Foods to help if you have Eczema
Dermatitis herpetiformis (DH) represents a bullous or pruritic autoimmune disorder with subepidermal blister formation which is considered to be a specific cutaneous manifestation of celiac disease, although most DH patients do not present gastrointestinal symptoms. The autoantigen of dermatitis herpetiformis, epidermal transglutaminase, is targeted by autoantibodies of the IgA class. Immunofluorescent staining of unin-volved perilesional skin biopsies reveals granular IgA deposition in the papillary dermis (Fig. 8.2K-M). DH patients show an intense pruritus with eruption of ery-thematous papules and herpetiform vesicles distributed symmetrically on the extensor surfaces. In addition to a gluten-free diet, the sulphonamide diamino-diphe-nyl sulfone (dapsone) is most commonly used in the treatment ofDH.
Many medical conditions associated with chronic stimulation of the immune system, such as repeated infections, allergic conditions, or autoimmune disease, have been reported to increase the risk of MM. In a case-control study, past history was abstracted from medical records for leukemia, n 299 non-Hodgkin's lymphoma (NHL), n 100 and MM, n 175 patients, and matched with 787 controls. Prior histories of eczema and musculoskeletal conditions were associated with higher risk for MM with no role identified for chronic antigenic stimulation in the etiology of leukemia or NHL.32 Another case-control study of 100 MM cases in whites showed no associations between MM and history of medical conditions that cause prolonged stimulation of the immune system, like
Eczema is a dermatitis that usually begins as patchy redness. If untreated, small breaks develop in the skin patches and can progress to scaling, thickening, and cracking. It most often occurs on the hands, but can appear anywhere on the skin. Although there are many triggers of eczema, one of the most common causes is food sensitivity. Eczema can also be caused by exposure to environmental agents such as chemicals, soaps, and detergents. Metal compounds in earrings, watches, or other jewelry (particularly metal alloys containing nickel) can trigger eczema.
A careful elimination diet (see pp.205) can identify food sensitivities that trigger eczema.17 The most common offending foods are milk, eggs, fish, cheese, nuts, and food additives. Cold-pressed nut and seed oils are high in beneficial EFAs important for skin health and should be consumed regularly. Disturbances in fatty acid metabolism in the skin can produce or aggravate eczema impaired production of omega-3 fatty acids and GLA can increase inflammation in the skin (see pp.89).18
P. cm. - (Current problems in dermatology v. 33) Includes bibliographical references and index. ISBN 3-8055-8121-1 (hard cover alk. paper) 1. Contact dermatitis. 2. Textile fabrics-Physiological aspects. 3. Biomedical materials. I. Hipler, U.-C. (Uta-Christina) II. Elsner, Peter, 1955- III. Series.
The skin exerts a number of essential protective functions ensuring homeostasis of the whole body. In the present review barrier function of the skin, thermoregulation, antimicrobial defence and the skin-associated immune system are discussed. Barrier function is provided by the dynamic stratum corneum structure composed of lipids and corneocytes. The stratum corneum is a conditio sine qua non for terrestrial life. Impairment of barrier function can be due to injury and inflammatory skin diseases. Textiles, in particular clothing, interact with skin functions in a dynamic pattern. Mechanical properties like roughness of fabric surface are responsible for non-specific skin reactions like wool intolerance or keratosis follicu-laris. Thermoregulation, which is mediated by local blood flow and evaporation of sweat, is an important subject for textile-skin interactions. There are age-, gender- and activity-related differences in thermoregulation of skin that should be considered for the...
This can present as one of two forms or a mixture of both. The more dramatic is acute allergic blepharitis in which the eyelids swell up rapidly, often in response to contact with a plant or eyedrops. The cause must be found and eliminated and treatment with local steroids might be needed. Chronic allergic blepharitis is seen in atopic individuals, for example hay fever sufferers or patients with a history of eczema. The diagnosis might require a histological examination of the conjunctival discharge. Drop treatment to alleviate symptoms includes mast cell stabilisers (such as lodoxamide) and histamine antagonists (such as emedastine), and these agents could take weeks to take effect. Patients with seasonal allergic conjunctivitis might require medication for a prolonged period over the spring and summer months each year.
Seborrheic dermatoses and other forms of scaly skin rash may respond to biotin, particularly when taken as part of a complete vitamin B complex in conjunction with essential fatty acids (omega-6 and omega-3 fatty acids). 1 These dermato-logic disorders may be due to impairments of essential fatty acid metabolism in the skin, produced by abnormal biotin metabolism or deficiency.
