aug;33(4):235-48 

Reusser P 

Department of Medicine, University Hospital, Basel, Switzerland. 

During the past decade, potent agents against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV) have become available. The increasing clinical use of acyclovir, ganciclovir, and foscarnet has been associated with the emergence of drug-resistant  herpesvirus strains.

Resistance to acyclovir or ganciclovir most frequently  results from deficient intracellular phosphorylation of these agents which  is required for drug activation. Resistance to foscarnet is due to viral  DNA polymerase mutants that permit viral replication despite the presence  of the drug.

In immunocompetent patients, herpesvirus resistance is rare  and generally does not correlate with clinical outcome. In contrast, in  immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly  detected, and may be associated with disease refractory to antiviral  therapy.

Foscarnet treatment has been used with some clinical benefit in  patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV.  For therapy of resistant mucocutaneous HSV disease, topical  trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have  yielded encouraging results that warrant further investigation. Improved  methods for detection of herpesvirus resistance, and validation of  alternative therapy for patients with documented resistance are required to  reduce the clinical impact of drug-resistant herpesviruses. 

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50.) Topical cidofovir for severe molluscum contagiosum. Lancet 1999 Jun 12;353(9169):2042 

Davies EG, Thrasher A, Lacey K, Harper J 

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51.) Abatement of cutaneous Kaposi's sarcoma associated with cidofovir  treatment. 

Clin Infect Dis 1998 Dec;27(6):1562 

Simonart T, Noel JC, De Clercq E, Snoeck R 

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52.) Treatment of verruca vulgaris with topical cidofovir. 

JAMA 1997 Oct 15;278(15):1236 

Zabawski EJ Jr, Sands B, Goetz D, Naylor M, Cockerell CJ 

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53.) Topical cidofovir for severe molluscum contagiosum. 

Lancet 1999 Jun 12;353(9169):2042 

Davies EG, Thrasher A, Lacey K, Harper J 

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54.) CIDOFOVIR, The product 

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VA CLASSIFICATION (Primary/Secondary);AM800 

Commonly used brand name(s): 

Vistide. 

Note: For a listing of dosage forms and brand names by country 

availability, see Dosage Forms section(s). 

Category 

Antiviral (systemic). 

Indications 

General considerations 

All cidofovir-resistant cytomegalovirus (CMV) isolates have been found to be resistant to ganciclovir, but remained susceptible to foscarnet1. 

Accepted 

Cytomegalovirus retinitis (treatment);Cidofovir is indicated, in combination with probenecid, for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome1. Safety and efficacy have not been established for the treatment of CMV disease in non-HIV infected people, other CMV infections, or congenital or neonatal CMV disease1. 

Pharmacology/Pharmacokinetics 

Physicochemical characteristics: 

Molecular weight; Cidofovir: 315.221  Cidofovir anhydrous: 279.191 

Mechanism of action/Effect: 

Cidofovir diphosphate, the active intracellular metabolite of cidofovir,  suppresses cytomegalovirus (CMV) replication by selectively inhibiting  viral DNA polymerase1. Cidofovir diphosphate inhibits herpesvirus  polymerases at concentrations that are 8- to 600-fold lower than those  needed to inhibit the human cellular polymerases alpha, beta, and gamma1.  Reduction in the rate of viral DNA synthesis is due to incorporation of  cidofovir into the growing viral DNA chain1. 

Distribution: 

Volume of distribution is 537 mL per kg (mL/kg) without concurrent  probenecid administration and 410 mL/kg with concurrent probenecid  administration1. 

Concentrations of cidofovir were undetectable 15 minutes after the end of a 1-hour infusion in one patient who had a corresponding serum concentration of 8.7 mcg per mL (mcg/mL)1. 

Protein binding: 

Low (less than 6%)1. 

Time to peak concentration: 

End of infusion1. 

Peak serum concentration: 

With concurrent probenecid administration; 3 mg per kg of body weight (mg/kg): 9.8 mcg/mL1. 

5 mg/kg: 19.6 mcg/mL1. 

Without concurrent probenecid administration; 3 mg/kg: 7.3 mcg/mL1. 

5 mg/kg: 11.5 mcg/mL1. 

Elimination: 

Renal (without concurrent probenecid administration);Approximately 80 to  100% of an administered cidofovir dose was recovered unchanged in the urine  within 24 hours1. 

