Developmental toxicity studies of lumefantrine and artemether in rats and rabbits

The combination of artemether plus lumefantrine is a type of artemisinin‐based combination therapy (ACT) recommended by the World Health Organization for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity in animals (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin, and artemether. Before recommending ACTs for use in the first trimester, the World Health Organization has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo‐fetal development studies of artemether alone, lumefantrine alone, and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no‐effect levels for lumefantrine were 300 mg/kg/day in rats (based on a 25% decrease in litter size at 1000 mg/kg/day) and 1000 mg/kg/day in rabbits. The calculated safety margins based on human equivalent dose and plasma C_max and AUC values were in the range of 2.5‐ to 17‐fold. The developmental no‐effect levels for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. Lumefantrine caused no teratogenicity and was not a potent embryotoxin in rats and rabbits. Expected artemisinin‐like findings were seen with artemether alone and with artemether/lumefantrine combined except that no malformations were observed. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether–lumefantrine in the first trimester compared to other ACTs.     

Formulation and characterization of nanoliposomal 5-fluorouracil for cancer nanotherapy

A scalable and safe method was developed to prepare nanoliposome carriers for the entrapment and delivery of 5-fluorouracil (5-FU). The carrier systems were composed of endogenously occurring dipalmitoylphosphatidylcholine (DPPC), negatively charged dicetylphosphate (DCP), cholesterol (CHOL) and glycerol (3%, v/v). Nanoliposomes were prepared by the heating method in which no harmful chemical or procedure is involved. Results indicated fast and reproducible formation of non-toxic liposomes that possess high entrapment efficiency (up to 96.9%) and vesicle size range of ca. 530–620?nm. Transmission electron and optical micrographs of the 5-FU liposomes revealed that they were spherical and some were multilayered. There was an increase in the release rate of 5-FU from the liposomes prepared with a high ratio of drug:lipid. The release data showed that the highest release rates were obtained for nanoliposomes containing 5-FU with the drug concentration of 500?mM and that it followed the diffusion model. Nanoliposome preparation method introduced here has the potential of large-scale manufacture of safe and efficient carriers of 5-FU.     

Development of Spray Dried Liposomal Dry Powder Inhaler of Dapsone

This investigation was undertaken to evaluate practical feasibility of site specific pulmonary delivery of liposomal encapsulated Dapsone (DS) dry powder inhaler for prolonged drug retention in lungs as an effective alternative in prevention of Pneumocystis carinii pneumonia (PCP) associated with immunocompromised patients. DS encapsulated liposomes were prepared by thin film evaporation technique and resultant liposomal dispersion was passed through high pressure homogenizer. DS nano-liposomes (NLs) were separated by ultra centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different carriers like lactose, sucrose, and hydrolyzed gelatin, and 15% l-leucine as antiadherent. The resultant dispersion was spray dried and spray dried formulation were characterized to ascertain its performance. In vitro pulmonary deposition was assessed using Andersen Cascade Impactor as per USP. NLs were found to have average size of 137 ± 15 nm, 95.17 ± 3.43% drug entrapment, and zeta potential of 0.8314 ± 0.0827 mV. Hydrolyzed gelatin based formulation was found to have low density, good flowability, particle size of 7.9 ± 1.1 μm, maximum fine particle fraction (FPF) of 75.6 ± 1.6%, mean mass aerodynamic diameter (MMAD) 2.2 ± 0.1 μm, and geometric standard deviation (GSD) 2.3 ± 0.1. Developed formulations were found to have in vitro prolonged drug release up to 16 h, and obeys Higuchi's Controlled Release model. The investigation provides a practical approach for direct delivery of DS encapsulated in NLs for site specific controlled and prolonged release behavior at the site of action and hence, may play a promising role in prevention of PCP.     

Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: formulation,optimization, evaluation and permeation studies

Zolmitriptan is the drug of choice for migraine, but low oral bioavailability (<50%) and recurrence of migraine lead to frequent dosing and increase in associated side effects. Increase in the residence time of drug at the site of drug absorption along with direct nose to brain targeting of zolmitriptan can be a solution to the existing problems. Hence, in the present investigation, thermoreversible intranasal gel of zolmitriptan-loaded nanoethosomes was formulated by using mucoadhesive polymers to increase the residence of the drug into the nasal cavity. The preparation of ethosomes was optimized by using 3² factorial design for percent drug entrapment efficiency, vesicle size, zeta potential, and polydispersity index. Optimized formulation E6 showed the vesicle size (171.67?nm) and entrapment efficiency (66%) when compared with the other formulations. Thermoreversible gels prepared by using poloxamer 407 showed the phase transition temperature at 32–33?°C which was in line with the nasal physiological temperature. The optimized ethosomes were loaded into the thermoreversible mucoadhesive gel optimized by varying concentrations of poloxamer 407, carbopol 934, HPMC K100, and evaluated for gel strength, gelation temperature, mucoadhesive strength, in vitro drug release, and ex vivo drug permeation, where G3 and G6 were found to be optimized formulations. In vitro drug release was studied by different kinetic models suggested that G3 (n?=?0.582) and G6 (n?=?0.648) showed Korsemeyer–Peppas (K_KP) model indicating non-Fickian release profiles. A permeation coefficient of 5.92 and 5.9?µg/cm² for G3 and G6, respectively, revealed very little difference in release rate after 24?h between both the formulations. Non-toxic nature of the gels on columnar epithelial cells was confirmed by histopathological evaluation.     

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

ABSTRACT: BACKGROUND: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. METHODS: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. RESULTS: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately fourfold higher apparent volume of distribution for dihydroartemisinin was obtained by noncompartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. CONCLUSION: The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.     

Towards a proteomic definition of CoArtem action in Plasmodium falciparum malaria

We have adopted a proteomic strategy to investigate the actions of the two active components of the new antimalarial CoArtem, artemether and lumefantrine, following pharmacologically relevant drug exposure in the human malaria parasite Plasmodium falciparum. Both drugs induced profound alterations in the parasite's proteome. Moreover, the pattern of proteome alteration was specific for the drug used. The two drugs induced opposing effects on key glycolytic enzymes while exerting similar influence of the expression of stress response proteins. These initial results demonstrate the power of this approach in the study of pleiomorphic mechanisms of drug action.     

Management of malaria in Thailand

The purpose of treatment for uncomplicated malaria is to produce a radical cure using the combination of: artesunate (4 mg/kg/day) plus mefloquine (8 mg/kg day) for 3 days: a fixed dose of artemether and lumefantrine (20/120 mg tablet) named Coartem (4 tablets twice a day for three days for adults weighing more than 35 kg): quinine 10 mg/kg 8-hourly plus tetracycline 250 mg 6-hourly for 7 days (or doxycycline 200 mg as an alternative to tetracycline once a day for 7 days) in patients aged 8 years and over: Malarone (in adult 4 tablets daily for 3 days). In treating severe malaria, early diagnosis and treatment with a potent antimalarial drug is recommended to save the patient's life. The antimalarial drugs of choice are: intravenous quinine or a parenteral form of an artemisinin derivative (artesunate i.v./i.m. for 2.4 mg/kg followed by 1.2 mg/kg injection at 12 and 24 hr and then daily for 5 dayss; artemether i.m. 3.2 mg/kg injection followed by 1.6 mg/kg at 12 and 24 hrs and then daily for 5 days; artemether i.m. (Artemotil) with the same dose of artemether or artesunate suppository (5 mg/kg) given rectally 12 hourly for 3 days. Oral artemisinin derivatives (artesunate, artemether, and dihydroartemisinin with 4 mg/kg/day) could replace parenteral forms when patients can tolerate oral medication. Oral mefloquine (25 mg/kg divided into two doses 8 hrs apart) should be given at the end of the artemisinin treatment course to reduce recrudescence.     

Nano-liposomal dry powder inhaler of tacrolimus: preparation, characterization, and pulmonary pharmacokinetics

