Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(C∧N)Cl] and [Cp*Ir(C∧N)L]BF4 with different degrees of π-expansion in the C∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.

Durable benefit after treatment of obstructive benign prostatic hyperplasia with a novel drug-device combination product: 2-year outcomes from the EVEREST-I study.

PURPOSE: To evaluate the safety and efficacy of the Optilume BPH Catheter System for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). METHODS: This open-label, single-arm study enrolled eighty subjects with LUTS secondary to BPH who were treated with the Optilume BPH Catheter System. Symptoms were recorded utilizing the International Prostate Symptom Score (IPSS) and Benign Prostatic Hyperplasia Impact Index (BPH-II). Functional improvement was measured utilizing peak urinary flow rate (Qmax) and post-void residual urine volume (PVR). Adverse events were systematically captured and reported at each follow-up visit. RESULTS: Subjects treated with the Optilume BPH Catheter System experienced a significant improvement in LUTS from baseline through 2 years of follow-up, as measured by IPSS (22.3 vs 8.2, p < 0.001) and BPH-II (6.9 vs 2.3, p < 0.001). Functional improvement was also significant, with Qmax improving from an average of 10.9 mL/s at baseline to 17.2 mL/s at the 2-year follow-up and PVR improving from 63.1 to 45.0 mL. Treatment-related adverse events were typically minor, with none occurring between 1- and 2-year post-treatment. CONCLUSIONS: The Optilume BPH Catheter System is a unique minimally invasive surgical therapy that combines mechanical and pharmaceutical aspects for the treatment of BPH. The functional and symptomatic improvements seen after treatment are significant and have been sustained through 2 years in this early feasibility study. REGISTRATION: NCT03423979, registered February 6, 2018.

A Drug-Coated Balloon Treatment for Urethral Stricture Disease: Three-Year Results from the ROBUST I Study.

Introduction: Endoscopic management of male anterior urethral stricture disease is common; however, repeat treatment is associated with high recurrence rates. Here, we report the 3-year results of the ROBUST I trial, which evaluated the safety and efficacy of the Optilume® drug coated balloon (DCB) in men with recurrent urethral strictures. Methods: Adult men with recurrent bulbar urethral strictures ≤2 cm in length and 1-4 prior endoscopic interventions were treated with the Optilume DCB. Functional success was defined as ≥50% reduction in International Prostate Symptom Score (IPSS) without need for retreatment. Other outcomes included quality of life, maximum flow rate, post-void residual urine volume, erectile function, and freedom from repeat intervention. Results: Of the 53 enrolled and treated men, 33 completed the 3-year visit, with 10 patients experiencing clinical failures at previous visits, giving a total of 43 subjects evaluable for the functional success endpoint. Functional success was achieved in 67% (29/43) and freedom from retreatment in 77% (33/43). Average IPSS improved from 25.2 at baseline to 5.5 at 3 years (p<0.0001). Significant improvements were observed in quality of life, flow rate, and post-void residual urine volume. Erectile function was not affected by treatment. Device-related adverse events were mild or moderate in nature and resolved quickly after onset. There were no serious treatment-related adverse events. Conclusion: Symptomatic improvement after treatment with the Optilume DCB was maintained through 3 years in a population highly susceptible to recurrent urethral stricture disease. This minimally invasive therapy is safe with no negative impact on sexual function.

Photocatalytic Aerobic Dehydrogenation of N-Heterocycles with Ir(III) Photosensitizers Bearing the 2(2'-Pyridyl)benzimidazole Scaffold.

Photoredox catalysis constitutes a very powerful tool in organic synthesis, due to its versatility, efficiency, and the mild conditions required by photoinduced transformations. In this paper, we present an efficient and selective photocatalytic procedure for the aerobic oxidative dehydrogenation of partially saturated N-heterocycles to afford the respective N-heteroarenes (indoles, quinolines, acridines, and quinoxalines). The protocol involves the use of new Ir(III) biscyclometalated photocatalysts of the general formula [Ir(C^N)2(N^N')]Cl, where the C^N ligand is 2-(2,4-difluorophenyl)pyridinate, and N^N' are different ligands based on the 2-(2'-pyridyl)benzimidazole scaffold. In-depth electrochemical and photophysical studies as well as DFT calculations have allowed us to establish structure-activity relationships, which provide insights for the rational design of efficient metal-based dyes in photocatalytic oxidation reactions. In addition, we have formulated a dual mechanism, mediated by the radical anion superoxide, for the above-mentioned transformations.

