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Robert Snoeck - One of the best experts on this subject based on the ideXlab platform.
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insights into the mechanism of action of Cidofovir and other acyclic nucleoside phosphonates against polyoma and papillomaviruses and non viral induced neoplasia
Antiviral Research, 2015Co-Authors: Graciela Andrei, Dimitrios Topalis, T De Schutter, Robert SnoeckAbstract:Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (Cidofovir). In addition, Cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why Cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that Cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.
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adjuvant low dose Cidofovir therapy for bk polyomavirus interstitial nephritis in renal transplant recipients
American Journal of Transplantation, 2005Co-Authors: Dirk Kuypers, Robert Snoeck, Lieve Naesens, Annkarolien Vandooren, Evelyne Lerut, Pieter Evenepoel, Kathleen Claes, Yves VanrenterghemAbstract:BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose Cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8–32 mL/min; p = 0.001) and no graft loss occurred in Cidofovir-treated recipients during 24.8 (8–41) months follow-up. Peak serum Cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for Cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no Cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant Cidofovir therapy lost their graft after median 8 (4–40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose Cidofovir therapy resulted in prolonged graft survival and stabilized graft function.
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intravesical instillation of Cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient
Clinical Infectious Diseases, 2005Co-Authors: Panagiotis Fanourgiakis, Aspasia Georgala, Agnes Triffet, Jeanmarc De Bruyn, Valerie Duchateau, Marc Vekemans, P. Martiat, Erik De Clercq, Robert Snoeck, Elke WollantsAbstract:Hemorrhagic cystitis that occurs late after bone marrow transplantation (BMT) in BMT recipients is often associated with adenovirus or polyomavirus BK infections. Intravesical instillation of Cidofovir in a BMT recipient with intractable hemorrhagic cystitis resulted in clinical improvement. Local Cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of Cidofovir.
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phase ii double blind placebo controlled study of the safety and efficacy of Cidofovir topical gel for the treatment of patients with human papillomavirus infection
Clinical Infectious Diseases, 2001Co-Authors: Robert Snoeck, Michel Bossens, Dominique Parent, B Delaere, H Degreef, M Van Ranst, Jean Christophe Noel, M S Wulfsohn, J F Rooney, H S JaffeAbstract:Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of Cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received Cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the Cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P=.006). None of the patients in the Cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.
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treatment of severe laryngeal papillomatosis with intralesional injections of Cidofovir s 1 3 hydroxy 2 phosphonylmethoxypropyl cytosine
Journal of Medical Virology, 1998Co-Authors: Robert Snoeck, Erik De Clercq, Willy Wellens, Christian Desloovere, Mark Van Ranst, Lieve Naesens, Louw FeenstraAbstract:Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treatment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of Cidofovir was assessed in 17 patients with severe respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anesthesia. Biopsies were taken before the treatment was started both for anatomopathology and viral typing. HPMPC kinetics in serum was monitored in three patients, the drug levels being determined by high-performance liquid chromatography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with Cidofovir. Of the three remaining patients, one progressed while under treatment with Cidofovir, after an initial marked response. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and extensive disease originally. Finally, one patient was lost to follow-up after four injections. Intratumoral injections of Cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Severe Laryngeal Papillomatosis With Intralesional Injections of Cidofovir
2016Co-Authors: Erik De Clercq, Louw FeenstraAbstract:Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treat-ment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of Cidofovir was assessed in 17 patients with se-vere respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anes-thesia. Biopsies were taken before the treatment was started both for anatomopathology and vi-ral typing. HPMPC kinetics in serum was moni-tored in three patients, the drug levels being de-termined by high-performance liquid chroma-tography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with Cidofovir. Of the three remain-ing patients, one progressed while under treat-ment with Cidofovir, after an initial marked re-sponse. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and ex-tensive disease originally. Finally, one patient was lost to follow-up after four injections. Intra-tumoral injections of Cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted. J. Med. Virol. 54:219
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intravesical instillation of Cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient
Clinical Infectious Diseases, 2005Co-Authors: Panagiotis Fanourgiakis, Aspasia Georgala, Agnes Triffet, Jeanmarc De Bruyn, Valerie Duchateau, Marc Vekemans, P. Martiat, Erik De Clercq, Robert Snoeck, Elke WollantsAbstract:Hemorrhagic cystitis that occurs late after bone marrow transplantation (BMT) in BMT recipients is often associated with adenovirus or polyomavirus BK infections. Intravesical instillation of Cidofovir in a BMT recipient with intractable hemorrhagic cystitis resulted in clinical improvement. Local Cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of Cidofovir.
