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Tacrolimus
 
 
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Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive
Immunosuppression

Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other conditions....
 drug
Medication

A pharmaceutical drug, also referred to as medicine or medicament, can be loosely defined as any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease....
 whose main use is after allogenic organ transplant
Organ transplant

Organ transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site....
 to reduce the activity of the patient's immune system
Immune system

An immune system is a collection of biological processes within an organism that protects against disease by identifying and killing pathogens and tumour cells....
 and so the risk of organ rejection
Transplant rejection

Transplant rejection occurs when a Organ transplant organ or tissue is not accepted by the body of the transplant recipient. This is explained by the concept that the immune system of the recipient attacks the transplanted organ or tissue....
. It is also used in a topical preparation in the treatment of severe atopic dermatitis
Atopic dermatitis

Atopic dermatitis is an inflammation, chronically relapsing, non-contagious and pruritis skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique"....
 (eczema
Eczema

Eczema is a form of dermatitis, or inflammation of the epidermis. The term eczema is broadly applied to a range of persistent skin conditions....
), severe refractory uveitis
Uveitis

Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye, with inflammation specifically of the uvea termed iridocyclitis....
 after bone marrow
Bone marrow

Bone marrow is the flexible biological tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells....
 transplants, and the skin condition vitiligo
Vitiligo

Vitiligo or leukoderma is a Chronic skin disorder that causes loss of Biological pigment, resulting in irregular pale patches of skin. It occurs when the melanocytes, cells responsible for skin pigmentation, die or are unable to function....
. It is a 23-membered macrolide
Macrolide

The macrolides are a group of Medication whose activity stems from the presence of a macrolide ring, a large macrocycle lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached....
 lactone
Lactone

A lactone is a cyclic ester in organic chemistry . It is the condensation reaction product of an alcohol functional group and a carboxylic acid group in the same molecule....
 discovered in 1984 from the fermentation broth of a Japan
Japan

Japan is an island country in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, People's Republic of China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south....
ese soil
Soil

Soil is the naturally occurring, unconsolidated or loose covering on the Earth's surface. Soil is composed of particles of broken rock that have been altered by chemical and environmental processes including weathering and erosion....
 sample that contained the bacteria
Bacteria

The Bacteria are a large group of unicellular microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals....
 Streptomyces tsukubaensis
Streptomyces tsukubaensis

Streptomyces tsukubaensis is a bacterium from which tacrolimus is derived....
.

olimus was discovered in 1984 by a Japanese team headed by T.






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Encyclopedia


Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive
Immunosuppression

Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other conditions....
 drug
Medication

A pharmaceutical drug, also referred to as medicine or medicament, can be loosely defined as any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease....
 whose main use is after allogenic organ transplant
Organ transplant

Organ transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site....
 to reduce the activity of the patient's immune system
Immune system

An immune system is a collection of biological processes within an organism that protects against disease by identifying and killing pathogens and tumour cells....
 and so the risk of organ rejection
Transplant rejection

Transplant rejection occurs when a Organ transplant organ or tissue is not accepted by the body of the transplant recipient. This is explained by the concept that the immune system of the recipient attacks the transplanted organ or tissue....
. It is also used in a topical preparation in the treatment of severe atopic dermatitis
Atopic dermatitis

Atopic dermatitis is an inflammation, chronically relapsing, non-contagious and pruritis skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique"....
 (eczema
Eczema

Eczema is a form of dermatitis, or inflammation of the epidermis. The term eczema is broadly applied to a range of persistent skin conditions....
), severe refractory uveitis
Uveitis

Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye, with inflammation specifically of the uvea termed iridocyclitis....
 after bone marrow
Bone marrow

Bone marrow is the flexible biological tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells....
 transplants, and the skin condition vitiligo
Vitiligo

Vitiligo or leukoderma is a Chronic skin disorder that causes loss of Biological pigment, resulting in irregular pale patches of skin. It occurs when the melanocytes, cells responsible for skin pigmentation, die or are unable to function....
. It is a 23-membered macrolide
Macrolide

The macrolides are a group of Medication whose activity stems from the presence of a macrolide ring, a large macrocycle lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached....
 lactone
Lactone

A lactone is a cyclic ester in organic chemistry . It is the condensation reaction product of an alcohol functional group and a carboxylic acid group in the same molecule....
 discovered in 1984 from the fermentation broth of a Japan
Japan

Japan is an island country in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, People's Republic of China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south....
ese soil
Soil

Soil is the naturally occurring, unconsolidated or loose covering on the Earth's surface. Soil is composed of particles of broken rock that have been altered by chemical and environmental processes including weathering and erosion....
 sample that contained the bacteria
Bacteria

The Bacteria are a large group of unicellular microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals....
 Streptomyces tsukubaensis
Streptomyces tsukubaensis

Streptomyces tsukubaensis is a bacterium from which tacrolimus is derived....
.