Rational design of mitochondria targeted thiabendazole-based Ir(III) biscyclometalated complexes for a multimodal photodynamic therapy of cancer.

Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)2(N^N')]Cl (N^N' = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and [3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action, which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both processes seem to be the result of photocatalytic oxidation processes.

Distinct mechanism of action for antitumoral neutral cyclometalated Pt(II)-complexes bearing antifungal imidazolyl-based drugs.

Three neutral Pt(II) complexes containing 1-Methylimidazole and the antifungal imidazolyl drugs Clotrimazole and Bifonazole have been prepared. The general formula of the new derivatives is [Pt(κ2-(C^N)Cl(L)], where C^N stands for ppy = 2-phenylpyridinate, and L = 1-Methylimidazole (MeIm) for [Pt-MeIm]; L = Clotrimazole (CTZ) for [Pt-CTZ] and L = Bifonazole (BFZ) for [Pt-BFZ]). The complexes have been completely characterized in solution and the crystal structures of [Pt-BFZ] and [Pt-CTZ] have been resolved. Complexes [Pt-MeIm] and [Pt-BFZ] present higher cytotoxicity than cisplatin in SW480 (colon adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian cancer) cell lines. [Pt-MeIm] shows the highest accumulation in A549 cells, in agreement with its inability to interact with serum albumin. By contrast, [Pt-CTZ] and [Pt-BFZ] interact with serum proteins, a fact that reduces their bioavailability. The strongest interaction with bovine serum albumin (BSA) is found for [Pt-BFZ], which is the least internalized inside the cells. All the complexes are able to covalently interact with DNA. The most cytotoxic complexes, [Pt-MeIm] and [Pt-BFZ] induce cellular accumulation in G0/G1 and apoptosis by a similar pathway, probably involving a reactive oxygen species (ROS) generation mechanism. [Pt-BFZ] turns out to be the most efficient complex regarding ROS generation and causes mitochondrial membrane depolarization, whereas [Pt-MeIm] induces the opposite effect, hyperpolarization of the mitochondrial membrane. On the contrary, the least cytotoxic complex, [Pt-CTZ] cannot block the cell cycle or generate ROS and the mechanism by which it induces apoptosis could be a different one.

Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand.

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.

Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(III) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand.

Photodynamic therapy is an alternative to classical chemotherapy due to its potential to reduce side effects by a controlled activation of a photosensitizer through local irradiation with light. The photosensitizer then interacts with oxygen and generates reactive oxygen species. Iridium biscyclometallated complexes are very promising photosensitizers due to their exceptional photophysical properties and their ability to target mitochondria. Four Ir(III) biscyclometallated complexes of formula [Ir(C^N)2(N^N')]Cl, where N^N' is a ligand containing a benzimidazolyl fragment, have been synthesized and characterized. The C^N ligands were 2-phenylpyridinate (ppy) and 2-(2,4-difluorophenyl)pyridinate (dfppy). The complexes exhibited high photostability. The electrochemical and photophysical properties were modulated by both the cyclometallating and the ancillary ligands. The dfppy derivatives yielded the highest emission energy values, quantum yields of phosphorescence and excited state lifetimes. All complexes generated 1O2 in aerated solutions upon irradiation. Biological studies revealed that these complexes have a moderate cytotoxicity in the dark against different human cancer cell lines: prostate (PC-3), colon (CACO-2) and melanoma (SK-MEL-28), and against non-malignant fibroblasts (CCD-18Co). However, derivatives with ppy ligands ([1a]Cl, [2a]Cl) yielded a relevant photodynamic activity upon light irradiation (450 nm, 24.1 J cm-2), with phototoxicity indexes (EC50,dark/EC50,light) of 20.8 and 17.3, respectively, achieved in PC-3 cells. Mechanistic studies showed that these complexes are taken up by the cells through endocytosis and preferentially accumulate in mitochondria. Upon photoactivation, the complexes induced mitochondrial membrane depolarization and DNA damage, thus triggering cell death, mainly by apoptosis. Complex [1a]Cl is also able to oxidize NADH. This mitochondria-targeted photodynamic mechanism greatly inhibited the reproductive capacity of cancer cells and provides a valuable alternative to traditional chemotherapy for the controlled treatment of cancer.

Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal.

An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity.

A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

One-year outcomes after treatment with a drug-coated balloon catheter system for lower urinary tract symptoms related to benign prostatic hyperplasia.

