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a protease inhibitor (trade name Viracept) used in treating HIV usually in combination with other drugs (同)Viracept

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/15 14:48:31」(JST)

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Nelfinavir (brand name Viracept) is an antiretroviral drug used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is generally used in combination with other antiretroviral drugs.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.^[1]

History

Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Japan Tobacco. Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. It is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV Healthcare.

The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997,^{[citation needed]} making it the twelfth^{[citation needed]} approved antiretroviral. The initial product launched proved to be the largest^{[citation needed]} "biotech launch" in the history of the pharmaceutical industry, achieving first full year sales exceeding $US335M.^{[citation needed]} Agouron's patent on the drug will expire in 2014.^{[citation needed]}

On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency^[2] put out an alert requesting the recall of any of the drug in circulation, because some batches may have been contaminated with potentially cancer-causing chemicals.

Pharmacology

Nelfinavir should be taken with food. The bioavailability of Nelfinavir is increased 2.5 to 5 times when taken with food.^{[citation needed]} Taking the drug with food also decreases the risk of diarrhea as a side effect.

Mechanism of action

Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. This protease^[which?] is an enzyme which splits viral protein molecules into smaller fragments, and it is vital to both the replication of the virus within the cell, and also to the release of mature viral particles from an infected cell. Though this mode of action^{[clarification needed]} is common to all protease inhibitors, the precise mode of binding of Nelfinavir to the enzyme may be sufficiently unique to reduce cross-resistance^{[clarification needed]} between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.

Toxicity

Nelfinavir can produce a range of adverse side effects. Flatulence, diarrhea or abdominal pain are common (i.e. experienced by more than one in one hundred patients). Fatigue, urination, rash, mouth ulcers or hepatitis are less frequent effects (experienced by one in one thousand to one in one hundred patients). Nephrolithiasis, arthralgia, Leukopenia, pancreatitis or allergic reactions may occur, but are rare (less than one in one thousand patients) .

Potential anti-cancer activity

Nelfinavir were under investigation, in 2009, for potential use as an anti-cancer agent.^[3] When applied to cancer cells in culture (in vitro), it can inhibit the growth of a variety cancer types and can trigger cell death (apoptosis). ^[4] When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. ^[5]^[6] In vitro tests showed it may work well with sorafenib^[7]

In the United States, several clinical trials were conducted in 2008 that sought to verify whether nelfinavir is effective as a cancer therapeutic agent in humans.^[8] In some of these trials, nelfinavir was used alone in monotherapy fashion, whereas in others it was combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy.

In 2008 very good phase I results were obtained for locally advanced pancreatic ductal adenocarcinoma (a form of pancreatic cancer).^[9] The phase I trial (of nelfinavir with radiotherapy), on 12 patients with inoperable pancreatic cancer, showed a doubling of survival times, and six patients had tumor regression to the extent that they became operable.^[10] A phase II trial of 80 patients is starting.^[10]^{[dated info]}

Interactions

Nelfinavir's interaction profile is similar to that of other protease inhibitors. Most interactions occur at the level of the Cytochrome P450 isozymes 3A4 and CYP2C19, by which nelfinavir is metabolised.

