Predictors of target lesion failure after percutaneous coronary intervention with a drug-coated balloon for de novo lesions.

BACKGROUND: There are limited data about determinant factors of target lesion failure (TLF) in lesions after percutaneous coronary intervention (PCI) using a drug-coated balloon (DCB) for de novo coronary artery lesions, including optical coherence tomography (OCT) findings. AIMS: The present study aims to investigate the associated factors of TLF in de novo coronary artery lesions with DCB treatment. METHODS: We retrospectively enrolled 328 de novo coronary artery lesions in 328 patients who had undergone PCI with a DCB. All lesions had been treated without a stent, and both pre- and post-PCI OCT had been carried out. Patients were divided into two groups, with or without TLF, which was defined as a composite of culprit lesion-related cardiac death, myocardial infarction, and target lesion revascularisation, and the associated factors of TLF were assessed. RESULTS: At the median follow-up period of 460 days, TLF events occurred in 31 patients (9.5%) and were associated with patients requiring haemodialysis (HD; 29.0% vs 10.8%), with a severely calcified lesion (median maximum calcium arc 215° vs 104°), and with the absence of OCT medial dissection (16.1% vs 60.9%) as opposed to those without TLF events. In Cox multivariable logistic regression analysis, HD (hazard ratio [HR]: 2.26, 95% confidence interval [CI]: 1.00-5.11; p=0.049), maximum calcium arc (per 90°, HR: 1.34, 95% CI: 1.05-1.72; p=0.02), and the absence of post-PCI medial dissection on OCT (HR: 8.24, 95% CI: 3.15-21.6; p<0.001) were independently associated with TLF. CONCLUSIONS: In de novo coronary artery lesions that received DCB treatment, factors associated with TLF were being on HD, the presence of a severely calcified lesion, and the absence of post-PCI medial dissection.

Sedation Therapy in Intensive Care Units: Harnessing the Power of Antioxidants to Combat Oxidative Stress.

In critically ill patients requiring intensive care, increased oxidative stress plays an important role in pathogenesis. Sedatives are widely used for sedation in many of these patients. Some sedatives are known antioxidants. However, no studies have evaluated the direct scavenging activity of various sedative agents on different free radicals. This study aimed to determine whether common sedatives (propofol, thiopental, and dexmedetomidine (DEX)) have direct free radical scavenging activity against various free radicals using in vitro electron spin resonance. Superoxide, hydroxyl radical, singlet oxygen, and nitric oxide (NO) direct scavenging activities were measured. All sedatives scavenged different types of free radicals. DEX, a new sedative, also scavenged hydroxyl radicals. Thiopental scavenged all types of free radicals, including NO, whereas propofol did not scavenge superoxide radicals. In this retrospective analysis, we observed changes in oxidative antioxidant markers following the administration of thiopental in patients with severe head trauma. We identified the direct radical-scavenging activity of various sedatives used in clinical settings. Furthermore, we reported a representative case of traumatic brain injury wherein thiopental administration dramatically affected oxidative-stress-related biomarkers. This study suggests that, in the future, sedatives containing thiopental may be redeveloped as an antioxidant therapy through further clinical research.

Synthesis of novel entecavir analogues having 4'-cyano-6''-fluoromethylenecyclopentene skeletons as an aglycone moiety as highly potent and long-acting anti-hepatitis B virus agent.

Encouraged by our recent findings that 4'-cyano-deoxyguanosine (2), entecavir analogues 4 and 5 are highly potent anti-hepatitis B virus (HBV) agents, we designed and synthesized 6 having a hybridized structure of 4 and 5. The chiral quaternary carbon portion at the 4'-position, which is substituted by cyano- and 5'-hydroxymethyl groups, was stereospecifically constructed by radical-mediated 5-exo-dig mode cyclization of 10. The introduction of the fluorine atom into the 6''-position was achieved by radical-mediated stannylation of sulfide (E)-11 and subsequent electrophilic fluorination of (E)-12. The desired (E)-6 was obtained after the introduction of the guanine base into (E)-18 under Mitsunobu conditions and following global deprotection. The stereoisomer (Z)-6 was also prepared by the same procedure using (Z)-12. Compound (E)-6 showed highly potent anti-HBV activity (EC50 = 1.2 nM) with favorable cytotoxicity (CC50 = 93 µM).