The studies were undertaken to evaluate feasibility of pulmonary delivery of liposomaly encapsulated tacrolimus dry powder inhaler for prolonged drug retention in lungs as rescue therapy to prevent refractory rejection of lungs after transplantation. Tacrolimus encapsulated liposomes were prepared by thin film evaporation technique and liposomal dispersion was passed through high pressure homogenizer. Tacrolimus nano-liposomes (NLs) were separated by centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different additives like lactose, sucrose, and trehalose, and L-leucine as antiadherent. The dispersion was spray dried and spray dried powders were characterized. In vitro and in vivo pulmonary deposition was performed using Andersen Cascade Impactor and intratracheal instillation in rats respectively. NLs were found to have average size of 140 nm, 96% +/- 1.5% drug entrapment, and zeta potential of 1.107 mV. Trehalose based formulation was found to have low density, good flowability, particle size of 9.46 +/- 0.8 microm, maximum fine particle fraction (FPF) of 71.1 +/- 2.5%, mean mass aerodynamic diameter (MMAD) 2.2 +/- 0.1 microm, and geometric standard deviation (GSD) 1.7 +/- 0.2. Developed formulations were found to have in vitro prolonged drug release up to 18 hours, following Higuchi's Controlled Release model. In vivo studies revealed maximal residence of tacrolimus within lungs of 24 hours, suggesting slow clearance from the lungs. The investigation provides a practical approach for direct delivery of tacrolimus encapsulated in NLs for controlled and prolonged retention at the site of action. It may play a promising role as rescue therapy in reducing the risk of acute rejection and chronic rejection.     

Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis

The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-α-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32?±?0.23 and 2.69?±?0.13?µm, respectively. Zeta potential of cationic liposomes was higher (30.38?±?0.3 mV), as compared to mannosylated liposomes (17.7?±?0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7%?±?3.1 and 41.9%?±?2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani–infected golden hamster, and results revealed that Amp B solution was reduced by 42.5?±?1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1?±?1.5 and 61.2?±?3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8?±?3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug.     

Design and evaluation of proniosomes as a carrier for ocular delivery of lomefloxacin HCl

The current investigation aims to develop and evaluate novel ocular proniosomal gels of lomefloxacin HCl (LXN); in order to improve its ocular bioavailability for the management of bacterial conjunctivitis. Proniosomes were prepared using different types of nonionic surfactants solely and as mixtures with Span 60. The formed gels were characterized for entrapment efficiency, vesicle size, and in vitro drug release. Only Span 60 was able to form stable LXN-proniosomal gel when used individually while the other surfactants formed gels only in combination with Span 60 at different ratios. The optimum proniosomal gel; P-LXN 7 (Span 60:Tween 60, 9:1) appeared as spherical shaped vesicles having high entrapment efficiency (>80%), appropriate vesicle size (187?nm) as well as controlled drug release over 12?h. Differential scanning calorimetry confirmed the amorphous nature of LXN within the vesicles. Stability study did not show any significant changes in entrapment efficiency or vesicle size after storage for 3 months at 4?°C. P-LXN 7 was found to be safe and suitable for ocular delivery as proven by the irritancy test. The antibacterial activity of P-LXN 7 evaluated using the susceptibility test and topical therapy of induced ocular conjunctivitis confirmed the enhanced antibacterial therapeutic efficacy of the LXN-proniosomal gel compared to the commercially available LXN eye drops.     

Dextrose modified bilosomes for peroral delivery: improved therapeutic potential and stability of silymarin in diethylnitrosamine-induced hepatic carcinoma in rats

Abstract

Hepatic carcinoma (HC) is one of the most prevalent cancers, ranked as the second most common cause of cancer-related deaths worldwide. Silymarin (SYL) has been reported for its anticarcinogenic activity against various types of cancer such as prostate, breast, ovary, colon, lung, bladder and liver. Due to poor solubility and low bioavailability SYL lacks satisfactory therapeutic value thus designing a suitable and effective delivery system of SYL can led to improved therapeutic potential. The present study was aimed to develop SYL-loaded dextrose (DEX) modified bilosomes for targeted delivery to HC cells. The DEX-modified bilosomes were prepared through thin-film hydration method and optimized employing Box Behnken design. The bilosomes were evaluated for percent entrapment, drug loading, in vitro release and cytotoxicity on Hep-G2 cells. The optimized DEX-SYL-BL exhibited a particle size of 219.3?±?2.99?nm, percent entrapment of 62.32?±?4.23%, drug loading of 34.56?±?1.23% and 84.96?±?2.76% drug release respectively over a period of 24?hr. The stability of bilosomes was ascertained in simulated gastric and intestinal fluids. Cytotoxicity studies revealed greater performance of DEX-SYL-BL in terms of reduced viability in Hep-G2 cell lines when compared with pure SYL and SYL-BL. Further DEX-modified bilosomes were evaluated in vivo for their therapeutic efficacy in DEN-induced (Diethylnitrosamine) hepatic carcinoma in animal model. The DEX-SYL-BL displayed higher therapeutic potential as revealed from enhanced survival and reduced tumour burden in animals. DEX-SYL-BL also displayed significant restoration of altered oxidative markers and SGOT, SGPT levels towards normal value when compared with pure SYL.     