Linear IgA bullous disease is an acquired autoimmune blistering disease that may be idiopathic or drug induced. In children the disease is referred to as chronic bullous disease of childhood. Cutaneous lesions of linear IgA bullous disease (LABD) are usually nonscarring blisters, often extensive on trunk and extremities. They are characterized by the cluster of jewels sign, with vesicles and bullae at edges of polycylic lesions (Fig. 7A). Linear IgA bullous disease resembles dermatitis herpetiformis or bullous pem-phigoid, but is usually not symmetric. Patients with LABD may occasionally have ocular involvement that can be indistinguishable from mucous membrane pemphigoid. Chronic bullous disease of childhood has a predilection for vesicles and blisters in the diaper area. Bullous lupus erythematosus bullous pemphigoid dermatitis herpetiformis
Contact dermatitis and periocular edema can also result. Other more severe effects, such as pulmonary edema, have been documented when concentrations are several hundred-fold above what produces intolerable symptoms or with trauma associated with the explosive device used to deliver the chemical agent (6,15).
Symptoms Confusion and or memory loss and more than three (3) of the following symptoms headache, skin rash, conjunctivitis, upper respiratory tract (URT) irritation and sensitivity, muscle cramps, and any type of gastrointestinal symptoms (abdominal cramps, nausea, vomiting, usually no diarrhea). Diagnosis By history of aerosol exposure only. Treatment Supportive only. Prognosis Symptoms resolve in 1-2 weeks. Prevention Avoid swimming, skiing, fishing, and all other recreational exposures in all waters with extensive fish kills citizens should immediately report large fish kills to state environmental and public health agencies and to the CDC.
The formation of tight complexes of the peptidomacrolides FK506 (also known as tacrolimus) and rapamycin (also known as sirolimus) with endogenous FKBP12 inhibits T cell proliferation via different pathways. Similar to CsA in the Cyp18 CsA complex, FK506 when bound to FKBP12 experiences gain of function that leads to calcineurin inhibition. The FKBP12 FK506 complex inhibits calcineurin more powerful when compared to Cyp18 CsA. Dissociation constants for ternary calcineurin FKBP FK506 complexes containing different FKBP range from 88 nmol L-1 to 27 imol L-1 87 . Recently it was found that FKBP12 is the only FKBP family member to play a key role in FK506-mediated immunosuppression 88 . A topically active FK506 derivative (pimecrolimus) with reduced system exposure and thus increased immunological safety has been launched for therapeutic application in atopic dermatitis, psoriasis, and allergic contact dermatitis 89 .
Naturopathic medicine encompasses Western medical diagnosis, combined with treatment and disease prevention using natural therapies. A primary goal of naturopathic medicine is to address the cause of epilepsy, rather than treat symptoms. Naturopathic doctors consider many possible causes or etiologies in dealing with epilepsy. often these etiologies are multifactorial and can be traced back to microbiology (e.g., parasitic infection), endocrinology (e.g., hormone imbalance), or immunology (e.g., eczema). Other causes can be due to imbalances of a nutritional or energetic nature (e.g., yin and yang or vital force).
Atopic dermatitis is a chronic inflammatory disease of the skin characterized by itchy rashes, in which IgE specific for environmental antigens and cells expressing high-affinity Fc receptors for IgE (FceRI) play a central role. Antigen-mediated cross-linking of FceRI on mast cells is important in many allergic diseases, as we will discuss in detail in Chapter 19, and mast cells are implicated in the pathogenesis of atopic dermatitis. In addition, FceRI is expressed on skin DCs, including Langerhans cells and plasmacytoid DCs, and DC activation also plays a central role in atopic dermatitis, as in psoriasis. However, in atopic dermatitis, the response of DCs to TLR signaling is believed to be influenced by FceRI signaling and by the cytokine thymic stromal lymphopoietin (TSLP), made by keratinocytes, leading to an initial TH2 response. Underlying the inflammatory cascade of atopic dermatitis may be genetically determined sensitivity to environmental antigens, perhaps because of...
