スルホニル尿素、スルホニルウレア、スルホニル尿素系薬剤、スルホニル尿素薬、スルホニル尿素剤、((俗))SU薬

ATP感受性K+チャネル阻害によりインスリンを分泌させる抗糖尿病薬

WordNet

antidiabetic consisting of any of several drugs that reduce the level of glucose in the blood; used to treat diabetes mellitus

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/10/14 23:13:52」(JST)

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General formula of a sulfonylurea, showing the sulfonylurea backbone itself in red and the side chains that distinguish each compound in blue.

Chlorpropamide

Tolazamide

Gliclazide

Glimepiride

Sulfonylurea (UK: sulphonylurea) derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.

Drugs in this class

First generation

Carbutamide
Acetohexamide
Chlorpropamide
Tolbutamide
Tolazamide

Second generation

Glipizide
Gliclazide
Glibenclamide (glyburide)
Glibornuride
Gliquidone
Glisoxepide
Glyclopyramide
Glimepiride

Some classify glimepiride as second-generation,^[1] while others classify it as third-generation.^[2]

Chemistry

All sulfonylureas contain a central S-phenylsulfonylurea structure (red) with a p- substituent on the phenyl ring (R) and various groups terminating the urea N′ end group (R₂).

Pharmacology

Mechanism of action

Sulfonylureas bind to an ATP-dependent K⁺(K_ATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca²⁺ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.

There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.

The K_ATP channel is an octameric complex of the inward-rectifier potassium ion channel K_ir6.2 and sulfonylurea receptor SUR1 which associate with a stoichiometry of K_ir6.2₄/SUR1₄.

Pharmacokinetics

Various sulfonylureas have different pharmacokinetics. The choice depends on the propensity of the patient to develop hypoglycemia – long-acting sulfonylureas with active metabolites can induce hypoglycemia. They can, however, help achieve glycemic control when tolerated by the patient. The shorter-acting agents may not control blood sugar levels adequately.

Due to varying half-life, some drugs have to be taken twice (e.g. tolbutamide) or three times a day rather than once (e.g. glimepiride). The short-acting agents may have to be taken about 30 minutes before the meal, to ascertain maximum efficacy when the food leads to increased blood glucose levels.

Some sulfonylureas are metabolised by liver metabolic enzymes (cytochrome P450) and inducers of this enzyme system (such as the antibiotic rifampicin) can therefore increase the clearance of sulfonylureas. In addition, because some sulfonylureas are bound to plasma proteins, use of drugs that also bind to plasma proteins can release the sulfonylureas from their binding places, leading to increased clearance.

Uses

Sulfonylureas are used primarily for the treatment of diabetes mellitus type 2. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.

Sulfonylureas can be used to treat neonatal diabetes. While historically patients with hyperglycemia and low blood insulin levels were diagnosed with Type I Diabetes by default, it has been found that patients who receive this diagnosis before 6 months of age are often, in fact, candidates for receiving sulfonylureas rather than insulin throughout life. ^[3]

Although for many years sulfonylureas were the first drugs to be used in new cases of diabetes, in the 1990s it was discovered that obese patients might benefit more from metformin.

In about 10% of patients, sulfonylureas alone are ineffective in controlling blood glucose levels. Addition of metformin or a thiazolidinedione may be necessary, or (ultimately) insulin. Triple therapy of sulfonylureas, a biguanide (metformin) and a thiazolidinedione is generally discouraged, but some doctors prefer this combination over resorting to insulin.

More recently, a pharmaceutical startup, Remedy Pharmaceuticals, Inc. has begun developing intravenous glyburide^[4] as a treatment for acute stroke, traumatic brain injury and spinal cord injury based on the identification of a non-selective ATP-gated cation channel which is upregulated in neurovascular tissue during these conditions and closed by sulfonylurea agents.^[5]^[6]

Some diabetes experts feel that sulfonylureas accelerate the loss of beta cells from the pancreas, and should be avoided.^{[citation needed]}

Side effects and cautions

Sulfonylureas, as opposed to metformin, the thiazolidinediones, exenatide, symlin and other newer treatment agents may induce hypoglycemia as a result of excesses in insulin production and release. This typically occurs if the dose is too high, and the patient is fasting. Some people attempt to change eating habits to prevent this, however it can be counter productive.

