5 research outputs found
Drug鈥揇rug Interactions within Protein Cavities Probed by Triplet鈥揟riplet Energy Transfer
A new direct and
noninvasive methodology based on transient absorption
spectroscopy has been developed to probe the feasibility of drug鈥揹rug
interactions within a common protein binding site. The simultaneous
presence of (<i>R</i>)-cinacalcet (CIN) and (<i>S</i>)-propranolol (PPN) within human or bovine 伪<sub>1</sub>-acid
glycoproteins (AAGs) is revealed by detection of <sup>3</sup>CIN*
as the only transient species after laser flash photolysis of CIN/PPN/AAG
mixtures at 308 nm. This is the result of triplet鈥搕riplet energy
transfer from <sup>3</sup>PPN* to CIN, which requires close contact
between the two drugs within the same biological compartment. Similar
results are obtained with nabumetone and CIN as donor/acceptor partners.
This new methodology can, in principle, be extended to a variety of
drug/drug/biomolecule combinations
Mechanistic Studies on the Photoallergy Mediated by Fenofibric Acid: Photoreactivity with Serum Albumins
The
photoreactivity of fenofibric acid (FA) in the presence of
human and bovine serum albumins (HSA and BSA, respectively) has been
investigated by steady-state irradiation, fluorescence, and laser
flash photolysis (LFP). Spectroscopic measurements allowed for the
determination of a 1:1 stoichiometry for the FA/SA complexes and pointed
to a moderate binding of FA to the proteins; by contrast, the FA photoproducts
were complexed more efficiently with SAs. Covalent photobinding to
the protein, which is directly related to the photoallergic properties
of the drug, was detected after long irradiation times and was found
to be significantly higher in the case of BSA. Intermolecular FA-amino
acid and FA-albumin irradiations resulted in the formation of photoproducts
arising from coupling between both moieties, as indicated by mass
spectrometric analysis. Mechanistic studies using model drug鈥揳mino
acid linked systems indicated that the key photochemical step involved
in photoallergy is formal hydrogen atom transfer from an amino acid
residue to the excited benzophenone chromophore of FA or (more likely)
its photoproducts. This results in the formation of caged radical
pairs followed by C鈥揅 coupling to give covalent photoaducts
Photophysical Probes To Assess the Potential of Cholic Acid Aggregates as Drug Carriers
The two enantiomers of the nonsteroidal antiinflammatory
drug naproxen
and of its methyl ester have been selected as representative probes
with markedly different hydrophobicity to assess the potential of
cholic acid aggregates as drug carriers by means of photophysical
techniques. The different distribution of the probes between bulk
solution and aggregates has been assessed by quenching of their singlet
and triplet excited states by iodide and nitrite anions, respectively.
This straightforward photophysical methodology can, in principle,
be extended to a variety of drugs containing a photoactive chromophore
TLR expression on moDC without or with stimuli.
<p><b>A</b>) RT-PCR analysis for mRNA expression of different TLRs on imDC from a representative DTH patient. <b>B</b>) Bars represent the median fold increase in TLR2, 4, 7 and 8 expression and MyD88 after stimulation with AX, PAM, LPS and R848 alone or in combination on DC from DTH patients (left) and controls (right). *p<0.05, **p<0.01, ***p<0.001.</p
DC maturation and lymphocyte proliferation after different stimuli.
<p><b>A</b>) Changes in CD86 expression on moDC after stimulation with AX alone or in combination with PAM, LPS or both (left) and with AX alone or in combination with R848 (right). <b>B</b>) Bars represent the percentage of positive cases of DC maturation after stimulation with AX, PAM, LPS and R848 alone or in combination in DC from DTH patients (N=15) (black bars) and controls (N=15) (grey bars). *, p<0.05, represents the significant differences after statistical comparisons (蠂<sup>2</sup> analysis) in the percentage of cases comparing DTH patients to controls. <b>C</b>) Changes in CD3<sup>+</sup> T-lymphocyte proliferation after stimulation with AX alone or in combination with PAM, LPS or both (left) and with AX alone or in combination with R848 (right). Histograms are representative of one DTH patient. <b>D</b>) Bars represent the percentage of positive cases of LTT after stimulation with AX, PAM, LPS and R848 alone or in combination in T cells from DTH patients (N=15) (black bars) and controls (N=15) (grey bars). *, p<0.05, represents the significant differences after statistical comparisons (蠂<sup>2</sup> analysis) in the percentage of cases comparing DTH patients to controls.</p