Formulating Spray-Dried Albumin-Modified Lipid Nanoparticles Encapsulating Acyclovir for Enhanced Pulmonary Drug Delivery.

BACKGROUND: Viral pneumonia, a pressing global health issue, necessitates innovative therapeutic approaches. Acyclovir, a potent ring-opening antiviral agent with broad-spectrum activity, faces water solubility, oral bioavailability, and drug resistance challenges. The aim of this study was to increase the efficacy of acyclovir through respiratory delivery by encapsulating it within albumin-modified lipid nanoparticles and formulate it as a spray. METHODS: Nanoparticles was synthesized via the reverse evaporation method; its physicochemical characteristics were rigorously evaluated, including particle size, zeta potential, morphology, encapsulation efficiency, drug loading, and release profile. Furthermore, the cytotoxicity of nanoparticles and its therapeutic potential against viral pneumonia were assessed through cellular and animal model experiments. Result s: Nanoparticles exhibited a spherical morphology, with a mean particle size of 97.48 ± 5.36 nm and a zeta potential of 30.28 ± 4.72 mv; they demonstrated high encapsulation efficiency (93.26 ± 3.27%), drug loading (11.36 ± 0.48%), and a sustained release profile of up to 92% under neutral conditions. Notably, nanoparticles showed low cytotoxicity and efficient intracellular delivery of acyclovir. In vitro studies revealed that nanoparticles significantly reduced interleukin-6 levels induced by influenza virus stimulation. In vivo, nanoparticles treatment markedly decreased mortality, attenuated the inflammatory markers interleukin-6 and tumor necrosis factor-α levels, and mitigated inflammatory lung injury in mice with viral pneumonia. CONCLUSIONS: In this study, albumin was modified with polyethylene glycol (PEG) containing cationic lipid nanoparticles (LN) to prepare albumin-modified lipid nanoparticles encapsulating acyclovir (ALN-Acy), which can effectively deliver Acy into tissues and cells, prolong the survival of mice, and reduce lung injury and inflammatory factors. White albumin LN can be used as efficient drug delivery carriers, and the delivery of Acy via albumin LN is expected to be a therapeutic strategy for treating inflammatory diseases.

Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk.

Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk-benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration-time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women's plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.

Vanillin enhances the passive transport rate and absorption of drugs with moderate oral bioavailability in vitro and in vivo by affecting the membrane structure.

Vanillin is a popular flavoring agent in the food, tobacco, and perfume industries. In this paper, we investigated the effect of vanillin on the transport rates of drugs with different levels of permeability (acyclovir, hydrochlorothiazide, propranolol and carbamazepine) through a Caco-2 cell bidirectional transport experiment. We also explored the underlying mechanism using an in silico technique and fluorescence anisotropy measurements. The influence of vanillin on the pharmacokinetics of drugs whose transport rates were affected by vanillin in vitro was then studied in vivo. Results showed that vanillin (100 µM) increased the cumulative amount of passively transported drugs (2.1-fold of hydrochlorothiazide, 1.49-fold of propranolol, 1.35-fold of acyclovir, and 1.34-fold of carbamazepine) in vitro. Molecular dynamics simulations revealed that vanillin disordered the structure of the lipid bilayer and reduced the energy barrier of drugs across the center of the membrane. The anisotropy of TMA-DPH also decreased in Caco-2 cells after treatment with vanillin (25 and 100 µM) and indicated an increase in membrane fluidity, which was dose-dependent. An oral bioavailability study indicated that vanillin (100 mg kg-1) significantly enhanced the Cmax and AUC0-6 of hydrochlorothiazide by 1.42-fold and 1.28-fold, respectively, and slightly elevated the Cmax of propranolol. In conclusion, vanillin can significantly increase the absorption of drugs with moderate oral bioavailability in vitro and in vivo by loosening the membrane. Thus, the concurrent consumption of drugs with food containing vanillin may result in increased drug plasma concentration and pose potential health risks.

Acyclovir Neurotoxicity in a Peritoneal Dialysis Patient: Report of a Case and Review of the Pharmacokinetics of Acyclovir.

