Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance.

DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity.

The immunobiology of corneal HSV-1 infection and herpetic stromal keratitis.

SUMMARYHuman alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains.

Mucosal Site Detection of Herpes Simplex Virus in Neonates.

From 2001 to 2023, 17 (14%) of 120 neonates with confirmed herpes simplex virus infection tested positive for herpes simplex virus by polymerase chain reaction (PCR) from only mucosal sites without a clinical mucosal lesion. Whether mucosal PCR positivity reflects early infection that may lead to recognizable disease, transient colonization, or a false-positive PCR result remains a clinical conundrum and warrants further study.

Israeli neonatal herpes simplex infection: Unique epidemiology and clinical profile.

To gather national level data on Israeli neonatal HSV (NHSV) infection and to evaluate the distinct clinical characteristics of NHSV and neonatal enteroviral meningitis (NEM). Israeli NHSV patients, hospitalized between January 2015 and April 2022 in 22 medical centers were assessed, together with NEM patients, hospitalized at Sheba Medical Center during the same period. NHSV demographic and clinical characteristics were documented and compared to those of NEM. Eighty-five NHSV (73% males) and 130 NEM (62% males) patients were included. The incidence of NHSV was 5.9/100 000 live births, the common phenotype and HSV type were SEM (53%) and HSV1 (91%), respectively. Horizontal transmission was suspected in 50% cases (of which 67% underwent a Jewish ritual circumcision with direct wound sucking, 33% had relatives with highly suspicious herpetic lesions). Compared with NEM, NHSV tends to present with rash (14% vs. 60%, p-value < 0.01) and seizures (0% vs. 6%, p-value 0.02), while fever, irritability and poor feeding appear more frequently in NEM (94% vs. 18%, p-value < 0.01; 37% vs. 1%, p-value < 0.01; 25% vs. 1%, p-value < 0.01 respectively). Of NEM patients, 28% were treated with acyclovir. Our results mark a decrease in the incidence rate of NHSV in Israel and a prominent mode of horizontal infection acquisition. We underscore the unique localized phenotype of NHSV, in contrast to enterovirus, which tends to cause a systemic disease with constitutional symptoms. These findings should be considered when evaluating the need for comprehensive empirical treatment for HSV in the context of neonatal fever, or according to a certain clinical presentation.

Development of pH-responsive Hydrogel from Copolymers of Artemisia vulgaris Seed Mucilage, Mucin, and poly(methacrylate) for Controlled Delivery of Acyclovir Sodium.

To cope with the constraints of conventional drug delivery systems, site-specific drug delivery systems are the major focus of researchers. The present research developed water-swellable, pH-responsive methacrylic acid-based hydrogel scaffolds of Artemisia vulgaris seed mucilage with mucin and loaded with acyclovir sodium as a model drug. The developed hydrogel discs are evaluated for diverse parameters. Drug loading efficiency in all formulations ranges from 63% to 75%. The hydrogels exhibited pH-dependent swelling, displaying optimum swelling in a phosphate buffer (pH 7.4), and insignificant swelling in an acidic buffer (pH 1.2), in addition, they responded well to electrolyte concentrations. The sol-gel fraction is estimated ranging from 60 to 95%. Dissolution studies unveiled sustained drug release for 24 h in a phosphate buffer of pH 7.4, exhibiting zero-order release kinetics. Moreover, FTIR spectra confirmed the drug-excipient compatibility. SEM photomicrographs revealed a rough and porous surface of hydrogel discs with several pores and channels. The PXRD diffractograms exposed the amorphous nature of the polymeric blends. The findings of acute toxicity studies proved the developed hydrogel network is biocompatible. Therefore, these outcomes connote the newly created network as a smart delivery system, able to dispatch acyclovir sodium into the intestinal segment for a prolonged period.

Varicella-Zoster Virus Reactivation After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation, Single-Center Experience of Acyclovir Prophylaxis.

BACKGROUND: Varicella-zoster virus (VZV) reactivation is the most common infectious complication in the late posthematopoietic stem cell transplantation (HSCT) period and is reported as 16%-41%. Acyclovir prophylaxis is recommended for at least 1 year after HSCT to prevent VZV infections. However, studies on the most appropriate prophylaxis are ongoing in pediatric patients. METHODS: Patients who underwent allogeneic HSCT between January 1, 1996 and January 1, 2020 were retrospectively analyzed to outline the characteristics of VZV reactivation after allogeneic HSCT in pediatric patients using 6 months acyclovir prophylaxis. RESULTS: There were 260 patients and 273 HSCTs. Median age was 10.43 (0.47-18.38), and 56% was male. Median follow-up was 2325 days (18-7579 days). VZV reactivation occurred in 21.2% (n = 58) at a median of 354 (55-3433) days post-HSCT. The peak incidence was 6-12 months post-HSCT (43.1%). Older age at HSCT, female gender, history of varicella infection, lack of varicella vaccination, low lymphocyte, CD4 count, and CD4/CD8 ratio at 9 and 12 months post-HSCT was found as a significant risk for herpes zoster (HZ) in univariate analysis, whereas history of varicella infection and low CD4/CD8 ratio at 12 months post-HSCT was an independent risk factor in multivariate analysis. CONCLUSIONS: Tailoring acyclovir prophylaxis according to pre-HCT varicella history, posttransplant CD4 T lymphocyte counts and functions, and ongoing immunosuppression may help to reduce HZ-related morbidity and mortality.

Virucidal effect of mouthwash on acyclovir-resistant herpes simplex virus.

OBJECTIVES: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains. MATERIALS AND METHODS: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system. RESULTS: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine. CONCLUSION: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients.

Efficacy of photobiomodulation therapy in recurrent herpes labialis management: a randomized controlled trial.

OBJECTIVES: This study is aimed at assessing the therapeutic efficacy of photobiomodulation therapy (PBMT) for the management of recurrent herpes labialis (RHL) by evaluating both pain and clinical recovery. MATERIAL AND METHODS: A randomized, double-blind, controlled trial was conducted on 40 patients with RHL, and they were randomly divided into two groups, where 20 patients received treatment with PBMT (650 nm, 100 mW, 4.7 J/cm2), continuous mode, for 120 s, and placebo cream, while another 20 patients (control group) were treated with acyclovir cream 5% (5 times/5 days) and passive laser. Pain was assessed at five different times. The day when the complete disappearance of the pain was observed and the day when the crust fell off spontaneously were also recorded. RESULTS: The pain level in the control group was significantly higher than that in the PBMT group after the second application of the laser, while the differences were not significant between the two groups at other times. The pain in the PBMT group disappeared faster than that in the control group, but the difference was not significant in terms of clinical recovery. CONCLUSIONS: Photobiomodulation therapy of herpes labialis reduced pain significantly faster than acyclovir, but there was no difference in healing time between the groups in light of the parameters used in this study. CLINICAL RELEVANCE: PBMT is a promising treatment that may be an effective alternative to acyclovir in the management of recurrent herpes labialis. TRIAL REGISTRATION ISRCTN: com ID: ISRCTN87606522.

First Acyclovir Determination Procedure via Electrochemically Activated Screen-Printed Carbon Electrode Coupled with Well-Conductive Base Electrolyte.

In this work, a new voltammetric procedure for acyclovir (ACY) trace-level determination has been described. For this purpose, an electrochemically activated screen-printed carbon electrode (aSPCE) coupled with well-conductive electrolyte (CH3COONH4, CH3COOH and NH4Cl) was used for the first time. A commercially available SPCE sensor was electrochemically activated by conducting cyclic voltammetry (CV) scans in 0.1 mol L-1 NaOH solution and rinsed with deionized water before a series of measurements were taken. This treatment reduced the charge transfer resistance, increased the electrode active surface area and improved the kinetics of the electron transfer. The activation step and high conductivity of supporting electrolyte significantly improved the sensitivity of the procedure. The newly developed differential-pulse adsorptive stripping voltammetry (DPAdSV) procedure is characterized by having the lowest limit of detection among all voltammetric procedures currently described in the literature (0.12 nmol L-1), a wide linear range of the calibration curve (0.5-50.0 and 50.0-1000.0 nmol L-1) as well as extremely high sensitivity (90.24 nA nmol L-1) and was successfully applied in the determination of acyclovir in commercially available pharmaceuticals.

