Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.     

Progressive multifocal leukoencephalopathy: value of diffusion-weighted and contrast-enhanced magnetic resonance imaging for diagnosis and treatment control

Progressive multifocal leukoencephalopathy (PML) is caused by the replication of JC virus in oligodendrocytes of immunocompromised patients. Diagnosis usually relies on the polymerase chain reaction (PCR)-based demonstration of JC virus DNA in the cerebrospinal fluid. As previous reports have suggested that some patients may benefit from antiviral therapy, non-invasive early diagnosis is highly desirable. Repetitive magnetic resonance imaging (MRI) examinations (two to nine) were obtained in seven patients (aged 40–67 years, six males, one female) with classical clinical and imaging findings of PML. Five patients had underlying hematological disorders and two acquired immune deficiency syndrome. PCR of the cerebrospinal fluid (CSF) specimen was positive for JC virus DNA in six patients. MRI sequences included T2-, T1- and diffusion-weighted (DW) images in all patients and diffusion-tensor imaging (DTI) in four cases. DTI was once performed at 3T, in the remaining patients at 1.5T. All patients received antiviral treatment with cidofovir in addition to the treatment of the underlying disorder. MRI showed areas of T2 hyperintensity with involvement of the subcortical U-fibers and restricted diffusion in all patients. Areas of diffusion abnormality correlated with disease progress. Contrast enhancement was encountered once after successful treatment and heralded clinical remission with virus elimination from the CSF. Hence, MRI including DW and contrast-enhanced images may be used to evaluate disease activity. Contrast enhancement may indicate an inflammatory response and thus herald immunologic virus elimination.     

Treatment of verruca vulgaris with topical cidofovir in an immunocompromised patient: a case report and review of the literature

Lesions caused by verrucus vulgaris are commonly refractory to therapy and may become large, painful, or disfiguring in immunocompromised patients. Cidofovir is a potent nucleoside analog antiviral agent shown to have in vitro and in vivo activity against a broad spectrum of DNA viruses. We report a successful use of topical cidofovir to treat verruca vulgaris lesions in a highly immunocompromised patient, who was not considered a candidate for conventional therapy.     

西多福韦的合成

目的:合成西多福韦。方法:以(R)-缩水甘油为原料,经保护羟基、与碱基缩合,保护氨基,与侧链缩合和脱保护等反应合成西多福韦。结果:目标化合物经核磁共振氢谱、红外、熔点等确证其化学结构,总收率达22%。结论:该路线反应条件温和,步骤较短,适合工业化生产。     

Intralesional cidofovir therapy for laryngeal papilloma in an adult cohort

OBJECTIVES: To confirm the safety and efficacy of intralesional cidofovir in the management of laryngeal papilloma and to identify variables that correlate with number of injections needed to achieve remission. STUDY DESIGN: An open-trial prospective evaluation of the efficacy of intralesional cidofovir in subjects with laryngeal papilloma. METHODS: Fourteen adult subjects with biopsy-proven laryngeal papilloma were enrolled in a treatment study of intralesional cidofovir. Preprotocol disease duration ranged from 1 to 30 years with a mean duration of 7 years. Subjects received monthly injections of cidofovir with a maximum dose of 37.5 mg per injection in 6 cc saline (6.25 mg/mL). Injections were repeated until no papilloma could be visually identified during an intraoperative evaluation. After disease remission was achieved, subjects received an additional injection. All injections occurred during suspension microlaryngoscopy. RESULTS: All subjects have achieved disease remission using an injection-only treatment protocol. No additional laryngeal scarring or systemic toxicity was identified. On average, 6 injections were required to achieve remission. Preprotocol disease duration and anatomical staging correlated positively with the number of injections required for disease remission. CONCLUSIONS: Intralesional injection of cidofovir is an excellent treatment option with limited local and systemic toxicities. The injection therapy regimen requires perseverance from both patient and surgeon. Remission of disease can be achieved in adults with laryngeal papilloma.     

Use of cidofovir in polyomavirus BK viral nephropathy in two renal allograft recipients

Polyomavirus BK viral allograft nephropathy is a potentially reversible cause of deteriorating function of kidney allografts. Initial treatment involves reducing immunosuppressive medications, with low-dose cidofovir an effective alternative in refractory cases. We describe two cases of BK viral allograft nephropathy responding to low-dose cidofovir after a reduction in immunosuppressive medications failed to clear the virus or stabilize the deterioration in renal function. There were no significant side-effects from this treatment in either patient.     

Local and systemic effects of intralaryngeal injection of cidofovir in a canine model

OBJECTIVE: The safety of intralaryngeal injection of cidofovir remains a concern. Our goal was to evaluate local and systemic effects of intralaryngeal injection of cidofovir. STUDY DESIGN: Animal study using a canine model. METHODS: Two groups of three young beagle dogs (6 vocal folds in each group) were used. Subepithelial vocal fold injections were performed in each group biweekly for 6 months with 0, 2.5, 5, 10, 20, and 37.5 mg cidofovir in a 0.5 mL volume. Direct laryngoscopy was performed at each injection interval. Complete blood cell count and renal parameters were measured at baseline and monthly thereafter. Histopathologic examination of the vocal folds was performed after the 6-month injection period in one group of animals and after an additional 6-month observation period in the second group. RESULTS: Endomysial edema with muscle fiber separation and dose-dependent atrophy and scarring of the vocal folds was present. Onset of atrophy and scarring was observed after 3, 7, and 11 injections in the vocal folds injected with 37.5, 20, and 10 mg cidofovir, respectively. After the 6-month observation period, recovery of histologic abnormalities was complete in the low-dose (0, 2.5 mg) vocal folds, near complete in the intermediate-dose (5, 10 mg) vocal folds, and no apparent recovery was seen in the high-dose (20, 37.5 mg) vocal folds. Leukocyte count and renal parameters remained unchanged at up to 4.26 mg/kg body weight of systemic dose of cidofovir. CONCLUSIONS: Intralaryngeal cidofovir leads to dose-dependent scarification of the vocal folds that appears irreversible at higher doses. Lower concentrations of this drug should be used in intralesional intralaryngeal use.     

Aryl Ester Prodrugs of Cyclic HPMPC. I: Physicochemical Characterization and In Vitro Biological Stability

Purpose. The chemical, enzymatic, and biological stabilities and physical properties of a series of salicylate and aryl ester prodrugs of the antiviral agent, cyclic HPMPC, were evaluated to support the selection of a lead compound for clinical development. Methods. Chemical stabilities of the prodrugs in buffered solutions at 37°C were determined. Stability was also studied in the presence of porcine liver carboxyesterases (PLCE) at pH 7.4 and 25°C. Tissue stabilities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined by reverse phase HPLC. Results. Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cyclic HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent. Conclusions. The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.