Treatment Of Herpes Simplex Research Articles

Epidemiology and treatment of herpes simplex virus in the neonatal intensive care unit.

Describe the epidemiology and clinical characteristics of infants in the neonatal intensive care unit (NICU) with acyclovir exposure and herpes simplex virus (HSV) infection. Our primary analysis was to evaluate the prevalence of HSV infection among infants in the NICU who received acyclovir. We compared characteristics of infants with and without HSV and used multivariable regression analyses to assess associations between infection and clinical outcomes. Of 1,057,061 infants, 17,910 (2%) received acyclovir. Of those who received acyclovir, 1090 (5%) had HSV. Infection was associated with lower gestational age and lower birth weight. Multivariable models demonstrated that infected infants had higher mortality, greater postmenstrual age at discharge, and longer length of stay. Infants in the NICU who received acyclovir and have HSV are more likely to be born at lower gestational age, have lower birth weight, and have higher morbidities and mortality.

Case Report: Herpes simplex virus type 2 (HSV-2) meningo-encephalitis associated with traumatic brain injury – a case report from Lao PDR

Background Neurological symptoms following head trauma are common; however, the cause may not always be obvious. In the absence of open wounds, fractures, or surgical interventions, infectious causes may not be considered, and investigations may not be targeted to investigate this possibility. Case A 39-year-old male presented with a severe headache, reduced consciousness, and confusion. Two days earlier, he had been discharged from the hospital, where he had been treated for traumatic brain injury with subarachnoid hemorrhage following a road traffic accident. Herpes simplex virus type 2 (HSV-2) was detected in the cerebrospinal fluid, confirming the diagnosis of viral meningoencephalitis. He was treated with oral aciclovir for two weeks and achieved full neurological recovery. Conclusions This case highlights the risk of viral reactivation following trauma, particularly head injuries. Central nervous system infections should be considered in cases of delayed deterioration following trauma. The optimal treatment of herpes simplex virus (HSV) encephalitis may be challenging in resource-limited settings.

Synthetic Naphthoquinone Inhibits Herpes Simplex Virus Type-1 Replication Targeting Na+, K+ ATPase.

Since 1970 acyclovir (ACV) has been the reference drug in treating herpes simplex virus (HSV) infections. However, resistant herpes simplex virus type 1 (HSV-1) strains have emerged, narrowing the treatment efficacy. The antiviral activity of classical Na+, K+ ATPase enzyme (NKA) inhibitors linked the viral replication to the NKA's activity. Herein, we evaluated the anti-HSV-1 activity of synthetic naphthoquinones, correlating their antiviral activity with NKA inhibition. We tested seven synthetic naphthoquinones initially at 50 μM on HSV-1-infected African green monkey kidney cells (VERO cells). Only one compound, 2-hydroxy-3-(2-thienyl)-1,4-naphthoquinone (AN-06), exhibited higher antiviral activity with a low cytotoxicity. AN-06 reduced the viral titer of 9 (log10) to 1.32 (log10) and decreased the steps of attachment and penetration. The addition of AN-06 up to 20 h postinfection (hpi) interfered with the viral cycle. The viral infection alone increases NKA activity 3 h postinfection (hpi), scaling up to 6 hpi. The addition of AN-06 in a culture infected with HSV-1 decreased NKA activity, suggesting that its antiviral action is linked to NKA inhibition. Also, docking results showed that this compound binds at the same site of NKA in which adenosine triphosphate (ATP) binds. AN-06 exhibited promising pharmacokinetic and toxicology properties. Thus, we postulate that AN-06 may be a good candidate for antiviral compounds with a mechanism of action targeting NKA activity.

A simple method for the determination of acyclovir concentrations in human plasma using high-performance liquid chromatography