Development and Validation of an HPLC-UV Method for the Quantification of Acyclovir and Ganciclovir in the Plasma of Pediatric Immunocompromised Patients.

Acyclovir and ganciclovir comprise the prophylaxis and treatment of herpesvirus and cytomegalovirus infections occurring in immunocompromised patients. Their therapeutic drug monitoring is fundamental because of interindividual variability leading to side effects and drug resistance and is performed through several techniques, such as liquid chromatography coupled with UV spectrophotometry (HPLC-UV) or mass spectrometry (LC-MS/MS). Therefore, we developed and validated a low-cost, non-time-consuming, and low-sample-consuming HPLC-UV method. Briefly, 100 µL of sample was used for sample preparation, mainly consisting of precipitation through organic solvent. In total, 20 µL was injected into the instrument. Chromatographic separation was obtained eluting mobile phases A (10 mM ammonium formiate 0.01% formic acid) and B (acetonitrile) on a Poroshell 120 SB-C8 2.1 × 150 mm, 2.7 µm for 12 min isocratically (97:3; A:B) at a flow rate of 0.2 mL/min. The linearity range (0.5-40 mg/L) of the method allowed us to quantify both the Cmin and Cmax of acyclovir and ganciclovir. Plasma concentrations measured on a small cohort of patients undergoing acyclovir (31) and ganciclovir (9) treatment by the proposed method and the LC-MS/MS methods, already in use, were significantly correlated. The proposed HPLC-UV method may be implemented in diagnostics as an alternative method in case of the unavailability of the LC-MS/MS system.

Degradation Acyclovir Using Sodium Hypochlorite: Focus on Byproducts Analysis, Optimal Conditions and Wastewater Application.

In recent years, the environmental impact of pharmaceutical residues has emerged as a pressing global concern, catalyzed by their widespread usage and persistence in aquatic ecosystems. Among these pharmaceuticals, acyclovir (ACV) stands out due to its extensive prescription during medical treatments for herpes simplex virus, chickenpox, and shingles, as well as its heightened usage amidst the COVID-19 pandemic. ACV is excreted largely unchanged by the human body, leading to significant environmental release through wastewater effluents. The urgency of addressing ACV's environmental impact lies in its potential to persist in water bodies and affect aquatic life. This persistence underscores the critical need for effective degradation strategies that can mitigate its presence in aquatic systems. This study focuses on employing sodium hypochlorite as an oxidative agent for the degradation of ACV, leveraging its common use in wastewater treatment plants. Our research aims to explore the kinetics of ACV degradation, identify and characterize its degradation byproducts, and optimize the conditions under which complete degradation can be achieved. By assessing the efficiency of sodium hypochlorite in real wastewater samples, this study seeks to provide practical insights into mitigating ACV contamination in aquatic environments. The novelty of this research lies in its comprehensive approach to understanding the degradation pathways of ACV and evaluating the feasibility of using sodium hypochlorite as a sustainable solution in wastewater treatment. By addressing the environmental concerns associated with ACV and offering practical solutions, this study contributes to the broader goal of sustainable pharmaceutical waste management and environmental stewardship.

ACV with/without IVM: a new talk on intestinal CDX2 and muscular CD34 and Cyclin D1 during Trichinella spiralis infection.

