A bivalent ß-carboline derivative inhibits macropinocytosis-dependent entry of pseudorabies virus by targeting the kinase DYRK1A.

Pseudorabies virus (PRV) has become a "new life-threatening zoonosis" since the human-originated PRV strain was first isolated in 2020. To identify novel anti-PRV agents, we screened a total of 107 ß-carboline derivatives and found 20 compounds displaying antiviral activity against PRV. Among them, 14 compounds showed better antiviral activity than acyclovir. We found that compound 45 exhibited the strongest anti-PRV activity with an IC50 value of less than 40 nM. Our in vivo studies showed that treatment with 45 significantly reduced the viral loads and protected mice challenged with PRV. To clarify the mode of action of 45, we conducted a time of addition assay, an adsorption assay, and an entry assay. Our results indicated that 45 neither had a virucidal effect nor affected viral adsorption while significantly inhibiting PRV entry. Using the FITC-dextran uptake assay, we determined that 45 inhibits macropinocytosis. The actin-dependent plasma membrane protrusion, which is important for macropinocytosis, was also suppressed by 45. Furthermore, the kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) was predicted to be a potential target for 45. The binding of 45 to DYRK1A was confirmed by drug affinity responsive target stability and cellular thermal shift assay. Further analysis revealed that knockdown of DYRK1A by siRNA suppressed PRV macropinocytosis and the tumor necrosis factor alpha-TNF-induced formation of protrusions. These results suggested that 45 could restrain PRV macropinocytosis by targeting DYRK1A. Together, these findings reveal a unique mechanism through which ß-carboline derivatives restrain PRV infection, pointing to their potential value in the development of anti-PRV agents.

Acyclovir-Loaded Nanoemulsions: Preparation, Characterization and Irritancy Studies for Ophthalmic Delivery.

Objective: The main goal of the present work was to develop and evaluate nanoemulsions (NEs) containing acyclovir (ACV) for ophthalmic drug delivery.Method: Firstly, component screening was performed by determining ACV solubility in various oils, surfactants, and co-surfactants. Different NE formulations were developed based on pseudo-ternary phase diagrams, and physicochemical assets were evaluated. Selected formulations were subjected to the drug release efficacy, stability studies, and ex-vivo trans-corneal permeation test. The safety of NEs was investigated by the modified Draize test and hen's egg test-chorioallantoic membrane (HET-CAM).Results: Based on the solubility studies, Tween 20, Triacetin, and Tramsectol®P were chosen to prepare NE formulations. Developed NEs showed desirable physiochemical properties, including a droplet size of less than 15 nm. Selected formulations (F1 and F2) exhibited a sustained drug release pattern compared to the control group (P < .001). ACV penetration from F1 and F2 to the excised bovine cornea was 2.85 and 2.9-fold more than the control, respectively. Furthermore, HET-CAM and modified Draize test confirmed that F1 and F2 were safe for ocular administration.Conclusion: Present investigation revealed that ACV-loaded NEs could be effective, and safe platform for ophthalmic delivery of ACV.

