Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postmenopausal hormone replacement therapy represents an area of outstanding importance in preventive medicine that greatly affects personal well-being as well as public health. The number of women living in the United States who are 50 years or older has been estimated at nearly 50 million. Many of those women are likely to be eligible for postmenopausal hormone replacement, which may consist either of estrogen replacement therapy (ERT) in women without a uterus or, more frequently, estrogen/progestin combination therapy (HRT) in women with a uterus. This chapter first presents an overview of general regulatory requirements pertaining to the design and conduct of clinical studies in support of marketing approval for a drug product. These requirements include, but are not restricted to, studies in HRT. The chapter next discusses the design and conduct of clinical trials in support of marketing approval for the indications: treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy; prevention of osteoporosis; and protection by adjunctive progestin against estrogen-induced endometrial hyperplasia/cancer in women with a uterus. Finally, data related to the potential cardioprotective action of HRT and its protection against Alzheimer's disease and colon cancer are discussed.
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PMID:Design and conduct of clinical trials in hormone replacement therapy. 1159 62

OBJECTIVES: To establish guidelines on the administration of hormone replacement therapy in Hong Kong for a primary audience of Fellows and Members of the Hong Kong College of Obstetricians and Gynaecologists and a secondary audience of all interested medical and paramedical personnel in Hong Kong. PARTICIPANTS: The Quality Assurance Committee established a consensus panel of four College Fellows who had expertise of treating menopausal women by giving hormone replacement therapy. All the panelists were qualified obstetricians and gynaecologists. EVIDENCE: The panelists drew their conclusions from the available scientific literature on hormone replacement therapy from Hong Kong and overseas. CONSENSUS PROCESS: The consensus reached within the panel was presented to the Quality Assurance Committee on 23 June 1998, and subsequently revised and presented three times. The final version was approved by the Quality Assurance Committee on 2 March 1999 and the Council of the Hong Kong College of Obstetrics and Gynaecology on 11 March 1999. CONCLUSIONS: The administration of hormone replacement therapy is effective in reducing the severity and frequency of menopausal hot flushes and sweating. Therapy protects against osteoporosis and reduces the risk of cardiovascular disease. There is some evidence to suggest that treatment also protects against Alzheimer's disease and carcinoma of the colon. The most serious problem attributed to using hormone replacement therapy is the possible increase in the risk of breast cancer development; the exact risk is unknown. Side effects include unwanted bleeding and breast tenderness and sensitivity. The risks and benefits of using hormone replacement therapy should be explained to postmenopausal women so that they can make an informed decision about using this treatment.
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PMID:Guidelines for the administration of hormone replacement therapy. The Hong Kong College of Obstetricians and Gynaecologists. 1182 92

Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the progression of several diseases, including colon cancer, lung cancer, breast cancer and Alzheimer disease (AD). Several studies have shown that NSAIDs can modulate cell cycle progression, especially in the G0/G1 phase. The main target of most NSAIDs is the enzyme cyclo-oxygenase (COX), which occurs in 2 isoforms, COX-1 and COX-2. In AD and non-demented control brain, COX-2 is expressed in neuronal cells. In this study the expression of COX-2, cyclin D1, and cyclin E was investigated at the immunohistochemical level in AD and non-demented control temporal cortex. COX-2, cyclin D1, and cyclin E expression was detected in pyramidal neurons in both AD and control patients. The number of COX-2-immunoreactive neurons positively correlated with the number of cyclin E- and cyclin D1-immunoreactive neurons. Moreover, immunostaining of sequential tissue sections and double immunofluorescence labeling revealed co-expression of COX-2 and cyclin D1 and E in neuronal cells. In addition, an inverse correlation was observed between the neuronal expression of COX-2 and cyclin E and the Braak score for amyloid beta deposits. Our findings suggest a relationship between the neuronal expression of COX-2 and cell cycle markers, which may be involved early in AD pathology.
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PMID:Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. 1215 83