Nanoliposomes protect against AL amyloid light chain protein-induced endothelial injury

Context: A newly-recognized pathogenic mechanism underlying light chain amyloidosis (AL) involves endothelial dysfunction and cell injury caused by misfolded light chain proteins (LC). Nanoliposomes (NL) are artificial phospholipid vesicles that could attach to misfolded proteins and reduce tissue injury.

Objective: To test whether co-treatment with NL reduces LC-induced endothelial dysfunction and cell death.

Methods: Abdominal subcutaneous adipose arterioles from 14 non-AL subjects were cannulated; dilator response to acetylcholine and papaverine were measured at baseline and following 1-hour exposure to LC (20?µg/mL, 2 purified from AL subjects’ urine, 1 from human recombinant LC [AL-09])?±?NL (phosphatidylcholine/cholesterol/phosphatidic acid 70/25/5 molar ratio) or NL alone. Human aortic artery endothelial cells (HAEC) were exposed to Oregon Green-labeled LC?±?NL for 24 hours and intracellular LC and apoptosis (Hoechst stain) were measured. Circular dichroism spectroscopy was performed on AL-09 LC?±?NL to follow changes in secondary structure and protein thermal stability.

Results: LC caused impaired dilation to acetylcholine that was restored by NL (control – 94.0?±?1.8%, LC – 65.0?±?7.1%, LC?+?NL – 95.3?±?1.8%, p?≤?0.001 LC versus control or LC?+?NL). NL protection was inhibited by L-NG-nitroarginine methyl ester. NL increased the beta sheet structure of LC, reduced endothelial cell internalization of LC and protected against LC-induced endothelial cell death.

Conclusions: LC induced human adipose arteriole endothelial dysfunction and endothelial cell death, which were reversed by co-treatment with NL. This protection may partly be due to enhancing LC protein structure and reducing LC internalization. Nanoliposomes represent a promising new class of agents to ameliorate tissue injury from protein misfolding diseases such as AL.     

Diacerein niosomal gel for topical delivery: development,in vitro and in vivo assessment

The purpose of this study was to load diacerein (DCR) in niosomes by applying response surface methodology and incorporate these niosomes in gel base for topical delivery. Box–Behnken design was used to investigate the effect of charge-inducing agent (X₁), surfactant HLB (X₂) and sonication time (X₃) on the vesicle size (Y₁), entrapment efficiency (Y₂) and cumulative drug released (Y₃). DCR niosomal formulations were prepared by thin film hydration method. The optimized formula was incorporated in different gel bases. DCR niosomal gels were evaluated for homogeneity, rheological behavior; in vitro release and pharmacodynamic activity by carrageenan-induced hind paw edema method in the rat compared with DCR commercial gel. The results revealed that the mean vesicle sizes of the prepared niosomes ranged from 7.33 to 23.72?µm and the entrapment efficiency ranged from 9.52% to 58.43% with controlled release pattern over 8?h. DCR niosomal gels exhibited pseudoplastic flow with thixotropic behavior. The pharmacodynamic activity of DCR niosomal gel in 3% HPMC showed significant, 37.66%, maximum inhibition of edema size in comparison with 20.83% for the commercial gel (p?相似文献   

Liposomes for (trans)dermal drug delivery: the skin-PVPA as a novel in vitro stratum corneum model in formulation development

Penetration potential of vesicles destined for trans(dermal) administration remains to be of great interests both in respect to drug therapy and cosmetic treatment. This study investigated the applicability of the phospholipid vesicle-based permeation assay (PVPA) as a novel in vitro skin barrier model for screening purposes in preformulation studies. Various classes of liposomes containing hydrophilic model drug were examined, including conventional liposomes (CLs), deformable liposomes (DLs) and propylene glycol liposomes (PGLs). The size, surface charge, membrane deformability and entrapment efficiency were found to be affected by the vesicle lipid concentration, the presence of the surfactant and propylene glycol. All liposomes exhibited prolonged drug release profiles with an initial burst effect followed by a slower release phase. The permeation of the drug from all of the tested liposomes, as assessed with the mimicked stratum corneum – PVPA model, was significantly enhanced as compared to the permeability of the drug in solution form. Although the DLs and the PGLs exhibited almost the same membrane elasticity, the permeability of the drug delivered by PGLs was higher (6.2?×?10^?6?cm/s) than DLs (5.5?×?10^?6?cm/s). Therefore, this study confirmed both the potential of liposomes as vesicles in trans(dermal) delivery and potential of the newly developed skin-PVPA for the screening and optimization of liposomes at the early preformulation stage.     

