Leishmaniasis and itraconazole: a controlled clinical trial on cutaneous subtypes

Ten patients each with the nodular and ulcerative forms of cutaneous leishmaniasis were selected by clinical and pathological criteria. Capsule itraconazole was given in a daily dose of 4 mg per kg body weight (max. 200 mg) for 6 weeks. Six patients (60.0%) of the nodular and nine patients (90.0%) of the ulcerative subgroups were cured by strict clinical and parasitological criteria. No major adverse effects were noted. Review after 6 months revealed no recurrences. In another ten patients (control group) not receiving any drug, the lesions showed no significant change except for one patient demonstrating spontaneous remission. Thus, itraconazole has a promising antileishmanial potential in India.     

Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell

Topical drug delivery against cutaneous leishmaniasis (CL) signifies an effective alternate for improving the availability and reducing the toxicity associated with the parenteral administration of conventional sodium stibogluconate (SSG) injection. The basic aim of the study was to develop nano-deformable liposomes (NDLs) for the dermal delivery of SSG against CL. NDLs were formulated by a modified thin film hydration method and optimized via Box–Behnken statistical design. The physicochemical properties of SSG-NDLs were established in terms of vesicle size (195.1?nm), polydispersity index (0.158), zeta potential (?32.8?mV), and entrapment efficiency (35.26%). Moreover, deformability index, in vitro release, and macrophage uptake studies were also accomplished. SSG-NDLs were entrapped within Carbopol gel network for the ease of skin application. The ex vivo skin permeation study revealed that SSG-NDLs gel provided 10-fold higher skin retention towards the deeper skin layers, attained without use of classical permeation enhancers. Moreover, in vivo skin irritation and histopathological studies verified safety of the topically applied formulation. Interestingly, the cytotoxic potential of SSG-NDLs (1.3?mg/ml) was higher than plain SSG (1.65?mg/ml). The anti-leishmanial activity on intramacrophage amastigote model of Leishmania tropica showed that IC₅₀ value of the SSG-NDLs was?～?fourfold lower than the plain drug solution with marked increase in the selectivity index. The in vivo results displayed higher anti-leishmanial activity by efficiently healing lesion and successfully reducing parasite burden. Concisely, the outcomes indicated that the targeted delivery of SSG could be accomplished by using topically applied NDLs for the effective treatment of CL.     

Triglyceride-coated nanoparticles: Skin toxicity and effect of UV/IR irradiation on them

Triglyceride (TG) is an important compound on the skin, produced by sebaceous glands, and may change cytotoxicity of different nanoparticles. To date, there is no report about toxicity of nanoparticles coated with TG. On the other hand, the use of ultraviolet (UV) and infrared (IR) with nanoparticles changes nanoparticle cytotoxicity. The combination of nanoparticles with UV or IR is applicable, because it may be used for treatment or detection of local cancers, surface microbial infections and other skin diseases. In this study, different nanoparticles including titanium dioxide, zinc oxide, magnesium oxide, silver, gold, and TG-coated form of these nanoparticles, were added to suspensions of Balb/c skin cells, and then incubated for 24 h at 37 °C. Additionally, TG-coated nanoparticles were treated with UV and IR irradiation for 1 h. Different methods were applied for evaluation of cytotoxicity, including 5-diphenyl-tetrazolium bromide assay, lactate dehydrogenase (LDH) assay, cell metabolic assay, ATP assay, and reactive oxygen species (ROS) generation assay. This research showed that TG-coated nanoparticles had less LDH release and ROS generation with higher cell viability, cell metabolic activity, and ATP level, compared with pristine nanoparticles. In contrast, the combination of UV and IR with TG-coated nanoparticles led to higher LDH release and ROS generation with less cell viability, cell metabolic activity, and ATP level, in comparison with pristine nanoparticles. Overall, pristine metal nanoparticles without irradiation had higher cytotoxicity than metal oxide nanoparticles.     

Evaluation of sodium stibogluconate in the treatment of cutaneous leishmaniasis in Syria

Summary

A series of 31 patients presenting with skin lcsions with positive stnears for leishmania parasites were treated with sodium stibogluconate (each ml of injection containing the equivalent of 100?mg pentavalent antimony). The drug was administered either intramuscularly at a dosage of 6 ml daily for at least 10 days or infiltrated around the lesion (maximum 2 ml per lesion) at weekly intervals for 3 to 4 consecutive weeks. Twenty-four (77%) of the patients were assessed as showing a successful response, with parasites absent from the smear and the lesions healing at the end of treatment. Poor results, however, were reported in 5 of the 16 patients treated solely by infiltration. Follow-up of n few patients at 3 months showed that the healing process was prompt and little disfiguration was produced, lesions on the trunk tending to heal more quickly than those on the face.     