Ample intake of the EFAs (see pp.89) is vital during infancy. Because infants absorb fat poorly and have low fat stores, they are particularly sensitive to EFA deficiency and quickly develop signs of deficiency if fat intake is low. Infants fed formulas deficient in li-noleic acid for just a few days may develop a dry, eczema-like, flaky skin rash, diarrhea, hair loss, and impaired wound healing. Deficiency also impairs platelet function and lowers resistance to infection. Regular intake of EFAs is therefore critical during infancy, and although breast milk is rich in EFAs, not all infant formulas have adequate amounts.
Particularly important is gamma-linoleic acid (GLA), a fatty acid that can be synthesized in small amounts from dietary linoleic acid. GLA is also found in high amounts in a few plant oils, including borage oil and evening primrose oil. Without adequate GLA and its products, skin will dry out, wrinkle, and age prematurely. Because the skin cannot easily synthesize adequate GLA during times of increased need - exposure to cold, dry air, allergens, aging, eczema, stress - supplementation with evening primrose oil rich in GLA can be beneficial.3 To protect and maintain the natural skin oils, ample vitamin E and beta-carotene are essential. (For a more detailed discussion of these important polyunsaturated fats, including GLA, see pp.89).
Among the 52 patients treated on the combined pilot and US multicenter trials, nausea was observed in 75 , cough in 65 , fatigue in 63 , headache in 60 , emesis in 58 , tachycardia in 55 , diarrhea in 53 , hypokalemia in 50 , and skin rash in 43 (34). The APL differentiation syndrome is reminiscent of the retinoic acid syndrome manifested as fever, rash, peripheral edema, pulmonary infiltrates, and pleural and pericardial effusions (64). In general, similar to the therapy for the retinoic acid syndrome, early administration of dexamethasone is effective when ATO is continued. In addition, hyperleukocy-tosis developed in 55 of patients in some reports, ranging from 11,900 L to 167,000 L (65,66).
Phase I trials have evaluated both intermittent administration (14 d of treatment followed by 14 d of observation) and continuous delivery (once daily for 28 d) of ZD1839. Oral dosing ranged from 50 to 1000 mg d. Patients were eligible if they had tumors known to express EGFR (HER-1) such as NSCLC, breast, colon, ovarian, prostate, and head and neck cancers. Both schedules of administration were well tolerated with minor toxicities such as grade 1-2 skin rash, nausea, vomiting, and diarrhea. Dose-limiting toxicity was grade 3 diarrhea, which occurred at doses 700 mg d. Although not a primary endpoint for these studies, objective responses as well as disease stabilization, especially in patients with NSCLC, were seen at several dose levels and were frequently associated with improvement of disease-related symptoms (42,43).
Trimethoprim-sulfamethoxazole (TMP-SMX) has been investigated as a prophylactic agent in a small, randomized, multicenter trial of newly diagnosed patients undergoing chemotherapy for MM.35 This antibiotic was chosen based on low expense, tolerabil-ity, and previous experience in other patients with other causes of immunocompromise.35 Fifty-seven patients with MM were randomized to receive prophylaxis consisting of two TMP-SMX 80 400 mg tablets every 12 hours for 2 months, or to a control group that received no prophylaxis. Chemotherapy was administered to all patients 50 received melphalan plus prednisone, while all others received more intensive combination chemotherapy. The two groups were well balanced with respect to age, gender, and stage of disease. Data collection continued for 3 months after the start of chemotherapy for patients in both groups. Fifty-four patients of the 57 entered were evaluable. Overall, 12 (46 ) of the patients assigned to the control group and five (18 )...
Brane but exposed to the interstitial matrix of the wound bed37(see chapter 8). In addition, in lesions of dermatitis herpetiformis a blistering skin disease characterized by inflammatory destructive changes in the basement membrane basal keratinocytes exhibited a prominent signal for collagenase-141 irrespective of their state of migration. Based on such data, it was hypothesized that contact with the main component of the dermal matrix, type I collagen, provides a mechanism for induction of collagenase-1 in wound edge epithelium. It was further proposed that collagenase is not only invariably present but also critical for keratinocyte migration and re-epithelialization to occur. The research group led by H.G. Welgus and W.C. Parks have in this model linked the induction of collagenase in keratinocytes plated on collagen to a mechanism which would provide the keratinocytes with a sense of direction during re-epithelialization. To function in this apparently complicated process,...
