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Luigi G. Marzilli - One of the best experts on this subject based on the ideXlab platform.
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X-ray structural characterization of the bis-Guanine Derivative of a cisplatin analogue having just one proton on each coordinated nitrogen and a head-to-head conformation: [Pt{(+/-)-N,N'-dimethyl-2,3-diaminobutane}(9-ethyl-Guanine)2]dinitrate.
Inorganic chemistry, 2010Co-Authors: Francesco P. Intini, Renzo Cini, Gabriella Tamasi, Michael B. Hursthouse, Luigi G. Marzilli, Giovanni NatileAbstract:The X-ray structural and NMR characterization of a bis-Guanine Derivative of a cisplatin analogue designed to reduce the rate of the Pt−N7 rotation of the coordinated Guanine nucleobases by more th...
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rotamer stability in cis pt dia g2 complexes dia diamine Derivative and g Guanine Derivative mediated by carrier ligand amine stereochemistry as revealed by circular dichroism spectroscopy
Chemistry: A European Journal, 2005Co-Authors: Michele Benedetti, Luigi G. Marzilli, Giovanni NatileAbstract:Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a Guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each Guanine leaning towards the cis-G. Such a "six-in" canting of the two Guanine ligands can be hampered by the steric interaction between the H8 of each Guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the Guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of Guanine O6 and the cis-amine N-H group. Such a Guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each Guanine further from the cis-Guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.
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Factors Influencing Conformer Equilibria in Retro Models of Cisplatin−DNA Adducts As Revealed by Moderately Dynamic (N,N‘-Dimethyl-2,3-diaminobutane)PtG2 Retro Models (G = a Guanine Derivative)
Inorganic chemistry, 2002Co-Authors: Jamil S. Saad, Giovanni Natile, Tommaso Scarcia, Luigi G. MarzilliAbstract:Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A2 = diamine or two amines; G = Guanine Derivative). Retro models have A2 carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: ΔHT and ΛHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5‘-GMP, 3‘-GMP, 5‘-IMP, and 3‘-IMP). The bases cant to the left (L) in (S,R,R,S)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other (“6-in” form) or farther out from each other (“6-out” form). Interligand interactions between ligand components near to Pt (first-first s...
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factors influencing conformer equilibria in retro models of cisplatin dna adducts as revealed by moderately dynamic n n dimethyl 2 3 diaminobutane ptg2 retro models g a Guanine Derivative
Inorganic Chemistry, 2002Co-Authors: Jamil S. Saad, Giovanni Natile, Tommaso Scarcia, Luigi G. MarzilliAbstract:Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A2 = diamine or two amines; G = Guanine Derivative). Retro models have A2 carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: ΔHT and ΛHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5‘-GMP, 3‘-GMP, 5‘-IMP, and 3‘-IMP). The bases cant to the left (L) in (S,R,R,S)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other (“6-in” form) or farther out from each other (“6-out” form). Interligand interactions between ligand components near to Pt (first-first s...
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Cisplatin-DNA cross-link retro models with a chirality-neutral carrier ligand: evidence for the importance of "second-sphere communication".
Inorganic chemistry, 2001Co-Authors: Sharon T. Sullivan, Antonella Ciccarese, Francesco Paolo Fanizzi, Luigi G. MarzilliAbstract:We employ retro models, cis-PtA2G2 (A2 = a diamine, G = Guanine Derivative), to assess the cross-linked head-to-head (HH) form of the cisplatin−DNA d(GpG) adduct widely postulated to be responsible...
George Mourad - One of the best experts on this subject based on the ideXlab platform.
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the Guanine hypoxanthine permease ghxp of erwinia amylovora facilitates the influx of the toxic Guanine Derivative 6 thioGuanine
Journal of Applied Microbiology, 2020Co-Authors: I.t. Gatchell, Regan B. Huntley, Neil P. Schultes, George MouradAbstract:Aim Erwinia amylovora is the causal agent of fire blight, a devastating disease of apples and pears. This study determines whether the E. amylovora Guanine-hypoxanthine transporter (EaGhxP) is required for virulence and if it can import the E. amylovora produced toxic analogue 6-thioGuanine (6TG) into cells. Methods and results Characterization of EaGhxP in Guanine transport deficient Escherichia coli reveals that it can transport Guanine, hypoxanthine and the toxic analogues 8-azaGuanine (8AG) and 6TG. Similarly, EaGhxP transports 8AG and 6TG into E. amylovora cells. EaGhxP has a high affinity for 6TG with a Ki of 3·7 µmol l-1 . An E. amylovora ⊿ghxP::Camr strain shows resistance to growth on 8AG and 6TG. Although EaGhxP is expressed during active disease propagation, it is not necessary for virulence as determined on immature apple and pear assays. Conclusions EaGhxP is not required for virulence, but it does import 6TG into E. amylovora cells. Significance and impact of the study As part of the disease establishment process, E. amylovora synthesizes and exports a toxic Guanine Derivative 6TG. Our results are counter intuitive and show that EaGhxP, an influx transporter, can move 6TG into cells raising questions regarding the role of 6TG in disease establishment.
