Infliximab is a chimeric monoclonal antibody biologic drug that works against tumor necrosis factor alpha and is used to treat autoimmune diseases. Infliximab was approved by the U. S. Food and Drug Administration for the treatment of Crohn's disease, ulcerative colitis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, it is used off-label outside its FDA approval for other conditions. Infliximab is administered by intravenous infusion at six- to eight-week intervals, it can not be given by mouth. Infliximab works by binding to TNF-α. TNF-α is a key part of the autoimmune reaction. In rheumatoid arthritis, infliximab seems to work by preventing TNF-α from binding to its receptor in the cell. Infliximab is an artificial antibody, it was developed in mice as a mouse antibody. Because humans have immune reactions to mouse proteins, the mouse common domains were replaced with similar human antibody domains, they have identical structures and affinities to the target. Because they are a combination of mouse and human antibody amino acid sequences, they are called a "chimeric monoclonal antibody".
In the United States, Remicade can cost as much as $19,000 per month. Infliximab biosimilars have been approved in the EU, USA. Three phenotypes, or categories of disease, are present in Crohn's disease: stricturing disease, penetrating disease, inflammatory disease. Infliximab was first used for closure of fistulae in Crohn's disease in 1999. In a 94-patient, phase II clinical trial, the researchers showed Infliximab was effective in closing fistulae between the skin and bowel in 56-68% of patients. A large, 296-patient Phase III clinical trial called the ACCENT 2 trial showed infliximab was additionally beneficial in maintaining closure of fistulae, with two-thirds of all patients treated with the three initial doses of infliximab having a fistula response after 14 weeks, 36% of patients maintaining closure of fistulae after a year, compared with 19% who received placebo therapy; this final trial resulted in the FDA approval of the drug to treat fistulizing disease. Infliximab has been used to maintain remission in inflammatory Crohn's disease.
The ACCENT 1 trial, a large, multicentre trial, found 39 to 45% of patients treated with infliximab, who had an initial response to it, maintained remission after 30 weeks, compared with 21% who received placebo treatment. It showed a mean maintenance of remission from 38 to 54 weeks compared with 21 weeks for patients who received placebo treatment. Crohn's patients have flares of their disease between periods of disease quiescence. Severe flares are treated with steroid medications to obtain remission, but steroids have many undesirable side effects, so some gastroenterologists are now advocating the use of infliximab as the first drug to try to get patients into remission; this has been called the top-down approach to treatment. Infliximab targets TNF, thought to be more related to Th1 cytokines. Ulcerative colitis was thought to be a Th2 disease, infliximab would be of limited use. However, patients with ulcerative colitis have begun to be treated with infliximab on the basis of two large clinical trials conducted in 2005 by Paul Rutgeerts and William Sandborn.
The Acute ulcerative Colitis Treatment trials to evaluate the utility of infliximab in ulcerative colitis showed 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared with 21% of patients who were treated with placebo medication. At two months, the response was 61-69% for patients treated with infliximab, 31% for those treated with placebo. Newer drugs such as Etrolizumab have similar efficacy to Infliximab with less adverse effects for treatment of ulcerative colitis. In psoriatic arthritis, inhibitors of TNF, such as infliximab, improve the symptoms. Several therapies with modest efficacy have been studied in nail psoriasis. Among available agents, higher quality data are available to support the efficacy of cyclosporine and infliximab. Based on studies in AS, the results suggest infliximab and adalimumab have the potential to reduce the signs and symptoms of moderate to active axial involvement in PsA in patients who have had an inadequate response to NSAID.
The anti-TNF agents are more effective for the treatment of enthesitis than traditional agents. Results suggest infliximab is effective for the treatment of dactylitis in PsA, it was approved for treating ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis. Infliximab is prescribed for the treatment of Behçet's disease. Infliximab is the most used biological agent in treating relapsing polychondritis. Half of the patients saw benefit from this treatment, a few other patients experienced infections that in some cases lead to death. There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases. Infliximab has been used off-label in treating refractory sarcoidoisis, where other treatments have not been effective. Infliximab has been tested in COPD but there was no evidence of benefit with the possibility of harm. Infliximab has adverse effects, some life-threatening, common to drugs in the class of TNF inhibiting
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, is a protective response involving immune cells, blood vessels, molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, initiate tissue repair; the five classical signs of inflammation are heat, redness and loss of function. Inflammation is a generic response, therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, atherosclerosis, rheumatoid arthritis, cancer. Inflammation is therefore closely regulated by the body. Inflammation can be classified as either chronic.
Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together when discussing an infection, the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be.
But because of how the two are correlated, words ending in the suffix -itis are sometimes informally described as referring to infection. For example, the word urethritis means only "urethral inflammation", but clinical health care providers discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis, it is useful to differentiate inflammation and infection because there are typical situations in pathology and medical diagnosis where inflammation is not driven by microbial invasion – for example, trauma and autoimmune diseases including type III hypersensitivity. Conversely, there is pathology where microbial invasion does not cause the classic inflammatory response – for example, parasitosis or eosinophilia. Acute inflammation is a short-term process appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus, it involves a coordinated and systemic mobilization response locally of various immune and neurological mediators of acute inflammation.
In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and ceases. It is characterized by five cardinal signs:An acronym that may be used to remember the key symptoms is "PRISH", for pain, immobility and heat; the traditional names for signs of inflammation come from Latin: Dolor Calor Rubor Tumor Functio laesa The first four were described by Celsus, while loss of function was added by Galen. However, the addition of this fifth sign has been ascribed to Thomas Sydenham and Virchow. Redness and heat are due to increased blood flow at body core temperature to the inflamed site. Loss of function has multiple causes. Acute inflammation of the lung does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings; the process of acute inflammation is initiated by resident immune cells present in the involved tissue resident macrophages, dendritic cells, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors, which recognize two subclasses of molecules: pathogen-associated molecular patterns and damage-associated molecular patterns.
PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related cell damage. At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes increased heat. Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue, which manifests itself as swelling; some of the released mediators such as bradykinin increase the sensitivity to pain. The mediator molecules alter the blood vessels to
International Standard Serial Number
An International Standard Serial Number is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is helpful in distinguishing between serials with the same title. ISSN are used in ordering, interlibrary loans, other practices in connection with serial literature; the ISSN system was first drafted as an International Organization for Standardization international standard in 1971 and published as ISO 3297 in 1975. ISO subcommittee TC 46/SC 9 is responsible for maintaining the standard; when a serial with the same content is published in more than one media type, a different ISSN is assigned to each media type. For example, many serials are published both in electronic media; the ISSN system refers to these types as electronic ISSN, respectively. Conversely, as defined in ISO 3297:2007, every serial in the ISSN system is assigned a linking ISSN the same as the ISSN assigned to the serial in its first published medium, which links together all ISSNs assigned to the serial in every medium.
The format of the ISSN is an eight digit code, divided by a hyphen into two four-digit numbers. As an integer number, it can be represented by the first seven digits; the last code digit, which may be 0-9 or an X, is a check digit. Formally, the general form of the ISSN code can be expressed as follows: NNNN-NNNC where N is in the set, a digit character, C is in; the ISSN of the journal Hearing Research, for example, is 0378-5955, where the final 5 is the check digit, C=5. To calculate the check digit, the following algorithm may be used: Calculate the sum of the first seven digits of the ISSN multiplied by its position in the number, counting from the right—that is, 8, 7, 6, 5, 4, 3, 2, respectively: 0 ⋅ 8 + 3 ⋅ 7 + 7 ⋅ 6 + 8 ⋅ 5 + 5 ⋅ 4 + 9 ⋅ 3 + 5 ⋅ 2 = 0 + 21 + 42 + 40 + 20 + 27 + 10 = 160 The modulus 11 of this sum is calculated. For calculations, an upper case X in the check digit position indicates a check digit of 10. To confirm the check digit, calculate the sum of all eight digits of the ISSN multiplied by its position in the number, counting from the right.