Investigation of Various Organic Radicals Dispersed in Polymethylmethacrylate Matrices Using the Electron Spin Resonance Spectroscopy Technique.

The electron spin resonance (ESR) spectroscopy technique was used to study various organic radicals, such as 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO), 4-hydroxy-TEMPO (TEMPOL), 2-X-nitronylnitroxide (2-X-NN, X = Ph, NO2Ph, or cyclohexyl), 4-Y-benzonitronylnitroxide (4-Y-PhBzNN, Y = Ph or NO2Ph), and 2-Z-iminonitroxide (2-Z-IN, Z = Ph or NO2Ph) dispersed in a polymethylmethacrylate (PMMA) matrix. The experiments were conducted at room temperature. The complex nature of the recorded ESR spectra could be attributed to the superposition of the rotational diffusion component of TEMPO (or TEMPOL) in the nanospace of the PMMA matrix with the rigid-limit component. A single component of the rigid-limit was observed for 2-X-NN and 4-Y-PhBzNN radicals dispersed in the PMMA matrix. The isotropic components of g and hyperfine ( A ) tensor, estimated by analyzing the solution spectra, were used to determine the g and A components of 4-Y-PhBzNN. Only the rotational diffusion component was observed for the 2-Z-IN radical. These results demonstrated that the PMMA matrix contains cylindrical nanospaces. Various radicals other than TEMPO derivatives could be used in the ESR spin probe technique as probe molecules for determining the structures, sizes, and shapes of the nanospaces.

Synthesis, Anti-HBV, and Anti-HIV Activities of 3'-Halogenated Bis(hydroxymethyl)-cyclopentenyladenines.

Synthesis of 3'-halogeno analogues (5a-d) of 9-[c-4,t-5-bis(hydroxymethyl)-cyclopent-2-en-r-1-yl]-9H-adenine (BCA, 3) was accomplished by means of dual utilization of the vinyl sulfone functional moieties in both 10 and 16 utilizing a SN2' conjugate-addition reaction and a sulfur-extrusive stannylation, respectively. Evaluation of the antiviral activities of 5a-d revealed that introduction of a halogeno-substituent into the 3'-position of (-)-BCA diminished its anti-HIV-1 activity but increased the inhibitory activity for the reverse transcriptase of HBV in that the 3'-fluorinated BCA 5d exhibited the highest activity without significant cytotoxicity.

A novel entecavir analogue constructing with a spiro[2.4]heptane core structure in the aglycon moiety: Its synthesis and evaluation for anti-hepatitis B virus activity.

Synthesis of a novel 2'-deoxy-guanine carbocyclic nucleoside 4 constructed with spiro[2.4]heptane core structure in the aglycon moiety was carried out. Radical-mediated 5-exo-dig mode cyclization and following cyclopropanation proceeded efficiently to furnish the spiro alcohol 10. Subsequent Mitsunobu-type glycosylation between 13 and 14, deoxygenation of the 2'-hydroxyl group of 16 and deprotection of 17 gave the title compound 4. Compound 4 demonstrated moderate anti-HBV activity (EC50 value of 0.12 ± 0.02 µM) and no cytotoxicity against HepG2 cells was observed up to 100 µM.

Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB1 receptor and cannabimimetic effects in mice.

Drug abusers most often smoke 'herbal incense' as a cigarette or inhale it using a smoking tool. Smoking may cause pyrolysis of the drug and produce decomposed products of which biological effect has never been investigated. The synthetic cannabinoid UR-144 is known to undergo thermal degradation, giving a ring-opened isomer, so-called UR-144 degradant. The present study demonstrates by using UR-144 as a model drug that the smoke of burned UR-144 contains the UR-144 degradant. The UR-144 degradant showed approximately four fold higher agonist activity to human CB1 receptor and augmented hypothermic and akinetic actions in mice compared to UR-144. These results indicate that smoking behavior may increase psychological actions of the certain synthetic cannabinoids.

Enantioselective α-Benzoyloxylation of Malonic Diesters by Phase-Transfer Catalysis.

A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited by the synthesis of a mineralocorticoid receptor antagonist.

