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RALTEGRAVIR- AN INTEGRASE INHIBITOR

by Selleckchem | Jul 30 2012

HIV-I AND INTEGRASE
HIV one of the most tricky viruses on earth that cause immunodeficiency in humans is being studied allot. It is responsible for a deathly disease known AIDS which is a focus of attention of many researchers since last decades. Due to its wide spread and occurrence throughout the world has compelled the scientists to look for a drug that may effectively cure the disease. HIV contains different types of enzymes and genes that help it to utilize the genes and proteins of its host. The most important among all is the integrase enzyme that helps it in integration of its genome into that of the host. Integrase has been an attractive target for the devising a therapy against the disease. A lot of research is being done on integrase inhibitors [1] and several integrase inhibitors have been discovered by high throughput screening that prevent the integration of genome of virus into that of the host hence preventing the proliferation of the host cell. These inhibitors have shown efficacious results when used against HIV-I [2]. One of the examples of such inhibitors is Raltegravir integrase inhibitor. This drug is first of such inhibitors to get FDA approval [3] and is a blessing for the patients of HIV [4].

PROPERTIES AND MODE OF ACTION
Raltegravir is a potassium salt and Raltegravir structure contains an oxadiazole ring in it. Raltegravir solubility can be achieved in organic solvents like methanol, ethanol, water and DMSO. The drug is administered orally and has been developed by the Merck pharmaceuticals. It is sold under the name of Isentress. 1 mg vial is available in Raltegravir price of $200. One can buy Raltegravir according to one’s need and purpose. Raltegravir is a very effective drug that acts rapidly [5] therefore it has been used against the patients of HIV who have developed resistance already [6]. This inhibitor was discovered by screening of compound library, different properties of the drug have been tested for example depositions tests and metabolic profile [7] by quantifying the metabolite in the plasma of the patient [8] using technique of HPLC [High performance liquid chromatography] [9]. Raltegravir has also shown promising results in the patients of herpes simplex virus [10]. As far as mechanism of action of the drug is concerned, Raltegravir inhibits viral genome integration into that of the host. Raltegravir when compared with other drugs is considered more efficacious and valuable against HIV [11]. Raltegravir can also be used in combinatorial therapy and has been tested with Tenofovir. Synergistic effects have been observed in this case [12].

RALTEGRAVIR IN CLINICS
Raltegravir has been used against the patients of HIV whether they were treated resistant or naïve. This drug needs to be studied more in the pharmacokinetic area in order to assess its efficacy, safety and tolerability [13]. Raltegravir clinical trial in phase II has proved the efficacy of the drug and has shown it to reduce viral replication effectively in the second phase [14]. The drug has also been studied in combination with other drugs and has shown to have minimum interaction profile therefore mitigates the need of changing the dose of any of the drugs used that are being used in combinatorial therapy [15]. Analysis of combination of Raltegravir with other drugs was done in a trial of 48 weeks in order to study the effects of the other drugs [16]. Confirmation of combinatorial treatment with other drugs was done in phase II clinical trial after combining Raltegravir with Etravirine, Darunavir and Ritonavir [17]. Raltegravir in a single drug therapy has shown quite promising results in clinical trials of phase I and III [18]. Resistance profile [20] of the drug when studied with an MDR virus [21] in clinical trial phase II, proved the drug to be the best choice among all the inhibitors against same virus [19] after that the dose kinetics of the drug was modified accordingly.

REFERENCES:
1. Savarino, A., A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs, 2006.
2. Serrao, E.e.a., Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology, 2009.
3. Cocohoba, J.a.D., B.J., Raltegravir: The first HIV integrase inhibitor. Clinical Therapeutics, 2008.
4. Summa, V., Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. J. Med. Chem., 2008.
5. Anker, M.a.C., R.B., Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opinion on Investigational Drugs, 2008.
6. Croxtall, J.D.a.K., S.J., Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs, 2009.
7. Kassahun, K.e.a., Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the HIV-1 Integrase Enzyme. Drug Metabolism and Disposition, 2007.
8. Heine, R.e.a., Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 2009.
9. Poirier, J.M.e.a., Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection. Journal of Chromatography B, 2008.
10. Steigbigel, R.T.e.a., Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med, 2008.
11. Marinello, J.e.a., Comparison of Raltegravir and Elvitegravir on HIV-1 Integrase Catalytic Reactions and on a Series of Drug-Resistant Integrase Mutants. Biochemistry, 2008.
12. Moss, D.M.e.a., Interaction between Raltegravir and Tenofovir. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011.
13. Markowitz, M.e.a., Antiretroviral Activity, Pharmacokinetics, and Tolerability of MK-0518, a Novel Inhibitor of HIV-1 Integrase, Dosed As Monotherapy for 10 Days in Treatment-Naive HIV-1-Infected Individuals. Journal of Acquired Immune Deficiency Syndromes, 2006.
14. Murray, J.M.e.a., Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS, 2007.
15. Anderson, M.S.e.a., Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects. Antimicrobial Agents and Chemotherapy, 2008.
16. Markowitz, M.e.a., Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr., 2007.
17. Yazdanpanah, Y.e.a., High Rate of Virologic Suppression with Raltegravir Plus Etravirine and Darunavir/Ritonavir among Treatment-Experienced Patients Infected with Multidrug-Resistant HIV: Results of the ANRS. Clin Infect Dis., 2009.
18. Steigbigel, R.T.e.a., Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials. Clin Infect Dis., 2010.
19. Lennox, J.L.e.a., Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. The Lancet, 2009.
20. Cooper, D.A.e.a., Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection. N Engl J Med, 2008.
21. Grinsztejn, B.e.a., Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. The Lancet, 2007.

Cat.No.	Product Name	Information
S2005	Raltegravir	Raltegravir is a potent integrase (IN) inhibitor for WT and S217Q PFV IN with IC50 of 90 nM and 40 nM in cell-free assays, respectively. It shows greater than 1000-fold selectivity for HIV-1 IN over several related Mg2+-dependent enzyme such as HCV polymerase, HIV reverse transcriptase, HIV RNaseH and human α-, β-, γ-polymerases.
S1401	Tenofovir	Tenofovir (GS-1278) blocks reverse transcriptase and hepatitis B virus infections.
S1185	Ritonavir	Ritonavir is a Cytochrome P450 3A and Protease Inhibitor; Also inhibits Cytochrome P450 2D6, P-Glycoprotein and induces Cytochrome P450 2C19, Cytochrome P450 1A2, Cytochrome P450 2C9, Cytochrome P450 2B6 and UDP Glucuronosyltransferases. Ritonavir induces apoptosis.