Oral delivery of allopurinol niosomes in treatment of gout in animal model

Context: Gout is a painful disorder which does not have an efficient delivery system for its treatment.

Objective: Development and in vitro, in vivo evaluation of allopurinol-loaded nonionic surfactant-based niosomes was envisaged.

Materials and methods: Niosomes were prepared with Span 20 and Tween 20 (1:1 molar ratio) using ether injection method. The formulations were screened for entrapment efficiency, particle size analysis, zeta potential, release kinetics, in vivo activity, and stability studies.

Result: Stable, spherical vesicles of average particle size 304?nm with zeta-potential and entrapment efficiency of 22.2?mV and 79.44?±?0.02%, respectively, were produced. In vitro release study revealed 82.16?±?0.04% release of allopurinol within 24?h. The niosomal formulation was further evaluated for its antigout potential in monosodium urate (MSU) crystal induced gout animal model. The formulation demonstrated significant uric acid level reduction and enhanced antigout activity when compared with the pure allopurinol.

Discussion: The better antigout activity displayed by niosomal formulation could be attributed to sustained release of drug, higher drug solubility within biological fluids, better membrane interaction, smaller size, and presence of cholesterol and surfactant.

Conclusions: This study reveals that niosomes can be an efficient delivery system for the treatment of gout.     

Development and Evaluation of Artesunate-Loaded Chitosan-Coated Lipid Nanocapsule as a Potential Drug Delivery System Against Breast Cancer

Artesunate (ART)—a well-known hydrophobic anti-malarial agent was incorporated in a polymer-lipid hybrid nanocolloidal system for anti-cancer therapeutic. The lipid negatively charged nanoemulsion was formulated by modified hot homogenization method then covered with positively charged chitosan via electrostatic interaction to obtain chitosan-coated lipid nanocapsule (ART-CLN). Physical properties of the system were characterized in terms of size, charge, morphology, drug loading capacity, and physical state. In addition, anti-cancer activities were confirmed by conducting MTT assay for ART and ART-CLN on different cancer cell lines. Obtained ART-CLN after coating chitosan revealed positive charge (13.2 ± 0.87 mV), small particle size (160.9 ± 3.5 nm), and spherical shape. High drug entrapment efficiency (95.49 ± 1.13%) and sustained release pattern were observed. Moreover, the good cellular uptake was recorded by flow cytometry as well as confocal image. Finally, ART-CLN exhibited stronger anti-cancer activity than free ART on breast cancer cell lines (MCF-7, MDA-MB-231). These results suggested that by loading ART into lipid core of polymer-lipid hybrid carrier, the activity and physical stability of ART can be significantly increased for cancer chemotherapy.KEY WORDS: anti-cancer, artesunate, breast cancer, chitosan, lipid nanoparticles     

