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Thiazolidinone scaffold has become a promising scaffold when it comes to therapeutic importance, and researchers are quite interested in it because of its wide range of applications in the different fields of chemistry. The capacity of this nucleus to interact with a variety of biological targets, including the peroxisome proliferator‐activated receptor (PPAR), protein tyrosine phosphatase 1B, aldose reductase, α‐glucosidase, and α‐amylase, has led to the observation of its antidiabetic effect. α‐Amylase (α‐1,4‐glucan‐4‐glucanohydrolase, EC 3.2.1.1) is one of the most important industrial endoamylases capable of hydrolyzing the internal α‐1,4‐glycosidic bonds in polysaccharides with net retention of α‐anomeric configuration in low molecular weight products, such as glucose, maltose, and maltotriose units. The inhibitors of α‐amylase have the ability to lower endogenous activity, which is crucial for the management of agricultural pests as well as the treatment and prevention of human disorders. In the present review, we attempted to compile the most recent studies on thiazolidinone‐based α‐amylase inhibitors, investigate their therapeutic potential in treating diabetes, comprehend the relationships between structure and activity, offer suggestions for future research and translation of these findings into clinical applications. This comprehensive review strives to be a valuable resource for researchers, medicinal chemists, and healthcare professionals involved in developing and applying novel therapeutics for treating metabolic disorders. [ABSTRACT FROM AUTHOR]

The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SO2NH2) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen–deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs.

Glitazones form an important class of oral drugs in the treatment of type 2 diabetes mellitus. After the exit of rosiglitazone due to cardiovascular safety concerns, pioglitazone has been associated with an increased risk of bladder cancer particularly with higher doses and longer use among males. Increasing awareness and Judicious use of pioglitazone, in low risk patients until more data is available appears prudent. [ABSTRACT FROM AUTHOR]

Abstract: Recent clinical trials have changed the management paradigm for diabetic macular edema (DME). There is an urgent need to identify the most effective ways of preventing retinopathy or intervening at an early, asymptomatic stage in order to preserve vision. The rise in the incidence of diabetes is a serious public health concern. Grading and screening programmes help to identify sight threatening diabetic retinopathy in the community early and facilitate timely referral to an ophthalmologist. Systemic therapies for DME target the key modifiable risk factors: metabolic and blood pressure control. There may also be a role for modification of the renin-angiotensin system and for lipid lowering agents. Improved glycemic and blood pressure control remain the most effective ways of reducing morbidity from DME. Fenofibrate also has beneficial effects, but the mechanism for this remains unclear. Multiple new treatments are in the pipeline, and these are expected to change our approach to DME for the first time in 30 years. [Copyright &y& Elsevier]

Aim: Sulphonylureas (SUs) are among the most widely used oral hypoglycaemic drugs that stimulate insulin secretion. In addition, SUs have pleiotropic effects on other tissues. Conflicting findings have been reported regarding the effects of SUs on adipocytes. We have now investigated the actions of glimepiride and glibenclamide (=glyburide) in primary human adipocytes. Methods: Primary cultured human white pre-adipocytes were differentiated in vitro according to a standard protocol. Lipid accumulation was assessed by Oil Red O staining and determination of triglyceride content; gene expression was measured by RT PCR and Western blotting. Results: Initially, we characterized the genes regulated during human pre-adipocyte differentiation by performing global microarray analysis. Treatment with glimepiride and glibenclamide caused an increased accumulation of lipid droplets and triglycerides. In addition, genes involved in lipid metabolism were induced and chemokine expression was decreased. Interestingly, the effects of SUs were generally qualitatively and quantitatively similar to those of pioglitazone. In direct comparison, glibenclamide was more potent than glimepiride with respect to the induction of fatty acid binding protein 4 (FABP4) (EC50 0.32 vs. 2.8 µM), an important adipocyte marker gene. SU-induced differentiation was virtually completely blocked by the peroxisome proliferator-activated receptor γ (PPAR γ)-antagonist T0070907 but not affected by diazoxide, indicating PPAR γ activation by SUs. Repaglinide had no effect on adipogenesis, although it causes insulin liberation like SUs. Conclusions: In primary human pre-adipocytes, glibenclamide and glimepiride strongly induced differentiation, apparently by activating PPAR γ. Thus, SUs but not repaglinide may be used to influence insulin resistance beyond their effect on insulin liberation. [ABSTRACT FROM AUTHOR]

