Cell viability is lowered by aciclovir sodium (3-100 µM; 24-72 hours; Jurkat, U937, and K562 leukemia cells) in a way that is dependent on both dose and time [1]. Aciclovir sodium (10-100 µM; 24-72 hours; Jurkat cells) raises the sub-G1 hypodiploid peak and inhibits DNA synthesis, stopping the cell cycle in the G2/M and S phases. 1]. Aciclovir sodium (10-100 µM; 24-72 hours; Jurkat cells) activates caspase-3 and fragments nuclear DNA to cause apoptosis [1].

Aciclovir sodium (20 mg/kg; oral; three times daily; 10 days) prevents skin lesions from forming and separates the formation of antibodies from DTH reactions. [3]

Cell Viability Assay[1]
Cell Types: Jurkat, U937 and K562 Leukemia cell
Tested Concentrations: 3, 10, 30 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: demonstrated a dose and time dependent decrease in cell viability.

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Apoptosis analysis[1]
Cell Types: Jurkat Cell
Tested Concentrations: 10 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: Increased caspase-3 activity and cleavage of internucleosomal DNA.

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Cell cycle analysis[1]
Cell Types: Jurkat cells
Tested Concentrations: 10 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: Dose-dependent accumulation of cells in S phase after 24 and 48 hrs (hours). After 72 hrs (hours), there was a dose-dependent increase in the sub-G1 hypodiploid peak.

Animal/Disease Models: Specific - Pathogen-free balb/c (Bagg ALBino) mouse (7 weeks old) infected with HSV-1 [3]
Doses: 20 mg/kg
Route of Administration: po (po (oral gavage)) three times daily; for 10 days
Experimental Results: Inhibition of skin The lesions develop and result in a dissociation between the DTH response and antibody production.

Absorption, Distribution and Excretion
The oral bioavailability of acyclovir is 10-20%, but decreases with increasing dose. The absorption rate of acyclovir ointment is <0.02-9.4%. The absorption rate of acyclovir oral tablets and eye ointment is extremely low. Food does not affect the bioavailability of acyclovir. The mean time to peak concentration (Tmax) of acyclovir is 1.1 ± 0.4 hours, the mean peak plasma concentration (Cmax) is 593.7-656.5 ng/mL, and the mean area under the curve (AUC) is 2956.6-3102.5 h/ng/mL. Most acyclovir is excreted unchanged in the urine. 90-92% of the drug is excreted unchanged via glomerular filtration and renal tubular secretion. Less than 2% of the drug is excreted, and less than 0.1% is excreted as carbon dioxide. The volume of distribution of acyclovir is 0.6 L/kg. The renal clearance of acyclovir is 248 ml/min/1.73 m². The total clearance in newborns is 105-122 ml/min/1.73 m². Absorption of acyclovir in the gastrointestinal tract is variable and incomplete. The absorption rate of oral doses is 15-30%. Some data suggest that gastrointestinal absorption of acyclovir may reach saturation. In a crossover study, healthy adults were given 200 mg capsules, 400 mg tablets, or 800 mg tablets six times daily. The results showed that absorption decreased with increasing dose, with bioavailability of 20%, 15%, and 10%, respectively. …This decrease in bioavailability appears to be a result of dose-increasing activity rather than dosage form differences. Furthermore, within the oral dosage range of 200-800 mg six times daily, steady-state plasma peak and trough concentrations of acyclovir were not dose-dependent, with mean values of 0.83 and 0.46 μg/mL for the 200 mg, 400 mg, and 800 mg dose groups, 1.21 and 0.63 μg/mL, and 1.61 and 0.83 μg/mL, respectively. Peak plasma concentrations typically occur within 1.5-2.5 hours after oral administration. In a multi-dose study of neonates under 3 months of age, intravenous infusions of 5, 10, or 15 mg/kg acyclovir every 8 hours for 1 hour resulted in mean steady-state serum peak concentrations of 6.8, 13.9, and 19.6 μg/mL, and mean steady-state serum trough concentrations of 1.2, 2.3, and 3.1 μg/mL, respectively. In another multidose study of pediatric patients, intravenous infusions of 250 or 500 mg/m² of acyclovir every 8 hours for 1 hour resulted in mean steady-state peak serum concentrations of 10.3 and 20.7 μg/ml, respectively. Acyclovir is widely distributed throughout the body's tissues and fluids, including the brain, kidneys, saliva, lungs, liver, muscles, spleen, uterus, vaginal mucosa and secretions, cerebrospinal fluid, and herpetic vesicular fluid. The drug is also distributed in semen; during chronic treatment with daily oral doses of 400 mg and 1 g, semen concentrations were approximately 1.4 times and 4 times higher than plasma concentrations, respectively. The apparent volume of distribution (VOD) of acyclovir in adults is reported to be 32.4–61.8 L/1.73 m², while the VODs in newborns under 3 months of age, children aged 1–2 years, children aged 2–7 years, and children aged 7–12 years are 28.8, 31.6, 42, or 51.2–53.6 L/1.73 m², respectively. Acyclovir crosses the placenta. Limited data suggest that the drug is distributed into breast milk at concentrations typically higher than maternal plasma concentrations, likely through an active transport mechanism. For more complete data on the absorption, distribution, and excretion of acyclovir (13 types), please visit the HSDB record page. Metabolites/Metabolites: Acyclovir is oxidized by alcohol dehydrogenase and aldehyde dehydrogenase, with less than 15% converted to 9-carboxymethoxymethylguanine; and by aldehyde oxidase 8-hydroxylation, with 1% converted to 8-hydroxyacyclovir. Viral thymidine kinase converts acyclovir to acyclovir monophosphate. Acyclovir monophosphate is then converted to its diphosphate form via guanylate kinase. Acyclovir diphosphate is then converted to acyclovir triphosphate via nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthase, phosphoenolpyruvate carboxylkinase, and adenosine succinate synthase. Acyclovir is partially metabolized to 9-carboxymethoxymethylguanine, and a small amount is metabolized to 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. In vitro studies have shown that in cells infected with herpesvirus, acyclovir is primarily metabolized to acyclovir monophosphate, diphosphate, and triphosphate through intracellular phosphorylation by viral-encoded thymidine kinase and various cellular enzymes. The clearance period for acyclovir is 2.5–3 hours, depending on the patient's creatinine clearance rate. During hemodialysis, the plasma half-life of acyclovir is approximately 5 hours. In patients aged 7 months to 7 years, the mean half-life is 2.6 hours. Plasma concentrations of acyclovir exhibit a biphasic decline. In adults with normal renal function, the mean initial phase half-life of acyclovir is 0.34 hours, and the mean terminal phase half-life is 2.1–3.5 hours. In adults with impaired renal function, both the initial and terminal phase half-lives may be prolonged, depending on the degree of renal impairment. A study in anuric adults showed a mean initial phase half-life of acyclovir of 0.71 hours. In multiple studies, the mean terminal phase half-life of acyclovir was 3, 3.5, or 19.5 hours in adults with creatinine clearance of 50–80 or 15–50 ml/min/1.73 m², and in anuric patients, respectively. In patients undergoing hemodialysis, the average end-stage half-life of acyclovir during hemodialysis is 5.4–5.7 hours. In newborns, the half-life of acyclovir depends primarily on the maturity of the renal excretion mechanism, which is determined by gestational age, chronological age, and body weight. In children over 1 year of age, the half-life appears to be similar to that in adults. At end-stage, the average half-life for newborns (under 3 months), children aged 1–2 years, children aged 2–12 years, or children aged 12–17 years is 3.8–4.1 hours, 1.9 hours, 2.2–2.9 hours, or 3.6 hours, respectively.

