Background and aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect.

Methods and results: A MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH-OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH-OR 1.11 [1.00, 1.23], p = 0.04).

Conclusions: This meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs.

Keywords: Insulin secretagogues; Major cardiovascular events; Metanalysis; Mortality; Type 2 diabetes.

Background: COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is currently outbreaking and posing significant threats to public health worldwide. It is notable that a substantial proportion of COVID-19 severe patients coexist diabetic conditions, indicating the progression and outcome of COVID-19 may relate to diabetes. However, it is still unclear that whether the diabetic treatment principles can be used for the treatment of COVID-19.

Methods: We conducted a computational approach to screened all commonly used clinical oral hypoglycemic drugs to identify the potential inhibitors for the main protease (M^pro ) of SARS-CoV-2, which is one of the key drug targets for anti-COVID-19 drug discovery.

Results: Six antidiabetic drugs with docking scores higher than 8.0 (cutoff value), including repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin, were predicted as the promising inhibitors of M^pro . Interestingly, repaglinide, one of the six antidiabetic drugs employed the highest docking score for M^pro , was similar to a previously predicted active molecule-nelfinavir, which is a potential anti-HIV and anti-COVID-19 drug. Moreover, we found repaglinide shared similar docking pose and pharmacophores with reported ligand (N3 inhibitor) and nelfinavir, demonstrating that repaglinide would interact with M^pro in a similar way.

Conclusion: These results indicated an extra effect on anti-COVID-19 may offer by above 6 antidiabetic drugs, while further researches are necessary to confirm these findings. This article is protected by copyright. All rights reserved.

Keywords: Antidiabetic agents; COVID-19; Diabetes; SARS-CoV-2.

Background: Ataxia telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition and altered body composition. In addition, evidence is rising for endocrine dysfunction. Objectives: To determine the evolution of diabetes and its prevalence in a larger A-T cohort. Methods: A retrospective analysis of the patient charts of 39 subjects from the Frankfurt A-T cohort was performed between August 2002 and 2018 concerning HbA1c and oral glucose tolerance (OGTT). The median follow-up period was 4 years (1-16 years). In addition, in 31 A-T patients aged 1 to 38 years HbA1c and fasting glucose were studied prospectively from 2018 to 2019. Results: In the retrospective analysis, we could demonstrate a longitudinal increase of HbA1c. The prospective analysis showed a significant increase of HbA1c and fasting glucose with age (r = 0.79, p ≤ 0.0001). OGTT has a good sensitivity for insulin resistance screening, whereas HbA1c can be used to evaluate individual courses and therapy response. Seven out of 39 (17.9%) patients suffered from diabetes. Metformin did not always lead to sufficient diabetes control; one patient was treated successfully with repaglinide. Conclusion: Diabetes is a common finding in older A-T patients and often starts in puberty. Our data clearly demonstrate the need for an annual diabetes screening in patients > 12 years.

Keywords: HbA1c; OGTT; ataxia telangiectasia; diabetes; diabetes therapy.

Background: Niosomes, bilayer vesicles formed by the self-assembly of nonionic surfactants, are receiving increasing attention as potential oral drug delivery systems but the impact of niosomal formulation parameters on their oral capability has not been studied systematically. The aim of this study was to investigate the impact of surfactant composition and surface charge of niosomes in enhancing oral bioavailability of repaglinide (REG) as a BCS II model drug.

Methods: Niosomes (13 formulations) from various nonionic surfactants having HLB in the range of 4-28 (Tweens, Spans, Brijs, Myrj, poloxamer 188, TPGS and Labrasol) were prepared and characterized concerning their loading efficiency, hydrodynamic diameter, zeta potential, drug release profile, and stability. The oral pharmacokinetics of the selected formulations were studied in rats (8 in vivo groups).

Results: The results revealed that type of surfactant markedly affected the in vitro and in vivo potentials of niosomes. The C_max and AUC values of REG after administration of the selected niosomes as well as the drug suspension (as control) were in the order of Tween 80> TPGS> Myrj 52> Brij 35> Span 60≈Suspension. Adding stearyl amine as a positive charge-inducing agent to the Tween 80-based niosomes, resulted in an additional increase in drug absorption and values of AUC and C_max were 3.8- and 4.7-fold higher than the drug suspension, respectively.