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The Guanine‐hypoxanthine permease GhxP of Erwinia amylovora facilitates the influx of the toxic Guanine Derivative 6‐thioGuanine
Journal of applied microbiology, 2020Co-Authors: I.t. Gatchell, Regan B. Huntley, Neil P. Schultes, George MouradAbstract:Aim Erwinia amylovora is the causal agent of fire blight, a devastating disease of apples and pears. This study determines whether the E. amylovora Guanine-hypoxanthine transporter (EaGhxP) is required for virulence and if it can import the E. amylovora produced toxic analogue 6-thioGuanine (6TG) into cells. Methods and results Characterization of EaGhxP in Guanine transport deficient Escherichia coli reveals that it can transport Guanine, hypoxanthine and the toxic analogues 8-azaGuanine (8AG) and 6TG. Similarly, EaGhxP transports 8AG and 6TG into E. amylovora cells. EaGhxP has a high affinity for 6TG with a Ki of 3·7 µmol l-1 . An E. amylovora ⊿ghxP::Camr strain shows resistance to growth on 8AG and 6TG. Although EaGhxP is expressed during active disease propagation, it is not necessary for virulence as determined on immature apple and pear assays. Conclusions EaGhxP is not required for virulence, but it does import 6TG into E. amylovora cells. Significance and impact of the study As part of the disease establishment process, E. amylovora synthesizes and exports a toxic Guanine Derivative 6TG. Our results are counter intuitive and show that EaGhxP, an influx transporter, can move 6TG into cells raising questions regarding the role of 6TG in disease establishment.
Giovanni Natile - One of the best experts on this subject based on the ideXlab platform.
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X-ray structural characterization of the bis-Guanine Derivative of a cisplatin analogue having just one proton on each coordinated nitrogen and a head-to-head conformation: [Pt{(+/-)-N,N'-dimethyl-2,3-diaminobutane}(9-ethyl-Guanine)2]dinitrate.
Inorganic chemistry, 2010Co-Authors: Francesco P. Intini, Renzo Cini, Gabriella Tamasi, Michael B. Hursthouse, Luigi G. Marzilli, Giovanni NatileAbstract:The X-ray structural and NMR characterization of a bis-Guanine Derivative of a cisplatin analogue designed to reduce the rate of the Pt−N7 rotation of the coordinated Guanine nucleobases by more th...
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rotamer stability in cis pt dia g2 complexes dia diamine Derivative and g Guanine Derivative mediated by carrier ligand amine stereochemistry as revealed by circular dichroism spectroscopy
Chemistry: A European Journal, 2005Co-Authors: Michele Benedetti, Luigi G. Marzilli, Giovanni NatileAbstract:Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a Guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each Guanine leaning towards the cis-G. Such a "six-in" canting of the two Guanine ligands can be hampered by the steric interaction between the H8 of each Guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the Guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of Guanine O6 and the cis-amine N-H group. Such a Guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each Guanine further from the cis-Guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.
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Factors Influencing Conformer Equilibria in Retro Models of Cisplatin−DNA Adducts As Revealed by Moderately Dynamic (N,N‘-Dimethyl-2,3-diaminobutane)PtG2 Retro Models (G = a Guanine Derivative)
Inorganic chemistry, 2002Co-Authors: Jamil S. Saad, Giovanni Natile, Tommaso Scarcia, Luigi G. MarzilliAbstract:Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A2 = diamine or two amines; G = Guanine Derivative). Retro models have A2 carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: ΔHT and ΛHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5‘-GMP, 3‘-GMP, 5‘-IMP, and 3‘-IMP). The bases cant to the left (L) in (S,R,R,S)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other (“6-in” form) or farther out from each other (“6-out” form). Interligand interactions between ligand components near to Pt (first-first s...