BACKGROUND: This is the first report of the 1-year outcomes of the EVEREST-I study evaluating the safety and efficacy of the Optilume® BPH Catheter System, a prostatic paclitaxel-coated balloon catheter system, for the treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). METHODS: Subjects were men >50 years old with moderate-to-severe LUTS secondary to BPH, peak urinary flow rate of 5-15 ml/s, prostatic urethra length 30-55 mm, and prostate volume 20-80 g. All were treated with the Optilume BPH Catheter System and followed at Foley removal, 2 weeks, 30 days, 3, 6, and 12 months after treatment. The primary endpoint was the proportion of subjects with ≥40% improvement in International Prostate Symptom Score (IPSS). The rate of post-procedural complications was evaluated. RESULTS: Eighty subjects were treated at six sites in Latin America and 75 completed the 1-year follow-up. The percent of subjects with an improvement ≥40% in IPSS from baseline was 81% at 3 months and 1 year. IPSS improved from 22.3 at baseline to 7.9 at 1 year, Qmax improved from 10.9 to 18.4 ml/s, and IPSS QoL improved from 4.6 to 1.3. Post-procedural complications included common urologic events and the rate of complications was significantly impacted by device diameter. CONCLUSIONS: Treatment with the minimally invasive Optilume BPH Catheter System is safe and showed subjective and objective improvements in LUTS. Benefits were rapid and persisted through 1 year. The initial results warrant further evaluation of this therapy as a treatment option for patients with LUTS related to BPH.

A drug-coated balloon treatment for urethral stricture disease: Two-year results from the ROBUST I study.

INTRODUCTION: Mechanical balloon dilation and direct visualization internal urethrotomy (DVIU) are the most widely used treatments for urethral stricture disease in the U.S., but recurrence rates are high, especially after re-treatment. This study investigates the safety and efficacy of the Optilume™ paclitaxel-coated balloon for the treatment of recurrent strictures. METHODS: Men with recurrent bulbar strictures ≤2 cm with 1-4 prior endoscopic treatments were treated with the Optilume™ drug-coated balloon. Patients were evaluated within 14 days, three, six, 12, and 24 months post-treatment. The primary safety endpoint was serious urinary adverse events. The primary efficacy endpoint was ≥50% improvement in International Prostate Symptom Score (IPSS) at 24 months. Secondary outcomes included quality of life, erectile function, flow rate, and post-void residual urine volume. RESULTS: A total of 53 subjects were enrolled and treated; 46 completed the 24-month followup. Forty-three percent of men had undergone >1 previous dilations, with a mean of 1.7 prior dilations. There were no serious adverse events related to treatment at two years. Success was achieved in 32/46 (70%), and baseline IPSS improved from a mean of 25.2 to 6.9 at 24 months (p<0.0001). Quality of life, flow rate, and post-void residual urine volumes improved significantly from baseline. There was no impact on erectile function. CONCLUSIONS: Two-year data indicates the Optilume™ paclitaxel-coated balloon is safe for the treatment of recurrent bulbar urethral strictures. Early efficacy results are encouraging and support further followup of these men through five years, as well as further investigation with a randomized trial.

A nucleus-directed bombesin derivative for targeted delivery of metallodrugs to cancer cells.

We have synthesized a set of bombesin derivatives with the aim of exploring their tumor targeting properties to deliver metal-based chemotherapeutics into cancer cells. Peptide QRLGNQWAVGHLL-NH2 (BN3) was selected based on its high internalization in gastrin-releasing peptide receptor (GRPR)-overexpressing PC-3 cells. Three metallopeptides were prepared by incorporating the terpyridine Pt(II) complex [PtCl(cptpy)]Cl (1) (cptpy = 4'-(4-carboxyphenyl)-2,2':6,2″-terpyridine) at the N-terminus of BN3 or at the NƐ- or Nα-amino group of an additional Lys residue (1-BN3, Lys-1-BN3 and 1-Lys-BN3, respectively). 1-Lys-BN3 displayed the best cytotoxic activity (IC50: 19.2 ±â€¯1.7 µM) and similar ability to intercalate into DNA than complex 1. Moreover, the polypyridine Ru(II) complex [Ru(bpy)2)(cmbpy)](PF6)2 (2) (bpy = 2,2'-bipyridine; cmbpy = 4-methyl-2,2'-bipyridine-4'-carboxylic acid), with proven activity as photosensitizer, was coupled to BN3 leading to metallopeptide 2-Lys-BN3. Upon photoactivation, 2-Lys-BN3 displayed 2.5-fold higher cytotoxicity against PC-3 cells (IC50: 7.6 ±â€¯1.0 µM) than complex 2. To enhance the accumulation of the drugs into the cell nucleus, the nuclear localization signal (NLS) PKKKRKV was incorporated at the N-terminus of BN3. NLS-BN3 displayed higher cellular internalization along with nuclear biodistribution. Accordingly, metallopeptides 1-NLS-BN3 and 2-NLS-BN3 showed increased cytotoxicity (IC50: 12.0 ±â€¯1.1 µM and 2.3 ±â€¯1.1 µM). Interestingly, the phototoxic index of 2-NLS-BN3 was 8-fold higher than that of complex 2. Next, the selectivity towards cancer cells was explored using 1BR3.G fibroblasts. Higher selectivity indexes were obtained for 1-NLS-BN3 and 2-NLS-BN3 than for the unconjugated complexes. These results prove NLS-BN3 effective for targeted delivery of metallodrugs to GRPR-overexpressing cells and for enhancing the cytotoxic efficacy of metal-based photosensitizers.

Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and Ir(III) bearing thiabendazole complexes.

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid-base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), both complexes are more internalized than cisplatin after 4 h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

Analysis of Ion Pairing in Solid State and Solution in p-Cymene Ruthenium Complexes.

The importance of ion pairing in different fields of chemistry is widely recognized. In this work, we have synthesized a set of cationic p-cymene ruthenium complexes of general formula [(p-cym)Ru(L')(κ2-O^N-L)]X (p-cym = p-cymene; L' = N-methylimidazole (MeIm), N-ethylpiperidylimidazole (EpipIm), 1,3,5-triaza-7-phosphaadamantane (PTA); L = 2-(1H-benzimidazol-2-yl)phenolato (L1), 2-(1,3-benzothiazol-2-yl)phenolato (L2); X = Cl-, BF4-, OTf-, BPh4-). X-ray diffraction studies on selected complexes revealed relatively strong anion-cation interactions in the solid state mainly based on N-H···X (X = Cl, F, O) and C-H···π interactions, also observed in the DFT-modeled complexes in the gas phase. Moreover, NMR studies showed that they exist as intimate ion pairs in solution and, remarkably, as head-to-tail quadruples in the particular case of the cation [(p-cym)Ru(MeIm)(κ2- O^N-L1)]+ ([1]+) with Cl- and BPh4- as counteranions. Furthermore, a value of ΔG = -2.9 kcal mol-1 at 299 K has been estimated for the equilibrium {[1]BPh4···[1]BPh4} ⇆ 2{[1]+···BPh4-} in concentrated CDCl3 solutions. In addition, preliminary studies concerning the cytotoxic properties against HeLa cell lines of the derivatives suggested a positive effect derived from the presence of the lipophilic BPh4- anion and also from the NH group of the benzimidazolyl fragment.

Non-emissive RuII Polypyridyl Complexes as Efficient and Selective Photosensitizers for the Photooxidation of Benzylamines.

Five new RuII polypyridyl complexes bearing N-(arylsulfonyl)-8-amidoquinolate ligands and three of their biscyclometalated IrIII congeners have been prepared and employed as photocatalysts (PCs) in the photooxidation of benzylamines with O2 . In particular, the new RuII complexes do not exhibit photoluminescence, rather they harvest visible light efficiently and are very stable in solution under irradiation with blue light. Their non-emissive behavior has been related to the low electrochemical energy gaps and rationalized on the basis of theoretical calculations (DFT analysis) that predict low S0 ←T1 energy values. Moreover, the RuII complexes, despite being non-emissive, display excellent activities in the selective photocatalytic transformation of benzylamines into the corresponding imines. The presence of an electron-withdrawing group (-CF3) on the arene ring of the N-(arylsulfonyl)-8-amidoquinolate ligand improves the photocatalytic activity of the corresponding photocatalyst. Furthermore, all the experimental evidence, including transient absorption spectroscopy measurements suggest that singlet oxygen is the actual oxidant. The IrIII analogues are considerably more photosensitive and consequently less efficient photosensitizers (PSs).

Appended Aromatic Moieties Determine the Cytotoxicity of Neutral Cyclometalated Platinum(II) Complexes Derived from 2-(2-Pyridyl)benzimidazole.