BackgroundAcyclovir is an anti-viral medication given to treat herpes simplex and herpes zoster infection. In some severe conditions such as herpes encephalitis, acyclovir is administered intravenously. However, high acyclovir doses may cause acute kidney injury and low acyclovir dose may predispose the patient to inadequate exposure to acyclovir which could be fatal in some conditions. In such cases, the acyclovir plasma concentrations will potentially guide the diagnosis and management of the kidney injury. In this study, we provide a simple and time-efficient method for analyzing acyclovir in human plasma using high-performance liquid chromatography (HPLC).ResultsThe process starts with a single protein precipitation step by adding acetonitrile to deproteinize 300 µL of plasma. The chromatographic separation conditions consist of a mobile phase of water: methanol (97:3, v/v), a flow rate of 1 mL/min, a run time of 17 min, and a detection wavelength of 254 nm. The calibration curve was linear over the range of (0.70–60 mg/L) (r2 ˃ 0.99). The retention times of acyclovir and the internal standard were around 15 and 12 min, respectively. The intra-day and inter-day analysis of acyclovir in plasma using this method exhibited accuracy and precision of less than 7%, which lies within the acceptable range. Different greenness assessment tools confirmed that the proposed method is eco-friendly.ConclusionThe proposed method of analysis of acyclovir in the plasma using HPLC is simple, green and accurate method. This method could be applied in clinical settings where monitoring acyclovir concentrations is essential as it has wide range of the concentrations that could be detected.

Stability Indicating Method Development and Validation for Estimation of Valacyclovir in Pharmaceutical Preparation

Valacyclovir is an antiviral drug that is frequently administered to treat herpes simplex and herpes zoster infections. A simple, rapid, and accurate method for quantifying valacyclovir hydrochloride in tablet and bulk form has been developed. Two distinct analysis approaches, UV and HPLC, were developed in the present study for the evaluation of valacyclovir hydrochloride in pharmaceutical preparation. The mobile phase employed in the UV technique was Methanol:10mM KH2PO4 Buffer (50:50) for estimation of the drug at 254nm, and the (VAL) achieved was 99.45%. The method's validation was completed in accordance with ICH Q2 R1 standards, and linearity was found in the 9–45g/ml range with a regression value of 0.997% and RSD values of accuracy, precision, and robustness that were less than 2. In the HPLC method, the estimation of (VAL) was assessed on a Cosmosil C-18 (250mm4.6ID, Particle size: 5) column with Methanol:10mM KH2PO4 Buffer (50:50), 1 ml/min of flow rate, detection wavelength of 254nm, and the time of retention observed to be approximately 5.03 minutes with the assay value of 99.56%. Additionally, the HPLC technique was verified in accordance with ICH standards, and linearity was found in the 10–50g/ml range with a regression coefficient value of 0.998. Precision, accuracy, and robustness all had RSDs that were under 2%. Using Methanol:10mM KH2PO4 Buffer (50:50), the HPLC technique was also used to evaluate forced degradation at 254nm. It is clear from this study that the proposed methods for valacyclovir estimate in pharmaceutical preparation are quick, efficient, and specific. They may also be applied in routine analysis for the quantification of the drug in a dosage form.

Harmol used for the treatment of herpes simplex virus induced keratitis.

Herpes simplex virus type 1 (HSV-1) infection of the eyes results in herpes simplex keratitis (HSK), which has led to vision loss and even blindness in patients. However, the rate of drug resistance in HSV is on the rise; therefore, new antiviral agents with sufficient safety profiles must be developed. At present, we assessed the anti-HSV-1 activity of 502 natural compounds and their ability to reduce the HSV-1-induced cytopathic effect. We chose harmol for further studies because it exhibited the highest antiviral activity. We found that harmol inhibited both HSV-1F and HSV-1/153 (a clinical drug-resistant strain) replication, with an EC50 of 9.34 µM and 5.84 µM, respectively. Moreover, harmol reduced HSV-1 replication in corneal tissues and viral progeny production in tears, and also alleviated early corneal surface lesions related to HSK. For example, harmol treatment preserved corneal thickness and nerve density in HSK mice. Interestingly, harmol also showed a promising antiviral effect on HSV-1/153 induced HSK in mouse model. Furthermore, harmol combined with acyclovir (ACV) treatment showed a greater antiviral effect than either one alone in vitro. Therefore, harmol may be a promising therapeutic agent for managing HSK.

Severe acyclovir induced neurotoxicity in an elderly woman with end-stage renal disease and herpes zoster : A case report

