Targeted dermal delivery of highly potent anti-varicella zoster virus nucleoside analogues from saturated solutions and ethanolic oil-in-water creams.

Varicella zoster virus (VZV) is responsible for causing chickenpox and shingles infections, the latter of which can lead to long-term post-herpetic neuralgia (PHN), the most common complication of VZV infections. A class of anti-VZV nucleoside analogues has been synthesised that shows up to 30,000 times the potency of aciclovir in vitro. The relatively high lipophilicities exhibited by the compounds led them to be selected for dermal delivery.

Confirming the validity and responsiveness of the Multiple Sclerosis Walking Scale-12 (MSWS-12).

The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a new, self-rated measure of walking ability. The scale has not been independently validated for use in differing MS populations. One hundred forty-nine patients in the community and 53 hospital outpatients with MS completed the MSWS-12 and other outcome measures.

Aryloxy phosphoramidate triesters as pro-tides.

We herein describe the development of aryloxy phosphoramidate triesters as an effective pro-tide motif for the intracellular delivery of charged bio-active antiviral nucleoside monophosphates. The review covers the discovery of such aryl phosphoramidates, their mechanism of action and structure-activity relationships. The application of this strategy to a range of antiviral nucleosides is highlighted.

Enhanced inhibition of the EDHF phenomenon by a phenyl methoxyalaninyl phosphoramidate derivative of dideoxyadenosine.

In rabbit arteries endogenous production of cAMP facilitates electrotonic signalling via gap junctions, thus explaining the ability of P-site inhibitors of adenylyl cyclase to attenuate EDHF-type responses. In the present study, we show that a lipophilic phosphoramidate pronucleotide derivative of dideoxyadenosine, 2',3'-ddA-PMAPh, exhibits enhanced activity as an inhibitor of EDHF-type smooth muscle hyperpolarizations induced by acetylcholine (ACh) compared to the parent nucleoside 2',3'-ddA, and that the effects of both compounds can be reversed by the cAMP phosphodiesterase inhibitor IBMX. Neither 2',3'-ddA nor 2',3'-ddA-PMAPh depress ACh-evoked endothelial hyperpolarization directly.

Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro.

The phosphoramidate triester prodrug approach is widely used to deliver nucleotide forms of nucleoside analogues into target cells. We investigated the stereoselective stability of a series of prodrugs of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (d4T). Chemical stability was evaluated in phosphate buffer at pH values of biological relevance (i.

Bicyclic anti-VZV nucleosides: thieno analogues bearing an alkylphenyl side chain have reduced antiviral activity.

Thieno analogues of the potent and selective furo-pyrimidine anti-VZV nucleoside family bearing a p-alkylphenyl side chain have been synthesised and tested for their antiviral activity against Varicella-Zoster virus (VZV). While the alkyl chain analogues were shown to retain full antiviral activity against VZV, these new analogues did not when compared to their furo parent nucleosides.

Synthesis and antiviral evaluation of some 3'-fluoro bicyclic nucleoside analogues.

The synthesis of 3'-fluoro analogues of recently discovered highly potent anti-VZV furanopyrimidine deoxynucleosides (BCNAs) is herein reported, for both the alkyl and alkylphenyl series. The compounds are tested against a range of herpes viruses and display poor activity, strongly supporting the notion of the importance of the presence of a 3'-OH for antiviral activity.

Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: action via a novel non-nucleosidic mechanism.

Following our discovery of the potent anti-varicella zoster virus action of lipophilic alkyl furano pyrimidine 2'-deoxynucleosides, we now report that 2',3'-dideoxy sugar analogues are devoid of anti-VZV activity but are potent and selective inhibitors of human cytomegalovirus (HCMV). The present compounds are active in vitro at ca. 1 microM with cytotoxicity only above 200 microM.

Latitudinal variation in the prevalence of multiple sclerosis in Ireland, an effect of genetic diversity.

Background: Northern Ireland has a high and rising prevalence rate of multiple sclerosis (MS). The most recent survey in 1996 found a rate of 168.7/100 000.

