Related Searches: acycloguanosine

acycloguanosine(CAS No. 59277-89-3)

acycloguanosine C8H11N5O3 (cas 59277-89-3) Molecular Structure

59277-89-3 Structure

Identification and Related Records

【Name】
acycloguanosine
【Iupac name】
2-amino-9-(2-hydroxyethoxymethyl)-3H-purin-6-one
【CAS Registry number】
59277-89-3
【Synonyms】
aciclovir
Acyclovir (Patented-No Supply)
N(9)-Oxyethoxymethylguanine (Acyclovir)
Acyclovir
9-[(2-Hydroxyethoxy)methyl]guanine
【EINECS(EC#)】
261-685-1
【Molecular Formula】
C8H11N5O3 (Products with the same molecular formula)
【Molecular Weight】
225.20464
【Inchi】
InChI=1S/C8H11N5O3/c9-8-11-6-5(7(15)12-8)10-3-13(6)4-16-2-1-14/h3,14H,1-2,4H2,(H3,9,11,12,15)
【InChIKey】
MKUXAQIIEYXACX-UHFFFAOYSA-N
【Canonical SMILES】
C1=NC2=C(N1COCCO)NC(=NC2=O)N
【MOL File】
59277-89-3.mol

Chemical and Physical Properties

【Appearance】
White to light yellow crystal powder
【Density】
1.77
【Melting Point】
256-257℃
【Boiling Point】
595 °C at 760 mmHg
【Flash Point】
595 °C at 760 mmHg
【Water】
Water solubility: 0.7 mg/mL
【Solubilities】
Water solubility: 0.7 mg/mL
【Color/Form】
white
【Stability】
Stable. Incompatible with strong oxidizing agents.
【Storage temp】
?20°C
【Computed Properties】
Molecular Weight:225.20464 [g/mol]
Molecular Formula:C8H11N5O3
XLogP3:-1.6
H-Bond Donor:3
H-Bond Acceptor:3
Rotatable Bond Count:4
Tautomer Count:9
Exact Mass:225.086189
MonoIsotopic Mass:225.086189
Topological Polar Surface Area:115
Heavy Atom Count:16
Formal Charge:0
Complexity:308
Isotope Atom Count:0
Defined Atom Stereocenter Count:0
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:3
Feature 3D Donor Count:4
Feature 3D Cation Count:1
Feature 3D Ring Count:2
Effective Rotor Count:4
Conformer Sampling RMSD:0.6
CID Conformer Count:26

Safety and Handling

【Hazard Codes】
Xi
【Risk Statements】
36/37/38
【Safety Statements 】
S22;S24/25;S36;S26
【Safety】

Hazard Codes:?IrritantXi
Risk Statements: 36/37/38?
R36/37/38: Irritating to eyes, respiratory system and skin.
Safety Statements: 22-24/25-36-26?
S22: Do not breathe dust.?
S24/25: Avoid contact with skin and eyes.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36: Wear suitable protective clothing.

【Transport】
OTH
【Formulations/Preparations】
Topical: Ointment: 5%, Zovirax (Biovail)
Oral: Capsules: 200 mg Zovirax (with parabens), (GlaxoSmithKline); Suspension: 200 mg/5mL Acyclovir Suspension (with parabens), (Alpharma), Zovirax (with glycerin parabens and sorbitol), (GlaxoSmithKline); Tablets: 400 mg Zovirax (with povidone), GlaxoSmithKline, 800 mg Zovirax (with povidone), GlaxoSmithKline.
Acyclovir sodium: Parenteral: For injection, concentrate, for IV infusion only: 25 mg (of acyclovir) per mL (500 mg, 1 g) Acyclovir Sodium Injection (Mayne), 50 mg (of acyclovir) per mL (500 mg, 1 g) Acyclovir Sodium Injection (American Pharmaceutical Partners), For Injection, for IV infusion only: 500 mg (of acyclovir) Acyclovir Sodium for Injection (Abbott, American Pharmaceutical Partners, Bedford), Zovirax (GlaxoSmithKline), 1 g (of acyclovir) Acyclovir Sodium for Injection (Abbott, Bedford), Zovirax (GlaxoSmithKline).
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl acyclovir sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Acyclovir Sodium/
【Specification】

?Acyclovir , its cas register number is 59277-89-3. It also can be called 9-[(2-Hydroxyethoxy)methyl]guanine ; 2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one ; and Acycloguanosine . It?is commonly marketed as tablets (200 mg, 400 mg, 800 mg and 1 gram), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%).