Renal (with concurrent probenecid administration);Approximately 70 to 85% of an administered cidofovir dose was recovered unchanged in the urine within 24 hours. The renal clearance of cidofovir was reduced to that of creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir1. 

In dialysis;The effect of hemodialysis on the pharmacokinetics of cidofovir is not known1. 

Precautions to Consider 

Carcinogenicity 

Cidofovir should be considered a carcinogen in rats and a potential carcinogen in humans1. 

Chronic, two-year carcinogenicity studies in rats and mice have not been done. However, a 26-week toxicology study was done in rats evaluating once weekly subscapular subcutaneous injections of cidofovir. The study was terminated at 19 weeks because palpable mammary adenocarcinomas were detected in females after only six doses. These masses developed at doses as low as 0.6 mg per kg (mg/kg) per week, which is equivalent to 0.04 times the human systemic exposure at the recommended cidofovir dose based on area under the plasma concentration-time curve (AUC) comparisons.1 

There was also a significant increase in mammary adenocarcinomas in female rats and a significant incidence of Zymbal's gland carcinomas in male and female rats administered 15 mg/kg of cidofovir once weekly; this was not seen at the 0.6 or 3 mg/kg doses. The 15 mg/kg dose is equivalent to 1.1  times the human systemic exposure at the recommended dose of cidofovir,  based on AUC.1 

Tumorigenicity 

No tumors were detected in cynomologus monkeys who received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, once a week for 52 weeks. This dose is equivalent to approximately 0.7 times the human systemic exposure. However, due to the small number of animals and the short duration of treatment, this study was not designed as a carcinogenicity study.1 

Mutagenicity 

There was no mutagenic response observed in microbial mutagenicity assays involving Salmonella typhimurium (Ames) and Escherichia coli in the presence and absence of metabolic activation. There was an increase in micronucleated polychromatic erythrocytes in vivo seen in mice receiving &sup3; 2000 mg/kg, a dose approximately 65-times higher than the maximum recommended clincial dose of cidofovir, based on body surface area estimations. Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation. At the four doses tested, the percentage of damaged metaphases and the number of aberrations per cell increased in a concentration-dependent manner.1 

Pregnancy/Reproduction 

Fertility;; Cidofovir was shown to cause inhibition of spermatogenesis in rats and monkeys. However, there were no reported adverse effects on fertility or  reproduction in male rats administered once-weekly intravenous injections  for thirteen consecutive weeks at doses up to 15 mg/kg per week; this is  equivalent to 1.1 times the recommended human dose based on AUC  comparisons. Female rats dosed intravenously at 1.2 mg/kg per week  (equivalent to 0.09 times the recommended human dose based on AUC) or  higher for up to six weeks prior to mating, and for two weeks after mating,  had decreased litter size and live births per litter, as well as an  increased incidence of early resorptions per litter. Peri- and postnatal  development studies in which female rats were administered subcutaneous  cidofovir at doses up to 1 mg/kg per day from day 7 of gestation through  day 21 postpartum (approximately five weeks) resulted in no adverse effects  on viability, growth, behavior, sexual maturation, or reproductive capacity  in the offspring.1 

Pregnancy;Adequate and well-controlled studies in humans have not been done. Cidofovir should be administered only if the potential benefit justifies the potential risk to the fetus.1 

Cidofovir was found to be embryotoxic (reduced fetal body weight) in rats administered 1.5 mg/kg per day and in rabbits given 1 mg/kg per day during the period of organogenesis; these doses were also maternotoxic. There was also an increased incidence of fetal external soft tissue and skeletal anomalies, such as meningocele, short snout, and short maxillary bones, seen in rabbits administered 1 mg/kg per day, which was also maternally toxic. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg per day) and in rabbits (0.25 mg/kg per day) were approximately 0.04 and 0.05 times the human maintenance dose, respectively, based on AUC. 

FDA Pregnancy Category C.1 

Breast-feeding 

It is not known whether cidofovir is distributed into breast milk. However, it is recommended that HIV-infected women not breast-feed their infants to avoid postnatal transmission of HIV to a child who may not be infected.1 

Pediatrics 

No information is available on the relationship of age to the effects of cidofovir in pediatric patients. Safety and efficacy have not been established. However, cidofovir should be used with caution in children with HIV infection because of the potential risk of long-term carcinogenicity and reproductive toxicity.1 

Geriatrics 

No studies have been done assessing the safety and efficacy of cidofovir in patients over the age of 601. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving cidofovir1. 

Drug interactions and/or related problems 

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate);not necessarily inclusive (>> = major clinical significance): 

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. >> Nephrotoxic medications (see Appendix II);(because cidofovir has been reported to be associated with severe renal function impairment, concurrent use with other nephrotoxic medications, such as aminoglycosides, amphotericin B, foscarnet, nonsteroidal anti-inflammatory drugs, and pentamidine, may increase the risk of nephrotoxicity and is contraindicated; it is recommended that patients undergo at least a 7-day washout period before receiving cidofovir2) 

>> Probenecid;(probenecid must be administered concurrently with  cidofovir; probenecid is known to interact with the metabolism or renal  tubular excretion of many medications, such as acetaminophen, acyclovir,  aminosalicylic acid, angiotensin-converting enzyme inhibitors,  barbiturates, benzodiazepines, bumetanide, clofibrate, famotidine,  furosemide, methotrexate, nonsteroidal anti-inflammatory agents,  theophylline, and zidovudine; these medications should be used with caution  when used concurrently with probenecid1) 

Zidovudine;(concurrent use with cidofovir, without probenecid, showed no evidence of an effect on the pharmacokinetics of zidovudine1) 

Laboratory value alterations 

The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate);not necessarily inclusive (>> = major clinical significance): 

With physiology/laboratory test values Creatinine, serum and1 Protein, urine1;(may be increased) 

Bicarbonate, serum and1 Neutrophils1;(may be decreased) 

Medical considerations/Contraindications 

The medical considerations/contraindications included have been selected on  the basis of their potential clinical significance (reasons given in  parentheses where appropriate);not necessarily inclusive (>> = major  clinical significance). 

Except under special circumstances, this medication should not be used when the following medical problem exists  >> Hypersensitivity to cidofovir or probenecid1; 

Risk-benefit should be considered when the following medical problem exists 

>> Renal function impairment1;(because cidofovir has been reported to be associated with severe renal function impairment, cidofovir is contraindicated in patients with a serum creatinine > 1.5 mL per dL, a creatinine clearance &pound; 55 mL per minute [0.92 mL per second], or a urine protein &sup3; 100 mg per dL [equivalent to &sup3; 2+ proteinuria]2) 

Patient monitoring 

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; >> = major clinical significance): 

>> Creatinine, serum and1 >> Protein, urine and1  >> White blood cell count with differential1;(because cidofovir has been reported to cause severe renal function impairment and cause neutropenia, these laboratory parameters should be monitored prior to each dose of cidofovir) 

>> Intraocular pressure1 >> Visual acuity1;(because cidofovir can cause ocular hypotony, especially  in patients with preexisting diabetes, intraocular pressure and visual  acuity should be monitored periodically) 

Side/Adverse Effects 

Note: Nephrotoxicity, the major dose-limiting toxicity of cidofovir  therapy, was manifested as > 1+ proteinuria, serum creatinine concentration  &sup3; 0.4 mg per dL, or a decrease in creatinine clearance to &pound; 55 mL per min (0.92 mL per second) in 53% of patients receiving a maintenance dose of 5 mg per kg of body weight every other week1. Proteinuria may be an early indicator of cidofovir-related nephrotoxicity and continued administration may lead to additional proximal tubular cell injury, resulting in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, and elevations in serum creatinine. Patients with these side effects and meeting a criteria of Fanconi's syndrome have been reported.1 There have also been reports of severe renal function impairment associated with cidofovir use2. To help reduce the risk of nephrotoxicity, patients must be pre-hydrated with at least 1 liter of 0.9% sodium chloride solution and probenecid must be administered at proper times.2 Dosage adjustment or discontinuation is necessary when changes in renal function occur during therapy. 