The current study assessed the efficacy of Acyclovir (ACV) and Ivermectin (IVM) as monotherapies and combined treatments for intestinal and muscular stages of Trichinella spiralis infection. One-hundred Swiss albino mice received orally 250 ± 50 infectious larvae and were divided into infected-untreated (Group-1), IVM-treated (Group-2), ACV-treated (Group-3), combined IVM+ACV (Group-4), and healthy controls (Group-5). Each group was subdivided into subgroup-A-enteric phase (10 mice, sacrificed day-7 p.i.) and subgroup-B-muscular phase (10 mice, sacrificed day-35 p.i.). Survival rate and body weight were recorded. Parasite burden and intestinal histopathology were assessed. In addition, immunohistochemical expression of epithelial CDX2 in the intestinal phase and CyclinD1 as well as CD34 in the muscular phase were evaluated. Compared, IVM and ACV monotherapies showed insignificant differences in the amelioration of enteric histopathology, except for lymphocytic counts. In the muscle phase, monotherapies showed variable disruptions in the encapsulated larvae. Compared with monotherapies, the combined treatment performed relatively better improvement of intestinal inflammation and reduction in the enteric and muscular parasite burden. CDX2 and CyclinD1 positively correlated with intestinal inflammation and parasite burden, while CD34 showed a negative correlation. CDX2 positively correlated with CyclinD1. CD34 negatively correlated with CDX2 and CyclinD1. IVM +ACV significantly ameliorated CDX2, CyclinD1, and CD34 expressions compared with monotherapies. Conclusion. T. spiralis infection-associated inflammation induced CDX2 and CyclinD1 expressions, whereas CD34 was reduced. The molecular tumorigenic effect of the nematode remains questionable. Nevertheless, IVM +ACV appeared to be a promising anthelminthic anti-inflammatory combination that, in parallel, rectified CDX2, CyclinD1, and CD34 expressions.

[Clinical features of acyclovir encephalopathy without acute kidney injury].

INTRODUCTION: Few reports have described acyclovir (ACV) encephalopathy without acute kidney injury (AKI). OBJECTIVE: This study clarified the clinical features of ACV encephalopathy without AKI compared to that with AKI. METHODS: Creatinine (Cre) levels were measured on admission. After admission, Cre was measured in a timely manner for the first seven hospital days. The minimum Cre level in these measurements was then determined. ACV encephalopathy was defined when two criteria were met: 1) neurological symptoms appeared after valacyclovir (VACV) administration, and 2) neurological symptoms improved after VACV discontinuation. AKI was defined when the Cre level on admission was >1.5 times higher than the minimum Cre level. The subjects were divided into AKI and non-AKI groups based on these findings. RESULTS: Eighteen patients had ACV encephalopathy (5 males, mean age 81.3±5.5 years old). All patients were prescribed VACV 3,000 mg/day. The minimum Cre was 1.93±1.76 mg/dL. AKI occurred in 10 (56.6%) patients. VACV was discontinued in all patients, and emergency hemodialysis treatment was administered in 10 (55.6%) patients. All patients recovered. Compared to the AKI group, the non-AKI group had a lower history of taking a Ca-blocker (33.3% vs 80.0%, p=0.092), a lower rate of emergency dialysis (16.9% vs 70.0%, p=0.059) and a longer time to clinical improvement (3.67±1.86 vs 2.20±0.63 days, p=0.073). CONCLUSION: ACV encephalopathy without AKI is characterized by a low rate of emergency dialysis, which may be linked to a prolonged duration of symptoms.

M2 Genotype of Varicella zoster virus associated with Severe Herpes zoster in Pakistan.

This case report is of herpes zoster which is caused by Varicella zoster virus (VZV). The patient was presented with acute renal failure associated with intravenous acyclovir administration for its management. A 50 years old man visited the hospital with rashes on his back. The serum sample was positive for anti-VZV IgM via Enzyme Linked Immunosorbent Assay (ELISA), and vesicular swab for VZV via polymerase chain reaction (PCR). Phylogenetic analysis identified it as M2-genotype. Patient was treated with intravenous acyclovir administration, which led to acute renal failure. Later with shift to oral acyclovir, renal functions were restored. Elderly patients with reactivation of VZV in Pakistan are at risk to contract herpes zoster. Acyclovir is drug of choice via intravenous route was found to be nephrotoxic, however oral acyclovir was safe and effective. This is first report on pathogenic VZV genotype from Pakistan and is presented to highlight that the herpes zoster cases of elderly patients' treatment option need to be revisited.

