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Frontiers in Pharmacology 2021Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil...
Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring. To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP). Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1. A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09-2.30) and 2.13 (95% CI, 1.04-4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54-8.18) and 2.85 (95% CI, 1.15-7.08), respectively. We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice.
PubMed: 35046808
DOI: 10.3389/fphar.2021.772768 -
Hepatology (Baltimore, Md.) May 2020Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the...
BACKGROUND AND AIMS
Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs.
APPROACH AND RESULTS
This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production.
CONCLUSIONS
Among NUCs, only ANPs have an additional pharmacological effect modulating LPS-mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.
Topics: Adenine; Adult; Aged; Antiviral Agents; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunomodulation; Interferon-alpha; Interleukin-10; Interleukin-12; Lamivudine; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Nucleosides; Organophosphonates; Proto-Oncogene Proteins c-akt; Tenofovir
PubMed: 31529730
DOI: 10.1002/hep.30956 -
Journal of Clinical Microbiology Sep 2021We developed a novel real-time PCR assay that simultaneously evaluates 11 major nucleos(t)ide antiviral (NA) drug resistance mutations (mt) in chronic hepatitis B...
Fast and Sensitive Real-Time PCR Detection of Major Antiviral-Drug Resistance Mutations in Chronic Hepatitis B Patients by Use of a Predesigned Panel of Locked-Nucleic-Acid TaqMan Probes.
We developed a novel real-time PCR assay that simultaneously evaluates 11 major nucleos(t)ide antiviral (NA) drug resistance mutations (mt) in chronic hepatitis B patients (CHB), including L180M, M204I/V, and V207M (lamivudine [LMV] resistance), N/H238A/T (adefovir [ADF] resistance), which are circulating in Vietnam; and T184G/L, S202I, and M250V (entecavir [ETV] resistance) and A194T (tenofovir resistance), which have been recently reported in several studies across the globe. We detected drug-resistant mt in hepatitis B virus (HBV) samples using our predesigned panel of allele-specific locked-nucleic acid (LNA) probes. Our assay had a high sensitivity of 5% in a low-HBV DNA population of ≥5 × 10 IU/ml and was validated in a cohort of 130 treatment-naive children and 98 NA-experienced adults with CHB. Single-point mt for LMV and ADF resistance were detected in 57.7% and 54.1% of the child and adult samples, respectively, with rtV207M (children, 42.3%; adults, 36.7%) and rtN238T/A (children, 15.4%; adults, 16.3%) being the most frequent mt in these populations. Multiple-point mt, including rtL180M-rtM204V- rtN238A and rtL180M-rtM204I, were identified in only two children, resulting in LMV-ADF resistance and reduced ETV susceptibility. In conclusion, this assay accurately identified the mt profile of children (98.4%) and adults (91.2%) with CHB, which is comparable to established methods. This fast and sensitive screening method can be used for the detection of major NA-resistant mt circulating in developing countries, as well as providing a model for the development of similar mt-detection assays, especially for use in nonhospitalized patients who need their results within half a day, before starting treatment.
Topics: Adult; Antiviral Agents; Child; DNA, Viral; Drug Resistance, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Real-Time Polymerase Chain Reaction
PubMed: 34319801
DOI: 10.1128/JCM.00936-21 -
ChemMedChem Jan 2022A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with...
A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC =9-18 nM), and one of them was more potent EF inhibitor (IC =12 nM), compared to adefovir diphosphate (PMEApp) with IC =18 nM for ACT and IC =36 nM for EF. Thus, these compounds represent the most potent ACT/EF inhibitors based on ANPs reported to date. The potency of the phosphonodiamidates to inhibit ACT activity in J774A.1 macrophage cells was somewhat weaker, where the most potent derivative had IC =490 nM compared to IC =150 nM of the analogous adefovir phosphonodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP-based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics.