Drug delivery systems for the topical treatment of cutaneous leishmaniasis

Introduction: The parenteral administration of pentavalent antimonials for the treatment of all forms of leishmaniasis, including cutaneous leishamniasis (CL), has several limitations. Therapy is long, requiring repeated doses and the adverse reactions are frequent. Topical treatment is an attractive alternative for CL, offering significant advantages over systemic therapy: fewer adverse effects, ease of administration, and lower costs.

Areas covered: This review covers, from 1984 to the present, the progress achieved for the development of topical treatment for CL, using different drugs such as paromomycin (PA), imiquimod, amphotericin B (AmB), miltefosine, and buparvaquone. PA is the most commonly studied drug, followed by AmB and Imiquimod. These drugs were incorporated in conventional dosage forms or loaded in lipid nanocarries, which have been used mainly for improved skin delivery and antileishmanial activity.

Expert opinion: Developing an effective topical treatment for CL using these antileishmanial drugs still remains a great challenge. Insights into the most promising delivery strategies to improve treatment of CL with PA and AmB using conventional dosage forms, lipid nanocarriers, and combined therapy are presented and discussed. The results obtained with combined therapy and alternative delivery systems are promising perspectives for improving topical treatment of CL.     

Nanoparticles as multifunctional devices for the topical treatment of cutaneous leishmaniasis

Introduction: Cutaneous and mucocutaneous leishmaniasis are major tropical skin diseases. Topical treatment is currently limited to the least severe forms of cutaneous leishmaniasis (CL) without risk of dissemination. It is also recommended in combination with systemic therapy for more severe forms. Progresses in this modality of treatment are hindered by the heterogeneity of the disease and shortcomings in the clinical trials.

Areas covered: This review overlooks three major modalities of topical therapies in use or under investigation against CL: chemotherapy, photodynamic therapy and immunotherapy; either with older compounds such as paramomycin or more recent nitric oxide donors, antimicrobial peptides or silver derivatives. The advantages and limitations of their administration with newer formulation strategies such as nanoparticles (NPs) are discussed.

Expert opinion: The efficacy of a topical treatment against CL depends not only on the intrinsic antileishmanial activity of the drug but also on the amount of drug available in the dermis. NPs as sustained release systems and permeation enhancers could favour the creation of a drug reservoir in the dermis. Additionally, certain NPs have immunomodulatory properties or wound healing capabilities of benefit in CL treatment. Pending task is the selective delivery of active compounds to intracellular amastigotes, because even small NPs are unable to penetrate deeply into the skin to encounter infected macrophages (except in ulcerative lesions).     

Clinical status of agents being developed for leishmaniasis

Leishmaniasis, which exists in both visceral and cutaneous forms, is currently treated with intramuscular antimony or intravenous amphotericin B. The primary unmet need is for oral therapy. Of the several drugs in clinical development, miltefosine is unique in being an oral agent with efficacy against both forms of the disease. Sitamaquine is an oral agent with substantial but not sufficient efficacy against visceral disease. Oral fluconazole has been shown to be more effective than placebo in one instance: for Leishmania major cutaneous disease from Saudi Arabia. Paromomycin is in widespread trial. Topical paromomycin formulations are being tested for cutaneous disease, and intramuscular paromomycin is in Phase III trial for Indian visceral disease. The most likely replacements for present therapy are oral miltefosine for many of the visceral and cutaneous syndromes, intramuscular paromomycin for visceral disease and topical paromomycin for some forms of cutaneous disease.     

Mixed formulation of conventional and pegylated liposomes as a novel drug delivery strategy for improved treatment of visceral leishmaniasis

Objective: Test the hypothesis that pegylated meglumine antimoniate-containing liposomes (LMA) and their mixture with non-pegylated (conventional) LMA may be more effective than conventional LMA against visceral leishmaniasis (VL), because of wider drug distribution among different mononuclear phagocyte system (MPS) tissues.

Methods: Sb was determined in the blood and MPS tissues after administration of pegylated or conventional LMA intravenously to mongrel dogs naturally infected with Leishmania infantum and Swiss mice. Pegylated and conventional LMA as well as their mixture were evaluated for their antileishmanial efficacy in BALB/c infected with L. infantum through determination of parasite load in liver, spleen and bone marrow.

Results: An improved targeting of Sb to the bone marrow of dogs was clearly evidenced, as an important impact of pegylation. In accordance with this data, pegylated LMA significantly reduced parasite load in bone marrow of infected mice, in contrast to conventional LMA. The mixed formulation of conventional and pegylated LMA promoted parasite suppression to a higher extent in both spleen and bone marrow, compared to pegylated or conventional LMA.

Conclusions: The present work establishes for the first time the potential of mixed formulations of conventional and pegylated liposomes as a drug delivery strategy for improved treatment of VL.     

