Nhung Dang

Development of intra-vaginal matrices from polycaprolactone for sustained release of antimicrobial agents:

Microporous poly(ɛ-caprolactone) matrices were loaded with an antibacterial agent, ciprofloxacin and an antifungal agent, miconazole nitrate, respectively, for investigations of their potential as controlled vaginal delivery devices. Ciprofloxacin loadings up to 15% w/w could be obtained by increasing the drug content of the poly(ɛ-caprolactone) solution, while the actual loadings of miconazole were much lower (1–3% w/w) due to drug partition into methanol during the solvent extraction. The kinetics of ciprofloxacin release in simulated vaginal fluid at 37℃ were characterised by a small burst release phase in the first 24 h, low drug release up to 7 days (10%) and gradual release of up to 80% of the drug content by day 30. Meanwhile, the release kinetics of miconazole-loaded matrices could be effectively described by the Higuchi model with 100% drug release from the highest loaded matrices (3.2% w/w) in 13 days. Ciprofloxacin or miconazole released over 30 and 13 days, respectively, from poly(ɛ-caprolactone) matrices into simulated vaginal fluid retained high levels of antimicrobial activity in excess of 80% of the activity of the free drug. This study confirms the potential of poly(ɛ-caprolactone) matrices for delivering antimicrobial agents in the form of an intra-vaginal device.

Antibiotics in the aquatic environment of Vietnam: Sources, concentrations, risk and control strategy

The presence of antibiotics in the aquatic environment is a serious concern because it may lead to the emergence of antibiotic resistance, thus lowering the therapeutic effect of antibiotics. In Vietnam, the problem is aggravated by the irrational use of antibiotics in different sectors of agriculture and human health service. Moreover, the residues of antibiotics in the aquatic environment can be spread widely due to the lack of proper wastewater treatment systems. In this paper, we aim to comprehensively review all relevant sources that discharge antibiotics to the aquatic environment in Vietnam. Apart from the common source of antibiotics from aquaculture, other activities that release considerable amounts of antibiotics into water environment are also included. Environmental concentrations of antibiotics related to those sources are studied to demonstrate their contributions to the presence of antibiotics in the aquatic environment in Vietnam. As antibiotic-contained water may be used as water supply for irrigation and even human consumption in rural areas, the essence of wastewater treatment is highlighted. Finally, we also discuss the new National Action plan from the Ministry of Health for controlling the issue of antibiotic resistance in Vietnam.

An Evaluation of Polycaprolactone Matrices for Vaginal Delivery of the Antiviral, Tenofovir, in Preventing Heterosexual Transmission of HIV

Tenofovir was incorporated in controlled-release polycaprolactone (PCL) matrices designed for production of vaginal inserts for prevention of HIV transmission. Rapid cooling of suspensions of the drug powder in PCL solution resulted in micro-porous matrices with tenofovir loadings up to 12% (w/w) and high incorporation efficiencies in excess of 90%. The release behaviour of tenofovir in simulated vaginal fluid (SVF) demonstrated high delivery efficiency of 85%-99% over 30 days and could be described effectively by a first-order kinetics model giving a mean value of 0.126 day-1 for the release constant (k1 ). Tenofovir released from PCL matrices into SVF exhibited high relative activity ranging from 70 to 90%, against pseudo-typed HIV-1-infected HeLa cells. The inhibitory activity of tenofovir standard solutions in SVF provided an IC50 value of 2.38 μM. Besides confirming high levels of in vitro antiviral activity, the predicted concentrations of tenofovir, which would be released from a PCL intra-vaginal ring in vivo, exceeded the IC50 value for HIV-1 by a factor of 35-200 and clinically protective concentrations by a factor of 50. These findings recommend further investigations of antiviral-loaded PCL matrices for controlling heterosexual transmission of HIV.

Effective cutaneous vaccination using an inactivated chikungunya virus vaccine delivered by Foroderm.

Foroderm is a new cutaneous delivery technology that uses high-aspect ratio, cylindrical silica microparticles, that are massaged into the skin using a 3D-printed microtextured applicator, in order to deliver payloads across the epidermis. Herein we show that this technology is effective for delivery of a non-adjuvanted, inactivated, whole-virus chikungunya virus vaccine in mice, with minimal post-vaccination skin reactions. A single topical Foroderm-based vaccination induced T cell, Th1 cytokine and antibody responses, which provided complete protection against viraemia and disease after challenge with chikungunya virus. Foroderm vaccination was shown to deliver fluorescent, virus-sized beads across the epidermis, with beads subsequently detected in draining lymph nodes. Foroderm vaccination also stimulated the egress of MHC II(+) antigen presenting cells from the skin. Foroderm thus has potential as a simple, cheap, effective, generic, needle-free technology for topical delivery of vaccines.

