Risk of major adverse events associated with gabapentinoid and opioid combination therapy: A systematic review and meta-analysis.

Background: The use of opioid-gabapentinoid combinations has increased, raising several safety concerns. However, meta-analysis studies focusing on this issue are limited. Objective: To evaluate the risk of central nervous system (CNS) depression, gastrointestinal (GI) adverse events, and mortality of combination therapy compared with those of opioid therapy and to explore the differences in the results according to study design and indications. Methods: Relevant studies were selected (published before 30 January 2022) by searching the MEDLINE, Embase, and CENTRAL databases. The pooled odds ratios (OR) with 95% confidence intervals (CI) of the outcomes were estimated using the Mantel-Haenszel method. Subgroup and meta-regression analyses were performed according to study characteristics. Quality assessment was conducted using the Risk of Bias 2 tool for randomized controlled trials (RCTs) and Cochrane Collaboration's Risk of Bias in non-RCTs tool for non-randomized trials. Results: Adverse events were reported in 26 RCTs and 7 non-RCTs, and mortality was reported in 10 non-RCTs. Compared to opioid therapy, dizziness, cognitive dysfunction, and respiratory depression in combination therapy significantly increased in non-RCTs (OR 3.26, 95% CI 1.82-5.85; OR 3.13, 95% CI 1.51-6.50; OR 1.71, 95% CI 1.31-2.24, respectively), and a similar trend for dizziness and cognitive dysfunction was also identified in the RCT analysis, although the difference was not significant. Combination therapy for cancer pain was associated with the highest risk of sedation in subgroup analysis. Combination therapy significantly decreased the risk of GI adverse events, including nausea, vomiting, and constipation. The mortality risk associated with combination therapy was higher than that associated with opioid therapy (OR 2.76, 95% CI 1.26-6.05). Conclusion: Opioid-gabapentinoid combination therapy could be associated with an increased risk of CNS depression and mortality, despite tolerable GI adverse events. These data suggest that combination therapy requires close monitoring of CNS depression, especially in cancer patients. Caution is needed in interpreting the clinical meanings owing to the lack of risk difference in respiratory depression in the RCT-only analysis and the absence of RCT or prospective studies investigating mortality.

Impact of flavonol extracts derived from green tea or targeted flavonols as secondary ingredients on intestinal glucose transport.

The purpose of the current study was to examine the effect of adding secondary ingredients such as green tea derived water-soluble polysaccharides (GTP) and flavonol aglycone rich fractions derived from cellulase treated green tea extract (FVN) into catechin rich green tea extracts (GTE) on wheat starch digestion and intestinal glucose transport using in vitro digestion with Caco-2 cells. Co-digestion of wheat starch with GTE (16.88 g L-1) or GTE + GTP + FVN (16.69 g L-1) appeared to promote starch hydrolysis compared to control (15.49 g L-1). In case of major flavonoids, addition of epigallocatechin gallate (EGCG), EGCG + myricetin (M) into wheat starch significantly increased the digestion of starch into glucose. Glucose transport rate decreased by 22.35% in wheat starch + GTE + GTP + FVN (1.39%), while the least amount of glucose (1.70%) was transported in EGCG mixed with M (1% of EGCG) as secondary ingredients among individual flavonoids formulation. It indicated that inhibitory effect on glucose transport was higher in addition of GTE, GTP, and FVN as excipients ingredients rather than targeted major flavonoids. Results from the current study suggest that whole green tea including flavonoid rich fractions could enhance hypoglycemic potential of GTE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05140-2.

Profiling of In Vitro Bioaccessibility and Intestinal Uptake of Flavonoids after Consumption of Commonly Available Green Tea Types.

The aim of this study was to profile the bioaccessibility and intestinal absorption of epicatechins and flavonols in different forms of green tea and its formulation: loose leaf tea, powdered tea, 35% catechins containing GTE, and GTE formulated with green tea-derived polysaccharide and flavonols (CATEPLUS™). The bioaccessibillity and intestinal absorption of epicatechins and flavonols was investigated by using an in vitro digestion model system with Caco-2 cells. The bioaccessibility of total epicatechins in loose leaf tea, powdered tea, GTE, and CATEPLUS™ was 1.27%, 2.30%, 22.05%, and 18.72%, respectively, showing that GTE and CATEPLUS™ had significantly higher bioaccessibility than powdered tea and loose leaf tea. None of the flavonols were detected in powdered tea and loose leaf tea, but the bioaccessibility of the total flavonols in GTE and CATEPLUS™ was 85.74% and 66.98%, respectively. The highest intestinal absorption of epicatechins was found in CATEPLUS™ (171.39 ± 5.39 ng/mg protein) followed by GTE (57.38 ± 9.31), powdered tea (3.60 ± 0.67), and loose leaf tea (2.94 ± 1.03). The results from the study suggest that formulating green tea extracts rich in catechins with second components obtained from green tea processing could enhance the bioavailability of epicatechins.

Hypoglycemic effect of soluble polysaccharide and catechins from green tea on inhibiting intestinal transport of glucose.

