Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.

Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone­sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.

Severe hypoglycemia in a diabetic patient with pituitary apoplexy: a case report.

INTRODUCTION: Hypoglycemia is a common occurrence in diabetic patients. But unlike non diabetic patients, its causes are frequently related to drugs they are receiving to control blood glucose. But this may not always be the case. Here we report a type 2 diabetic patient with severe hypoglycemia owing to acute hypopituitarism secondary to pituitary apoplexy. CASE PRESENTATION: A 45 year old male diabetic patient from Ethiopia taking 2 mg of oral glimepiride daily who presented with change in mentation of 30 minutes and blood glucose recording of 38 mg/dl upon arrival to the emergency room. Brain magnetic resonance imaging showed pituitary macroadenoma with hemorrhage suggestive of pituitary apoplexy. Blood work up showed low adrenocorticotropic hormone, cortisol, and serum sodium levels. Subsequently transsphenoidal hypophysectomy was done. CONCLUSION: The occurrence of hypoglycemia in a diabetic patient taking sulphonylurea monotherapy is common. But when it is severe enough to cause altered mentation, patients should be approached differently. In the presence of clinical clues suggesting cortisol deficiency, hypopituitarism can be a possible cause.

Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double-blinded, prospective clinical trial.

BACKGROUND: Grapiprant is a novel anti-inflammatory drug approved for the treatment of pain associated with osteoarthritis in dogs. OBJECTIVE: Compare the efficacy of grapiprant vs meloxicam for the management of postoperative joint pain in dogs. ANIMALS: Forty-eight dogs presented with cranial cruciate ligament disease and treated by tibial plateau leveling osteotomy (TPLO) between May 2020 and May 2022. METHODS: In this randomized, double blinded, prospective clinical trial, client-owned dogs with naturally occurring unilateral cruciate ligament rupture were enrolled on the day of surgery. The day after surgery, all animals received a subcutaneous injection of 0.2 mg/kg of meloxicam and were randomly assigned to receive either oral grapiprant (2 mg/kg) or meloxicam (0.1 mg/kg), once a day for 14 days, in a blinded manner. The primary endpoint of the study was the pain severity (PSS) and interference (PIS) scores, assessed by the Canine Brief Pain Inventory (CBPI) at day 3, 7, 10 and 15 after the surgery. RESULTS: Three days after surgery, grapiprant treated dogs had lower PSS compared to meloxicam treated dogs with a mean ± SD of 2.76 ± 0.18 vs 3.25 ± 0.23, respectively (difference of -0.49 [95% CI -0.94 to -0.04], P = .032). Pain Interference Score was also lower in grapiprant group at day 3 (4.11 ± 0.18 vs 4.69 ± 0.16 in meloxicam group [difference of -0.58 {95% CI -1.03 to -0.13}, P = .013]) and at day 10 (2.23 ± 0.13 vs 2.72 ± 0.28 [difference of -0.49 {95% CI -0.92 to -0.01}, P = .049]). CONCLUSIONS AND CLINICAL IMPORTANCE: Our study supports the use of grapiprant as an alternative analgesic to meloxicam for management of postoperative joint pain in dogs.

Management of Type 2 Diabetes Mellitus With Noninsulin Pharmacotherapy.

Type 2 diabetes mellitus is a chronic disease that is increasing in global prevalence. An individualized approach to pharmacotherapy should consider costs, benefits beyond glucose control, and adverse events. Metformin is the first-line therapy due to its low cost and effectiveness. Sulfonylureas and thiazolidinediones are additional low-cost oral hypoglycemic classes available in the United States; however, evidence shows variability in weight gain and hypoglycemia. Thiazolidinediones increase fluid retention and are not recommended in patients with New York Heart Association class III or IV heart failure. Newer medications, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, have demonstrated weight loss, reduced cardiovascular events, decreased renal disease, and improved all-cause morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors are recommended for people with known cardiovascular disease, heart failure, and chronic kidney disease but carry an increased risk of urinary tract and mycotic infections. Glucagon-like peptide-1 receptor agonists are contraindicated in patients with active multiple endocrine neoplasia type 2 or a personal or family history of medullary thyroid carcinoma; adverse effects include gastrointestinal upset and pancreatitis. Dipeptidyl-peptidase-4 inhibitors have a low risk of hypoglycemia but may increase the risk of pancreatitis and require a renal dose adjustment. Public and private programs to increase access to newer hypoglycemic medications are increasing; however, there are limitations to access, particularly for uninsured and underinsured people.