Conclusion: Cationic Tween 80-based niosomes may represent a promising platform to develop oral delivery systems for BCS II drugs.

Keywords: BCS II; HLB; niosome; oral bioavailability; repaglinide; surface charge; surfactant type.

Objective: This research study attempted to develop spray-dried solid dispersion, to enhance the solubility of repaglinide, an antidiabetic drug.

Significance: Aqueous solubility plays a major role in drug delivery because any chemical entity has to be in a dissolved state at the site of absorption, in order to get absorbed. Solid dispersion (SD) is one of the widely used techniques to enhance solubility and hence dissolution rate of poorly soluble drugs.

Methods: Repagnilide, in hypromellose acetate succinate (HPMCAS) solution, was dried by spray drying to obtain spray-dried solid dispersion (SDSD). Plackett-Burman and Box-Behnken designs were used for screening formulation as well as process parameters, and optimization respectively. DSC, XRD, SEM were carried out to confirm the preparation of solid dispersion. SDSD was evaluated for in vitro dissolution, flow properties, Percentage yield and in vivo oral glucose tolerance test.

Result: Spray dried solid dispersion comprising (w/w) drug:polymer ratio of 1:3.82, 2.56% of aerosil and inlet temperature of 90 °C, corresponded to the best formulation obtained in this work. It showed t ₈₅% of less than 15 min and a significant reduction in blood glucose level in rats as compared to pure drug and marketed formulation.

Conclusion: Thus, it can be concluded that spray-dried solid dispersion prepared using HPMCAS is a useful technique for solubility and dissolution enhancement of repaglinide.

Keywords: HPMCAS; Spray dried solid dispersion; amorphization; antidiabetic drug; bioavailability; oral glucose tolerance test.

Background and aims: Evaluation of long-term efficacy and safety of various anti-hyperglycaemic agents (AHA) for glycaemic control in NODAT, in stable kidney transplant recipients (KTRs) during 1-year outpatient follow-up.

Methods: We collected FPG, PPG, HbA1c, serum creatinine, eGFR, blood tacrolimus level, hypoglycaemia and body weight values from an existing database of KTRs diagnosed to have NODAT. Those newly initiated on AHA over 3 months post-transplant; received standard triple immunosuppressive therapy; and followed up for 1-year after referral, were included.

Results: In ninety-five patients' (Male = 65), mean decrease at 1-year from baseline in FPG (185.01 ± 62.11 mg/dL), PPG (293.21 ± 85.23 mg/dL) and HbA1c (8.48 ± 1.08%) was 67.09, 126.11 and 1.4 respectively (p < 0.0001). At 1-year, mean HbA1c was 7.08 ± 0.38%, ninety-one patients achieving HbA1c ≤ 7.5%. Fifty-two patients received oral combination therapy based on linagliptin/metformin/repaglinide/gliclazide, 19 received insulin-based regimen, and 24 received linagliptin monotharapey. Thirty patients reported hypoglycaemia (10 with gliclazide and 15 with insulin) and fifty patients gained body-weight at 1-year. Mean serum creatinine and eGFR significantly improved by 0.29 and 15.77 from baseline of 1.56 ± 0.62 mg/dL and 53.95 ± 16.10 mL/min/1.73 m² respectively.

Conclusions: Significant proportion of NODAT patients achieved long-term glycemic control with improved renal function. Combination therapy was needed in most within 1-year. Linagliptin monotherapy was effective, without producing hypoglycaemia or weight gain.

Keywords: Allograft survival; Immunosuppressive therapy; Linagliptin; NODAT; PTDM; Renal transplant.

