Treatment of intraurethral condylomata acuminata with surgery and cidofovir instillations in two immunocompromised patients and review of the literature.

Condylomata acuminata (CA) or anogenital warts are benign proliferative lesions caused by low-risk human papillomaviruses (HPV). Treating CA can be very frustrating for patients and clinicians due to the high recurrence rates. Immunosuppression is associated with larger size of CA that are more frequently resistant to treatment. Surgical approaches tend to be poorly effective in the long-term because of high recurrence rates related to the persistence of HPV-infected cells. In our search to find an agent to treat intraurethral CA with minor or no side effects, we evaluated intraurethral cidofovir in two male patients, who were under immunosuppressing therapy due to organ transplantation and suffered from extensive urethral HPV lesions. Both patients underwent biopsy of the lesions and initial transurethral resection. In our first case, intraurethral cidofovir instillations were started after 2 months due to recurrence after surgical treatment. In our second case, intraurethral cidofovir was administered after surgery because of incomplete resection of extensive lesions. Because of persistent or rapidly recurrent lesions despite intraurethral cidofovir instillations, the first patient needed two additional surgical interventions while the second patient underwent one additional surgical intervention. After surgical intervention, both patients received again adjuvant cidofovir instillations without side effects. Over a period of 56 weeks, both patients received each a total of 28 instillations with cidofovir. Following 3.5 years (patient 1) of the last cidofovir instillation, no recurrences were observed in our first patient. Following 6 months of the last cidofovir instillation (patient 2), two very small recurrent lesions in the most distal part of the urethra were observed in our second patient for which he will receive a cycle of 6 cidofovir instillations in the near future. Intraurethral cidofovir is a safe, easy-to-use, well-tolerated and an effective adjuvant to surgery for extensive intraurethral CA in immunocompromised patients.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 1. Polymerized anionic surfactants.

A series of polyanionic compounds was synthesized and evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. Several compounds, i.e., 2p, 3p, 8p, 13p, 14p, 15p, 17p, 18p, and 19p, proved active against HIV-1 within the concentration range of 0.1-3 micrograms/mL while not being toxic to the host cells (CEM, MT-4) at concentrations up to 100 micrograms/mL or higher. As a rule, these polyanionic compounds proved also active, albeit at somewhat higher concentrations than those required for HIV-1 inhibition, against a number of other enveloped viruses, including HIV-2, human cytomegalovirus, influenza A virus, respiratory syncytial virus, and arenaviruses (Junin and Tacaribe). Among the most potent HIV-1 inhibitors ranked compounds 18p and 19p, the sodium salts of N-methylamides obtained by polymerization of monomers prepared starting from 10-undecenoyl chloride and omega-aminoalkanoic acids.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 5. Telomerized anionic surfactants derived from amino acids.

omega-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1 or HIV-2) and various other RNA and DNA viruses. With regard to their anti-HIV activity, a minimum number of anionic groups was necessary to achieve an inhibitory effect. Moreover, to be active the overall conformation of the polyanion must be such that the anionic groups are located on the external site of the molecule. With some of the polyanions, a 50% inhibition concentration (IC50) as low as 1 microgram/ mL, or even 0.1 microgram/mL, was noted against HIV-1 in CEM-4 and MT-4 cells, respectively. The most potent polyanions also proved active against human cytomegalovirus and herpex simplex virus at concentrations of 5-10 and 20-40 micrograms/mL, respectively. No activity was observed against any of the other viruses tested (i.e., vesicular stomatitis, Sindbis, Semliki forest, parainfluenza, Junin, Tacaribe, Coxsackie, polio, reo, and vaccinia). No toxicity for the host cells was observed at concentrations up to 200 micrograms/mL.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 6. Micelle-like anti-HIV polyanionic compounds based on a carbohydrate core.

A new class of polyanionic compounds, inhibitors of human immunodeficiency virus, was obtained from radical addition of mercapto acid or mercapto ester on a perallylated carbohydrate under UV irradiation with a catalytic amount of AIBN. Unlike the polyanions that we have previously prepared by polymerization reactions, the compounds are structurally well defined. Polyanions bearing 16 carboxylate groups showed a 50% inhibitory concentration (IC50) of 0.1-4.1 micrograms/mL against HIV-1 in MT-4 cells while not being toxic to the host cells at concentrations up to 125 micrograms/mL. The most potent polyanions also proved active against human cytomegalovirus at concentrations of 1-14 micrograms/mL. No activity was observed against any of the other viruses tested (i.e., herpes simplex virus, vesicular stomatitis virus, Sindbis, Semliki forest, parainfluenza-3, Junin, Tacaribe, Coxsackie B4, polio-1, reo-1, or vaccinia virus).

Sensitive, reproducible and convenient fluorometric assay for the in vitro evaluation of anti-cytomegalovirus agents.

Fluorescein diacetate (FDA), a non-fluorescent diacetyl fluorescein ester that becomes fluorescent upon hydrolysis by cytoplasmic esterases, permitted the easy distinction by fluorometry between non-infected and human cytomegalovirus (CMV)-infected HEL cell cultures. As a result of enhanced cytoplasmic esterase activity after CMV infection, FDA-derived fluorescence intensity was brighter for infected than non-infected HEL cells. A similar increase in fluorescence intensity was observed after loading the cells with Indo-1/AM, a non-fluorescent ester of Indo-1 that becomes fluorescent upon cleavage by cytoplasmic esterases. The 50% effective concentrations of a number of anti-CMV agents as determined by the fluorometric assay were very similar to those obtained by the conventional and more time-consuming microscopic evaluation. The fluorometric assay appears very suitable for an automated evaluation of anti-CMV compounds, and also allows rapid determination of the cytotoxicity of potential antiviral compounds.

Sulfated polymers inhibit the interaction of human cytomegalovirus with cell surface heparan sulfate.

Several sulfated polysaccharides (dextran sulfate, pentosan polysulfate, heparin) and copolymers of acrylic acid with vinylalcohol sulfate have proved to be potent inhibitors of human cytomegalovirus (CMV) infectivity in vitro. Sulfated alpha-cyclodextrins are only weak inhibitors of CMV. A close correlation was found between the 50% inhibitory concentrations of the sulfated polymers for CMV cytopathogenicity, virus-cell binding, and expression of immediate early antigens (IEA) in human embryonic lung (HEL) cells. CMV particles bound specifically to heparin-Sepharose. Sulfated polymers specifically eluted the virus particles from this matrix. Enzymatic digestion of cell surface heparan sulfate, but not of chondroitin sulfate, prevented the cells from being infected with CMV. Moreover, radiolabeled CMV bound efficiently to, and were infective for wild-type Chinese hamster ovary (CHO) cells, whereas virus binding to, and infection of, mutant CHO cell lines that were deficient in either all glycosaminoglycans or heparan sulfate only was significantly impaired. The mechanism of action of the sulfated polymers can be attributed to an inhibitory effect on the binding of CMV particles to the host cells. Presumably, the sulfated polymers interact with the viral envelope site(s) involved in the attachment of the CMV virions to cell surface heparan sulfate.