Are the cardiovascular properties of GLP-1 receptor agonists differentially modulated by sulfonylureas? Insights from post-hoc analysis of EXSCEL.

AIMS: To examine whether the cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are attenuated by concurrent sulfonylurea (SU) therapy in a post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). METHODS: We investigated whether SUs, as a class or by specific type, modulated the effects of once-weekly exenatide (EQW) on EXSCEL cardiovascular outcomes in intent-to-treat analyses of all trial participants, categorized as SU users or nonusers. Marginal structural models were used to evaluate whether there were differential EQW effects by SU category on major adverse cardiovascular events (MACE), depending on duration of SU use (6, 12, and 18 months). EQW-by-SU type interaction p-values and hazard ratios (95 % CIs) for EQW versus placebo for each baseline SU type (glibenclamide, gliclazide, glimepiride, other SUs) were calculated. RESULTS: Neither SU use nor baseline SU type modified the effect of EQW on time to MACE (pinteraction = 0.88 and 0.78, respectively), nor did individual SU types, including glibenclamide (a systemically wide-acting SU). CONCLUSIONS: SUs did not modulate the effect of EQW on cardiovascular outcomes, suggesting that SU treatment choices need not be altered to optimize the cardiovascular effects of GLP-1 receptor agonists in people with type 2 diabetes.

Evaluation of the analgesic efficacy of grapiprant compared with robenacoxib in cats undergoing elective ovariohysterectomy in a prospective, randomized, masked, non-inferiority clinical trial.

OBJECTIVES: The main objective of this study was to compare the postoperative analgesic effects of grapiprant with those of robenacoxib in cats undergoing ovariohysterectomy (OVH). METHODS: In total, 37 female cats (age range 4 months-10 years, weighing ⩾2.5 kg) were enrolled in a prospective, randomized, masked, non-inferiority (NI) clinical trial. Cats received oral robenacoxib (1 mg/kg) or grapiprant (2 mg/kg) 2 h before OVH. Analgesia was assessed via the Feline Grimace Scale (FGS), the Glasgow Composite Measure Pain Scale-Feline (CMPS-F), von Frey monofilaments (vFFs) and pressure algometry (ALG) 2 h before treatment administration, at extubation, and 2, 4, 6, 8, 18 and 24 hours after extubation. Hydromorphone (<8 h postoperatively) or buprenorphine (>18 h postoperatively) were administered to cats with scores of ⩾5/20 on CMPS-F and/or ⩾4/10 on FGS. NI margins for CMPS-F and vFFs were set at 3 and -0.2, respectively. A mixed-effect ANOVA was used for FGS scores (P <0.05). Data are reported as mean ± SEM. RESULTS: The data from 33 cats were analyzed. The upper limit of the 95% confidence interval (CI) (0.35) was less than the NI margin of 3 for CMPS-F, and the lower limit of the 95% CI (0.055) was greater than the NI margin of -0.2 for vFFs, indicating NI of grapiprant. The FGS scores were greater than baseline at extubation for both treatments (1.65 ± 0.63; P = 0.001); however, there was no difference between treatments. There was no difference between treatments, nor treatment by time interaction, for vFFs (P <0.001). The CMPS-F scores for both treatments were higher at extubation but returned to baseline after 4 h (P <0.001). For ALG, there was no difference in treatment or treatment by time interaction. The robenacoxib group had lower pressure readings at extubation and 6 h compared with baseline. CONCLUSIONS AND RELEVANCE: These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown.

A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life.

AIMS/HYPOTHESIS: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. METHODS: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. RESULTS: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. CONCLUSIONS/INTERPRETATION: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease.