History

Tacrolimus was discovered in 1984 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was among the first macrolide
Macrolide

The macrolides are a group of Medication whose activity stems from the presence of a macrolide ring, a large macrocycle lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached....
 immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975. Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from 'Tsukuba
Tsukuba, Ibaraki

is a city located in Ibaraki Prefecture, Japan. It is known as the location of the , a planned city developed in the 1960s.As of 2008, the city has an estimated population of 207,394 and a population density of 730 persons per square kilometer....
 macrolide immunosuppressant'.

The drug is owned by Astellas Pharma Inc.
Astellas Pharma

is a Japanese pharmaceutical company, formed on 1 April, 2005 from the merger of and .Astellas' franchise areas are urology, immunology , dermatology, cardiology, and infectious disease....
, and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506 (Fermentek
Fermentek

Fermentek Ltd. is a biotechnology company, located in Jerusalem, Israel, specializing in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae....
 catalogue number 506). It was first approved by the Food and Drug Administration
Food and Drug Administration

The U.S. Food and Drug Administration is an Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, dietary supplements, Medications, vaccines, Biopharmaceutical, blood transfusion, medical devices, Electromagnetic radiation-emitting devices, veteri...
 (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

Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin
Calcineurin

Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B . Calcineurin activates NFATC1 , a transcription factor by dephosphorylation it....
 thus inhibiting both T-lymphocyte
Lymphocyte

A lymphocyte is a type of white blood cell in the vertebrate immune system.By their appearance under the light microscope, there are two broad categories of lymphocytes, namely the large granular lymphocytes and the small lymphocytes....
 signal transduction and IL-2 transcription. Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin. Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.

Indications


Immunosuppresion following transplantation

It has similar immunosuppressive properties to cyclosporin, but is much more potent in equal volumes. Also like cyclosporin it has a wide range of adverse interactions, including that with grapefruit
Grapefruit

The grapefruit is a subtropics citrus tree grown for its bitter fruit which was originally named the "forbidden fruit" of Barbados.These evergreen trees are usually found at around 5-6 m tall, although they can reach 13-15 m ....
 which increases plasma-tacrolimus concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increase drug levels by competing for degradative enzymes. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with cyclosporin-based immunosuppression (30.7% vs 46.4%) in one study. Clinical outcome is better with tacrolimus than with emulsified cyclosporin during the first year of liver transplantation.

Use in treating ulcerative colitis

In recent years, Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis
Ulcerative colitis

Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon , that includes characteristic Peptic ulcer, or open sores, in the colon....
, a form of inflammatory bowel disease
Inflammatory bowel disease

In medicine, inflammatory bowel disease is a group of inflammation conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.....
. Although almost exclusively used in trial cases only, Tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.

Dermatological use

See also: Immunomodulators in the treatment of eczema
Eczema

Eczema is a form of dermatitis, or inflammation of the epidermis. The term eczema is broadly applied to a range of persistent skin conditions....


As an ointment
Ointment

An ointment is a viscous semisolid preparation used topically on a variety of body surfaces. These include the skin and the mucus membranes of the eye , vagina, anus, and nose....
 (Protopic), tacrolimus is a recent addition in the treatment of eczema
Eczema

Eczema is a form of dermatitis, or inflammation of the epidermis. The term eczema is broadly applied to a range of persistent skin conditions....
, particularly atopic dermatitis
Atopic dermatitis

Atopic dermatitis is an inflammation, chronically relapsing, non-contagious and pruritis skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique"....
. It suppresses inflammation in a similar way to steroid
Steroid

A steroid is a terpenoid lipid characterized by a carbon skeleton with four fused rings, generally arranged in a 6-6-6-5 fashion.Steroids vary by the functional groups attached to these rings and the oxidation state of the rings....
s, 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
Atrophy

Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include poor nourishment, poor circulatory system, loss of hormone support, loss of nerve supply to the target Organ , disuse or lack of exercise or disease intrinsic to the tissue itself....
), or other steroid related side-effects. It may therefore be used continuously on the body (clinical trials of up to one year in length have occurred), and applied to the thinner skin over the face and eyelids. Recently it has also been used to treat segmental vitiligo in children,especially on the face.

The most common adverse events associated with the use of Protopic included the sensation of skin burning, itching, flu-like symptoms, and headache. The use of Protopic should be avoided on known or suspected malignant lesions. The use of Protopic on patients with Netherton's syndrome or similar skin diseases is not recommended. Patients should minimize or avoid natural or artificial sunlight exposure. Skin infections should be cleared prior to application, and there may be an increased risk of certain skin infections. Protopic should not be used with occlusive dressings ().