Skin sensitization, sometimes referred to as allergic contact dermatitis (ACD), is considered to be one of the largest causes of occupational injury in the USA.84 It often develops as a result of repeated exposure to a sensitizing chemical agent, and can cause severe and sometimes fatal reactions on subsequent exposure to the chemical. It is thought that skin sensitization occurs when a chemical first reacts with skin proteins either directly or after metabolic activation. In order for this reaction to occur, the chemical must first penetrate the skin at least as far as the viable epidermis. The resulting conjugate is then recognized as a foreign body, and elicits an immune reaction, producing an inflammatory response in the skin.85 Due to the long-lasting memory of the immune system, once an individual is sensitized, he or she can remain sensitive to further exposure of a chemical for a long period of time.
The study was designed to investigate the possible influence of this prebiotic mixture on the cumulative incidence of atopic dermatitis during the first 6 months of life in formula-fed infants at risk to develop allergy (paternal history of allergy). The study was performed as a prospective, double-blind, randomized, placebo (GOS lcFOS was replaced by maltodextrin in the placebo formula) controlled study. Two hundred fifty nine infants with a family history of atopy were enrolled in the study. Fifty three infants left the trial before completing the study. The main reason for dropping out was the continuation or reestablishment of breastfeeding. One hundred two infants in the prebiotic group and 104 infants in the placebo group completed the study. The infants were seen on a monthly basis. The interview of the parents was based on a diary kept by the parents. The primary outcome of the study was the cumulative incidence of atopic dermatitis during the first 6 months of life. The skin...
The propensity to develop allergies is influenced by the inheritance of several genes. Abnormally high levels of IgE synthesis and associated atopy often run in families. Family studies have shown clear autosomal transmission of atopy, although the full inheritance pattern is multi-genic. Within the same family, the target organ of atopic disease is variable. Thus, hay fever, asthma, and eczema can be present to various degrees in different members of the same kindred. All these individuals, however, will show higher than average plasma IgE levels.
Allergic reactions in the skin are manifested as urticaria and eczema. Urticaria, which is essentially an acute wheal and flare reaction induced by mast cell mediators, occurs in response to direct contact with the allergen or after an allergen enters the circulation through the intestinal tract or by injection. Because the reaction that ensues is mediated largely by histamine, antihistamines (H1 receptor antagonists) can block this response almost completely. The urticaria may persist for several hours, probably because antigen persists in the plasma. Chronic eczema (also called atopic dermatitis) is a common skin disorder that may be caused by a late-phase reaction to an allergen in the skin. In the cutaneous late-phase reaction, TNF, IL-4, and other cytokines, probably derived from TH2 cells and mast cells, act on the venular endothelial cells to promote inflammation. As may be expected for a cytokine-mediated response, the late-phase inflammatory reaction is not inhibited by...
Pemphigus and pemphigoid are considered to be pro-totypic bullous disorders based on their well-characterized immune pathogenesis. Apart from pemphigus and BP, there is only circumstantial evidence that auto-reactive T cells are present and involved in the patho-genesis of the autoimmune bullous disorders epider-molysis bullosa acquisita and dermatitis herpetiformis. In PV and BP, autoreactive CD4+ T lymphocytes that are presumably crucial in initiating the autoimmune response recognize distinct epitopes of the extracellular portions of Dsg3 and BP180, components of desmo-somal and hemidesmosomal adhesion complexes of human skin, respectively. Dsg3- and BP180-reactive T cells produce T-helper 2 (Th2) cytokines, such as IL-4,
Angioimmunoblastic T-cell lymphoma is a relatively rare disorder with distinctive clinical behavior and generally poor outcome. This entity is part of a spectrum of clinical conditions ranging from angioim-munoblastic lymphadenopathy with dysproteineimia (AILD) to malignant lymphoma. Patients with AILD are at risk of developing malignant lymphomas that may be of either T-cell or B-cell lineage, while clonal populations of T cells may also be seen in AILD cases without overt histologic evidence of malignant lymphoma. Furthermore, investigators have reported cases of de novo lymphomas that have histologic features similar to those of lymphomas arising from an AILD background. Patients with angioimmunoblastic T-cell lymphoma often exhibit systemic disease with generalized lymphadenopathy, fever, weight loss, malaise, and skin rash. They tend to be older males with nodal and extranodal disease and numerous adverse risk factors. Laboratory studies reveal anemia (often positive for direct...