Ivosidenib is a potent, targeted, orally active, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that has been approved in the United States for the treatment of adults with newly diagnosed acute myeloid Leukemia (AML) who are ≥75 years of age or ineligible for intensive chemotherapy, and those with relapsed or refractory AML, with a susceptible IDH1 mutation. Ivosidenib is an inducer of the CYP2B6, CYP2C8, CYP2C9, and CYP3A4 and an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptide-1B1/1B3 (OATP1B1/1B3), and organic anion transporter-3 (OAT3) in vitro. A physiologically-based PK (PBPK) model was developed to predict DDIs of ivosidenib in patients with AML. The in vivo CYP3A4 induction effect of ivosidenib was quantified using 4β-hydroxycholesterol and was subsequently verified with the PK data from an ivosidenib and venetoclax combination study. The verified model was prospectively applied to assess the effect of multiple doses of ivosidenib on a sensitive CYP3A4 substrate, midazolam. The simulated midazolam geometric mean AUC and C_max ratios were 0.18 and 0.27, respectively, suggesting ivosidenib is a strong inducer. The model was also used to predict the DDIs of ivosidenib with CYP2B6, CYP2C8, CYP2C9, P-gp, OATP1B1/1B3, and OAT3 substrates. The AUC ratios following multiple doses of ivosidenib and a single dose of CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 (warfarin), P-gp (digoxin), OATP1B1/1B3 (rosuvastatin), and OAT3 (methotrexate) substrates were 0.90, 0.52, 0.84, 1.01, 1.02, and 1.27, respectively. Finally, in accordance with regulatory guidelines, the Simcyp modeling platform was qualified to predict CYP3A4 induction using known inducers and sensitive substrates.

Keywords: PBPK model; cytochrome P450 (CYP) enzymes induction; drug-drug interactions (DDIs); ivosidenib; perpetrator; transporter inhibition.

Acanthamoeba keratitis is a sight-endangering eye infection, and causative organism Acanthamoeba presents a significant concern to public health, given escalation of contact lens wearers. Contemporary therapy is burdensome, necessitating prompt diagnosis and aggressive treatment. None of the contact lens disinfectants (local and international) can eradicate Acanthamoeba effectively. Using a range of compounds targeting cellulose, ion channels, and biochemical pathways, we employed bioassay-guided testing to determine their anti-amoebic effects. The results indicated that acarbose, indaziflam, terbuthylazine, glimepiride, inositol, vildagliptin and repaglinide showed anti-amoebic effects. Compounds showed minimal toxicity on human cells. Therefore, effects of the evaluated compounds after conjugation with nanoparticles should certainly be the subject of future studies and will likely lead to promising leads for potential applications.

Keywords: Acanthamoeba; Contact lens disinfectants; Eye infection; Keratitis.

Diabetes mellitus is a multifactorial disorder characterized by a chronic elevation in blood glucose levels. Currently, antidiabetic drugs are available to counteract the associated pathologies. Their concomitant effects necessitate the investigation for an effective and safe drug aimed to diminish blood glucose levels with fewer side effects. Several researchers are taking new initiatives to explore plant sources as they are known to contain a wide variety of active agents. Hence, the present study was undertaken to study the role of natural products using in silico interaction studies. Erythrin a compound present in lichens was selected as a potential anti-diabetic agent. Molecular docking studies were carried out with 14 target proteins to evaluate its antidiabetic potential. Molecular docking analysis resulted in favourable binding energy of interaction ranging as low as - 119.676 to - 92.9545 kcal/mol for erythrin, Analogue showed the highest interactions with <b>3C45</b> (- 119.676 kcal/mol) followed by <b>2Q5S</b> (- 118.398 kcal/mol), <b>1XU7</b> (- 117.341 kcal/mol), <b>3K35</b> (- 114.267 kcal/mol). Erythrin was found to fare better than the three clinically used antidiabetic compounds, metformin, repaglinide and sitagliptin. Further, the molecular interactions between erythrin and the diabetes related target proteins was established by analysing the interactions with associated amino acids. In silico pharmacokinetics and toxicity profile of erythrin using admetSAR software predicted erythrin as non-carcinogenic and non-mutagenic. The drug-likeliness was calculated using molsoft software respecting Lipinski's rule of five. The compound was found to comply with Lipinksi rules violating only one filter criterion. The study suggested that erythrin could be a potential anti-diabetic agent.

Keywords: Diabetes; Docking; Erythrin; Insilico analysis; admetSAR.

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC₅₀ of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0-18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53-5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a K_i of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and C_max) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Keywords: drug-phytochemical interaction; hepatic metabolism; mixed inhibition; quercetin; repaglinide.

