Huagongshe화공사 화학 정보 인쇄 보고서 · 연구 참고용
Cidofovir
Vistide · Cidovir · cidofovir anhydrous · HPMPC · GS-504 · CS-1956 · CIDOFOVIR · (S)-HPMPC
식별자 및 물리적 특성
| CAS No. | 113852-37-2 |
|---|---|
| 분자식 | C8H14N3O6P |
| 평균 분자량 | 279.19 g/mol |
| 단동위원소 질량 | 279.06202217 g/mol |
| SMILES | Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1 |
| InChIKey | VWFCHDSQECPREK-LURJTMIESA-N |
| PubChem CID | 60613 |
| ChEMBL | CHEMBL152 |
| ChEBI | CHEBI:3696 |
| DTXSID | DTXSID3043734 |
화학 및 물리적 성질
| XLogP | -3.6 |
|---|---|
| 극성 표면적 | 146 |
| 수소 결합 공여자 수 | 4 |
| 수소 결합 수용자 수 | 6 |
| 회전 가능 결합 수 | 6 |
| 무거운 원자 수 | 18 |
| 형식 전하 | 0 |
| 복잡도 | 417 |
| LogP(분배 계수) | -3.9log Kow = -3.3 @ pH 7.1 |
| Color/Form | Fluffy white powderWhite crystalline powder |
| 용해도 | =170 mg/mL at pH 6-8Aqueous solubility >=170 mg/ml @ pH 6-81.15e+01 g/L탈이온수: ≥5mg/mL(가온) |
| 녹는점 | 480260 °C (dec)480 °C260° (dec) |
| Optical Rotation | Specific optical rotation at 20 °C for the D (sodium) line: -97.3 deg (c=0.80 in water) |
| Physical Description | Solid |
| Stability/Shelf Life | It is recommended that cidofovir admixtures be administered within 24 hours of preparation and that refrigeration or freezer storage not be used to extend this 24 hour limit. |
| Other Experimental Properties | UV maximum (pH 2): 279 nm (E 13,000) /Monohydrate/ |
| 끓는 점 | 609.5±65.0 °C(Predicted) |
| 밀도 | 1.76±0.1 g/cm3(Predicted) |
| 저장 조건 | Keep in dark place,Sealed in dry,Store in freezer, under -20°C |
| 물리적 상태 | 가루 |
| pKa(산도 계수) | 2.29±0.10(Predicted) |
| 색상 | White to off-white |
| 용해도 | Soluble to 12 mg/mL (42.98 mM) in Water |
| InChI | InChI=1S/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)/t6-/m0/s1 |
| InChIKey | VWFCHDSQECPREK-LURJTMIESA-N |
| SMILES | P(CO[C@H](CO)CN1C(=O)N=C(N)C=C1)(=O)(O)O |
안전 및 규제
| 규제 정보 | Hazard Traits - CarcinogenicityDevelopmental ToxicityReproductive ToxicityAuthoritative List - Prop 65Report - regardless of intended function of ingredient in the product |
|---|---|
| FDA 요건 | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cidofovir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Special Reports | An overview of the pharmacology, pharmacokinetics, efficacy, side effects and dosage of cidofovir for the treatment of cytomegalovirus retinitis.[Levien T, Baker DEHosp Pharm 31: 1604-20 (1996)] |
| 처리 방법 | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.Partially used vials of cidofovir and diluted solutions should be discarded by high temperature incineration. |
| Preventive Measures | Caution should be exercised in preparing, administering, and discarding solutions of cidofovir according to guidelines for handling mutagenic substances. If cidofovir concentrate for injection or a dilute solution of the drug comes in contact with the skin or mucosa, the affected area should be washed immediately and thoroughly with soap and water. |
| Personal Protective Equipment (PPE) | Due to the mutagenic potential of cidofovir, use of appropriate safety equipment is recommended for preparation, administration, and disposal of cidofovir. The National Institutes of Health recommends that cidofovir be prepared in a class II laminar flow biological safety cabinet and that personnel preparing this medication wear surgical gloves and a closed-front surgical-type gown with kint cuffs. |
| 체내 부담 | Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 ug 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. |
| 상호 작용 | Concomitant administration of cidofovir with potentially nephrotoxic agents (e.g., amphotericin B, aminoglycosides, foscarnet, nonsteriodal antiinflammatory agents, IV pentamidine, vancomycin) is contraindicated, and the manufacturer recommends that at least 7 days elapse between discontinuance of such drugs and administration of cidofovir.Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotony in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant. |
| Hepatotoxicity | Intravenous cidofovir therapy is associated with mild-to-moderate elevations in serum ALT levels in a proportion of patients, but the elevations are usually self-limited and do not require dose modification. Nephrotoxicity is often dose limiting, which may account for the absence of clinically significant cases of liver injury associated with cidofovir therapy. Cases of clinically apparent liver injury have been reported during cidofovir therapy, but the role of this agent has been difficult to define because most patients who receive cidofovir have severe immunodeficiency and are receiving multiple other agents, some of which are known hepatotoxins. Several instances of acute liver failure, lactic acidosis and fatty liver have been described in patients taking cidofovir, but other nucleoside analogues such as zidovudine, stavudine or didanosine were being taken concurrently.Likelihood score: E (unlikely cause of clinically apparent liver injury). |
