Oral Administration of Artemisone for the Treatment of Schistosomiasis: Formulation Challenges and In Vivo Efficacy

Zech, Johanna; Gold, Daniel; Salaymeh, Nadeen; Sasson, Netanel Cohen; Rabinowitch, Ithai; Golenser, Jacob; Mäder, Karsten

doi:10.3390/pharmaceutics12060509

Cited by 13 publications

(38 citation statements)

References 37 publications

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“…Likewise, Steyn et al report that absorption of dissolved ART from their "Pheroid TM " delivery system in a mouse is almost five-fold higher than from a drug suspension (18). Furthermore, for the treatment of schistosomiasis in mice, we found that 40 mg/kg per dose was sufficient if ART was dissolved in our SMEDDS (15), while to obtain similar results with a suspension required 400 mg/kg of the drug (19).…”

Section: Downloaded Fromsupporting

confidence: 68%

“…Consequently, it has a longer t 1/2 in vivo and is about 3-5 times more active than artesunate, in vitro and in vivo (4,7). ART toxicity has not been extensively evaluated in vivo but we have not seen any immediate effects after using our formulation in the current and previous experiments (8). In vitro studies revealed a decreased toxicity compared to artesunate (9).…”

Section: Introductionmentioning

confidence: 64%

“…Unfortunately, no stability data have been reported for these formulations. With the water-free SMEDDS, and even with a ME formed from SMEDDS and 50% water, we achieved good ART stability even at high ambient temperatures (at least 3 months, 30°C) (15).…”

Section: Tablementioning

confidence: 90%

“…compliance. Oral administration of this formulation by gavage has been found very efficient in mice infected with Schistosoma mansoni (15).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Recently, we developed a new formulation for ART that overcomes the limitation of the lipophilic drug by dissolution in a self-microemulsifying drug delivery system [SMEDDS] / microemulsion [ME] (15). Its delivery is simple and may overcome problems related to on February 21, 2021 by guest http://aac.asm.org/…”

Section: Introductionmentioning

confidence: 99%

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Efficient Treatment of Experimental Cerebral Malaria by an Artemisone-SMEDDS System: Impact of Application Route and Dosing Frequency

Zech

Salaymeh

Hunt

et al. 2021

Antimicrob Agents Chemother

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Artemisone (ART) has been successfully tested in vitro and in animal models against several diseases. However, its poor aqueous solubility and limited chemical stability are serious challenges. We developed a self-microemulsifying drug delivery system (SMEDDS) that overcomes these limitations. Here, we demonstrate the efficacy of this formulation against experimental cerebral malaria in mice and the impact of its administration using different routes (gavage, intranasal delivery and parenteral injections) and frequency on the efficacy of the treatment. The minimal effective oral dose was 20 mg/kg. We found that splitting a dose of 20 mg/kg ART given every 24 hours, by administering two doses of 10 mg/kg each every 12 hours, was highly effective and gave far superior results compared to 20 mg/kg once daily. We obtained the best results with nasal treatment, oral treatment was ranked second and the least effective route of administration was intraperitoneal injection. A complete cure of experimental cerebral malaria could be achieved through choosing the optimal route of application, dose and dosing interval. Altogether, the developed formulation combines easy manufacturing with high stability, and is a successful and very versatile carrier for the delivery of ART in treatment of human severe malaria.

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confidence: 68%

Section: Introductionmentioning

confidence: 64%

Section: Tablementioning

confidence: 90%

“…compliance. Oral administration of this formulation by gavage has been found very efficient in mice infected with Schistosoma mansoni (15).…”

Section: Downloaded Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficient Treatment of Experimental Cerebral Malaria by an Artemisone-SMEDDS System: Impact of Application Route and Dosing Frequency

Zech

Salaymeh

Hunt

et al. 2021

Antimicrob Agents Chemother

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Applicability of Redirecting Artemisinins for New Targets

