158-649: Paclitaxel , sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer , esophageal cancer , breast cancer , lung cancer , Kaposi's sarcoma , cervical cancer , and pancreatic cancer . It is administered by intravenous injection. There is also an albumin-bound formulation . Common side effects include hair loss , bone marrow suppression , numbness , allergic reactions , muscle pains , and diarrhea . Other side effects include heart problems, increased risk of infection, and lung inflammation . There are concerns that use during pregnancy may cause birth defects . Paclitaxel
316-480: A glycopeptide isolated from Streptomyces verticillus , also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion , becomes chemically reduced and reacts with oxygen . Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA. Most chemotherapy is delivered intravenously , although a number of agents can be administered orally (e.g., melphalan , busulfan , capecitabine ). According to
474-479: A new drug application (NDA), which was given FDA approval at the very end of 1992. Although there was no patent on the compound, the provisions of the Waxman-Hatch Act gave Bristol-Myers Squibb five years exclusive marketing rights. In 1990, BMS applied to trademark the name taxol as Taxol(R) . This was controversially approved in 1992. At the same time, paclitaxel replaced taxol as the generic ( INN ) name of
632-459: A nucleobase , a sugar and a phosphate group . The nucleobases are divided into purines ( guanine and adenine ) and pyrimidines ( cytosine , thymine and uracil ). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups . These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting
790-498: A 10-deacetylbaccatin-type core containing the ABCD ring system, followed generally by last stage addition of the "tail" to the 13- hydroxyl group . While the "political climate surrounding [paclitaxel] and [the Pacific yew] in the early 1990s ... helped bolster [a] link between total synthesis and the [paclitaxel] supply problem," and though total synthesis activities were a requisite to explore
948-404: A blockage caused by the actual stent. The major benefit of drug-eluting stents (DES) when compared to bare-metal stents (BMS) is the prevention of in-stent restenosis (ISR). Restenosis is a gradual re-narrowing of the stented segment that occurs most commonly between 3–12 months after stent placement. High rates of restenosis associated with BMS prompted the development of DES, which resulted in
1106-407: A blockage in those arteries. Symptoms can include: In a medical setting, it's not very useful for doctors to rely solely on what people say about where their pain comes from or how it feels, because the way people describe chest pain caused by reduced blood flow to the heart can vary greatly and may not match what is typically taught in medical education or described in books and articles. DES
1264-405: A catheter (not by open-chest surgery), it is the medical procedure used to place a DES in narrowed coronary arteries. PCI procedures are performed by an interventional cardiologist using fluoroscopic imaging techniques to see the location of the required DES placement. PCI uses larger peripheral arteries in the arms or the legs to thread a catheter/DES device through the arterial system and place
1422-414: A certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates , fluoropyrimidines, deoxynucleoside analogues and thiopurines . The anti-folates include methotrexate and pemetrexed . Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate . When
1580-549: A coronary stent have different needs depending on their medical condition. Some patients are actually having a heart attack and need immediate life-saving emergency care. Other patients are at high risk of having a heart attack in the very near future. For people from each of these groups, PCI procedures may vary slightly, with particular modifications as to how they are sedated, pain management, and broader intensive care issues such as breathing support. Many people who are not in critical care situations are usually fully awake during
1738-412: A crucial role in inhibiting the formation of scar tissue within the stent and subsequent re-narrowing of the blood vessel. PCI is a minimally invasive procedure. It involves the placement of a drug-eluting stent (DES) in a coronary artery. This procedure, previously known as angioplasty with a stent, is considered non-surgical as it is performed through a small puncture in a peripheral artery, avoiding
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#17328773343501896-668: A deal with Bristol-Myers Squibb (BMS) to license their semisynthesis and future patents. In 1992, Holton patented an improved process with an 80% yield, and BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew. In early 1993, BMS announced that it would cease reliance on Pacific yew bark by the end of 1995, effectively terminating ecological controversy over its use. This announcement also made good their commitment to develop an alternative supply route, made to
2054-451: A heart attack and their hearts may have trouble pumping oxygen-rich blood to the body. Rehabilitation activities are tailored to each person's needs. DES are an improvement over older BMS devices as they reduce the chances of in-stent blockages. This reduces the incidence of serious post-stenting events such as, angina occurrence or recurrence, heart attacks, and death. They also reduce the likelihood of requiring another PCI procedure to open
2212-444: A high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right hemicolectomy to prevent recurrence. Nausea , vomiting , anorexia , diarrhea , abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough, or when
2370-546: A large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow , digestive tract and hair follicles . This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence that also immunosuppression ), mucositis (inflammation of
2528-453: A medical device or drug in a way not specified in the original or current approved labeling is often referred to as " off-label " use. In regions were cardiac stenting has become commonplace, think tanks and advocacy groups express concern about the overzealous use of stents, because patients who received stents for unapproved reasons often have worse outcomes compared to patients who received stents for approved uses. People who receive
2686-776: A month (21 December 1993 versus 24 January 1994), the near coincidence of the publications arising from each of these massive, multiyear efforts—11–18 authors appearing on each of the February 1994 publications—has led the ending of the race to be termed a "tie" or a "photo finish", though each group has argued that their synthetic strategy and tactics were superior. As of 2006, five additional research groups had reported total syntheses of paclitaxel: Wender et al. in 1997, and Kuwajima et al. and Mukaiyama et al. in 1998 with further linear syntheses , and Danishefsky et al. in 1996 and Takahashi et al. in 2006 with further convergent syntheses . As of that date, all strategies had aimed to prepare
2844-928: A natural product in Taxomyces andreanae , a newly described endophytic fungus living in the yew tree. It has since been reported in a number of other endophytic fungi, including Nodulisporium sylviforme , Alternaria taxi , Cladosporium cladosporioides MD2, Metarhizium anisopliae , Aspergillus candidus MD3, Mucor rouxianus , Chaetomella raphigera , Phyllosticta tabernaemontanae , Phomopsis , Pestalotiopsis pauciseta , Phyllosticta citricarpa , Podocarpus sp., Fusarium solani , Pestalotiopsis terminaliae , Pestalotiopsis breviseta , Botryodiplodia theobromae , Gliocladium sp., Alternaria alternata var. monosporus , Cladosporium cladosporioides , Nigrospora sp. and Pestalotiopsis versicolor . However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production