| Human Toxicity Excerpts | /HUMAN EXPOSURE STUDIES/ The major complication of cidofovir therapy is renal toxicity, which is sometimes irreversible, results in renal failure, and requires dialysis to prevent death./CASE REPORTS/ A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to < or =16 mEq/L occurred in 16% of cidofovir-treated patients. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving /cidofovir/. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)CidofovirAmbiguous-DILI-concern5Adverse reactionsDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ /A study was conducted/ to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir-induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concs of 25, 200, 625 and 2000 ug/ml. Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concs of 625 and 2000 ug/ml. A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 micrograms of cidofovir intravitreally (vitreous concentration of 25 ug/ml) is the highest non-toxic dose in the guinea pigthe IOP was unchanged at two and four wks after injection with this dosehistologically the eyes were normal. A single injection of 50 ug of cidofovir intravitreally (vitreous concentration of 200 ug/ml) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 ug and 500 ug of cidofovir (vitreous concentrations of 625, and 2000 ug/ml, respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 ug cidofovir intravitreally (vitreous concentration of 625 ug/ml)retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 micrograms of cidofovir intravitreally (vitreous concentration of 2000 ug/ml): retina was relatively well preserved. The guinea pig eye shows similar reduction in/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... A 26 wk toxicology study was done in rats evaluating once weekly subscapular sc injections of cidofovir. The study was terminated at 19 wks because palpable mammary adenocarcinomas were detected in females after only 6 doses. These masses developed at doses as low as 0.6 mg/kg/wk... . There was also a significant incr in mammary adenocarcinomas in female rats and a significant incidence of Zymbal's gland carcinomas in male and female rats administered 15 mg/kg of cidofovir once weeklythis was not seen at the 0.6 or 3 mg/kg doses./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In animals ...iv admin of... cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly iv bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg/dose via oral gavage 1 hr prior to cidofovir admin). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspermia) changes were increased in monkeys admin cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid. Renal drug clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose groups and resulted in an incr systemic exposure to cidofovir... that was significantly greater in monkeys admin cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decr in renal clearance in monkeys receiving chronic iv cidofovir treatment./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Cidofovir was found to be embryotoxic (reduced fetal body weight) in rats administered 1.5 mg/kg per day and in rabbits given 1.0 mg/kg during the period of organogenesisthese doses were also maternotoxic. There was also an increased incidence of fetal external soft tissue and skeletal anomalies, such as meningocele, short snout, and short maxillary bones seen in the rabbits administered 1.0 mg/kg per day, which was also maternally toxic./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies showed that cidofovir caused inhibition of spermatogenesis in rats and monkeys. However, no adverse effects on fertility or reproduction were seen following once weekly iv injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/wk... . Female rats dosed iv once weekly at 1.2 mg/kg/wk...or higher, for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births/litter and increased early resorptions/litter. Peri- and post-natal development studies in which female rats received sc injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approx 5 weeks) resulted in no adverse effects on viability, growth, behavior, sexual maturation or reproductive capacity in the offspring. |
| Antidote and Emergency Treatment | Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/Hemodialysis and probenecid should reduce plasma concentrations in the event of an overdose.Two cases of cidofovir overdose have been reported. These patients received single doses of /cidofovir/ at 16.3 mg/kg and 17.4 mg/kg respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid and vigorous iv hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during LactationNo information is available on the use of cidofovir during breastfeeding. Until more safety data become available, an alternate drug is preferred. Individuals with smallpox are recommended to not breastfeed their infant because of the risk of passing variola virus to the infant through direct contact. Providing pumped milk to the infant may be possible if no lesions are near the breast and adequate precautions are taken with respect to cleaning hands, breasts, breast pumps and any other apparatuses used to provide milk to the infant. Individuals with Mpox should feed their infants with pasteurized donor milk or infant formula until all of their lesions are healed. Numerous other safety precautions are advised for mothers with Mpox.[1]◉ Effects in Breastfed InfantsRelevant published information was not found as of the revision date.◉ Effects on Lactation and Breastmilk |
| 수질 위해 등급(WGK) | 3 |
| RTECS 번호 | SZ6545000 |
| 운송 번호(UN) | UN 2811 6.1 / PGIII |
| 위험 문구(R) | 25-38 |
| 위험 표시 | T |
| 안전 문구(S) | 36-37-45 |
| 위험 등급 | Acute Tox. 3 OralSkin Irrit. 2 |
| 저장 분류 | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| 유해 물질 데이터 | 113852-37-2(Hazardous Substances Data) |
용도
개요
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.
용도
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.
일반 설명
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.