Neutropenia (&pound; 500 cells/mm3) occurred in 20% of patients receiving the 5 mg per kg of body weight maintenance dose in clinical trials. Granulocyte  colony stimulating factor was used in 34% of patients.1 

Ocular hypotony (&sup3; 50% change from baseline) was reported in 5 of 42  patients receiving the 5 mg per kg of body weight maintenance dose in  clinical studies. Hypotony was reported in one patient with concomitant  diabetes mellitus; the risk of ocular hypotony may be increased in patients  with pre-existing diabetes.1 

Two percent of study patients were diagnosed with Fanconi's syndrome, manifested by multiple abnormalities of proximal tubule function. Decreases in serum bicarbonate to &pound; 16 milliequivalents per liter associated with evidence of renal tubular damage occurred in approximately 9% of patients.1 

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate);not necessarily inclusive: 

Those indicating need for medical attention 

Incidence more frequent Nephrotoxicity1 decreased urination; increased thirst and urination); neutropenia1 (fever, chills, or sore throat) 

Incidence less frequent; Fever 

Incidence rare Ocular hypotony decreased vision or any change in vision) 

Those indicating need for medical attention only if they continue or are bothersome 

Incidence more frequent:  Gastrointestinal effects (diarrhea; loss of appetite; nausea; vomiting); headache 

Incidence less frequent Asthenia (generalized weakness; loss of strength) 

Overdose 

Overdosage with cidofovir has not been reported. However, probenecid may reduce potential nephrotoxicity through reduction of active tubular secretion. Hemodialysis and hydration may reduce plasma cidofovir concentrations.1 

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing). 

Patient Consultation 

In providing consultation, consider emphasizing the following selected information (>> = major clinical significance) 

Before using this medication 

>> Conditions affecting use, especially: 

Hypersensitivity to cidofovir or probenecid 

CarcinogenicityCidofovir is a carcinogen in animals and should be considered a potential carcinogen in humans 

Pregnancy;Cidofovir was embryotoxic and maternotoxic in animals; cidofovir should be administered only if the potential benefit justifies the potential risk to the fetus 

Breast-feeding;It is not known whether cidofovir is distributed into breast milk; however, it is recommended that HIV-infected women not breast-feed their infants to avoid postnatal transmission of HIV to a child who may not be infected 

Use in children;Safety and efficacy have not been established; however, cidofovir should be used with caution in HIV-infected children because of the potential risk of long-term carcinogenicity and reproductive toxicity 

Other medications, especially nephrotoxic medications and probenecid 

Other medical problems, especially renal function impairment 

Proper use of this medication 

>> Importance of receiving medication for full course of therapy and on a  regular schedule 

>> Proper dosing 

Precautions while using this medication 

>> Regular visits to physician to check blood counts 

>> Regular visits to ophthalmologist to examine eyes since progression of retinitis and visual loss may occur during cidofovir therapy 

Side/adverse effects 

Signs of potential side effects, especially, nephrotoxicity, neutropenia, fever, and ocular hypotony 

General Dosing Information 

Cidofovir must not be administered by intraocular injection. Direct injection may result in significant decreases in intraocular pressure and vision impairment.1 

Because cidofovir has been reported to be associated with severe renal  function impairment, the recommended dosage, frequency, or infusion rate  must not be exceeded. Cidofovir must be diluted in 100 mL of 0.9% sodium  chloride injection prior to administration. Probenecid and intravenous  sodium chloride prehydration must be administered with each cidofovir  infusion to minimize potential nephrotoxicity. The dose of cidofovir must  be reduced or discontinued if changes in renal function occur during  therapy. Serum creatinine and urine protein must be monitored within 48  hours prior to each dose of cidofovir.1,2 

The dose of cidofovir must be reduced or discontinued if changes in renal function occur during therapy. For increases in serum creatinine of 0.3 to 0.4 mg per dL (mg/dL) above baseline, the dose of cidofovir must be reduced from 5 mg per kg (mg/kg) to 3 mg/kg. Cidofovir must be discontinued for an increase in serum creatinine of 0.5 mg/dL above baseline or development of 

3+ proteinuria. Patients with 2+ proteinuria should be observed carefully; dose reduction or temporary discontinuation of treatment should be considered.2 

Two grams of probenecid should be administered 3 hours prior to each dose of cidofovir and 1 gram should be administered 2 and 8 hours after the completion of the 1-hour infusion (total 4 grams)1. 