The modulus 11 of the sum must be 0. There is an online ISSN checker. ISSN codes are assigned by a network of ISSN National Centres located at national libraries and coordinated by the ISSN International Centre based in Paris; the International Centre is an intergovernmental organization created in 1974 through an agreement between UNESCO and the French government. The International Centre maintains a database of all ISSNs assigned worldwide, the ISDS Register otherwise known as the ISSN Register. At the end of 2016, the ISSN Register contained records for 1,943,572 items. ISSN and ISBN codes are similar in concept. An ISBN might be assigned for particular issues of a serial, in addition to the ISSN code for the serial as a whole. An ISSN, unlike the ISBN code, is an anonymous identifier associated with a serial title, containing no information as to the publisher or its location. For this reason a new ISSN is assigned to a serial each time it undergoes a major title change. Since the ISSN applies to an entire serial a new identifier, the Serial Item and Contribution Identifier, was built on top of it to allow references to specific volumes, articles, or other identifiable components.
Separate ISSNs are needed for serials in different media. Thus, the print and electronic media versions of a serial need separate ISSNs. A CD-ROM version and a web version of a serial require different ISSNs since two different media are involved. However, the same ISSN can be used for different file formats of the same online serial; this "media-oriented identification" of serials made sense in the 1970s. In the 1990s and onward, with personal computers, better screens, the Web, it makes sense to consider only content, independent of media; this "content-oriented identification" of serials was a repressed demand during a decade, but no ISSN update or initiative occurred. A natural extension for ISSN, the unique-identification of the articles in the serials, was the main demand application. An alternative serials' contents model arrived with the indecs Content Model and its application, the digital object identifier, as ISSN-independent initiative, consolidated in the 2000s. Only in 2007, ISSN-L was defined in the
Neutrophils are the most abundant type of granulocytes and the most abundant type of white blood cells in most mammals. They form an essential part of the innate immune system, their functions vary in different animals. They are formed from stem cells in the bone marrow and differentiated into subpopulations of neutrophil-killers and neutrophil-cagers, they are short-lived and motile, or mobile, as they can enter parts of tissue where other cells/molecules cannot. Neutrophils may be banded neutrophils, they form part of the polymorphonuclear cells family together with eosinophils. The name neutrophil derives from staining characteristics on hematoxylin and eosin histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Neutrophils contain a nucleus divided into 2–5 lobes. Neutrophils are a type of phagocyte and are found in the bloodstream. During the beginning phase of inflammation as a result of bacterial infection, environmental exposure, some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.
They migrate through the blood vessels through interstitial tissue, following chemical signals such as Interleukin-8, C5a, fMLP, Leukotriene B4 and H2O2 in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance. Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation; when adhered to a surface, neutrophil granulocytes have an average diameter of 12–15 micrometers in peripheral blood smears. In suspension, human neutrophils have an average diameter of 8.85 µm. With the eosinophil and the basophil, they form the class of polymorphonuclear cells, named for the nucleus' multilobulated shape; the nucleus has the separate lobes connected by chromatin. The nucleolus disappears as the neutrophil matures, something that happens in only a few other types of nucleated cells. In the cytoplasm, the Golgi apparatus is small and ribosomes are sparse, the rough endoplasmic reticulum is absent.
The cytoplasm contains about 200 granules, of which a third are azurophilic. Neutrophils will show increasing segmentation. A normal neutrophil should have 3–5 segments. Hypersegmentation occurs in some disorders, most notably vitamin B12 deficiency; this is noted in a manual review of the blood smear and is positive when most or all of the neutrophils have 5 or more segments. Neutrophils are the most abundant white blood cells in humans; the stated normal range for human blood counts varies between laboratories, but a neutrophil count of 2.5–7.5 x 109/L is a standard normal range. People of African and Middle Eastern descent may have lower counts. A report may divide neutrophils into segmented bands; when circulating in the bloodstream and inactivated, neutrophils are spherical. Once activated, they change shape and become more amorphous or amoeba-like and can extend pseudopods as they hunt for antigens. Neutrophils have a preference to engulf refined carbohydrates over bacteria. In 1973 Sanchez et al. found that the neutrophil phagocytic capacity to engulf bacteria is affected when simple sugars are digested, that fasting strengthens the neutrophils' phagocytic capacity to engulf bacteria.
