Treatment of a bowenoid papulosis of the penis with local applications of cidofovir in a patient with acquired immunodeficiency syndrome.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
R Snoeck
Publications and source records attributed to R Snoeck.
Bicyclic anti-VZV nucleosides: Thieno analogues retain full antiviral activity.
Thieno analogues of the potent and selective furo-pyrimidine anti-VZV nucleoside family are herein reported. The compounds retain full antiviral potency in comparison to the furo parent.
Antiviral Agents↗
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.
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.
Adult↗
Bicyclic nucleoside inhibitors of Varicella-Zoster Virus (VZV): the effect of terminal unsaturation in the side chain.
Novel bicyclic nucleoside analogues bearing long alkyl side chains are prepared and tested as inhibitors of VZV. In particular, analogues with terminal unsaturation in the side chain are reported. Whilst terminal alkenyl derivatives are potent antivirals, the corresponding terminal alkynyls are poorly active.
Antiviral Agents↗
Systemic cidofovir in papillomatosis.
An 8-year-old patient with severe recurrent respiratory papillomatosis and pulmonary spread was treated by systemic administration of cidofovir in association with laser treatment for tracheal lesions. Complete disappearance of the lesions in the pharynx and larynx and a significant yet incomplete regression in the bronchi and lung parenchyma were observed without deleterious side effects. This is the first case report of systemic use of cidofovir to treat recurrent respiratory papillomatosis.
Antiviral Agents↗
Successful treatment of recurrent vulvar intraepithelial neoplasia resistant to interferon and isotretinoin with cidofovir.
Vulvar intraepithelial neoplasias are difficult to eradicate completely without extensive surgical intervention. Cidofovir, a deoxycytidine monophosphate analog, may have a therapeutic role in this disease. A 43-year-old woman with a 20-year history of genital warts presented with extensive vulvar intraepithelial neoplasia III, and refused surgical resection. Topical cidofovir 1% in Beeler base completely eradicated the lesion. Successive treatment applications, however, were necessary. Cidofovir is a promising topical antiviral compound for HPV induced vulvar intraepithelial neoplasia.
Administration, Oral↗
A case of human orf in an immunocompromised patient treated successfully with cidofovir cream.
Immunocompromised patients may have severe forms of infections. Since there is an increasing number of patients maintained under immunosuppressive therapy, we will be confronted with increasing frequency with these infectious problems. Effective treatments will be of great value. The case is described of a renal transplant with a giant orf lesion, which continued growing instead of regressing spontaneously as is observed usually. The treatment options in such patients are limited. It was decided to treat the patient with the antiviral drug cidofovir (HPMPC, Vistide. Topical cidofovir treatment resulted in complete regression of the lesion. This case is discussed in the context of the known literature on orf (ecthyma contagiosum).
Administration, Topical↗
Synthesis and antiviral/antitumor evaluation of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes and related compounds as a new class of diarylsulfones.
Based on general SARs previously described for anti-HIV-1 diarylsulfone derivatives, a series of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes has been prepared and evaluated as potential antiviral and antitumor agents. In cell culture, some of the 2-aminothiophenes exhibited moderate and selective activity against HIV-1, with 2-amino-3-(2-nitrophenylsulfonyl)thiophene (7e) being most attractive (EC(50)=3.8 microg/mL, CC(50)=>100 microg/mL). In broad-spectrum antiviral assays, the 3-arylsulfonyl-2-(trifluoroacetamido)thiophenes (8c-g) and 2-acetamido-3-arylsulfonyl-5-nitrothiophenes (9f-g) proved considerably active (IC(50)=0.1-10 microg/mL) against human cytomegalovirus (CMV) and/or varicella zoster virus (VZV). Based on the activity of the trifluoroacetamides, ring-modified furan, N-(substituted)pyrrole, phenyl, and 3,4-thiophene analogues were prepared, and these compounds were also active against CMV and/or VZV, with the notable exception of the 3,4-thiophene derivative. In contrast to other amines, the 2-aminopyrrole precursors (13a-d) also exhibited potent activity against CMV. Unfortunately, most of these compounds displayed significant cytotoxicity against human fibroblasts, the cells supporting CMV and VZV replication, and thus selectivity indices were low. The most notable exception to this was the naphthyl-substituted aminopyrrole 13d, which exhibited both potent (IC(50)=0.3 microg/mL) and selective (CC(50)=>50 microg/mL) activity against CMV. Finally, thiophene aryl amides 8i-k displayed moderate in vitro activity against certain leukemia, breast, and colon cancer cell lines.