Antiviral activity of castor oil plant (Ricinus communis) leaf extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Ricinus communis L., commonly known as castor oil plant, is a precious traditional medicine with a history of thousands of years in the world. Castor oil plant has high traditional and medicinal values for treating liver infections, stomach ache, flatulence, constipation, inflammation, warts, colic, enteritis, fever, headache, and as a counter irritant. Its diverse phytochemicals have a wide range of valuable medicinal activities including hepatoprotective, anti-nociceptive, antioxidant, antiulcer, anticancer, anti-inflammatory, central analgesic, antidiabetic, antimicrobial, antiviral, and wound healing activity. AIM OF THE WORK: To provide a complete characterization of the composition of Ricinus communis leaves using ultra-performance liquid chromatography coupled with hybrid triple time-of-flight mass spectrometry (UPLC-Triple TOF-MS/MS) and different chromatographic techniques and to evaluate its antiviral potential using three mechanisms against three common viruses. MATERIALS AND METHODS: R. communis leaves were extracted with 70% methanol and further partitioned with solvents of increasing polarities: petroleum ether, dichloromethane (CH2Cl2), ethyl acetate, and n-butanol. The CH2Cl2 and n-butanol fractions were subjected to repeated chromatographic separation to isolate the phytochemicals, and their structures were elucidated using nuclear magnetic resonance spectroscopy. UPLC-Triple TOF-MS/MS was performed to determine the different phytochemicals in the ethyl acetate fraction. The antiviral activity of the extracts was investigated using the maximum nontoxic concentration of each against the challenge dose of the virus (CDV) and 1/10 and 1/100 dilutions of the CDV for Coxsackie B virus type 4 (COXB4), herpes simplex virus type 1 (HSV1), and hepatitis A virus (HAV) using Vero cell cultures that were treated according to three protocols to test for anti-replicative, protective, and anti-infective antiviral activity. Cell viability was evaluated using the MTT colorimetric assay and each experiment is repeated three times independently of each other. RESULTS: R. communis leaves possessed antiviral activity. Evaluation of the anti-replicative activity showed that all extracts possessed high anti-replicative activity against HAV especially methanol and methylene chloride fractions and moderate activity against COXB4; butanol > methylene chloride and ethyl acetate > methanol. All extracts showed protective activity against HAV, especially butanol extract, while methanol extracts showed higher non-significant antiviral protective activity against HSV1 vs Acyclovir. Almost no anti-infective effects were recorded for any extract against the studied viruses. CONCLUSION: The discriminatory effect against each virus by different mechanisms suggests the presence of different chemical compounds. The alkaloid and phenolic derivatives of the extracts of R. communis leaves may help develop a drug to prevent or treat common viral infections. Further investigations are recommended to define the bioactive antiviral properties of R. communis leaves.

Electropharmacological Characterization of Aciclovir in the Halothane-Anesthetized Dogs: A Proposal of Evaluation Method for Cardiovascular Safety Pharmacology of Anti-virus Drugs.

Given limited information regarding the pathophysiology underlying aciclovir-associated, clinically observed cardiovascular adverse events including chest pain, tachycardia, bradycardia, palpitation, arrhythmia, hypertension and hypotension, we investigated its electropharmacological effects using the halothane-anesthetized beagle dogs. Aciclovir in doses of 2 and 20 mg/kg was sequentially infused over 10 min with an interval of 20 min (n = 4), which would achieve sub-therapeutic to supra-therapeutic levels of plasma concentrations. Aciclovir decreased the total peripheral vascular resistance along with the blood pressure in a dose-related manner, which increased the heart rate, ventricular contraction and atrioventricular nodal conduction speed probably via a reflex-mediated increase of sympathetic tone. No significant change was detected in the intra-atrial or intra-ventricular conduction, indicating that aciclovir may not inhibit atrial or ventricular INa. Aciclovir prolonged the repolarization period in a dose-related as well as in a reverse frequency-dependent manners, indicating that aciclovir may inhibit IKr, which was supported by the Tpeak - Tend prolongation. Aciclovir transiently prolonged the J - Tpeakc possibly through a reflex-mediated increase of sympathetic tone, indicating an increase of net inward current in the early repolarization phase. Thus, aciclovir may directly inhibit IKr, and also have the potential to indirectly induce Ca2+ overload leading to early afterdepolarization. These in vivo electropharmacological profile of aciclovir would partly explain the onset mechanism of clinical adverse events.

Determination of acyclovir in renal microdialysis fluid and confirmation of renal function index.

Acyclovir (ACV) is a nucleoside antivirus-free agent that was developed and marketed by Burroughs Well-come of the United States. Renal damage from ACV has been a major factor limiting its clinical application. Thus, the renal toxicity mechanism of ACV requires systematic study. In our previous study, we speculated that the nephrotoxicity of ACV may be associated with oxidative stress. In addition to the study of ACV's toxic effect in vivo, it is also necessary to explore the absorption and distribution of ACV in the body to further investigate the changes to ACV in the body. In this study, the toxicokinetics ACV in the kidney of the rat were explored using microdialysis, and the renal function of rats was measured. The results showed that high-dose ACV is associated with renal toxicity after a single intravenous injection or successive administration.

