Role of Metal Ions and Hydrogen Bond Acceptors in the Tautomeric Equilibrium of Nitro-9[(Alkylamino)Amino]-Acridine Drugs

3-nitro-9-[2-(dialkylamino)ethyl)]aminoacridines (alkyl = methyl or ethyl) have been used as ligands towards platinum(If). The end product is a complex in which the acridine acts as a tridentate ligand contributing the two exocyclic nitrogen atoms and one of the two peri carbons. The metallation takes place predominantly at the peri position of the unsubstituted ring. The coordinated acridine is in the imino tautomeric form although, in the free state, it occurs exclusively in the amino form (both in the solid state and in solution). The imino tautomer is considered to be the biologically active form. In the platinated species the N(10)H of the acridine can be involved in strong hydrogen bonding with a chloride ion leading to formation of an association complex, the formation constant has been found to be 1.4±103 M−1. The N(10)H┄CI interaction can influence the tautomeric equilibrium of the acridine dye also in the uncoordinated species, however, the shift in favor of the imino tautomer is not complete

Antitumor Trans Platinum DNA Adducts: NMR and HPLC Study of the Interaction Between a trans-Pt Iminoether Complex and the Deoxy Decamer d(CCTCGCTCTC)·d(GAGAGCGAGG)

The single-stranded oligonucleotide 5′-d(CCTCGCTCTC) (I) was reacted with the antitumor trans platinum iminoderivative trans-[PtCl2{E-HN = C(OMe)Me}2] (trans-EE) and subsequently annealed with its complementary strand 5′-d(GAGAGCGAGG) (II). The platinated duplex was characterized by 1D and 2D proton NMR spectroscopy at 600 MHz. In agreement with previous studies by different techniques trans-EE was found to form a monofunctional adduct with the duplex involving the guanine residue. The modification by trans-EE has been found to induce only minor local distortion in the duplex geometry. Two key crosspeaks observed in the NOESY map corresponding to a close contact between G5-H8 and the methoxy and the methyl group, respectively, enabled us to dock the trans-EE complex with the duplex by geometry optimization. The results support the idea that the antitumor activity of trans-EE is related to lesion of DNA fundamentally different from that of cisplatin. Unexpectedly, the NOESY spectra indicated that at the high NaCl concentration used (0.2 M) the duplex was found to undergo slow deplatination. This was subsequently proved by HPLC. In a separate experiment on platination of the single strand in a salt free environment the HPLC analysis showed that the monofunctional adduct was not deplatinated, however, after 24 hours, additidnal minor isomers were detected

Hydroxyapatite nanocrystals as a smart, pH sensitive, delivery system for kiteplatin

Hydroxyapatite (HA) nanocrystals are important inorganic constituents of biological hard tissues in vertebrates and have been proposed as a bone substitute or a coating material for prostheses in biomedicine. Hydroxyapatite is also amenable for its capacity to bind to a great variety of biomolecules and therapeutic agents. As drug carriers, apatite nanoparticles also have the advantage of pH dependent solubility and low toxicity. Thus HA nanoparticles are negligibly soluble at physiological pH but their dissolution is accelerated at lower pH such as that typically found in the vicinity of tumors. In the present study we have investigated the adsorption on and the release from biomimetic HA nanoparticles of two platinum derivatives of cis-1,4-diaminocyclohexane ([PtX2(cis-1,4-DACH)], X2 = Cl2 (1) and 1,1-cyclobutanedicarboxylate (CBDCA, 2)). The first of the two compounds proved to be active against colon cancer cells also resistant to oxaliplatin. The release has been investigated as a function of pH to mimic the different physiological environments of healthy tissues and tumors, and the in vitro cytotoxicity of the releasates from the HA matrices has been assessed against various human cancer cell lines. The results fully confirmed the potential of 1-loaded HA nanoparticles as bone-specific drug delivery devices

Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D

In Situ Formation of Zwitterionic Ligands: Changing the Passivation Paradigms of CsPbBr3 Nanocrystals

CsPbBr3 nanocrystals (NCs) passivated by conventional lipophilic capping ligands suffer from colloidal and optical instability under ambient conditions, commonly due to the surface rearrangements induced by the polar solvents used for the NC purification steps. To avoid onerous postsynthetic approaches, ascertained as the only viable stability-improvement strategy, the surface passivation paradigms of as-prepared CsPbBr3 NCs should be revisited. In this work, the addition of an extra halide source (8-bromooctanoic acid) to the typical CsPbBr3 synthesis precursors and surfactants leads to the in situ formation of a zwitterionic ligand already before cesium injection. As a result, CsPbBr3 NCs become insoluble in nonpolar hexane, with which they can be washed and purified, and form stable colloidal solutions in a relatively polar medium (dichloromethane), even when longly exposed to ambient conditions. The improved NC stability stems from the effective bidentate adsorption of the zwitterionic ligand on the perovskite surfaces, as supported by theoretical investigations. Furthermore, the bidentate functionalization of the zwitterionic ligand enables the obtainment of blue-emitting perovskite NCs with high PLQYs by UV-irradiation in dichloromethane, functioning as the photoinduced chlorine source.publishedVersionPeer reviewe

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys