PubMed · 7968780
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A Jung, W B Schill. 1994. [Corpus cavernosum autoinjection therapy in erectile dysfunction?].. https://pubmed.ncbi.nlm.nih.gov/7968780/
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Although radical changes in drug regulation are rare (e.g., the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendment to the Act creating an effectiveness requirement), regulations and guidance do evolve significantly in the face of new problems and accumulating experience. Recent changes have been driven by the Food and Drug Administration Modernization Act (FDAMA), user fee legislation, the International Conference on Harmonization, recent safety related drug withdrawals, and concerns about trial ethics and investigator conflict of interest. FDAMA and guidance developed in response to it has helped circumstances in which FDA would rely on a single study to support effectiveness and the circumstances in which surrogate endpoints could support approval. An ICH Document 'Choice of control group and related design issues in clinical trials' focussed attention on the ethics of placebo controls (acceptable, even if there is existing therapy, when the placebo-treated patient will suffer no irreversible injury) and the design of 'equivalence' or 'non-inferiority' trials. There has been greatly increased attention to obtaining good dose-response information and to assessing need for modifying treatment in demographic (age, gender, race) and concomitant disease (renal or hepatic function abnormalities) subgroups, and in assessing drug-drug interactions. Other important trends are increasing reliance on non-U.S. data, increasing numbers of FDA-industry meetings during drug development, and new focus on risk assessment and risk management.
Histone deacetylase inhibitors have generated keen interest as potential chemopreventive and chemotherapeutic agents due to their ability to induce cell cycle arrest, differentiation, and apoptosis in a diverse group of cancer derived cell lines. Activation of the 60 kDa non-receptor tyrosine kinase, c-Src, has been a consistent finding in many tumors and tumor derived cell lines, and has been implicated in these same cellular processes. We have shown that the histone deacetylase inhibitors, sodium butyrate and Trichostatin A, repressed c-Src mRNA and protein expression in a dose-dependent manner in cell lines derived from cancers of the colon, breast and liver. Our group has previously identified two distinct promoters that are responsible for SRC transcription, separated by a distance of approximately 1 kb. Sodium butyrate and Trichostatin A strongly inhibited activity of each of these highly disparate SRC promoters, demonstrating histone deacetylase inhibitors directly repress SRC transcription. This repression did not require protein neosynthesis and was not associated with a decrease in binding of protein factors essential for either promoter's activity. Our finding that sodium butyrate and Trichostatin A inhibit both SRC promoters suggest this oncogene may be a major target of these agents, and may explain in part their anti-cancer activity.
Humans live on chemicals, and no exposure to any chemicals is incompatible with life. Chemicals produced by different organisms are in no basic way different from the man-made chemicals, and often chemicals are produced by both. Natural chemicals include the most potent acutely toxic chemicals known, and also include very potent mutagens and human carcinogens. Thus the fact that a chemical is 'natural' does not mean that it is any safer than a man-made chemical, and the fact that a chemical is man-made does not make it any more harmful than 'natural' chemicals. Exposure to chemicals varies widely, to a large variety of chemicals people are exposed from the environment, via drinking water, food and inhaled air and exposure e.g. at the work-place is only quantitatively different from the exposure of the general public. Zero exposure is meaningless without an operational definition. It is a major challenge to the society to determine what is the safe exposure level to different chemicals, and for chemicals for which no exposure level is safe, to define the acceptable risk, and in both cases, make sure that the exposure limits thus determined are complied with.