BACKGROUND The elderly population in the United States and the world is rapidly increasing. With aging, immunity and kidney function decrease, thus predisposing people to viral illnesses for which there is no effective prophylaxis. Herpes zoster afflicts the elderly and other immunocompromised patients, like those with end-stage renal disease, transplant recipients, and cancer patients, causing significant morbidity and sometimes mortality. Treating herpes zoster becomes problematic when the regular pharmacokinetics of the antiviral drugs are disturbed. CASE REPORT An 83-year-old African American man with end-stage kidney disease (ESRD) and on chronic peritoneal dialysis (PD) developed herpes zoster, for which he received the manufacturer-recommended intravenous dose of acyclovir. Shortly after taking the medication, he developed confusion, disorientation, and visual hallucinations. He was switched from PD to hemodialysis (HD), with successful recovery. Examination of the cerebrospinal fluid for meningitis and imaging studies of the head were negative. Serum levels of acyclovir were elevated. CONCLUSIONS Even when the acyclovir dose is properly adjusted for kidney function based on the current manufacturer's recommendations, it can cause neurotoxicity. Here, we discuss the pharmacokinetics of acyclovir and make some recommendations with regard to dose adjustment in patients with ESRD.

Síndrome de Ramsay Hunt tipo II en mujer mayor de 90 años / Ramsay Hunt Syndrome type II in women older than 90 years of age

El Síndrome de Ramsay Hunt o Herpes Zóster Ótico, se define por la asociación de parálisis facial periférica con la presencia de erupción eritemato-vesicular en el oído externo, por el virus de la Varicela-Herpes Zóster. Objetivo: Establecer la evolución de la reactivación del virus de la varicela en personas mayores de 90 años. Presentación del Caso clínico: paciente femenina de 91 años, con antecedente de artritis reumatoide e hipertensión arterial no controlada; inicia con erupción maculo papular en hemicara izquierda que evoluciona a vesículas, acompañada de fiebre y mal estado general; concomitante presenta otalgia. Es ingresada por el servicio de Medicina Interna al Hospital Escuela Universitario donde se instaura tratamiento: Aciclovir 500mg intravenoso cada 8 horas, Pregabalina 1 cápsula vía oral cada 12 horas y Prednisona 50mg vía oral cada día, con buena respuesta terapéutica; se da de alta con mejoría de sus síntomas y resolución de lesiones faciales. Conclusión: Para la aparición del síndrome de Ramsay Hunt II en esta paciente, el principal factor de riesgo fue la edad; su evolución fue favorable y sin secuelas al instaurarse el tratamiento en forma oportuna...(AU)

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.

In vitro evaluation of cutaneous penetration of acyclovir from semisolid commercial formulations and relation with its effective antiviral concentration

ABSTRACT The evaluation of drug permeation/penetration of semisolid formulations into animal skin can be useful to supplement the pharmaceutical equivalence. This paper describes the in vitro assessment of acyclovir (ACV) into porcine skin from commercial formulations with etermination of drug concentration in different layers of cutaneous tissue to correlate with effective antiviral concentration in order to improve the equivalence decision. Studies were conducted using Franz cells and porcine skin. Selected pharmaceutical creams containing ACV had identical (reference and generic) and different (similar) excipients. A software program was employed for the simulation of antiviral effectiveness in the skin. Regarding ACV skin penetration, the first batch of the generic product showed a significant difference from reference and similar products, while in the second batch all products demonstrated equivalent drug penetration in the skin. Simulation studies suggest that formulations analysed exhibit a pharmacological effect even when in contact with Herpes simplex strains of high IC50 (inhibitory concentration required to reduce viral replication by 50%). According to results, it can be assumed that the in vitro cutaneous permeation/penetration study does not supply sensitivity information regarding small alterations of ACV semisolid formulations due to the variability inherent to the method, although it can be relevant to pharmaceutical equivalence studies in the development of semisolid products.

Topical distribution of acyclovir in normal equine skin and equine sarcoids: An in vitro study.