Anti-HIV Agents↗
Kaposi's sarcoma, oncogenic viruses, and iron.
INTRODUCTION: Iron is required for many cellular processes, but it is also toxic in excess quantities. Therefore, iron homeostasis and utilization must be strictly maintained, and defects in iron absorption or transport result in iron depletion or accumulation. Most research has been directed to enteral and placental transfer of iron, but little is known about iron entry through the skin. We present evidence that exposure to wet clay soils in Africa is an important risk factor for Kaposi's sarcoma (KS) and speculate that iron may be responsible for soil toxicity contributing to the pathogenesis of KS. STUDY DESIGN: Evidence gathered from case control studies and related investigations in Uganda between 1995 and 1998 are summarized. RESULTS: A large case control study of KS in HIV-infected adults disclosed affluence and mobility that suggest enhanced sexual exposure to human herpesvirus-8, the putative aetiologic agent of KS. Another study in endemic KS (HIV-negative) also showed affluence and mobility as risk factors. In addition, barefoot exposure to wet soil was an important risk factor for men with endemic KS. Other studies point to diminish delayed hypersensitivity in the lower limbs of KS patients. Geographic similarities of KS to podoconiosis (non-filarial elephantiasis) in Africa implicate soil absorbtion through the skin in the pathogenesis of KS and podoconiosis. CONCLUSION: The hypothesis of soil exposure as a risk for endemic KS has been strengthened by recent investigation. Particulate soil exposure may cause localized microtrauma and inflammation, predisposing to KS on the extremities in HHV-8 infected men. A role for iron toxicity is yet to be determined.
Case-Control Studies↗
Synthesis of imidazo[1,2-a]pyridine derivatives as antiviral agents.
The synthesis and antiviral activity of original dibromoimidazo[1,2-a]pyridines bearing a thioether side chain are reported. Molecular modeling was used to identify biophoric structural patterns that are common to 16 compounds. Structure-activity relationship (SAR) studies identified hydrophobicity (logP) as the most important factor for activity. From these SAR studies, the antiviral activity could be predicted.
Anti-HIV Agents↗
Synthesis and anti-HIV activity of thymidine analogues bearing a 4'-cyanovinyl group and some derivatives thereof.
Treatment of 3'-O-tert-butyldimethylsilyl-2',5'-dideoxy-5'-oxothymidine (4) with potassium or magnesium nitromethanide afforded in good yield the resolvable epimeric mixture of the expected blocked nitronucleosides 5 which upon dehydration led to the corresponding E-nitroenofuranosylthymidine 6. Nucleophilic attack of cyanide onto the nitrovinyl group led to a nucleoside analogue bearing a terminal 1-cyanovinyl group (7), a soft electrophilic group which, upon reaction with benzeneselenol, underwent a conjugate addition to the phenylselenonucleoside derivative 9. All these compounds, eventually de-O-silylated, were subject of in vitro biological testing, some exhibiting interesting cytotoxic or antiviral properties.
Animals↗
Furano pyrimidines as novel potent and selective anti-VZV agents.
Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.
Antiviral Agents↗
Bicyclic nucleoside inhibitors of varicella-zoster virus (VZV): Pd-catalysed synthesis of 5-aryl derivatives and their biological evaluation.
We have recently reported the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual fluorescent bicyclic furano base moieties. In order to probe structure activity relationships we prepared a series of 5-aryl derivatives of the lead structures. We herein report the synthesis, characterization, and antiviral evaluation of these novel compounds. 5-Aryl derivatives of the parent nucleosides were synthesized from the corresponding alkynyl deoxyuridines using a simple, versatile and efficient one-step conversion, based on a palladium-catalysed cyclization. As previously noted for the lead compounds, a long alkyl side-chain on the base moiety is essential for antiviral activity. Even with the optimal (C8-C10) side-chain, most of the present compounds are markedly less active than their parent structures. However, some of the synthesized compounds still retained antiviral activity at non-cytotoxic concentrations, being only two- to fivefold less active than the current clinical agent acyclovir. Possible reasons for this structure activity relationship are discussed.
Acyclovir↗
Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine.
We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.
Acyclovir↗
3-Benzamido, ureido and thioureidoimidazo[1,2-a]pyridine derivatives as potential antiviral agents.