Hepatotoxicity
Despite the widespread use of acyclovir, there is little evidence that oral acyclovir causes serious liver injury. Serum enzyme levels typically do not change during oral acyclovir treatment. High-dose intravenous acyclovir is associated with renal impairment and thrombocytopenia, and occasionally causes transient, mild to moderate elevations in serum ALT levels, but these elevations are usually asymptomatic and resolve spontaneously. A few cases have been reported where acyclovir or valacyclovir (a prodrug of acyclovir, which is better absorbed orally) can cause acute, clinically significant liver injury, but the evidence for these cases is insufficient. Some degree of liver injury, even jaundice, can occur during herpes simplex or varicella-zoster infections, and these complications may be misdiagnosed as drug-induced liver injury. Furthermore, in the reported cases, patients were taking other medications concurrently and had other potential comorbidities that could lead to liver injury. Probability Score: D (Possibly a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Even if the mother takes the highest dose, the amount of acyclovir in breast milk is only about 1% of the typical dose for the infant, and no adverse effects are expected on breastfed infants. Topical application of acyclovir to a small area of skin away from the breast does not pose a risk to the infant. Only water-soluble creams or gels should be applied to the breast, as ointments may expose the infant to high concentrations of mineral oil through licking. [1]
◉ Effects on breastfed infants
No adverse reactions were observed in the breastfed infant of a mother who was taking acyclovir (800 mg five times daily). [5]
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
Acyclovir is bound to 9-33% of the protein in plasma.
Interactions
Acyclovir has been used concurrently with zidovudine…no evidence of increased toxicity was found; however, at least one patient with acquired immunodeficiency syndrome (AIDS) reported neurotoxicity (deep somnolence and stupor) during combination therapy with this drug, which relapsed upon re-administration. This patient developed neurotoxicity 30–60 days after initiation of intravenous acyclovir treatment, and while symptoms improved with oral acyclovir, they persisted and resolved upon discontinuation of acyclovir.
This study reports the effects of azidothymidine combined with acyclovir on pluripotent (spleen colony-forming units) and directed (granulocyte-macrophage colony-forming units; erythroid burst-forming units) hematopoietic progenitor cells in mice. Azidothymidine alone caused severe hematologic toxicity, manifested by a significant reduction in all tested hematopoietic progenitor cell populations (including spleen colony-forming units, granulocyte-macrophage colony-forming units, and erythroid burst-forming units). However, hematopoietic function subsequently recovered rapidly. Acyclovir alone did not alter the hematological parameters studied, while the combination of azidothymidine and acyclovir resulted in changes in peripheral blood cells and bone marrow hematopoietic progenitor cells, but overall, these changes were not significantly different from those observed with azidothymidine alone. Only the reduction in spleen colony-forming units was more significant, but its recovery was as rapid as that of directed progenitor cells. Therefore, under the experimental conditions, adding acyclovir to azidothymidine did not appear to increase the latter's hematologic toxicity. The combined effects of acyclovir and chlorhexidine on herpes simplex virus replication and DNA synthesis were investigated. Acyclovir and chlorhexidine showed a synergistic effect in inhibiting viral replication, partly by enhancing the reduction in viral DNA synthesis. These data suggest that combination therapy with acyclovir and chlorhexidine may help control oral herpes infections. Acyclovir may reduce the renal clearance of other drugs actively cleared by the kidneys (e.g., methotrexate). For more complete data on interactions of acyclovir (6 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice > 10,000 mg/kg
Intraperitoneal LD50 in mice 1,000 mg/kg