A new family of neutral chiral cyclometalated platinum(II) complexes with formula [Pt(κ2-(C^N))Cl(κ1-(L))], where (C^N) = 2-phenylpyridinate and (L) = 2-(2-pyridyl)benzimidazole (L1) or (N-(CH2)-Ar-(2-(2-pyridyl)benzimidazole) ligands; (Ar = phenyl (L2), naphthyl (L3), pyrenyl (L4)), have been synthesized and completely characterized. The unexpected κ1 coordination mode of the 2-(2-pyridyl)benzimidazole-derived ligands has been confirmed by spectroscopic techniques and X-ray diffraction. The aromatic moieties on the ligands in the new platinum(II) complexes have a remarkable influence on the cytotoxicity and in the binding mode to DNA. [Pt-L1]-[Pt-L4] complexes internalized more than cisplatin in the SW480 cancer cells even though only [Pt-L1] and [Pt-L2] display high cytotoxicity. 1H NMR and 13P{1H}NMR pointed out that [Pt-L1] and [Pt-L2] complexes bind covalently to dGMP, while the electrophoresis assays and CD experiments indicate that only [Pt-L2] is able to covalently interact with DNA, inducing the same conformational changes in the plasmid DNA as cisplatin. Although the complex [Pt-L4] intercalates into DNA, probably through the pyrenyl moiety, no biological activity is observed.

A drug-coated balloon treatment for urethral stricture disease: Interim results from the ROBUST I study.

INTRODUCTION: We aimed to investigate the safety and preliminary efficacy of the Optilume™ paclitaxel-coated balloon for the treatment of recurrent urethral stricture. METHODS: Men with bulbar urethral strictures ≤2 cm with 1-4 prior endoscopic treatments were enrolled at four study sites after ethics committee approvals. All subjects were treated with mechanical balloon dilation or direct visualization internal urethrotomy prior to drug-coated balloon treatment. Patients were evaluated at 2-5 days, 14 days, three, six, and 12-months post-treatment. The primary safety endpoint was serious complications through 90 days post-procedure. The preliminary efficacy endpoint was anatomic success, defined as urethral lumen ≥14 Fr at 12 months. RESULTS: A total of 53 subjects were enrolled and treated; 46 completed the 12-month followup. Forty-three percent of men had undergone >1 previous dilation; the mean for the overall study population was 1.7 prior dilations. There were no serious adverse events related to the treatment within 90 days. Anatomic success was achieved in 32/46 (70%; 95% confidence interval [CI] 54-82%) at 12 months. The 14 failures included seven cystoscopic recurrences, five retreatments, and two patients who exited the study early due to symptom recurrence. CONCLUSIONS: One-year data indicates the Optilume paclitaxel-coated balloon is safe for the treatment of recurrent bulbar urethral strictures. Early efficacy results are encouraging and support further followup of these men through five years, as well as further investigation with a randomized trial.

Efecto de la cocción sobre el índice glicémico del plátano (Musa paradisiaca) y la yuca (Manihot esculenta) / Effect of cooking on the glycemic index of the banana (Musa paradisiaca) and the yuca (Manihot esculenta)

Introducción: se evaluó el efecto que distintos tipos de cocción tienen sobre el índice glicémico del plátano (Musa paradisiaca) maduro y la yuca (Manihot esculenta), alimentos que comúnmente consume población venezolana. Materiales y métodos: el estudio fue de tipo descriptivo. Los alimentos se adquirieron en mercados locales y se probaron las técnicas de horneado, hervido (sancochado) y frito. Se trabajó con la preparación artesanal tipo "casabe" como el equivalente a la yuca horneada. Se seleccionó una muestra de 35 individuos sanos, de sexo masculino, entre 20 y 25 años de edad, quienes se dividieron de manera completamente aleatoria en siete grupos de cinco personas cada uno para suministrarles el plátano y la yuca en sus diferentes preparaciones, y un grupo como control para suministrarle el pan blanco (alimento control). A los sujetos se les midió la glicemia basal y se le suministraron 50 g del alimento; se tomaron muestras de sangre capilar a intervalos de 15 minutos hasta alcanzar su glicemia basal. Con estos datos se calcularon los índices glicémicos. Resultados: se encontró que para el plátano frito el IG fue de 12,16±2,67, signifcativamente menor (p<0,001) al horneado (IG=91,13±11,52) o sancochado (IG=48,43±9,73). En el caso de la yuca, se observó que el grupo que consumió casabe exhibió el mayor IG=65±5,79, signifcativamente superior (p<0,001) al ocasionado por la yuca sancochada (IG=24±3,51) y la sancochada/frita (IG=32±4,45). Conclusiones: los hallazgos obtenidos en el estudio determinaron que la aplicación de distintos procesos de cocción sobre el mismo alimento altera signifcativamente su índice glicémico.