The Caco-2 cellular monolayer is a widely accepted in vitro model to predict human permeability but suffering from several and critical limitations. Therefore, some alternative cell cultures to mimic the human intestinal epithelium, as closely as possible, have been developed to achieve more physiological conditions, as the Caco-2/HT29-MTX coculture and the triple Caco-2/HT29-MTX/Raji B models. In this work the permeability of 12 model drugs of different Biopharmaceutical Classification System (BCS) characteristics, in the coculture and triple coculture models was assessed. Additionally, the utility of both models to classify compounds according to the BCS criteria was scrutinized. The obtained results suggested that the coculture of Caco-2/HT29-MTX and the triple coculture of Caco-2/HT29-MTX/Raji B were useful models to predict intestinal permeability and to classify the drugs in high or low permeability according to BCS. Moreover, to study thoroughly the transport mechanism of a specific drug, using a more complex model than Caco-2 monocultures is more suitable because coculture and triple coculture are more physiological models, so the results obtained with them will be closer to those obtained in the human intestine.
A new trinuclear copper(II) complex has been synthesized and structurally characterized: [Cu(3)(L)(2)(HCOO)(2)(OH)(2)](infinity) (HL = (N-pyrid-2-ylmethyl)benzenesulfonylamide). In the complex, the central copper ion is six-coordinated. The coordination spheres of the terminal copper atoms are square pyramidal, the apical positions being occupied by a sulfonamido oxygen of the contiguous trimer. As a consequence, the complex can be considered a chain of trinuclear species. The three copper atoms are in a strict linear arrangement, and adjacent coppers are connected by a hydroxo bridge and a bidentate syn-syn carboxylato group. The mixed bridging by a hydroxide oxygen atom and a bidentate formato group leads to a noncoplanarity of the adjacent basal coordination planes with a dihedral angle of 61.4(2) degrees. Susceptibility measurements (2-300 K) reveal a strong ferromagnetic coupling, J = 79 cm(-1), leading to a quartet ground state that is confirmed by the EPR spectrum. The ferromagnetic coupling arises from the countercomplementarity of the hydroxo and formato bridges. The trinuclear complex cleaves DNA efficiently, in the presence of hydrogen peroxide/sodium ascorbate. tert-Butyl alcohol and sodium azide inhibit the oxidative cleavage, suggesting that the hydroxyl radical and singlet oxygen are involved in the DNA degradation.
A new dinuclear copper(II) complex has been synthesized and structurally characterized: [Cu(mu-ade)(tolSO3)(phen)]2.2H2O (Hade = adenine, tolSO3- = toluenesulfonate anion). Its magnetic properties and electronic paramagnetic resonance (EPR) spectra have been studied in detail. The compound has two metal centers bridged by two adeninate NCN groups. The coordination geometry of the copper(II) ions in the dinuclear entity is distorted square pyramidal, with the four equatorial positions occupied by two phenanthroline N atoms and two N atoms from different adenine molecules. The axial position is occupied by one sulfonate O atom. Magnetic susceptibility data show antiferromagnetic behavior with an estimated exchange constant of -2J = 65 cm-1. The EPR spectrum has been obtained at both X- and Q-band frequencies; a study at different temperatures has been carried out at the latter. Above 20 K, the Q-band spectra are characteristic of S = 1 species with a small zero-field splitting parameter (D = 0.0970 cm-1). A detailed study of the DNA-complex interaction has been performed. The title complex efficiently cleaves the pUC18 plasmid in the presence of reducing agents. Both the kinetics and the mechanism of the cleavage reaction are examined and described herein.
organometallic gold(III) and platinum(II) complexes containing
iminophosphorane ligands are described. Most of them are more cytotoxic
to a number of human cancer cell lines than cisplatin. Cationic Pt(II)
derivatives 4 and 5, which differ only in
the anion, Hg2Cl62– or PF6– respectively, display almost identical
IC50 values in the sub-micromolar range (25–335-fold
more active than cisplatin on these cell lines). The gold compounds
induced mainly caspase-independent cell death, as previously reported
for related cycloaurated compounds containing IM ligands. Cycloplatinated
compounds 3, 4, and 5 can also
activate alternative caspase-independent mechanisms of death. However,
at short incubation times cell death seems to be mainly caspase dependent,
suggesting that the main mechanism of cell death for these compounds
is apoptosis. Mercury-free compound 5 does not interact
with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies
of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high
permeability profile for this compound (comparable to that of metoprolol
or caffeine) and an estimated oral fraction absorbed of 100%, which
potentially makes it a good candidate for oral administration.
Copper-based transition metal complexes performing single- and double-strand scission of DNA have been studied. The dinuclear complexes [Cu(2)(L)(2)(OCH(3))(2)(NH(3))(2)] and [Cu(2)(L)(2)(OCH(3))(2)(DMSO)(2)] are more active than the corresponding mononuclear [Cu(L)(2)(py)(2)] (where HL= N-(4-methylbenzothiazol-2-yl)benzenesulfonamide), suggesting that the dinuclearity is an important factor in the oxidative cleavage of DNA. The cleavage efficiency of the complexes depends on the reducing agent used in the process, the tandem ascorbate/H(2)O(2) being the most efficient. PAGE analyses have shown that these complexes cleave DNA without sequence selectivity. The DNA degradation process takes place mainly by C1' oxidation, but C4' and C5' oxidations cannot be ruled out as minor pathways. These copper complexes preferably oxidize guanine under mild conditions, but under more drastic conditions the oxidation reactivity appears to be T>G>C>A, suggesting the intervention of hydroxyl radicals as active species.
Giardia intestinalis infection causes enterocytes damage and loss of brush border of the
epithelial cells of the intestine that leads to shortening of microvilli and altered epithelial barrier function.
This pathology results in aqueous diarrhoea, steatorrhea, nausea, abdominal pain, vomiting and
weight loss. However, most infections are asymptomatic. The main consequence of Giardia colonization
is nutrients malabsorption. Several families of drugs with good efficacy are used for Giardia treatment,
but sometime dosing regimens are suboptimal and emerging resistance begins to question their
clinical value. Moreover, some of these drugs can cause side effects that result in patient discomfort and
low adherence to the treatment. This paper reviews the drugs currently used for the treatment against
Giardia: the mechanism of action, the efficacy, the normal dosing, side effects and in vitro and clinical
studies. In addition, new therapies against Giardia such as those based on phytochemicals, Lactobacillus
and nanotechnology are collected in this paper, trying to find the ideal treatment for this disease with
maximum efficacy and minimum adverse effects.
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