Objectives We intend to investigate the feasibility of using repaglinide as initial therapy in patients with newly diagnosed type 2 diabetes mellitus naive to the oral anti-hyperglycemic agents by validating the effects of repaglinide on glycemic control (HbA1c) in comparison with metformin monotherapy. Methodology This parallel-controlled, randomized study was carried at the outpatient department of a tertiary care hospital. Two-hundred patients of both genders with newly diagnosed type 2 diabetes mellitus were included. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, HbA1c, and lipid profile. We divided the patients into two subgroups based on the lottery method. Group A was prescribed metformin, and group B was prescribed repaglinide, while the dosages were adjusted according to the blood sugar levels. All data were analyzed using SPSS Software 25.0 (SPSS Inc., Chicago, USA). We reported the data as means along with the standard error. Results All patients completed the study. There was a decline in fasting blood glucose levels after three months of therapy, both in the metformin (135 mg/dl ± 6 mg/dl versus 115 mg/dl ± 7 mg/dl, p < 0.01) and repaglinide groups (145 ± 6 mg/dl versus 122 ± 6 mg/dl, p < 0.01). Similarly, significant reductions in HbA1c were seen in both metformin (7.12 ± 0.15% versus 6.67 ± 0.06%, p < 0.01) and repaglinide treatment groups (7.83 ± 0.67% versus 6.81 ± 0.07%, p < 0.01). After three months of treatment, body mass index (BMI) was significantly decreased in the metformin group (26.87±1.1 kg/m² versus 25.11 ± 0.44 kg/m², p < 0.05). However, the patients in repaglinide group demonstrated a very slight decrease in BMI (27.11 ± 1.6 kg/m² versus 26.47 ± 0.40 kg/m²). On follow-up, we found a significant decrease in triglyceride levels in both groups (p < 0.01 and p < 0.05. respectively). We also found that only the patients in metformin group showed some improvements in total cholesterol and low-density lipoprotein (LDL) levels (p < 0.05). Conclusion Our study concluded that both metformin and repaglinide have similar anti-hyperglycemic effects. Repaglinide can be prescribed as an alternative drug to metformin in patients with new-onset diabetes mellitus.

Keywords: diabetes mellitus; fbs; hba1c; metformin; monotherapy; rbs; repaglinide.

The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20-40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m² and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m². Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.

Keywords: GLP-1RA; SGLT2i; cardiovascular disease; diabetic kidney disease; insulin.

BackgroundCombination therapy with an alpha-glucosidase inhibitor or glinide plus a dipeptidyl peptidase-4 inhibitor is thought to be effective for glycemic control because of its effects on postprandial hyperglycemia. However, no studies have directly compared the efficacy and safety of these two combination therapies.MethodsEighteen patients with type 2 diabetes were studied. All had diabetes not adequately controlled with diet and exercise therapy and an HbA1c level of ≥7.5%; none were receiving any medication for diabetes. The patients were randomized to either miglitol- or repaglinide-based combination therapy with alogliptin. Patients received miglitol or repaglinide monotherapy for 3 months (the miglitol and repaglinide groups, respectively), after which alogliptin was added to each group as combination therapy for 3 months. A meal tolerance test (MTT) was performed before the start of treatment and at the end of monotherapy and combination therapy.ResultsDuring the study period, decreases in HbA1c and glycated albumin were significantly greater in the repaglinide group than in the miglitol group; however, there was no significant difference between treatment groups at the end of the study. At the end of monotherapy, insulin secretion relative to glucose elevation (ISG_0-30: area under the curve of insulin from 0 to 30 min during MTT [AUC_0-30 of IRI]/AUC_0-30 of plasma glucose) was significantly increased only in the repaglinide group; ISG_0-30 did not significantly increase in either group after the addition of alogliptin.ConclusionsThe addition of alogliptin to repaglinide monotherapy did not cause glucose-independent inappropriate insulin secretion and did not appear to increase the incidence of hypoglycemia.

Keywords: alogliptin; miglitol; postprandial hyperglycemia; repaglinide.

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as "interplay of transporters and enzymes". Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug-drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug-drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5-2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

Keywords: drug transporters; drug–drug interaction; pharmacokinetics; physiologically based pharmacokinetic model; the interplay of transporters and enzymes.

