Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases.

Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.

Silk Fibroin-Modified Disulfiram/Zinc Oxide Nanocomposites for pH Triggered Release of Zn2+ and Synergistic Antitumor Efficacy.

Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proven to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent antitumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/DSF@ZnO) to solubilize and stabilize DSF, and, more importantly, achieve pH triggered Zn2+ release and subsequent synergistic antitumor activity. The prepared SF/DSF@ZnO nanocomposites were spherical and had a high drug loading. Triggered by the lysosomal pH, SF/DSF@ZnO could induce the rapid release of Zn2+ under the acidic conditions and caused nanoparticulate disassembly along with DSF release. In vitro experiments showed that cytotoxicity of DSF could be enhanced by the presence of Zn2+, and further amplified when encapsulated into SF/DSF@ZnO nanocomposites. It was confirmed that the significantly amplified cytotoxicity of SF/DSF@ZnO was resulted from pH-triggered Zn2+ release, inhibited cell migration, and increased ROS production. In vivo study showed that SF/DSF@ZnO nanocomposites significantly increased the tumor accumulation and prolonged the retention time. In vivo antitumor experiments in the xenograft model showed that SF/DSF@ZnO exerted the highest tumor-inhibition rate among all the drug treatments. Therefore, this exquisite study established silk fibroin-modified disulfiram/zinc oxide nanocomposites, SF/DSF@ZnO, where ZnO not only acted as a delivery carrier but also served as a metal ion reservoir to achieve synergistic antitumor efficacy. The established DSF nanoformulation displayed excellent therapeutic potential in future cancer treatment.

Is Alcohol in Hand Sanitizers Absorbed Through the Skin or Lungs? Implications for Disulfiram Treatment.

AIM: In view of the increase in the use of ethanol-containing hand sanitizers throughout the world due to the current COVID-19 pandemic, we wished to review the possible risks to patients treated with disulfiram, following a case report in which an apparent DER (disulfiram-ethanol reaction) was attributed to the cutaneous absorption of alcohol from hand sanitizers as well as by inhalation of vapour. METHOD: Simple experiments to assess the levels of absorption by each route separately. RESULTS: Our results strongly suggest that while amounts of alcohol sufficient to cause a DER may be inhaled when hand sanitizers are used in confined spaces, absorption can be avoided by dispersal of the fumes, and absorption from the skin alone does not occur in pharmacologically significant quantities. CONCLUSION: Warnings about absorption of alcohol through the skin from hand sanitizers and products such as perfumes, deodorants and after-shave (whose use is often warned against when disulfiram is prescribed) should be modified accordingly.

A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.

Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.

An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens.

Disulfiram (DSF) is a dimer of diethyldithiocarbamate (DDC) that we previously added to a solution of 2-hydroxypropyl-ß-cyclodextrin (DSF solution). We found that the instillation of this DSF solution delayed lens opacification in a hereditary cataractous ICR/f rat. In this study, we attempted to design an ophthalmic formulation containing DSF nanoparticles for use as a lens targeted drug delivery system (nano-DSF suspension), and investigated the changes in drug content in the lens after the instillation of DSF solution or nano-DSF suspension. The nano-DSF suspension was prepared by a bead mill method to yield a mean particle size of nano-DSF of 181 nm. Following the instillation of 1.4% DSF solution or the nano-DSF suspension, DDC was detected only in the aqueous humor and lens; in both, the area under the curve (AUC) and mean residence time (MRT) for the nano-DSF suspension were higher than for the DSF solution. In addition, we found that the DDC residence time in the cortex and nucleus of the lens was higher than in the capsule-epithelium. Although DDC was not detected in the cortex and nucleus of lenses following the instillation of the 1.4% DSF solution, the instillation of a 1.4% nano-DSF suspension led to the accumulation of DDC in both areas. In conclusion, it is possible that the instillation of a nano-DSF suspension can supply more DDC into the aqueous humor and lens than a conventional formulation, and these findings provide information significant for the prevention of cataracts and the design of a lens targeted drug delivery system.

A nanoparticle formulation of disulfiram prolongs corneal residence time of the drug and reduces intraocular pressure.