Importance: Several oral antidiabetic drug (OAD) classes can potentially improve patient outcomes in nonalcoholic fatty liver disease (NAFLD) to varying degrees, but clinical data on which class is favored are lacking. Objective: To investigate which OAD is associated with the best patient outcomes in NAFLD and type 2 diabetes (T2D). Design, Setting, and Participants: This retrospective nonrandomized interventional cohort study used the National Health Information Database, which provided population-level data for Korea. This study involved patients with T2D and concomitant NAFLD. Exposures: Receiving either sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, each combined with metformin for 80% or more of 90 consecutive days. Main Outcomes and Measures: The main outcomes were NAFLD regression assessed by the fatty liver index and composite liver-related outcome (defined as liver-related hospitalization, liver-related mortality, liver transplant, and hepatocellular carcinoma) using the Fine-Gray model regarding competing risks. Results: In total, 80 178 patients (mean [SD] age, 58.5 [11.9] years; 43 007 [53.6%] male) were followed up for 219 941 person-years, with 4102 patients experiencing NAFLD regression. When compared with sulfonylureas, SGLT2 inhibitors (adjusted subdistribution hazard ratio [ASHR], 1.99 [95% CI, 1.75-2.27]), thiazolidinediones (ASHR, 1.70 [95% CI, 1.41-2.05]), and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.31-1.59]) were associated with NAFLD regression. SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression when compared with thiazolidinediones (ASHR, 1.40 [95% CI, 1.12-1.75]) and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.30-1.62]). Only SGLT2 inhibitors (ASHR, 0.37 [95% CI, 0.17-0.82]), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas. Conclusions and Relevance: The results of this cohort study suggest that physicians may lean towards prescribing SGLT2 inhibitors as the preferred OAD for individuals with NAFLD and T2D, considering their potential benefits in NAFLD regression and lower incidences of adverse liver-related outcomes. This observational study should prompt future research to determine whether prescribing practices might merit reexamination.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

Glucagon like peptide-1 receptor agonists and the risk of skin cancer among patients with type 2 diabetes: Population-based cohort study.

AIMS: The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. RESULTS: Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. CONCLUSIONS: In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.

Novel synergistic cross-linking ameliorate ready-to-eat sea cucumber deterioration and its quantum chemical analysis.

Synergistic cross-linkers could improve the taste acceptability of ready-to-eat sea cucumber (RSC). Besides, the hardness of RSC was increased by 331.00% and 266.87% after synergistic cross-linking. Synergistic cross-linking treatment could ameliorate the non-enzymatic degradation of RSC collagen and polysaccharides. Gaussian calculations results showed that dipeptides containing asparagine residues may have different reaction pathways. The main cleavage pathways of CH3CO-Asn-Gly-NHCH3 (NG) might be water-assisted side chain cyclization, stepwise cyclamide hydrolysis via a Gemdiol Intermediate, deamination, and peptide bond breakage. The relative free energy of cyclamide hydrolysis process of NG was increased by 8.2 kcal/mol after synergistic cross-linking. The mass spectrometry results showed that typical peptides could cleavage at NG, CH3CO-Asn-Lys-NHCH3 (NK) and CH3CO-Asn-Leu-NHCH3 (NL) sites after heating, which justified the breakage pattern of peptides in Gaussian calculations. It can offer a comprehensive theoretical basis for the processing of the ready-to-eat sea cucumber with storage stability.

Discovery of small molecule c-Maf inhibitors using molecular docking-based virtual screening, molecular dynamics simulation, and biological evaluation.

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c-Maf in most MM patients, targeting c-Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA-approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI-8226 cell line. Moreover, both compounds simultaneously downregulated c-Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c-Maf inhibitors in the future.

An observational multi-center study on type 2 diabetes treatment prescribing pattern and patient adherence to treatment.