Keywords: buoyancy effect; floating microspheres; guar gum; repaglinide; x-ray image.

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC₅₀ 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC₅₀ 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.

Keywords: ALR1; ALR2; Eparlestat; Meglitinides; Repaglinide; SUR1.

This review aimed to evaluate the clinical success of clopidogrel dosing based on CYP2C19 genotype and to identify the relevant additional factors that may be useful for consideration by the clinician when dosing individuals with clopidogrel. The results indicated that genotype-guided dosing in individuals with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is frequently practiced, although the advantages remain controversial. Demographic factors such as age, ethnicity and some comorbidities such as diabetes mellitus can potentially contribute to further refinement of clopidogrel dosage but additional clinical studies to guide these practices are required. Drugs that are CYP2C19 or CYP3A4 inhibitors may reduce the effectiveness of clopidogrel and should be carefully considered during co-administration. In particular, as stated in the clopidogrel label, concomitant use with strong or moderate CYP2C19 inhibitors such as omeprazole should be avoided. Increased exposure and response to clopidogrel has been observed in smokers. Noteworthy, is a very recent study that has shown that smoking cessation in clopidogrel patients may result in reduced response and carries the risk of high on-clopidogrel platelet reactivity. Recent studies have shown clinically significant increases in exposure to CYP2C8 substrates (repaglinide, dasabuvir, desloratidine) and a CYP2B6 substrate (s-sibutramine) following co-administration with clopidogrel, indicating that therapeutic strategies with clopidogrel should avoid these drugs.

Keywords: CYP2C19 polymorphisms; clopidogrel DDIs; clopidogrel dosing; clopidogrel therapeutic strategies; ethnicity; genotype-guided dosing.

Trimethoprim is a frequently-prescribed antibiotic and therefore likely to be co-administered with other medications, but it is also a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8. The aim of this work was to develop a physiologically-based pharmacokinetic (PBPK) model of trimethoprim to investigate and predict its drug-drug interactions (DDIs). The model was developed in PK-Sim^®, using a large number of clinical studies (66 plasma concentration-time profiles with 36 corresponding fractions excreted in urine) to describe the trimethoprim pharmacokinetics over the entire published dosing range (40 to 960 mg). The key features of the model include intestinal efflux via P-glycoprotein (P-gp), metabolism by CYP3A4, an unspecific hepatic clearance process, and a renal clearance consisting of glomerular filtration and tubular secretion. The DDI performance of this new model was demonstrated by prediction of DDIs and drug-drug-gene interactions (DDGIs) of trimethoprim with metformin, repaglinide, pioglitazone, and rifampicin, with all predicted DDI and DDGI AUC_last and C_max ratios within 1.5-fold of the clinically-observed values. The model will be freely available in the Open Systems Pharmacology model repository, to support DDI studies during drug development.

Keywords: cytochrome P450 2C8 (CYP2C8); drug–drug interaction (DDI); multidrug and toxin extrusion protein (MATE); organic cation transporter (OCT); physiologically-based pharmacokinetic (PBPK) modeling; trimethoprim.

Abstract: Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are one of the most frequently prescribed anti-diabetic agents in Japan, and they are often used in combination with insulin secretagogues, such as sulfonylureas and glinides. In the present study, we determined the efficacy and safety of the use of repaglinide or glimepiride, a sulfonylurea, in combination with a DPP-4I, in Japanese patients with type 2 diabetes mellitus (T2DM). This study was an investigator-initiated, open-label, randomized, multi-center prospective study. Patients with T2DM, which was inadequately controlled using a DPP-4I, were randomized to a repaglinide group or a glimepiride group and treated for 48 weeks. The primary outcomes were the reductions in glycated hemoglobin (HbA1c) and glucose oscillation, identified using continuous glucose monitoring, after 12 weeks. The secondary outcome was the change in carotid intima-media thickness (IMT), measured by ultrasonography, after 48 weeks. A total of 61 patients were recruited and analyzed in the study. Twelve weeks of treatment with 1.5 mg repaglinide or 1 mg glimepiride significantly reduced HbA1c, and a larger reduction in HbA1c occurred in the repaglinide group than the glimepiride group. Mean subcutaneous glucose concentration was significantly reduced in both groups, but the glucose oscillation did not decrease. Interestingly, the mean left IMT significantly increased in the glimepiride group, but not in the repaglinide group. More hypoglycemic events were observed in the glimepiride group. These data suggest that repaglinide reduces HbA1c more effectively than glimepiride when used in combination with a DPP-4I, and causes fewer hypoglycemic events.

