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Actas Dermo-sifiliograficas Mar 2006The systemic treatment of herpes zoster shortens the healing process, and prevents or alleviates pain and other acute or chronic complications, especially when it is... (Review)
Review
The systemic treatment of herpes zoster shortens the healing process, and prevents or alleviates pain and other acute or chronic complications, especially when it is administered in the first 72 hours after symptoms appear. This treatment is especially indicated in patients over the age of 50 and in those who, regardless of age, have head and neck involvement, especially in herpes zoster ophthalmicus. The drugs approved in Europe for the systemic treatment of herpes zoster are aciclovir, valaciclovir, famciclovir and brivudine. Brivudine shows greater effectiveness against the varicella-zoster virus than aciclovir and its derivatives, and can be given just once a day for seven days, compared to multiple doses of the latter. As opposed to the others, brivudine is a non-nephrotoxic drug that should not be administered to immunodepressed patients or to those being treated with 5-fluorouracil. The treatment of herpes zoster to reduce pain should be combined with analgesics and neuroactive agents (amitriptyline, gabapentin, etc). While corticosteroids are of dubious efficacy in the treatment of post-herpes neuralgia, the intensity and duration of the pain can be reduced with some topical treatments (capsaicin, lidocaine patches, etc). Finally, this review discusses treatment guidelines for special locations (cranial nerves) and different subpopulations (children, pregnant women, immunodepressed patients, etc).
Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Algorithms; Analgesics; Antiviral Agents; Chickenpox Vaccine; Child; Cranial Nerve Diseases; Drug Resistance, Viral; Female; Herpes Zoster; Humans; Immunocompromised Host; Immunotherapy, Active; Male; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Risk Factors
PubMed: 16595111
DOI: 10.1016/s0001-7310(06)73360-9 -
BioRxiv : the Preprint Server For... Jun 2023Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and...
Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM). Sets of conditional anticancer compounds span phases of clinical development and include non-oncology drugs. Among these, we characterize a unique dual-mechanism of action for brivudine, an agent otherwise approved for antiviral treatment. Using an integrative approach, we find that brivudine affects two independent targets in folate metabolism. We also traced conditional phenotypes for several drugs to the availability of nucleotide salvage pathway substrates and verified others for compounds that seemingly elicit off-target anticancer effects. Our findings establish generalizable strategies for exploiting conditional lethality in HPLM to reveal therapeutic candidates and mechanisms of action.
PubMed: 37333068
DOI: 10.1101/2023.06.04.543621 -
Clinical Microbiology Reviews Oct 1997This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes... (Review)
Review
This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.
Topics: Antiviral Agents; DNA, Viral; HIV Infections; HIV-1; Hepadnaviridae Infections; Herpesviridae Infections; Humans; Molecular Structure; Retroviridae Infections; Species Specificity; Virus Diseases; Viruses
PubMed: 9336668
DOI: 10.1128/CMR.10.4.674 -
Frontiers in Cellular Neuroscience 2021Neural progenitor cell (NPC) transplants are a promising therapy for treating spinal cord injury (SCI), however, their long-term role after engraftment and the relative...
Neural progenitor cell (NPC) transplants are a promising therapy for treating spinal cord injury (SCI), however, their long-term role after engraftment and the relative contribution to ongoing functional recovery remains a key knowledge gap. Selective human cell ablation techniques, currently being developed to improve the safety of progenitor cell transplant therapies in patients, may also be used as tools to probe the regenerative effects attributable to individual grafted cell populations. The Herpes Simplex Virus Thymidine Kinase (HSV-TK) and ganciclovir (GCV) system has been extensively studied in the context of SCI and broader CNS disease. However, the efficacy of brivudine (BVDU), another HSV-TK prodrug with potentially reduced bystander cytotoxic effects and toxicity, has yet to be investigated for NPC ablation. In this study, we demonstrate successful generation and ablation of HSV-TK-expressing human iPSC-derived NPCs with a >80% reduction in survival over controls. We validated an HSV-TK and GCV/BVDU synergistic system with iPSC-NPCs using an efficient gene-transfer method and ablation in a translationally relevant model of SCI. Our findings demonstrate enhanced ablation efficiency and reduced bystander effects when targeting all rapidly dividing cells with combinatorial GCV and BVDU treatment. However, for use in loss of function studies, BVDU alone is optimal due to reduced nonselective cell ablation.
PubMed: 34938162
DOI: 10.3389/fncel.2021.638021 -
Molecules (Basel, Switzerland) Feb 2021Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV),... (Review)
Review
Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy) against HIV and HBV infections and adefovir dipivoxil (Hepsera) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex) against HSV-1 and VZV infections and stavudine (Zerit) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex, Zelitrex) against HSV and VZV and rabacfosadine (Tanovea-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.
Topics: Anniversaries and Special Events; Antiviral Agents; Drug Discovery; History, 20th Century; History, 21st Century; Humans; Nucleosides; Nucleotides; Virus Diseases; Viruses
PubMed: 33572409
DOI: 10.3390/molecules26040923 -
Science (New York, N.Y.) Feb 2019The gut microbiota is implicated in the metabolism of many medical drugs, with consequences for interpersonal variation in drug efficacy and toxicity. However,...
The gut microbiota is implicated in the metabolism of many medical drugs, with consequences for interpersonal variation in drug efficacy and toxicity. However, quantifying microbial contributions to drug metabolism is challenging, particularly in cases where host and microbiome perform the same metabolic transformation. We combined gut commensal genetics with gnotobiotics to measure brivudine drug metabolism across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by these measurements, we built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure, as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics. Clonazepam studies illustrate how this approach disentangles microbiome contributions to metabolism of drugs subject to multiple metabolic routes and transformations.