Synergistic activity of tenofovir and nevirapine combinations released from polycaprolactone matrices for potential enhanced prevention of HIV infection through the vaginal route

Polycaprolactone (PCL) matrices were simultaneously loaded with the antiviral agents, tenofovir (TFV) and nevirapine (NVP), in combination to provide synergistic activity in the prevention of HIV transmission through the vaginal route. TFV and NVP were incorporated in PCL matrices at theoretical loadings of 10%TFV-10% NVP, 5%TFV-5%NVP and 5%TFV-10%NVP, measured with respect to the PCL content of the matrices. Actual TFV loadings ranged from 2.1% to 4.2% equating to loading efficiencies of about 41-42%. The actual loadings of NVP were around half those of TFV (1.2-1.9%), resulting in loading efficiencies ranging from 17.2% to 23.5%. Approximately 80% of the initial content of TFV was released from the PCL matrices into simulated vaginal fluid (SVF) over a period of 30 days, which was almost double the cumulative release of NVP (40-45%). The release kinetics of both antivirals over 30 days were found to be described most satisfactorily by the Higuchi model. In vitro assay of release media containing combinations of TFV and NVP released from PCL matrices confirmed a potential synergistic/additive effect of the released antivirals on HIV-1 infection of HeLa cells. These findings indicate that PCL matrices loaded with combinations of TFV and NVP provide an effective strategy for the sustained vaginal delivery of antivirals with synergistic/additive activity.

Can wastewater-based epidemiology be used to evaluate the health impact of temperature? – An exploratory study in an Australian population

ABSTRACT Ambient temperature is known to have impact on population health but assessing its impact by the traditional cohort approach is resource intensive. Wastewater‐based epidemiology (WBE) could be an alternative for the traditional approach. This study was to provide the first evaluation to see if WBE can be used to assess the impact of temperature exposure to a population in South East Queensland, Australia using selected pharmaceuticals and personal care products (PPCPs) as biomarkers. Daily loads of eight PPCPs in wastewater collected from a wastewater treatment plant were measured from February 2011 to June 2012. Corresponding daily weather data were obtained from the closest weather station. Missing data of PPCPs were handled using the multiple imputation (MI) method, then we used a one‐way between‐groups analysis of variance to examine the seasonal effect on daily variation of PPCPs by seasons. Finally, an MI estimate was performed to evaluate the continuous relationship between daily average temperature and each multiply‐imputed PPCP using time‐series regression analysis. The results indicated that an increase of 1 °C in average temperature associated with decrease at 1.3 g/d (95% CI: −2.2 to (−0.4), p<0.05) for atenolol, increase at 36.5 g/d (95% CI: 25.2–47.8, p<0.01) for acesulfame, and increase at 0.8 g/d (95% CI: 0.02–1.55, p=0.05) for naproxen. No significant association was observed between temperature and the remaining PPCPs, comprising: caffeine, carbamazepine, codeine, hydrochlorothiazide, and salicylic acid. The findings suggested that consumption of sweetened drinks, risk of worsening cardiovascular conditions and pains are associated with variation in ambient temperature. WBE can thus be used as a complementary method to traditional cohort studies in epidemiological evaluation of the association between environmental factors and health outcomes provided that specific biomarkers of such health outcomes can be identified. HighlightsFirst evaluation on health risk of ambient temperature using WBE.Temperatures changes associated with sweetened drinks, cardiovascular conditions and pains.It is possible to use WBE for examining health risks of ambient temperature.More specific biomarkers could improve the applicability of WBE.

Evaluation of Polycaprolactone Matrices for Sustained Vaginal Delivery of Nevirapine in the Prevention of Heterosexual HIV Transmission

