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Abstract 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. Highlights • Cidofovir is a safe, effective and well-tolerated treatment for intraurethral CA and an effective adjuvant to surgery. • Immunosuppression is associated with larger size of CA that are more frequently resistant to treatment. • A combination of surgery and adjuvant cidofovir instillations is a good treatment option for intraurethral CA. • In case of persistent or atypical lesions despite treatment it is important to repeat a biopsy to rule out malignancy. [ABSTRACT FROM AUTHOR]

Summary: Haemophagocytic lymphohistiocytosis (HLH) constitutes a spectrum of immunological disorders characterized by uncontrolled immune activation and key symptoms such as fever, splenomegaly, pancytopenia, haemophagocytosis, hyperferritinaemia and hepatitis. In genetic or primary HLH, hyperactivated CD8+ T cells are the main drivers of pathology. However, in acquired secondary HLH, the role of lymphocytes remains vague. In the present study the involvement of lymphocytes in the pathogenesis of a cytomegalovirus‐induced model of secondary HLH was explored. We have previously reported CD8+ T cells to be redundant in this model, and therefore focused on CD4+ helper and regulatory T cells. CD4+ T cells were activated markedly and skewed towards a proinflammatory T helper type 1 transcription profile in mice displaying a severe and complete HLH phenotype. Counter to expectations, regulatory T cells were not reduced in numbers and were, in fact, more activated. Therapeutic strategies targeting CD25high hyperactivated T cells were ineffective to alleviate disease, indicating that T cell hyperactivation is not a pathogenic factor in cytomegalovirus‐induced murine HLH. Moreover, even though T cells were essential in controlling viral proliferation, CD4+ T cells, in addition to CD8+ T cells, were dispensable in the development of the HLH‐like syndrome. In fact, no T or B cells were required for induction and propagation of HLH disease, as evidenced by the occurrence of cytomegalovirus‐associated HLH in severe combined immunodeficient (SCID) mice. These data suggest that lymphocyte‐independent mechanisms can underlie virus‐associated secondary HLH, accentuating a clear distinction with primary HLH. [ABSTRACT FROM AUTHOR]

Three acyclic nucleoside phosphonates (ANPs) have been formally approved for clinical use in the treatment of 1) cytomegalovirus retinitis in AIDS patients (cidofovir, by the intravenous route), 2) chronic hepatitis B virus (HBV) infections (adefovir dipivoxil, by the oral route), and 3) human immunodeficiency virus (HIV) infections (tenofovir disoproxil fumarate, by the oral route). The activity spectrum of cidofovir {( S )-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [( S )-HPMPC)]}, like that of ( S )-HPMPA {( S )-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine} and ( S )-HPMPDAP {( S )-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine}, encompasses a broad spectrum of DNA viruses, including polyoma-, papilloma-, adeno-, herpes-, and poxviruses. Adefovir {9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)} and tenofovir {( R )-9-[2-(phosphonomethoxy) propyl]adenine [( R )-PMPA)]} are particularly active against retroviruses (i.e., HIV) and hepadnaviruses (i.e., HBV); additionally, PMEA also shows activity against herpes- and poxviruses. We have recently identified a new class of ANPs, namely 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, named, in analogy with their alkylpurine counterparts, HPMPO-DAPy, PMEO-DAPy, and ( R )-PMPO-DAPy. These compounds exhibit an antiviral activity spectrum and potency that is similar to that of ( S )-HPMPDAP, PMEA, and ( R )-PMPA, respectively. Thus, PMEO-DAPy and ( R )-PMPO-DAPy, akin to PMEA and ( R )-PMPA, proved particularly active against HIV-1, HIV-2, and the murine retrovirus Moloney sarcoma virus (MSV). PMEO-DAPy and ( R )-PMPO-DAPy also showed potent activity against both wild-type and lamivudine-resistant strains of HBV. HPMPO-DAPy was found to inhibit different poxviruses (i.e., vaccinia, cowpox, and orf) at a similar potency as cidofovir. HPMPO-DAPy also proved active against adenoviruses. In vivo, HPMPO-DAPy proved equipotent to cidofovir in suppressing vaccinia virus infection (tail lesion formation) in immunocompetent mice and promoting healing of disseminated vaccinia lesions in athymic-nude mice. The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections. [ABSTRACT FROM AUTHOR]