Acyclovir (ACV) is a widely utilized antiviral medication for treating herpes simplex virus, cytomegalovirus, and varicella-zoster virus (VZV). Despite its usefulness, ACV can lead to adverse effects like acute renal impairment. ACV is predominantly eliminated through the kidneys, and in cases of renal impairment, there exists a potential for elevated levels, posing a risk of subsequent neurotoxicity. This case highlights the challenges posed by ACV use in patients with compromised renal function. A 64-year-old female presented with unconsciousness persisting for several hours. She had recently self-administered acyclovir (5x800 mg) to manage a herpes zoster outbreak. She had history of Chronic Kidney Disease (CKD) Stage V but refused hemodialysis. She had irregular heart rate of 140-180 beats per minute (with EKG confirming Atrial Fibrillation Rapid Response), a respiratory rate of 26 breaths per minute. Other vital sign was stable. Physical examination identified herpes zoster lesions on the right abdomen. Laboratory results shown blood urea nitrogen of 266 mg/dL, creatinine 13.2 mg/dL, and potassium of 6.9 mmol/L . A month earlier, the level of blood urea nitrogen was 100 mg/dL and creatinine was 7.9 mg/dL, indicating a progressive deterioration in renal function. Given the severity of the patient's condition, hemodialysis was initiated. Over the course of five days, there was a notable improvement in both the patient's clinical condition and level of consciousness.

Prevention and Treatment of Persistent Epithelial Defects After Common Refractive Surgery Procedures.

To discuss the prevention and treatment of persistent epithelial defects after the most common refractive surgeries-photorefractive keratectomy, laser in situ keratomileusis, or small incision lenticule extraction. PubMed was used to search the medical literature. Persistent epithelial defects are infrequent after photorefractive keratectomy, laser in situ keratomileusis, or small incision lenticule extraction. In the authors' opinion, any persistent epithelial defect present at 1 week or beyond after surgery should be treated aggressively with a properly fit bandage contact lens, lubrication with non-preserved artificial tears, and treatment of any eyelid abnormalities, including nocturnal lagophthalmos. Consideration should be given for presumptive treatment for herpes simplex virus or varicella zoster virus infection. If the persistent epithelial defect does not close within 2 weeks, then other measures should be considered, such as autologous serum drops, topical losartan, amniotic membranes, and topical human recombinant nerve growth factor to limit corneal scarring fibrosis and microbial infection. Persistent epithelial defects are among the most feared complications of refractive surgery. Timely and aggressive treatment should be instituted to close the epithelium prior to the development of scarring fibrosis and/or microbial corneal infection. [J Refract Surg. 2024;40(2):e117-e124.].

Exploring the potential of Moringa oleifera Lam in skin disorders and cosmetics: nutritional analysis, phytochemistry, geographical distribution, ethnomedicinal uses, dermatological studies and cosmetic formulations.

Moringa oleifera Lam. is a pan-tropical plant well known to the ancient world for its extensive therapeutic benefits in the Ayurvedic and Unani medical systems. The ancient world was familiar with this tree, but it has only lately been rediscovered as a multifunctional species with a huge range of possible therapeutic applications. It is a folk remedy for skin diseases, edema, sore gums, etc. This review comprises the history, ethnomedicinal applications, botanical characteristics, geographic distribution, propagation, nutritional and phytochemical profile, dermatological effects, and commercially available cosmeceuticals of Moringa oleifera Lam.Compilation of all the presented data has been done by employing various search engines like Science Direct, Google, PubMed, Research Gate, EBSCO, SciVal, SCOPUS, and Google Scholar.Studies on phytochemistry claim the presence of a variety of substances, including fatty acids, phenolic acids, sterols, oxalates, tocopherols, carotenoids, flavonoids, flavonols glycosides, tannins, terpenoids, terpene, saponins, phylates, alkaloids, glucosinolates, glycosides, and isothiocyanate. The pharmacological studies have shown the efficacy of Moringa oleifera Lam. as an antibacterial, antifungal, anti-inflammatory, antioxidant, anti-atopic dermatitis, antipsoriatic, promoter of wound healing, effective in treating herpes simplex virus, photoprotective, and UV protective. As a moisturizer, conditioner, hair growth promoter, cleanser, antiwrinkle, anti-aging, anti-acne, scar removal, pigmentation, and control for skin infection, sores, as well as sweating, it has also been utilized in a range of cosmeceuticals.he Moringa oleifera Lam. due to its broad range of phytochemicals can be proven boon for the treatment of dermatological disorders.

