Whether and How Disutilities of Adverse Events were Used in the Economic Evaluation of Drug Therapy for Cancer Treatment.

BACKGROUND: The disutilities of adverse events (AEs) are important inputs for cost-utility analysis (CUA), reflecting the impacts of AEs on health outcomes. Health technology assessment institutions and scholars have proposed recommendations for applying disutility values in economic evaluations. OBJECTIVES: This study aimed to identify the current use of disutilities of AEs as model parameters in the CUA of cancer drug therapy and to compare the discrepancies between the use of disutilities and published recommendations. METHODS: A systematic search was conducted on the PubMed, Web of Science, and Cochrane Library databases, as well as the official websites of the National Institute for Health and Care Research (NIHR), the Institute for Clinical and Economic Review (ICER), the Institute for Quality and Efficiency in Health Care (IQWiG), the Canadian Agency for Drugs and Technologies in Health (CADTH), and the Centre for Reviews and Dissemination (CRD) for CUAs of drug therapy for cancer published in English from January 2019 to April 2022. Information about the use of disutilities of AEs (whether and how disutilities were used, or why they were not used) in selected studies was extracted and compared with published recommendations. Descriptive analyses were used to summarize the results. RESULTS: A total of 467 CUAs were included, 54% (254/467) of which included disutilities of AEs in their model. The proportion that included these disutilities increased from 2019 to 2021, ranging from 47% (51/107) to 61% (116/190). Only 6% (15/254) of the CUAs using disutilities of AEs considered all five recommendations about the justification for inclusion and exclusion, description of values and sources, grades of AEs, calculation, and uncertainty analyses. Only 15% (72/467) provided a clear justification for inclusion and exclusion of disutilities of AEs, and 7% (17/254) did not provide values or sources. In total, 69% (175/254) of the analyses focused on AEs of grade 3 or greater, and 11% (28/254) applied utility decrements for grades 1 and 2. Disutilities of AEs were generally calculated using the incidence rates, which were clearly stated in 49% (65/132) of the analyses. Uncertainty analyses were conducted in 84% (214/254) of the CUAs. CONCLUSIONS: The current use of disutilities of AEs in CUAs shows some discrepancies with recommendations proposed in the literature. One is that detailed information about the use of disutilities of AEs was not reported and the other is that essential methods to analyze the impact of AEs on quality-adjusted life-years were not thoroughly conducted. Therefore, it is suggested that researchers should attach importance to the impact of AEs on health-related quality of life. Furthermore, an application process was developed for the disutilities of AEs to remind and guide researchers to correctly use the disutilities of AEs as parameters in the decision-analytic model.

The effects of berberine on inflammatory markers in Chinese patients with metabolic syndrome and related disorders: a meta­analysis of randomized controlled trials.

BACKGROUND: A meta-analysis of randomized controlled trials (RCTs) was conducted to systematically evaluate the effects of berberine on the inflammatory markers of metabolic syndrome (MetS) and related disorders. METHOD: Databases that were searched from inception to October 2020 included PubMed, Web of Science, the Cochrane Library, CNKI, VIP, WanFang Data, and ClinicalTrials.gov. Two reviewers independently selected articles and extracted data. The pooled evaluations were entered and analyzed in Review Manager 5.3. RESULTS: Of the 7387 publications screened, 52 studies were included, and the related trials involved 4616 patients. Pooled estimates showed that the use of berberine could significantly reduce the concentration level of C-reactive protein (CRP) [standardized mean difference (SMD) = - 1.54, 95% confidence intervals (CI) - 1.86, - 1.22, p < 0.05], tumor necrosis factor-α (TNF-α) [SMD = - 1.02, 95% CI - 1.27, - 0.77, p < 0.05], and interleukin 6 (IL-6) [SMD = - 1.17, 95% CI - 1.53, - 0.81, p < 0.05] among patients with MetS and related disorders. However, it did not affect the level of interleukin 1ß (IL-1ß) [SMD = - 0.81, 95% CI - 1.80, 0.17, p = 0.11]. CONCLUSION: Overall, the use of berberine in patients with MetS and related disorders appeared to significantly decrease several inflammatory markers. Further multi-center and rigorous investigations with larger patient populations are encouraged to confirm the effect of berberine on MetS and related disorders.

Rational design of few-layer MoSe2 confined within ZnSe-C hollow porous spheres for high-performance lithium-ion and sodium-ion batteries.

Rechargeable battery systems, including Li-ion batteries and Na-ion batteries, have attracted great interest in energy storage because of their high energy density, low cost, efficient energy storage and suitable redox potential. Nevertheless, their rapid development is still greatly hampered by some typical constraints including low coulombic efficiency, large volume changes and severe particle agglomeration and pulverization during the charge-discharge process. Here, we fabricate a few-layer MoSe2 confined within a ZnSe-C hollow porous sphere nanocomposite through a simple self-assembly strategy followed by selenization, which efficiently circumvents these problems. The fabricated ZnSe/MoSe2@C electrode demonstrates diverse advantages, including the existence of a few-layer structure, an in situ porous carbon matrix, multicomponent coordination and excellent pseudocapacitive behavior. When used as an anode material, it displays extraordinarily attractive electrochemical performance for both lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). The reversible capacity of ZnSe/MoSe2@C for LIBs reaches as high as 1051 mA h g-1 at 0.2 A g-1 (150 cycles). A long-term high-rate cycling test reveals an excellent stability of 524 mA h g-1 at 4 A g-1 after 600 cycles. In addition, for SIBs, ZnSe/MoSe2@C also manifests a high initial coulombic efficiency of 89% at 0.2 A g-1 and a remarkable reversible capacity of 381 mA h g-1 at a high current density of 4 A g-1 even after 250 cycles with negligible capacity loss. This is one of the best performances of ZnSe-based anode materials for SIBs reported so far. The regulation strategy reported in the present work is expected to offer new insights into the fabrication of high performance anode materials for SIBs.

Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition.

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.

Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists.

The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.

Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human ß3 adrenergic receptor agonists.

A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.

Highly regioselective palladium-catalyzed direct arylation of oxazole at C-2 or C-5 with aryl bromides, chlorides, and triflates.

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.

Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

Catalyst-controlled regioselective Suzuki couplings at both positions of dihaloimidazoles, dihalooxazoles, and dihalothiazoles.

Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.

Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent.

The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.

(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.

Discovery of potent and selective phenylalanine based dipeptidyl peptidase IV inhibitors.

anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. These are among the most potent compounds reported to date lacking an electrophilic trap. The most potent compound among these is 5-oxo-1,2,4-oxadiazole 44, which is a 3 nM DPP-IV inhibitor.

Substituted piperazines as novel dipeptidyl peptidase IV inhibitors.

Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP.

Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors.

Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice.

4-Amino cyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors.

Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.

Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors.

Aryldihydropyridazinones and aryldimethylpyrazolones with 2-benzyl vinylogous amide substituents have been identified as potent PDE3B subtype selective inhibitors. Dihydropyridazinone 8a (PDE3B IC(50)=0.19 nM, 3A IC(50)=1.3 nM) was selected for in vivo evaluation of lipolysis induction, metabolic rate increase, and cardiovascular effects.