References

^ Zhang KE, Wu E, Patick AK, et al. (April 2001). "Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities". Antimicrob. Agents Chemother. 45 (4): 1086–93. doi:10.1128/AAC.45.4.1086-1093.2001. PMC 90428. PMID 11257019.
^ Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination
^ Chow WA, Jiang C, Guan M (2009). "Anti-HIV drugs for cancer therapeutics: back to the future?". Lancet Oncol 10 (1): 61–71. doi:10.1016/S1470-2045(08)70334-6. PMID 19111246.
^ Gills, JJ; Lopiccolo, J; Tsurutani, J; Shoemaker, RH; Best, CJM; Abu-Asab, MS; Borojerdi, J; Warfel, NA et al. (September 2007). "Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo". Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 13 (17): 5183–94. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. |displayauthors= suggested (help)
^ Pyrko, P.; Kardosh, A; Wang, W; Xiong, W; Schönthal, AH; Chen, TC (2007). "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67 (22): 10920–10928. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837.
^ Yang, Y; Ikezoe, T; Takeuchi, T; Adachi, Y; Ohtsuki, Y; Takeuchi, S; Koeffler, HP; Taguchi, H (July 2005). "HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling". Cancer Science 96 (7): 425–33. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514.
^ Brüning, A; Burger, P; Vogel, M; Gingelmaier, A; Friese, K; Burges, A (October 2010). "Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib". Investigational New Drugs 28 (5): 535–42. doi:10.1007/s10637-009-9281-1. PMID 19554262.
^ http://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer
^ Brunner, TB; Geiger, M; Grabenbauer, GG; Lang-Welzenbach, M; Mantoni, TS; Cavallaro, A; Sauer, R; Hohenberger, W et al. (June 2008). "Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26 (16): 2699–706. doi:10.1200/JCO.2007.15.2355. PMID 18509182. |displayauthors= suggested (help)
^ ^a ^b "'Last year, I was dying of cancer. Now I might be cured'". The Sunday Telegraph. 28 November 2010.

Pai, VB; Nahata, MC (March 1999). "Nelfinavir mesylate: a protease inhibitor". The Annals of Pharmacotherapy 33 (3): 325–39. doi:10.1345/aph.18089. PMID 10200859.
Bardsley-Elliot, A; Plosker, GL (March 2000). "Nelfinavir: an update on its use in HIV infection". Drugs 59 (3): 581–620. doi:10.2165/00003495-200059030-00014. PMID 10776836.
Actual photo of Nelfinavir and further Nelfinavir information

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. HIVプロテアーゼ阻害剤 hiv protease inhibitors
2. HIV抗レトロウイルス療法に関する臨床試験：3剤療法と4剤療法の比較 clinical trials of hiv antiretroviral therapy three versus four drug regimens
3. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤 clinical trials of hiv antiretroviral therapy protease inhibitors
4. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤と非ヌクレオシド
系逆転写酵素阻害剤の比較 clinical trials of hiv antiretroviral therapy protease inhibitors versus non nucleoside reverse transcriptase inhibitors
5. 成人に対する抗レトロウイルス剤の液体製剤 liquid preparations of antiretroviral agents for adults

English Journal

Yeast cells as a tool for analysis of HIV-1 protease susceptibility to protease inhibitors, a comparative study.

Ravaux I, Perrin-East C, Attias C, Cottalorda J, Durant J, Dellamonica P, Gluschankof P, Stein A, Tamalet C.Author information Service des Maladies Infectieuses Hôpital de la Conception, 147 Bd Baille, 13385 Marseille Cedex 05, France. Electronic address: isabelle.ravaux@ap-hm.fr.AbstractHIV develops drug resistance at a high rate under drug selection pressure. Resistance tests are recommended to help physicians optimize antiretroviral drug therapies. For this purpose, genotypic and phenotypic tests have been developed. In order to propose a new phenotypic test that will be less laborious, expensive, and time consuming than the standard ones, a new procedure to measure HIV-1 protease susceptibility to protease inhibitor (PIs) in Saccharomyces cerevisiae yeast cells was developed. This procedure is based on HIV-1 protease expression in yeast. While the viral protein induces yeast cell death, its inhibition by PIs in the culture medium allows the cell to grow in a dose-dependent manner. In a comparative study of standard genotypic analysis vs. yeast cell-based phenotypic tests, performed on HIV-1 protease coding DNA in 17 different plasma samples from infected individuals, a clear match was found between the results obtained using the two technologies. This suggests that the yeast-based procedure is at least as accurate as standard genotypic test in defining susceptibility to protease inhibitors. This encouraging result should be the basis for large-scale validation of the new phenotypic resistance test.
Journal of virological methods.J Virol Methods.2014 Jan;195:180-4. doi: 10.1016/j.jviromet.2013.08.019. Epub 2013 Sep 18.
HIV develops drug resistance at a high rate under drug selection pressure. Resistance tests are recommended to help physicians optimize antiretroviral drug therapies. For this purpose, genotypic and phenotypic tests have been developed. In order to propose a new phenotypic test that will be less lab
PMID 24056262

Comparative analysis of ER stress response into HIV protease inhibitors: Lopinavir but not darunavir induces potent ER stress response via ROS/JNK pathway.