Abundances of Triacylglycerol Positional Isomers and Enantiomers Comprised of a Dipalmitoylglycerol Backbone and Short- or Medium-chain Fatty Acids in Bovine Milk Fat.

Bovine milk fat (BMF) is composed of triacylglycerols (TAG) rich in palmitic acid (P), oleic acid (O), and short-chain or medium-chain fatty acids (SCFAs or MCFAs). The composition and binding positions of the fatty acids on the glycerol backbone determine their physical and nutritional properties. SCFAs and MCFAs are known to characteristically bind to the sn-3 position of the TAGs in BMF; however, there are very few non-destructive analyses of TAG enantiomers binding the fatty acids at this position. We previously reported a method to resolve the enantiomers of TAGs, binding both long-chain saturated fatty acid and unsaturated fatty acid at the sn-1 and 3 positions, in palm oil, fish oil, and marine mammal oil using chiral HPLC. Here, we further developed a method to resolve several TAG enantiomers containing a dipalmitoyl (PP) glycerol backbone and one SCFA (or MCFA) in BMF. We revealed that the predominant TAG structure in BMF was homochiral, such as 1,2-dipalmitoyl-3-butyroyl-sn-glycerol. This is the first quantitative determination of many TAG enantiomers, which bind to a SCFA or MCFA, in BMF was evaluated simultaneously. Furthermore, the results indicated that the amount ratios of the positional isomers and enantiomers of TAGs consisting of a dipalmitoyl (PP) glycerol backbone and SCFA (or MCFA), resembled the whole TAG structures containing the other diacylglycerol backbones consisting of P, O, myristic acid, and/or stearic acid in BMF.

Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids.

A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.

Partial cDNA sequence of a relaxin-like factor (RLF) receptor, LGR8 and possible existence of the RLF ligand-receptor system in goat testes.

Relaxin-like factor (RLF), also known as insulin-like factor 3 (INSL3), is produced by testicular Leydig cells, but its specific receptor LGR8 (leucine-rich repeat family of G-protein-coupled receptor 8) has not been identified in goats. This study aimed to identify complementary DNA (cDNA) sequences of goat LGR8, and characterize the expression of both RLF and LGR8 in goat testes by RT-PCR and immunohistochemistry. Testes were collected from immature (3-month-old) and mature (24-month-old) Saanen goats, and partial cDNA sequences of the goat homologue of human LGR8 were identified. The sequence encoded a reduced peptide sequence of 167 amino acids, which corresponded to transmembrane regions 2 through 5, followed by the beginning of intracellular loop 3 of human LGR8. Expression of both LGR8 and RLF genes was drastically increased in mature testes compared with immature ones. Although RLF protein was restricted to Leydig cells, LGR8 protein was detected in both Leydig cells and seminiferous epithelial cells (possibly germ cells and Sertoli cells). These results reveal a possible existence of the RLF-LGR8 ligand-receptor system within the goat testis, suggesting that RLF may play a role in testicular function through LGR8 on Leydig cells and seminiferous epithelial cells in an autocrine and/or paracrine manner.

Synthesis and antiviral evaluation of 4'-alkoxy analogues of 9-(beta-D-xylofuranosyl)adenine.

BACKGROUND: Motivated by the reported biological activity of 9-(beta-D-xylofuranosyl)adenine (xylo-A), the synthesis of its 4'-alkoxy analogues was carried out. METHODS: The starting material 9-(3-deoxy-beta-D-glycero-pento-3-enofuranosyl)adenine (1) was prepared from adenosine. Compound 1 was converted to the 2',5'-bis-O-(tert-butyldimethylsilyl) derivative (2) and then to the N(6)-pivaloyl derivative (3). When 3 was reacted with meta-chloroperbenzoic acid in the presence of a series of alcohols, the beta-D-isomer of the respective 4'-alkoxy derivative was obtained exclusively in high yield. Deprotection of these products led to the isolation of the desired 4'alkoxy analogues (8a-l) of xylo-A. RESULTS: Antiviral evaluation revealed that none of these analogues showed inhibitory activity against a wide variety of DNA and RNA viruses. CONCLUSIONS: We assume that conformational difference of the sugar moiety of 8a-l from that of xylo-A could be attributable to their inactivity.