Nutritional Recommendations for Type 2 Diabetes: An International Review of 15 Guidelines.

OBJECTIVES: Recommendations from clinical practice guidelines (CPGs) for individuals with type 2 diabetes mellitus (T2DM) may be inconsistent, and little is known about their quality. Our aim in this study was to systematically review the consistency of globally available CPGs containing nutritional recommendations for T2DM and to assess the quality of their methodology and reporting. METHODS: PubMed, China Biology Medicine and 4 main guideline websites were searched. Four researchers independently assessed quality of the methodology and reporting using the Appraisal of Guidelines for Research and Evaluation, second edition (AGREE II) instrument and the Reporting Items for Practice Guidelines in HealThcare (RIGHT) checklist. RESULTS: Fifteen CPGs include 65 nutritional recommendations with 6 sections: 1) body weight and energy balance; 2) dietary eating patterns; 3) macronutrients; 4) micronutrients and supplements; 5) alcohol; and 6) specific, functional foods. Current nutritional recommendations for individuals with T2DM on specific elements and amounts are not completely consistent in different CPGs and fail to assign the specific supporting evidence and strength of recommendations. To use nutritional recommendations to guide and manage individuals with T2DM, it is important to address the current challenges by establishing a solid evidence base and indicating the strength of recommendations. Overall, 8 CPGs classified as recommended for clinical practice used AGREE II. Fifteen CPGs adhere to <60% of RIGHT checklist items. CONCLUSIONS: High-quality evidence is needed to potentially close knowledge gaps and strengthen the recommendation. The AGREE II instrument, along with the RIGHT checklist, should be endorsed and used by CPG developers to ensure higher quality and adequate use of their products.

Electro-acupuncture vs. sham electro-acupuncture for chronic severe functional constipation: A systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy of electro-acupuncture (EA) relative to sham electro-acupuncture (sham EA) in treating chronic severe functional constipation (CSFC). METHODS: A comprehensive search for relevant studies published between January 1, 1951 and May 14, 2020 was conducted in PubMed, the Cochrane Library, Chinese Biomedical Literature Database, Web of Science, and EMbase. Two investigators independently selected studies, extracted data, and assessed the quality of the included studies. The software Endnote X9 was used for screening articles, and the Review Manager 5.3 for analyzing data. RESULTS: The meta-analyses involved 6 studies and 1457 individuals. The pooled results favored the EA group for the increase of complete spontaneous bowel movements (CSBMs) per week in the fourth week (MD = 0.80, P = 0.001) during treatment, and further improved in the eight weeks (MD = 1.25, P < 0.001). During the follow-up period, significant changes in CSBMs per week were seen in the experimental group (MD = 1.38, P = 0.008); the effect decreased in the twelfth week (MD = 0.87, P < 0.001). There was no significant difference in the Bristol stool scale score between the two groups in the fourth week (MD = 0.40, P = 0.08), but significant differences were observed in the eighth week (MD = 0.40, P = 0.03). A significant reduction in patient assessment of constipation quality of life (PAC-QOL) score were observed in the EA group during treatment (SMD = -0.83, P < 0.001). No serious adverse events were reported. CONCLUSIONS: EA had favorable effects on CSFC, and the longer the treatment duration was, the better was the effect, but the effect showed a certain period of validity. However, the results may be influenced by the clinical heterogeneity of acupuncture points, depth of needling, intensity, and frequency of EA.

The effectiveness and safety of acupuncture for depression: An overview of meta-analyses.

PURPOSE: To provide an overview of existing meta-analysis (MAs) on the efficacy and safety of acupuncture for depression, and assess the methodological quality and the strength of evidence of the included MAs. METHODS: We searched MAs of randomized trials that have evaluated the effects of acupuncture on depression in three international and three Chinese databases from their inception until August 2019. The methodological quality of included MAs was evaluated with the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), and the strength of evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). We used the intra-class correlation coefficient (ICC) to assess reviewer agreement in the pre-experiment. RESULTS: We included 31 MAs and 59 RCTs. The results of included MAs were conflicting, our meta-analyses found that acupuncture may confer small benefit in reducing the severity of depression by end of treatment than no treatment/wait list/treatment as usual(SMD -0.74, 95% CI -1.06 to -0.41, eight trials, 624 participants), control acupuncture (invasive, non-invasive sham controls) (SMD 0.27, 95% CI -0.51 to -0.04, 20 trials, 1055 participants), antidepressants(Selective serotonin reuptake inhibitors (SSRI)/ Tetracyclic antidepressants(TCAs)) (SMD -0.28, 95% CI -0.46 to -0.10, 30 trials, 3068 participants), acupuncture plus antidepressants versus antidepressants(SSRI/TCAs) (SMD -0.99, 95% CI -1.37 to -0.61, 17 trials, 1110 participants). Subgroup analyses showed that there was no difference between electro-acupuncture and invasive control (P = 0.37), electro-acupuncture and non-invasive control (P = 0.90), manual acupuncture and Tetracyclic antidepressants (P = 0.57), electro-acupuncture and Tetracyclic antidepressants (P = 0.07). Six MAs concluded that acupuncture reduced the incidence of adverse events compared with antidepressants. The evaluation with AMSTAR-2 showed that the quality of included MAs was low or critically low. The results of the GRADE evaluation showed that the strength of evidence was low to very low for most outcomes. CONCLUSIONS: Although acupuncture appears to be more effective and safer than no treatment, control acupuncture and antidepressants, the quality of the available evidence was very low. Further methodologically rigorous and adequately powered primary studies are needed to confirm the effectiveness of acupuncture for depression.

