Table 50.1: Novel anti-proliferative immunosuppressants cardiac) transplantation and is a more effective alternative than azathioprine. Mycophenolate mofetil may also be effective in the treatment of other autoimmune disorders, such as rheumatoid arthritis and psoriasis. Mechanism of action In vivo the active entity, mycophenolic acid, inhibits inosine monophosphate dehydrogenase (a pivotal enzyme in purine synthesis). It suppresses proliferation both of T and B lymphocytes. In addition, mycophenolic acid inhibits the production of pro-inflammatory cytokines. Adverse effects These include the following: • gastro-intestinal disturbances – diarrhoea and haemorrhage; • bone marrow suppression, especially leukopenia and anaemia; • CMV infection; • lymphomas. Pharmacokinetics Mycophenolate mofetil is a prodrug ester of mycophenolic acid, with improved absorption. After oral administration in humans, the ester is rapidly and completely cleaved to mycophenolic acid. Mycophenolic acid undergoes hepatic elimination to its inactive glucuronide metabolite. Drug interactions Antacids decrease mycophenolate absorption. For novel anti-proliferative agents, such as sirolimus and everolimus – see Table 50.1. BIOLOGIC IMMUNOSUPPRESSANTS POLYCLONAL ANTIBODIES ANTILYMPHOCYTE GLOBULIN Antilymphocyte globulin (ALG, also known as antithymocyte globulin) is prepared by injecting human T lymphocytes into animals (e.g. rabbits or horses) to raise antibodies. The active immunoglobulin is largely in the IgG fraction and ALG is a polyclonal antilymphocyte antibody with inherent variability from batch to batch. The major effect is probably to prevent antigen from accessing the antigen-recognition site on the T-helper cells. It is given intravenously for acute organ transplant rejection. Adverse effects include anaphylaxis and serum sickness. MONOCLONAL ANTIBODIES ANTI-CD3 ANTIBODY (MUROMONAB-CD3) Uses These monoclonal antibodies are used as adjuvant (often as second-line) immunosuppressive therapy in patients with acute transplant rejection. They are IgG2a antibodies produced from murine hybridoma cells and are given intravenously. After a 10- to 14-day course, some patients develop neutralizing antibodies. Mechanism of action Anti-CD3 antibodies bind CD3 protein, blocking antigen binding to the T-cell antigen–recognition complex, and decreasing the number of circulating CD3-positive lymphocytes. In addition, binding of anti-CD3 to its receptor causes cytokine release (see Adverse effects below). The overall effect is to reduce T-cell activation in acute solid-organ graft rejection. Adverse effects These include the following: IMMUNOSUPPRESSIVE AGENTS 403 Drug Comments on use Side effects Pharmacokinetics Sirolimus (rapamycin) Used with ciclosporin to Mild gastro-intestinal Well absorbed. Elimination t1/2 is prevent graft rejection disturbances. Thrombocytopenia 57 h. Hepatic metabolism by CYP3A. leukopenia, anaemia, increased cholesterol and triglycerides. Not nephrotoxic Linear kinetics Molecular target/mechanism: Drug interactions similar to Therapeutic drug monitoring advised binds and inhibits mTOR, a ciclosporin. Sirolimus AUC protein kinase involved in increased if given with cell cycle progression ciclosporin Everolimus Analogue of sirolimus Shorter t 1/2 than sirolimus mTOR, mammalian target of rapamycin. • cytokine release syndrome, with chest pain, wheezing and dyspnoea (pulmonary oedema occurs after the first dose in 1% of patients); • hypersensitivity reactions ranging from anaphylaxis to an acute influenza-like syndrome; • CNS effects – seizures, reversible meningo-encephalitis and cerebral oedema.