Golenser,

Hunt,

Birman

et al. 2023

Global Challenges

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Employing new therapeutic indications for drugs that are already approved for human use has obvious advantages, including reduced costs and timelines, because some routine steps of drug development and regulation are not required. This work concentrates on the redirection of artemisinins (ARTS) that already are approved for clinical use, or investigated, for malaria treatment. Several mechanisms of action are suggested for ARTS, among which only a few have been successfully examined in vivo, mainly the induction of oxidant stress and anti‐inflammatory effects. Despite these seemingly contradictory effects, ARTS are proposed for repurposing in treatment of inflammatory disorders and diverse types of diseases caused by viral, bacterial, fungal, and parasitic infections. When pathogens are treated the expected outcome is diminution of the causative agents and/or their inflammatory damage. In general, repurposing ARTS is successful in only a very few cases, specifically when a valid mechanism can be targeted using an additional therapeutic agent and appropriate drug delivery. Investigation of repurposing should include optimization of drug combinations followed by examination in relevant cell lines, organoids, and animal models, before moving to clinical trials.

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Meeting the Needs of a Potent Carrier for Malaria Treatment: Encapsulation of Artemisone in Poly(lactide‐co‐glycolide) Micro‐ and Nanoparticles

Heidari

Golenser

Greiner

2022

Part & Part Syst Charact

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the death of about 435 000 people especially in tropical and subtropical regions. [3] Among artemisinin derivatives, artemisone (ART) is considered a most potent agent for treatment of malaria, owing to its lack of neurotoxicity, anti-plasmodial, anti-inflammatory, and significant therapeutic effect against cerebral malaria. Most importantly, it is not converted to dihydroxyartemisinin, to which some parasite resistance was found. [4][5][6] Additionally, ART is regarded as a crystalline drug with a hydrophobic structure. [5,6] The main concern related to ART is its low bioavailability and its poor solubility in aqueous solutions. [7] To overcome these drawbacks, studies have been carried out to incorporate the drug into various types of nanoand microcarriers. [8][9][10] Different types of carriers such as liposomes and polymeric particles have been evaluated for the controlled delivery of drugs. [11][12][13] Specifically, great attention is drawn toward the polymeric nano-and microparticles as drug delivery systems due to their controlled and sustained drug delivery behavior. [14][15][16] In comparison with free drugs, polymeric particles exhibit some advantages ranging from improved drug bioavailability to the ability of releasing the drug in a controlled manner and being compatible with varying administration routes. Compared with liposomes, polymeric particles have the advantage of increased storage capacity, lower cytotoxicity, [15,18] improved in vivo stability [19] against enzymatic degradation [11] and increased drug solubility in aqueous medium, [20] reducing drug side effects. [21] These lead to extended drug circulation time, lower dosing frequency and consequently and most important increased patient compliance. [22,23] Poly(lactide-co-glycolide) (PLGA), an aliphatic polyester which is known as a biocompatible and biodegradable polymer has been widely used for nanoparticle fabrication and drug delivery systems. [24][25][26] It hydrolyzes within the body, to produce glycolic acid, which is a nontoxic biodegradable monomer. [27] Characteristics such as particle size, zeta potential, and drug loading could be tuned accurately by changing the type and quantity of polymer, amount of drug, solvent, and surfactant. [17] The resulting size of the particle is of great importance, as it plays a significant role in the stability of the particle dispersion, drug release, and cellular uptake. For an efficient drug delivery, Biodegradable polymer nano-and microparticles are of interest as drug carriers due to their capability to modulate drug release. Two different methods, including solvent displacement and spray drying, are used, resulting in the fabrication of Artemisone (ART)-loaded polymeric nano-and microparticles, respectively. Scanning electron microscopy, transmission electron microscopy, dynamic light scattering, and asymmetric flow field flow fractionation (AF4) are employed to evaluate the morphology and size of the particles. The encapsulation and loading efficiency of the drug as well as cumulative rel...

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Oral Administration of Artemisone for the Treatment of Schistosomiasis: Formulation Challenges and In Vivo Efficacy

Cited by 13 publications

References 37 publications

Efficient Treatment of Experimental Cerebral Malaria by an Artemisone-SMEDDS System: Impact of Application Route and Dosing Frequency

Efficient Treatment of Experimental Cerebral Malaria by an Artemisone-SMEDDS System: Impact of Application Route and Dosing Frequency

Applicability of Redirecting Artemisinins for New Targets

Meeting the Needs of a Potent Carrier for Malaria Treatment: Encapsulation of Artemisone in Poly(lactide‐co‐glycolide) Micro‐ and Nanoparticles

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