Improving the solubility of the antichagasic drug benznidazole through formation of inclusion complexes with cyclodextrins

Sobrinho, José Lamartine Soares; Soares, Mônica Felts de La Roca; Labandeira, Juan J. Torres; Alves, Lariza Darlene Santos; Rolim-Neto, Pedro José

doi:10.1590/s0100-40422011000900010

Cited by 22 publications

(14 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among Chagas patients, following cessation of benznidazole treatment, a subset of individuals reverted from PCR-negative status to having detectable parasite DNA, indicating parasite persistence in such cases ( 8 , 25 ). Several explanations have been proposed to account for this lack of sterilizing cure by benznidazole in humans, including inadequate biodistribution, low solubility, high levels of serum binding, and low bioavailability through extensive liver metabolism ( 51 – 54 ). On the basis of our current findings, it is conceivable that the flexibility of the T. cruzi amastigote may serve to protect tissue resident parasites from insufficient exposure to drug.…”

Section: Discussionmentioning

confidence: 99%

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes

Dumoulin

Burleigh

2018

mBio

View full text Add to dashboard Cite

The mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inherent capacity to tolerate changing environments. To examine this potential, we studied proliferation and cell cycle dynamics of intracellular T. cruzi amastigotes experiencing transient metabolic perturbation or drug pressure in the context of an infected mammalian host cell. Parasite growth plasticity was evident and characterized by rapid and reversible suppression of amastigote proliferation in response to exogenous nutrient restriction or exposure to metabolic inhibitors that target glucose metabolism or mitochondrial respiration. In most instances, reduced parasite proliferation was accompanied by the accumulation of amastigote populations in the G1 phase of the cell cycle, in a manner that was rapidly and fully reversible upon release from the metabolic block. Acute amastigote cell cycle changes at the G1 stage were similarly observed following exposure to sublethal concentrations of the first-line therapy drug, benznidazole, and yet, unlike the results seen with inhibitors of metabolism, recovery from exposure occurred at rates inversely proportional to the concentration of benznidazole. Our results show that T. cruzi amastigote growth plasticity is an important aspect of parasite adaptation to stress, including drug pressure, and is an important consideration for growth-based drug screening.

show abstract

Section: Discussionmentioning

confidence: 99%

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes

Dumoulin

Burleigh

2018

mBio

View full text Add to dashboard Cite

show abstract

“…on drug direct contact, elimination of unpleasant odors or taste and prevention of drug-additive interactions [ 42 , 43 , 44 , 45 ]. Although early studies focused on naturally occurring CDs, at present numerous chemical modifications of the CDs are available and are preferentially used for pharmaceutical purposes due to their better technological and biological properties [ 46 ]. In particular, hydroxypropyl-β-cyclodextrins have been widely investigated as drug carriers because of their high water solubility and their ability to avoid the formation of crystalline cholesterol complexes that could lead to kidney damaging effects.…”

Section: Drug Delivery Systemsmentioning

confidence: 99%

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

et al. 2018

View full text Add to dashboard Cite

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives.

show abstract

“…Numerous chemical modifications of the CDs have been synthesized and novel derivatives are constantly being developed. Since each CD hydroxyl group differs in its chemical reactivity, the random substitution produces an important increase in solubility due to the decrease in the crystalline state and may also be helpful to overcome the formation of kidney damaging crystalline cholesterol complexes and also to achieve efficient drug delivery systems [8] .…”

Section: Introductionmentioning

confidence: 99%

Modified β-Cyclodextrin Inclusion Complex to Improve the Physicochemical Properties of Albendazole. Complete In Vitro Evaluation and Characterization

et al. 2014

View full text Add to dashboard Cite

The potential use of natural cyclodextrins and their synthetic derivatives have been studied extensively in pharmaceutical research and development to modify certain properties of hydrophobic drugs. The ability of these host molecules of including guest molecules within their cavities improves notably the physicochemical properties of poorly soluble drugs, such as albendazole, the first chosen drug to treat gastrointestinal helminthic infections. Thus, the aim of this work was to synthesize a beta cyclodextrin citrate derivative, to analyze its ability to form complexes with albendazole and to evaluate its solubility and dissolution rate. The synthesis progress of the cyclodextrin derivative was followed by electrospray mass spectrometry and the acid-base titration of the product. The derivative exhibited an important drug affinity. Nuclear magnetic resonance experiments demonstrated that the tail and the aromatic ring of the drug were inside the cavity of the cyclodextrin derivative. The inclusion complex was prepared by spray drying and full characterized. The drug dissolution rate displayed exceptional results, achieving 100% drug release after 20 minutes. The studies indicated that the inclusion complex with the cyclodextrin derivative improved remarkably the physicochemical properties of albendazole, being a suitable excipient to design oral dosage forms.

show abstract

Improving the solubility of the antichagasic drug benznidazole through formation of inclusion complexes with cyclodextrins

Cited by 22 publications

References 16 publications

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes

Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

Modified β-Cyclodextrin Inclusion Complex to Improve the Physicochemical Properties of Albendazole. Complete In Vitro Evaluation and Characterization

Contact Info

Product

Resources

About