3002-417: A number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms . All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction
3160-512: A positive opinion, recommending the granting of a marketing authorization for the medicinal product Naveruclif, intended for the treatment of metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer. The applicant for this medicinal product is Accord Healthcare S.L.U. Naveruclif was approved for medical use in the European Union in January 2024. In May 2024,
3318-767: A preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy. However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of typhlitis , a very serious and potentially life-threatening medical emergency that requires immediate treatment. Anemia can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as bleeding , blood cell destruction ( hemolysis ), hereditary disease, kidney dysfunction, nutritional deficiencies or anemia of chronic disease . Treatments to mitigate anemia include hormones to boost blood production ( erythropoietin ), iron supplements , and blood transfusions . Myelosuppressive therapy can cause
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#17328773343503476-651: A previously unknown mechanism of action involving the stabilization of microtubules. Together with formulation problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to collect 20,000 lb (9,100 kg) of bark. Animal toxicology studies were completed by June 1982, and in November, the NCI applied for the IND necessary to begin clinical trials in humans. Phase I clinical trials began in April 1984, and
3634-434: A process also called atherosclerosis. In the context of stents, stenosis is a significant concern. Stents are inserted into a narrowed artery during a procedure known as angioplasty. The stents help to open up the narrowed artery and improve blood flow. However, over time, the treated artery can close up again, a condition known as restenosis. Restenosis, or in-stent restenosis, is a blockage or narrowing that comes back in
3792-601: A recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans. There are many intravenous methods of drug delivery, known as vascular access devices. These include the winged infusion device , peripheral venous catheter , midline catheter, peripherally inserted central catheter (PICC), central venous catheter and implantable port . The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent. Depending on
3950-459: A series of oxygenations. Following the oxygenations, two acetylations and a benzoylation occur on the intermediate. The oxygenation of the taxane core is believed to occur on C5 and C10, C2 and C9, C13 followed by C7, and a C1 hydroxylation later on in the pathway. Later in the pathway, an oxidation at C9 forms a ketone functional group and an oxetane, forming the intermediate baccatin III. The final steps of
4108-445: A side-chain hydroxylation. This finally yields the product taxol. By 1992, at least thirty academic research teams globally were working to achieve a total synthesis of this natural product , with the synthesis proceeding from simple natural products and other readily available starting materials. This total synthesis effort was motivated primarily by the desire to generate new chemical understanding, rather than with an expectation of
4266-602: A single Pacific yew tree in a forest north of the town of Packwood, Washington , as part of a four-month trip to collect material from over 200 different species. The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's samples was found to be cytotoxic in a cellular assay on 22 May 1964. Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh Taxus samples, isolating
4424-401: A state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in
4582-524: A tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of platelets in the blood, which can result in bruises and bleeding . Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover. Drug-eluting stent A drug-eluting stent (DES)
4740-450: A tertiary cation and creating the first ring closure (step 2). Another electrophilic attack occurs, further cyclizing the structure by creating the first 6-membered ring and creating another tertiary cation (step 3). An intramolecular proton transfer occurs, attacking the verticillyl cation (step 4) and creating a double bond, yielding a tertiary cation. An electrophilic cyclization occurs in step 5, and an intramolecular proton transfer attacks
4898-452: A transformative role in the management of coronary artery disease. These stents are tiny, flexible mesh tubes employed during percutaneous coronary intervention (PCI) to address narrowed coronary arteries. What sets them apart is their special coating, which incorporates a drug delivery system that enables controlled release of medication over a specific period, typically within the first 30 to 45 days following implantation. This medication plays
Paclitaxel - Misplaced Pages Continue
5056-414: A week or two of the procedure. People who get a coronary stent usually have more check-ups every three to six months for the first year, but this can vary. They usually do not need to have another coronary angiography , which is a test that uses a special dye and X-rays to see the arteries of the heart. If the doctors suspect that the heart disease is getting worse, they can prescribe a stress test, which
5214-443: Is plavix , which is a potent blood thinner that comes as a pill. Other medicines that thin the blood are also used, and it's typical to combine aspirin with plavix . For people who have had a heart attack, the length of hospitalization is dependent on the degree of heart muscle damage caused by the event. A catheter with DES is a medical device, so people who receive it are given a medical device card. This card has information on
5372-484: Is systemic therapy for cancer: they are introduced into the blood stream (the system) and therefore can treat cancer anywhere in the body. Systemic therapy is often used with other, local therapy (treatments that work only where they are applied), such as radiation , surgery , and hyperthermia . Traditional chemotherapeutic agents are cytotoxic by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To
5530-479: Is a "life-threatening gastrointestinal complication of chemotherapy." Typhlitis is an intestinal infection which may manifest itself through symptoms including nausea , vomiting , diarrhea , a distended abdomen , fever , chills , or abdominal pain and tenderness. Typhlitis is a medical emergency . It has a very poor prognosis and is often fatal unless promptly recognized and aggressively treated. Successful treatment hinges on early diagnosis provided by
5688-515: Is a chronic disease that affects the large and medium-sized arteries. It is characterized by the accumulation of calcium, fats (such as cholesterol) and other substances in the innermost layer of the endothelium, a layer of cells that line the interior surface of blood vessels. Atherosclerosis is considered to be the most common form of arteriosclerosis, which refers to the loss of arterial elasticity caused by thickening and stiffening of blood vessels. Atherosclerosis can begin as early as childhood with