Topical acyclovir application is an owner-friendly treatment for occult equine sarcoids, without the caustic side-effects other topical treatments have. Variable clinical success rates have been described, but it is not known to what rate and extent acyclovir penetrates in and through equine skin from a topical formulation. In the current study, an in vitro Franz diffusion model was used to determine the permeation parameters for a generic 5% acyclovir cetomacrogol cream for both healthy and sarcoid equine skin. The distribution of acyclovir between different layers of both skin types was also evaluated. While acyclovir penetrated through both skin types, significantly less acyclovir permeated to the deep dermis of sarcoid skin (197.62ng/mm(3)) compared to normal skin (459.41ng/mm(3)). Within sarcoid skin samples, significantly higher acyclovir concentrations were found in the epidermis (983.59ng/mm(3)) compared to the superficial dermis (450.02ng/mm(3)) and the deep dermis. At each sample point, significantly more acyclovir permeated to the receptor fluid through normal skin compared to sarcoid skin, which is reflected in the significantly higher permeation parameters of normal skin. Normal skin was found to be more permissive for acyclovir, but even in sarcoid skin, enough acyclovir reached the deep dermis to treat a Herpes simplex virus infection. In the case of equine sarcoids, the treatment is aimed at the Bovine papillomavirus and no information is available on the susceptibility of the DNA polymerase of this virus for acyclovir. Therefore, further research is needed to determine the efficacy of acyclovir to treat equine sarcoids.

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients.

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m(2), respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.).

Drug interaction studies reveal that simotinib upregulates intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells.

HYPOTHESIS: Simotinib hydrochloride (SIM6802), which is a new epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is often prescribed for cancer patients with comorbidities and has serious adverse effects on gastrointestinal physiology. The drug-drug interactions (DDIs) between simotinib and other drugs in combination and the underlying mechanism of its gastrointestinal toxicity remain unclear. We hypothesized that the DDIs and the gastrointestinal toxicity of simotinib were related to its effects on the permeability of the intestine. METHODS: To determine the intestinal absorption capacity, pharmacokinetic studies and an in situ loop assay were used. The intestinal permeability was measured by a Caco-2 Transwell model. Real time PCR and Western blots were applied to detecting the expression changes of cell junction genes. RESULTS: Our research demonstrated that simotinib upregulated the absorption of cefaclor, valaciclovir and acyclovir. The increase of non-selective absorption was caused by the low expression of cell junction gene afadin-6 and the increase in paracellular permeability in intestinal epithelial cells after simotinib treatment. CONCLUSION: These findings revealed that simotinib upregulated intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells. Our research provides theoretical bases for better formulation of EGFR-TKIs to alleviate adverse gastrointestinal effects and also provides guidance for clinical administration of simotinib.

Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model.

OBJECTIVES: We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. METHODS: Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. RESULTS: Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8±9.1 L/h and clearance from the aqueous humour was 8.2×10(-5) L/h. AUCs were 25.4±10.2 and 6.6±1.8 µg·h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28±0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. CONCLUSIONS: Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartments.

Vitreous pharmacokinetics and electroretinographic findings after intravitreal injection of acyclovir in rabbits

OBJECTIVES: Acute retinal necrosis is a rapidly progressive and devastating viral retinitis caused by the herpesvirus family. Systemic acyclovir is the treatment of choice; however, the progression of retinal lesions ceases approximately 2 days after treatment initiation. An intravitreal injection of acyclovir may be used an adjuvant therapy during the first 2 days of treatment when systemically administered acyclovir has not reached therapeutic levels in the retina. The aims of this study were to determine the pharmacokinetic profile of acyclovir in the rabbit vitreous after intravitreal injection and the functional effects of acyclovir in the rabbit retina. METHODS: Acyclovir (Acyclovir; Bedford Laboratories, Bedford, OH, USA) 1 mg in 0.1 mL was injected into the right eye vitreous of 32 New Zealand white rabbits, and 0.1 mL sterile saline solution was injected into the left eye as a control. The animals were sacrificed after 2, 9, 14, or 28 days. The eyes were enucleated, and the vitreous was removed. The half-life of acyclovir was determined using high-performance liquid chromatography. Electroretinograms were recorded on days 2, 9, 14, and 28 in the eight animals that were sacrificed 28 days after injection according to a modified protocol of the International Society for Clinical Electrophysiology of Vision. RESULTS: Acyclovir rapidly decayed in the vitreous within the first two days after treatment and remained at low levels from day 9 onward. The eyes that were injected with acyclovir did not present any electroretinographic changes compared with the control eyes. CONCLUSIONS: The vitreous half-life of acyclovir is short, and the electrophysiological findings suggest that the intravitreal delivery of 1 mg acyclovir is safe and well tolerated by the rabbit retina.