Acyclic nucleoside phosphonate derivatives containing a pyrimidine base preferably bearing amino groups at C-2 and C-4(DAPym), and linked at the C-6 position to(S)-[3-hydroxy-2-(phosphonomethoxy)propoxy](HPMPO), 2-(phosphonomethoxy) ethoxy(PMEO) or(R)-[2-(phosphonomethoxy)propoxy](PMPO), display an antiviral sensitivity spectrum that closely mimic that of the parental(S)-HPMP-, PME- and(R)-PMP-purine derivatives. Several PMEO-DAPym derivatives proved as potent as PMEA(adefovir) and(R)-PMPA(tenofovir) in inhibiting Moloney murine sarcoma virus(MSV)-induced tumor formation in newborn NMRI mice. The HPMPO-, PMEO- and PMPO-DAPym derivatives represent a novel well-defined subclass among the acyclic nucleoside phosphonates endowed with potent and selective antiviral activity. [ABSTRACT FROM AUTHOR]

Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus [i.e. herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2),varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV)] infections. In recent years, several new guanosine analogues have been developed, including the 3-membered cyclopropylmethyl and-methenyl derivatives (A-5021 and synguanol) and the 6-membered D-and L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guanosine analogues has been determined against a wide spectrum of viruses, including the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The new guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced TK. Marked antiviral activity was also noted with A-5021 against HHV-6 and with D- and L-cyclohexenyl G against HCMV and HBV. The antiviral activity of the acyclic/carbocyclic nucleoside analogues could be markedly potentiated by mycophenolic acid, a potent inhibitor of inosine 5′-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 and D- andL-cyclohexenyl G) hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also an antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transduced by the viral (HSV-1, VZV) TK gene. [ABSTRACT FROM AUTHOR]

(D)- and (L)-cyclohexeneyl-G were synthesized enantioselectively starting from (R)-carvone. Both show potent and selective anti-herpesvirus activity (HSV-1, HSV-2, VZV, CMV). Molecular modeling demonstrates that both isomers are bound in the active site of HSV-1 thymidine kinase in a high-energy conformation with the base moiety orienting in an equatorial position. It is believed that the flexibility of the cyclohexene ring is essential for their antivirial activity. [ABSTRACT FROM AUTHOR]

Varicella zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella, chickenpox) as well as reactivation (zoster, shingles) infections. In immunocompetent patients, the course of varicella is generally benign. For varicella zoster, post-herpetic neuralgia is the most common complication. In immunocompromised patients (particularly those with AIDS), transplant recipients and cancer patients, VZV infections can be life-threatening. For these patients and also for immunocompetent patients at risk such as pregnant women or premature infants, the current treatment of choice is based on either intravenous or oral aciclovir (acyclovir). The low oral bioavailability of aciclovir, as well as the emergence of drug-resistant virus strains, have stimulated efforts towards the development of new compounds for the treatment of individuals with VZV infections. Among these new compounds, penciclovir, its oral prodrug form famciclovir and the oral prodrug form of aciclovir (valaciclovir), rank among the most promising. As with aciclovir itself, all of these drugs are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation (phosphorylation), and, upon conversion to their triphosphate form, they act as inhibitors/alternative substrate of the viral DNA polymerase. Therefore, cross-resistance to these drugs may be expected for those virus mutants that are TK-deficient and thus resistant to aciclovir. Other classes of nucleoside analogues dependent for their phosphorylation on the viral TK that have been pursued for the treatment of VZV infections include sorivudine, brivudine, fialuridine, fiacitabine and netivudine. Among oxetanocins, which are partially dependent on viral TK, lobucavir is now under clinical evaluation. Foscarnet, which does not require any previous metabolism to interact with the viral DNA polymerase, is used in the clinic when TK-deficient VZV mutants emerge during aciclovir treatment. TK-deficient mutants are also sensitive to the acyclic nucleoside phosphonates (i.e. [s]-1-[3-hydroxy-2-phosphonylmethoxypropyl]cytosine; HPMPC); these agents do not depend on the virus-encoded TK for their phosphorylation but depend on cellular enzymes for conversion to their diphosphoryl derivatives which then inhibit viral DNA synthesis. Vaccination for VZV has now come of age. It is recommended for healthy children, patients with leukaemia, and patients receiving immunosuppressive therapy or those with chronic diseases. The protection induced by the vaccine seems, to some extent, to include zoster and associated neuralgia. Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women). [ABSTRACT FROM AUTHOR]