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Cidofovir in the treatment of poxvirus infections
Antiviral Research, 2002Co-Authors: Erik De ClercqAbstract:Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] has since 1996 been licensed for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir has broad-spectrum activity against virtually all DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among the poxviruses, vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, molluscum contagiosum and orf have proven sensitive to the inhibitory effects of Cidofovir. In vivo, Cidofovir has shown high efficacy, even after administration of a single systemic (intraperitoneal) or intranasal (aerosolized) dose, in protecting mice from a lethal respiratory infection with either vaccinia or cowpox. Cidofovir has also demonstrated high effectiveness in the treatment of vaccinia virus infection in severe combined immune deficiency mice. In humans, Cidofovir has been used successfully in the treatment, by both the topical and intravenous route, of recalcitrant molluscum contagiosum and orf in immunocompromised patients. Taken together, these data indicate that Cidofovir should be effective in the therapy and short-term prophylaxis of smallpox and related poxvirus infections in humans, as well as the treatment of the complications of vaccinia that may arise in immunocompromised patients inadvertently inoculated with the smallpox vaccine (vaccinia).
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the effects of Cidofovir 1 with and without cyclosporin a 1 as a topical treatment of acute adenoviral keratoconjunctivitis a controlled clinical pilot study
Ophthalmology, 2002Co-Authors: Jost Hillenkamp, Erik De Clercq, Thomas Reinhard, R S Ross, Daniel Bohringer, Olaf Cartsburg, Michael Roggendorf, Erhard Godehardt, Rainer SundmacherAbstract:Abstract Objective To evaluate the efficacy of Cidofovir 1% eyedrops with and without cyclosporin A 1% eyedrops as a treatment of acute adenoviral keratoconjunctivitis (AKC). Design Randomized, controlled trial. Participants Thirty-four patients with acute adenoviral keratoconjunctivitis of recent onset. Methods Patients were divided into 4 treatment groups: 1) Cidofovir four times daily, 2) Cidofovir 10 times daily, 3) Cidofovir four times daily and cyclosporin A four times daily, and 4) sodium chloride four times daily (control). The diagnosis was confirmed by adenoviral polymerase chain reaction from conjunctival swabs. Duration of treatment was 21 days. Main outcome measures Severity of conjunctival injection, conjunctival chemosis, punctate epithelial keratitis during the course of treatment, and presence and severity of corneal subepithelial infiltrates were evaluated by a clinical score. Duration until subjective improvement of symptoms was recorded. Results The frequency of severe corneal opacities was lower with Cidofovir ( P = 0.048). Cidofovir was toxic locally to the skin of the eyelids and the conjunctiva in a dose-dependent manner. Symptoms of local toxicity were clinically similar to the signs of the initial viral inflammation. They first appeared 8 to 12 days after beginning of treatment and completely subsided 7 to 28 days after discontinuation of Cidofovir. The outcome measures of local inflammation did not differ between the four treatment groups. Cyclosporin A did not alter the course of the infection. Conclusions Cidofovir lowers the frequency of severe corneal opacities, but its clinical use 4 to 10 times daily at a 1% concentration is limited by local toxicity. Further clinical studies to find an efficacious yet tolerable dosage regimen of Cidofovir, possibly using an improved pharmaceutical preparation, are required.
