Thiazolidinedione

Source: Wikipedia, the free encyclopedia.

Functional group

The thiazolidinediones

diabetes mellitus type 2
that were introduced in the late 1990s.

Mechanism of action

Thiazolidinediones or TZDs act by activating

carbohydrates, more specifically glucose, in order to yield energy for other cellular processes.[3]

PPARγ transactivation

Thiazolidinedione ligand dependent transactivation is responsible for the majority of anti-diabetic effects.

The activated PPAR/RXR

PPARγ
):

TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.[6]

PPARγ transrepression

Thiazolidinedione ligand dependent transrepression mediates the majority of anti-inflammatory effects.

Binding of PPARγ to coactivators appears to reduce the levels of coactivators available for binding to pro-inflammatory transcription factors such as NF-κB; this causes a decrease in transcription of a number of pro inflammatory genes, including various interleukins and tumour necrosis factors.[citation needed]

Members of the class

The chemical structure of thiazolidinedione and rhodanine

Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:

  • Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[7]
  • Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions. [citation needed]
  • Lobeglitazone (Duvie), approved for use in Korea

Experimental, failed and non-marketed agents include:

Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a rhodanine.

Uses

The only approved use of the thiazolidinediones is in

carotid arteries.[8]

Research

Experimental investigations on TZDs have been carried out since 2005 in

autism,[12] ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells),[13] lichen planopilaris, and other conditions.[14]

Several forms of

breast carcinoma development.[citation needed
]

Evidence was emerging in 2008 that

non-alcoholic steatohepatitis due to their combined antioxidant and insulin sensitizing effects, producing histological improvements in steatosis severity.[15]

Side effects and contraindications

The withdrawal of

liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazone and pioglitazone have been free of this problem.[citation needed
]

The main side effect of all thiazolidinediones is water retention, leading to edema, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA grade III or IV heart failure).[citation needed]

Though older studies suggested there may be an increased risk of

coronary heart disease and heart attacks with rosiglitazone,[16] pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression.[17][18][19] These studies led to a period of Food and Drug Administration advisories (2007 - 2013) that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease.[20] The new recommendations were largely based on the reasoning that prior meta-analyses leading to the original restrictions were not designed to assess cardiac outcomes and, thus, not uniformly collected or adjudicated. In contrast, one of the largest trials (RECORD trial) that was specifically designed to assess cardiac outcomes found no increased risk of myocardial infarction with rosiglitazone use, even after independent re-evaluation for FDA review.[21]

A 2013

cigarette smoking, family history, or exposure to certain forms of chemotherapy.[22]

A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke or end-stage renal disease when comparing metformin monotherapy to Thiazolidinedione for treatment of type 2 diabetes.[23]

Thiazolidinediones reduce

bone marrow stromal cells away from osteoblast differentiation and toward adipocyte formation.[24]

References

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  6. ^ "Avandia diabetes drug suspended". nhs.uk. 24 September 2010.
  7. ^ Santo M (June 2011). "Diabetes Drug Actos Sales Suspended in France and Germany". HULIQ.com.
  8. PMID 29197071
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  9. PMID 17135584
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  10. ^ Clinical trial number NCT00227110 for "Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)" at ClinicalTrials.gov
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  14. ^ Clinical Trials for Rosiglitazone - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health[verification needed]
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  16. ^ "Avandia to Carry Stronger Heart Failure Warning - Forbes.com". Forbes. Archived from the original on 21 October 2007. Retrieved 15 August 2007.
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  18. S2CID 36703728
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  19. PMID 18378631
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  20. ^ "FDA requires removal of certain restrictions on the diabetes drug Avandia". U.S. Food and Drug Administration. 25 November 2013. Archived from the original on 9 February 2014.
  21. PMID 23895806
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  22. S2CID 24856013
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  23. PMID 32501595
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  24. PMID 26604937
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