Antileishmanial activity, uptake, and biodistribution of an amphotericin B and poly(α-Glutamic Acid) complex.

A noncovalent, water-soluble complex of amphotericin B (AMB) and poly(α-glutamic acid) (PGA), with AMB loadings ranging from 25 to 55% (wt/wt) using PGA with a molecular weight range of 50,000 to 70,000, was prepared as a potential new treatment for visceral leishmaniasis (VL). The AMB-PGA complex was shown to be as active as Fungizone (AMB deoxycholate) against intracellular Leishmania donovani amastigotes in differentiated THP-1 cells. The in vitro uptake of the AMB-PGA complex by differentiated THP-1 cells was similar to that of Fungizone and higher than that of AmBisome (liposomal AMB). The AMB-PGA complex also displayed a dose-response profile similar to that of AmBisome in vivo in BALB/c mice against L. donovani, with 50% effective doses (ED50s) of 0.24 ± 0.03 mg/kg of body weight for the AMB-PGA complex and 0.24 ± 0.06 mg/kg for AmBisome. A biodistribution study with mice indicated that the AMB-PGA complex cleared more rapidly from plasma than AmBisome, with a comparable low level of distribution to the kidneys.

Noncovalent complexation of amphotericin-B with Poly(α-glutamic acid).

A noncovalent complex of amphotericin B (AmB) and poly(α-glutamic acid) (PGA) was prepared to develop a safe and stable formulation for the treatment of leishmaniasis. The loading of AmB in the complex was in the range of ∼20-50%. AmB was in a highly aggregated state with an aggregation ratio often above 2.0. This complex (AmB-PGA) was shown to be stable and to have reduced toxicity to human red blood cells and KB cells compared to the parent compound; cell viability was not affected at an AmB concentration as high as 50 and 200 µg/mL respectively. This AmB-PGA complex retained AmB activity against intracellular Leishmania major amastigotes in the differentiated THP-1 cells with an EC50 of 0.07 ± 0.03-0.08 ± 0.01 µg/mL, which is similar to Fungizone (EC50 of 0.06 ± 0.01 µg/mL). The in vitro antileishmanial activity of the complex against Leishmania donovani was retained after storage at 37 °C for 7 days in the form of a solution (EC50 of 0.27 ± 0.03 to 0.35 ± 0.04 µg/mL) and for 30 days as a solid (EC50 of 0.41 ± 0.07 to 0.63 ± 0.25 µg/mL). These encouraging results indicate that the AmB-PGA complex has the potential for further development.

Recent advances in development of amphotericin B formulations for the treatment of visceral leishmaniasis.

PURPOSE OF REVIEW: Amphotericin B (AmpB) is considered the first-line treatment for visceral leishmaniasis in areas in which resistance to antimony is prevalent. This review describes recent advances in clinically available and novel drug delivery systems of AmpB to treat visceral leishmaniasis. RECENT FINDINGS: Over the past two decades, lipid-based AmpB formulations developed to tackle the toxicity of AmpB have been used clinically for the treatment of visceral leishmaniasis. Liposomal AmpB (AmBisome) has been the most successful lipid formulation, and recent clinical studies on visceral leishmaniasis have shown the potential of single-dose AmBisome treatment as well as its use in short course combinations with other antileishmanial drugs. Current research is focussed on the development of more stable and affordable nonlipid formulations of AmpB. Although a diverse range of nonlipid-based AmpB formulations have been evaluated, none have yet reached the clinic. SUMMARY: Liposomal AmpB (AmBisome) has become a standard treatment, by intravenous infusion, for visceral leishmaniasis and the basis for new short course treatments. There have been extensive efforts to develop new AmpB formulations on the basis of polymers, lipids or physical aggregates of AmpB to replace the costly lipid-based formulations. However, no nonlipid-based AmpB delivery systems have yet reached the clinic.

The control of conjunctival fibrosis as a paradigm for the prevention of ocular fibrosis-related blindness. "Fibrosis has many friends".

The processes involved in ocular fibrosis after disease or ocular tissue injury, including surgery play an important part in the development or failure of treatment of most blinding diseases. Ocular fibrosis is one of the biggest areas of unmet need in ophthalmology. Effective anti-scarring therapies could potentially revolutionise the management of many diseases like glaucoma worldwide. The response of a quiescent or activated conjunctiva to glaucoma surgery and aqueous flow with different stimulatory components and the response to different interventions and future therapeutics is a paradigm for scarring prevention in other parts of the eye and orbit. Evolution in our understanding of molecular and cellular mechanisms in ocular fibrosis is leading to the introduction of new and re-purposed therapeutic agents, targeting a wide range of key processes. This review provides current and futures perspectives on different approaches to conjunctival fibrosis following glaucoma surgery and highlights the challenges faced in implementing these therapies with maximal effect and minimal side effects.

Narrow Molecular Weight Distribution Precursors for Polymer-Drug Conjugates.

Atom transfer polymerization has been used to prepare a narrow molecular weight distribution (MWD), active ester homopolymer that acted as a precursor to prepare families of narrow MWD polymer-drug conjugates during preclinical studies.

New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery.

Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery. The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications. A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets. These include transforming factor ß, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases. While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects.

Modulation of wound healing during and after glaucoma surgery.

Following all types of glaucoma filtration surgery (GFS), scarring still poses the major threat to long-term success. The healing and scarring determine the percentage of patients achieving low final intraocular pressures (IOPs) that are associated with virtually no glaucoma progression. The use of antifibrotic agents to inhibit scarring of trabeculectomy blebs is now a well-established clinical practice. Unfortunately, severe complications such as leakage, infection, hypotony, and endophthalmitis with complete loss of vision may occur. In addition, surgery still fails in some individuals despite maximal doses of current antifibrotics. Better therapeutic agents are needed. Many promising new agents are being evaluated clinically and in vitro. In this chapter, we will discuss our current understanding of the wound healing process after glaucoma surgery and promising new treatment modalities.

The molecular interactions that influence the plasticizer dependent dissolution of acrylic polymer films.

Poly(methacrylic acid-methyl methacrylate, 1:2) (Eudragit S) is a commonly used pH-responsive polymer that can facilitate delivery to the ileo-colonic region of the gastrointestinal tract. Different plasticizers have been used to reduce the brittleness of Eudragit S films for the coating of solid dosage forms. To better correlate the dissolution rates of Eudragit S films, we have examined their dielectric response to understand the specific polymer-plasticizer interactions. Solvent cast Eudragit S films were prepared with one of four citrate plasticizers ranging from low to moderate aqueous solubility. Film dissolution was determined using a two-compartment permeation cell. Dielectric properties were measured by thermally stimulated depolarisation currents (TSDC). Secondary relaxations were deconvoluted and identified. The glass transition temperature (T(g)) was measured using TSDC, differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). Dissolution of the films was influenced by the solubility and structure of the plasticizers. While no correlation was found among the T(g)'s obtained by TSDC, DSC, and DMA with dissolution time, the low temperature TSDC spectra showed a relationship of the total secondary relaxation area and relaxation of the carboxylic acid functional group with dissolution time. Dielectric secondary relaxations may be a good probe to predict plasticizer influence on dissolution of Eudragit S polymer films.