Dual agents loaded PLGA nanoparticles: Systematic study of particle size and drug entrapment efficiency

PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and quercetin (QC) were prepared via O/W emulsion solvent evaporation. Six independent processing parameters and PLGA characteristics were assessed systematically to enhance the incorporation of the dual agents with different properties (VCR and QC, hydrophilic and hydrophobic molecule, respectively) into PLGA nanoparticles and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and the controlling of particle size included the influence of the molecular weight (MW) of PLGA and the lactide-to-glycolide (L:G) ratio of PLGA, PLGA concentration, PVA concentration, initial QC content, acetone-to-dichloromethane (A/D) volume ratio, aqueous phase pH and aqueous to organic phase (W/O) volume ratio. The nanoparticles produced by optimal formulation were submicron size (139.5+/-4.3 nm, n=3) with low polydispersity index (0.095+/-0.031, n=3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined by high performance liquid chromatography (HPLC) by ultracentrifuge method were 92.84+/-3.37% for VCR and 32.66+/-2.92% for QC (n=3). The drug loadings were 0.0037+/-0.0001% for VCR and 1.36+/-0.12% for QC (n=3).     

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis

Objective: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL).

Methods: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy.

Results: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system.

Conclusions: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.     

Characterization of the size,shape, and state of dispersion of nanoparticles for toxicological studies

This paper describes the issues relating to the measurement of nanoparticle size, shape and dispersion when evaluating the toxicity of nanoparticles. Complete characterization of these materials includes much more than size, size distribution and shape; nonetheless, these attributes are usually the essential foundation. The measurement of particle size, particularly at scales of 100 nm or less, can be challenging under the best of conditions. Measurements that are routine in the laboratory setting become even more difficult when made under the physiological conditions relevant to toxicity studies, where the environment of the particles can be quite complex. Passive and active cellular responses, as well as the presence of a variety of nano-scale biological structures, often complicate the collection and interpretation of size and shape data. In this paper, we highlight several of the common issues faced when characterizing nanoparticles for toxicity testing and suggest general protocols to address these problems.     

Ecotoxicity of engineered nanoparticles to aquatic invertebrates: a brief review and recommendations for future toxicity testing

Based on a literature review and an overview of toxic effects of engineered nanoparticles in aquatic invertebrates, this paper proposes a number of recommendations for the developing field of nanoecotoxicology by highlighting the importance of invertebrates as sensitive and relevant test organisms. Results show that there is a pronounced lack of data in this field (less than 20 peer-reviewed papers are published so far), and the most frequently tested engineered nanoparticles in invertebrate tests are C(60), carbon nanotubes, and titanium dioxide. In addition, the majority of the studies have used Daphnia magna as the test organism. To date, the limited number of studies has indicated acute toxicity in the low mg l(-1) range and higher of engineered nanoparticles to aquatic invertebrates, although some indications of chronic toxicity and behavioral changes have also been described at concentrations in the high microg l(-1) range. Nanoparticles have also been found to act as contaminant carriers of co-existing contaminants and this interaction has altered the toxicity of specific chemicals towards D. magna. We recommend that invertebrate testing is used to advance the level of knowledge in nanoecotoxicology through standardized short-term (lethality) tests with invertebrates as a basis for investigating behaviour and bioavailability of engineered nanoparticles in the aquatic environment. Based on this literature review, we further recommend that research is directed towards invertebrate tests employing long-term low exposure with chronic endpoints along with more research in bioaccumulation of engineered nanoparticles in aquatic invertebrates.     

Chitosan-based macrophage-mediated drug targeting for the treatment of experimental visceral leishmaniasis

The potential of chitosan microparticles as a carrier of doxorubicin for the treatment of visceral leishmaniasis was evaluated by macrophage-mediated drug targeting approach. Cationic charge of doxorubicin was masked by complexing it with dextran sulphate (a poly anion) in order to facilitate its incorporation into cationic chitosan microparticles. Prior to in vitro and in vivo studies, characterization studies were carried out systematically: particle size (～1.049?µm), surface morphology (fluorescence microscopy – spherical structured microparticles), Fourier transform infrared spectroscopy (to characterize effective cross-linking) and differential scanning calorimetry. In vitro studies were carried out in J774.1 in order to check the effective endocytotic uptake of microparticles by macrophages. In vivo studies were conducted in Syrian golden hamsters as per well-established protocols and the results drawn from in vivo studies displayed substantial reduction in leishmanial parasite load for doxorubicin-encapsulated chitosan microparticles: ～78.2?±?10.4%, when compared to the control (free doxorubicin): 33.3?±?2.4%.     

A drug safety evaluation of mogamulizumab for the treatment of cutaneous T-Cell lymphoma

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states’ varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease.

Areas covered: The authors discuss basic information about CTCL and mogamulizumab’s mechanism of action. Then, the authors discuss the agent’s efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL.

Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.     