Effective reconstruction of functional organotypic kidney spheroid for in vitro nephrotoxicity studies.

Stable and reproducible kidney cellular models could accelerate our understanding of diseases, help therapeutics development, and improve nephrotoxicity screenings. Generation of a reproducible in vitro kidney models has been challenging owing to the cellular heterogeneity and structural complexity of the kidney. We generated mixed immortalized cell lines that stably maintained their characteristic expression of renal epithelial progenitor markers for the different lineages of kidney cellular compartments via the BMP7 signaling pathway from a mouse and a human whole kidney. These cells were used to generate functional and matured kidney spheroids containing multiple renal lineages, such as the proximal tubule, loop of Henle, distal tubules, and podocytes, using extracellular matrix and physiological force, named spheroid-forming unit (SFU). They expressed all apical and basolateral transporters that are important for drug metabolism and displayed key functional aspects of the proximal tubule, including protein endocytosis and increased gamma-glutamyltransferase activity, and cyclic AMP responded to external cues, such as parathyroid hormone. Following exposure, cells fluxed and took up drugs via proximal tubule-specific apical or basolateral transporters, and displayed increased cell death and expression of renal injury marker. Here, we developed a new differentiation method to generate kidney spheroids that structurally recapitulate important features of the kidney effectively and reproducibly using mixed immortalized renal cells, and showed their application for renal toxicity studies.

Neurologic Acyclovir Toxicity in the Absence of Kidney Injury.

BACKGROUND: Herpes zoster (zoster) also commonly known as "shingles," occurs following re-activation of the varicella zoster virus. It contributes a large cost burden to the U.S. health care system, with an estimated 1 million cases costing $1 billion annually. The current gold standard treatment is acyclovir, which limits viral replication. However, acyclovir has been reported to cause neurotoxicity in patients with acute or chronic kidney disease. CASE REPORT: This case presents an occurrence of acyclovir-induced toxic encephalopathy in a patient with normal renal function. A 63-year-old male presented to the emergency department with ataxia, tremors, fluctuating aphasia, confusion, agitation, and fatigue. Results of imaging, lumbar puncture, and laboratory studies directed clinicians toward acyclovir toxicity, despite a normal creatinine level. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians will likely be the first point of contact in the health care system following the onset of acyclovir toxicity. With an increasing incidence of zoster disease, such atypical toxic manifestations may increase. Early recognition is important to avoid permanent neurologic compromise.

Fracaso renal agudo y neurotoxicidad severa tras sobredosis accidental por valaciclovir en población geriátrica: a propósito de un caso / Acute renal failure and severe neurotoxicity after unintentional overdose of valacyclovir in a geriatric population: A case report

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Apigenin, a novel candidate involving herb-drug interaction (HDI), interacts with organic anion transporter 1 (OAT1).

BACKGROUND: Apigenin is a flavonoid compound, widely distributed in natural plants. Various studies have suggested that apigenin has inhibitory effects towards several drug transporters, such as the organic anion transporting (OAT) polypeptides, 1B1 and 1B3 (OATP1B1 and OATP1B3). However, the mechanism by which apigenin interacts with OAT1 has not been well studied. METHODS: MDCK cells stably-expressing OAT1 were used to examine the inhibitory effects of apigenin on OAT1. UPLC-MS/MS was used to evaluate the in vitro and in vivo effects of apigenin on the uptake of acyclovir by OAT1. Cytotoxicity was determined by the cell viability, MTT assays. RESULTS: Apigenin effectively inhibited the activity of OAT1 in a dose-dependent manner with an IC50 value of 0.737µM. Pre-incubation of cells with apigenin caused a time-dependent inhibition (TDI) of OAT1. Additionally, we examined the interactions between apigenin and acyclovir or adefovir. Data showed that apigenin (1µM) significantly blocked the uptake of acyclovir by OAT1 in vitro with an inhibition rate of 55%. In vivo, apigenin could increase the concentration of acyclovir in plasma when co-administered with acyclovir. Importantly, the MTT assays showed that, at a dose of 50µM, apigenin significantly reduced the cytotoxicity of adefovir and substantially increased cell viability from 50.6% to 112.62%. CONCLUSION: Our results demonstrate that apigenin regulates OAT1, and can cause TDI or herb-drug interaction (HDI) when used in combination with acyclovir or adefovir. Therefore, apigenin could be used as a nephroprotective agent when used in combination with the substrates of OAT1.