Acyclovir-resistant HSV-1 isolates among immunocompromised patients in southern Taiwan: Low prevalence and novel mutations.

Herpes simplex virus type 1 (HSV-1) can establish latency in humans and easily relapse in immunocompromised patients, with significant mortality. Treatment with acyclovir (ACV) can result in the emergence of HSV resistance. A total of 440 frozen HSV-1 isolates collected from 318 patients from January 2014 to July 2019 were obtained from National Cheng Kung University Hospital in southern Taiwan. These 440 isolates were subjected to phenotypic studies for ACV-resistance by initial screening with the plaque reduction assay (PRA) and further validation by the DNA reduction assay (DRA). The ACV-resistant strains were further investigated by Sanger sequencing for the full-length UL23 and UL30 genes, which encode thymidine kinase and DNA polymerase, respectively. Hematological malignancies or hematopoietic stem-cell transplantation patients accounted for 56.9% (124/218) among the immunocompromised patients (218/318) in this study. Repeated sampling for HSV testing was 50% (109/218) in immunocompromised patients. Only 1.38% (3/218) of immunocompromised patients and 0.9% (3/318) of all patients developed ACV-resistant HSV-1 as measured by phenotypic screening assays. It is noteworthy that a novel Y248D mutation in the UL23 gene from an immunocompromised patient was found by both PRA and DRA. In 3D protein predicting analysis, uncharged Y248 was located at an alpha-helix and substituted by negative-charged D248, which may alter the function of viral thymidine kinase. Besides, three unreported mutations related to natural polymorphism were found in virus isolates from two immunocompetent patients, including 683-688 deletion, R227H, and A351D in the UL30 gene. These data show that the prevalence of ACV-resistant HSV-1 among immunocompromised patients in southern Taiwan is low. These results will be helpful for the clinical management and treatment of HSV infections.

Pharmacokinetic profile of acyclovir in a child receiving continuous kidney replacement therapy for acute liver failure.

BACKGROUND: Continuous venovenous hemodiafiltration (CVVHDF) is one of the treatments of critically ill children presenting severe acute liver failure. This affliction might be induced by HSV infection requiring a treatment by acyclovir. Continuous kidney replacement therapy (CKRT) can alter its pharmacokinetics, according to its physicochemical properties and CVVHDF settings. CASE-DIAGNOSIS/TREATMENT: The patient was a 21-month-old female presenting liver failure with hyperammonemia treated by acyclovir with presumed HSV infection. CKRT was initiated on day 1 with substantial replacement and dialysate flow rates (respectively 75 and 220 mL/kg/h). Acyclovir was intravenously administered every 8 h with a 1-h infusion of 500 mg/m2. Plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry assay to estimate the area under a curve (AUC) and CKRT clearance by 2 methods (one based on pre- and post-filter concentrations and the other one on dialysate flow rates). Clearance was estimated between 19.2 and 26.3 mL/min with the first method and between 27.6 and 44.3 mL/min with the second one. Concentrations were highly above the therapeutic index (peak concentration was measured at 28 mg/L), but AUC was appropriate. CONCLUSIONS: This case describes acyclovir pharmacokinetics during CKRT in a pediatric patient treated by acyclovir. The patient was treated with adapted exposure with the usual dosing, but lower dosing should be investigated with complementary studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02539407.

A decreasing plasma concentration of a toxicologically active metabolite 9-carboxymethoxymethylguanine after dialysis - A potential new clinical biomarker for improving encephalopathy in patients treated with acyclovir.

Although acyclovir is a key drug for the treatment of herpes infections, a consciousness disorder known as "acyclovir encephalopathy" is among its side effects. We encountered a patient with encephalopathy and measured the plasma and cerebrospinal fluid concentrations of acyclovir and its toxicologically active metabolite 9-carboxymethoxymethylguanine (CMMG). Before dialysis, cerebrospinal fluid concentrations of acyclovir and CMMG in this patient with a consciousness disorder were approximately 10% and 1%, respectively, of their plasma concentrations. After 3 days of dialysis, plasma CMMG levels decreased to detectable but below quantitative levels (<0.1 µg/mL), resulting in normal consciousness. These results suggest that decreasing plasma CMMG concentration could be one of clinical biomarkers for improving consciousness in patients with encephalopathy associated with acyclovir.