Chronic uncontrolled pain may be the greatest health care crisis facing the United States. It is the major symptom for which patients seek medical care and is associated with substantial economic and psychosocial costs. For many patients, particularly the elderly and those suffering from cancer, chronic pain is often undertreated. Because pain has an emotional component and is frequently accompanied by depression and/or anxiety, patients benefit from a comprehensive assessment and multidisciplinary approach to treatment. It is likely that coxibs (cyclooxygenase or COX-2-selective inhibitors) will assume an increasingly prominent role in the treatment of chronic pain associated with arthritis, cancer, and other diseases either as monotherapy or in combination with other drugs. In addition, the role of COX-2 inhibition in the prevention and treatment of colon cancer, Alzheimer's disease (AD), and other chronic health problems is an area currently undergoing intense investigation.
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PMID:Pain management and beyond: evolving concepts and treatments involving cyclooxygenase inhibition. 1220 82

Cyclooxygenases-1 and -2 (COX-1 and COX-2, also known as prostaglandin H2 synthases-1 and -2) catalyze the committed step in prostaglandin synthesis. COX-1 and -2 are of particular interest because they are the major targets of nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2-selective inhibitors. Inhibition of the COXs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces the incidence of fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of COXs relate mechanistically to cyclooxygenase and peroxidase catalysis and how alternative fatty acid substrates bind within the COX active site. We further examine how NSAIDs interact with COXs and how differences in the structure of COX-2 result in enhanced selectivity toward COX-2 inhibitors.
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PMID:The structure of mammalian cyclooxygenases. 1257 66

Predictive genetic tests are now available for assessing susceptibility to a variety of conditions, including breast and colon cancer, hemochromatosis, and Alzheimer and Huntington disease. Much controversy surrounds the application of these tests, stemming from their similarities to and differences from other tests commonly used in asymptomatic persons. Some have argued that genetic tests are unique and therefore justify special consideration with regard to informed consent and privacy. This paper examines the arguments for such "genetic exceptionalism" and concludes that no clear, significant distinctions between genetic and nongenetic tests justify a different approach to testing by clinicians. Nevertheless, with many genetic tests, the results may cause stigmatization, family discord, and psychological distress. Regardless of whether a test is genetic, when this combination of characteristics is present and when health care providers are not specifically trained to interpret results, testing should be performed with particular caution and the highest standards of informed consent and privacy protection should be applied.
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PMID:"Genetic exceptionalism" in medicine: clarifying the differences between genetic and nongenetic tests. 1266 27

Since the synthesis of aspirin in 1897, aspirin-like or nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstay of therapy for rheumatoid arthritis. Although of diverse chemical structure, these drugs not only exhibit the same antipyretic, analgesic and antiinflammatory therapeutic actions, but they also manifest identical toxic actions on the gastric mucosa and the kidney. This indicated that a single pharmacological effect was responsible for the properties of NSAIDs, a theory that was confirmed by the epochal discovery by Vane in 1971, that inhibition of the enzyme-producing prostanoids (cyclooxygenase [COX]) produced both the therapeutic and side effects of aspirin-like drugs. However, at equivalent antiinflammatory doses, different NSAIDs exhibited different degrees of toxicity. The reason for this was resolved by the discovery that prostaglandins at sites of tissue damage were synthesized by an inducible COX (COX-2) formed by a gene distinct from that producing the constitutive enzyme (COX-1), responsible for the formation of prostaglandins that serve an essential physiological function. Modification of the structure of drugs showing a moderately selective effect on COX-2, and the elucidation of the crystal structure of both enzymes, has paved the way for the synthesis of NSAIDs that are highly selective for the inducible enzyme and which are, therefore, antiinflammatory without the typical side effects of the classical NSAIDs. The focus on COX-2 has also expanded our knowledge of the pathophysiological significance of prostanoids and raised the possibility of new uses for selective COX-2 inhibitors, for example, in colon cancer, premature labor and possibly Alzheimer's disease. However, the clinical effects of chronic administration of potent, selective COX-2 inhibitors must await the results of ongoing clinical trials.
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PMID:Nonsteroidal antiinflammatory agents. 1297 28