Comparison of three cell-based drug screening platforms for HSV-1 infection.

Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.

A metabolic profiling analysis of the nephrotoxicity of acyclovir in rats using ultra performance liquid chromatography/mass spectrometry.

Acyclovir (ACV) exposure is a common cause of acute kidney injury (AKI). The toxicity mechanism of ACV has always been a matter of debate. The present study investigated into the time-effect relationship and dose-effect relationship of ACV-induced nephrotoxicity in rats using metabonomics. Twenty-four rats were randomly divided into four groups: a 0.9% NaCl solution group, and 100, 300, and 600mg/kg ACV-treated groups; the ACV or vehicle solution was administered with a single intravenous injection. Urine was collected at different time periods (12h before administration, and 0-6h, 7-12h, and 13-24h after administration). Routine urinalysis was conducted by a urine automatic analyzer. Renal markers, including urine urea nitrogen, urine creatinine, and urinary N-acetyl-ß-d-glucosaminidase (NAG) activity, were determined using established protocols. Urinary metabolites were evaluated using ultra performance liquid chromatography/mass spectrometry (UPLC/MS). In the ACV-treated rats, increased levels of protein (PRO), occult blood (BLD), white blood cell (WBC), and NAG activity in urine were observed, while the urine creatinine and urea nitrogen levels showed a decrease compared with the control. Moreover, urine metabolites significantly changed after the treatment with ACV, and all the effects induced by ACV were dose-time dependent. Finally, 4 metabolites (guanine, 4-guanidinobutyric acid, creatinine, and urea) were identified, which can be used for further research on the mechanism of ACV-induced nephrotoxicity.

Effects of four nucleoside analogues used as antiviral agents on rat Sertoli cells (SerW3) in vitro.

Some nucleoside analogues are used to treat herpes simplex and other viral infections. They are known to impair spermatogenesis, but published data are scarce. We studied the effects of four nucleosides on SerW3 cells, a rat Sertoli cell line. Cells were cultured for 3 days in DMEM supplemented with four different concentrations of each drug. Aciclovir and ganciclovir were added at concentrations of 0.3, 1, 3 and 10 mg/l medium; penciclovir and its prodrug famciclovir were used at higher concentrations (3, 10, 30, 100 mg/l medium). After a culture period of 3 days, we analysed the expression of connexin43, N-cadherin and the cytoskeleton protein vimentin by Western blot. Aciclovir caused a clear-cut effect at the highest concentration tested (10 mg/l), which is less than the peak plasma concentration achieved in patients during intravenous therapy with the drug. Connexin43, vimentin and N-cadherin content decreased to 49.8 ± 17, 44.0 ± 4 and 75.4 ± 1.5 % of the control values, respectively (n = 3; mean ± SD). Similar effects were observed with the prodrug ganciclovir (43.2 ± 10.8; 54.1 ± 11.9; 84.4 ± 10.8 % of controls). Penciclovir caused less pronounced effects at 10 mg/l medium (82.1 ± 20.6; 90.0 ± 12.0; 76.5 ± 17.7 % of controls). Only a slight effect was observed with famciclovir. Even at a 10-fold concentration (100 mg/l), just moderate changes were induced. In summary, we observed clear-cut effects with aciclovir and ganciclovir on Sertoli cells in vitro at therapeutically relevant concentrations and identified connexin43 as the most sensitive marker.

Indirect photochemical transformations of acyclovir and penciclovir in aquatic environments increase ecological risk.