Taura M, Kariya R, Kudo E, Goto H, Iwawaki T, Amano M, Suico MA, Kai H, Mitsuya H, Okada S.Author information Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.AbstractHIV protease inhibitor (PI)-induced ER stress has been associated with adverse effects. Although it is a serious clinical problem for HIV/AIDS patients, comparative analyses of ER stress induction by clinically used PIs have rarely been done. Especially, there is no report on the differential ER stress response between lopinavir (LPV) and darunavir (DRV), although these PIs are the most clinically used PIs. We show here that LPV induces the most potent CHOP expression, ER stress marker, among the 9 Food and Drug Administration (FDA)-approved PIs in human peripheral blood mononuclear cells, several human epithelial cells, and mouse embryonic fibroblasts. LPV induced the most potent ROS production and JNK activation in 9 PIs. A comparison among the most clinically used PIs, ritonavir (RTV), LPV, and DRV, revealed that LPV potently and RTV moderately but not DRV induced ER stress via ROS-dependent JNK activation rather than proteasome inhibition. Finally, we analyzed ER stress induction in tissues of mice intraperitoneally injected with RTV, LPV, and DRV. RTV and LPV but not DRV showed ER stress induction in several mice tissues. In conclusion, we first identify LPV as the most potent ER stress inducing PI among 9 FDA-approved PIs in human cells, and although clinical verification is necessary, we show here that DRV has the advantage of less ROS and ER stress induction potential compared with LPV in vitro and in vivo.
Free radical biology & medicine.Free Radic Biol Med.2013 Dec;65:778-88. doi: 10.1016/j.freeradbiomed.2013.08.161. Epub 2013 Aug 20.
HIV protease inhibitor (PI)-induced ER stress has been associated with adverse effects. Although it is a serious clinical problem for HIV/AIDS patients, comparative analyses of ER stress induction by clinically used PIs have rarely been done. Especially, there is no report on the differential ER str
PMID 23973637

Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.

Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY.Author information State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.AbstractOBJECTIVES: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
The Journal of infection.J Infect.2013 Dec;67(6):606-16. doi: 10.1016/j.jinf.2013.09.029. Epub 2013 Oct 3.
OBJECTIVES: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effe
PMID 24096239

Japanese Journal

Pharmacokinetics of Human Immunodeficiency Virus Protease Inhibitor, Nelfinavir, in Poloxamer 407-Induced Hyperlipidemic Model Rats(Biopharmacy)

, , [他], ,
Biological & pharmaceutical bulletin 32(2), 269-275, 2009-02-01
… The effect of hyperlipidemia (HL) on the pharmacokinetics of nelfinavir (NFV), a human immunodeficiency virus protease inhibitor, was investigated, focusing on the change of NFV distribution in plasma using poloxamer 407-induced HL model rats (HL rats). …
NAID 110007042143

High Molecular Weight Form of Adiponectin in Antiretroviral Drug-induced Dyslipidemia in HIV-Infected Japanese Individuals Based on in vivo and in vitro Analyses

, , , , ,
Internal Medicine 48(20), 1799-1875, 2009
… EFV, ritonavir (RTV) and nelfinavir (NFV) inhibited the expression of adiponectin mRNA in mature 3T3-L1 and to a greater extent in pre-mature 3T3-L1. …
NAID 130000122185

Synthesis and Biological Evaluation of Novel Isopropanolamine Derivatives as Non-peptide Human Immunodeficiency Virus Protease Inhibitors

, , [他], , , ,
Chemical & pharmaceutical bulletin 56(8), 1147-1152, 2008-08-01
… Novel potential human immunodeficiency virus (HIV) protease inhibitors were designed by a combination of nelfinavir and amprenavir motifs. …
NAID 110006838323

