Mary Katherine Newman's Public Library

02 Nov 09

the Drug Monitor - COX-2 Inhibitors - Nasr Anaizi, PhD

www.thedrugmonitor.com/coxi.html - Preview

Non-steroidal anti-inflammatory drugs (NSAIDs) remain among the most widely prescribed drugs worldwide.
exert their actions primarily by inhibiting the production of prostaglandins (PGs)
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- (COX)
- the key enzyme catalyzing the biosynthesis of PGs,
- Prostaglandins are ubiquitous fatty-acid derivatives that serve as autocrine / paracrine mediators involved in many different physiological processes in addition to their well recognized role in inflammation and immune response modulation
- COX isoforms are similar in size, substrate specificity, and kinetics, but vary in their expression and distribution
- COX-1, "the good COX", is a constitutively expressed isoform that is always present in most cells throughout the body and catalyzes the formation of PGs involved in physiological, "housekeeping" processes.
- COX-2, "the bad COX", is an inducible isoform that is found mainly in inflammatory and immune cells (neutrophils, macrophages, mast cells, etc). Pro-inflammatory cytokines and growth factors induce COX-2, which suggests that it may play an important role not only in the process of inflammation but also in the control of cell growth.
- COX-2 is also strongly expressed in human colon cancer cells, and NSAIDs are thought to delay the progress of colon tumors possibly by causing apoptosis (programmed cell death) of the tumor cells.
- Inhibitory potency and selectivity of the conventional, 1^st generation NSAIDs (aspirin, diclofenac, ibuprofen, indomethacin, naprosyn, and piroxicam, etc) for COX-1 and COX-2 vary greatly.
- n general, NSAIDs have comparable efficacy but different safety profiles probably due to differences in their ability to inhibit COX-1 at therapeutic doses.
- In this respect, the different NSAIDs are evaluated by comparing their IC₅₀ values. The IC₅₀ is the drug concentration that inhibits the activity of the enzyme by 50%. Therefore, the lower the IC₅₀ value the stronger is the drug.
- The IC₅₀ values (micromoles/L) for COX-2 and COX-1 are determined is vitro and their ratio is calculated (COX-2 IC₅₀ divided by COX-1 IC₅₀) to provide a quantitative measure of the drug's selectivity.
- The smaller this ratio the more selective is the drug for COX-2.

29 Oct 09

EBSCOhost: RURAL PREGNANT COCAINE USERS: AN IN-DEPTH SOCIODEMOGRAPHIC COMPARISON

MOTHERS!

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EBSCOhost: No simple answer

One-page commentary on crack baby myth--Dr. Lester

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Is Genetic Evolution Predictable? -- Stern and Orgogozo 323 (5915): 746 -- Science

www.sciencemag.org/...746 - Preview

Genetic evolution is constrained bygene function, the structure of genetic networks, and populationbiology.
The genetic basis of evolution may be predictable tosome extent, and further understanding of this predictabili
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- tyrequires incorporation of the specific functions and characteristicsof genes into evolutionary theory
- One hundred and fifty years ago, Charles Darwin and Alfred RussellWallace proposed that biological diversity results from naturalselection acting on heritable variation in populations.
- Population geneticists treated genes and alleles asgeneric entities, particles that were inherited and somehowcaused variation in the appearance, behavior, and physiologyof organisms—what we call collectively the phenotype.
- Patternsin these data suggest that a synthesis of molecular developmentalbiology with evolutionary the
- ory will reveal new general principlesof genetic evolution.
- variation [evolutionarily relevant mutations (2)] are not distributedrandomly across all genetic regions.
- Recent studies suggest that the mutations contributing to phenotypic
- parallel evolution
- One explanation for parallel genetic evolution is that mostgenes play specialized roles during development, and only somegenes can evolve to generate particular phenotypic variants.
- During development, multiple cell-signalingpathways and transcription factors act together to progressivelydivide the embryo into a virtual map that specifies when andwhere organs will form
- Pleiotropy. Some mutations generate specific phenotypic changes,whereas pleiotropic mutations alter several seemingly unrelatedtraits.
- Epistasis is extremely common in natural populations and itmay sometimes reduce the rate of evolution
- Populations exposed to repeated environmental changesmay evolve genetic mechanisms that produce different phenotypessuited to different environmental conditions: so-called phenotypicplasticity.
- trength of selection. When an environmental change favors aphenotype that is vastly different from the mean phenotype ina population, mutations causing large phenotypic changes towardthe new optimum will be favored, at least initially (18).
- Population history. The past and current sizes of a populationalso influence genetic evolution. Small population size increasesthe effects of random sampling of alleles, so-called geneticdrift.
- Instead, in comparison with large populations,adaptive mutations of relatively large effect will tend to evolveby natural selection in small populations.
- Although mutations are thought to occur randomly in the genome,the distribution of mutations that cause biological diversityappears to be highly nonrandom. Gene function, gene structure,and the roles of genes and gene products in genetic networksall influence whether particular mutations will contribute tophenotypic evolution.
- he genetic basis of phenotypic evolution thus appears to besomewhat predictable.
- More precise quantitative predictions about the mutations responsiblefor phenotypic evolution will probably result from further synthesisof molecular biology and population genetics.
- the fact that long-term genetic evolution may representa biased subset of mutations has applied consequences, fromthe development of more efficient computer algorithms that utilizeevolutionary search strategies to the improvement of agriculturalcrops and animals.
- Domestication often selects for mutationsthat have pleiotropic deleterious effects. Long-term evolution,in contrast, selects for mutations with specific phenotypiceffects, and this class of mutations might be exploited to engineerdomesticated races that possess desirable characteristics withoutassociated unfavorable properties