【Octanol/Water Partition Coefficient】
log Kow = -1.56
【Disposal Methods】
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

Reaction of 2,6-dichloro-9-(2-benzoyloxyethoxymethyl) purine with methanolic ammonia, followed by treatment with nitrous acid and then with methanolic ammonia yields acyclovir.
【Usage】

Orally active acyclic nucleoside with inhibitory activity towards several herpes viruses. Antiviral

Biomedical Effects and Toxicity

【Biological Activity】
Antiviral agent, active against herpes simplex viruses HSV-1 and HSV-2 (EC 50 values are 0.85 and 0.86 μ M respectively). Interferes with viral DNA polymerization through competitive inhibition with guanosine triphosphate. Induces apoptosis in cells transfected with HSV-TK (suicidal gene therapy).
【Pharmacological Action】
- Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.
【Therapeutic Uses】
Antimetabolites; Antiviral Agents
Oral acyclovir is indicated in the treatment of initial episodes of genital herpes infection in immunocompetent and immunocompromised patients. Parenteral acyclovir is indicated in the treatment of severe initial episodes of genital herpes infection in immunocompetent patients and in patients who are unable to take (or absorb) oral acyclovir. /Included in US product labeling/
Oral acyclovir is indicated in the treatment of frequently recurrent (>/= to 6 episodes per year) or intermittent episodes of genital herpes injection in immunocompetent and immunocompromised patients. /Included in US product labeling/
Parenteral (and oral /NOT included in US product labeling/) acyclovir are indicated in the treatment of initial and recurrent mucocutaneous herpes simplex (HSV-1 and HSV-2) infections in immunocompromised patients. /Included in US product labeling/
Parenteral acyclovir is indicated in the treatment of neonatal herpes simplex virus infections. /Included in US product labeling/
Parenteral acyclovir is indicated in the treatment of herpes simplex encephalitis in immunocompetent patients. /Included in US product labeling/
Oral acyclovir is indicated in the treatment of herpes zoster infections (singles) caused by varicella-zoster virus (VZV) in any adult patient with herpes zoster. Therapy is most effective when started within 48 hours of the onset of rash. Parenteral acyclovir is indicated in the treatment of herpes zoster infections (shingles) caused by VZV in immunocompromised patients (and disseminated herpes zoster in immunocompetent patients /NOT included in US product labeling/). /Included in US product labeling/
Oral acyclovir is indicated in the treatment of varicella infections (chickenpox) in immunocompetent patients when started within 24 hours of the onset of a typical chickenpox rash. (Parenteral acyclovir is used in the treatment of varicella injections (chicken pox) caused by VZV in immunocompromised patients /NOT included in US product labeling/). /Included in US product labeling/
Parenteral and oral acyclovir are used in the prophylaxis of herpes simplex virus (HSV) in infections in patients who are immunocompromised, including transplant patients receiving immunosuppressant therapy, human immunodeficiency virus (HIV)-infected patients, and patients receiving chemotherapy. /NOT included in US product labeling/
Oral acyclovir is used in the prophylaxis of herpes zoster infections (singles) caused by VZV, after an initial period of treatment with parenteral acyclovir, in any immunocompromised patient, including transplant patients receiving immunosuppressant therapy. HIV-infected patients, and patients receiving chemotherapy. /NOT included in US product labeling/
Oral and parenteral acyclovir are indicated in the treatment of herpes zoster ophthalmicus. /NOT included in US product labeling/
Topical acyclovir is indicated in the treatment of initial episodes of genital herpes simplex virus infections and limited non-life-threatening mucocutaneous herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised patients; however, systemic acyclovir is more effective and may be preferred. /Included in US product labeling/
Topical acyclovir is used as adjunctive therapy to improve cutaneous healing of localized herpes zoster in immunosuppressed persons being treated systemically with other treatment regimens for herpes zoster. /Included in US product labeling/
【Biomedical Effects and Toxicity】
Absorption of acyclovir from the GI tract is variable and incomplete. 15-30% of an oral dose of the drug is absorbed. Some data suggest that GI absorption of acyclovir may be saturable; in a crossover study in which acyclovir was administered orally to healthy adults as 200 mg capsules, 400 mg tablets, or 800 mg tablets 6 times daily, the extent of absorption decreased with increasing dose, resulting in bioavailabilities of 20, 15, or 10%, respectively. ... This decrease in bioavailability appears to be a function of increasing dose, not differences in dosage forms. In addition, steady-state peak and trough plasma acyclovir concentrations were not dose proportional over the oral dosing range of 200-800 mg 6 times daily, averaging 0.83 and 0.46, 1.21 and 0.63, or 1.61 and 0.83 ug/ml for the 200, 400, or 800 mg dosing regimens, respectively. Peak plasma concentrations usually occur within 1.5-2.5 hours after oral administration.
In a multiple dose study in neonates up to 3 months of age, IV infusion over 1 hour of 5, 10, or 15 mg/kg of acyclovir every 8 hours resulted in mean steady state peak serum concentrations of 6.8, 13.9, and 19.6 ug/ml, respectively, and mean steady state trough serum concentration of 1.2, 2.3, and 3.1 ug/ml, respectively. In another multiple dose study in pediatric patients, IV infusion over 1 hour of 250 or 500 mg/sq m of acyclovir every 8 hours resulted in mean steady state peak serum concentrations of 10.3 and 20.7 ug/ml, respectively.