Acyclovir and penciclovir, 2 antiviral drugs, are increasingly detected in aquatic environments. The present study explores the natural photochemical transformation mechanisms and fate of these drugs, examining direct and indirect photochemical transformation under simulated sunlight irradiation. The 2 antiviral drugs are photostable under certain conditions but significantly degrade in the presence of chromophoric dissolved organic matter (DOM). The degradation rate associated with the drugs' indirect photochemical transformation scaled with chromophoric DOM concentration. Quenchers and sensitizers were used to identify indirect photochemical transformation mechanism. Results suggested that both pharmaceuticals could be transformed by reacting with (1)O2, (•)OH, and excited chromophoric DOM. The (1)O2 played an important role in indirect photochemical transformation. Furthermore, the reaction kinetics between their substructural molecules, guanine, isocytosine, and imidazole, with different reactive oxygen species were evaluated to determine which substrate functionalities were most susceptible to singlet oxygenation. Imidazole was identified as the reaction site for (1)O2, and preliminary (1)O2 oxidation mechanisms were further evaluated based on liquid chromatographic-tandem mass spectrometric results. Finally, aquatic ecotoxicity assessment of phototransformed solutions revealed that the degradation of acyclovir and penciclovir may not ultimately diminish environmental risk because of either formation of more toxic intermediates than parent pharmaceuticals or some synergistic effects existing between the intermediates.

Proteomic characterization of acyclovir-induced nephrotoxicity in a mouse model.

Acyclovir (ACV) is an effective and widely used antiviral agent. However, its clinical application is limited by severe nephrotoxicity. We assessed ACV-induced nephrotoxicity and identified the differentially expressed proteins using mass spectrometry-based proteomic analysis. In total, 30 ICR mice were intraperitoneally administrated ACV (150 or 600 mg/kg per day) for 9 days. After administration of ACV, levels of serum creatinine and urea nitrogen increased significantly. In addition, mouse kidneys exhibited histopathological changes and reduced expression levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR2. In the proteomic analysis, more than 1,000 proteins were separated by two-dimensional polyacrylamide gel electrophoresis, and a total of 20 proteins were up- or down-regulated in the ACV group compared with the saline group. Among these, six proteins (MHC class II antigen, glyoxalase 1, peroxiredoxin 1, αB-crystallin, fibroblast growth factor receptor 1-IIIb, and cytochrome c oxidase subunit Vb) were identified in association with ACV-induced nephrotoxicity. These findings were confirmed by Western blotting analysis. The differential expression levels of α-BC, Prx1, Glo I and CcO Vb suggest that oxidative damage and mitochondrial injury may be involved in ACV-induced nephrotoxicity. Furthermore, VEGF and FGF may play a role in tissue repair and the restoration process following ACV nephrotoxicity.

Testicular effects following in utero exposure to the antivirals acyclovir and ganciclovir in rats.

In utero exposure to the antivirals acyclovir and ganciclovir has been reported to induce gross structural defects in rat offspring. The present study investigated the effects of maternal antiviral treatment on gestation day 10 on reproductive and nonreproductive organs in male rat offspring with a particular focus on the testes. Vehicle and two doses of acyclovir and ganciclovir, 75 and 300 mg/kg, were administered to rat dams. The total doses were fractioned into three subcutaneous applications (3 × distilled water, 3 × 25 mg/kg, and 3 × 100 mg/kg) that were administered on gestation day 10 at 8:00 a.m., 1:00 p.m., and 6:00 p.m. The antiviral concentrations were measured in the serum of the dams 1 h after the last administration. Exposure to 300 mg/kg ganciclovir induced germ cell deficiency in both fetal and adult testes, an effect that was not seen in any other treatment group. Adult rats exposed in utero to this high ganciclovir dose exhibited Sertoli cell-only tubules intermingled with seminiferous tubules that displayed a normal size and normal cell counts, alterations that resemble focal Sertoli cell-only syndrome in humans. The serum concentrations of ganciclovir were markedly higher than those of acyclovir, particularly at the high dose tested. However, although 300 mg/kg acyclovir did not induce germ cell deficiency, other specific effects were seen in exposed animals, including incomplete eye opening and reduced thymus weight.