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topical treatment of acute adenoviral keratoconjunctivitis with 0 2 Cidofovir and 1 cyclosporine a controlled clinical pilot study
Archives of Ophthalmology, 2001Co-Authors: Jost Hillenkamp, Erik De Clercq, Thomas Reinhard, R S Ross, Daniel Bohringer, Olaf Cartsburg, Michael Roggendorf, Erhard Godehardt, Rainer SundmacherAbstract:Objective To evaluate the efficacy of 0.2% Cidofovir eyedrops and 1% cyclosporine eyedrops administered 4 times daily (qid) to treat acute adenoviral keratoconjunctivitis. Methods A randomized, controlled, double-masked study was conducted on 39 patients with acute adenoviral keratoconjunctivitis of recent onset. Patients were divided into 4 treatment groups: (1) Cidofovir qid, (2) cyclosporine qid,(3) Cidofovir + cyclosporine qid, and (4) sodium chloride qid (control). The diagnosis was confirmed using adenoviral polymerase chain reaction from conjunctival swabs. Duration of treatment was 21 days. Main Outcome Measures Severity of conjunctival hyperemia, conjunctival chemosis, superficial punctate keratitis during treatment, and presence and severity of corneal subepithelial infiltrates were evaluated using a clinical score. Duration until subjective improvement of symptoms was recorded. Results Subjective improvement of local symptoms was accelerated in the cyclosporine group. All other clinically relevant variables showed no statistically significant difference among the 4 treatment groups. Particularly, we did not find a difference in the frequency of corneal subepithelial infiltrates at the end of treatment. Conclusions Use of Cidofovir, cyclosporine, or both did not accelerate the improvement of clinical symptoms of acute adenoviral keratoconjunctivitis compared with the natural course of the infection as demonstrated by this pilot study. This might be because of the wide spectrum of the clinical course of the infection, low sensitivity to Cidofovir, too low of a concentration of Cidofovir, or early cessation of viral replication in the course of the infection. The effect of a higher concentration of topical Cidofovir with and without cyclosporine requires investigation in a larger group of patients.
H S Jaffe - One of the best experts on this subject based on the ideXlab platform.
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phase ii double blind placebo controlled study of the safety and efficacy of Cidofovir topical gel for the treatment of patients with human papillomavirus infection
Clinical Infectious Diseases, 2001Co-Authors: Robert Snoeck, Michel Bossens, Dominique Parent, B Delaere, H Degreef, M Van Ranst, Jean Christophe Noel, M S Wulfsohn, J F Rooney, H S JaffeAbstract:Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of Cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received Cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the Cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P=.006). None of the patients in the Cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.
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intravenous Cidofovir for peripheral cytomegalovirus retinitis in patients with aids a randomized controlled trial
Annals of Internal Medicine, 1997Co-Authors: Jacob Lalezari, Francoise Kramer, W L Drew, R J Stagg, Baruch D Kuppermann, Gary N Holland, David V Ives, M Youle, Michael R Robinson, H S JaffeAbstract:Background: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. Objective: To determine whether intravenous Cidofovir delays progression of previously untreated CMV retinitis. Design: Randomized, controlled trial comparing immediate with deferred Cidofovir treatment. Patients in the deferred treatment group were eligible to receive Cidofovir after progression of CMV retinitis was documented by retinal photography. Setting: Eight academic medical centers and an independent center that read retinal photographs. Patients: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). Intervention: Intravenous Cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each Cidofovir infusion. Measurements: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. Results: The median time to progression of CMV retinitis was 22 days (95% Cl, 10 to 27 days) in the deferred treatment group and 120 days (Cl, 40 to 134 days) in the immediate treatment group (P< 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to Cidofovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). Conclusions: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before Cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity.