Acyclovir is widely distributed into body tissues and fluids including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, cerebrospinal fluid, and herpetic vesicular fluid. The drug also is distributed into semen, achieving concentrations about 1.4 and 4 times those in plasma during chronic oral therapy at dosages of 400 mg and 1 g daily, respectively. The apparent volume of distribution of acyclovir is reported to be 32.4-61.8 liter/1.73 sq m in adults and 28.8, 31.6, 42, or 51.2-53.6 liter/1.73 sq m in neonates up to 3 months of age, children 1-2 years; 2-7 years; or 7-12 years of age, respectively.
Acyclovir crosses the placenta. Limited data indicate that the drug is distributed into milk, generally in concentrations greater than concurrent maternal plasma concentrations, possibly via an active transport mechanism.
Following IV administration, acyclovir generally diffuses well into cerebrospinal fluid, in patients with uninflamed meninges, cerebrospinal fluid concentration of acyclovir are reported to be approximately 50% of concurrent serum acyclovir concentrations.
In vitro, acyclovir is approximately 9-33% bound to plasma proteins at plasma concentrations of 0.41-5.2 ug/ml.
Acyclovir is excreted principally in urine via glomerular filtration and tubular secretion. Most of a single IV dose of acyclovir is excreted in urine as unchanged drug within 24 hours after administration. In adults with normal renal function, approximately 30-90% of a single IV dose is excreted unchanged in urine within 72 hours; approximately 8-14% and less than 0.2% are excreted in urine as 9-carboxymethoxymethylguanine and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine, respectively, within 72 hours. In a study in neonates up to 2 months of age, 62-72% of a single dose was excreted in urine unchanged. Less than 2% of a single IV dose of acyclovir is recovered in feces and only trace amounts in expired CO2; the drug apparently does not accumulate in tissues.
Total body clearance of acyclovir is reported to be 327, 248, 190, or 29 ml/min per 1.73 sq m in patients with creatinine clearances of greater than 80, 50-80, 15-50, or 0 ml/minute per 1.73 sq m, respectively.
Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks gestation until delivery. The mean + or - standard deviation plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 + or - 0.6 and 2.3 + or - 1.0 umol/l; steady-state trough, 0.7 + or - 0.3 and 0.8 + or - 0.6 umol/l; steady-state peak, 1.9 + or - 1.0 and 3.3 + or - 1.0 umol/l. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumulation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding suppression of herpes simplex virus recurrences during the last weeks of pregnancy. [Frenkel LM et al; Am J Obstet Gynecol 164 (2): 569-76 (1991)] PubMed Abstract
The pharmacokinetics and safety of high dose oral acyclovir for suppression of cytomegalovirus disease were evaluated in 12 patients (aged 22-57 yr) undergoing renal transplantation who received tablet doses of 800-3200 mg/day of acyclovir, based on renal function, beginning 24 hr before transplant for 12 wk. Acyclovir plasma concentrations were measured by radioimmunoassay on post transplant days or 2 and 5, 6, or 7. Mean peak and trough concentrations on days 5, 6, or 7 were 25 and 18 umol/l, respectively. Two of 6 adverse events were attributable to acyclovir; both resolved with dose modification. It was concluded that the dosage and adjustment scheme and pharmacokinetic model allowed safe administration of acyclovir immediately after transplantation. [Fletcher CV et al; Clin Pharmacol Ther 44 (Aug): 158-63 (1988)] PubMed Abstract
Eighteen children from 3 weeks to 6.9 years of age were given an oral acyclovir suspension for herpes simplex or varicella zoster virus infections. Thirteen patients who were 6 months to 6.9 years old received 600 mg/sq m per dose, and three infants and two children less than 2 years old were given 300 mg/sq m per dose. The drug was given four times a day, except to one infant who was treated with three doses a day. Among the 13 children who received the 600 mg/sq m dose, the maximum concentration in plasma was 0.99 + or - 0.38 microgram/ml (mean + or - standard deviation), the time to maximum concentration was 3.0 + or - 0.86 hr, the area under the curve was 5.56 + or - 2.1 micrograms hr/ml, and the elimination half-life was 2.59 + or - 0.78 hr. The three infants less than 2 months of age who received the 300 mg/sq m dose had a maximum concentration in plasma of 1.88 + or - 1.11 micrograms/ml, a time to maximum concentration of 4.10 + or - 0.48 hr, an area under the curve of 6.54 + or - 4.32 micrograms.hr/ml, and a t1/2 elimination half-life of 3.26 + or - 0.33 hr. The acyclovir suspension was well tolerated by young children. No adverse effects requiring discontinuation of the drug occurred. [Sullender WM et al; Antimicrob Agents Chemother 31 (11): 1722-6 (1987)] PubMed Abstract
A 39-year-old pregnant woman, presumed to be at 30 weeks of gestation, was treated with aciclovir (350 mg, or 15 mg/kg bw) intravenously every 8 hr throughout the remainder of gestation. At 38-53 hr after the last dose, aciclovir was found at a concentration of 0.2-2.8 ug/mL in the urine of the infant, delivered by caesarean section.
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant rats were treated during organogenesis with sc injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crown-rump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 a similar but slightly more pronounced outcome was found. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt were measured. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 uM). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (+ or - standard deviation) of 60.3 + or - 14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6 + or - 16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. [Stahlmann R et al; Arch Toxicol 61 (6): 468-79 (1988)] PubMed Abstract

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