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a protease inhibitor (trade name Crixivan) used for treating HIV (同)Crixivan

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/28 13:54:46」(JST)

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Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS.

HIV-1 protease in complex with indinavir. PDB entry 2avo^[1]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[2]

Medical uses

Unfortunately, indinavir wears off quickly after dosing, so requires very precise dosing every eight hours to thwart HIV from forming drug-resistant mutations, including resistances to other protease inhibitors. It has restrictions on what sorts of food may be eaten concurrently. For these reasons it is now rarely used.

Side effects

The most common side effects of indinavir include:^[3]

Gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting)
General malaise and fatigue
Nephrolithiasis/urolithiasis (the formation of kidney stones), which sometimes may lead to more severe condition including kidney failure
Metabolic alterations including hyperlipidemia (cholesterol or triglyceride elevations) and hyperglycemia
Alterations in body shape (lipodystrophy), colloquially known as "Crix belly"

Indinavir inhibits urinary nitrous oxide production and may inhibit nitric oxide production. Treatment with this drug is frequently associated with renal abnormalities, sterile leukocyturia, and reduced creatinine clearance.^[4]

Indinavir impairs endothelial function in healthy HIV-negative men and may accelerate atherosclerotic disease.^[5]

History

The Food and Drug Administration approved indinavir on March 13, 1996, making it the eighth approved antiretroviral. Indinavir is much more powerful than any prior antiretroviral drug; using it with dual NRTIs set the standard for treatment of HIV/AIDS and raised the bar on design and introduction of subsequent antiretroviral drugs. Protease inhibitors changed the very nature of the AIDS epidemic from one of a terminal illness to a somewhat manageable one.

Increasingly, it is being replaced by newer drugs that are more convenient to take and less likely to promote virus resistance, such as lopinavir or atazanavir.

Synthesis

Indinavir synthesis:^[6]

References

^ Liu, F.; Boross, P. I.; Wang, Y. F.; Tozser, J.; Louis, J. M.; Harrison, R. W.; Weber, I. T. (2005). "Kinetic, Stability, and Structural Changes in High-resolution Crystal Structures of HIV-1 Protease with Drug-resistant Mutations L24I, I50V, and G73S". Journal of Molecular Biology 354 (4): 789–800. doi:10.1016/j.jmb.2005.09.095. PMC 1403828. PMID 16277992.
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ "Crixivan^® (indinavir sulfate) Capsules. Prescribing Information. Revised December 2013" (PDF). Merck & Co., Inc. Retrieved 6 February 2014.
^ M. Eira, M. Araujo and A.C. Seguro. Urinary NO₃ excretion and renal failure in indinavir-treated patients. Brazilian Journal of Medical and Biological Research (2006) 39: 1065-1070.
^ Shankar SS, Dubé MP, Gorski JC, Klaunig JE, Steinberg HO. Indinavir impairs endothelial function in healthy HIV-negative men. Am Heart J. 2005 Nov;150(5):933.
^ Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K. M.; Volante, R. P.; Reider, P. J. (1994). "Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524". Tetrahedron Letters 35 (5): 673. doi:10.1016/S0040-4039(00)75787-X. edit

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1. HIVプロテアーゼ阻害剤 hiv protease inhibitors
2. 結晶誘発性急性腎障害（急性腎不全） crystal induced acute kidney injury acute renal failure
3. 好酸球の生物学および好酸球増多症の原因 eosinophil biology and causes of eosinophilia
4. 抗レトロウイルス療法の潜在的副作用に関するHIV感染患者を対象としたカウンセリング counseling hiv infected patients regarding potential side effects of antiretroviral therapy
5. HIV薬剤耐性検査の解釈についての手引 primer on interpretation of hiv drug resistance testing

English Journal

Liquid chromatography tandem mass spectrometric studies of indinavir sulphate and its forced degradation products.

Rao RN, Vali RM, Raju SS.SourceAnalytical Chemistry Division, Discovery Laboratory, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India. rnrao55@yahoo.com
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2013 Feb 23;74:101-10. doi: 10.1016/j.jpba.2012.10.025. Epub 2012 Oct 29.
Indinavir sulphate was subjected to forced degradation under hydrolysis (acidic, basic and neutral), oxidation, photolysis and thermal stress as prescribed by ICH guidelines. It was degraded under acidic, basic, neutral and oxidative stress conditions, while it was stable under other conditions. Aft
PMID 23245240

Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.