Topics: Animals; Bacteroides thetaiotaomicron; Biological Availability; Biotransformation; Bromodeoxyuridine; Clonazepam; Gastrointestinal Microbiome; Germ-Free Life; Mice
PubMed: 30733391
DOI: 10.1126/science.aat9931 -
Global & Regional Health Technology... 2020This observational study aimed to investigate the incidence of herpes zoster (HZ) among at-risk subjects aged ≥50 years, characterize them and assess annual healthcare...
PURPOSE
This observational study aimed to investigate the incidence of herpes zoster (HZ) among at-risk subjects aged ≥50 years, characterize them and assess annual healthcare utilization and costs from the Italian National Health System (NHS) perspective.
METHODS
Records of reimbursed drug prescriptions, hospitalizations and outpatient specialist care from the Fondazione ReS database were linked to identify patients aged ≥50 years at HZ risk (i.e. cardiovascular disease/chronic obstructive pulmonary disease/diabetes/immunosuppression, according to the Italian National Vaccine Prevention Plan - PNPV 2017-2019) in 2013. New HZ events (incidence per 1,000) were researched in 2 years, and subjects with HZ in the previous year were excluded. Antiviral and pain therapy consumptions, hospitalizations for HZ and costs paid by NHS were assessed annually.
RESULTS
From 12,562,609 inhabitants in 2013, a total of 1,004,705 patients (18.5% aged ≥50 years) at risk without a previous event were selected. The 2-year incidence of HZ was 5.9 per 1,000 (mean age 74 ± 10 years; 54.3% female). Patients aged 80-89 (7.2 per 1,000), females (6.7 per 1,000) and immunosuppressed subjects (6.9 per 1,000) had the highest incidence rates. One year after the new HZ episode, 82.2% were treated with specific antivirals (79.3% brivudine), generating an annual average cost/treated of €106; 8.0% were hospitalized for HZ, with an average cost/hospitalized of €3,927; the overall mean cost/incident patient was €402.
CONCLUSIONS
This analysis provided HZ incidence in subjects aged ≥50 years considered at risk by the PNPV and its burden from the NHS perspective. Our findings can help health governance to improve clinical decisions and economic positioning concerning zoster vaccine plan.
PubMed: 36627965
DOI: 10.33393/grhta.2020.2026 -
PloS One 2015Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate...
Structure of the Varicella Zoster Virus Thymidylate Synthase Establishes Functional and Structural Similarities as the Human Enzyme and Potentiates Itself as a Target of Brivudine.
Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP de novo. To study substrate binding, the complex structure of TSVZV with dUMP was determined to a resolution of 2.9 Å. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TSHS) in an open conformation. The interactions between TSVZV with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TSVZV binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TSVZV and in vitro phosphorylated brivudine (BVDUP), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDUP to TSVZV was further confirmed by the complex structure of TSVZV and BVDUP solved at a resolution of 2.9 Å. BVDUP binds similarly as dUMP in the TSHS but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDUP is likely to inhibit TSVZV by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TSVZV and BVDUP are consistent with that TSVZV is indeed a target of brivudine in vivo. The work also provided the structural basis for rational design of more specific TSVZV inhibitors.
Topics: Antiviral Agents; Apoenzymes; Binding Sites; Bromodeoxyuridine; Herpesvirus 3, Human; Humans; Models, Molecular; Phosphorylation; Protein Binding; Protein Conformation; Thymidylate Synthase
PubMed: 26630264
DOI: 10.1371/journal.pone.0143947 -
Annals of Agricultural and... 2013Although smallpox was eradicated over 30 years ago, the disease remains a major threat. High mortality, high infectivity and low resistance of the contemporary... (Review)
Review
Although smallpox was eradicated over 30 years ago, the disease remains a major threat. High mortality, high infectivity and low resistance of the contemporary population make the smallpox virus very attractive to terrorists. The possible presence of illegal stocks of the virus or risk of deliberate genetic modifications cause serious concerns among experts. Hence, it is reasonable to seek effective drugs that could be used in case of smallpox outbreak. This paper reviews studies on compounds with proven in vitro or in vivo antipoxviruses potential, which show various mechanisms of action. Nucleoside analogues, such as cidofovir, can inhibit virus replication. Cidofovir derivatives are developed to improve the bioavailability of the drug. Among the nucleoside analogues under current investigation are: ANO (adenozine N1-oxide) and its derivatives, N-methanocarbothymidine [(N)-MCT], or derivatitives of aciklovir, peninclovir and brivudin. Recently, ST-246 - which effectively inhibits infection by limiting release of progeny virions - has become an object of attention. It has been also been demonstrated that compounds such as: nigericin, aptamers and peptides may have antiviral potential. An interesting strategy to fight infections was presented in experiments aimed at defining the role of individual genes (E3L, K3L or C6L) in the pathogenesis, and looking for their potential blockers. Additionally, among substances considered to be effective in the treatment of smallpox cases, there are factors that can block viral inhibitors of the human complement system, epidermal growth factor inhibitors or immunomodulators. Further studies on compounds with activity against poxviruses are necessary in order to broaden the pool of available means that could be used in the case of a new outbreak of smallpox.
Topics: Animals; Antiviral Agents; Humans; Orthopoxvirus; Poxviridae Infections
PubMed: 23540204
DOI: No ID Found -
Anales Del Sistema Sanitario de Navarra Aug 2018
Topics: Aged; Antimetabolites, Antineoplastic; Antiviral Agents; Bromodeoxyuridine; Diagnostic Errors; Drug Interactions; Fatal Outcome; Fluorouracil; Herpes Zoster; Humans; Male
PubMed: 29943764
DOI: 10.23938/ASSN.0297