Folic acid-preventable spina bifida and anencephaly are pandemic, affecting 225,000 children a year. These birth defects are as preventable as polio. As we near the eradication of polio, it is time to make the commitment to global prevention of all folic acid-preventable spina bifida and anencephaly (FA-P SBA) by 2010. Folic acid fortification of centrally processed foods, such as wheat and corn flour, could immediately prevent all of these birth defects for much of the world's population. These fortification programs will also help adults by increasing serum folate concentration, eradicating folate deficiency anemia, providing human genome stability and reducing homocysteine serum concentration, which will probably prevent heart attacks and strokes, and may prevent colon cancer and Alzheimer's disease. Where there is no centrally processed and distributed food to fortify, intense efforts must be made to increase consumption of synthetic folic acid through vitamin supplements. Geneticists can play a major role in preventing FA-P SBA by helping to create the political will in each country to implement fortification and supplement programs to eliminate disease caused by the current pandemic of folate deficiency.
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PMID:Global prevention of all folic acid-preventable spina bifida and anencephaly by 2010. 1496 Sep 2

Cellular and humoral defence mechanisms are essential for the survival of individuals and species. Thus, DNA repair prevents mutations and cytotoxicity from DNA damage, thereby reducing the risks of inappropriate cell death, developmental defects, premature ageing and cancer. Similarly, antigen-dependent acquired immune responses prevent infections and also have a role in cancer prevention. DNA repair is highly complex and functions in an intricate network that also involves transcription, replication, cell cycle regulation, and the immune system. DNA damage is repaired by at least four major mechanisms, each requiring many different proteins. In addition there are "subpathways", and back-up mechanisms both within and between pathways. Various defects in DNA repair result in different forms of cancer, e.g. the rare syndrome Xeroderma pigmentosum and the more common diseases early-onset breast cancer and hereditary non-polyposis colon cancer. Surprisingly, recent research has revealed molecular interactions between the ancient DNA repair mechanisms and the much younger acquired immune system. Thus, the classical base excision enzyme uracil-DNA glycosylase encoded by the UNG gene is also involved in somatic hypermutation and class switch recombination, e.g. from IgM antibodies to IgG, yielding secreted high affinity antibodies. Mutations in both alleles of UNG result in a hyper-IgM syndrome with life-threatening infections. Furthermore, it has recently become clear that not only DNA, but also RNA and proteins are repaired. Thus, certain aberrant methylations in RNA are repaired by oxidative demethylation in one step restoring the normal base, and at least in a bacterial model system this increases survival several-fold after exposure to methylating agents. Proteins are repaired both at the peptide amino acid level and at the structural level. RNA and protein repair are likely to be important to prevent the formation of cytotoxic protein aggregates of the types known to cause neurodegenerative diseases e.g. Alzheimer's, Parkinson's and Huntington's diseases, and other diseases as well. In conclusion, recent research has demonstrated an unexpected complexity of cellular defence mechanisms that function in intricate networks, rather than as independent mechanisms. The new knowledge opens for interventions that are based on a deeper understanding of the mechanisms of defence.
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PMID:Novel aspects of macromolecular repair and relationship to human disease. 1498 56

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause damage in the upper gastrointestinal (GI) tract by impairing the ability of the mucosa to resist and respond to injury. Many of these effects of NSAIDs can be attributed to their ability to suppress mucosal prostaglandin synthesis. Selective inhibitors of cyclooxygenase (COX)-2 are less likely to disrupt mucosal defence and do not interfere with platelet aggregation. Thus, their use is associated with a reduced incidence of serious GI adverse events; however, a significant risk of such events still persists. At least in animal models, selective COX-2 inhibitors interfere with ulcer healing to the same extent as conventional NSAIDs. In contrast, COX-inhibiting nitric oxide donors (CINODs) produce anti-inflammatory and analgesic effects comparable or superior to those of NSAIDs, but with greatly reduced GI toxicity. Unlike NSAIDs and selective COX-2 inhibitors, CINODs do not interfere with ulcer healing. Moreover, because CINODs suppress the activity of both COX-1 and COX-2, they do not share with selective COX-2 inhibitors the lack of cardioprotection afforded by significant suppression of platelet aggregation. Because of their safety profile, CINODs may be particularly useful for long term prevention applications, such as for colon cancer, cardiovascular disease and Alzheimer's disease.
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PMID:Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors. 1505 99


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