Abstract: The prevalence of diabetes is growing in many countries. Prescription oral medications have been developed to treat the disease since the 1950s. More recently, a group of diabetes drugs, known as the glitazones, have been developed and introduced on to North American and European markets since the late 1990s. When first introduced, the glitazones were widely regarded as ‘innovative’ pharmaceuticals and have remained on the American and EU markets, among others, throughout the 2000s. Yet, enormous uncertainties about their therapeutic value have remained since they came on the market a decade ago. This paper investigates how socio-political systems of drug development and regulation generate such pharmaceutical uncertainty consequent upon the limited informational value that diabetes drug trials provide about the health risks and benefits of such medications when used in clinical practice. Drawing on documentary research and fieldwork interviews, the first in-depth analysis of regulation of ‘innovative’ pharmaceuticals in both the US and supranational EU is presented. It is argued that these pharmaceutical uncertainties can be explained by reference to four key factors: regulatory paradigms using surrogate markers for drug efficacy; drug approval standards in policy and legislation; ideological expectations of innovation within regulatory agencies; and pharmaceutical industry shaping of drug evaluation. [Copyright &y& Elsevier]

Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are markers of endothelial injury and repair. We compared the effects of pioglitazone versus metformin on the circulating numbers of EMPs and EPCs in patients with newly diagnosed type 2 diabetes. This was a randomized, double-blind, comparator-controlled, 24-week single-centre trial conducted in a Teaching Hospital in Naples, Italy. One hundred and ten people with newly diagnosed type 2 diabetes who were never treated with antihyperglycaemic drugs and had haemoglobin A1c (HbA1c) levels between 7 and 10% were given pioglitazone hydrochloride (15-45 mg/day) (n = 55) or metformin (1000-2000 mg/day) (n = 55) as an active comparator. Absolute change from baseline to final visit in circulating EMPs and EPCs and their ratio were the main outcomes. Baseline characteristics did not differ between the study groups. The decrease in circulating EMPs CD31+ [intergroup difference, −32 counts/µl (95% CI −51 to −9)] and the increase in EPCs CD34+/KDR+ [intergroup difference, 33 cells/10 events (95% CI 13 to 55)] were greater with pioglitazone versus metformin. EMPs/EPCs ratio was reduced with pioglitazone and unchanged with metformin [difference, −1.5 (95% CI −2.6 to −0.5), p < 0.001]. Participants assigned to pioglitazone gained more weight and experienced greater improvements in some coronary risk measures [high-density lipoprotein (HDL)-cholesterol, triglycerides, adiponectin and C-reactive protein (CRP)] than did those assigned to metformin. Compared with metformin, pioglitazone treatment improved the imbalance between endothelial damage and repair capacity and led to more favourable changes in coronary risk factors in patients with newly diagnosed type 2 diabetes. [ABSTRACT FROM AUTHOR]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Glitazones are known to exhibit antihyperglycemic activity by decreasing peripheral insulin resistance. In the present study, we have designed some novel glitazones based on the structure–activity relationships as possible PPAR-γ agonists. The manually designed glitazones were synthesized by using the appropriate synthetic schemes and screened for their in vitro antihyperglycemic activity by estimating glucose uptake by rat hemi-diaphragm, both in the absence and in the presence of external insulin. Some of the glitazones exhibited good antihyperglycemic activity in presence of insulin. Illustration about their design, synthesis, evaluation, and structure–activity relationships is described. [Copyright &y& Elsevier]

Abstract: Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0μM. In vivo efficacy of 3e as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Significant improvement of glucose tolerance was observed. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA. Compound 3e was also found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action. [Copyright &y& Elsevier]

Abstract: Diabetes mellitus is a growing epidemic with a prevalence among patients with heart failure (HF) approaching 30%. Diabetes worsens the prognosis of HF, and the pathophysiology is complex and multifactorial. Early detection of subtle alterations in cardiac function by modern tools, such as Doppler echocardiography or brain natriuretic peptide dosage, is thus important in these patients. All drugs known to be effective in HF with systolic dysfunction are also effective in patients with diabetes. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists also seem particularly useful. Overall, however, little is known about the treatment of diabetic patients with HF, especially in case of preserved systolic function. Ongoing and future trials should help to determine the best treatment for these patients with or without associated diabetes. This review assesses the relationships between diabetes mellitus and HF and discusses the various medical strategies. [Copyright &y& Elsevier]