404 CLINICAL IMMUNOPHARMACOLOGY Other humanized monoclonal antibodies used as immunosuppressants include: • Daclizumab and basilixumab (organ transplant rejection) which are anti-IL-2 receptor antibodies, inhibiting IL-2mediated T-cell activation. They have similar toxicities as the anti-CD-3 monoclonal antibody, but do not cause cytokine release syndrome on first dose. • Infliximab and etanercept (which bind to TNF-alpha) are used in the treatment of refractory rheumatoid arthritis and inflammatory bowel disease (Chapter 34). • Natalizumab (an anti-alpha-4 beta-3 integrin monoclonal antibody) used in patients with progressive multiple sclerosis. Other drugs that attenuate the immune response include penicillamine, gold and chloroquine. These drugs are used in an attempt to modify disease progression in patients with severe rheumatoid arthritis (Chapter 26). CHEMICAL MEDIATORS OF THE IMMUNE RESPONSE AND DRUGS THAT BLOCK THEIR ACTIONS Several important therapeutic drugs block the release or action of mediators of immune reactions. HISTAMINE Histamine is widely distributed in the body and is derived from the decarboxylation of histidine. It is concentrated in mast-cell and basophil granules. The highest concentrations are found in the lung, nasal mucous membrane, skin, stomach and duodenum (i.e. at interfaces between the body and the outside environment). Histamine is liberated by several basic drugs (usually when these are given in large quantities intravenously), including tubocurarine, morphine, codeine, vancomycin and suramin. Histamine controls some local vascular responses, is a neurotransmitter in the brain, releases gastric acid (Chapter 34) and contributes to allergic responses. There are two main types of histamine receptors, H 1 and H 2. H1-RECEPTORS In humans, stimulation of H1-receptors causes dilatation of small arteries and capillaries, together with increased permeability, which leads to formation of oedema. Histamine induces vascular endothelium to release nitric oxide, which causes vasodilatation and lowers systemic blood pressure. Inhaled histamine induces bronchospasm. In fetal vessels (e.g. the umbilical artery), histamine causes vasoconstriction. Histamine contributes to the triple response to mechanical stimulation of the skin which consists of localized pallor, which gives way to a wheal (localized oedema caused by increased vessel permeability and attributable to histamine) surrounded by a more distant and slowly developing flare (due to arteriolar dilatation via an axon-reflex mechanism and involving tachykinins such as substance P, rather than histamine). Local injection of histamine causes itching and sometimes pain due to stimulation of peripheral nerves. Inhaled histamine is used as a challenge to determine bronchial hyperreactivity and assist in the diagnosis of asthma. H2- AND H3-RECEPTORS H2-receptors are principally concerned with the stimulation of gastric acid release (Chapter 34). Their contribution to most vascular responses is minor, but some (e.g. in the pulmonary vasculature) are H2-receptor mediated. H3-receptors are involved in neurotransmission. HYPERSENSITIVITY REACTIONS INVOLVING HISTAMINE RELEASE Anaphylactic shock (acute anaphylaxis) In certain circumstances, injection of an antigen is followed by the production of reaginic IgE antibodies. These coat mast cells and basophils, and further exposure to the antigen results in rapid degranulation with release of histamine and other mediators, including tachykinins, prostaglandin D2 and leukotrienes. Clinically, the patient presents a picture of shock and collapse with hypotension, bronchospasm and oropharyngeal-laryngeal oedema, often accompanied by urticaria and flushing. A similar so-called ‘anaphylactoid reaction’ may occur after the non-IgE-mediated release of mediators by x-ray contrast media. Key points Anaphylaxis and anaphylactoid reactions • Anaphylaxis: – is IgE-mediated hypersensitivity (type-1) that occurs in a previously sensitized individual; – its pathophysiology is major cardiovascular and respiratory dysfunction due to vasoactive mediator release from mast cells; – common causes are penicillins, cephalosporins and many other drugs, insect stings and food allergies (e.g. strawberries, fish, peanuts). • Anaphylactoid reactions: – are due to drug dose-related pharmacologically induced mediator release from mast cells and basophils; – common causes include aspirin, NSAIDs and radiographic contrast media. Atopy Some individuals with a hereditary atopic diathesis have a propensity to develop local allergic reactions if exposed to appropriate antigens, causing hay fever, allergic asthma or urticaria. This is due to antigen combining with mast-cell-associated IgE in the mucosa of the respiratory tract or the skin.
Soliman s Auricular Therapy Textbook: New Localizations and Evidence Based Therapeutic Approaches was created ( M.D. Nader Soliman )
with customer reviews [BEST]
Soliman s Auricular Therapy Textbook This textbook is considered the finest ever written in the field of auricular therapy. The auricular acupuncture microsystem is one of the most widely used special acupuncture techniques. This textbook is dedicated to teaching the sound foundations of this unique approach as introduced by its founder Dr. Paul Nogier of France. The scientific bases of the acupuncture microsystem with its three dime... Full description
To Download Please Click http://yp.filetrends.club/?book=1434328597