Related Pictures

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★リンクテーブル★

リンク元	「ネルフィナビル」
拡張検索	「nelfinavir mesilate」

「ネルフィナビル」

Nelfinavir
Systematic (IUPAC) name
	(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide
Clinical data
Trade names	Viracept
AHFS/Drugs.com	monograph
MedlinePlus	a697034
Licence data	US FDA:link
Pregnancy cat.	B (US)
Legal status	℞-only (US)
Routes	oral
Pharmacokinetic data
Bioavailability	Uncertain; improved by taking with food
Protein binding	>98%
Metabolism	Hepatic metabolism by CYP450 incl. CYP3A4
Half-life	3.5 - 5 hours
Excretion	Metabolites eliminated in faeces
Identifiers
CAS number	159989-64-7
ATC code	J05AE04
PubChem	CID 64143
DrugBank	DB00220
ChemSpider	57718
UNII	HO3OGH5D7I
KEGG	D08259
ChEMBL	CHEMBL1159655
NIAID ChemDB	028590
Chemical data
Formula	C32H45N3O4S
Mol. mass	567.784 g/mol
	SMILES O=C(c1cccc(O)c1C)N[C@@H](CSc2ccccc2)[C@H](O)CN4[C@H](C(=O)NC(C)(C)C)C[C@@H]3CCCC[C@@H]3C4;
	InChI InChI=1S/C32H45N3O4S/c1-21-25(15-10-16-28(21)36)30(38)33-26(20-40-24-13-6-5-7-14-24)29(37)19-35-18-23-12-9-8-11-22(23)17-27(35)31(39)34-32(2,3)4/h5-7,10,13-16,22-23,26-27,29,36-37H,8-9,11-12,17-20H2,1-4H3,(H,33,38)(H,34,39)/t22-,23+,26-,27-,29+/m0/s1 ; Key:QAGYKUNXZHXKMR-HKWSIXNMSA-N ;
Physical data
Melt. point	349.94 °C (662 °F)
(what is this?) (verify);

　　[★]

英: nelfinavir, NFV
化: メシル酸ネルフィナビル nelfinavir mesilate
商: ビラセプト Viracept

「nelfinavir mesilate」

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メシル酸ネルフィナビル

関: nelfinavir

[1] Zhang KE, Wu E, Patick AK, et al. (April 2001). "Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities". Antimicrob. Agents Chemother. 45 (4): 1086–93. doi:10.1128/AAC.45.4.1086-1093.2001. PMC 90428. PMID 11257019.

[2] Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination

[3] Chow WA, Jiang C, Guan M (2009). "Anti-HIV drugs for cancer therapeutics: back to the future?". Lancet Oncol 10 (1): 61–71. doi:10.1016/S1470-2045(08)70334-6. PMID 19111246.

[pmid17785575-4] Gills, JJ; Lopiccolo, J; Tsurutani, J; Shoemaker, RH; Best, CJM; Abu-Asab, MS; Borojerdi, J; Warfel, NA et al. (September 2007). "Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo". Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 13 (17): 5183–94. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. |displayauthors= suggested (help)

[5] Pyrko, P.; Kardosh, A; Wang, W; Xiong, W; Schönthal, AH; Chen, TC (2007). "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67 (22): 10920–10928. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837.

[6] Yang, Y; Ikezoe, T; Takeuchi, T; Adachi, Y; Ohtsuki, Y; Takeuchi, S; Koeffler, HP; Taguchi, H (July 2005). "HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling". Cancer Science 96 (7): 425–33. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514.

[pmid19554262-7] Brüning, A; Burger, P; Vogel, M; Gingelmaier, A; Friese, K; Burges, A (October 2010). "Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib". Investigational New Drugs 28 (5): 535–42. doi:10.1007/s10637-009-9281-1. PMID 19554262.

[8] ttp://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer

[pmid18509182-9] Brunner, TB; Geiger, M; Grabenbauer, GG; Lang-Welzenbach, M; Mantoni, TS; Cavallaro, A; Sauer, R; Hohenberger, W et al. (June 2008). "Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26 (16): 2699–706. doi:10.1200/JCO.2007.15.2355. PMID 18509182. |displayauthors= suggested (help)

[NR-10] "'Last year, I was dying of cancer. Now I might be cured'". The Sunday Telegraph. 28 November 2010.

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nelfinavir