Trail registry: This study is registered with UMIN-CTR (UMIN000018321).

Keywords: Atherosclerosis; Dipeptidyl peptidase-4 inhibitor; Glucose oscillation; Hypoglycemia; Insulin secretagogue.

The emergence and spread of drug resistance in Plasmodium falciparum, the parasite causing the most severe form of human malaria, is a major threat to malaria control and elimination programs around the globe. With P. falciparum having evolved widespread resistance against a number of previously widely used drugs, currently, artemisinin (ART) and its derivatives are the cornerstones of first-line treatments of uncomplicated malaria. However, growing incidences of ART failure reflect the spread of ART-resistant P. falciparum strains. Despite current efforts to understand the primary cause of ART resistance due to mutations in the Kelch 13 gene (PfK13), the mechanism underlying ART resistance is still not completely unclear and no feasible strategies to counteract the causes and thereby restoring the efficiency of ART have been developed. We use a polypharmacology approach to identify potential drugs that can be used for the novel purpose (target). Of note, we have designed a multimodal stratagem to identify approved drugs with a potential antimalarial activity using computational drug reprofiling. Our investigations suggest that oxetacaine, simvastatin, repaglinide, aclidinium, propafenone, and lovastatin could be repurposed for malaria control and prevention.

Keywords: In silico; Kelch 13; artemisinin (ART); drug re-profiling; drug resistance; virtual screening (VS).

Background: The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.

Objectives: To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.

Search methods: We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).

Selection criteria: We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention.

Data collection and analysis: Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.

Main results: We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence). Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence). We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review.

Authors' conclusions: Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Trial registration: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00220961 https://clinicaltrials.gov/show/NCT00352287 https://clinicaltrials.gov/show/NCT00708175 https://clinicaltrials.gov/show/NCT00276497 https://clinicaltrials.gov/ct2/show/NCT00994682 https://clinicaltrials.gov/ct2/show/NCT00015626 NCT00306826 https://clinicaltrials.gov/show/NCT00470262 http://clinicaltrials.gov/show/NCT00633282 https://clinicaltrials.gov/ct2/show/NCT00722631 https://clinicaltrials.gov/show/NCT01006018.

Purpose: Compared with newer prandial anti-diabetes agents, repaglinide and acarbose are unique in being globally available in generic versions, being oral, and being the cheapest of all. The aim of this study was to compare their efficacy when used alone or in combination.

Methods: In a randomized, double-blind, prospective study, 358 recently diagnosed type 2 diabetes (T2D) patients, who on a combined therapy with metformin and insulin glargine had a fasting plasma glucose (FGP) of <7.2 mmol/L but a 2-h postprandial plasma glucose (2hPPG) >10 mmol/L, were assigned to three groups of additional treatment with either repaglinide, acarbose, or repaglinide-plus-acarbose for 4 months.

Results: With intention-to-treat analysis, 63% of repaglinide group, 45.4 percent of acarbose group, and 75.7% of repaglinide-plus-acarbose group reached the primary endpoint of 2hPPG < 10 mmol/L while maintaining FPG < 7.2 mmol/L. Treatment adherence rate was 75.6% with repaglinide, 61.4% with acarbose, and 81.3% with repaglinide-plus-acarbose (p = 0.001). Among the groups, weight was significantly lower in acarbose group (p < 0.05). Twenty-one percent of repaglinide patients, 4.9% of acarbose subjects, and 10.3% of repaglinide-plus-acarbose cases reported at least one episode of hypoglycemia (p < 0.005). HbA1C and basal insulin requirement were significantly lower in repaglinide group (p = 0.004, p = 0.0002). Triglycerides were lowest in acarbose group (p = 0.005).