Like insulin, sulfonylureas can induce weight gain, mainly as a result their effect to increase insulin levels and thus utilization of glucose and other metabolic fuels. Other side-effects are: abdominal upset, headache and hypersensitivity reactions.

Sulfonylureas are potentially teratogenic and cannot be used in pregnancy or in patients who may become pregnant. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. As other anti-diabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in hepatic and renal failure, although some of the newer agents offer potentially better options.

Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. All sulfonylureas carry an FDA-required warning about increased risk of cardiovascular death. The ADVANCE trial (Action in Diabetes and Vascular Disease), a randomized trial sponsored by the vendor of gliclazide, found no benefit from tight control with gliclazide for the outcomes of heart attack (myocardial infarction), cardiovascular death, or all-cause death.^[7] Similarly, ACCORD (Action to Control Cardiovascular Risk in Diabetes)^[8] and the VADT (Veterans Affairs Diabetes Trial)^[9] studies showed no reduction in heart attack or death in patients assigned to tight glucose control with various drugs.

Interactions

Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include acetylsalicylic acid and derivatives, allopurinol, sulfonamides, and fibrates. Drugs that worsen glucose tolerance, contravening the effects of antidiabetics, include corticosteroids, isoniazide, oral contraceptives and other estrogens, sympathomimetics, and thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance.^[10]^[11]

History

Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers,^[12] who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals.^[13]

References

^ Triplitt CL, Reasner CA (2011). "Chapter 83: diabetes mellitus". In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathophysiologic approach (8th ed.). New York, NY: McGraw-Hill. pp. 1274. ISBN 0-07-170354-3.
^ Davidson J (2000). Clinical diabetes mellitus: a problem-oriented approach. Stuttgart: Thieme. pp. 422. ISBN 0-86577-840-X. http://books.google.co.uk/books?id=CRA5N-felmMC&pg=PA422&lpg=PA422.
^ Greeley, Siri; Susan E. Tucker, Rochelle N. Naylor, Graeme I. Bell, and Louis H. Philipson (2010). "Neonatal diabetes mellitus: A model for personalized medicine". Trends Endocrinol Metabolism 21 (8): 464-472.
^ "Breakthrough Discovery Offers Hope to Stroke Victims". Carrot Capital. http://www.carrotcapital.com/news_080705.html. Retrieved 2008-01-06.
^ Kunte H, Schmidt S, Eliasziw M, del Zoppo GJ, Simard JM, Masuhr F, Weih M, Dirnagl U (2007). "Sulfonylureas Improve Outcome in Patients With Type 2 Diabetes and Acute Ischemic Stroke". Stroke 38 (9): 2526–30. doi:10.1161/STROKEAHA.107.482216. PMC 2742413. PMID 17673715. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2742413/.
^ Simard JM, Woo SK, Bhatta S, Gerzanich V (2007). "Drugs acting on SUR1 to treat CNS ischemia and trauma". Curr Opin Pharmacol 8 (1): 42–9. doi:10.1016/j.coph.2007.10.004. PMC 2265539. PMID 18032110. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2265539/.
^ Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F (June 2008). "Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes". N. Engl. J. Med. 358 (24): 2560–72. doi:10.1056/NEJMoa0802987. PMID 18539916.
^ Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Probstfield JL, Simons-Morton DG, Friedewald WT (June 2008). "Effects of intensive glucose lowering in type 2 diabetes". N. Engl. J. Med. 358 (24): 2545–59. doi:10.1056/NEJMoa0802743. PMID 18539917.
^ Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD (January 2009). "Glucose control and vascular complications in veterans with type 2 diabetes". N. Engl. J. Med. 360 (2): 129–39. doi:10.1056/NEJMoa0808431. PMID 19092145.
^ Haberfeld, H, ed. (2009) (in German). Austria-Codex (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
^ Dinnendahl, V.; Fricke, U., eds. (2010) (in German). Arzneistoff-Profile. 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ Janbon M, Chaptal J, Vedel A, Schaap J (1942). "Accidents hypoglycémiques graves par un sulfamidothiodiazol (le VK 57 ou 2254 RP)". Montpellier Med. 441: 21–22.
^ Patlak M (2002). "New weapons to combat an ancient disease: treating diabetes". FASEB J. 16 (14): 1853. PMID 12468446. http://www.fasebj.org/cgi/content/full/16/14/1853e.

