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Background Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. Methods Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM ® . Results The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/ F ) with FF CL/ F 35% lower in patients of Japanese heritage across all treatments and FF CL/ F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/ F and weight on apparent volume of distribution (V2/ F ) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/ F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/ F and approximately an 8% increase in UMEC V2/ F . For a subject with COPD who smoked, UMEC CL/ F was 28% higher. For VI, weight on CL/ F and smoking status on V2/ F with an approximately 4% increase in VI CL/ F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/ F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. Conclusions All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Patients with early-stage COPD were assigned to usual care plus tiotropium or placebo. Tiotropium resulted in better FEV 1 values. The annual decline in the prebronchodilator FEV 1 was similar in the two groups, but a benefit from tiotropium was seen in postbronchodilator FEV 1 .

Purpose This study aimed to evaluate the effect of Pyridostigmine on IGF-1 and GH levels and the outcomes of COS cycles in women with POR. Methods A total of 110 eligible women were randomly allocated to Pyridostigmine (n: 55) and control (n: 55) groups. COS outcomes, including gonadotrophin doses, COS duration, cycle cancellation rate, number of retrieved oocytes, number of MII oocytes, and fertilization rate, were compared between the groups. Also, IGF-1 and GH levels were measured at three time points: baseline, on the 5th day of the cycle, and on the trigger day. Results A total of 92 participants (Pyridostigmine: 44, Control: 48) were included in the final analysis. The Pyridostigmine group required significantly lower gonadotrophin doses (P < 0.0022) and had a shorter COS duration (P = 0.0019). No significant differences were observed in cycle cancellation rate, number of retrieved oocytes, number of MII oocytes, or fertilization rate. Pyridostigmine significantly accelerated GH levels over time compared to the Control group, with larger mean differences observed at each time point. The interaction between time and group indicated that the effect of the intervention on GH levels varied over the course of the COS cycle. Specifically, the intervention augmented the effect of COS agents on GH levels, as evidenced by the higher GH levels observed in the intervention group compared to the control group. For IGF-1 levels, time had a highly significant effect (P < 0.0001), but the interaction between Time and Group was not significant (P = 0.5067). Mean IGF-1 levels were higher in the Pyridostigmine group, though not statistically significant. Conclusion Pyridostigmine improved COS efficiency by reducing gonadotrophin doses and COS duration. Further research is needed to explore its potential benefits in enhancing ovarian response in women with POR. Trial registry information Iranian Registry of Clinical Trials (IRCT). Registration date: 2023-08-05, Registration number: IRCT20100518003950N8.

Objectives Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. Design After a 9-day baseline period, 30 patients (mean±SEM age 50±2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. Results 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean±SEM 1.98±0.17 (baseline), 1.84±0.16 (treatment)), pyridostigmine accelerated (1.96±0.18 (baseline), 2.45±0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p≤0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p=0.14) than with placebo. Conclusions Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation. Clinical trial registration number TrialRegNo (NCT 00276406).

Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C–C bonds, particularly in the production of unsaturated scaffolds 1 . However, alkyl cross-couplings using native sp 3 -hybridized functional groups such as alcohols remain relatively underdeveloped 2 . In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C–O bonds 3 , but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners 4 . We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon–carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis. A metallaphotoredox-based cross-coupling platform is capable of activating a wide range of free alcohols using N-heterocyclic carbene salts, cleaving C–O bonds to form free carbon radicals that are then used to form new C–C bonds.

One shortcoming of olefin metathesis has been that acyclic alkenyl halides could not be generated efficiently and stereoselectively; but now halo-substituted molybdenum alkylidene species are shown to be able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z -alkenyl halides. Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z -alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules. Catalytic olefin metathesis Olefins with a halide substituent are a mainstay in synthetic chemistry. However, the scope for the efficient stereoselective synthesis of acyclic alkenyl halides — a class of compound common that includes many biologically active natural products — has been limited. Amir Hoveyda and colleagues show here that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and can participate in high-yielding olefin metathesis reactions that produce acyclic 1,2-disubstituted Z -alkenyl halides. Many alkenyl chlorides, bromides and fluorides can be obtained in up to 91% yield and complete Z selectivity.