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factors influencing conformer equilibria in retro models of cisplatin dna adducts as revealed by moderately dynamic n n dimethyl 2 3 diaminobutane ptg2 retro models g a Guanine Derivative
Inorganic Chemistry, 2002Co-Authors: Jamil S. Saad, Giovanni Natile, Tommaso Scarcia, Luigi G. MarzilliAbstract:Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A2 = diamine or two amines; G = Guanine Derivative). Retro models have A2 carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: ΔHT and ΛHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5‘-GMP, 3‘-GMP, 5‘-IMP, and 3‘-IMP). The bases cant to the left (L) in (S,R,R,S)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other (“6-in” form) or farther out from each other (“6-out” form). Interligand interactions between ligand components near to Pt (first-first s...
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retro models of pt anticancer drug dna adducts chirality controlling chelate ligand restriction of Guanine dynamic motion in 2 2 bipiperidine ptg2 complexes g Guanine Derivative
Inorganic Chemistry, 1999Co-Authors: Susan O Ano, Francesco P. Intini, Giovanni Natile, Luigi G. MarzilliAbstract:Features of cisplatin-type anticancer drug adducts with nucleic acids and their constituents are clouded because they exist as a fluxional mixture of conformers. Retro-model adducts containing the ...
Antona J. Wagstaff - One of the best experts on this subject based on the ideXlab platform.
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famciclovir a review of its pharmacological properties and therapeutic efficacy in herpesvirus infections
Drugs, 1995Co-Authors: Caroline M. Perry, Antona J. WagstaffAbstract:: Famciclovir, a synthetic acyclic Guanine Derivative, is a prodrug which, after oral administration, is rapidly metabolised to the highly bioavailable antiviral compound penciclovir. Penciclovir is active in vitro against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus (VZV). Famciclovir is an effective treatment of immunocompetent patients with acute herpes zoster (shingles) caused by VZV. Comparative studies have demonstrated that famciclovir has therapeutic efficacy similar to that of oral aciclovir (acyclovir) in attenuating the acute signs and symptoms of infection (including pain during the acute phase of infection). In a placebo-controlled study, famciclovir significantly reduced the duration of postherpetic neuralgia; this effect was more pronounced (almost a 3-fold reduction) in patients aged > or = 50 years. In immunocompetent patients with recurrent genital herpes infection, suppressive treatment with oral famciclovir effectively prolonged the time to recurrence of symptomatic episodes of infection compared with placebo. In addition, famciclovir significantly reduced the duration of viral shedding, accelerated healing of genital herpes lesions and reduced the duration of symptoms. Famciclovir is reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions. Famciclovir is a well-tolerated drug with a tolerability profile similar to that of placebo and aciclovir. Thus, famciclovir is now established as an effective treatment of immunocompetent patients with herpes zoster or genital herpes infection, particularly as famciclovir is administered in a convenient dosage regimen that may improve compliance compared with aciclovir.
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Famciclovir
Drugs, 1995Co-Authors: Caroline M. Perry, Antona J. WagstaffAbstract:Synopsis Famciclovir, a synthetic acyclic Guanine Derivative, is a prodrug which, after oral administration, is rapidly metabolised to the highly bioavailable antiviral compound penciclovir. Penciclovir is active in vitro against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus (VZV). Famciclovir is an effective treatment of immunocompetent patients with acute herpes zoster (shingles) caused by VZV. Comparative studies have demonstrated that famciclovir has therapeutic efficacy similar to that of oral aciclovir (acyclovir) in attenuating the acute signs and symptoms of infection (including pain during the acute phase of infection). In a placebo-controlled study, famciclovir significantly reduced the duration of postherpetic neuralgia; this effect was more pronounced (almost a 3-fold reduction) in patients aged ≥50 years. In immunocompetent patients with recurrent genital herpes infection, suppressive treatment with oral famciclovir effectively prolonged the time to recurrence of symptomatic episodes of infection compared with placebo. In addition, famciclovir significantly reduced the duration of viral shedding, accelerated healing of genital herpes lesions and reduced the duration of symptoms. Famciclovir is reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions. Famciclovir is a well-tolerated drug with a tolerability profile similar to that of placebo and aciclovir. Thus, famciclovir is now established as an effective treatment of immunocompetent patients with herpes zoster or genital herpes infection, particularly as famciclovir is administered in a convenient dosage regimen that may improve compliance compared with aciclovir. Antiviral Activity After oral administration famciclovir is metabolised to penciclovir, an antiviral compound with activity against herpes simplex virus (HSV) and varicella zoster virus (VZV). Penciclovir is selectively phosphorylated (initially by viral thymidine kinase) in herpesvirus-infected cells (in preference to uninfected host cells) to yield high intracellular concentrations of penciclovir triphosphate. Thereafter, by interacting with viral DNA polymerases, penciclovir triphosphate inhibits viral replication. The descending order of viral susceptibility to