This work reports the synthesis and the antiviral activities of 3-benzamido, 3-phenylureido and 3-phenylthioureido derivatives in the imidazo[1,2-a]pyridine series. The structure was proven by NMR spectroscopy. The synthesized compounds were evaluated against a large number of viruses. The 3-phenylthioureido derivative 7 showed moderate activity against human cytomegalovirus (HCMV) in vitro. The crystallographic data for 8 are also reported and explain the absence of activity against human immunodeficiency virus (HIV).
Anti-HIV Agents↗
Evaluating phenotype and genotype of drug-resistant strains in herpesviruses.
The isolation of drug-resistant strains of herpesviruses, including Herpes Simplex Virus type I (HSV-1) and type 2 (HSV-2), Varicella-Zoster Virus (VZV), and cytomegalovirus (CMV), has been reported with increasing frequency in immunocompromised patients and is a matter of major concern. Determination of antiviral drug susceptibilities is a prerequisite for the management of drug-resistant herpesvirus infections. Phenotyping studies should be correlated with genotyping, i.e., characterization of the mutations in the target genes. The isolation of drug-resistant virus in the laboratory and the determination of their phenotype and genotype may be useful to clarify the mechanisms of selective drug action. We describe here the procedures used for in vitro selection of drug-resistant herpesvirus mutants and the determination of their patterns of drug-susceptibility. The subcloning of the HSV-1 DNA polymerase gene is described as an example of the methodology followed to determine the mutation(s) in the drug-target viral gene that are associated with the resistant phenotype. To avoid the introduction of mutations by PCR amplification, all subcloning experiments were executed directly on viral DNA. Viral DNA was prepared from each plaque-purified viral strain and a 3.4 kb BamHI fragment containing 87% of the HSV-1 DNA polymerase gene coding region was purified and further digested with SacI; the two resulting fragments were subcloned into pU18 and propagated in Escherichia coli. Plasmid DNA was isolated and the inserts were sequenced using dideoxynucleotide chain termination method with T7 DNA polymerase and Taq DNA polymerase in an automated laser fluorescent DNA sequencer. pUC/M13 reverse, universal primers and oligonucleodite primers based on the wild-type virus sequence were used. The nucleotide sequences of the DNA polymerase genes of the different mutants was then compared with the nucleotide sequence of the wild-type HSV-1 KOS strain.
Animals↗
Cidofovir in the treatment of HPV-associated lesions.
The acyclic nucleoside phosphonate cidofovir (CDV) has proved efficacious in the treatment of different clinical manifestations of HPV-induced epithelial cell proliferation. Local intratumor injections of CDV in an immunocompetent patient with hypopharyngeal/esophageal papillomatous lesions, PCR-positive for HPV types 16 and 18, resulted in a complete regression of the tumor. Similarly, CDV, injected locally in patients with recurrent respiratory papillomatosis resulted in complete disappearance or partial remission of the lesions. Recently, a child with disseminated respiratory papillomatosis was treated with systemic (intravenous) CDV, resulting in stabilization of the disease. In addition, CDV topical gel has been successfully used for the treatment of severe, relapsing anogenital HPV lesions and cervical intraepithelial neoplasia (CIN) grade III. In vitro, treatment of HPV-positive cells (compared to normal primary human keratinocytes) with CDV has resulted in a concentration- and time-dependent inhibition of cell proliferation. Different parameters of apoptosis, i.e., (i) induction of CPP32 (caspase-3) protease activity, (ii) translocation of phosphatidylserine (PS) from the inner part of the plasma membrane to the outer layer, (iii) disintegration of the nuclear matrix protein (NMP), (iv) DNA fragmentation, (v) number of cells in apoptotic phase following cell cycle analysis, showed that the mechanism of cell death following treatment with CDV is based on apoptosis. Induction of apoptosis in HPV-positive cells by CDV was associated with accumulation of the tumor suppressor proteins p53 and pRb and the cyclin-dependent kinase inhibitor p21/WAF-1. In conclusion, CDV has great potential in the treatment of severe HPV-induced proliferative lesions, either laryngeal, esophageal/pharyngeal or genital. As CDV has proved able to induce apoptosis, in a time- and concentration-dependent manner, in a number of HPV-positive cell lines, the regression of papillomatous tumors observed with CDV in patients, may be due, at least in part, to the induction of apoptosis.
Administration, Topical↗
Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain.
In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2'-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index values >/= 1 000 000. From a range of DNA and RNA viruses tested, only VZV was inhibited by these compounds indicating their extreme selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, makes them of considerable interest for potential drug development for VZV infections.
Antiviral Agents↗