5846-1054: Is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death. Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. The deoxynucleoside analogues include cytarabine , gemcitabine , decitabine , azacitidine , fludarabine , nelarabine , cladribine , clofarabine , and pentostatin . The thiopurines include thioguanine and mercaptopurine . Anti-microtubule agents are plant -derived chemicals that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin . They are hollow, rod-shaped structures that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in
6004-410: Is a test that measures how the heart works during physical activity. People who have symptoms or show signs of reduced blood flow to the heart in a stress test may need to have a diagnostic cardiac re-catheterization. After PCI-stenting procedures, physical examinations are important. People who have a high risk of complications or more complex coronary problems may need to have angiography. This may be
6162-475: Is a tube made of a mesh-like material used to treat narrowed arteries in medical procedures both mechanically (by providing a supporting scaffold inside the artery) and pharmacologically (by slowly releasing a pharmaceutical compound). A DES is inserted into a narrowed artery using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards
6320-400: Is also used extensively in biological and biomedical research as a microtubule stabilizer. In general, in vitro assays involving microtubules, such as motility assays, rely on paclitaxel to maintain microtubule integrity in the absence of the various nucleating factors and other stabilizing elements found in the cell. For example, it is used for in vitro tests of drugs that aim to alter
6478-563: Is an important factor in achieving better treatment outcomes. Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen. The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%. The FOLFOX study also demonstrated an improvement in treatment outcomes. Positive response increased from 46% in
Paclitaxel - Misplaced Pages Continue
6636-495: Is an independent prognostic predictor of survival in various cancer types. Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I , there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins , RNA and DNA . This ability to bind covalently to DNA via their alkyl group
6794-617: Is associated with the solvent Cremophor EL in which it is dissolved for delivery. Abraxis BioScience developed Abraxane, in which paclitaxel is bonded to albumin as an alternative delivery agent to the often toxic solvent delivery method. This was approved by the FDA in January 2005, for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. It has since been approved for locally advanced or metastatic non-small cell lung cancer and metastatic adenocarcinoma of
6952-469: Is attributed to its impact on the colloidal stability of protein solution, as it was observed that paclitaxel inhibited lysozyme fibrillation by inducing the formation of "off-pathway" oligomeric intermediates, subsequently increasing the colloidal stability. Paclitaxel is sometimes used for in vivo studies as well. It can be fed to test organisms, such as fruit flies , or injected into individual cells, to inhibit microtubule disassembly or to increase
7110-474: Is different from other types of stents in that it has a coating that delivers medication directly into the blood vessel wall. The stent slowly releases a drug to prevent the growth of scar tissue and new obstructive plaque material which caused the original blood vessel stenosis, this clogging of a stent is termed restenosis . A DES is fully integrated with a catheter delivery system and is viewed as one integrated medical device . DESs are commonly used in
7268-665: Is given prior to paclitaxel infusion to mitigate some of the side effects. A number of these side effects are associated with the excipient used, Cremophor EL, a polyoxyethylated castor oil . Allergies to cyclosporine , teniposide , and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel. Paclitaxel is one of several cytoskeletal drugs that target tubulin . Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation , and cell division . Unlike other tubulin-targeting drugs, such as colchicine , that inhibit microtubule assembly, paclitaxel stabilizes
7426-707: Is in the taxane family of medications. It works by interference with the normal function of microtubules during cell division . Paclitaxel was isolated in 1971 from the Pacific yew and approved for medical use in 1993. It is on the World Health Organization's List of Essential Medicines . It has been made from precursors, and through cell culture . Paclitaxel is approved in the UK for ovarian, breast, lung, bladder , prostate , melanoma , esophageal, and other types of solid tumor cancers as well as Kaposi's sarcoma . It
7584-528: Is not recommended in some cases as it may do more harm than good. DES is not suitable: Bleeding disorders make DES unsuitable because of the need for anticoagulation drugs (blood thinners) during the procedure and in post-stenting aftercare. Other factors that could rule out the use of stents include a history of in-stent blockage, bleeding problems, complex or unsuitable coronary anatomy, or a short life expectancy due to other serious medical conditions. Stent placement risks include bleeding, allergic reactions to
7742-531: Is obtained from the Chinese ornamental tree Camptotheca acuminata . Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death ( apoptosis ). These agents include etoposide , doxorubicin , mitoxantrone and teniposide . The second group, catalytic inhibitors, are drugs that block
7900-417: Is often coated with a polymer to control the release of drugs. The role of polymers in drug delivery is crucial as they regulate the rate at which the drug is released into the surrounding tissue. There are also polymer-free stents where the drug is directly coated on the stent or contained in reservoirs within the stent. The design of the stent includes struts, which are thin wire structures that make up
8058-901: Is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer , which is called medical oncology . The term chemotherapy now means the non-specific use of intracellular poisons to inhibit mitosis (cell division) or to induce DNA damage (so that DNA repair can augment chemotherapy). This meaning excludes the more-selective agents that block extracellular signals ( signal transduction ). Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer), are now called hormonal therapies . Other inhibitions of growth-signals, such as those associated with receptor tyrosine kinases , are targeted therapy . The use of drugs (whether chemotherapy, hormonal therapy, or targeted therapy)
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#17328773343508216-579: Is recommended in National Institute for Health and Care Excellence (NICE) guidance of June 2001 for non-small-cell lung cancer in patients unsuitable for curative treatment, and in first-line and second-line treatment of ovarian cancer. In September 2001, NICE recommended paclitaxel for the treatment of advanced breast cancer after the failure of anthracyclic chemotherapy , but that its first-line use should be limited to clinical trials. In September 2006, NICE recommended paclitaxel should not be used in
8374-428: Is recorded on video and may be used in cases when further treatment is needed. For many people the stenting procedure does not require staying in the hospital for any extended time period, most people leave the hospital the same day. Much of the time immediately after the stenting is spent in a recovery area to make sure the access site is not bleeding and to ensure vital signs are stable. In most hospital settings,