Drug Repurposing of the Antiviral Drug Acyclovir: New Pharmaceutical Salts

Drug repurposing is becoming interesting in terms of offering advantages over the traditional drug development, once drug discovery is a costly, time-consuming, and highly risky process. In particular, with the coronavirus disease (COVID-19) declared by World Health Organization as a global pandemic, there has emerged a considerable need to develop therapeutic agents capable of preventing viral outbreaks. Concomitantly, well-known and long-used drugs such as acyclovir (Acv) have been tested against COVID-19. Acv is a guanosine analogue that acts as an antiviral drug, commonly used to treat herpes simplex virus (HSV), genital herpes, and varicella zoster virus (VZV). Acv showed to inhibit viral proteases, multiple viral genes expression, and RNA-Dependent RNA Polymerase, helping to recover COVID-19 patients. However, ACV is a BCS class III/IV drug, with low permeability and/or slight water solubility (concentration-dependent). Given the repurposing eligibility of Acv, in this work, two new salts of this drug are presented (nitrate and sulfate), with the aim of improving its pharmacokinetic properties. The new salts were evaluated by X-ray diffraction, and thermal and spectroscopic analyses. A third salt, a chloride one, was also characterized and used for comparison.

Development, Optimization and In Vitro Characterization of Eudragit-Ganciclovir Nanosuspension or Treating Herpes Simplex Keratitis

Development, Optimization and In Vitro Characterization of Eudragit-Ganciclovir Nanosuspension or Treating Herpes Simplex Keratitis

Manipulation of Oxidative Stress Responses by Non-Thermal Plasma to Treat Herpes Simplex Virus Type 1 Infection and Disease.

Herpes simplex virus type 1 (HSV-1) is a contagious pathogen with a large global footprint, due to its ability to cause lifelong infection in patients. Current antiviral therapies are effective in limiting viral replication in the epithelial cells to alleviate clinical symptoms, but ineffective in eliminating latent viral reservoirs in neurons. Much of HSV-1 pathogenesis is dependent on its ability to manipulate oxidative stress responses to craft a cellular environment that favors HSV-1 replication. However, to maintain redox homeostasis and to promote antiviral immune responses, the infected cell can upregulate reactive oxygen and nitrogen species (RONS) while having a tight control on antioxidant concentrations to prevent cellular damage. Non-thermal plasma (NTP), which we propose as a potential therapy alternative directed against HSV-1 infection, is a means to deliver RONS that affect redox homeostasis in the infected cell. This review emphasizes how NTP can be an effective therapy for HSV-1 infections through the direct antiviral activity of RONS and via immunomodulatory changes in the infected cells that will stimulate anti-HSV-1 adaptive immune responses. Overall, NTP application can control HSV-1 replication and address the challenges of latency by decreasing the size of the viral reservoir in the nervous system.

A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice.

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.

Nanocarrier-Based Drug-Delivery System in Herpes Simplex Virus Treatment

Herpes simplex virus (HSV) is a highly contagious DNA virus that affects the majority of people worldwide. HSV establishes a latent infection in the ganglia, where it can reactivate, leading to recurrent disease. Currently, there are many experimental vaccines against HSV, but none have been used to treat herpes infections. At the same time, the therapeutic effect of existing anti-HSV drugs is limited. Nanocarriers, which deliver drugs to specific targets, have been used in different diseases, including viral infections. Nanocarriers could be designed to encapsulate drugs and directly target infected cells. This review will describe in detail the use of nanocarriers for targeted therapy of HSV infection.

A REVIEW: ZINC AS AN ANTIVIRUS ALTERNATIVE TREATMENT FOR HERPES SIMPLEX VIRUS INFECTION

This study aimed to review zinc's effectiveness as an antivirus in treating herpes simplex virus infection. The authors use international journals published from 2000-2022, and use search engines such as Google Scholar, PubMed, and Science Direct with the keywords "zinc and herpes simplex virus". The herpes simplex virus that often causes symptoms in humans are HSV type 1 and type 2. The lesions appear as vesicles which then rupture into ulcers. Zinc is one of the most abundant nutrients or metals in the human body besides iron. Studies about the effects of zinc on HSV have shown that it has the function of inhibiting the viral life cycle. HSV attaches to the host cells to replicate and synthesize new viral proteins. Zinc can inhibit this process by depositing on the surface of the virion and inactivating the enzymatic function which is required for the attachment to the host cell, disrupting the surface glycoprotein of the viral membrane so it could not adhere and carry out the next life cycle, it can also inhibit the function of DNA polymerase that works for viral replication in the host cell. This article showed that zinc has effectiveness as an antivirus against the herpes simplex virus, therefore, patients infected with HSV can be treated with zinc as an alternative to an antivirus drug.

Enhanced Topical Co-delivery of Acyclovir and Lidocaine Gel Formulation Across Dermatomed Human Skin.