The goal in the search for successful therapies for glaucoma is the reduction of intraocular pressure (IOP), and the search for effective eye drops that reduce IOP is a high priority. We previously reported the potential of a 2-hydroxypropyl-ß-cyclodextrin (HPßCD) solution containing 0.5% DSF (DSF solution) to provide effective anti-glaucoma treatment in eye drop form. In this study, we designed new ophthalmic formulations containing 0.5% DSF nanoparticles prepared by a bead mill method (DSFnano dispersion; particle size 183 ± 92 nm, mean ± S.D.), and compared the IOP-reducing effects of a DSFnano dispersion with those of a DSF solution. The high stability of the DSFnano dispersion was observed until 7 days after preparation, and the DSFnano dispersion showed high antimicrobial activity against Escherichia coli (ATCC 8739). In transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while no DSF was detected. The DDC penetration level (area under the curve, AUC) and corneal residence time (mean residence time, MRT) of the DSFnano dispersion were approximately 1.45- and 1.44-fold higher than those of the DSF, respectively. Moreover, the IOP-reducing effects of the DSFnano dispersion were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, DSFnano dispersion are tolerated better by a corneal epithelial cell than DSF solution and commercially available timolol maleate eye drops. It is possible that dispersions containing DSF nanoparticles will provide new possibilities for the effective treatment of glaucoma, and that an ocular drug delivery system using drug nanoparticles may expand their usage as therapy in the ophthalmologic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma drugs.

A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy.

BACKGROUND: Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo. METHODS: We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells. RESULTS: Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01). CONCLUSIONS: Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.

Pharmacokinetic and pharmacodynamic evaluation of the anti-cataract effect of eye drops containing disulfiram and low-substituted methylcellulose using ICR/f rats as a hereditary cataract model.

We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens opacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35°C, close to body temperature. In in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The opacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (τ) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and τ using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea.

[Disulfiram and addiction: reminders and new perspectives of use]. / Le disulfirame (Esperal(®)) dans le traitement des addictions : rappels et nouvelles perspectives d'utilisation.

Disulfiram is a relatively old molecule, which today remains marginal in the treatment of alcoholics diseases. Using this type of treatment is the subject of ethical debate. The prescription of this therapeutic requires clinical and biological rigorous evaluations before treatment. Its main action in treatment of alcoholism is related to the restraint of acetaldehyde dehydrogenase action causing the antabuse reaction. Prescription of disulfiram, supported by specialized programs of compartmental integrated care, brings significant benefit for alcoholic patients. Recently, following the discovery of its action on dopamine metabolism, disulfiram has been a renewed interest in the treatment of addictions to cocaine and pathological gambling. Although current data are insufficient to generalize its use in routine practice, they constitute a line of research interest for the future.

Hyaluronic acid/polyethyleneimine nanoparticles loaded with copper ion and disulfiram for esophageal cancer.

In the clinical treatment of cancer, improving the effectiveness and targeting of drugs has always been a bottleneck problem that needs to be solved. In this contribution, inspired by the targeted inhibition on cancer from combination application of disulfiram and divalent copper ion (Cu2+), we optimized the concentration of disulfiram and Cu2+ ion for inhibiting esophageal cancer cells, and loaded them in hyaluronic acid (HA)/polyethyleneimine (PEI) nanoparticles with specific scales, in order to improve the effectiveness and targeting of drugs. The in vitro cell experiments demonstrated that more drug loaded HA/PEI nanoparticles accumulated to the esophageal squamous cell carcinoma (Eca109) and promoted higher apoptosis ratio of Eca109. Both in vitro and in vivo biological assessment verified that the disulfiram/Cu2+ loaded HA/PEI nanoparticles promoted the apoptosis of cancer cells and inhibited the tumor proliferation, but had no toxicity on other normal organs.

Disulfiram-gold-nanorod integrate for effective tumor targeting and photothermal-chemical synergistic therapy.