Management of oral herpes simplex virus infections: The problem of resistance. A narrative review.

Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.

Preparation and Characterization of Poly(vinyl acetate-co-2-hydroxyethyl methacrylate) and In Vitro Application as Contact Lens for Acyclovir Delivery.

A series of poly(vinyl acetate-co-2-hydroxyethylmethacrylate)/acyclovir drug carrier systems (HEMAVAC) containing different acyclovir contents was prepared through bulk free radical polymerization of 2-hydroxyethyl methacrylate with vinyl acetate (VAc) in presence of acyclovir (ACVR) as the drug using a LED lamp in presence of camphorquinone as the photoinitiator. The structure of the drug carrier system was confirmed by FTIR and 1HNMR analysis, and the uniform dispersion of the drug particles in the carrier was proved by DSC and XRD analysis. The study of the physico-chemical properties of the prepared materials, such as the transparency, swelling capacity, wettability and optical refraction, was carried out by UV-visible analysis, a swelling test and measurement of the contact angle and the refractive index, respectively. The elastic modulus and the yield strength of the wet prepared materials were examined by dynamic mechanical analysis. The cytotoxicity of the prepared materials and cell adhesion on these systems were studied by LDH assay and the MTT test, respectively. The results obtained were comparable to those of standard lenses with a transparency of 76.90-89.51%, a swelling capacity of 42.23-81.80% by weight, a wettability of 75.95-89.04°, a refractive index of 1.4301-1.4526 and a modulus of elasticity of 0.67-1.50 MPa, depending on the ACVR content. It was also shown that these materials exhibit no significant cytotoxicity; on the other hand, they show significant cell adhesion. The in vitro dynamic release of ACVR in water revealed that the HEMAVAC drug carrier can consistently deliver uniformly adequate amounts of ACVR (5.04-36 wt%) over a long period (7 days) in two steps. It was also found that the solubility of ACVR obtained from the release process was improved by 1.4 times that obtained by direct solubility of the drug in powder form at the same temperature.

A randomized phase II study of acyclovir for the prevention of chemotherapy-induced oral mucositis in patients undergoing autologous hematopoietic stem cell transplantation.

OBJECTIVES: To prove our hypothesis that acyclovir prophylaxis in autologous hematopoietic stem cell transplantation (AHSCT) recipients with hematologic malignancies (HM) reduces the incidence of chemotherapy-induced oral mucositis (CIOM) by inhibiting the intraoral HSV reactivation during the neutropenic period, we conducted a randomized phase II study of acyclovir for the prevention of CIOM in adult HSV sero-positive AHSCT recipients. METHODS: Patients were randomized to either the study group (acyclovir 400 mg PO bid until neutrophil engraftment) or the control group (no prophylaxis) and received AHSCT. Oral examination and sampling for HSV were performed at three timepoints of AHSCT. RESULTS: In 54 patients who were randomized (for intention-to-analysis), the incidence of CIOM was 16.0% (4/25 patients) and 58.6% (17/29 patients) in the study group and the control group, respectively (P = 0.001). In 49 patients who completed the study (for per-protocol analysis), the incidence of CIOM was 13.0% (3/23 patients) and 61.5% (16/26 patients) in the study group and the control group, respectively (P = 0.001). In addition, HSV-1 PCR positivity in the study group was significantly lower than that the control group (4.3% vs. 46.2%, P = 0.001). A strong association between the HSV-1 reactivation status and CIOM was reconfirmed. CONCLUSIONS: Prophylactic use of oral acyclovir effectively reduced the incidence of CIOM in patients with HM who were undergoing AHSCT. TRIAL REGISTRATIONS: This trial was registered at the Clinical Research Information Service in the Republic of Korea under the number KCT0003885 (registration date 03/05/2019).