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Cidofovir a new agent with potent anti herpesvirus activity
Antiviral Chemistry & Chemotherapy, 1996Co-Authors: Michael J M Hitchcock, H S Jaffe, John C Martin, R J StaggAbstract:Cidofovir is a potent, broad spectrum antiviral agent with activity in vitro and in vivo against cytomegalovirus and other members of the herpesvirus family, as well as certain other DNA viruses. After uptake into cells it is converted enzymatically to Cidofovir diphosphate, a structural analogue of deoxycytidine triphosphate, which selectively inhibits viral DNA polymerases relative to host cell polymerases. Cross-resistance to Cidofovir is not usually seen with human cytomegalovirus isolates that are foscarnet-resistant, or isolates that are ganciclovir-resistant due to a deficiency in ganciclovir phosphorylation. Cross-resistance is seen, however, with isolates that are ganciclovir resistant due to polymerase mutations. A prolonged elimination phase seen in vivo, correlates with a long intracellular half-life seen in vitro and allows for efficacy in animal models of virus infection with infrequent dosing or prophylaxis. Clinical studies of intravenous Cidofovir in cytomegalovirus retinitis in patients ...
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clinical pharmacokinetics of Cidofovir in human immunodeficiency virus infected patients
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: Kenneth C Cundy, Michael J M Hitchcock, Jacob Lalezari, J Flaherty, P E Fisher, Brent G Petty, Michael A Polis, M Wachsman, Paul S Lietman, H S JaffeAbstract:The pharmacokinetics of Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of Cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of Cidofovir. The steady-state volume of distribution of Cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with Cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous Cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of Cidofovir at a 3.0-mg/kg dose. At higher Cidofovir doses, probenecid appeared to block tubular secretion of Cidofovir and reduce its renal clearance to a level approaching glomerular filtration.
Jacob Lalezari - One of the best experts on this subject based on the ideXlab platform.
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randomized controlled study of the safety and efficacy of intravenous Cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with aids
Journal of Acquired Immune Deficiency Syndromes, 1998Co-Authors: Jacob Lalezari, Francoise Kramer, Baruch D Kuppermann, Gary N Holland, David V Ives, G F Mckinley, Carol A Kemper, R Nelson, W D Hardy, D W NorthfeltAbstract:To assess the effect of intravenous Cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of Cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction Cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each Cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to Cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.
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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
The Journal of Infectious Diseases, 1997Co-Authors: Jacob Lalezari, Lawrence Corey, Timothy W Schacker, Judith Feinberg, Joseph Gathe, Tony Cheung, Francoise Kramer, Harold A Kessler, Lawrence W Drew, John BoggsAbstract: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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intravenous Cidofovir for peripheral cytomegalovirus retinitis in patients with aids a randomized controlled trial
Annals of Internal Medicine, 1997Co-Authors: Jacob Lalezari, Francoise Kramer, W L Drew, R J Stagg, Baruch D Kuppermann, Gary N Holland, David V Ives, M Youle, Michael R Robinson, H S JaffeAbstract:Background: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. Objective: To determine whether intravenous Cidofovir delays progression of previously untreated CMV retinitis. Design: Randomized, controlled trial comparing immediate with deferred Cidofovir treatment. Patients in the deferred treatment group were eligible to receive Cidofovir after progression of CMV retinitis was documented by retinal photography. Setting: Eight academic medical centers and an independent center that read retinal photographs. Patients: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). Intervention: Intravenous Cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each Cidofovir infusion. Measurements: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. Results: The median time to progression of CMV retinitis was 22 days (95% Cl, 10 to 27 days) in the deferred treatment group and 120 days (Cl, 40 to 134 days) in the immediate treatment group (P< 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to Cidofovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). Conclusions: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before Cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity.