Aqueous nanomicellar formulation for topical delivery of biotinylated lipid prodrug of acyclovir: formulation development and ocular biocompatibility.

PURPOSE: The objective of this study was to develop a clear, aqueous nanomicellar formulation and evaluate its in vitro ocular biocompatibility as a novel carrier for topical ocular delivery of biotinylated lipid prodrug for the treatment of herpetic keratitis. METHODS: Micellar formulation of Biotin-12Hydroxystearic acid-acyclovir (B-12HS-ACV) was prepared by solvent evaporation/film hydration method with two nonionic surfactants, vitamin E TPGS and octoxynol-40. The optimized formulation was characterized for various parameters including micelle size, polydispersity index (PDI), and zeta-potential and in vitro prodrug release. Human corneal epithelial cells (HCECs) were employed for studying the cytotoxicity of the formulation. Further, mRNA expression levels of various cytokines were also studied with quantitative real-time PCR (qPCR). RESULTS: Average size was 10.46±0.05 nm with a PDI of 0.086 for blank nanomicelles, and 10.78±0.09 nm with a PDI of 0.075 for prodrug-loaded nanomicelles. Both unloaded and prodrug-loaded nanomicelles had low negative zeta potential. Prodrug encapsulation efficiency of mixed nanomicelles was calculated to be ∼90%. Transmission electron microscopy analysis revealed that nanomicelles were spherical, homogenous, and devoid of aggregates. B-12HS-ACV release from nanomicelles was slow with no significant burst effect. Results show a sustained release of the prodrug from nanomicelles over a period of 4 days. Neither the blank formulation nor the prodrug-loaded micellar formulation demonstrated any cytotoxic effects. Further, incubation of HCECs with blank and prodrug-loaded nanomicellar groups did not significantly alter the expression levels of IL-1ß, IL-6, IL-8, IL-17, TNF-α, and IFN-γ. CONCLUSIONS: In summary, a topical clear, aqueous nanomicellar formulation comprised of vitamin E TPGS and octoxynol-40 loaded with 0.1% B-12HS-ACV was successfully developed. B-12HS-ACV-loaded nanomicelles are small in size, spherical, and homogenous, without any aggregates. The micellar formulations were perfectly transparent similar to pure water. Ocular biocompatibility studies indicated that mixed nanomicelles were nontoxic and noninflammatory to corneal epithelial cells. Therefore, nanomicellar technology represents a promising strategy for the delivery of biotinylated lipid prodrugs of ACV.

TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.

Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs-acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)-we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3'-ends. We also show that Tdp1-/- cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1-/- cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs.

Galactose decorated PLGA nanoparticles for hepatic delivery of acyclovir.

The present study explores prospective of surface tailored nanoparticles for targeted delivery of acyclovir along with the interception of minimal side effects. Acyclovir loaded plain and galactosylated poly lectic co glycolic acid (PLGA) nanoparticles were efficiently prepared and characterized by Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), size, polydispersity index, zeta potential, and entrapment efficiency. The formulations were evaluated for in vitro drug release and hemolysis. Further, biodistribution study and fluorescent microscopic studies were carried out to determine the targeting potential of formulations. SEM revealed smooth morphology and spherical shape of the nanoparticles. In vitro, the galactosylated nanoparticles were found to be least hemolytic and exhibited a sustained release pattern. In vivo studies exhibited an augmented bioavailability, increased residence time and enhanced delivery of acyclovir to the liver upon galactosylation. It may therefore be concluded that galactose conjugated PLGA nanoparticles can be used suitably as vehicles for delivery of bioactives specifically to the hepatic tissues and may be thus exploited in the effective management of various liver disorders.

Neurotoxicidad por aciclovir-valaciclovir en enfermos con insuficiencia renal / Acyclovir and valacyclovir neurotoxicity in patients with renal failure

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