In 2021, the International Diabetes Federation (IDF) reported that the prevalence of diabetes in Pakistan was 9.6%, higher than the global average. However, adherence to treatment guidelines, e.g., American Diabetes Association and Pakistan Endocrine Society and prescription patterns for Oral anti-diabetes (OAD), is poorly understood in Pakistan. Therefore, this study aimed to examine the prescribing practices of anti-diabetic medications, an association of lifestyle modification with drugs prescribed, and their effectiveness in preserving ideal glycemic levels in diabetic patients undergoing treatment in tertiary care teaching hospitals in rural and urban Pakistan. In this cross-sectional study, data were collected from prescriptions of outpatient diabetic patients from different rural and urban tertiary care hospitals between October 2021 and February 2022. 388 participants were enrolled in the study for a detailed interview on prescription evaluation and glycemic control. The coinvestigators conducted an interview with the patient and used a pre-validated questionnaire to collect the data. The relationship between following treatment guidelines and clinical and demographic factors was found using chi-square tests for bivariate analyses. The study reported that out of 388, the mean ages of the patients were 48 ± 12.4, and the majority were female. It was observed that 60.1% and 66.5% have uncontrolled fasting and random blood glucose, respectively. The education level of the study participants was also below par to have a complete understanding of the medical condition and self-management therapy. Even though they were taking the right medications-an average prescription regimen included 5.08 medications-52.1% of the studied people had glycated haemoglobin (HbA1c) levels higher than the therapeutic threshold set by the International Diabetes Federation. In this modern era, it was observed that the prescribing trend was still focused on traditional therapeutic options Biguanides, sulfonylureas, and dipeptidyl peptidase-4 inhibitors were prescribed in 64.6% of the patients. A significant association was found between glycemic control and body mass index, adherence to lifestyle modifications, and the number of medications prescribed (p-value < 0.05). The study reveals that Pakistan's prescribing practices do not align with international and national guidelines, leading to a high prevalence of uncontrolled diabetes and widespread use of polypharmacy among patients. To address this issue, policymakers should prioritize establishing a comprehensive national diabetes action plan. Additionally, there is a pressing need to develop diabetes education and awareness programs emphasizing the importance of lifestyle modifications for effective diabetes management.

Dipeptidyl peptidase-4 inhibitors and the risk of skin cancer among patients with type 2 diabetes: a UK population-based cohort study.

INTRODUCTION: The dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. RESEARCH DESIGN AND METHODS: Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96 739 DPP-4 inhibitor users and 209 341 sulfonylurea users, and 96 411 DPP-4 inhibitor users and 208 626 sulfonylurea users for non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma skin cancer, separately. RESULTS: Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs 65.3 per 100 000 person-years, respectively; HR 0.77, 95% CI 0.61 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15). CONCLUSIONS: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas.

Fine-tuned photochromic sulfonylureas for optical control of beta cell Ca2+ fluxes.

We previously developed, synthesized and tested light-activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light-dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push-pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine-tuned, light-activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine-, pyrrolidine- and piperidine-based sulfonylureas all increased beta cell Ca2+ -spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine-based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine-azobenzenes as chemical photoswitches across drug classes.

[Use of antidiabetic medications in the course of bariatric/metabolic surgery]. / Gestion des médicaments antidiabétiques dans le décours d'une chirurgie bariatrique/métabolique.

The management of type 2 diabetes (T2D) after a gastric bypass or a sleeve gastrectomy requires some cautions depending on the timing after the surgical procedure and the patient evolution. Even before the intervention, gliflozins should be interrupted to avoid euglycemic diabetic ketoacidosis while sulphonylureas should be stopped and insulin doses should be reduced (with caution) to limit the risk of hypoglycemia. If a remission of T2D occurs, the maintenance of metformin or of a glucagon-like peptide-1 receptor agonist should be considered with the main objective to prolong the remission. Finally, if T2D remains or if a relapse occurs, the management of hyperglycemia should a priori follow the same rules as those used for patients with T2D who are not treated with bariatric/metabolic surgery.

Gérer le diabète de type 2 (DT2) dans les suites d'une dérivation gastrique (bypass) ou d'une gastrectomie en manchon (sleeve) demande une attention particulière en fonction du moment considéré et de l'évolution du patient. Dès avant l'intervention, il faut arrêter les gliflozines pour éviter une acidose diabétique euglycémique, stopper les sulfamides et réduire (prudemment) les doses d'insuline pour limiter le risque d'hypoglycémie. Si une rémission du DT2 s'installe, le maintien de la metformine ou d'un analogue du glucagon-like peptide-1 doit être discuté pour prolonger cette phase de rémission. Enfin, si le DT2 persiste après la chirurgie ou en cas de rechute, l'hyperglycémie devra être traitée avec, a priori, les mêmes règles que celles dévolues aux patients avec DT2 qui n'ont pas subi de chirurgie bariatrique/métabolique.

Pharmacokinetics of a single oral dose of grapiprant in juvenile pigs (Sus scrofa domestica).