Each dose of cidofovir should be administered with 1 liter of 0.9% sodium chloride injection, infused over 1 to 2 hours immediately before the cidofovir infusion. If the patient can tolerate the fluid load, a second liter of 0.9% sodium chloride injection should be started either at the beginning of the cidofovir infusion or immediately afterwards, over a 1- to 3-hour period.1 

Ingestion of food before each dose of probenecid may reduce nausea and vomiting associated with probenecid administration. Administration of an antiemetic may also reduce the potential for nausea. 

Safety considerations for handling this medication 

Due to the mutagenic potential of cidofovir, use of appropriate safety equipment is recommended for the preparation, administration, and disposal of cidofovir. The National Institutes of Health recommends that cidofovir be prepared in a Class II laminar flow biological safety cabinet and that personnel preparing this medication wear surgical gloves and a closed-front surgical-type gown with knit cuffs. If cidofovir contacts the skin, membranes should be washed and flushed thoroughly with water. Excess cidofovir and materials used in the admixture and administration procedures should be placed in a leak-proof, puncture-proof container. High temperature incineration is the recommended method of disposal.1 

Parenteral Dosage Forms 

CIDOFOVIR INJECTION 

Usual adult dose 

Antiviral; 

Induction: Intravenous infusion, 5 mg per kg of body weight, administered 

continuously over one hour, once a week for two consecutive weeks.  Probenecid must be administered with each dose of cidofovir. Two grams of  probenecid should be administered three hours prior to each dose of  cidofovir and 1 gram should be administered two and eight hours after the  completion of the one-hour infusion (total 4 grams).1 

Maintenance: Intravenous infusion, 5 mg per kg of body weight, administered  continuously over one hour, once every two weeks. Probenecid must be  administered with each dose of cidofovir. Two grams of probenecid should be  administered three hours prior to each dose of cidofovir and 1 gram should  be administered two and eight hours after the completion of the one-hour  infusion (total 4 grams).1 

Note: Cidofovir has not been studied in patients with pre-existing renal function impairment. The most appropriate dose of cidofovir for patients with a serum creatinine > 1.5 mg per mL or a creatinine clearance &pound; 55 mL per min (mL/min) is not known. However, the following doses (in mg per kg of body weight) are recommended when the benefits of cidofovir exceed the potential risks1: 

Creatinine Induction (once Maintenance (once every 2 Clearance weekly for 2 weeks) (mL/min) weeks) 41-55 2 mg per kg 2 mg per kg 30-40 1.5 mg per kg 1.5 mg per kg 20-29 1 mg per kg 1 mg per kg &pound; 19 0.5 mg per kg 0.5 mg per kg 

Usual pediatric dose 

Safety and efficacy have not been established.1 

Strength(s) usually available 

U.S.; 375 mg per 5 mL (Rx)[Vistide]. 

Packaging and storage: 

Store at room temperature between 20 and 25 &deg;C (68 and 77 &deg;F).1 

Preparation of dosage form: 

The vial should be visually inspected for particulate matter and discoloration prior to administration and discarded if particulate matter or discoloration is observed.1 

The appropriate volume of cidofovir should be extracted from the vial and  the dose transferred to an infusion bag containing 100 mL of 0.9% sodium  chloride solution. The entire volume should be infused into the patient at  a constant rate over a 1-hour period. It is recommended that a standard  infusion pump be used for administration.1 

Stability: 

It is recommended that cidofovir admixtures be administered within 24 hours of preparation and that refrigeration or freezer storage not be used to  extend this 24-hour limit.1 

If admixtures are not intended for immediate use, they may be refrigerated (between 2 and 8 &deg;C [36 and 46 &deg;F]) for no more than 24 hours. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.1 

Incompatibilities: 

Compatibility with Ringer's solution, Lactated Ringer's solution, or bacteriostatic infusion fluids has not been evaluated.1 

The chemical stability of cidofovir admixtures was determined in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles.1 

Note: Great care should be taken to prevent exposure of the skin to  cidofovir. The use of gloves is recommended. Any cidofovir that comes in  contact with the skin should be washed off thoroughly with soap and water.1 

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DATA-MÉDICOS/DERMAGIC-EXPRESS No (70) 15/09/99 DR. JOSÉ LAPENTA R. 

UPDATED 16 JUNE 2025

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Produced by Dr. José Lapenta R. Dermatologist

Venezuela 1.998-2.025