Acyclovir a widely used drug in the treatment of herpes simplex virus (HSV) infections and lidocaine a local anesthetic were combined in a topical gel formulation. The topical gel with Transcutol P (TP) or N-methyl 2-pyrrolidone (NMP) was prepared and tested for in vitro skin permeation across the intact and microneedle-treated human cadaver skin. The topical gels containing 5% each of acyclovir and lidocaine showed optimal pH, spreadability, and 100% drug release. The transdermal flux and skin retention of the gels were significantly higher compared to Generic 5% acyclovir ointment (Zovirax) (p < 0.001), and 5% lidocaine gel (numb gel) (p < 0.05). As expected, topical gels showed a very high increase in the skin permeation across microporated skin versus intact skin. In viral infections, skin is inflamed, and barrier integrity may be disrupted. The results of the present study are significant because the co-delivery formulation showed a very high increase in the skin permeation across intact and microporated skin (versus respective commercial formulations). The results of this study demonstrate enhanced co-delivery of acyclovir and lidocaine in a topical formulation across skin (intact or barrier compromised) for the treatment of herpes virus infections.

Effects of Astragalus Polysaccharides on CD8+ Tissue-Resident Memory T Cells in Mice with Herpes Simplex.

Objective This study aimed to explore whether astragalus polysaccharides (APS) could treat herpes simplex by increasing tissue-resident memory CD8+ T cells (CD8+ TRM cells) and analyze its potential mechanism using the network pharmacologic approach. Methods C57BL/6J male mice aged 6–8 weeks were divided into a model group with HSV-1 infection treated by saline, a control group without HSV-1 infection but treated by saline, and an APS group with HSV-1 infection treated by APS. Clinical signs were observed, and the disease score was recorded every day. The skin lesions on day 9 after infection were taken for flow cytometric analysis to evaluate CD8+ TRM cells. Network pharmacologic analysis was performed to select the potential protein targets of astragalus associated with herpes simplex. Besides, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. The peripheral blood from the retroorbital venous plexus was collected to evaluate the levels of serum interferon-γ (IFN-γ) and interleukin 12 (IL-12). The comparisons of clinical signs, the disease score, CD8+ TRM cells, the serum IFN-γ, and IL-12 levels were performed among the three groups. Results Compared with the model group, the disease score in the APS group was significantly lower (p < 0.05). On the day 9 after HSV-1 infection, there was no significant difference in the body weight of mice among the three groups. However, compared with the control group or model group, the spleen weight in the APS group increased significantly (p < 0.05). The surface antigens of CD8+ TRM cells had no significant difference between the control group and the model group, while compared with the model group, the surface antigens of CD8 (p < 0.05), CD69 (p < 0.05), and CD103 (p < 0.05) in the APS group increased significantly. Moreover, the serum IL-12 (p < 0.05) and IFN-γ (p < 0.01) levels in the APS group increased significantly compared with the model group. Conclusion Our study suggested that APS could alleviate the symptoms of the mice infected with HSV-1, and CD8+ TRM cells in the skin lesions and the levels of IL-12 and IFN-γ in the serum of mice with HSV-1 infection increased after the APS treatment, of which the specific underlying mechanism requires further experiments to clarify. In addition, the antiviral effect of APS might be worthy of further development and utilization.

Incidence, patterns, risk factors and clinical outcomes of intravenous acyclovir induced nephrotoxicity

ObjectivesAcyclovir is approved to treat herpes simplex virus (HSV) type 1, type 2 and varicella-zoster virus. It is mainly eliminated via the kidneys, for which drug crystals accumulation might lead to nephrotoxicity. This study aimed to determine the incidence, risk factors, preventive measures, and clinical outcomes of acyclovir induced-nephrotoxicity. MethodsThis is a retrospective cohort study of patients >12 years of age at Sultan Qaboos University Hospital (SQUH) receiving IV acyclovir therapy between January 2016 and December 2020. ResultsOut of 191 included patients, 40 (20.1%) developed acyclovir induced-nephrotoxicity. Age (per year older: OR 1.04, 95 %CI 1.01–1.07), total duration of treatment (per day OR1.19, 95 %CI 1.06–1.33), and concomitant use of vancomycin (OR 5.96, 95 %CI 1.87–19.01) were significant independent risk factors for acyclovir induced-nephrotoxicity development. Nine patients (4.5%) died during the same hospitalization, including those three patients who required renal replacement therapy (1.5%). ConclusionFrequent monitoring of kidney function for older patients with concurrent use of vancomycin and IV hydration is essential to prevent IV acyclovir induced-nephrotoxicity. Antimicrobial stewardship is a crucial method to reduce the duration of treatment with IV acyclovir as appropriate.