Unfortunately, patients with asthma and eczema can experience recurrent itching and irritation of the conjunctiva. Although atopic conjunctivitis tends to improve over a period of many years, it might result in repeated discomfort and anxiety for the patient, especially as the cornea can become involved, showing a superficial punctate keratitis or, in the worst cases, ulcer formation and scarring.
Skin DCs take up foreign proteins, transport them to draining lymph nodes, and present processed peptides from these proteins to T cells or pass the protein antigens to other lymph node-resident DCs. When Langerhans cells encounter microbes, they are activated by engagement of Toll-like receptors (see Chapter 6). The cells lose their adhesiveness for the epidermis, enter lymphatic vessels, begin to express the CCR7 chemokine receptor, and migrate to the T cell zones of draining lymph nodes in response to chemokines produced in that location. The Langerhans cells also mature into efficient antigen-presenting cells. What remains unclear is the relative contribution of the different skin DC subsets to the initiation of T cell responses. Mouse models have been developed in which langerin-expressing DCs can be selectively eliminated, and under the proper conditions, the mice lack Langerhans cells but have dermal DCs. Using these models, investigators have shown that some T cell responses...
Mast cell degranulation is a central component of all allergic diseases, and the clinical and pathologic manifestations of the diseases depend on the tissues in which the mast cell mediators have effects as well as the chronicity of the resulting inflammatory process. Atopic individuals may have one or more manifestations of allergic disease. The most common forms of these diseases are allergic rhinitis (hay fever), bronchial asthma, atopic dermatitis (eczema), and food allergies. The clinical and pathologic features of allergic reactions vary with the anatomic site of the reaction, for several reasons. The point of contact with the allergen determines the organs or tissues that are involved. For example, inhaled antigens cause rhinitis or asthma, ingested antigens often cause vomiting and diarrhea, and injected antigens cause systemic effects on the circulation. The concentration of mast cells in various target organs influences the severity of responses. Mast cells are particularly...
Respiratory sensitization is often characterized by episodes of wheezing, coughing, and chest tightness.102 The condition can be severe and sometimes fatal.103 The mechanisms by which chemicals can induce this adverse response are uncertain, but are assumed to be immune mediated with some pharmacological and neurological involvement. Currently there are no accepted, well-validated in vitro or in vivo models for the detection of respiratory sensitizers.85 However, preliminary work by Dearman and co-workers has shown, for a limited number of respiratory sensitizers at least, that these chemicals all elicit a response in the LLNAused for the detection of allergic contact dermatitis.104'105 Therefore, the suggestion can be made that chemicals that do not cause ACD will be unlikely to cause respiratory sensitization. However, there are significant differences between the mechanisms of these adverse effects that mean that not all contact allergens will necessarily be respiratory allergens.85
Adverse effects The major adverse effect associated with ibritumomab tiuxetan is myelosuppression, consisting mainly of neutropenia and thrombocytopenia.45 46 Because of this, several parameters must be met before patients can be treated with this agent. Qualifications for therapy include 100,000 cells mm3, and no history of hypocellular marrow or failed stem cell collection.28 The average time to neutrophil nadir is 62 days, while platelets typically nadir around day 53. Cells recover after approximately 22-35 days.43 Additional adverse effects include those seen with other anti-CD20 agents, such as fever, hypotension, chills, skin rash, and rarely nausea and vomiting.45 individuals because of fluctuating clearance rates of the compound.1 The major dose-limiting toxicity of 131I tositumomab is myelosuppression, similar to that seen with 90Y ibritumomab. Therefore, patients must have 100,000 cells mm3, and no history of hypocellular marrow or failed stem-cell collection in order to...
Variable degrees of T and B cell immunodeficiency occur in certain congenital diseases with a wide spectrum of abnormalities involving multiple organ systems. One such disorder is Wiskott-Aldrich syndrome, an X-linked disease characterized by eczema, thrombocytopenia (reduced blood platelets), and susceptibility to bacterial infection. Some of the abnormalities in this disorder can be traced to defective T cell activation, although intrinsic loss of B cell function also contributes to the pathogen-esis. In the initial stages of the disease, lymphocyte numbers are normal, and the principal defect is an inability to produce antibodies in response to T cell-independent polysaccharide antigens, because of which these patients are especially susceptible to infections with encapsulated bacteria. The lymphocytes (and platelets) are smaller than normal. With increasing age, the patients show reduced numbers of lymphocytes and more severe immunodeficiency. The defective gene responsible for...
