Citrus And Statins. —Citrus And Statins “” “How Foods and Drugs Collide” provided my first knowledge that 5-geranoxy psoralen (bergamottin) had been identified as the active agent in grapefruit juice implicated in interfering with the so-called statin drugs
( C&ENCitrus And Statins, Sept. 27, page 55 William L. Stanley Carmel, Calif. /articles/88/i49/Citrus-Statins.html 20101206 88 49 /magazine/88/8849.html /departments/letters.html Citrus And Statins Letters Citrus And Statins Chemical & Engineering News Citrus And Statins ACS 2009 IRS Form 990 Available The American Chemical Society’s 2009 Form 990 is now available on ACS’s website.
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Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot orange, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6′,7′-dihydroxybergamottin, it is believed to be responsible for thegrapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.
Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived fromgeraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4. This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.
Normally, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition. Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.
Biosynthesis of bergamottin
Bergamottin is derived from components originating in the shikimate pathway. The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product which is formed via the alkylation of the umbelliferone (2) compound. The alkylation of the umbelliferone is initiated with the use of dimethylallyl pyrophosphate, more commonly known as DMAPP. The cyclization of an alkyl group occurs to form marmesin (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst. This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6). Bergaptol (6) is next methylated with SAM, S-Adenosyl methionine, to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or geranyl pyrophosphate, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).
- ^ David G. Bailey, J. Malcolm, O. Arnold, J. David Spence (1998). “Grapefruit juice-drug interactions”. Br J Clin Pharmacol 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x.PMC 1873672. PMID 9723817.
- ^ Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila (2006). “Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes”. Bioorganic & Medicinal Chemistry 14 (8): 2606–2612. doi:10.1016/j.bmc.2005.11.039. PMID 16338240.
- ^ E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard (2006). “Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4”. Org. Biomol. Chem. 4(8): 1604–1610. doi:10.1039/b601096b. PMID 16604230.
- ^ Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim (2002). “Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers”. European Journal of Clinical Pharmacology 58 (8): 515–520. doi:10.1007/s00228-002-0516-8. PMID 12451428.
- ^ Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.
- ^ Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.
- ^ Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. J. Biol. Chem. 1992, 267, 14669-14676.
- ^ Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. J. Pharmacol. Exp. Ther. 2006, 318, 992-1005
(NaturalNews) Men who like pizza, pasta with red sauce, and lasagna have a new excuse to eat more of those dishes upon discovering that lycopene in tomato sauce promotes prostate health. This news has been around for some time.
NaturalNews) If you need more zest and zip in your life, the secret to these states and more can be found in a set of simple (yet profound) yogic exercises known as the “Five Tibetans.” Developed by Buddhist monks and brought to the West in the 1930s, Tibetan yoga is a series of five movements that improve digestion and circulation while dispelling fatigue and depression. Advocates of the practice rave about the boundless energy, clarity and vitality the short daily sessions produce. And many also believe Tibetan yoga reverses the hands of time, promoting an ageless and disease free body.
August 28, 2013 | By Márcio Barra
Last Friday, INFARMED, the Portuguese National Competent Authority on Medicines, triggered an inspection in order to identify the causes of the reported difficulties some patients are having in accessing the Parkinson’s disease drug Azilect (Rasagiline).
According to a statement issued by INFARMED, in the course of this operation a total of 133 inspections were conducted – 129 pharmacies and four distributors – alongside telephone surveys with 111 pharmacies to collect additional information.
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July 17 2013 | By Márcio Barra
NICE, the UK price regulatory agency, has released this Tuesday preliminary draft guidance rejecting Pfizer’s Bosulif (bosutinib) for previously treated patients with chronic myeloid leukaemia (CML). According to the draft release, Bosulif did not represent good enough value for use in the treatment of patients, even though the drug would be provided to the UK’s NHS patients through a patient access scheme. This follows two earlier rebuffs for new cancer drugs developed by Pfizer this year: lung cancer drug Xalkori and kidney cancer drug Inlyta.
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February 09, 2013 | By Márcio Barra
The final part of my article on the orphan drug market.
The price question
The answer to the question is that the patient doesn’t pay for the drug. First, it’s worth noting that these drugs have a different commercial circuit than normal drugs. They are usually only prescribed at hospitals, under the management of physicians that participated in the trials for the orphan drug.
In the case of the European Union, member states evaluate the drug to decide if their national health systems reimburse the drug. The pricing of the drug itself follows the same logic as drug pricing in general: the price of the orphan drug is set up by the manufacturer in an attempt to recoup R&D…
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December 20, 2012 | By Márcio Barra
After Pfizer Inc. and Johnson & JohnsonBapineuzumab failure and Eli Lilly Solaneuzumab not so great results in meeting the clinical endpoints in a phase III trial back in August, it would be expected that pharma companies would steer clear from the amyloid hypothesis which has dominated alzheimer research these last two decades. However, while other theories have re-emerged – the Tau theory, a hypothesis which states if the Tau proteins are hyperphosphorylated they can lead to the creation of tangles in brain cells –, the amyloid theory is still backed up by a number of stakeholders. Eli Lilly’s Solaneuzumab, while ineffective in lower stages of the disease, has “showed a 34% reduction in cognitive decline”, in patients with mild disease, and so many companies are focusing to create therapies that intervene before the damage is done and identify affected people much…
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Eating lots of broccoli may slow down and even prevent osteoarthritis, UK researchers believe.
The University of East Anglia team is starting human trials following on from successful lab studies.
Tests on cells and mice showed that a broccoli compound – which humans can also get from Brussels sprouts and cabbage – blocked a key destructive enzyme that damages cartilage.
They are asking 20 patients to eat a daily dose of “super-charged” broccoli.
This special cruciferous vegetable has been bred to be extra rich in nutrients – it is a cross between standard broccoli and a wild relative from Sicily.
Our body takes this glucoraphanin compound and turns it into another, called sulforaphane, which appears to protect the joints.
“I can’t imagine it would repair or reverse arthritis… but it might be a way to prevent it”
Dr Rose Davidson Lead researcher
The volunteers will have two weeks…
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April 26, 2013 | By Márcio Barra
When planning a clinical trial, the question that the sponsor wishes to address is the starting point, and where the rest of the trial planning hangs. While the objective of the trial is often obvious to the investigator designing the trial, the question itself can be phrased poorly. Thus, writing a scientific, clear research question is a most valuable action when starting and establishing the study (1).
After coming up with a sound research question, the study design has to be elected. This choice is deeply connected with the desired information that the sponsor wishes to obtain regarding the drug product.
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August 27, 2013 | By Márcio Barra
Following the news yesterday on Amgen’s $10.4 billion Onyx buyout, Bayer AG announced today that the FDA has put its drug Nexavar, sold for liver and kidney cancer in the US in partnership with Onyx, on priority review for thyroid-cancer approval.
The priority review designation granted to Nexavar is for the treatment of locally advanced or metastatic radioactive iodine (RAI)-refractory differentiated thyroid cancer, with the submission being based on the results of the DECISION clinical trial. In this trial, a total of 417 patients with locally advanced or metastatic, RAI-refractory, differentiated thyroid cancer – a type of cancer that doesn’t respond to treatment with radioactive iodine – that hadn’t receive prior therapy for thyroid cancer were randomized to receive 400 mg of oral Nexavar twice daily (207 patients) or matching placebo (210 patients). Nexavar doubled progression-free survival, to a median of 10.8 months…
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