Cidofovir

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H301：Giftig bei Verschlucken.

  H315：Verursacht Hautreizungen.

• Sicherheit

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

Cidofovir Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Cidofovir launched as a first-line treatment for CMV retinitis in AIDS patients. It is a nucleotide analog with potent activity against a broad spectrum of DNA viruses, e.g., HSVl, HSV2, CMV, adenovirus and papillomavirus. Cidofovir can be synthesized by a number of methods, the most efficient involves ring openning of (R)-glycidol with cytosine. Metabolically, cidofovir does not require intracellular activation by virally-encoded enzymes like similar compounds, e.g., aciclovir or ganciclovir. It is rapidly converted to its active form, cidofovir diphosphate, which inhibits viral DNA polymerase at concentrations up to 600 fold lower than that required for human DNA polymerase. It is a competitive inhibitor of dCTP incorporation or if incorporated into viral DNA slows down further DNA synthesis and causes the destabilization of the viral DNA. There are three intracellular metabolites which are also active thus giving rise to the long half-life. This results in lower dosing times (once every 1-2 weeks) and the ability to protect previously uninfected cells from subsequent infection.

• Originator

  Gilead Sciences (USA)

• Verwenden

  An injectable antiviral medication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription. It is used in the treatment of acyclovir resistant herpes as well as a complementary intralesional therapy against papillomatosis caused by human papillomavirus (HPV).

• Verwenden

  Cidofovir suppresses virus replication by selective inhibition of viral DNA synthesis.
  
  Cidofovir, a monophosphorylated nucleotide analog, does not require viral thymidine kinase phosphorylation to act and therefore has activity against herpes simplex infections with deficient or altered thymidine kinase activity. It is ineffective against rare strains with mutations in DNA polymerase. It is administered intravenously, 5 mg/kg/week for acyclovir-resistant infections in immunocompromised hosts. Associated side effects include nephrotoxicity and neutropenia. Concomitant administration of cidofovir with probenecid and saline hydration decreases the nephrotoxicity. Cidofovir resistance has not been documented.

• Definition

  ChEBI: Cytosine substituted at the 1 position by a 3-hydroxy-2-(phosphonomethoxy)propyl group (S configuration). A nucleoside analogue, it is an injectable antiviral used for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients.

• Indications

  Cidofovir (Vistide) is an acyclic phosphonate cytosine analogue with activity against herpesviruses including CMV, HSV-1, HSV-2, EBV, and VZV. It also inhibits adenoviruses, papillomaviruses, polyomaviruses, and poxviruses. Activation of cidofovir requires metabolism to a diphosphate by host cellular enzymes. Because this activation does not depend upon viral enzymes, similar levels of cidofovir diphosphate are seen in infected and uninfected cells. Cidofovir diphosphate competes with deoxycytidine triphosphate (dCTP) for access to viral DNA polymerase and also acts as an alternative substrate. The incorporation of one cidofovir molecule into the growing DNA chain slows replication; sequential incorporation of two molecules halts DNA polymerase activity.

• Manufacturing Process

  By the alkylation of N-benzoyl uracil with the chiral 2-trityloxy-oxirane was obtained glycoside-like derivative N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo- 1,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide as a single isomer. From N- [1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-1,2-dihydroxypyrimidin-4-yl]-Nmethylbenzamide and toluene-(4-sulfomethyl)phosphonic acid diethyl ester was prepared [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1- trityloxymethylethoxymethyl]phosphonic acid diethyl ester. As a result of
  treatment of the product with hydrogen chloride was synthesized [2- [(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-hydroxymethylethoxymethyl]phosphonic acid diethyl ester. Sequential reaction with trimethylsilyl bromide and ammonium hydroxide cleaves the phosphite ethyl groups and saponifies the benzamide function to afford (1S)-1-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine (Cidofovir).

• Trademarks

  Vistide (Gilead Sciences).

• Therapeutic Function

  Antiviral

• Antimicrobial activity

  The phosphonate group enables it to mimic a nucleotide and bypass virus-dependent phosphorylation. Cellular enzymes convert it to the triphosphate, which has in-vitro and in-vivo activity against CMV and other herpesviruses, including aciclovir- resistant HSV. Oral hairy leukoplakia resolved on therapy, suggesting that it has activity against EBV. Activity against adenovirus and papillomaviruses is also reported.