Herein, we successfully constructed a combination therapeutic nanoplatform with high tumor targeting for cancer treatment by integrating gold nanorods with disulfiram (denoted Au-DSF). The Au-DSF integrates possess a uniform length (70 nm), excellent photothermal conversion ability and a high DSF loading content (23.2%), and the loaded DSFs show glutathione-, acid-, and laser-responsive release properties. The Au-DSF integrates show significantly enhanced cellular uptake efficiency in breast cancer cells due to the ability of DSF to chelate to the intracellular copper (Cu) which is present at high concentrations. Furthermore, the Au-DSF exhibits improved circulation time (mean residence time = 28.4 h) and increased tumor accumulation (12.0%), due to the targeting of DSF to the abundant Cu ions at the tumor site. Moreover, the DSF/Cu complexes potently elevate reactive oxygen species, which effectively induce cancer cell apoptosis. In vivo experiments show that the Au-DSF integrates dramatically decrease tumor size via photothermal therapy and chemotherapy. Hematoxylin-eosin and TUNEL staining show that the Au-DSF integrates induce necrosis and apoptosis in cancer cells. The high therapeutic efficiency of the Au-DSF integrates for breast cancer is further demonstrated by the reduced elasticity seen in ultrasound elastography, and the absence of perfusion of the contrast agent in contrast-enhanced ultrasound imaging in tumors.

Delayed and prolonged coma after acute disulfiram overdose.

We report the case of a 35-year-old man presenting with a delayed and prolonged coma due to an intentional overdose with disulfiram without simultaneous alcohol ingestion. The clinical features--comprising a severe toxic encephalopathy with coma and convulsions, in combination with a quadriparesis outlasting the loss of consciousness--are summarized, and the physiopathology is reviewed.

Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy.

BACKGROUND: Disulfiram (DSF) has a long history of being used as a first-line promising therapy for treatment of alcoholism in human. Besides its prominence in the treatment of alcoholism, extensive investigations have been carried out to explore other biomedical and pharmacological effects of DSF. Amongst other biomedical implications, plenty researches have shown evidence of promising anticancer efficacy of this agent for treatment of wide range of cancers such as breast cancer, liver cancer and lung carcinoma. METHODS: Electronic databases, including Google scholar, PubMed and Web of science were searched with the keywords disulfiram, nanoparticles, cancer, drug delivery systems. RESULT: Despite its excellent anticancer efficacy, the pharmaceutical significance and clinical applicability of DSF are hampered due to poor stability, low solubility, short plasma half-life, rapid metabolism, and early clearance from systemic circulation. Various attempts have been made to eradicate these issues. Nanotechnology based interventions have gained remarkable recognition in improving pharmacokinetic and pharmacodynamic profile of DSF by improving its stability and avoiding its degradation. CONCLUSION: The aim of the present review is to critically analyse all recent developments in designing various nanotechnology-based delivery systems, to ponder their relevance in improving stability, pharmacokinetic and pharmacodynamic profile, and achieving target-specific delivery of this agent to cancer cells to effectively eradicate cancer and abolish its metastasis. Nanotechnology is a novel approach for overcoming such obstacles faced presently, the results obtained so far using different novel drug delivery systems seem to be very promising to increase the stability and half-life of DSF. Graphical abstract Nanocrrier mediated drug delivery systems for disulfiram.

Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial.

Disulfiram (DSF) was well tolerated and activated viral transcription (cell-associated unspliced (CA-US) and plasma human immunodeficiency virus (HIV) RNA) in a phase II dose-escalation trial in HIV+ antiretroviral therapy (ART)-suppressed participants. Here, we investigated whether exposure to DSF and its metabolites predicted these changes in HIV transcription. Participants were administered 500 (N = 10), 1,000 (N = 10), or 2,000 (N = 10) mg of DSF for 3 consecutive days. DSF and four metabolites were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Changes in CA-US and plasma HIV RNA were quantified by polymerase chain reaction (PCR) and analyzed in NONMEM. A seven-compartment pharmacokinetic (PK) model demonstrated nonlinear elimination kinetics. The fitted median area under the curve values for 72 hours (AUC0-72 ) were 3,816, 8,386, and 22,331 mg*hour/L, respectively. Higher exposure predicted greater increases in CA-US (maximum effect (Emax ) = 78%, AUC50  = 1,600 µg*hour/L, P = 0.013) but not plasma HIV RNA. These results provide support for further development of DSF as an important drug for future HIV cure strategies.

Drug-delivering-drug approach-based codelivery of paclitaxel and disulfiram for treating multidrug-resistant cancer.

