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A compound used to solubilize drugs surprisingly improves the symptoms of a rare genetic disorder, Niemann-Pick type C, and a new study in PNAS provides some clues as to how. Researchers at the University of Texas Southwestern Medical School in Dallas fed NPC mice a form of cyclodextrin, a doughnut-shaped chemical with a water-soluble ring and a fat-soluble hole that enables the compound to solubilize an otherwise insoluble molecule, such as a drug. The hallmark of NPC is disrupted cholestero

By | January 26, 2009

A compound used to solubilize drugs surprisingly improves the symptoms of a rare genetic disorder, Niemann-Pick type C, and a new study in PNAS provides some clues as to how. Researchers at the University of Texas Southwestern Medical School in Dallas fed NPC mice a form of cyclodextrin, a doughnut-shaped chemical with a water-soluble ring and a fat-soluble hole that enables the compound to solubilize an otherwise insoluble molecule, such as a drug. The hallmark of NPC is disrupted cholesterol trafficking inside cells, causing the substance to accumulate and leading to problems in the liver and brain. When the researchers, led by linkurl:John Dietschy,;http://www.utsouthwestern.edu/findfac/professional/0,,11822,00.html administered one dose of cyclodextrin to young NPC mice, the amount of accumulated cholesterol in cells decreased markedly, liver function and neural function improved, and the mice lived longer than untreated NPC mice.
Chemical structure of beta-cyclodextrin
"There are major biochemical shifts, very suddenly," Dietschy told The Scientist. "This was very surprising. We've never seen this with any other compound." Previous research has shown that cyclodextrin can improve NPC. What makes this study exciting, said linkurl:Charles Vite,;http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=33885 who was not involved in the study but is trying cyclodextrin in linkurl:cats with NPC;http://www.the-scientist.com/article/display/55157/ at the University of Pennsylvania in Philadelphia, is that it shows why cyclodextrin works. Specifically, it enters cells and causes cholesterol to move to where it can be processed, either within the cytosol or outside, perhaps excreted into bile. "I don't think anybody had a clue how" cyclodextrin was working in NPC, Vite told The Scientist. The paper shows that cyclodextrin is "returning the cell back to its normal function," he said. "It seems really exciting." Dietschy added that he hopes cyclodextrin will help reveal even more clues about how cholesterol moves inside cells. "We view cyclodextrin as merely a tool to view this process," which remains largely a mystery, Dietschy said. "There's a big black box inside the cell." Currently, patients with NPC (a disorder linkurl:profiled in our November issue);http://www.the-scientist.com/2008/11/1/32/1/ have few treatment options. The only prescription drug available, an inhibitor of glycosphingolipid synthesis, normally treats another lysosomal storage disorder, and is prohibitively expensive (one family, the linkurl:subject of the November story,;http://www.the-scientist.com/2008/11/1/32/1/ spends up to $160,000 per year to treat two children with the medication, called Zavesca). Unfortunately, the drug simply delays progression, and children with NPC inevitably develop liver problems and dementia, before dying prematurely. Cyclodextrin fell within NPC researchers' radars after an experiment that showed a steroid hormone solubilized with cyclodextrin had an effect on the disease. Gradually, scientists began to realize it was the solubilizer, and not the drug, that was doing the work. In the current study, Dietschy and his team gave one dose of a form of cyclodextrin to 7-day-old mice with NPC, and observed its effect inside cells. The researchers saw changes in tissues within a few hours after giving the mice the drug, Dietschy said, adding that he and his team now have data on hour-by-hour changes inside cells following a dose of cyclodextrin, and are testing the effects of repeated doses. Thomas Ohm, who linkurl:studies NPC;http://www.ingentaconnect.com/content/jws/path/2003/00000200/00000001/art01320?crawler=true at Charité - University Medicine Berlin and was not involved in the study, cautioned that although the treated mice lived longer than untreated mice, they did not live nearly as long as mice without NPC. And cyclodextrin did not appear to lengthen lifespan any more than other experimental drugs for NPC, he added in an email. "It is intriguing that all kinds of different approaches in our endeavors to find a safe treatment lead only to a very limited magnitude in improvements," Ohm wrote, "though the effects are most often highly statistically significant."
**__Related stories:__***linkurl:An Uncommon Colony;http://www.the-scientist.com/article/display/55157/
[November 2008]*linkurl:Twin Disorders;http://www.the-scientist.com/2008/11/1/32/1/
[November 2008] Image courtesy of Wikipedia
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Comments