UpToDate Contents

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1. 糖尿病の治療におけるスルホニル尿素およびメグリチニド sulfonylureas and meglitinides in the treatment of diabetes mellitus
2. スルホニル尿素剤中毒 sulfonylurea agent poisoning
3. 成人の2型糖尿病における血糖の初期マネージメント initial management of blood glucose in adults with type 2 diabetes mellitus
4. 高齢患者における2型糖尿病の治療 treatment of type 2 diabetes mellitus in the older patient
5. 2型糖尿病における持続性高血糖のマネージメント management of persistent hyperglycemia in type 2 diabetes mellitus

English Journal

Effects of chlorimuron ethyl on terrestrial and wetland plants: Levels of, and time to recovery following sublethal exposure.

Carpenter D, Boutin C, Allison JE.SourceEnvironment Canada, Science & Technology Branch, National Wildlife Research Centre, 1125 Colonel By Drive, Carleton University, Ottawa, Ontario, Canada K1A 0H3.
Environmental pollution (Barking, Essex : 1987).Environ Pollut.2013 Jan;172:275-82. doi: 10.1016/j.envpol.2012.09.007. Epub 2012 Nov 6.
Current pesticide registration guidelines call for short-term testing of plants; long-term effects on vegetative parts and reproduction remain untested. The aims of our study were to determine level of recovery and recovery times for plants exposed to the sulfonylurea herbicide chlorimuron ethyl usi
PMID 23137550

Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase.

Lee YT, Cui CJ, Chow EW, Pue N, Lonhienne T, Wang JG, Fraser JA, Guddat LW.AbstractThe sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl) sulfamoyl)benzoate (10c), which has a Ki value of 3.8 nM for C. albicans AHAS and an MIC90 of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity towards C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell.
Journal of medicinal chemistry.J Med Chem.2012 Dec 13. [Epub ahead of print]
The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans attenuation of virulence is achieved, s
PMID 23237384

Genetic Polymorphisms and Drug Interactions Leading to Clopidogrel Resistance: Why the Asian Population Requires Special Attention.

Hasan MS, Basri HB, Hin LP, Stanslas J.Source1Neurology Unit, Department of Medicine and Institute of Gerontology, Faculty of Medicine and Health Sciences, University Putra Malaysia , Serdang, Selangor Darul Ehsan , Malaysia.
The International journal of neuroscience.Int J Neurosci.2012 Dec 6. [Epub ahead of print]
ABSTRACT Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is
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Japanese Journal

Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging.

Kimura Hiroyuki,Matsuda Hirokazu,Fujimoto Hiroyuki,Arimitsu Kenji,Toyoda Kentaro,Mukai Eri,Nakamura Hiroshi,Ogawa Yu,Takagi Mikako,Ono Masahiro,Inagaki Nobuya,Saji Hideo
Bioorganic & medicinal chemistry 22(13), 3270-3278, 2014-07-01
… FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. …
NAID 120005456028

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NAID 40020053538

Diurnal patterns of plasma glucose in patients with type 2 diabetes receiving sulfonylurea and effectiveness of once daily lispro mix 50/50 injections

Mashitani Tsuyoshi,Tsujii Satoru,Hayashino Yasuaki [他]
Diabetology international 5(1), 30-35, 2014
NAID 40020028026

血糖変動指標としての1,5-AG測定の有用性と治療効果判定への応用

徳山芳治,柳澤葉子
糖尿病 57(4), 227-234, 2014
1,5-anhydroglucitol（AG）の血糖変動指標としての有用性を検証するため，連続血糖測定システム（CGM）で得られた血糖変動と1,5-AGとの相関，治療法によるHbA1cと1,5-AGの分布の相違，DPP-4阻害薬投与前後でHbA1cと1,5-AGの変化を調べた．1,5-AGはCGMで得られた血糖値の標準偏差およびMAGEと負の相関が認められた．治療法による検討では，HbA1c値によ …
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