Topics: Adenylate Cyclase Toxin; Adenylyl Cyclase Inhibitors; Antigens, Bacterial; Bacillus anthracis; Bacterial Toxins; Bordetella pertussis; Dose-Response Relationship, Drug; Halogens; Molecular Structure; Organophosphonates; Structure-Activity Relationship; Thiazoles
PubMed: 34636150
DOI: 10.1002/cmdc.202100568 -
Antiviral effects of a niobium-substituted heteropolytungstate on hepatitis B virus-transgenic mice.Drug Development Research Dec 2019To study the efficacy of a polyoxometalate, Cs K Na[SiW Nb O ]·H O, as an antiviral treatment in HBV transgenic mice. HBV transgenic mice were treated with Cs K Na[SiW...
To study the efficacy of a polyoxometalate, Cs K Na[SiW Nb O ]·H O, as an antiviral treatment in HBV transgenic mice. HBV transgenic mice were treated with Cs K Na[SiW Nb O ]·H O by intragastric administration. Adefovir and distilled water were administered as controls. Serum HBV DNA, liver HBV RNA levels were measured by quantitative RT-PCR. Serum HBsAg levels were measured by ELISA. The hepatitis B virus surface antigen (HBsAg) in liver cells was detected by immunohistochemistry (IHC). Pathological changes in the liver tissues were also observed by light and electron microscopy. Cs K Na[SiW Nb O ]·H O significantly decreased serum HBsAg and HBV DNA levels. Cs K Na[SiW Nb O ]·H O resulted in a 98% decrease in serum HBV DNA at 28 days, from 4.3 log copies/ml at baseline to 2.5 log copies/ml after treatment, and the inhibition rate of HBV DNA was higher than ADV at the same dose. The HBV replication levels in each group slightly increased at 7 days after withdrawal, but rebounded slightly more in the Cs K Na[SiW Nb O ]·H O treatment group compared to the H O control group (p < .05). There were no differences in HBV RNA levels. No significant differences were observed in the pathology, but there were decreased HBsAg levels in the Cs K Na[SiW Nb O ]·H O-treated group compared to the control group. The results demonstrated that Cs K Na[SiW Nb O ]·H O displayed potent anti-HBV activity in HBV transgenic mice and supported for future clinic study.
Topics: Animals; Antiviral Agents; DNA, Viral; Disease Models, Animal; Female; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Liver; Male; Mice; Mice, Transgenic; Random Allocation; Tungsten Compounds; Virus Replication
PubMed: 31396981
DOI: 10.1002/ddr.21586 -
Microorganisms Oct 2023Several nucleotide analogues have been approved for use in treating hepatitis B virus (HBV) infection. Long-term exposure to therapy leads to the emergence of mutations...
Several nucleotide analogues have been approved for use in treating hepatitis B virus (HBV) infection. Long-term exposure to therapy leads to the emergence of mutations within the HBV DNA polymerase gene, resulting in drug resistance, a major factor contributing to therapy failure. Chronic HBV patients from the Khyber Pakhtunkhwa province, Pakistan, who had completed 6 months of therapy participated in this study. Samples were collected from 60 patients. In this study, the entire reverse transcriptase domain of the HBV polymerase gene was amplified using nested polymerase chain reaction and sequenced. Drug-resistant mutations were detected in nine (22.5%) patients. All of these patients had lamivudine-resistant mutations (rtM204V + L180M), while seven individuals (17.5%) had both lamivudine- plus entecavir-resistant mutations (L180M + M204V + S202G). N236T, a mutation that gives rise to tenofovir and adefovir resistance, was observed in two (5%) patients. T184A, a partial drug-resistant mutation to entecavir, was found in five (12.5%) patients. Furthermore, other genotypic variants (100%) and vaccine escape mutations (5%) were additionally observed. Moreover, pN459Y (35%), pN131D (20%), pL231S (20%), pP130Q (17.5%), pS189Q (12.5%), pP161S (5%), pH160P (2.5%), pT322S (2.5%), and pA223S (2.5%) mutations in the polymerase gene, as well as sA166V (17.5%), sQ181K (12.5%), sV184R (7.5%), sA17E (5%), sP153S/K (5%), sW156C (5%), sC76Y (2.5%), and S132F (2.5%) mutations in the small surface gene, were identified for the first time in this study. Phylogenetic analysis showed that genotype D was predominant amongst the HBV carriers. Subtype D1 was found in most patients, while two patients were subtype D9. These novel findings may contribute to the body of knowledge and have clinical significance for treating and curing HBV infections in Pakistan.