8532-668: Is required. Because only a fraction of the cells in a tumor die with each treatment ( fractional kill ), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity. The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some leukemias , to being ineffective, such as in some brain tumors , to being needless in others, like most non-melanoma skin cancers . Dosage of chemotherapy can be difficult: If
8690-490: Is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide . Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II . When the DNA double-strand helix is unwound, during DNA replication or transcription , for example,
8848-426: Is that they interrupt cell division . The most important subgroup is the anthracyclines and the bleomycins ; other prominent examples include mitomycin C and actinomycin . Among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium Streptomyces peucetius . Derivatives of these compounds include epirubicin and idarubicin . Other clinically used drugs in
9006-455: Is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division , or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis . Alkylating agents will work at any point in
9164-409: Is then captured directly from the suspension broth by a resin allowing concentration to highly enriched powder containing about 40% paclitaxel. The compound is then purified by one chromatographic step followed by crystallization . Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy. In 1993, paclitaxel was discovered as
9322-456: Is typically contingent on the extent of the coronary artery disease present and the number of diseased coronary arteries that require treatment. DESs have emerged as the primary therapeutic approach for managing symptomatic peripheral arterial disease (PAD). These specialized stents are now widely utilized in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares similarities with coronary artery disease but affects
9480-405: Is unlikely. Taxol is a tetracyclic diterpene , and the biosynthesis of diterpenes starts with an FPP molecule being elongated by the addition of an IPP molecule in order to form geranylgeranyl diphosphate ( GGPP ). The biosynthesis of Taxol contains nineteen steps. These 19 steps can be considered in several steps, with the first step being the formation of the taxane skeleton, which then undergoes
9638-659: The General Accounting Office in 2003, which concluded the NIH had failed to ensure value for money. In related CRADAs with the USDA and Department of the Interior , Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of Taxus brevifolia . This exclusive contract lead to some criticism for giving BMS a "cancer monopoly ". Eighteen months after the CRADA, BMS filed
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#17328773343509796-828: The PICC line . These have a lower infection risk, are much less prone to phlebitis or extravasation , and eliminate the need for repeated insertion of peripheral cannulae. Isolated limb perfusion (often used in melanoma ), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases . Topical chemotherapies, such as 5-fluorouracil , are used to treat some cases of non-melanoma skin cancer . If
9954-463: The adjuvant treatment of early node-positive breast cancer. It is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers. Albumin-bound paclitaxel (brand name Abraxane , also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nanoparticles. Much of the clinical toxicity of paclitaxel
10112-399: The amino , carboxyl , sulfhydryl , and phosphate groups in biologically important molecules. Non-classical alkylating agents include procarbazine and hexamethylmelamine. Anti-metabolites are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are nucleotides ; a molecule comprising
10270-521: The immune system , often by paralysing the bone marrow and leading to a decrease of white blood cells , red blood cells , and platelets . Anemia and thrombocytopenia may require blood transfusion . Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 10 / litre ) can be improved with synthetic G-CSF ( granulocyte -colony-stimulating factor, e.g., filgrastim , lenograstim , efbemalenograstim alfa ). In very severe myelosuppression , which occurs in some regimens, almost all
10428-400: The structure-activity relationships of paclitaxel via generation of analogs for testing, the total synthesis efforts were never seen "as a serious commercial route" to provide significant quantities of the natural product for medical testing or therapeutic use. The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program. A number of years later it was isolated from
10586-528: The total synthesis of paclitaxel, efforts motivated by the desire to generate new chemical understanding rather than to achieve practical commercial production. In contrast, the French group of Pierre Potier at the Centre national de la recherche scientifique (CNRS) addressed the matter of overall process yield, showing that it was feasible to isolate relatively large quantities of the compound 10-deacetylbaccatin from
10744-468: The 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA. In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA. The incidence of debilitating grades of diarrhea
10902-597: The BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group. One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm
11060-514: The CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Apexelsin, intended for the treatment of metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer. The applicant for this medicinal product is WhiteOak Pharmaceutical B.V. Apexelsin was approved for medical use in the European Union in July 2024. As of 2006,
11218-502: The CRADA, including the American firm Bristol-Myers Squibb (BMS), which was selected as the partner in December 1989. The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992. While it seems clear the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by
11376-405: The DES in the narrowed coronary artery or arteries. Multiple stents are often used depending on the degree of blockage and the number of diseased coronary arteries that are being treated. A Drug-Eluting Stent (DES) is a small mesh tube that is placed in the arteries to keep them open in the treatment of vascular disease. The stent slowly releases a drug to block cell proliferation, thus preventing
11534-455: The European yew, Taxus baccata , which grew on the CNRS campus and whose needles were available in large quantity. By virtue of its structure, 10-deacetylbaccatin was seen as a viable starting material for a short semisynthesis to produce paclitaxel. By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel. The view of the NCI, however,
11692-492: The NCI in their cooperative research and development agreement (CRADA) application of 1989. As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel. Another company which worked with BMS until 2012, Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology. By cultivating a specific Taxus cell line in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations. Paclitaxel
11850-476: The PCI procedure and DES placement, but they receive local anesthetic at the site of catheter entry, to ensure there is no pain. Different sedation and pain management practices are used by different medical institutions and practitioners, but patient comfort is always a primary consideration. The catheter/stent system is inserted into the body by piercing a peripheral artery (an artery in the arm or leg) and moved through
