Indinavir

Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus. It is no longer recommended for use in HIV/AIDS treatment due to its side effects. Furthermore, it is controversial for many reasons starting from its development to its usage. It was patented in 1991 and approved for medical use in 1996, on March 13 by the United States Food and Drug Administration, on October 1 by the Australian Therapeutic Goods Administration and on October 4 by the European Medicines Agency.

Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus. It is no longer recommended for use in HIV/AIDS treatment due to its side effects. Furthermore, it is controversial for many reasons starting from its development to its usage. It was patented in 1991 and approved for medical use in 1996, on March 13 by the United States Food and Drug Administration, on October 1 by the Australian Therapeutic Goods Administration and on October 4 by the European Medicines Agency.

Side effects

The most common side effects of indinavir include: 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" Increased levels of Bilirubin, causing skin and white parts of the eyes to turn yellow Inhibits urinary nitrous oxide production and may inhibit nitric oxide production. Renal abnormalities, sterile leukocyturia, and reduced creatinine clearance. Impairs endothelial function in healthy HIV-negative men and may accelerate atherosclerotic disease.

History

The official start to its development started in December 1986 when Merck's president, Edward Scolnick, announced that they would start a comprehensive AIDS research program. They started a laboratory dedicated to AIDS research in West Point, Pennsylvania and placed Emilio Emini in charge of the laboratory. A couple months later in January 1987, a team of researchers consisting of Emilio Emini, Joel Huff, and Irving Sigal, kickstarted their studies by basing their project off of earlier research on the protease enzyme, renin. They were the ones who started the process of research and development into protease inhibitors and its relation to the virus. Over a year later, in July 1988, Nancy Kohl, Emilio Emini, et al., published in the Proceedings of the National Academy of the Science about the idea of inhibiting the protease. In February 1989, Manuela Navia, Paula Fitzgerald, et al., published a paper that showed the three-dimensional structure of HIV's protease enzyme. Other researchers claim that this study helped determine the future trajectory of the development of the inhibitor. After much research, in March 1990, researchers under Reider received a patent to synthesize part of L-689, 502 compound. These were similar to existing inhibitors. However, it failed safety assessments because of its toxicity. Seeing that the research on their drug was heading in the direction of eventually getting it on the market, Merck decided to formulate a community advisory board composed of AIDS activists who would help with the development effort of the drug in March 1991. Later on, Merck faced serious backlash from community members who though did not like the pricing and distribution of the drug. In January 1992, researchers synthesized indinavir sulfate (Crixivan), which was assigned compound number L-735,524. They started to test L-735,524 on animals a couple months later and found that it was safe for animals. Consequently, the company decided that it was safe to start human trials on September of the same year. Bruce D. Dorsey, James P. Guare, Joseph P. Vacca, M. Katherine Holloway and Randall W. Hungate were named inventors of the year by the Intellectual Property Owners for Crixivan. The Food and Drug Administration (FDA) approved indinavir in March 1996, making it the eighth antiretroviral drug approved. It was first given its blessing by the FDA on March 1 then approved merely 42 days after the company filed the drug to the FDA. A major reason for this fast approval was the presentation Merck gave to the committee with results from Study 035 (see below). The fact that they had fast approval ran into trouble with groups like Treatment Action Group who thought that accelerated drug approval was not beneficial for people infected with HIV/AIDS. From then on, indinavir used with dual NRTIs set a new standard for treatment of HIV/AIDS. Protease inhibitors changed the nature of AIDS from a terminal illness to a somewhat manageable one. It significantly increased life expectancies and decreased noticeable symptoms from infectious diseases that were the result of a weakened immune system from the virus. Currently, it is being replaced by newer drugs that are more convenient to take, less likely to promote virus resistance, and less toxic, such as darunavir or atazanavir.

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