Abstract: Novel 5-benzyl and 5-benzylidene-thiazolidine-2,4-diones carrying 2,3-dihydrobenzo[1,4]dioxin pharmacophore were synthesized and their glycogen phosphorylase inhibitor activity was also studied. [Copyright &y& Elsevier]

Prospective studies of prediabetic subjects have shown that obesity and its duration are major risk factors for type 2 diabetes. Longitudinal studies are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity‐induced insulin resistance. Inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The adipose tissue has been recognized as an important source of metabolically active secretory products (adipocytokines), free fatty acids, leptin, TNF‐α, Iinterleucin‐6, plasminogen activator inhibitor‐1, adiponectin and resistin. Prevention of insulin resistance by weight loss, diet and exercise is very effective in reducing the progression from glucose intolerance to type 2 diabetes in obese subjects. Since insulin resistance is a key disturbance in early type 2 diabetes additional drug treatment with insulin‐sensitizing drugs might be helpful to reduce the progression to both beta‐cell failure and macrovascular late complications. The PROACTIVE study will determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The incidence of diabetes has reached epidemic proportions across the world. In patients with diabetes, there is a two to four times increased risk of developing coronary artery disease (CAD). Diabetes seems to eliminate the protective benefits of hormones in women against CAD. Patients with type II diabetes also have hypertension, dyslipidemia, obesity, endothelial dysfunction and prothrombotic factors, called ‘the metabolic syndrome’. Not only the incidence of CAD is higher in diabetes, the mortality of the diabetic patients after a cardiac event is significantly increased as compared to non-diabetics, including sudden death. Although in the past 35 years there has been a decline in the rate of death due to CAD in the general population, this has not been seen among patients with diabetes. Primary prevention can play an important role in decreasing the incidence of CAD in diabetic patients. Aggressive treatment of hyperlipidemia and hypertension is essential. Recent knowledge about the protective effects of aspirin, statins, angiotension converting enzyme inhibitors, and glitazones in the diabetic patients, if used appropriately will go a long way in primary and secondary prevention of CAD in patients with diabetes. [Copyright &y& Elsevier]

The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SO2NH2) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen–deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: This report describes the case of a 75-year-old male type 2 diabetic Caucasian who was admitted to the clinical ward because of acute pain and cramps in both calf muscles. Materials and methods: Neuromuscular function was assessed by electromyography and electroneurography of the right leg. An open biopsy was taken from the left vastus lateralis muscle for histological and histochemical analyses. Southern blotting was performed to detect defects in mitochondrial DNA and tRNA. Cytochrome P450 (CYP-P450) polymorphisms were analysed in blood cells. Results: Fifteen weeks before admission, the patient's lipid-lowering medication was switched from simvastatin to fenofibrate because of predominant hypertriglyceridaemia; this did not affect creatine kinase levels. Three weeks before admission, rosiglitazone was added to his existing metformin therapy because of worsening metabolic control. Upon admission, serum enzymes indicating myopathy were elevated (creatine kinase 6897 U/l, myoglobin 902 ng/ml) and kidney function was impaired (creatinine 0.116 mmol/l, blood urea nitrogen 2.3 mmol/l). Electrophysiology revealed myopathy and sensory polyneuropathy. Histology showed multiple damage of the myofibrillar architecture. There was no evidence of defects in mitochondrial DNA or tRNA. Furthermore, no functional limitations in CYP2C9, CYP2C19 and CYP2D6 were detected. Following withdrawal of the oral medication and intravenous hydration, clinical symptoms and laboratory parameters gradually decreased. Conclusions/ interpretation: Until more data from controlled trials are available, we recommend that combination therapy with fibrates and thiazolidinediones should be monitored frequently by measurements of serum creatine kinase and creatinine, specifically in patients with pre-existing nephropathy and polyneuropathy. [ABSTRACT FROM AUTHOR]