Multidrug resistance (MDR) is a common intractable barrier in success of clinical cancer chemotherapy. Codelivery of two drugs using nanocarriers is a commonly used approach to treat the MDR cancer. However, the drug payload in the conventional nanocarriers is low and thus compromises the treatment outcomes. Disulfiram (DSF) is promising to reverse MDR and increases the sensitivity of cancer cells to chemotherapy. While, paclitaxel (PTX) is one of the frequently used anticancer drug. Here, by using a drug-delivering-drug (DDD) strategy based on nanocrystals, hybrid PTX-DSF nanocrystals (PTX-DSF Ns) were developed for codelivery of PTX and DSF to reverse MDR in cancer. The 160-nm PTX-DSF Ns with rod-like morphology had drug-loading up to 43% at mass ratio of 5:1. Interestingly, the nanoparticles entered cells via caveolar endocytosis. By reducing intracellular ATP level and GST activity, PTX-DSF Ns killed the Taxol resistant A549 cells with higher efficiency than PTX alone, exhibiting as 6-fold increase of apoptosis in MDR tumor. The nanoparticles circulated in blood over time, accumulated in tumor efficiently and reduced the tumor volume by 12-fold in MDR tumor-bearing BALB/c nude mice and allowed 12-fold apoptosis in tumor. Additionally, the immunohistochemical examination demonstrated the safety of the nanoparticles. Overall, the DDD strategy-based PTX-DSF Ns have promising potential for the treatment of MDR cancer.

[Recent results in relaps prevention of alcoholism with Disulfiram]. / Aktueller Stand der pharmakotherapeutischen Rückfallprophylaxe mit Disulfiram.

OBJECTIVE: For more than 50 years, disulfiram has been approved for the treatment of chronic alcohol dependence. In the last years there has been observed an increase in the prescription of disulfiram in germany. It acts as a psychological deterrence of a possible disulfiram-alcohol reaction. This paper describes the current clinical impact and possible future of disulfiram. METHODS: Clinical trials using disulfiram for the treatment of alcohol dependence were discussed. Furthermore, the options of combining disulfiram with novel anti-craving agents were considered. Moreover, experiences and results of a cross section of the Mannheimer Disulfiram program will be presented. RESULTS AND CONCLUSIONS: Nowadays there exists consent in the matter that Disulfiram should only be adminsitered as part of a comprehensive therapy program, this means in the context of an intake under medical supervision. This paper is supposed to help estimate the value of disulfiram in recent addiction medicine.

Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers.

Disulfiram (DSF), an alcohol-aversion drug, has been explored for cancer treatment. Copper diethyldithiocarbamate (Cu(DDC)2) complex formed by DSF and copper ions is a major active ingredient for its anticancer activity. Direct administration of Cu(DDC)2 is a promising strategy to enhance the anticancer efficacy of DSF. However, efficient drug delivery remains a significant challenge for Cu(DDC)2 and hinders its clinical use. In this study, we developed a facile stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)2 nanoparticles (NPs). The SMILE method could prepare Cu(DDC)2 NPs with different types of stabilizers including 1,2-distearoyl- sn-glycerol-3-phosphoethanolamine-poly(ethylene glycol) (PEG) 2000, d-α-tocopherol PEG 1000 succinate, methoxy PEG 5000- b-poly(l-lactide) 5000, and other generally recognized as safe excipients approved by the US Food and Drug Administration. The optimized formulations demonstrated excellent drug-loading efficiency (close to 100%), high drug concentrations (increased drug concentration by over 200-fold compared to the traditional micelle formulation), and an optimal particle size in the sub-100 nm range. Cu(DDC)2 NPs exhibited outstanding stability in serum for 72 h and can also be stored at room temperature for at least 1 month. The anticancer effects of Cu(DDC)2 NP formulations were determined by multiple assays including 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu(DDC)2 NPs showed excellent activity against drug-resistant prostate cancer cells and other cancer cells with a half-maximal inhibitory concentration (IC50) of around 100 nM. Our study also demonstrated that Cu(DDC)2 NPs induced cell death in drug-resistant prostate cancer cells (DU145-TXR) through paraptosis, which is a nonapoptotic cell death. To our best knowledge, the SMILE method provides, for the first time, a simple yet efficient process for generating Cu(DDC)2 NPs with high drug concentration, excellent loading efficiency, and desirable physicochemical properties. This method could potentially address drug delivery challenges of DSF/copper-based chemotherapy and facilitate its clinical translation.

