משתמש:גלנוס/ארגז חול3
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| שם IUPAC | |
|---|---|
|
3S-[3R*[E(1S*,3S*,4S*)] ,4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a -hexadecahydro-5, 19-dihydroxy -3-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14,16-dimethoxy -4,10,12,18-tetramethyl-8-(2-propenyl) -15,19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H) -tetrone, monohydrate | |
| שמות מסחריים בישראל | |
| פרוגרף, פרוטופיק | |
| נתונים כימיים | |
| כתיב כימי | C44H69NO12 |
| מסה מולרית | 804.018 גרם/מול |
| נתונים פרמוקוקינטיים | |
| זמינות ביולוגית | 20%, ופחות בנטילה לאחר ארוחה שומנית |
| מטבוליזם | בכבד CYP3A4 |
| זמן מחצית חיים | ממוצע 11.3 שעות, טווח 3.5 - 40.6 שעות |
| הפרשה | בעיקר בצואה |
| בטיחות | |
| מעמד חוקי | Rx, תרופת מרשם |
| קטגוריית סיכון בהריון | C |
| סיכון לתלות | אין |
| דרכי מתן | מתן עורי מקומי, פומי ותוך ורידי (I.V.) |
| אינטראקציות עם תרופות אחרות | יש, עם תרופות המפונות באותו מסלול. אסור עם מיץ אשכוליות |
Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis ("eczema"), severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.
History
[עריכת קוד מקור | עריכה]Tacrolimus was discovered in 1987 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was the first macrolide immunosuppressant discovered.[1] Like ciclosporin, it was found in a soil fungus, although it is produced by a type of bacteria, Streptomyces tsukubaensis.[2] The name tacrolimus is reportedly derived from 'Tsukuba macrolide immunosuppressant'.
The drug is owned by Astellas Pharma Inc. (Merging of Fujisawa Pharmaceutical Co.,Ltd. and Yamanouchi Pharmaceutical Co., Ltd as of April 1, 2005) and is sold under the tradename Prograf®. It is sometimes referred to as FK-506, an early name relating to its action. It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.
Pharmacology
[עריכת קוד מקור | עריכה]Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.[3] Although this activity is similar to ciclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.citation needed
Indications
[עריכת קוד מקור | עריכה]Immunosuppresion following transplantation
[עריכת קוד מקור | עריכה]It has similar immunosuppressive properties to ciclosporin, but is much more potent in equal volumes. Also like ciclosporin it has a wide range of adverse interactions, including that with grapefruit which increases plasma-tacrolimus concentration. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study.[4]
Dermatological use
[עריכת קוד מקור | עריכה]As an ointment (Protopic®), tacrolimus is a recent addition in the treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy), or other steroid related side-effects. It may therefore be used continuously on the body and applied to the thinner skin over the face and eyelids.
Contraindications and Precautions
[עריכת קוד מקור | עריכה]- breast-feeding
- hepatic disease
- immunosuppression
- infants
- infection
- intravenous administration
- neoplastic disease
- occlusive dressing
- oliguria
- pregnancy
- QT prolongation
- skin cancer
- sunlight (UV) exposure
Side effects
[עריכת קוד מקור | עריכה]From oral and intravenous administration
[עריכת קוד מקור | עריכה]Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion, loss of appetite, hyperglycemia, weakness, depression, cramps, and neuropathy, as well as potentially increasing the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.
From topical use
[עריכת קוד מקור | עריכה]A common side effect of tacrolimus ointment, if used over a wide area, is to cause a burning or itching sensation on the first one or two applications.
Cancer risks
[עריכת קוד מקור | עריכה]תבנית:See Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. Whereas current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.[5]
Dermatologists agree that the drug should be used as a second-line remedy only after conventional methods of treatment have failed.
References
[עריכת קוד מקור | עריכה]- ^ Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987). "FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics". J Antibiot (Tokyo). 40 (9): 1249–55. PMID 2445721.
{{cite journal}}: תחזוקה - ציטוט: multiple names: authors list (link) - ^ Pritchard D (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discov Today. 10 (10): 688–91. PMID 15896681. Supports source organism, but not team information
- ^ Liu J, Farmer J, Lane W, Friedman J, Weissman I, Schreiber S (1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes". Cell. 66 (4): 807–15. PMID 1715244.
{{cite journal}}: תחזוקה - ציטוט: multiple names: authors list (link) - ^ McCauley, Jerry (2004-05-19). "Long-Term Graft Survival In Kidney Transplant Recipients". Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. נבדק ב-2006-06-06.
- ^ N H Cox and Catherine H Smith (2002). "Advice to dermatologists re topical tacrolimus" (DOC). Therapy Guidelines Committee. British Association of Dermatologists.
{{cite web}}: פרמטר לא ידוע|month=(עזרה)