Timentin (ticarcillin plus clavulanic acid) plus amikacin was administered as an empirical regimen to 52 febrile granulocytopenic patients with cancer and appeared as effective as the other commonly recommended combinations of antimicrobial agents. A favourable response was observed in 61% of episodes with bacteraemia and in 83% of the episodes without bacteraemia. However, the efficacy in Grampositive bacteraemia was suboptimal and the emergence of superinfections caused by Gram-positive cocci may represent a clinical challenge. [ABSTRACT FROM PUBLISHER]

Bicyclic furanopyrimidines were recently discovered by us to be potent and selective inhibitors of VZV. Related studies to investigate the role of the sugar in this activity uncovered dideoxy furanopyrimidines as inhibitors of HCMV and this led to the preparation of highly modified long alkyl chain furanopyrimidines from the N- and O-alkylation of their parent bases. Herein we describe their synthesis and subsequent biological evaluation against HCMV. O-alkylated derivatives were almost invariably found to be at least equiactive with their N-alkylated counterparts. At this point, little change in activity has been found with large variation in N- and O-substituent. [ABSTRACT FROM AUTHOR]

2′,3′-Dideoxy furanopyrimidines were shown to display anti-HCMV activity via a non-nucleoside mechanism. Further studies into highly modified sugar derivatives led to the preparation of N-and O-alkylated C 10 furanopyrimidine analogues, and this work is described herein. These compounds were tested against HCMV strains, and the first case of submicromolar activity was observed. [ABSTRACT FROM AUTHOR]

Considers the synthesis of a novel unusual bicyclic furano pyrimidine nucleosides bearing unsaturated supply chain as a potential inhibitors of varicella-zoster virus (VZV). Process that determined the shape and size of the presumed lipophilic pocket of the target enzyme; Description of the alkenylphenyl iodide; Evaluation of the target bicyclic compounds.

We have recently discovered bicyclic furopyrimidines as potent and selective inhibitors of VZV. In order to investigate the structural requirements for antiviral activity we have succesfully synthesised some 3′-chloro and 5′-chloro derivatives. The compounds have been tested against VZV and CMV, but displayed no significant in vitro activity. [ABSTRACT FROM AUTHOR]

Reports on the synthesis and biological evaluation of some novel 2',3'-dideoxy-3'-flouro and 2'deoxy-xylo derivatives of the most active compounds, with octyl and p-pentylphenyl side chains respectively. Selective inhibitors of varicella-zoster virus (VZV); Activity of some 2',3'-dideoxy furano pyrimidine nucleosides bearing alkyl side chains against human cytomegalovirus.

Presents a study which identified a unique class of bicyclic nucleoside analogues (BCNA) and found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. Findings of previous studies on the VZV strains deficient in the virus-encoded thymidine kinase; Conversion of the BCNA to their 5'-mono and 5'-diphosphate derivatives.

During a six year period, 11 cases of bacteremia caused by Bacillus spp. were observed corresponding to 1 % of all bacteremic episodes in our hospital. Most patients had cancer as underlying disease. All cases of positive blood cultures were associated with a clinical syndrome compatible with sepsis including high fever. None of the subsequent deaths could be related to the bacteremia caused by Bacillus spp. Four of eight cases of Bacillus subtilis bacteremia were associated with the absorption of an oral preparation containing Bacillus subtilis spores, which was administered empirically in some units of the hospital to reduce what was considered to be tubefeeding related diarrhea. [ABSTRACT FROM AUTHOR]