Ein CO‐Fänger: Ein supramolekularer Eisen(II)porphyrin‐Cyclodextrin‐Komplex (hemoCD) mit gebundenem O2, der in eine Rattenvene injiziert wird, reagiert unter Ligandenaustausch mit internem CO, und das hemoCD mit gebundenem CO wird sofort in den Urin ausgeschieden (siehe Bild). Diese Wirkungsweise von hemoCD als CO‐Rezeptor ermöglichte die quantitative Bestimmung von endogenem CO in einem lebenden Organismus.

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

A CO stripper: The O2‐bound form of an iron(II) porphyrin cyclodextrin supramolecular complex (hemoCD) infused into a rat vein reacted with internal CO through ligand exchange, and the CO‐bound hemoCD was immediately excreted in the urine (see picture). The hemoCD acting as a CO receptor made it possible to quantify endogenous CO in a living organism.

No abstract

Interactions of multivalent anionic porphyrins and their iron(III) complexes with cationic peptides, V3(Ba-L) and V3(IIIB), which correspond to those of the V3 loop regions of the gp120 envelope proteins of the HIV-1(Ba-L) and HIV-1(IIIB) strains, respectively, are studied by UV/Vis, circular dichroism, (1)H NMR, and EPR spectroscopy, a microcalorimetric titration method, and anti-HIV assays. Tetrakis(3,5-dicarboxylatophenyl)porphyrin (P1), tetrakis[4-(3,5-dicarboxylatophenylmethoxy)phenyl]porphyrin (P2), and their ferric complexes (Fe(III)P1 and Fe(III)P2) were used as the multivalent anionic porphyrins. P1 and Fe(III)P1 formed stable complexes with both V3 peptides (binding constant K>10(6) M(-1)) through combined electrostatic and van der Waals interactions. Coordination of the His residues in V3(Ba-L) to the iron center of Fe(III)P1 also played an important role in the complex stabilization. As P2 and Fe(III)P2 form self-aggregates in aqueous solution even at low concentrations, detailed analysis of their interactions with the V3 peptides could not be performed. To ascertain whether the results obtained in the model system are applicable to a real biological system, anti-HIV-1(BA-L) and HIV-1(IIIB) activity of the porphyrins is examined by multiple nuclear activation of a galactosidase indicator (MAGI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. There is little correlation between chemical analysis and actual anti-HIV activity, and the size rather than the number of the anionic groups of the porphyrin is important for anti-HIV activity. All the porphyrins show high selectivity, low cytotoxicity, and high viral activity. Fe(III)P1 and Fe(III)P2 are used for the pharmacokinetic study. Half-lives of these iron porphyrins in serum of male Wistar rats are around 4 to 6 h owing to strong interaction of these porphyrins with serum albumin.

The supramolecular complexation of 5,10,15,20‐tetrakis(4‐sulfonatophenyl)porphyrin (TPPS) with heptakis(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin (TMCD) has been known to be highly specific in aqueous media. In this study, we have used NMR spectroscopy to reveal that this supramolecular system also works even in biologically crowded media such as serum, blood, and urine. A 13C‐labeled heptakis(2,3,6‐tri‐O‐methyl‐13C)‐β‐cyclodextrin (13C‐TMCD) was synthesized and studied using one‐dimensional (1D) HMQC spectroscopy in serum and blood. The 1D HMQC spectrum of 13C‐TMCD showed clear signals due to the 2‐, 3‐, and 6‐O13CH3 groups, whose chemical shifts changed upon addition of TPPS due to quantitative formation of the 13C‐TMCD/TPPS=2/1 inclusion complex in such biological media. The 1H NMR signals of non‐isotope‐labeled TPPS included by 13C‐TMCD were detected using the 13C‐filtered ROESY technique. A pharmacokinetic study of 13C‐TMCD and its complex with TPPS was carried out in mice using the 1D HMQC method. The results indicated that (1) 1D HMQC is an effective technique for monitoring the inclusion phenomena of 13C‐labeled cyclodextrin in biological media and (2) the intermolecular interaction between 13C‐TMCD and TPPS is highly selective even in contaminated media like blood, serum, and urine.

No abstract

Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN – ) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (Fe III TPPS, F), two methyl-β-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na 2 S 2 O 4 , S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN – once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN – mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN – resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN – levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.