A series of amide-based mono and dimeric pyridinium bromides were synthesized using conventional and microwave-assisted solvent-free methods. The quaternization reactions of m -xylene dibromide and 4-nitrobenzylbromide with amide-based substituted pyridine proceeded efficiently, whereas 1,6-dibromohexane required reflux conditions. A comparative analysis of the solvent-free microwave-assisted reactions revealed a significant reduction in reaction time (up to 20-fold) and increased yields, accompanied by simplified work-up procedures. Notably, these reactions exhibited 100% atom economy and generated no environmental waste. The cytotoxic effects of the synthesized compounds were assessed using the MTT assay, nuclear staining, and Real Time-Polymerase Chain Reaction (PCR) on the lung cancer cell line (A-549).Molecular docking studies were performed to investigate the interaction and binding of B-Raf kinase inhibitors with the amide-based mono and dimeric pyridinium bromides. Furthermore, the toxicity of the drug molecules was assessed using the BOILED-Egg plot at the central nervous system.

Cariogenic oral biofilms cause recurrent dental caries around composite restorations, resulting in unprosperous oral health and expensive restorative treatment. Quaternary ammonium monomers that can be copolymerized with dental resin systems have been explored for the modulation of dental plaque biofilm growth over dental composite surfaces. Here, for the first time, we investigated the effect of bis(2-methacryloyloxyethyl) dimethylammonium bromide (QADM) on human overlying mature oral biofilms grown intra-orally in human participants for 7–14 days. Seventeen volunteers wore palatal devices containing composite specimens containing 10% by mass of QADM or a control composite without QADM. After 7 and 14 days, the adherent biofilms were collected to determine bacterial counts via colony-forming unit (CFU) counts. Biofilm viability, chronological changes, and percentage coverage were also determined through live/dead staining. QADM composites caused a significant inhibition of Streptococcus mutans biofilm formation for up to seven days. No difference in the CFU values were found for the 14-day period. Our findings suggest that: (1) QADM composites were successful in inhibiting 1–3-day biofilms in the oral environment in vivo; (2) QADM significantly reduced the portion of the S. mutans group; and (3) stronger antibiofilm activity is required for the control of mature long-term cariogenic biofilms. Contact-killing strategies using dental materials aimed at preventing or at least reducing high numbers of cariogenic bacteria seem to be a promising approach in patients at high risk of the recurrence of dental caries around composites.

Despite advances in carbon–carbon fragment couplings, the ability to forge carbon–oxygen bonds in a general fashion via nickel catalysis has been largely unsuccessful; here, visible-light-excited photoredox catalysts are shown to provide transient access to Ni( iii ) species that readily participate in reductive elimination, leading to carbon–oxygen coupling. C–heteroatom coupling via nickel catalysis Despite advances in carbon–carbon fragment couplings, the ability to create carbon–oxygen bonds via nickel catalysis has been largely unsuccessful. Here David MacMillan and colleagues show that visible-light-excited photoredox catalysts can provide transient access to Ni( III ) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, the authors develop a highly efficient and general carbon–oxygen coupling reaction using alcohols and aryl bromides. Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon – carbon and carbon – heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C−C bond-forming reactions, most notably Negishi, Suzuki – Miyaura, Stille, Kumada and Hiyama couplings 1 , 2 . Despite the tremendous advances in C−C fragment couplings, the ability to forge C−O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C–O bond-forming step (formally known as the reductive elimination step) to occur via a Ni( iii ) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni( iii ) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon – oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to ‘switch on’ important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

The asymmetric cross-coupling reaction is developed as a straightforward strategy toward 1,1-diaryl alkanes, which are a key skeleton in a series of natural products and bioactive molecules in recent years. Here we report an enantioselective benzylic C(sp 3 )−H bond arylation via photoredox/nickel dual catalysis. Sterically hindered chiral biimidazoline ligands are designed for this asymmetric cross-coupling reaction. Readily available alkyl benzenes and aryl bromides with various functional groups tolerance can be easily and directly transferred to useful chiral 1,1-diaryl alkanes including pharmaceutical intermediates and bioactive molecules. This reaction proceeds smoothly under mild conditions without the use of external redox reagents. Chiral 1,1-diaryl alkanes are important targets in pharmaceutical industry. Here, the authors report report a redox-neutral enantioselective benzylic C−H bond arylation via photoredox/nickel dual catalysis accessing chiral 1,1-diarylalkane compounds under mild conditions.