The placebo phenomenon and the underlying mechanisms.

The clinical role of the placebo effect is a topic of increasing interest for the scientific community. Focus is shifting from the inert role of placebos in randomized controlled trials (RCTs) to potential effects in clinical applications, since the phenomenon is thought to be inherent in routine clinical practice, affecting therapy success rates. Mediation of the mind-brain-body relationship involves both psychosocial and neurobiological factors, the interaction of which comprises the placebo mechanisms. Psychosocial factors include environmentally induced expectations, reward expectations, and even conditioned responses to certain stimuli. Expectations also depend on previous experience of the patient with a similar procedure and can affect future responses. Moreover, the supportive bedside behavior of the clinician and the positive framing of information provided to the patient have proven to be of great importance, setting the foundations for reconsideration of standardized practices. Neurobiological mechanisms mediate these effects through neurotransmitter and neuromodulator pathways. The best understood mechanisms are those regulating non-opioid- and opioid-mediated analgesic responses that implicate specific brain regions of pain control and activation of endogenous opioids. Other responses concern, among others, hormonal control, motor performance, and antidepressant responses. Although mechanisms underlying placebo responses are not as yet completely elucidated, there is substantial evidence suggesting that placebo effects are indicative of healthy functioning of intact brain structures and occur through actual functional changes, and are not simply subjective symptom reports. These effects can be utilized in treatment optimization while maintaining an ethical and respectful manner toward the patient and the standardized disclosure procedures.

New (99m)Tc(CO)(3) mannosylated dextran bearing S-derivatized cysteine chelator for sentinel lymph node detection.

The aim of the present study is to synthesize new mannosylated dextran derivative that can be labeled with Tc-99m for potential use in sentinel lymph node detection (SLND). The compound was designed to have a dextran with molecular weight of 10 kDa as a backbone, mannose for binding to mannose receptors of the lymph node and S-derivatized cysteine as a suitable chelator for labeling with [(99m)Tc(H(2)O)(3)(CO)(3)](+) precursor. Reaction of allyl bromide with dextran (MW 11800) yielded the intermediate allyl-dextran (1) with about 40% coupling. Addition of cysteine to allyl-dextran resulted in the S-derivatized cysteine, compound DC15 (2). The final product DCM20 (3) was obtained in good yield after in situ hydrolysis and activation of cyanomethyl tetraacetyl-1-thio-d-mannopyranoside and coupling to DC15. All derivatives were purified by ultrafiltration and characterized by NMR. DC15 and DCM20 were quantitatively labeled with (99m)Tc (>95% radiochemical purity) using the fac-[(99m)Tc(OH(2))(3)(CO)(3)](+) precursor and ligand concentration of 1.5 × 10(-6) M at neutral pH. Both (99m)Tc-labeled compounds (99m)Tc(CO)(3)-DC15 (6) and (99m)Tc(CO)(3)-DCM20 (7) remained stable after 6 h incubation at 37 °C in the presence of excess histidine or cysteine, as well as even after 20-fold dilution and incubation for 24 h at room temperature. The characterization of the compounds 6 and 7 was performed by comparing their HPLC radiochromatograms with those of their rhenium surrogates Re(CO)(3)-DC15 (4) and Re(CO)(3)-DCM20 (5) respectively that were prepared using the precursor [NEt(4)](2)fac-[ReBr(3)(CO)(3)] and characterized by IR and NMR spectroscopy. When injected subcutaneously from the foot pad of mice, (99m)Tc-labeled mannosylated dextran (7) showed accumulation in the popliteal lymph node (SLN in this model) higher than that of non-mannosylated analogue (6) and the (99m)Tc-phytate serving as standard. Compound 7 also exhibited lower radioactivity levels at the injection site compared to (99m)Tc-phytate. The SPECT/CT studies in mice confirmed that 7 accumulated in the popliteal lymph node allowing its clear visualization. The present findings demonstrate that compound 7 ((99m)Tc(CO)(3)-DCM20) is promising and merits further evaluation as a radiopharmaceutical for sentinel lymph node detection.