PubMed: 38004634
DOI: 10.3390/microorganisms11112622 -
Pathogens (Basel, Switzerland) Oct 2021Hepatitis B virus (HBV) infection remains a major public health threat in the Middle East and North Africa (MENA). Phylogenetic analysis of HBV can be helpful to study...
Hepatitis B virus (HBV) infection remains a major public health threat in the Middle East and North Africa (MENA). Phylogenetic analysis of HBV can be helpful to study the putative transmission links and patterns of inter-country spread of the virus. The objectives of the current study were to analyze the HBV genotype/sub-genotype (SGT) distribution, reverse transcriptase (), and surface () gene mutations and to investigate the domestic transmission of HBV in the MENA. All HBV molecular sequences collected in the MENA were retrieved from GenBank as of 30 April 2021. Determination of genotypes/SGT, and mutations were based on the Geno2pheno (hbv) 2.0 online tool. For the most prevalent HBV SGTs, maximum likelihood phylogenetic analysis was conducted to identify the putative phylogenetic clusters, with approximate Shimodaira-Hasegawa-like likelihood ratio test values ≥ 0.90, and genetic distance cut-off values ≤ 0.025 substitutions/site as implemented in Cluster Picker. The total number of HBV sequences used for genotype/SGT determination was 4352 that represented a total of 20 MENA countries, with a majority from Iran ( = 2103, 48.3%), Saudi Arabia ( = 503, 11.6%), Tunisia ( = 395, 9.1%), and Turkey ( = 267, 6.1%). Genotype D dominated infections in the MENA (86.6%), followed by genotype A (4.1%), with SGT D1 as the most common in 14 MENA countries and SGT D7 dominance in the Maghreb. The highest prevalence of antiviral drug resistance was observed against lamivudine (4.5%) and telbivudine (4.3%). The proportion of domestic phylogenetic clustering was the highest for SGT D7 (61.9%), followed by SGT D2 (28.2%) and genotype E (25.7%). The largest fraction of domestic clusters with evidence of inter-country spread within the MENA was seen in SGT D7 (81.3%). Small networks (containing 3-14 sequences) dominated among domestic phylogenetic clusters. Specific patterns of HBV genetic diversity were seen in the MENA with SGT D1 dominance in the Levant, Iran, and Turkey; SGT D7 dominance in the Maghreb; and extensive diversity in Saudi Arabia and Egypt. A low prevalence of lamivudine, telbivudine, and entecavir drug resistance was observed in the region, with almost an absence of resistance to tenofovir and adefovir. Variable proportions of phylogenetic clustering indicated prominent domestic transmission of SGT D7 (particularly in the Maghreb) and relatively high levels of virus mobility in SGT D1.
PubMed: 34684283
DOI: 10.3390/pathogens10101333 -
Organic Process Research & Development Apr 2021Di--butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient... (Review)
Review
Di--butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di--butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OBu) as the base for the alkylation of ()-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di--butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).
PubMed: 37556249
DOI: 10.1021/acs.oprd.0c00473 -
Medicinal Research Reviews Mar 2022John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral...
John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.
Topics: Antiviral Agents; Humans; Tenofovir
PubMed: 34636044
DOI: 10.1002/med.21858 -
Cancers Apr 2023Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to...
Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene's gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes.
PubMed: 37046823
DOI: 10.3390/cancers15072163