Conclusions: Both acarbose and repaglinide were vastly effective in lowering postprandial hyperglycemia of recently diagnosed T2D. When combined, they were even more efficacious and the disease had a better outcome. Compared with newer peers, these two are particularly useful where and when cost consideration in diabetes treatment is a prime concern.

Keywords: Acarbose; Postprandial hyperglycemia; Repaglinide; Treatment adherence; Type 2 diabetes (T2D).

Objective: The contribution ratios (CR) of metabolic enzymes to the systemic clearance of a drug can be estimated from in vitro studies. Another feasible approach is to calculate them based on the increase in the area under the time-concentration curve (AUC) caused by the co-administration of a potent and selective inhibitor in a clinical drug-drug interaction (DDI) study. However, some factors, such as the inhibitory potency of the inhibitor and the inhibition of first-pass metabolism, might affect the estimation of CR based on clinical DDI studies. We aimed to validate the accuracy of the DDI-based estimation of CR using an in silico approach.

Materials and methods: An in silico DDI study was conducted using a population-based physiological pharmacokinetic simulator to estimate the CR of cytochrome P450 (CYP)3A4 for zolpidem, sildenafil, omeprazole, triazolam, and repaglinide. The ratio of the AUC value seen in the presence of an inhibitor (ketoconazole or itraconazole) to that observed in the absence of the inhibitor (AUC ratio) was also calculated. The CR for CYP3A4 obtained using the simulator (CR_def) were compared with those calculated from the AUC ratio (CR_est).

Results: When ketoconazole was used, good correlations between the CR_est and CR_def were obtained for all examined substrates (inconsistencies were seen in < 10% of subjects). CR estimates derived from the AUC ratio were found to be accurate. Some underestimation was observed, possibly due to incomplete inhibition, and some overestimation caused by extensive first-pass metabolism was noted.

Conclusion: This study verified that CR obtained from AUC ratios in DDI studies are quite reliable.

The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is important to estimate unbound liver concentration for drugs that are substrates of hepatic organic anion transporting peptide (OATP) transporters with asymmetric distribution into the liver relative to plasma. Herein, we explored the utility of PXB chimeric mice with humanized liver that are highly repopulated with human hepatocytes to predict human hepatic disposition of OATPs substrates, including rosuvastatin, pravastatin, pitavastatin, valsartan and repaglinide. In vitro total uptake clearance and transporter-mediated active uptake clearance in C57 mouse hepatocytes were greater than PXB chimeric mouse hepatocytes for rosuvastatin, pravastatin, pitavastatin and valsartan. Consistent with in vitro uptake data, enhanced hepatic uptake and resulting total systemic clearance were observed with the above four compounds in control SCID than in PXB chimeric mouse, which suggest that mouse has a stronger transporter-mediated hepatic uptake than human. In vivo liver-to-plasma Kpuu from PXB chimeric and SCID control mice were also compared, and rosuvastatin and pravastatin Kpuu in SCID mouse were more than 10-fold higher than that in PXB chimeric mouse, whereas, pitavastatin, valsartan and repaglinide Kpuu in SCID mouse were comparable with Kpuu in PXB chimeric mouse. Finally, PXB chimeric mouse liver-to-plasma Kpuu values were compared with the reported human Kpuu, and a good correlation was observed as the PXB Kpuu vales were within 3-fold of human Kpuu. Our results indicate that PXB mice could be a useful tool to delineate hepatic uptake and enable prediction of human liver-to-plasma Kpuu of hepatic uptake transporter substrates. Significance Statement We evaluated PXB mouse with humanized liver for its ability to predict human liver disposition of five OATP transporter substrates. Both in vitro and in vivo data suggest that mouse liver has a stronger transporter-mediated hepatic uptake than the humanized liver in PXB mouse. More importantly, PXB liver-to-plasma Kpuu values were compared with the reported human Kpuu, and a good correlation was observed. PXB mice could be a useful tool to project human liver-to-plasma Kpuu of hepatic uptake transporter substrates.

Keywords: Organic anion uptake / efflux (OATs, OATPs); Species differences; Transporter-mediated drug/metabolite disposition; hepatic uptake; liver/hepatic; transporters.