Holmstock N, Bruyn TD, Bevernage J, Annaert P, Mols R, Tack J, Augustijns P.SourceLaboratory for Pharmacotechnology and Biopharmacy, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: nico.holmstock@pharm.kuleuven.be.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2013 Feb 9. pii: S0928-0987(13)00053-5. doi: 10.1016/j.ejps.2013.01.012. [Epub ahead of print]
Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, explo
PMID 23402972

Indinavir and nelfinavir inhibit proximal insulin receptor signalling and salicylate abrogates inhibition: Potential role of the NFkappa B pathway.

Ismail WI, King JA, Anwar K, Pillay TS.SourceDivision of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa; Division of Pharmaceutical Biotechnology, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia.
Journal of cellular biochemistry.J Cell Biochem.2013 Feb 5. doi: 10.1002/jcb.24513. [Epub ahead of print]
The molecular basis of insulin resistance induced by HIV protease inhibitors (HPIs) remains unclear. In this study, Chinese hamster ovary cells transfected with high levels of human insulin receptor (CHO-IR) and 3T3-L1 adipocytes were used to elucidate the mechanism of this side effect. Indinavir an
PMID 23386514

Japanese Journal

CH05-10, a novel indinavir analog, is a broad-spectrum antitumor agent that induces cell cycle arrest, apoptosis, endoplasmic reticulum stress and autophagy

YOU Jianlan,HE Zhengxiang,CHEN Lili,DENG Gang,LIU Wei,QIN Li,QIU Fayang,CHEN Xiaoping
Cancer science 101(12), 2644-2651, 2010-12-10
NAID 10027834910

末期腎不全に至ったHIV患者10症例の臨床的検討

関谷紀貴,中村裕也,柳澤如樹 [他],菅沼明彦,今村顕史,味澤篤,安藤稔
日本透析医学会雑誌 = Journal of Japanese Society for Dialysis Therapy 43(7), 581-586, 2010-07-28
… ら7例（70％），高血圧は3例（30％）から9例（90％），高脂血症は1例（10％）から6例（60％）に増加した．腎毒性を有する抗レトロウイルス薬の代表であるTenofovir disoproxil fumarate（TDF）の内服歴は1例もなく，Indinavir（IDV）の内服歴は2例にあった．その他の腎毒性のある薬剤では，trimethoprim-sulfamethoxazole（ST）合剤の内服歴が4例，nonsteroidal anti-inflammatory drugs（NSAIDs）の内服歴が3例にあった．ESRDに至ったHIV感染者10例は，HAA …
NAID 10026547437

A liquid chromatography-tandem mass spectrometry assay for quantification of nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc in the plasma of patients infected with HIV

MARTIN J.,DESLANDES G.,DAILLY E.,RENAUD C.,RELIQUET V.,RAFFI F.,JOLLIET P.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 877(27), 3072-3082, 2009-10-01
NAID 10028025117

Related Pictures

★リンクテーブル★

リンク元	「急性尿細管間質性腎炎」「インジナビル」
拡張検索	「indinavir sulfate ethonolate」

「急性尿細管間質性腎炎」

Indinavir
Systematic (IUPAC) name
	(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}butyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide
Clinical data
Trade names	Crixivan
AHFS/Drugs.com	monograph
MedlinePlus	a696028
Licence data	US FDA:link
Pregnancy; category	US: C (Risk not ruled out);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	~65%
Protein binding	60%
Metabolism	Hepatic via CYP3A4
Biological half-life	1.8 (± 0.4) hours
Identifiers
CAS Registry Number	150378-17-9
ATC code	J05AE02
PubChem	CID: 5362440
DrugBank	DB00224
ChemSpider	4515036
UNII	9MG78X43ZT
KEGG	C07051
ChEBI	CHEBI:44032
ChEMBL	CHEMBL540914
NIAID ChemDB	005824
PDB ligand ID	MK1 (PDBe, RCSB PDB)
Chemical data
Formula	C36H47N5O4
Molecular mass	613.79 g/mol
	SMILES CC(C)(C)NC(=O)[C@@H]1CN(CCN1C[C@H](C[C@@H](Cc2ccccc2)C(=O)N[C@H]3c4ccccc4C[C@H]3O)O)Cc5cccnc5 ;
	InChI InChI=1S/C36H47N5O4/c1-36(2,3)39-35(45)31-24-40(22-26-12-9-15-37-21-26)16-17-41(31)23-29(42)19-28(18-25-10-5-4-6-11-25)34(44)38-33-30-14-8-7-13-27(30)20-32(33)43/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45)/t28-,29+,31+,32-,33+/m1/s1 ; Key:CBVCZFGXHXORBI-PXQQMZJSSA-N ;
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