Combined antimalarial therapy using artemisinin

The existing armamentarium of drugs for the treatment and prevention of malaria is limited primarily by resistance (and cross-resistance between closely related drugs). However, most of these drugs still have a place and their life-span could be prolonged if better deployed and used, and also by rationally combining them based on pharmacodynamic and pharmacokinetic properties. Newer compounds are also being developed. The nature of malaria disease and its prevalence in the developing world call for innovative approaches to develop new affordable drugs and to safeguard the available ones. According to WHO, the concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination. Combination therapy (CT) with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. In the context of this definition, multiple-drug therapies that include a nonantimalarial drug to enhance the antimalarial effect of a blood schizontocidal drug are not considered combination therapy. Similarly, certain antimalarial drugs that fit the criteria of synergistic fixed-dose combinations are operationally considered as single products in that neither of the individual components would be given alone for anti-malarial therapy. An example is sulfadoxine-pyrimethamine. Artemisinin-based combination therapies have been shown to improve treatment efficacy and also contain drug resistance in South-East Asia. However, major challenges exist in the deployment and use of antimalarial drug combination therapies, particularly in Africa. These include: 1) the choice of drug combinations best suited for the different epidemiological situations; 2) the cost of combination therapy; 3) the timing of the introduction of combination therapy; 4) the operational obstacles to implementation, especially compliance. As a response to increasing levels of antimalarial resistance, the World Health Organization (WHO) recommends that all countries experiencing resistance to conventional monotherapies, such as chloroquine, amodiaquine or sulfadoxine/pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs--artemisinin-based combination therapies) for malaria caused by Plasmodium falciparum. There is a promising role of such compounds in replacing or complementing current options. Since 1979, several different formulations of artemisinin and its derivatives have been produced and studied in China in several thousand patients for either P. falciparum or P. vivax malaria. To date, there is no evidence of drug resistance to these compounds. The use of artemisinin, artemether, arteether and artesunate for either uncomplicated or severe malaria is now spreading through almost all malarious areas of the world, although some of they have no patent protection, their development (with few exceptions) has not followed yet full international standards. Both artesunate, artemether and arteether are rapidly and extensively converted to their common bioactive metabolite, dihydroarte-misinin. WHO currently recommends the following therapeutic options: 1) artemether/lumefantrine; 2) artesunate plus amodiaquine; 3) artesunate plus sulfadoxine/pyrimethamine (in areas where SP efficacy remains high); 4) artesunate plus mefloquine (in areas with low to moderate transmission); and 5) amodiaquine plus sulfadoxine/pyrimethamine, in areas where efficacy of both amodiaquine and sulfadoxine/pyrimethamine remains high (mainly limited to countries in West Africa). This non artemisinin-based combination therapy is reserved as an interim option for countries, which, for whatever reason, are unable immediately to move to ACTs.     

Synthesis and characterization of a novel chitosan based E. coli cytosine deaminase nanocomposite for potential application in prodrug enzyme therapy

Cytosine deaminase is a non-mammalian enzyme of widespread interest for prodrug enzyme therapy due to its ability to convert prodrug 5-fluorocytosine into anticancer drug 5-fluorouracil. Cytosine deaminase enzyme has been purified to homogeneity from E. coli K-12 MTCC 1302 strain. K_m values for cytosine and 5-fluorocytosine were found to be 0.26 mM and 1.82 mM, respectively. We developed a chitosan-entrapped cytosine deaminase nanocomposite. Atomic force microscopy and transmission electron microscopy images showed an elongated sphere shape nanocomposite with an average size of 80 nm diameter. Fourier transform infrared spectroscopy and X-ray diffraction results confirmed gel formation and entrapment of cytosine deaminase within the nanocomposite. Sustained release of cytosine deaminase from the nanocomposite up to one week depicted its potential implication in prodrug inducted enzyme therapy.     

Niosome-Encapsulated Gentamicin for Ophthalmic Controlled Delivery

The objective of the present research was to investigate the feasibility of using non-ionic surfactant vesicles (niosomes) as carriers for the ophthalmic controlled delivery of a water soluble local antibiotic; gentamicin sulphate. Niosomal formulations were prepared using various surfactants (Tween 60, Tween 80 or Brij 35), in the presence of cholesterol and a negative charge inducer dicetyl phosphate (DCP) in different molar ratios and by employing a thin film hydration technique. The ability of these vesicles to entrap the studied drug was evaluated by determining the entrapment efficiency %EE after centrifugation and separation of the formed vesicles. Photomicroscopy and transmission electron microscopy as well as particle size analysis were used to study the formation, morphology and size of the drug loaded niosomes. Results showed a substantial change in the release rate and an alteration in the %EE of gentamicin sulphate from niosomal formulations upon varying type of surfactant, cholesterol content and presence or absence of DCP. In-vitro drug release results confirmed that niosomal formulations have exhibited a high retention of gentamicin sulphate inside the vesicles such that their in vitro release was slower compared to the drug solution. A preparation with 1:1:0.1 molar ratio of Tween 60, cholesterol and DCP gave the most advantageous entrapment (92.02% ± 1.43) and release results (Q_8h = 66.29% ± 1.33) as compared to other compositions. Ocular irritancy test performed on albino rabbits, showed no sign of irritation for all tested niosomal formulations.