Monitoring of bystander effect of herpes simplex virus thymidine kinase/acyclovir system using fluorescence resonance energy transfer technique.

Cytotoxic gene therapy mediated by gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene followed by acyclovir (ACV) treatment has been reported to inhibit malignant tumor growth in a variety of studies. The magnitude of "bystander effect" is an essential factor for this anti-tumor approach in vivo. However, the mechanism by which HSV-tk/ACV brings "bystander effect" is poorly understood. In this report, the plasmid CD3 (ECFP-CRS-DsRed) and TK-GFP were transferred to the human adenoid cystic carcinoma line ACC-M cell line. The CD3-expressing cells apoptosis was monitored using fluorescence resonance energy transfer (FRET) technique. First, CD3 and TK-GFP co-expressing ACC-M cells apoptosis was monitored using FRET technique. The apoptosis was induced by ACV and initiated by caspase3. The FRET efficient was remarkably decreased and then disappeared during cellular apoptosis, which indicated that the TK-GFP expressing ACC-M cells apoptosis, induced by ACV, was via a caspase3-dependent pathway. Secondly, CD3 and TK-GFP mixed expressing ACC-M cells apoptosis, induced by ACV, were monitored using FRET technique. The apoptotic phenomena appeared in the CD3-expressing ACC-M cells. The results show that HSV-tk/ACV system killed ACC-M cells using its bystander effect. These results confirm that HSV-tk/ACV system is potential for cancer gene therapy.

Acyclovir is a substrate for the human breast cancer resistance protein (BCRP/ABCG2): implications for renal tubular transport and acyclovir-induced nephrotoxicity.

The human breast cancer resistance protein (BCRP/ABCG2) is widely expressed in human tissues, including the kidney. In mice, Bcrp1 (murine BCRP ortholog) mediates the transport of acyclovir into breast milk. It is plausible that acyclovir is also a substrate for the human BCRP. The objective of the study was to determine whether acyclovir is a substrate for human BCRP. Transfected human embryonic kidney (HEK293) cells (containing the wild-type ABCG2 gene) were exposed to [8-(14)C]acyclovir (1 µmol/L) in the presence or absence of the BCRP inhibitor fumitremorgin C (FTC). Intracellular acyclovir accumulation was assessed using a liquid scintillation counter. Coexposure to FTC resulted in a significant (5-fold) increase in the intracellular accumulation of acyclovir. The results suggest that acyclovir is a substrate for human BCRP. The study is the first to provide direct evidence for the role of human BCRP in acyclovir transport and its potential significance with respect to renal tubular transport of acyclovir and the direct renal tubular insult induced by the drug.

An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay

The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step-gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established.

Rheological and mucoadhesive characterization of poly(vinylpyrrolidone) hydrogels designed for nasal mucosal drug delivery.

Poly(vinylpyrrolidone) (PVP) hydrogels were crosslinked by gamma irradiation to add structure and rigidity, and then rheological and mucoadhesive properties were evaluated. The effects of PVP concentration, radiation dose, and additives, such as poly(ethylene glycol) (PEG) and glycerol, on rheological properties were investigated. In an oscillatory analysis, an increase in polymer concentrations increased the storage modulus (G') and the loss modulus (G″) but decreased the loss tangent (tan δ < 1). The relationships between G'or G″ and the frequency levelled off at higher frequencies, which is indicative of polymer chain entanglement and network formation. Each of the 6% PVP hydrogels exhibited plastic flow with rheopectic behavior. PVP concentration, radiation dose, and the presence of PEG or glycerol influenced the rheological and mucoadhesive properties of the hydrogels. However, adding acyclovir to the formulation did not have a profound effect on the rheological behavior of the hydrogels. The results suggest that a 3% PVP hydrogel with 1% PEG crosslinked with 20 kGy is the most appropriate hydrogel. The results demonstrated the successful complementary application of oscillatory and flow rheometry to characterize and develop a hydrogel for mucosal drug administration.

Ionic liquid-in-oil microemulsion as a potential carrier of sparingly soluble drug: characterization and cytotoxicity evaluation.