Bullous pemphigoid is an acquired blistering disease of the elderly, usually over the age of 60. Multiple medications have been reported to induce bullous pemphigoid, however, only furosemide has been convincingly implicated. Tense bullae form on flexor arms and legs, abdomen, and groin that heal without scarring. In urticarial BP, there are erythe-matous edematous plaques without overt blisters that resemble urticaria and sometimes eczema (Fig. 3A).
Swelling, redness, and tenderness, although frequently caused by trauma, are not specific signs of injury. Although it is important to record whether these features are present, it must be remembered that there also may be nontraumatic causes for these lesions (e.g., eczema dermatitis or impetigo).
Topical nitrogen mustard has been used for management of MF since 19 5 9.24 Many investigators have demonstrated the efficacy of topical nitrogen mustard in patch and or plaque disease of MF.25 A recent update of 203 patients with MF (clinical stage I-III) treated with topical nitrogen mustard demonstrated CR rates of 76-80 for patients with stage IA and 35-68 for those with stage IB disease.26 Fewer than 10 of patients developed progression of disease. Most common side effects were irritant contact dermatitis. No secondary malignancies related to therapy were reported. Topical Carmustine (BCNU) showed similar results, with an 86 CR rate however, patients may develop progressing teleangiec-tasias from treatment.27 Mild leukopenia occurred in 3.7 of the patients.
Figure 15.19 Toxicodendron radicans (Poison Ivy) Leaves. The Toxicodendron group of vines and shrubs can induce severe chemical contact dermatitis on exposure to their oily resin, toxicodendrol, which contains the suspended active toxin, urushiol. The Toxico-dendron group of plants includes poison ivy as shown (Toxicodendron radicans), poison oak (Toxicodendron toxicarium), and poison sumac (Toxicodendron ver-nix). Note poison ivy's cluster of three leaves on red stems. (Courtesy of Charles P. Sea, M.D., Department of Emergency Medicine, Ochsner Clinic Foundation Hospital, New Orleans, LA. Original Source U.S. Government Document, U.S. Department of Health and Human Services, 1981, Common Poisonous and Injurious Plants. ) Figure 15.19 Toxicodendron radicans (Poison Ivy) Leaves. The Toxicodendron group of vines and shrubs can induce severe chemical contact dermatitis on exposure to their oily resin, toxicodendrol, which contains the suspended active toxin, urushiol. The Toxico-dendron...
A chimeric mouse-human monoclonal antibody, cetuximab (C-225, Erbitux), which prevents activation of EGFR by inhibiting ligand binding to the extracellular ligand-binding domain of the receptor,207 has been approved for the treatment of metastatic colorectal cancer. Side effects related to the mechanism of action include an acneiform skin rash, which appears to be typical of EGFR signaling inhibition. The first small-molecule EGFR tyrosine kinase inhibitors to reach the clinic and obtain regulatory approval have been gefitinib (27)208-212 and erlotinib (28).213-215 Both compounds act by binding reversibly at the ATP-binding site of the activated kinase domain of the protein. Gefitinib has an IC50 for inhibition of the EGFR kinase of 23 nM (ATP concentration 20 mM), and shows good selectivity over the erbB2 kinase. Inhibition of EGFR-driven cellular growth of KB cells is seen at 0.08 mM. The compound has good pharmacokinetic properties, and is active in vivo against a range of human...
Because of the hypersensitive disposition of patients with malignancies, probiotic therapy requires a lot of tact and experience with these patients. It is therefore not recommended that one gets into probiotic therapy by treating such severe diseases. Rather, one should first gain experience and confidence in dealing with microbial preparations and autovaccines by starting with less complicated syndromes, such as chronic infections, mycoses, pollinosis, or atopic dermatitis. Because of the hypersensitive disposition of cancer patients, probiotic therapy should be approached with special care (Tables 17.4 and 17.5).