12008-572: The US would require the destruction of 360,000 trees annually. For the first time, serious consideration was given to the problem of supply. Because of the practical and, in particular, the financial scale of the program needed, the NCI decided to seek association with a pharmaceutical company, and in August 1989, it published a Cooperative Research and Development Agreement (CRADA) offering its current stock and supply from current bark stocks, and proprietary access to
12166-782: The active ingredient in September 1966 and announcing their findings at an April 1967 American Chemical Society meeting in Miami Beach . They named the pure compound taxol in June 1967. Wall and his colleague Wani published their results, including the chemical structure, in 1971. The NCI continued to commission work to collect more Taxus bark and to isolate increasing quantities of taxol. By 1969, 28 kg (62 lb) of crude extract had been isolated from almost 1,200 kg (2,600 lb) of bark, although this ultimately yielded only 10 g (0.35 oz) of pure material, but for several years, no use
12324-410: The activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin , merbarone, and aclarubicin , which also have other significant mechanisms of action. The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication
12482-560: The adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes. Two topoisomerase I inhibitors, irinotecan and topotecan , are semi-synthetically derived from camptothecin , which
12640-409: The advent of DES technology, the incidence of ISR has significantly decreased. DES have been shown to be superior to BMS in reducing short-term complications of stenting in saphenous vein grafts. However, the use of DESs in bypass grafts was not their originally intended use nor within the scope of originally regulatory approval ( US FDA , European Medicines Agency , etc.). The practice of using
12798-405: The anthracycline group are pirarubicin , aclarubicin , and mitoxantrone . The mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition. Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis . Bleomycin,
12956-432: The arterial narrowing that can occur after stent implantation. These drugs are also used for other purposes, that involve moderating the immune system or treating cancer. They work by inhibiting cell growth. In DES, they are used in very small amounts and for a short time, and only in the area where the stent is placed. There is a distinction between coronary stents and peripheral stents. While both are used to prevent
13114-423: The arterial narrowing that can occur after stent implantation. While such stents can be used in various arteries throughout the body, they are commonly placed in the coronary arteries to treat coronary heart disease. DES is a medical device with several key properties: it functions as a structural scaffold, physically keeping an artery open to ensure blood flow; the device has specific drug delivery features, and
13272-407: The arterial system to deliver the DES into the blocked coronary artery. The stent is then expanded to widen (open) blocked or narrowed coronary arteries (narrowed by plaque buildup), caused by a condition called atherosclerosis. Peripheral arterial access is usually through the femoral (upper leg) or the radial artery (arm/wrist) and less often done through the brachial or ulnar artery (wrist/arm). In
13430-633: The assembly of tubulin into microtubules. The original vinca alkaloids are natural products that include vincristine and vinblastine . Following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer ), vindesine , and vinflunine . These drugs are cell cycle -specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase . Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel ,
13588-410: The balloon of the device, and it is small enough to be passed through relatively narrow peripheral arteries. When in position, the balloon is inflated by introducing physiological saline, and this pushes the overlaying stent firmly into the diseased artery wall, inflation time and pressure are recorded during this placement procedure. After placement, the balloon is deflated, and the device is removed from
13746-489: The bark of the Pacific yew, Taxus brevifolia , hence its name "taxol". The discovery was made by Monroe E. Wall and Mansukh C. Wani at the Research Triangle Institute , Research Triangle Park , North Carolina, in 1971. These scientists isolated the natural product from the bark of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing. The compound
13904-465: The behavior of microtubule motor proteins , or for studies of mutant motor proteins. Paclitaxel has also been used in vitro to inhibit insulin fibrillation. In a molar ratio of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. Isothermal titration calorimetry (ITC) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonds and van der Waals forces . The inhibitory role of paclitaxel
14062-491: The body, leaving the expanded stent in place and opening up the artery. The interventional cardiologist decides how to treat the blockage in the best way during the PCI/DES placement, based on real-time data. The cardiologist uses imaging data provided by both intravascular ultrasound (IVUS), and fluoroscopic imaging (combined with a radiopaque dye). During the procedure, the information obtained from these two sources enables
14220-645: The bone marrow stem cells (cells that produce white and red blood cells ) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow. Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in
14378-469: The cancer cells. Following this, cell cycle arrest occurs, which induces programmed cell death ( apoptosis ). These drugs can also affect blood vessel growth , an essential process that tumours utilise in order to grow and metastasise. Vinca alkaloids are derived from the Madagascar periwinkle , Catharanthus roseus , formerly known as Vinca rosea . They bind to specific sites on tubulin, inhibiting
14536-589: The cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered. Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years. Virtually all chemotherapeutic regimens can cause depression of
14694-524: The cardiologist to track the path of the catheter-DES device as it moves through the arterial blood vessels. This information also helps determine both the location and characteristics of any plaque causing narrowing in the arteries. Data from these two techniques is used to correctly position the stent and to obtain detailed information relating to the coronary arterial anatomy. Given that this anatomy varies greatly among individuals, having this information becomes crucial for effective treatment. The obtained data
14852-406: The case even if the results of non-invasive stress tests, which are tests that measure how the heart works during physical activity, appear normal. Cardiac rehabilitation activities depend on many factors, but mainly on how much the heart muscle was damaged before the PCI/DES procedure. Many people who have this procedure have not had a heart attack, and their hearts may be fine. Others may have had
15010-418: The catheter enters the artery in the arm or leg. There is usually soreness and bruising at this site. This bruising and soreness usually get better after a week or so. People are advised to rest for a week or two and not to lift heavy things. This is mainly to make sure the access site heals well. It is normal to have follow-up appointments with a cardiologist or a primary care provider/general practitioner within