Phenotypic and genotypic acyclovir resistance surveillance of genital herpes simplex virus 2 in South Africa

Acyclovir (ACV) is currently included in the syndromic management algorithm for genital ulcer disease in South Africa, and is the recommended first-line treatment for herpes simplex virus 2 (HSV-2). In the majority of cases, HSV-2 resistance to ACV is due to amino acid changes within the viral thymidine kinase (TK). Phenotypic and genotypic ACV resistance surveillance of HSV-2 derived from genital ulcer disease swab specimens was conducted at a primary healthcare facility in Johannesburg between 2018 and 2020. The objectives of this surveillance were to identify ACV resistance-associated mutations and polymorphisms in HSV-2 TK, and to determine the phenotypic ACV resistance profiles of the corresponding clinical HSV-2 isolates. Genotypic analysis of TK from 67 HSV-2 positive genital ulcer swabs revealed 48 specimens with TK mutations, conferring 113 nucleotide changes. No resistance-associated mutations were found, however, we identified nine known natural polymorphisms (R26H, A27T, S29A, G39E, N78D, L140F, T159I, R220K and R284S) and five amino acid changes of unknown significance (R18C, G39K, M70R, P75S and L263P). Phenotypic susceptibility testing of 52 cultivable HSV-2 isolates revealed all to be susceptible to ACV with IC50 values of <2 μg/ml. The five amino acid changes of unknown significance identified by genotypic testing were not correlated to phenotypic ACV resistance, and therefore grouped as natural polymorphisms. We did not detect any unknown or resistance-associated mutations in specimens that could not be phenotypically tested for ACV resistance. Our findings will supplement existing databases of HSV antiviral resistance-associated mutations and polymorphisms that could be used for genotypic ACV resistance screening.

Acyclovir Brain Disposition: Interactions with P-gp, Bcrp, Mrp2, and Oat3 at the Blood-Brain Barrier.

Acyclovir is effective in treating herpes simplex virus infections of the central nervous system. The purpose of this study was to investigate the interactions between acyclovir and the efflux pumps P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), multidrug resistance protein 2 (Mrp2), and organic anion transporter 3 (Oat3) at the blood-brain barrier (BBB). Acyclovir concentrations in the blood and brain were evaluated by microdialysis and high-performance liquid chromatography. Acyclovir pharmacokinetic parameters, including the area under the unbound blood concentration-time curve (AUCu,blood), the area under the unbound brain concentration-time curve (AUCu,brain), and the ratio of AUCu,brain to AUCu,blood (Kp.uu.brain), were evaluated in the presence and absence of elacridar (P-gp/Bcrp inhibitor, 7.5 mg/kg), tariquidar (P-gp/Bcrp inhibitor, 7.5 mg/kg), MK571 (Mrp2 inhibitor, 7.5 mg/kg), cyclosporine (P-gp/Bcrp/Mrp2 inhibitor, 25 mg/kg), and probenecid (Oat3 inhibitor, 50 mg/kg). The average AUCu,blood, AUCu,brain, and Kp.uu.brain in rats who received acyclovir (25 mg/kg, intravenous) alone were 1377.7 min·μg/ml, 435.4 min·μg/ml, and 31.6%, respectively. Probenecid drastically increased the AUCu,blood of acyclovir 1.73-fold, whereas coadministration with elacridar, tariquidar, MK571, and cyclosporine did not alter the blood pharmacokinetic parameters of acyclovir. Elacridar, tariquidar, MK571, cyclosporine, and probenecid significantly increased the AUCu,brain of acyclovir 1.51-, 1.54-, 1.47-, 1.95-, and 2.34-fold, respectively. Additionally, the Kp.uu.brain of acyclovir markedly increased 1.48-, 1.63-, 1.39-, 1.90-, and 1.35-fold following elacridar, tariquidar, MK571, cyclosporine, and probenecid administration, respectively. The present study demonstrated that P-gp, Bcrp, Mrp2, and Oat3 inhibition increased the penetration of acyclovir across the BBB, supporting the hypothesis that these efflux pumps restrict the distribution of acyclovir in the brain.