[1]. Acyclovir induces cell cycle perturbation and apoptosis in Jurkat leukemia cells, and enhances chemotherapeutic drug cytotoxicity. Life Sci. 2018 Dec 15;215:80-85.

[2]. Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2006 Nov;72(2):157-61.

[3]. Acyclovir treatment of skin lesions results in immune deviation in mice infected cutaneously with herpes simplex virus. Antivir Chem Chemother. 1999 Sep;10(5):251-7.

[4]. Oral acyclovir as prophylaxis for bacterial infections during induction therapy for acute leukaemia in adults. The Leukemia Group of Middle Sweden. Support Care Cancer. 1993 May;1(3):139-44.

Therapeutic Uses
Antiviral Drugs
Intravenous acyclovir sodium is used to treat primary and recurrent mucocutaneous herpes simplex virus (HSV-1 and HSV-2) infections, as well as varicella-zoster infection in immunocompromised adults and children; to treat severe primary genital herpes infection in immunocompetent individuals; and to treat HSV encephalitis and neonatal HSV infection.
Oral acyclovir is used to treat primary and recurrent genital herpes; to treat acute herpes zoster in immunocompetent individuals; and to treat varicella in immunocompetent individuals.
Oral acyclovir is indicated for the treatment of primary genital herpes infection in immunocompetent and immunocompromised patients. Acyclovir for injection is indicated for the treatment of severe primary genital herpes infection in immunocompetent patients and patients who cannot take (or absorb) oral acyclovir. /US Product Label Contains/
For more complete data on the therapeutic uses of acyclovir (15 in total), please visit the HSDB record page.

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Drug Warning
Treatment with injectable acyclovir may cause signs and symptoms of encephalopathy. …Acyclovir should be used with caution in patients with underlying neurological abnormalities, severe renal, hepatic, or electrolyte abnormalities, or severe hypoxia. Caution should be exercised when using this drug in patients with a history of neurological reactions to cytotoxic drugs, or in patients currently receiving intrathecal methotrexate or interferon. Acyclovir should be used with caution in patients concurrently taking other nephrotoxic drugs, as these patients have an increased risk of acyclovir-induced renal impairment and/or reversible central nervous system symptoms. Patients receiving intravenous acyclovir should maintain adequate hydration; however, for patients with encephalitis, the recommended fluid volume should be weighed against the risk of cerebral edema. Because rapid intravenous administration of acyclovir increases the risk of kidney injury, acyclovir should only be administered by slow intravenous infusion (over 1 hour).
Currently, there are no adequate and controlled studies on the use of acyclovir in pregnant women. Therefore, it should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.
Maternal use generally compatible with breastfeeding: Acyclovir: Infant-reported signs or symptoms or effects on lactation: None. (Excerpt from Table 6)
For more complete data on drug warnings for acyclovir (20 in total), please visit the HSDB record page.

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Pharmacodynamics
Acyclovir is a nucleoside analog that inhibits the activity of viral DNA polymerase and the DNA replication of various herpesviruses. Acyclovir has a wide therapeutic window, and overdose is rare in healthy patients.

C8H10N5NAO3

247.18

247.068

69657-51-8

Acyclovir;59277-89-3;Acyclovir alaninate;84499-64-9

135398513

Crystals from methanol
Crystals from ethanol
White, crystalline powder

613.1ºC at 760 mmHg

0.099

3

5

4

16

308

0

C1=NC2=C([N]1COCCO)N=C(N=C2[O-])N.[Na+]

MKUXAQIIEYXACX-UHFFFAOYSA-N

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)

2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one

Aciclovir sodiumAcyclovir sodium

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)