15168-933: The cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug. The subtypes of alkylating agents are the nitrogen mustards , nitrosoureas , tetrazines , aziridines , cisplatins and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine , cyclophosphamide , melphalan , chlorambucil , ifosfamide and busulfan . Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin . Tetrazines include dacarbazine , mitozolomide and temozolomide . Aziridines include thiotepa , mytomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin , carboplatin and oxaliplatin . They impair cell function by forming covalent bonds with
15326-423: The chosen drug is critical for its effectiveness—this drug, selected for its suitability in inhibiting restenosis and its pharmacokinetics, is a crucial component of the device. Apart from the drug, the materials used in the fabrication of the device are also essential and are carefully chosen for their biocompatibility and durability in a biological environment, such as human blood; these materials must also withstand
15484-466: The compound. Critics, including the journal Nature , argued the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested the trademark should not have been awarded and the BMS should renounce its rights to it. BMS argued changing the name would cause confusion among oncologists and possibly endanger the health of patients. BMS has continued to defend its rights to
15642-589: The constant motion of the heart’s beat and be suitable for future patient imaging using MRI technologies, which employ high magnetic fields. DES products are integrated medical devices and are part of a percutaneous coronary intervention (PCI) delivery system; other components, such as the catheter design, also play significant roles in the device’s overall functionality and effectiveness. DES are typically composed of metal alloys, most commonly stainless steel or cobalt-chromium, but can also be made of other materials such as platinum-chromium or nickel-titanium. The stent
15800-424: The contrast agents used to visualize the coronary arteries, and myocardial infarction. With percutaneous coronary intervention (PCI), the requirement for emergency coronary artery bypass graft (CABG) surgery has decreased as better practices have been introduced. In some situations, coronary stenting is permitted in hospitals without cardiac surgery facilities, but such permission remains controversial because of
15958-581: The cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, was about £4,000 (approx. $ 6,000). Caffeine has been speculated to inhibit paclitaxel-induced apoptosis in colorectal cancer cells. In 2016, in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes . Doses 98% less than common dosing had the same effect. Also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis. Aside from its direct clinical use, paclitaxel
16116-436: The data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. In the words of Goodman and Welsh, authors of a substantial scholarly book on taxol, "The NCI was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)". Although the offer was widely advertised, only four companies responded to
16274-439: The decision to start Phase II trials was made a year later. These larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase II trials to begin by the end of 1986. But by then it was recognized that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. This unprecedentedly large amount brought ecological concerns about
16432-522: The development of small "fatty streaks" within arteries. These streaks are essentially deposits of fat. Over time, these initial lesions grow larger and become thicker, forming atheromas (atherosclerotic plaques). Drug-eluting stents (DESs) are used in the treatment of atherosclerosis in both coronary interventions and peripheral arterial interventions: DESs play a crucial role in the management of atherosclerosis in both coronary and peripheral arterial interventions. They help improve blood flow and reduce
16590-452: The dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity ( side-effects ) will be intolerable to the person receiving it. The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram , using the recipient's weight and height, rather than by direct measurement of body area. This formula
16748-622: The enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division. Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme thymidylate synthase , but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase . The fluoropyrimidines include fluorouracil and capecitabine . Fluorouracil
16906-443: The enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death ( apoptosis ) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at
17064-582: The formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream. As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs. In other words, if two people receive
17222-476: The front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place. A DES
17380-456: The higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes , a process normally activated during mitosis. Paclitaxel binds to the beta-tubulin subunits of microtubules. The nomenclature for paclitaxel is structured on a tetracyclic 17-atom skeleton. There are a total of 11 stereocenters. The active stereoisomer is (−)-paclitaxel (shown here). From 1967 to 1993, almost all paclitaxel produced
17538-536: The immune system is suppressed to a critically low level. In Japan , the government has approved the use of some medicinal mushrooms like Trametes versicolor , to counteract depression of the immune system in people undergoing chemotherapy. Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function. Due to immune system suppression, neutropenic enterocolitis (typhlitis)
17696-461: The impact on yew populations into focus for the first time, as local politicians and foresters expressed unease at the program. The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer. At this point, Gordon Cragg of the NCI's Natural Product Branch calculated the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in
17854-403: The implanted DES and a medical device serial number. This information is important for future medical procedures, because it helps the doctors to know what type of device is in the person's body. Some arterial closure systems, which are devices that help to seal the access site after the procedure, are also medical devices and have their own informational cards. The access site is the place where
18012-410: The interventional cardiologist who performed the procedure will speak directly with the patient/family and give them information about how things went, and follow-up instructions. The nursing staff will keep an eye on the person's condition and use tools like ECG to monitor their heart. To prevent a blood clot from forming in the stent, medications are given right after the procedure. One common medication
18170-529: The isolation who named the compound taxol and it was not referred to in any other way for more than twenty years. Annual sales peaked in 2000, reaching US$ 1.6 billion; paclitaxel is now available in generic form. Paclitaxel was approved for medical use in the European Union in 2008. In November 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted
18328-586: The joints of the arms or legs lasting two to three days, changes in the color of the nails, and tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain, redness or swelling at the injection site, hand-foot syndrome , change in normal bowel habits for more than two days, fever, chills, cough, sore throat , difficulty swallowing , dizziness, shortness of breath , severe exhaustion, skin rash , facial flushing , female infertility by ovarian damage, and chest pain can also occur. Neuropathy may also occur. Dexamethasone