Creutzfeldt-Jakob disease in Ireland: epidemiological aspects 1980-2002.

Surveillance for Creutzfeldt-Jakob disease (CJD) has been carried out in the Republic of Ireland since 1980. Initial surveillance was passive and based on consented autopsy confirmation of CJD in patients in whom there was a high index of clinical suspicion. Since 1999, an active surveillance programme involving formal notification of all suspect CJD cases has been in place.

Inactivity of the bicyclic pyrimidine nucleoside analogues against simian varicella virus (SVV) does not correlate with their substrate activity for SVV-encoded thymidine kinase.

Simian varicella virus (SVV) and human varicella-zoster virus (VZV) are closely related viruses that share many structural and functional properties. 5-Substituted 2'-deoxyuridine derivatives (e.g.

The multiple sclerosis impact scale (MSIS-29) is a reliable and sensitive measure.

Objective: The aim of this study was to assess the psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) for patients in the community and in a hospital setting.

Methods: During an epidemiological study, 172 people with multiple sclerosis (MS) were examined and completed the MSIS-29, the London Handicap Scale, and Beck's Depression Inventory; disability was assessed by the Kurtzke Expanded Disability Status Score (EDSS) and the Multiple Sclerosis Functional Composite. At the hospital neurology clinic, 102 MS patients completed the MSIS-29 and EDSS assessments were performed; 41 of these patients had repeat evaluations six months later.

Novel bicyclic furanopyrimidines with dual anti-VZV and -HCMV activity.

Several novel bicyclic furanopyrimidine deoxy nucleosides have been designed, prepared and evaluated as anti-Varicella Zoster Virus agents. The compounds have long ether side chains. Uniquely amongst compounds of this family to date the present agents show dual anti- (VZV) and human cytomegalovirus (HCMV) activity.

The normal population distribution of PRNP codon 129 polymorphism.

Objectives: The common prion protein gene (PRNP) codon 129 polymorphism modifies the susceptibility to and the phenotype of prion diseases. However, no truly representative normal population-based data, or data stratified according to age or gender are available on the distribution of this polymorphism.

Material And Methods: Allelic variation of codon 129 in three Finnish populations representing different age groups, and among Finnish, British and Irish blood donors were examined.

Phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine and related nucleosides with potent activity against HIV and HBV.

Syntheses of phosphoramidate protides of several 2',3'-dideoxy-3'-fluoroadenosine derivatives by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleoside against HIV and HBV. Especially marked was the improvement in potency of phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine against both HIV and HBV.

Bicyclic nucleoside inhibitors of varicella-zoster virus: 5'-chloro and 3'-chloro derivatives.

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.

Stereoselective and concentration-dependent polarized epithelial permeability of a series of phosphoramidate triester prodrugs of d4T: an in vitro study in Caco-2 and Madin-Darby canine kidney cell monolayers.

Nucleoside analogs are successful, widely used antiviral and anticancer therapeutics. Nucleotide prodrugs (i.e.

Halophenyl furanopyrimidines as potent and selective anti-VZV agents.

Bicyclic furano pyrimidines have been previously reported by us to be highly potent and selective inhibitors of varicella zoster virus (VZV). p-Alkyl phenyl analogues are particularly potent with EC50 values below 1 nM. In this article we report the synthesis and anti-VZV activity of a series of halophenyl analogues, with variation in the nature (F, Cl, Br) and location (o, m, p) of the halogen substituent.

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.

ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins.

Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins.

Bicyclic nucleoside inhibitors of varicella-zoster virus: effect of terminal aryl substitution in the side-chain.

We have previously reported the discovery and preliminary structure-activity relationships of a new class of inhibitors of varicella-zoster virus (VZV). These novel furanopyrimidine nucleosides bear unusual bicyclic base moieties and exhibit complete specificity for VZV. Limited in vitro cytotoxicity has been detected and the bicyclic nucleosides are now well established as a new family of potent antivirals.