Ginger for health care: An overview of systematic reviews.

OBJECTIVES: To summarize the evidence from systematic reviews (SRs) and meta-analyses that evaluated the efficacy of ginger in treating any conditions and critically assess the quality of these evidence. METHODS: A systematic search of the literature was conducted from inception until February 28, 2019 using the PubMed, EMBASE, Web of science, Cochrane library, and four Chinese databases. Literature selection and data extraction were conducted by two independent reviewers. The quality of SRs was evaluated using the AMSTAR-2 tool. The GRADE system was used to assess the quality of evidence. RESULTS: Twenty-seven SRs were included. The number of included studies were various, range from 3 to 27. The condition with the most included SRs was nausea and vomiting (n = 12, 44.4%). Many SRs showed a promising efficacy of ginger, including nausea and vomiting, metabolic syndrome and pain, while the effect of ginger for platelet aggregation failed to draw a certain conclusion. The quality of SRs was heterogeneous. All of included SRs well complied with the Item 1 ("research questions included the components of PICO") and Item 3 ("explained selection of the study designs for inclusion"). Twenty review failed to provide registration information. Only one SR reported the sources of funding for studies included. CONCLUSIONS: In our overview, most of SRs suggest ginger is a promising herbal medicine for health care, which is beneficial for nausea and vomiting, metabolic syndrome and pain. However, considering the limited quality of included evidence and heterogeneity of different clinical trials, more well-design studies are required to confirm the conclusion further.

High-throughput liquid chromatography/mass spectrometry method for the quantitation of small molecules using accurate mass technologies in supporting discovery drug screening.

RATIONALE: Drug discovery samples are routinely analyzed using liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods on triple quadrupole mass spectrometers employing multiple reaction monitoring (MRM). In order to improve analysis throughput, quantitation of small molecules on a quadrupole time-of-flight (QqTOF) instrument using TOF scan and high-resolution MRM (MRM-HR) modes was evaluated in this study. METHODS: Cassette dosed plasma and brain samples from nine compounds were extracted using a protein precipitation method. Separation was achieved by reversed-phase liquid chromatography. Mass spectrometric analysis was performed using TOF scan and high-resolution MRM approaches on a QqTOF mass spectrometer with turbo-ionspray ionization. Results were compared to those obtained on a triple quadrupole mass spectrometer. RESULTS: The dynamic range varied depending on compounds and instruments and was similar between the MRM on QqQ and full TOF scan mode on QqTOF. Linear or quadratic regression and 1/x(2) weighting were used. Resolution on the QqTOF instrument was around 32000 and mass accuracy was within 4.4 ppm. The MRM-HR method showed better sensitivity compared to the TOF scan method, and was comparable to the MRM on a QqQ mass spectrometer. Assay accuracy was within ±25%. CONCLUSIONS: A TOF scan method allowed the use of the generic method without compound-specific optimization and was an alternative choice for routine high-throughput quantitation of small molecules. The MRM-HR method on the QqTOF showed good sensitivity which was comparable to that obtained by the MRM method on the triple quadrupole mass spectrometer.

Preclinical stereoselective disposition and toxicokinetics of two novel MET inhibitors.