In vitro cell culture model for anti-cataract drug penetration studies.

Immortalized human corneal epithelial cells (HCECs) and human lens epithelial cells (HLECs) were cultured in vitro. Cells were observed under a phase-contrast microscope and the integrity of cell monolayers was assayed by transepithelial electrical resistance (TEER) determination. The permeability of disulfiram (DSF) through a HCECs monolayer was compared with that of DSF through an excised rabbit cornea. The permeability coefficients of DSF through a HCECs monolayer and excised rabbit cornea were 29.5 +/- 4.8 x 10(-6) cm/s and 34.7 +/- 5.2 x 10(-6) cm/s, respectively. Diethyldithiocarbamate (DDC) had high permeability through HLECs monolayer with a permeability coefficient of 44.6 +/- 7.1 x 10(-6) cm/s. The cytotoxicity of DDC against HLECs was investigated using the trypan blue exclusion test. For a DDC concentration of 5 mmol/l, more than 85% cells were viable. DH3a1 mRNA was expressed in cultured HLECs. The expression of aldehyde dehydrogenase 3a1 (ALDH3a1), which may be be responsible for DSF-DDC conversion, was detected using RT-PCR and agarose gels electrophoresis. These results demonstrate that the permeability of DSF can be detected and intra-ocular drug action may be predicted using the cultured HCEC and HLEC monolayers as model.

Personalized Medicine of Alcohol Addiction: Pharmacogenomics and Beyond.

Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine medications, behavioral treatment and peer support. The drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence are disulfiram, naltrexone and acamprosate. For many patients, however, these treatments are not effective. Evidence from a number of studies suggests that various factors, both psychosocial and economic, as well as genetic variation, are significant contributors to interindividual variation both of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss different aspects of personalized medicine of alcohol addiction. We focus on pharmacogenomics and beyond, to include the genetics and epigenetics of alcohol addiction as well as other psychosocial and even economic factors that may affect response to alcohol addiction pharmacotherapy. It is anticipated that, within the next 5-10 years, personalized medicine of alcohol addiction will be a reality and it will help reduce the burden of alcoholism from society and increase the well-being and productivity of individuals addicted to alcohol.

Octa-arginine modified lipid emulsions as a potential ocular delivery system for disulfiram: A study of the corneal permeation, transcorneal mechanism and anti-cataract effect.

The purpose of the study was to design a novel octa-arginine (R8) modified lipid emulsion (LE) system for the ocular delivery of the lipophilic drug disulfiram (DSF). The influence of the particle size of the lipid emulsions and the presence of R8 on corneal permeation was studied. DSF-loaded lipid emulsions with different particle sizes (DSF-LE1, DSF-LE2, DSF-LE3) and DSF-loaded lipid emulsions modified with R8 (DSF-LE1-R8 and DSF-LE2-R8) were prepared. The Zeta potential of the lipid emulsions was changed from negative to a positive value after modification of R8. The mucoadhesion of different preparations was investigated, and DSF-LE1-R8 was found to produce the strongest mucoadhesion. The in vitro corneal penetration study and in vivo ocular distribution study showed that the R8 modified lipid emulsion (DSF-LE1-R8) with a nano particle size, exhibited the highest permeability and the largest amount of DDC distributed in ocular issues. Coumarin-6 labelled LE1-R8 displayed more homogeneous fluorescence with the deeper penetration into the cornea compared with other preparations at various times. Confocal laser scanning microscopy showed that, in addition to paracellular routes, LE-R8 could also transport across the corneal epithelium by transcellular routes as a result of increased uptake due to the R8 modification. Furthermore, the anti-cataract effect was evaluated and it was found that DSF-LE1-R8 exhibited a marked anti-cataract effect. Therefore, the lipid emulsions with nano-sized particles and modification of R8 were proposed as a potential ocular delivery system to improve the corneal penetration and ocular delivery of DSF.