Contraindications and precautions

  • breast-feeding
  • hepatic disease
  • immunosuppression
  • infant
    Infant

    An infant or baby is the term used to refer to the young offspring of humans....
    s
  • infection
    Infection

    An infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host resources to multiply ....
  • intravenous administration
  • neoplastic disease, such as:
    • skin cancer
      Skin cancer

      Skin cancer is a malignant growth on the skin which can have many causes. The most common skin cancers are basal cell cancer, squamous cell cancer, and melanoma....
    • lung cancer
      Lung cancer

      Lung cancer is a disease of uncontrolled cell growth in tissue of the lung. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the lungs....
  • occlusive dressing
  • oliguria
    Oliguria

    Oliguria and anuria are the decreased or absent production of urine, respectively. The decreased production of urine may be a sign of dehydration, renal failure or urinary obstruction/urinary retention....
  • pregnancy
    Pregnancy

    Pregnancy is the carrying of one or more offspring, known as a fetus or embryo, inside the uterus of a female. In a pregnancy, there can be multiple gestations, as in the case of twins or Multiple birth....
  • QT prolongation


  • sunlight
    Sunlight

    Sunlight, in the broad sense, is the total spectroscopy of the electromagnetic radiation given off by the Sun. On Earth, sunlight is Filter ed through the Earth's atmosphere, and the solar radiation is obvious as daylight when the Sun is above the horizon....
     (UV) exposure
  • grapefruit
    Grapefruit

    The grapefruit is a subtropics citrus tree grown for its bitter fruit which was originally named the "forbidden fruit" of Barbados.These evergreen trees are usually found at around 5-6 m tall, although they can reach 13-15 m ....
     juice


Side effects


From oral and intravenous administration

Side effects can be severe and include blurred vision, liver and kidney
Kidney

The kidneys are Organ that have numerous biological roles. Their primary role is to maintain the homeostasis balance of bodily fluids by filtering and secreting Metabolomics#Metabolitess and minerals from the blood and excreting them, along with water , as urine....
 problems (it is nephrotoxic), seizure
Seizure

An epileptic seizure is a transient symptom of abnormal, excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms ....
s, tremor
Tremor

Tremor is an unintentional, somewhat rhythmic, muscle movement involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, head, face, vocal cords, trunk, and legs....
s, hypertension
Hypertension

Hypertension, also referred to as high blood pressure, HTN or HPN, is a medical condition in which the blood pressure is chronically elevated....
, hypomagnesemia, diabetes mellitus
Diabetes mellitus

Diabetes mellitus , often referred to simply as diabetes , is a syndrome of disordered metabolism, usually due to a combination of genetic disorder and environmental causes, resulting in abnormally high blood sugar levels ....
, hyperkalemia
Hyperkalemia

Hyperkalemia Hyperkalaemia is an elevated blood level of the electrolyte potassium. The prefix hyper- means high . The middle kal refers to kalium, which is neo-Latin for potassium....
, itch
Itch

Itch is an unpleasant sensation that evokes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience....
ing, insomnia
Insomnia

Insomnia is a symptom of a sleep disorder characterized by persistent difficulty falling sleep or staying asleep despite the opportunity. Insomnia is a symptom, not a stand-alone diagnosis or a disease....
, confusion, loss of appetite, hyperglycemia
Hyperglycemia

Hyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma....
, weakness, depression, cramps, and neuropathy, as well as potentially increasing the severity of existing fungal or infectious conditions such as herpes zoster or polyoma
Polyomavirus

Polyomavirus is the sole genus of viruses within the family Polyomaviridae. Polyomaviruses are DNA virus , small , and icosahedron in shape, and do not have a lipoprotein envelope....
 viral infections.

From topical use

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. Less common side effects include flu-like symptoms, headache, cough and burning eyes.

Cancer risks

Tacrolimus and a related drug for eczema (pimecrolimus
Pimecrolimus

Pimecrolimus is an immunomodulator used in the treatment of atopic dermatitis . It is currently available as a topical cream, once marketed by Novartis under the trade name Elidel....
) 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. However, current practice by UK
United Kingdom

The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom , the UK or Britain,is a sovereign state located off the northwestern coast of continental Europe....
  dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.

Dermatologists agree that the drug should be used as a second-line remedy only after conventional methods of treatment have failed.

External links

  • product page from Fermentek
    Fermentek

    Fermentek Ltd. is a biotechnology company, located in Jerusalem, Israel, specializing in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae....