Testosterone structure activity relationship of imatinib

Imatinib - Wikipedia

Imatinib does affect testosterone and LDH level significantly, but this effect is [6] But reports on effect of imatinib on reproductive function and on testicular function are scanty. These sample time ( weeks) establishes the treatment of spermatozoa in the There were dose response relations for changes in testosterone. Imatinib, the first clinically viable Abl kinase inhibitor, is the result of a medicinal chemistry project Analysis of structure activity relationships showed that. analysis of structure activity relationships was that substitutions at the 6-position of the that imatinib potently inhibits all of the ABL tyrosine kinases. This follow-up. For example, gynecomastia and low testosterone levels.

Some tumor cellshowever, have a dependence on bcr-abl. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The main metaboliteN-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine.

The half-lives of imatinib and its main metabolite are 18 h and 40 h, respectively. As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases.

An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazoleclarithromycingrapefruit juiceamong others.

John's Wort reduce the drug's activity, risking therapy failure.

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Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatinciclosporinpimozidewarfarinmetoprololand possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein.

With high-throughput screeningthey identified 2- phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib. However, favorable results in studies with monkeys and in vitro human cells allowed testing to continue in humans. The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid.

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Inmore than cancer specialists published a letter in Blood saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States couldn't afford them, and that the level of prices, and profits, was so high as to be immoral. Other physicians have complained about the cost. When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population,[ clarification needed ] and Novartis raised the price of Gleevec to match them.

The patent application at the center of the case was filed by Novartis in India inafter India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement.

As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions.

Most of the drugs are genotoxins and induce irreversible effect on genetic makeup. These mutagenic changes are proportionally related to carcinogenesis.


This is alarmingly dangerous in youth and children, since these effects last longer, affecting fertility or forming basis for carcinogenesis. There is paucity of reports on planned studies of imatinib on the testicular function. Hence, the study was planned to assess the effects of imatinib on biochemical markers of testicular functions in male Swiss albino mice. Male Swiss albino mice were treated with imatinib and sacrificed at the end of first, second, fourth, fifth, seventh, and tenth week after the last exposure to imatinib.

The testis were removed, weighed, and processed for biochemical analysis. The intratesticular lactate dehydrogenase LDH level was significantly increased by imatinib in all treated groups up to week 5. Imatinib does affect testosterone and LDH level significantly, but this effect is reversible once the drug is withdrawn. This finding may help the clinicians to plan and address the fertility-related issues in young patients of reproductive age who are being treated with imatinib for gastrointestinal tumors and chronic myeloid leukemia.

Imatinib, lactate dehydrogenase, testosterone Introduction Treatment of cancers with cytotoxic agents such as tyrosine kinase inhibiting drugs often, but not always, results in transient to permanent testicular dysfunction.

Many drugs are used to combat human diseases in spite of their genotoxicity. Over the last 10—20 years, there has been overwhelming interest in addressing this question as more people are being exposed to agents that alter fertility parameters.

A number of animal studies as well as human epidemiological studies have demonstrated that exposure of males to various agents could result in abnormal reproductive, pregnancy, or progeny outcomes.

In general, they are not recognized till andrological examination for infertility. A transient or permanent inhibition of male fertility is possible by drugs[ 3 ] via the interference of one of the following functions: Imatinib mesylate is white to off-white to brownish or yellowish tinged crystalline powder. It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.

It is indicated for the treatment of patients with chronic myeloid leukemia.