PD-0332991
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PD-0332991
Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy. Mechanism of action It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. In the G1 phase of the cell cycle, mammalian cells must pass a checkpoint, known as the restriction point "R", in order to complete the cell cycle and divide. CDK4 and CDK6 complex with cyclin D drive the phosphorylation of the retinoblastoma protein, Rb, which allows the cell to pass R and commit to division. Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However, by inhibiting CDK4/6, palbociclib ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing R and exiting G1 ...
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Oral Administration
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are intended to have a systemic effect, reaching different parts of the body via the bloodstream, for example. Oral administration can be easier and less painful than other routes, such as injection. However, the onset of action is relatively low, and the effectiveness is reduced if it is not absorbed properly in the digestive system, or if it is broken down by digestive enzymes before it can reach the bloodstream. Some medications may cause gastrointestinal side effects, such as nausea or vomiting, when taken orally. Oral administration can also only be applied to conscious patients, and patients willing and able to swallow. Terminology ''Per os'' (; ''P.O.'') is an adverbial phrase meaning literally from Latin "through the mouth" or "by mouth ...
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Cell Division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces Haploidisation, haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. In cell biology, mitosis (Help:IPA/English, /maɪˈtoʊsɪs/) is a part of the cell cycle, in which, replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis (division of the nucleus) is preceded by the S stage of interph ...
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Scottish Medicines Consortium
Healthcare Improvement Scotland (HIS) is the national healthcare improvement organisation for Scotland. It is a public body which is part of the Scottish National Health Service, created in April 2011. History NHS Quality Improvement Scotland (NHS QIS) was established on 1 January 2003 as a special health board with a remit to improve the quality of healthcare in Scotland. Healthcare Improvement Scotland (HIS) was established by the Public Services Reform (Scotland) Act 2010, taking over the work of QIS and the regulatory functions, in regard to independent healthcare provision, previously conducted by the Care Commission, now renamed the Care Inspectorate. The first chair of HIS, serving from 2010 to 2018, was Dame Denise Coia. The function of this body is to implement the healthcare priorities of the Scottish Government, in particular the Healthcare Quality Strategy of NHS Scotland. Units Healthcare Improvement Scotland incorporates several organisations: * Healthcare Envi ...
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NHS Scotland
NHS Scotland, sometimes styled NHSScotland, is the publicly funded healthcare system in Scotland and one of the four systems that make up the National Health Service in the United Kingdom. It operates 14 territorial NHS boards across Scotland, 7 special non-geographic health boards, and NHS Health Scotland. At the founding of the National Health Service in the United Kingdom, three separate institutions were created in Scotland, England and Wales and Northern Ireland. The NHS in Scotland was accountable to the Secretary of State for Scotland rather than the Secretary of State for Health as in England and Wales. Prior to 1948, a publicly funded healthcare system, the Highlands and Islands Medical Service, had been established in Scotland in 1913, recognising the geographical and demographic challenges of delivering healthcare in that region. Following Scottish devolution in 1999, health and social care policy and funding became devolved to the Scottish Parliament. It is curren ...
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Agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist. Etymology From the Greek αγωνιστής (agōnistēs), contestant; champion; rival < αγων (agōn), contest, combat; exertion, struggle < αγω (agō), I lead, lead towards, conduct; drive


Types of agonists

can be activated by either endogenous agonists (such as

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Aromatase Inhibitor
Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer. Aromatase is the enzyme that catalyzes a key aromatization step in the synthesis of estrogen. It converts the enone ring of androgen precursors such as testosterone, to a phenol, completing the synthesis of estrogen. As such, AIs are estrogen synthesis inhibitors. Because hormone-positive breast and ovarian cancers are dependent on estrogen for growth, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors. Medical uses Cancer In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries, in postmenopausal women estrogen is mainly produced in peripheral tissues of the bo ...
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Myelotoxic
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia. Nonsteroidal anti-inflammatory drugs (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow. When myelosuppression is severe, it is called myeloablation. Many other drugs including common antibiotics may cause bone marrow suppression. Unlike che ...
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Accelerated Approval
The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endpoints. Drug approval typically requires clinical trials with endpoints that demonstrate a clinical benefit, such as increased survival for cancer patients. Drugs with accelerated approval can initially be tested in clinical trials that use a surrogate endpoint, or something that is thought to predict clinical benefit. Surrogate endpoints typically require less time, and in the case of a cancer patient, it is much faster to measure a reduction in tumor size, for example, than overall patient survival. Drugs approved under the FDA Accelerated Approval Program still need to be tested in clinical trials using endpoints that demonstrate clinical benefit, and those trials are known as phase 4 confirmatory trials. If the drug later proves una ...
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Estrogen Receptor Positive
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs) (GPER (GPR30), ER-X, and Gq-mER), which are mostly G protein-coupled receptors. This article refers to the former (ER). Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding. As hormone receptors for sex steroids (steroid hormone receptors), ERs, androgen receptors (ARs), and progesterone receptors (PRs) are important in sexual maturation and gestation. Proteomics There are two different forms of the estrogen receptor, usually referred to as α and β ...
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Breakthrough Therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "breakthrough therapy" designation is not intended to imply that a drug is actually a "breakthrough" or that there is high-quality evidence of treatment efficacy for a particular condition; rather, it allows the FDA to grant priority review to drug candidates if preliminary clinical trials indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases. The FDA has other mechanisms for expediting the review and approval process for promising drugs, including fast track designation, accelerated approval, and priority review. Requirements A breakthrough therapy designation can be assigned to a drug if "it is a drug which is intended alone or in combination with ...
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Priority Review
Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program is a program that grants a voucher for priority review to a drug developer as an incentive to develop treatments for disease indications with limited profitability. Priority review vouchers are currently earned by pharmaceutical companies for the development and approval of drugs treating neglected tropical diseases, rare pediatric diseases, and "medical countermeasures" for terrorism. The voucher can be used for future drugs that could have wider indications for use, but the company is required to pay a fee (approximately $2.8 million) to use the voucher. When seeking approval for a drug, manufacturers can apply to the FDA for priority review. This is granted when a drug is intended to treat a serious condition and would "provide a si ...
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