penciclovir in plaque reduction assays is HSV-1, HSV-2 and VZV. After removal of penciclovir, a prolonged antiviral effect has been demonstrated in HSV-1, HSV-2 and VZV infected cell cultures. For antiviral agents, intracellular pharmacokinetics is a key factor in their efficacy. The prolonged intracellular half-life of penciclovir triphosphate in cells infected with HSV (10–20 hours) and VZV (7–14 hours), compared with aciclovir triphosphate (≤1 hour), may contribute to the demonstrated clinical efficacy of famciclovir despite its less frequent oral administration than aciclovir. Combinations of penciclovir with aciclovir or ganciclovir exhibited additive in vitro activity against HSV-1 and HSV-2, and synergistic activity occurred with combinations of penciclovir and human interferon-α, interferon-β or interferon-γ against the same viruses. Combination of penciclovir with foscarnet produced synergistic activity against HSV-1 and additive effects against HSV-2 in vitro. In in vitro cross-resistance studies, most aciclovir-resistant strains of HSV and VZV were also resistant to penciclovir. The aciclovir-resistant strains that were susceptible to penciclovir had altered thymidine kinase and DNA polymerase substrate specificity. Oral famciclovir and oral, intravenous and subcutaneous penciclovir were effective inhibitors of HSV-1 and HSV-2 in mice; topical penciclovir was an effective inhibitor of HSV-1 in guinea-pigs. Pharmacokinetic Properties After oral administration, famciclovir is rapidly metabolised in the intestine and liver to yield penciclovir. Penciclovir (from oral famciclovir) is highly bioavailable (77%) and has a linear dose-proportional pharmacokinetic profile over the 125 to 750mg dose range. In healthy volunteers or patients with uncomplicated herpes zoster infection, maximum plasma concentrations of penciclovir ranged from 2.73 to 3.97 mg/L within 1 hour of a single oral 500mg dose of famciclovir. Penciclovir is excreted primarily by the renal route, and elimination of famciclovir was found to decrease in patients with varying degrees of renal impairment. Following administration of single doses of famciclovir 125, 500, and 750mg to healthy volunteers, plasma elimination half-life values for penciclovir ranged from 2.06 to 2.66 hours. In formal interaction studies, no clinically significant pharmacokinetic interactions have been observed between famciclovir and allopurinol, digoxin, cimetidine, theophylline or zidovudine. Therapeutic Efficacy Clinical trials of famciclovir have included approximately 1200 immunocompetent patients (aged ≥18 years) with herpes zoster (shingles). A double-blind, placebo-controlled clinical trial demonstrated that famciclovir, initiated within 72 hours of the onset of zoster rash, was significantly more effective than placebo in attenuating symptoms of the zoster rash and, in patients with >50 lesions at enrolment, in resolving acute phase zoster pain. In addition, the duration of post-herpetic neuralgia was significantly less in recipients of famciclovir 500 and 750mg administered 3 times a day for 7 days than in placebo recipients. This benefit was more pronounced in a subgroup of patients aged ≥50 years, in whom the duration of postherpetic neuralgia was reduced by almost 3-fold. Randomised double-blind comparisons of famciclovir with aciclovir demonstrated equal efficacy in healing cutaneous lesions and in attenuating acute phase pain (while the zoster rash was present). Famciclovir 250, 500 or 750mg 3 times daily for 7 days significantly reduced the duration of zoster-associated pain (measured as a continuum from onset to complete cessation of pain) by about 1.5-fold compared with aciclovir 800mg 5 times a day, when patients received treatment within 48 hours of rash onset. Data are accumulating on the therapeutic efficacy of famciclovir in immuno-competent patients with genital herpes infection, although studies published to date have been in abstract form only. A randomised double-blind placebo-controlled study of suppressive famciclovir treatment reported a significant prolongation of the time to recurrence of symptomatic episodes of genital herpes. Other placebo-controlled studies of short term treatment demonstrated that famciclovir was significantly more effective than placebo in reducing the time to cessation of viral shedding, healing cutaneous lesions, and reducing the time to cessation of symptoms. Oral famciclovir and aciclovir appear to be equally effective in treating the acute symptoms of patients with symptomatic episodes of genital herpes. Famciclovir has been reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions. Tolerability Preliminary tolerability data indicate that famciclovir is a well-tolerated drug with a profile similar to that of placebo and aciclovir. Headache, nausea and diarrhoea were the most commonly observed adverse events. Higher total daily doses of famciclovir did not appear to correlate with an increased incidence of adverse events compared with lower doses of the drug. Dosage and Administration Famciclovir treatment should be initiated as soon as signs and symptoms of herpes zoster infection become apparent and within 72 hours of the onset of zoster rash. The recommended oral dosage of the drug is 250 or 500mg 3 times daily (depending on different country recommendations) for 7 days. Dosage modification is not required in elderly patients. In patients with moderate to severe renal impairment, prolongation of the dosage interval is necessary to avoid penciclovir accumulation. In the treatment of first episode genital herpes, the recommended oral dosage of famciclovir is 250mg 3 times a day for 5 days; for acute recurrent genital herpes infection the dosage is 125mg twice a day for 5 days.
I.t. Gatchell - One of the best experts on this subject based on the ideXlab platform.
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the Guanine hypoxanthine permease ghxp of erwinia amylovora facilitates the influx of the toxic Guanine Derivative 6 thioGuanine
Journal of Applied Microbiology, 2020Co-Authors: I.t. Gatchell, Regan B. Huntley, Neil P. Schultes, George MouradAbstract:Aim Erwinia amylovora is the causal agent of fire blight, a devastating disease of apples and pears. This study determines whether the E. amylovora Guanine-hypoxanthine transporter (EaGhxP) is required for virulence and if it can import the E. amylovora produced toxic analogue 6-thioGuanine (6TG) into cells. Methods and results Characterization of EaGhxP in Guanine transport deficient Escherichia coli reveals that it can transport Guanine, hypoxanthine and the toxic analogues 8-azaGuanine (8AG) and 6TG. Similarly, EaGhxP transports 8AG and 6TG into E. amylovora cells. EaGhxP has a high affinity for 6TG with a Ki of 3·7 µmol l-1 . An E. amylovora ⊿ghxP::Camr strain shows resistance to growth on 8AG and 6TG. Although EaGhxP is expressed during active disease propagation, it is not necessary for virulence as determined on immature apple and pear assays. Conclusions EaGhxP is not required for virulence, but it does import 6TG into E. amylovora cells. Significance and impact of the study As part of the disease establishment process, E. amylovora synthesizes and exports a toxic Guanine Derivative 6TG. Our results are counter intuitive and show that EaGhxP, an influx transporter, can move 6TG into cells raising questions regarding the role of 6TG in disease establishment.
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The Guanine‐hypoxanthine permease GhxP of Erwinia amylovora facilitates the influx of the toxic Guanine Derivative 6‐thioGuanine
Journal of applied microbiology, 2020Co-Authors: I.t. Gatchell, Regan B. Huntley, Neil P. Schultes, George MouradAbstract:Aim Erwinia amylovora is the causal agent of fire blight, a devastating disease of apples and pears. This study determines whether the E. amylovora Guanine-hypoxanthine transporter (EaGhxP) is required for virulence and if it can import the E. amylovora produced toxic analogue 6-thioGuanine (6TG) into cells. Methods and results Characterization of EaGhxP in Guanine transport deficient Escherichia coli reveals that it can transport Guanine, hypoxanthine and the toxic analogues 8-azaGuanine (8AG) and 6TG. Similarly, EaGhxP transports 8AG and 6TG into E. amylovora cells. EaGhxP has a high affinity for 6TG with a Ki of 3·7 µmol l-1 . An E. amylovora ⊿ghxP::Camr strain shows resistance to growth on 8AG and 6TG. Although EaGhxP is expressed during active disease propagation, it is not necessary for virulence as determined on immature apple and pear assays. Conclusions EaGhxP is not required for virulence, but it does import 6TG into E. amylovora cells. Significance and impact of the study As part of the disease establishment process, E. amylovora synthesizes and exports a toxic Guanine Derivative 6TG. Our results are counter intuitive and show that EaGhxP, an influx transporter, can move 6TG into cells raising questions regarding the role of 6TG in disease establishment.