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clinical pharmacokinetics of Cidofovir in human immunodeficiency virus infected patients
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: Kenneth C Cundy, Michael J M Hitchcock, Jacob Lalezari, J Flaherty, P E Fisher, Brent G Petty, Michael A Polis, M Wachsman, Paul S Lietman, H S JaffeAbstract:The pharmacokinetics of Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of Cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of Cidofovir. The steady-state volume of distribution of Cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with Cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous Cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of Cidofovir at a 3.0-mg/kg dose. At higher Cidofovir doses, probenecid appeared to block tubular secretion of Cidofovir and reduce its renal clearance to a level approaching glomerular filtration.
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s 1 3 hydroxy 2 phosphonylmethoxy propyl cytosine Cidofovir results of a phase i ii study of a novel antiviral nucleotide analogue
The Journal of Infectious Diseases, 1995Co-Authors: Jacob Lalezari, W L Drew, E Glutzer, C J James, D Miner, J Flaherty, P E Fisher, K Cundy, J Hannigan, J C MartinAbstract:Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase I/II study with 2 regimens of Cidofovir: Cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and Cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all Cidofovir regimens > or = 3.0 mg/kg. The dose-limiting toxicity of Cidofovir was dose- and schedule-dependent nephrotoxicity. Four of 20 patients had serum creatinine levels > or = 2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg Cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean Cidofovir exposure, 32.2 mg/kg). The clinical efficacy of Cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.
Louw Feenstra - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Severe Laryngeal Papillomatosis With Intralesional Injections of Cidofovir
2016Co-Authors: Erik De Clercq, Louw FeenstraAbstract:Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treat-ment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of Cidofovir was assessed in 17 patients with se-vere respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anes-thesia. Biopsies were taken before the treatment was started both for anatomopathology and vi-ral typing. HPMPC kinetics in serum was moni-tored in three patients, the drug levels being de-termined by high-performance liquid chroma-tography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with Cidofovir. Of the three remain-ing patients, one progressed while under treat-ment with Cidofovir, after an initial marked re-sponse. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and ex-tensive disease originally. Finally, one patient was lost to follow-up after four injections. Intra-tumoral injections of Cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted. J. Med. Virol. 54:219
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treatment of severe laryngeal papillomatosis with intralesional injections of Cidofovir s 1 3 hydroxy 2 phosphonylmethoxypropyl cytosine
Journal of Medical Virology, 1998Co-Authors: Robert Snoeck, Erik De Clercq, Willy Wellens, Christian Desloovere, Mark Van Ranst, Lieve Naesens, Louw FeenstraAbstract:Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treatment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of Cidofovir was assessed in 17 patients with severe respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anesthesia. Biopsies were taken before the treatment was started both for anatomopathology and viral typing. HPMPC kinetics in serum was monitored in three patients, the drug levels being determined by high-performance liquid chromatography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with Cidofovir. Of the three remaining patients, one progressed while under treatment with Cidofovir, after an initial marked response. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and extensive disease originally. Finally, one patient was lost to follow-up after four injections. Intratumoral injections of Cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted.
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treatment of severe laryngeal papillomatosis with intralesional injections of Cidofovir s 1 3 hydroxy 2 phosphonylmethoxypropyl cytosine
Journal of Medical Virology, 1998Co-Authors: Robert Snoeck, Erik De Clercq, Willy Wellens, Christian Desloovere, Lieve Naesens, Mark Van Ranst, Louw FeenstraAbstract:Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treatment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of Cidofovir was assessed in 17 patients with severe respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anesthesia. Biopsies were taken before the treatment was started both for anatomopathology and viral typing. HPMPC kinetics in serum was monitored in three patients, the drug levels being determined by high-performance liquid chromatography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with Cidofovir. Of the three remaining patients, one progressed while under treatment with Cidofovir, after an initial marked response. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and extensive disease originally. Finally, one patient was lost to follow-up after four injections. Intratumoral injections of Cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted. J. Med. Virol. 54:219– 225, 1998. © 1998 Wiley-Liss, Inc.