Polymeric colloidal particulate systems: intelligent tools for intracellular targeting of antileishmanial cargos

Introduction: Targeted cargo delivery systems can overcome drawbacks associated with antileishmanials delivery, by defeating challenges of physiological barriers. Various colloidal particulate systems have been developed in the past; few of them even achieved success in the market, but still are limited in some ways.

Areas covered: This review is focused on the pathobiology of leishmaniasis, interactions of particulate systems with biological environment, targeting strategies along with current conventional and vaccine therapies with special emphasis on polymeric nanotechnology for effective antileishmanial cargo delivery.

Expert opinion: The problems concerned with limited accessibility of chemotherapeutic cargos in conventional modes to Leishmania-harboring macrophages, their toxicity, and resistant parasitic strain development can be sorted out through target-specific delivery of cargos. Vaccination is another therapeutic approach employing antigen alone or adjuvant combinations delivered by means of a carrier, and can provide preventive measures against human leishmaniasis (HL). Therefore, there is an urgent need of designing site-specific antileishmanial cargo carriers for safe and effective management of HL. Among various colloidal carriers, polymeric particulate systems hold tremendous potential as an effective delivery tool by providing control over spatial and temporal distribution of cargos after systemic or localized administration along with enhancing their stability profile at a comparatively cost-effective price leading to improved chances of commercial applicability.     

肝靶向阿柔比星A聚氰基丙烯酸异丁酯毫微粒药物动力学研究

为提高阿柔比星（aclarubicin A,ACRA)体内抗肝癌效果,降低其对正常组织器官的毒副作用,以氰基丙烯酸异丁酯（isobutylcyanoacrylate,IBC)为载体材料,制备出肝靶向阿柔比星A聚氰基丙烯酸异丁酯毫微粒（aclarubicin A polyisobutylcyanoacrylate nonopaticles,ACR-IBC-NP),以3H－ACR A为示踪物,采用液体闪烁计数技术研究了ACR－IBC－NP灌胃与尾静脉注射两种给药途径在小鼠血液及靶器官肝脏中的药物动力学规律,结果表明,灌胃给药时ACR－IBC－NP在血液与肝脏中的药时数据均可以用血管外给药的二室模型描述：尾静脉注射给药时ACR－IBC－NP在血液与肝脏中的药时数据虽然可以分别用二室模型与血管外给药的二室模型进行较好地描述,但是,靶向至肝脏的ACR－IBC－NP作为药物储库,使血液中药时曲线出现双峰,常规药物动力学模型均不能很好地拟合,提示具靶向缓释特点的药物传输系统的药物动力学模型有待进一步研究,ACR－IBC－NP的体内过程表明,ACR－IBC－NP在尾静脉注与灌胃两种给药途径时均具有肝靶向作用与缓释作用,以靶向效率（targeting efficiency,TE;TE=AUC靶器官／AUC血液）为指标评价ACR0－IBC－NP的靶向效果,尾静脉注射与灌胃两种给药途径的TE分别是14．41与28．47,灌胃给药时,ACR－IBC－NP的绝对生物利用度为38．53％,由于靶向药物传输系统希望靶器官药物浓度水平与维持时间适宜,作者认为,血管外给药时,靶器官中药物的利用速度与程度应该作为靶向药物传输系统的重要质量参数,参考常规的药物生物利用度概念,作者首次定义靶器官生物利用率（F）按下式计算,F靶器官＝AUC靶器官,血管外给药／AUC靶器官,静脉给药×100％,得出ACR－IBC－NP灌胃给药的靶器官生物利用为76．01％。     

Seek and destroy: improving PK/PD profiles of anticancer agents with nanoparticles

Introduction: The Pharmacokinetics/pharmacodynamics (PK/PD) relationships with cytotoxics are usually based on a steepening concentration–effect relationship; the greater the drug amount, the greater the effect. The Maximum Tolerated Dose paradigm, finding the balance between efficacy, while keeping toxicities at their manageable level, has been the rule of thumb for the last 50-years. Developing nanodrugs is an appealing strategy to help broaden this therapeutic window. The fact that efficacy and toxicity with cytotoxics are intricately linked is primarily due to the complete lack of specificity toward the tumor tissue during their distribution phase. Because nanoparticles are expected to better target tumor tissue while sparing healthy cells, accumulating large amounts of cytotoxics in tumors could be achieved in a safer way.

Areas covered: This review aims at presenting how nanodrugs present unique features leading to reconsidering PK/PD relationships of anticancer agents.

Expert commentary: The constant interplay between carrier PK, interactions with cancer cells, payload release, payload PK, target expression and target engagement, makes picturing the exact PK/PD relationships of nanodrugs particularly challenging. However, those improved PK/PD relationships now make the once contradictory higher efficacy and lower toxicities requirement an achievable goal in cancer patients.