However, the digestion of normal starches has no effect. It was concluded that the function, not the number, of phagocytes in engulfing bacteria was altered by the ingestion of sugars. In 2007 researchers at the Whitehead Institute of Biomedical Research found that given a selection of sugars, neutrophils engulf some types of sugar preferentially; the average lifespan of inactivated human neutrophils in the circulation has been reported by different approaches to be between 5 and 90 hours. Upon activation, they marginate and undergo selectin-dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days. Neutrophils are much more numerous than the longer-lived monocyte/macrophage phagocytes. A pathogen is to first encounter a neutrophil; some experts hypothesize. The short lifetime of neutrophils minimizes propagation of those pathogens that parasitize phagocytes because the more time such parasites spend outside a host cell, the more they will be destroyed by some component of the body's defenses.
Because neutrophil antimicrobial products can damage host tissues, their short life limits damage to the host during inflammation. Neutrophils will be removed after phagocytosis of pathogens by macrophages. PECAM-1 and phosphatidylserine on the cell surface are involved in this process. Neutrophils undergo a process called chemotaxis via amoeboid movement, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gr
Tacrolimus known as fujimycin or FK506, is an immunosuppressive drug used after allogeneic organ transplant to lower the risk of organ rejection. It achieves this by inhibiting the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, which are vital to the body's learned immune response. Tacrolimus is used in the treatment of other T cell-mediated diseases such as eczema, severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, Kimura's disease, the skin condition vitiligo. Chemically it is a 23-membered macrolide lactone, first discovered in 1987 from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis. Tacrolimus is used to treat dry eye syndrome in cats and dogs, it is much more potent. Immunosuppression with tacrolimus was associated with a lower rate of acute rejection compared with ciclosporin-based immunosuppression in one study. Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.
Long-term outcome has not been improved to the same extent. Tacrolimus is prescribed as part of a post-transplant cocktail including steroids, IL-2 receptor inhibitors such as basiliximab. Dosages are titrated to target blood levels. In recent years, tacrolimus has been used to suppress the inflammation associated with ulcerative colitis, a form of inflammatory bowel disease. Although exclusively used in trial cases only, tacrolimus has shown to be effective in the suppression of outbreaks of UC; as an ointment, tacrolimus is used in particular atopic dermatitis. It suppresses inflammation in a similar way to steroids, is as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin thinning, or other steroid related side effects, it is applied on the active lesions until they heal off, but may be used continuously in low doses, applied to the thinner skin over the face and eyelids. Clinical trials of up to one year have been conducted.
It has been used to treat segmental vitiligo in children in areas on the face. Lupus Nephritis Tacrolimus has been shown to reduce the risk of serious infection in lupus nephritis, when compared to other agents. Contraindications and precautions include: Breast-feeding Hepatic disease Immunosuppression Infants Infection Neoplastic disease, such as: Skin cancer Lung cancer Oliguria Pregnancy QT interval prolongation Sunlight exposure Grapefruit juice Occlusive dressing Known or suspected malignant lesions Netherton's syndrome or similar skin diseases Certain skin infections Side effects can be severe and include infection, cardiac damage, blurred vision and kidney problems, hypomagnesemia, diabetes mellitus, lung damage, various neuropsychiatric problems such as loss of appetite, posterior reversible encephalopathy syndrome, weakness, vivid nightmares, neuropathy, seizures and catatonia. In addition, it may increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.
In people receiving immunosuppressants to reduce transplant graft rejection, an increased risk of malignancy is a recognised complication. The most common cancers are non-Hodgkin's skin cancers; the risk appears to be related to the duration of treatment. The most common adverse events associated with the use of topical tacrolimus ointments if used over a wide area, include a burning or itching sensation on the initial applications, with increased sensitivity to sunlight and heat on the affected areas. Less common are flu-like symptoms, headache and burning eyes. Tacrolimus and a related drug for eczema 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 dermatologists is not to consider this a significant real concern and they are recommending the use of these new drugs.
Like cyclosporin, it has a wide range of interactions. Tacrolimus is metabolised by the cytochrome P450 system of liver enzymes, there are many substances that interact with this system and induce or inhibit the system's metabolic activity. Interactions include that with grapefruit; as infections are a major cause of morbidity and mortality in the post-transplant patient, the most reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals of the azole class, increase tacrolimus levels by competing for cytochrome enzymes. Tacrolimus is a macrolide calcineurin inhibitor. In T-cells, activation of the T-cell receptor increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin dephosphorylates the transcription factor nuclear factor of activated T-cells, which moves to the nucleus of the T-cell and i