• Allgemeine Beschreibung

  Cidofovir, (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine(HPMPC, Vistide), is an acyclonucleotide analog thatpossesses broad-spectrum activity against several DNAviruses. Unlike other nucleotide analogs that are activated tonucleoside phosphates, Cidofovir is a phosphonic acid derivative.The phosphonic acid is not hydrolyzed by phosphatasesin vivo but is phosphorylated by cellular kinases to yield adiphosphate. The diphosphate acts as an antimetabolite to deoxycytosinetriphosphate (dCTP). Cidofovir diphosphate is acompetitive inhibitor of viral DNA polymerase and can beincorporated into the growing viral DNA strand, causingDNA chain termination.
  Cidofovir possesses a high therapeutic index against CMVand has been approved for treating CMV retinitis in patientswith AIDS. Cidofovir is administered by slow, constant intravenousinfusion in a dose of 5 mg/kg over a 1-hour periodonce a week for 2 weeks. This treatment is followed by amaintenance dose every 2 weeks.

• Hazard

  A severe skin irritant.

• Pharmazeutische Anwendungen

  An acyclic cytosine analog administered by intravenous infusion.

• Biochem/physiol Actions

  Selective inhibitor of viral DNA synthesis through the selective inhibition of viral DNA polymerase.

• Mechanism of action

  Cidofovir is a synthetic acyclic pyrimidine nucleotide analogue of cytosine. It is a phosphorylated nucleotide that is additionally phosphorylated by host cell enzymes to its active intracellular metabolite, cidofovir diphosphate. This reaction occurs without initial virus-dependent phosphorylation by viral nucleoside kinases. It has antiviral effects by interfering with DNA synthesis and inhibiting viral replication.

• Pharmakokinetik

  Oral absorption： <5%
  C_max 3 mg/kg intravenous infusion： 7.7 mg/L end infusion
  10 mg/kg intravenous infusion： 23 mg/L end infusion
  Plasma half-life： c. 3–4 h
  Volume of distribution： c. 0.6 L/kg
  Plasma protein binding： <6%
  The intracellular half-life of the diphosphate is 17–65 h. It is excreted unchanged by the kidney by glomerular filtration and tubular secretion.

• Clinical Use

  Cidofovir is approved for the treatment and prophylaxis of CMV retinitis in AIDS patients. It has also been used in the treatment of acyclovir-resistant (viral thymidine kinase-deficient) HSV infections, polyomavirusassociated progressive multifocal leukoencephalopathy, condylomata acuminata (anogenital warts), and molluscum contagiosum.

• Clinical Use

  Treatment of CMV retinitis
  Because of nephrotoxicity it is a drug of last resort. It has been used experimentally in the treatment of adenovirus pneumonia and BK virus in transplant patients and juvenile laryngeal papillomatosis.

• Nebenwirkungen

  The most immediately serious adverse effect associated with cidofovir therapy is nephrotoxicity. Accumulation of the drug within the proximal tubule epithelial cells can lead to proteinuria, azotemia, glycosuria, elevated serum creatinine, and rarely, Fanconi’s syndrome. Probenecid is administered along with cidofovir to block its uptake into the proximal tubule epithelial cells and thereby inhibit its tubular secretion as well as its toxicity. Probenecid carries its own adverse effects, including gastrointestinal upset, hypersensitivity reactions, and a decrease in the elimination of drugs that also undergo active tubular secretion (e.g. nonsteroidal antiinflammatory drugs [NSAIDs], penicillin, acyclovir, zidovudine).
  Anterior uveitis and neutropenia are fairly common side effects of cidofovir therapy. Ocular hypotony and metabolic acidosis are rare. Exposure to therapeutic levels of cidofovir causes cancer in rats; therefore, this drug should be considered a potential human carcinogen. Animal studies have also shown cidofovir to produce embryotoxic and teratogenic effects and to impair fertility.

• Nebenwirkungen

  Nephrotoxicity, heralded by proteinuria, occurred at weekly doses of ≤3 mg/kg in two of five patients after 6 and 14 consecutive weeks of therapy. Two of five patients given 10 mg/kg developed nephrotoxicity, manifested as a Fanconi-like syndrome, after only two doses. Biopsy revealed proximal tubular effects. Prehydration and extended dosing intervals seem to be nephroprotective.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antivirals: avoid concomitant use with tenofovir.

• Stoffwechsel

  After IV doses of cidofovir, serum concentrations decline with a reported terminal half-life of about 2.2 hours (the intracellular half-life of the active diphosphate may be up to 65 hours).
  Cidofovir is eliminated mainly by renal excretion, both by glomerular filtration and tubular secretion. About 80-100% of a dose is recovered unchanged from the urine within 24 hours. Use with probenecid may reduce the excretion of cidofovir to some extent by blocking tubular secretion, although 70-85% has still been reported to be excreted unchanged in the urine within 24 hours.

Cidofovir Upstream-Materialien And Downstream Produkte

Cidofovir Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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