Pharmaceutical industries have posed challenges in the topical and transdermal administration of drugs which are poorly soluble or insoluble in water and most of organic solvents. In an approach to overcome this limitation, ionic liquid-in-oil (IL/o) microemulsions (MEs) were employed to increase the solubility of a sparingly soluble drug to enhance its topical and transdermal delivery. The formulation of MEs was composed of a blend of nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20), isopropyl myristate (IPM) as an oil phase, and IL [C(1)mim] [(CH(3)O)(2)PO(2)] (dimethylimidazolium dimethylphosphate) as a pseudophase. Among various weight ratios of Tween-80 to Span-20 investigated in the ME systems, the ratio 3:2 showed excellent solubility and skin permeation enhancing effect for acyclovir (ACV) used as a model sparingly soluble drug. The size and size distribution of the ME droplets with and without drug were determined by dynamic light scattering. The permeability study of ACV incorporated in IL droplets as well as other formulations was performed into and across the Yucatan micropig (YMP) porcine skin, and the use of IL/o MEs has been shown to dramatically increase ACV administration. Finally, the cytotoxicity of the new carrier was evaluated in vitro using the reconstructed human epidermal model LabCyte™ EPI-MODEL12. It was found that the cell viability of IL/o MEs containing 4wt% IL was over 80% compared to Dulbecco's Phosphate-Buffered Salines, indicating low cytotoxicity of the carrier. Taken together these results, it can be assumed that IL-assisted nonaqueous ME could serve as a versatile and efficient nanodelivery system for insoluble or sparingly soluble drug molecules that require solubilizing agents for delivery.

Wild Type p53 gene sensitizes rat C6 glioma cells to HSV-TK/ACV treatment in vitro and in vivo.

Suicide gene therapy using herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV), has been extensively tested for the treatment of glioma. Our previous study showed that exogenous wild type p53 (wt-p53) enhanced the anti-tumor effect of HSV-TK/GCV therapy. However, the use of GCV is hindered by its low penetration to the brain and its toxicity when used at higher dose. In the present study, we used another pro-drug, acyclovir (ACV), and examined the therapeutic efficacy of HSV-TK/ACV combining with wt-p53 in C6 glioma cells. We observed that wt-p53 combined with HSV-TK/ACV resulted in the super-additive anti-tumor effect in vitro. Exogenous wt-p53 significantly enhanced the sensitivity of TK positive C6 cells to ACV in vitro. Our in vivo experiment demonstrated that the effect of wt-p53 and HSV-TK/ACV combination therapy was better than that of HSV-TK/ACV alone. The survival time of tumor-bearing rats treated with wt-p53 in combination with HSV-TK/ACV was also significantly prolonged than those treated with HSV-TK/ACV alone. These results suggest that wt-p53 can enhance the therapeutic efficacy of HSV-TK/ACV both in vitro and in vivo. These findings are considerably valuable with the respect of using less toxic ACV as prodrug. This novel strategy could provide benefit to HSV-TK/prodrug gene therapy.

Valacyclovir pharmacokinetics and exploratory pharmacodynamics in young adults with Epstein-Barr virus infectious mononucleosis.

Primary Epstein-Barr virus (EBV) infection often results in infectious mononucleosis and is associated with serious sequelae. No treatment is approved for EBV infection, and an antiviral intervention would be significant. The objectives of this study are to characterize the pharmacokinetics and explore the pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects receiving 7 days of valacyclovir 1500 mg twice daily for EBV infectious mononucleosis. Virologic and clinical responses are assessed over 12 days. Acyclovir is measured by liquid chromatography/ultraviolet detection. EBV DNA is quantitated by TaqMan polymerase chain reaction. NONMEM VI and linear regression are used for data analysis. Acyclovir profiles in plasma and oral washings are consistent with a 1-compartment model. Final model estimates of clearance, volume of distribution, and fraction of acyclovir in oral wash supernatant are 49.9 L/h, 74.1 L, and 1.14%, respectively. The quantity of EBV DNA in oral washings and blood, and the severity of illness, measured by a graded scale, decrease during treatment. After treatment, viral rebound occurs in oral washings but not in blood, and the severity of illness continues to decline. Acyclovir pharmacokinetic parameters do not correlate with response metrics. These results support further studies of valacyclovir for EBV infectious mononucleosis.

Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine.

The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro K(m) value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.