The R- and S-enantiomer of N-(4-(3-(1-ethyl-3,3-difluoropiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide are novel MET kinase inhibitors that have been investigated as potential anticancer agents. The effect of the chirality of these compounds on preclinical in vivo pharmacokinetics and toxicity was studied. The plasma clearance for the S-enantiomer was low in mice and monkeys (23.7 and 7.8 mL min(-1) kg(-1), respectively) and high in rats (79.2 mL min(-1) kg(-1)). The R/S enantiomer clearance ratio was 1.5 except in rats (0.49). After oral single-dose administration at 5 mg kg(-1) the R/S enantiomer ratio of AUC(inf) was 0.95, 1.9 and 0.41 in mice, rats and monkeys, respectively. In an oral single-dose dose-ranging study at 200 and 500 mg kg(-1) and multi-dose toxicity study in mice plasma AUC exposure was approximately 2- to 3-fold higher for the R-enantiomer compared to the S-enantiomer. Greater toxicity of the S-enantiomer was observed which appeared to be due to high plasma C(min) values and tissue concentrations approximately 24 h after the final dose. Both enantiomers showed low to moderate permeability in MDCKI cells with no significant efflux, no preferential distribution into red blood cells and similar plasma protein binding in vitro. Overall, the differences between the enantiomers with respect to low dose pharmacokinetics and in vitro properties were relatively modest. However, toxicity results warrant further development of the R-enantiomer over the S-enantiomer.

Preclinical absorption, distribution, metabolism, excretion, and pharmacokinetic-pharmacodynamic modelling of N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, a novel MET kinase inhibitor.

GNE-A (AR00451896; N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide) is a potent, selective MET kinase inhibitor being developed as a potential drug for the treatment of human cancers. Plasma clearance was low in mice and dogs (15.8 and 2.44 mL/min/kg, respectively) and moderate in rats and monkeys (36.6 and 13.9 mL/min/kg, respectively). The volume of distribution ranged from 2.1 to 9.0 L/kg. The mean terminal elimination half-life ranged from 1.67 h in rats to 16.3 h in dogs. Oral bioavailability in rats, mice, monkeys, and dogs were 11.2%, 88.0%, 72.4%, and 55.8%, respectively. Allometric scaling predicted a clearance of 1.3-7.4 mL/min/kg and a volume of distribution of 4.8-11 L/kg in human. Plasma protein binding was high (96.7-99.0% bound). Blood-to-plasma concentration ratios (0.78-1.46) indicated that GNE-A did not preferentially distribute into red blood cells. Transporter studies in MDCKI-MDR1 and MDCKII-Bcrp1 cells suggested that GNE-A is likely a substrate for MDR1 and BCRP. Pharmacokinetic-pharmacodynamic modelling of tumour growth inhibition in MET-amplified EBC-1 human non-small cell lung carcinoma tumour xenograft mice projected oral doses of 5.6 and 13 mg/kg/day for 50% and 90% tumour growth inhibition, respectively. Overall, GNE-A exhibited favourable preclinical properties and projected human dose estimates.

CD4-anchoring HIV-1 fusion inhibitor with enhanced potency and in vivo stability.

In this study, we describe a novel CD4-targeting bifunctional human immunodeficiency virus (HIV-1) fusion inhibitor (CD4-BFFI) that blocks HIV-1 entry by inhibiting both HIV-1 attachment and fusion and is highly potent against both R5 and X4 HIV-1 viruses in various antiviral assays, including peripheral blood mononuclear cell (PBMC) infection assays. Previously, we have reported a CCR5 antibody-based bifunctional HIV-1 fusion inhibitor (BFFI) that was highly active in blocking R5 HIV-1 infection but was ineffective against X4 viruses infecting human PBMCs (Kopetzki, E., Jekle, A., Ji, C., Rao, E., Zhang, J., Fischer, S., Cammack, N., Sankuratri, S., and Heilek, G. (2008) Virology J. 5, 56-65). CD4-BFFI, which consists of two HIV-1 fusion inhibitor (FI) T-651 variant peptides recombinantly fused to the Fc end of a humanized anti-CD4 monoclonal antibody, has demonstrated more than 100-fold greater antiviral activity than T-651 variant or the parental CD4 monoclonal antibody. Mechanistic studies revealed that CD4-BFFI primarily blocks the HIV-1-cell fusion step through its FI peptide moieties. The enhanced antiviral activity of CD4-BFFI is most likely due to avid binding of the bivalent FI peptides as well as the increased local concentration of CD4-BFFI via attachment to the target cell surface receptor CD4. In vivo pharmacokinetic studies demonstrated that CD4-BFFI was stable in monkey blood, and a dose of 10 mg/kg maintained serum concentrations greater than 2,000-fold over the IC(90) value for 7 days postdosing. This novel bifunctional inhibitor with improved potency and favorable pharmacokinetic properties may offer a novel approach for HIV-1 therapy.

Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration.

This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.