18486-417: The lining of the digestive tract), and alopecia (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity ). These include rheumatoid arthritis , systemic lupus erythematosus , multiple sclerosis , vasculitis and many others. There are
18644-432: The market, each with different concentrations of drugs and showing varying efficacy. Among the different DESs, sirolimus-eluting stents and everolimus-eluting stents were found to be more effective than paclitaxel-eluting stents. PCI and stent placement are considered when someone shows signs of reduced blood flow in the arteries that supply the heart or when tests, such as different types of coronary artery imaging, show
18802-630: The microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division. The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but other studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At
18960-399: The name in the courts. BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying "It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17". This quote is, strictly speaking, accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing
19118-479: The narrowing of arteries, coronary stents are specifically for the coronary arteries , while peripheral stents are for any other arteries in the body. Peripheral stents are mostly bare metal ones; some peripheral DES, of the self-expanding type, are used in arteries of the legs. Bioresorbable DES are made of materials that can be absorbed by the body over time, potentially reducing potential long-term complications associated with permanent stents. Atherosclerosis
19276-419: The need to open the chest wall. While bleeding from the puncture site was once a concern, advancements in PCI practices have mitigated this issue through the use of pressure bands and arterial closure systems. Modern DES/PCI procedures are generally painless, although some mild discomfort may be experienced. In PCI, multiple DES are sometimes implanted within a single patient; the decision to use multiple stents
19434-468: The newly stented area, thereby reducing the potential for blockage within the stent area itself. Such blockage is termed in-stent restenosis (ISR). This in-stent blockage is most often caused by excessive cell proliferation or thrombi (blood clots). Anticoagulation therapy (blood thinners), has become a standard treatment following the placement of DES. This therapy significantly reduces the occurrence of adverse events post-stenting. DESs have played
19592-401: The number of microtubules in the cell. Paclitaxel induces remyelination in a demyelinating mouse in vivo and inhibits human peptidylarginine deiminase 2 (hPAD2) in vitro though its methyl ester side chain. In 1999, Angiotech Pharmaceuticals Inc. began phase II clinical trials of micellar paclitaxel as treatment for secondary progressive multiple sclerosis , but reported in 2002 that
19750-430: The pancreas as well. Taxanes , including paclitaxel, 10-deacetylbaccatin III , baccatin III , paclitaxel C, and 7-epipaclitaxel, have been found in the leaves and shells of hazel . The finding of these compounds in shells, which are considered discarded material and are mass-produced by many food industries, is of interest for the future availability of paclitaxel. Paclitaxel is used as an antiproliferative agent for
19908-418: The past, controlling bleeding at the point of arterial access after the procedure was a problem. Modern arterial pressure bands and arterial closure systems now exist, which have helped control bleeding after the procedure, but it is still a concern. Modern catheter/stent systems are integrated medical devices, made of a guidewire, catheter, balloon, and stent. The stent tube mesh is initially collapsed onto
20066-427: The pathway include the formation of a C13-side chain which is attached to baccatin III. The biosynthesis of Taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme taxadiene synthase (TS on the figure). Taxol's biosynthesis begins with E,E,E-GGPP losing pyrophosphate via an SN1 mechanism (step 1 in the figure). The double-bond attacks the cation via electrophilic addition, yielding
20224-442: The peripheral arteries. By deploying DESs, healthcare professionals can effectively address and alleviate the complications associated with PAOD, enhancing patient outcomes and quality of life. The use of DESs in peripheral arterial interventions has shown encouraging results in terms of primary patency (PP) and target lesion revascularization (TLR) compared with bare-metal stents (BMSs). Different types of DESs are available on
20382-412: The person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with antiemetic drugs. Low-certainty evidence also suggests that probiotics may have
20540-818: The person's own gastrointestinal tract (including oral cavity ) and skin. This may manifest as systemic infections, such as sepsis , or as localized outbreaks, such as Herpes simplex , shingles , or other members of the Herpesviridea . The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. Quinolones show effective prophylaxis mainly with hematological cancer. However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. Sometimes, chemotherapy treatments are postponed because
20698-511: The person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line , the Port-a-Cath , and
20856-410: The portion of the artery previously treated with a stent. Restenosis tends to happen three to six months after the procedure. Restenosis is even more likely to occur if a stent would not have been used. When restenosis occurs, another procedure may be needed to correct the problem, such as the placement of a DES that gradually release a drug compound that suppresses cellular growth, thereby reducing
21014-461: The potential for blockage within the stent area itself. This therapy significantly reduces the occurrence of adverse events post-stenting. Technically, a DES in a mesh tube implant devices that is used in angioplasty procedures to treat stenosis of blood vessels and prevent restinosis: the stent, which elutes drugs, is implanted into the blood vessel to help keep the vessel open and improve blood flow. Specifically, drug-eluting stents are used in
21172-513: The practical commercial production of paclitaxel. The first laboratories to complete the total synthesis from much less complex starting materials were the research groups of Robert A. Holton , who had the first article to be accepted for publication , and of K. C. Nicolaou who had the first article to appear in print (by a week, on 7 February 1994). Though the Holton submission preceded the Nicolaou by
21330-576: The prevention of restenosis (recurrent narrowing) of coronary and peripheral stents ; locally delivered to the wall of the artery , a paclitaxel coating limits the growth of neointima (scar tissue) within stents. Paclitaxel drug-eluting stents for coronary artery placement are sold under the trade name Taxus by Boston Scientific in the United States. Paclitaxel drug-eluting stents for femoropopliteal artery placement are also available. Common side effects include nausea and vomiting, loss of appetite , change in taste , thinned or brittle hair, pain in
21488-440: The rare but unpredictable risk of coronary artery perforation. A complication of coronary stenting is stent thrombosis (blood clots). This occurs when a new clot forms within the stent and occludes blood flow, causing a heart attack. DES were designed to specifically combat issues of restenosis that occurred with older bare-metal stents (BMS). Though less frequent with drug-eluting stents, restenosis can still occur. Since