Erlotinib (28) is closely related to gefitinib it is a reversible ATP-competitive inhibitor of the kinase (IC50 2 nM), inhibits EGF-driven cellular growth (IC50 0.1 mM), and is orally active in disease models at 10-100mgkg_ 1 daily doses.219 Phase I trials achieved target blood levels dosing at 100 mg day_ 1 or greater.220 The MTD is 150 mg, and a familiar pattern of toxicity including diarrhea and skin rash was seen. The human half-life is about 24 h (approximately 48 h for gefitinib), and some antitumor activity was observed in these trials. Recent data from a Phase III trial, dosing erlotinib at 150mgday _ 1, shows a statistically significant increase in life expectancy compared with controls in patients with NSCLC, and the drug has been approved in the USA for this condition.221
PTK787 (56) was well tolerated in Phase I trials (in metastatic renal cell carcinoma) at 1200mgday_ 1, with 19 of patients showing measurable responses, and 64 with stable disease. The compound has been used in combination studies with standard cytotoxic regimens (colorectal cancer and glioblastoma), with toxicities reported to include hypertension, nausea, vomiting, transaminase elevation, and fatigue. PTK787 (56) is currently in Phase III trials in metastatic colorectal cancer at a dose of 1250 mg day_ 1 in combination with FOLFOX (folinic acid, 5-fluorouracil, and oxiplatin). ZD6474 (57) is well tolerated at doses up to 500mgday_ 1, with dose-limiting toxicities including diarrhea, hypertension, thrombocytopenia, and QT prolongation. Acneiform skin rash is also seen as a less serious side effect, and may be attributable to EGFR inhibition. ZD6474 (57) is currently in Phase II trials.
Compound 78 has progressed to the clinic,387 where it was given at a dose of 1600 mg once daily or 800 mg twice daily, with the latter regime resulting in better exposure. Side effects seen included fatigue, skin rash, and diarrhea, but target therapeutic plasma levels were achieved, and stable disease was seen in 30 of patients. However, Phase II trials in patients with advanced NSCLC, breast, colon, and pancreatic cancers, dosing at 800 mg twice daily, no objective responses were seen.377 This may be due to the relatively poor pharmacokinetic and physicochemical properties of the compound, leading to variable absorption and blood levels. A second-generation inhibitor, PD0325901 (79), which has a number of advantages including improved aqueous solubility, achieved by introducing a hydrophilic side chain, is already in Phase I studies.388
A variety of small-molecule approaches to the inhibition of Raf have been reported,430,432 the most advanced being BAY 43-9006 (97) (Figure 18).433,434 The compound was developed from a bis-aryl lead series, and interacts at the ATP-binding site of the kinase (B-raf IC50 22 nM). Compound 97 has additional kinase activity, notably against c-Kit, Flt3, and KDR, and also inhibits the common V599E mutant of B-raf. It shows oral activity in mice bearing a range of human tumor xenografts with mutant K-ras, and entered Phase I clinical studies in 2000.435 These studies showed it to be well tolerated, and, at a dose of 400 mg twice daily, side effects were diarrhea, skin rash, and fatigue. Some disease stabilization was seen and BAY 43-9006 (97) (Nexavar, Sorafenib) has recently been approved for the treatment of renal cell carcinoma.436 Further work in this series has been undertaken to address the poor aqueous solubility of 97.437
Toxicity Gastrointestinal dermal CNS Gastrointestinal Caustic hemorrhagic gastroenteritis, necrotic mucosal ulcerations, late esophageal stricture. Dermal Caustic burns, contact dermatitis (iodophor), ioderma acne (iodide). CNS Metabolic acidosis, delirium, vasomotor collapse. Treatment No emesis careful aspiration lavage with starch, milk, or sodium thiosulfate to reduce most toxic elemental iodine (I2) to the least toxic iodide (I-) activated charcoal (AC) and early endoscopy.
Aromatherapy usually is well tolerated, but it is not risk-free. When applied to the skin, some oils may produce a skin rash (this type of allergic reaction may be detected by applying a small amount of oil to the skin and monitoring for a response for 24 hours). Cinnamon or clove oil should not be applied directly to the skin. Basil, fennel, lemon grass, rosemary, and verbena oils may cause skin irritation the use of these oils should be discontinued if skin irritation occurs. Approximately 5 percent of people appear to be allergic to fragrances. Because of possible toxic effects, oil should not be taken internally by mouth or any other method (this is especially true for eucalyptus, hyssop, mugwort, thuja, pennyroyal, sage, and wormwood). Pregnant women probably should avoid aromatherapy because the use of some oils may lead to miscarriage. Odors may provoke headaches in people with migraines and cause breathing difficulties in those with asthma. Some oils (rosemary, fennel, hyssop,...
Curing Eczema Naturally
Do You Suffer From the Itching, Redness and Scaling of Chronic Eczema? If so you are not ALONE! It strikes men and women young and old! It is not just