BACKGROUND: Water soluble polysaccharide derived from green tea (WSP) is produced as byproducts when catechins were extracted from green tea. Although inhibitory effect of green tea catechins on the glucose transport in small intestine has been studied, the hypoglycemic efficacy of the WSP or its combinational effect has not been studied. In order to investigate hypoglycemic efficacy of the WSP or its combinational effect with green tea extract (GTE), co-consumption of GTE and WSP with wheat starch was investigated using in vitro digestion coupled with Caco-2 cells. The mechanism of the intestinal glucose transport was elucidated throughout the gene expression of the intestinal glucose transporters, which included sodium dependent glucose transporter (SGLT1) and glucose transporter 2 (GLUT2), using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The co-digestion of wheat starch with GTE during the small intestinal phase was the most rapidly digested into reducing sugar (73.96 g L-1 ) compared to itself (48.44 g L-1 ), WSP (60.35 g L-1 ), and GTE + WSP (61.81 g L-1 ). Intestinal glucose transport was 11.82, 7.59, 4.49, and 2.40% for wheat starch, wheat starch with GTE, WSP, and GTE + WSP, respectively. The highest decreased expression pattern in SGLT1 was observed when cells treated with wheat starch + GTE + WSP (0.66-fold) compared to GTE or WSP treatment. CONCLUSION: The results suggested that co-consumption of green tea derived products with wheat starch could delay the intestinal absorption of glucose. Results from the current study suggested that GTE and WSP could be the useful supplements of dietary therapy for hyperglycemia to delay glucose absorption. © 2020 Society of Chemical Industry.

Addition of flavonols and polysaccharides as excipient ingredients into epicatechin rich green tea extract inhibited free radical formation and glucose uptake.

It was revealed that excipient ingredients such as flavonols (FVN) or polysaccharides (GTP) which could be derived from green tea enhanced catechin absorption. We hypothesized that the addition of FVN or GTP as excipient ingredients into epicatechin rich green tea extracts (GTE) may improve the health benefits that accompany its consumption. When FVN8.7 (8.7% of GTE, w/w) was added to the GTE (20 mg) as an excipient ingredient, the bioaccessibility and intestinal absorption of total epicatechins was 1.2 and 1.5 times higher than that of only GTE, respectively. This was due to the free radical scavenging capacity of flavonols, showing 114.23 ± 3.07 µmol TE per g for GTE 100 + FVN8.7 and 113.64 ± 1.61 µmol TE per g for GTE 100 + FVN2, respectively. This was significantly higher than the GTE or GTE 100 + OW2 (onion peel and whangchil extracts, 2% of GTE, w/w) which have the same amount of total flavonols. Regarding potential hypoglycemic effects, co-digestion of GTE (20 mg) + green tea polysaccharides (2 mg) + FVN (5 mg) with wheat starch significantly reduced glucose intestinal absorption by 41.85 ± 1.75% compared to only the wheat starch. The results from the current study suggest that whole green tea components rich in flavonols and polysaccharides could be potential hypoglycemic excipient ingredients for green tea catechins.

In vitro model for predicting acute inhalation toxicity by using a Calu-3 epithelium cytotoxicity assay.

INTRODUCTION: As the current methods to predict the inhalation toxicity of chemicals using animal models are limited, alternative methods are required. We present a new in vitro prediction method for acute inhalation toxicity using the Calu-3 epithelial cytotoxicity assay applicable for water-soluble inhalable chemicals. METHOD: To confirm the characteristics of the optimal Calu-3 epithelium, tight-junction formation, morphology, and mucus secretion were verified using scanning electron microscopy, transepithelial electrical resistance analysis, and immunofluorescence after growth in an air-liquid interface (ALI). Sixty chemicals, including 38 positive and 22 negative for acute inhalation toxicity, were selected from the European Chemical Agency chemical database. The cell viability of the exposed cells was assessed using an MTT assay to predict the acute inhalation toxicity by calculating the area under the receiver operating characteristic (ROC) curve and accuracy. RESULTS: When cultivated in an ALI, the epithelium was thicker and secreted more mucin than that under submerged cultivation, characteristic of the in vivo respiratory epithelium. The areas under the ROC curve were 0.75 and 0.78 when exposed to chemicals at concentrations of 2.5 and 5%, respectively. The highest accuracy of the methods was 68 and 78% at cut-off values of 85 and 40% cell viability, respectively. DISCUSSION: The in vitro model was moderately accurate with good prediction. It is replicable because of its advantages, i.e., the use of cultured cells and the simplicity of the method. Overall, the Calu-3 epithelial cytotoxicity assay may be a useful and simple approach to identify substances that cause acute inhalation toxicity.

Hypoglycemic potential of whole green tea: water-soluble green tea polysaccharides combined with green tea extract delays digestibility and intestinal glucose transport of rice starch.

Green tea is being studied extensively for its postprandial hypoglycemic effect due to its abundant catechins. Along with catechins, water-soluble green tea polysaccharides are also currently gaining attention due to their natural hypoglycemic properties. The current study investigated the combinational effect of green tea extract (GTE) and crude green tea polysaccharides (CTP) in inhibiting glucose transport after digestion of rice starch, using an in vitro digestion model with a Caco-2 cell. Co-digestion of rice starch with GTE (16.09 ± 1.02 g L-1), CTP (16.83 ± 0.81 g L-1), or GTE + CTP (17.79 ± 0.80 g L-1) hydrolyzed less starch into glucose compared with the control (18.24 ± 0.45 g L-1). Glucose transport from digesta to the Caco-2 cell after 120 min incubation was significantly inhibited with GTE + CTP (53.26 ± 4.34%). Gene expression of intestinal glucose transporters, which included sodium-dependent glucose transporter (SGLT1) and glucose transporter 2 (GLUT2), was not altered by GTE, CTP or GTE + CTP, except for the GTE-mediated upregulation of GLUT2. It is concluded that GTE + CTP lowered digestibility of rice starch with glucose and also delayed glucose uptake to the intestinal epithelium. This finding suggests a potential for green tea polysaccharides as a natural postprandial hypoglycemic substance.