21646-496: The relatively low and often highly variable yields obtained. Early in the 1990s, coincident with increased sensitivity to the ecology of the forests of the Pacific Northwest , paclitaxel was extracted on a clinically useful scale from these sources. Concurrently, synthetic chemists in the U.S. and France had been interested in paclitaxel, beginning in the late 1970s. As noted, by 1992 extensive efforts were underway to accomplish
21804-509: The results showed no statistical significance. Chemotherapy medication Chemotherapy (often abbreviated chemo , sometimes CTX and CTx ) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents ) in a standard regimen . Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim only to prolong life or to reduce symptoms ( palliative chemotherapy). Chemotherapy
21962-500: The right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed. For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed. There has been controversy over
22120-402: The risk of restenosis, thereby improving patient outcomes. The use of DESs is accompanied by appropriate medical therapy and lifestyle modifications to manage atherosclerosis effectively. Stenosis of blood vessels refers to the narrowing of the blood vessels, which can restrict blood flow to the organs and tissues. This condition is often caused by the buildup of fatty deposits in the arteries,
22278-429: The same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person. This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs. The result of this pharmacokinetic variability among people is that many people do not receive
22436-401: The size of the wild population of the Pacific yew and the magnitude of the eventual demand for paclitaxel were uncertain, it was clear that an alternative, sustainable source of the natural product would be needed. Initial attempts to broaden its sourcing used needles from the tree, or material from other related Taxus species, including cultivated ones, but these attempts were challenged by
22594-431: The stent frame. The strut thickness can influence the stent's performance, with thinner struts generally being associated with lower restenosis rates and reduced thrombosis risk. Most DES are balloon-expandable, meaning they are mounted on a balloon catheter and expand when the balloon is inflated. There are also self-expanding stents, which automatically expand when deployed. The very first stent, introduced in 1986,
22752-413: The taxenyl cation (step 6). This forms the fused ring structure intermediate known as taxadiene. Taxadiene then undergoes a series of 10 oxidations via NADPH , forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). A series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin III, which undergoes a further series of esterifications and
22910-442: The treatment of narrowed arteries in the heart ( coronary artery disease ), but also elsewhere in the body, especially the legs ( peripheral artery disease ). Over the last three decades, coronary stenting has matured into a primary minimally invasive treatment tool in managing CAD. Coronary artery stenting is inherently tied to percutaneous coronary intervention (PCI) procedures. PCI is a minimally invasive procedure performed via
23068-447: The treatment of various medical conditions usually at the site of stenotic or occlusive arterial lesions, but one of the primary medical uses is in the treatment of coronary artery disease. Stents are inserted into narrowed coronary arteries, where the narrowing is primarily caused by atherosclerosis. Stents are then expanded to open up the narrowed artery. Such stents gradually release a drug compound that suppresses cellular growth , into
23226-473: The use of BSA to calculate chemotherapy doses for people who are obese . Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of overdosing . In many cases, this can result in sub-optimal treatment. Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced. In
23384-417: Was derived from bark of the Pacific yew, Taxus brevifolia , the harvesting of which kills the tree in the process. The processes used were descendants of the original isolation method of Monroe Wall and Mansukh Wani ; by 1987, the U.S. National Cancer Institute (NCI) had contracted Hauser Chemical Research of Boulder, Colorado , to handle bark on the scale needed for phase II and III trials. While both
23542-482: Was employed there from 1958 onwards, had experience with natural product derived compounds, and began a plant screening operation. After some years of informal arrangements, in July 1960, the NCI commissioned the United States Department of Agriculture (USDA) botanists to collect samples from about 1,000 plant species per year. On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from
23700-404: Was made of the compound by the NCI. In 1975, it was shown to be active in another in vitro system; two years later, a new department head reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process. This required increasing quantities of purified taxol, up to 600 g (21 oz), and in 1977 a further request for 7,000 lb (3,200 kg) of bark
23858-487: Was made. In 1978, two NCI researchers published a report showing that taxol was mildly effective in leukaemic mice. In November 1978, taxol was shown to be effective in xenograft studies. Meanwhile, taxol began to be well known in the cell biology, as well as the cancer communities, with a publication in early 1979 by Susan B. Horwitz , a molecular pharmacologist at Albert Einstein College of Medicine , showing that taxol had
24016-443: Was of this type; The stent tube mesh is initially collapsed onto the catheter—in this collapsed state, it is small enough to be passed though relatively narrow arteries and then expanded in its destination place, pushing firmly to the diseased artery wall. The pharmaceutical compounds that DES emit are antiproliferative agents such as sirolimus , everolimus , zotarolimus , paclitaxel and biolimus . These drugs help prevent
24174-438: Was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The study only included nine human subjects. When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option. The validity of this method in calculating uniform doses has been questioned because
24332-510: Was originally extracted from Taxus brevifolia , the Pacific yew. Now this drug and another in this class, docetaxel , are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata . Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple ( Podophyllum peltatum ) and Himalayan mayapple ( Sinopodophyllum hexandrum ). It has anti-microtubule activity, and its mechanism
24490-412: Was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months. Completing the course of treatment
24648-482: Was that even this route was not practical. The group of Robert A. Holton had also pursued a practical semisynthetic production route; by late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process. The main innovation was "Ojima−Holton coupling", a ring-opening method independently discovered by Holton and Ojima. Florida State University , where Holton worked, signed
24806-508: Was then developed commercially by BMS, who had the generic name assigned as "paclitaxel". In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies. Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who
24964-508: Was used in the clinical trials cited above and resulted in significantly improved treatment outcomes. Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin and busulfan dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate , 5-FU, paclitaxel , and docetaxel . The serum albumin level immediately prior to chemotherapy administration
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