Both pet and research pigs can suffer from some degree of pain from surgery, injuries, or osteoarthritis (OA). Despite this, there is a paucity of data on safe and effective analgesia agents in pigs. Grapiprant is an EP4 antagonist that blocks the action of the pro-inflammatory prostanoid, PGE2 . It has shown efficacy in attenuating pain associated with ovariohysterectomy and OA in dogs. However, there are no data regarding grapiprant in pigs. Therefore, the pharmacokinetic profile of orally administered grapiprant to juvenile pigs (Sus scrofa domestica) was evaluated in this study. Seven juvenile pigs received 12 mg/kg grapiprant orally. Blood was collected from an indwelling jugular catheter using the push-pull method at set timepoints up to 48 hours. Sample analysis was performed with high-performance liquid chromatography. Mean grapiprant plasma concentration was 164.3 ± 104.7 ng/mL which occurred at 0.8 ± 0.3 h. This study demonstrated that grapiprant concentrations consistent with analgesia in dogs were reached at this dosage in pigs. Further studies are needed to evaluate the efficacy of grapiprant in pigs.

Diabetes, metformin use, and survival in esophageal cancer: a population-based cohort study.

BACKGROUND: It is unclear how diabetes and metformin use is associated with survival of esophageal cancer. METHODS: This population-based cohort study included new cases of esophageal cancer reported in Sweden from 2006 to 2018 with follow-up through 2019. Diabetes status and metformin use were analyzed in relation to all-cause and disease-specific mortality using multivariable Cox regression. The hazard ratios (HRs) with 95% confidence intervals (CIs) were adjusted for age, sex, calendar year, obesity, comorbidity, and use of nonsteroidal anti-inflammatory drugs or statins. For comparison reasons, 3 other antidiabetic medications were also analyzed (ie, sulfonylureas, insulin, and thiazolidinedione). RESULTS: Among 4851 esophageal cancer patients (8404 person-years), 4072 (84%) died during follow-up. Compared with esophageal cancer patients with diabetes but not using metformin, decreased all-cause mortality was indicated among nondiabetic patients (without metformin) (HR = 0.86, 95% CI = 0.77 to 0.96) and diabetic patients who used metformin (HR = 0.86, 95% CI = 0.75 to 1.00). The hazard ratios of all-cause mortality decreased with a higher daily dose of metformin (Ptrend = .04). The corresponding hazard ratios for disease-specific mortality were similar but slightly attenuated. The results were also similar in separate analyses of esophageal cancer patients with adenocarcinoma or squamous cell carcinoma, with tumor stage I-II or III-IV, and in those who had or had not undergone surgery. No associations with mortality outcomes were found for use of sulfonylureas, insulin, or thiazolidinedione. CONCLUSIONS: Diabetes was associated with an increased all-cause mortality, whereas metformin use was associated with decreased all-cause mortality among esophageal cancer patients. More research is needed to determine if metformin affects survival in esophageal cancer.

Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls.

BACKGROUND: Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may not be long enough to capture the true effect of this medication on longevity. METHODS: We searched medical records for Wales, UK, using the Secure Anonymised Information Linkage dataset for type 2 diabetes patients treated with metformin (N = 129,140) and sulphonylurea (N = 68,563). Non-diabetic controls were matched on sex, age, smoking, and history of cancer and cardiovascular disease. Survival analysis was performed to examine survival time after first treatment, using a range of simulated study periods. FINDINGS: Using the full twenty-year period, we found that type 2 diabetes patients treated with metformin had shorter survival time than matched controls, as did sulphonylurea patients. Metformin patients had better survival than sulphonylurea patients, controlling for age. Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment. INTERPRETATION: While metformin does appear to confer benefits to longevity in the short term, these initial benefits are outweighed by the effects of type 2 diabetes when patients are observed over a period of up to twenty years. Longer study periods are therefore recommended for studying longevity and healthy lifespan. EVIDENCE BEFORE THIS STUDY: Work examining the non-diabetes outcomes of metformin therapy has suggested that there metformin has a beneficial effect on longevity and healthy lifespan. Both clinical trials and observational studies broadly support this hypothesis, but tend to be limited in the length of time over which they can study patients or participants. ADDED VALUE OF THIS STUDY: By using medical records we are able to study individuals with Type 2 diabetes over a period of two decades. We are also able to account for the effects of cancer, cardiovascular disease, hypertension, deprivation, and smoking on longevity and survival time following treatment. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: We confirm that there is an initial benefit to longevity of metformin therapy, but this benefit does not outweigh the negative effect on longevity of diabetes. Therefore, we suggest that longer study periods are required for inference to be made about longevity in future research.

Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus.

BACKGROUND: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. METHODS: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified. RESULTS: Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]). CONCLUSION: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.