Nevirapine (NVP) was loaded in polycaprolactone (PCL) matrices to produce vaginal inserts with the aim of preventing HIV transmission. NVP dispersions in PCL were prepared, at 10% (w/w) theoretical loading, measured with respect to the PCL content of the matrices, in the form of (1) NVP only, (2) a physical mixture of NVP with polyethylene glycol (PEG) 6000 or (c) a solid dispersion (SD) with PEG produced by co-dissolution in ethanol. Characterisation of SD by differential scanning calorimetry and attenuated total reflectance-Fourier transform infrared spectroscopy suggested transformation of the crystalline structure of NVP to an amorphous form which consequently increased the dissolution rate of drug. A low-loading efficiency of 13% was obtained for NVP-loaded matrices and less than 20% for matrices prepared using physical mixtures of drug and PEG. The loading efficiency was improved significantly to around 40% when a 1:4 NVP-PEG SD was used for matrix production. After 30 days, 40% of the drug content was released from NVP-loaded matrices, 55% from matrices containing 1:4 NVP-PEG physical mixtures and 60% from matrices loaded with 1:4 NVP-PEG SDs. The in vitro anti-viral activity of released NVP was assessed using a luciferase reporter gene assay following the infection of HeLa cells with pseudo-typed HIV-1. NVP released from PCL matrices in simulated vaginal fluid retained over 75% anti-HIV activity compared with the non-formulated NVP control. In conclusion, 1:4 NVP-PEG SDs when loaded in PCL matrices increase drug loading efficiency and improve release behaviour.

The fractional laser-induced coagulation zone characterized over time by laser scanning confocal microscopy-A proof of concept study: FRACTIONAL LASER-INDUCED COAGULATION ZONE

Ablative fractional laser (AFXL) is an acknowledged technique to increase uptake of topical agents in skin. Micro thermal ablation zones (MAZs) consist of ablated vertical channels surrounded by a coagulation zone (CZ). Laser scanning confocal microscopy (LSCM) images individual MAZs at 733 nm (reflectance confocal microscopy (RCM)). Further, LSCM can image sodium fluorescein (NaF) fluorescence with 488 nm excitation (fluorescence confocal microcopy (FCM)), a small hydrophilic test molecule (370 MW, log P ‐1.52), which may simulate uptake, bio‐distribution and kinetics of small hydrophilic drugs.

Occurrence of antibiotic residues and antibiotic-resistant bacteria in effluents of pharmaceutical manufacturers and other sources around Hanoi, Vietnam

Pharmaceutical manufacturers in Vietnam are producing a wide variety of antibiotics for human and veterinary use. Consequently, the water discharged from those facilities can contain residues of antibiotics, which could have adverse impact on the environment. However, studies on the occurrence of antibiotics in the wastewater from pharmaceutical manufacturers in Vietnam are almost non-existent. In this study, water samples were collected at around the outlets of four pharmaceutical manufacturing plants as well as from a hospital and an aquaculture farm around Hanoi in 2016 and 2017. Fifteen antibiotics from four major classes (β-lactam, quinolones, macrolides, sulfonamides) were monitored, using a validated LC-MS/MS method, based on their number of registrations at the Ministry of Health. Ten antibiotics, ampicillin, cefuroxime, cefotaxime, clarithromycin, azithromycin, sulfamethoxazole, trimethoprim, ofloxacin, norfloxacin, and ciprofloxacin were detected in the samples at different concentrations. Notably, sulfonamides and quinolones were occasionally detected at very high concentration, such as sulfamethoxazole (252 μg/L), trimethoprim (107 μg/L), ofloxacin (85 μg/L), and ciprofloxacin (41 μg/L). In this study, concentrations of antibiotic residues in effluent of pharmaceutical plants were higher than those from other sources. The antibiotic-resistance tests indicated the widespread resistance to common antibiotics like quinolone and sulfonamides in the collected samples. This finding suggests that wastewater from pharmaceutical manufacturers could be an important source of antibiotics and antibiotic-resistant bacteria in the aquatic environment of Vietnam.

Controlled delivery of the antiprotozoal agent (tinidazole) from intravaginal polymer matrices for treatment of the sexually transmitted infection, trichomoniasis

Abstract Microporous polymeric matrices prepared from poly(ɛ-caprolactone) [PCL] were evaluated for controlled vaginal delivery of the antiprotozoal agent (tinidazole) in the treatment of the sexually transmitted infection, trichomoniasis. The matrices were produced by rapidly cooling co-solutions of PCL and tinidazole in acetone to −80 °C to induce crystallisation and hardening of the polymer. Tinidazole incorporation in the matrices increased from 1.4 to 3.9% (w/w), when the drug concentration in the starting PCL solution was raised from 10 to 20% (w/w), giving rise to drug loading efficiencies up to 20%. Rapid ‘burst release’ of 30% of the tinidazole content was recorded over 24 h when the PCL matrices were immersed in simulated vaginal fluid. Gradual drug release occurred over the next 6 days resulting in delivery of around 50% of the tinidazole load by day 7 with the released drug retaining antiprotozoal activity at levels almost 50% that of the ‘non-formulated’ drug in solution form. Basic modelling predicted that the concentration of tinidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration against Trichomonas vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of antiprotozoal agents in the treatment and prevention of sexually transmitted infections.