Avatar of: Paul Stein

Paul Stein

Posts: 23

January 27, 2009

Ohm readily points out the problem that every investigator must realize about statistics. With large numbers of animals per group and tight standard deviations, one can get a P<0.0001 when there is a 10% or less difference; something that is clinically insignificant (dictionary, not statistical, definition).\n\nThe results of this research, however, are quite interesting. Once the experimentation expands in cats, experimental design improving the dosage regimens may begin to produce true clinically significant results. At the very least, newer, more potent drugs, based on the cyclodextrin model may be developed giving better patient outcomes. In addition, combination therapies should produce compounding effects.
Avatar of: James Wilmer

James Wilmer

Posts: 18

January 27, 2009

This is a very interesting article. Beta-Cyclodextrin, a seemingly inert additive, has exhibited significant drug activity. It is disconcerting to discover than this material is apparently resistant to enzymatic degradation and can be carried into or diffuse inside cells. This substance is being used increasingly as a delivery vehicle for lipophilic drugs and nutritional supplements. Why wouldn't an oddly shaped molecule have been given closer scrutiny for biological activity?

January 27, 2009

Crystal lattice plane of hologram for optical frequency combing of coherence and chaotic emissions interpret a genetic continuity and discontinuity-reg [Incident: 090127-000101}nes@nature.com\nThere has always been such complaints about using of such addictive drugs even to win sportive activities to win the race in Geremany which was seriously investigatedled to female turing male genetic activity for chromosomal changes involved which was finalised as criminal offence.This may give a clue for "Robin Cook novel" and a "Hollywood film" under steroid applications.\nNormally Brain line of the plam print drooping downwards due to Lunar -Venus Glauber gravity stimulated frequency converged stimulations on basic stem cells along helium laser biostimulation hologram planes. Crystal lattice plane of hologram for optical frequency combing of coherence and chaotic emissions interpret a genetic continuity and discontinuity-reg [Incident: 090127-000101 news@nature.com]\nOxford astro genetics dept is interested in Hologram crystal lattices to be\nmade references along Frequency optical combing from coherence to chaotic\nemissions on the planetary boundary must have a meaning on human genetic\nholograms out of sun's emissions and interference at the planetary\nboundaries as helium cluster emissions can be interpreted by the palm print\nof brain line ,fate line and sun line may be evaluated on genetic plane of\nefficiency as a comparative marker. This means there is definite interference\nalong the crystal lattice oscillations of space with reference to ever\nchanging magnetic field emissions of solar boundary controlling the genetic\nactivity of human beings which requires a thorough investigation. This decides\nfurther breaking symmetry of genetic planes for further higher plane\nevolutions. \nThe university astro mathematics team is intersted in evaluation of Euler-Fourier mathematical function f(x)that may be applied along helium crystal lattice collections at the planetary boundaries and Glauber laser spectrum emissions in understanding the concept of genetic continuity and discontinuous Glauber laser emissions related genetic biostimulations at the point of genetic continuity and discontinuity with reference to solar magnetic field crystallographic oscillations along frequency converged emissions of spectrum analysis on the planetary boundaries along the plane of genetic hologram.\n There are two important parameters of an optical lattice: the well depth and the periodicity. The well depth of the optical lattice can be tuned in real time by changing the power of the laser, which is normally controlled by an AOM (acousto-optic modulator). The periodicity of the optical lattice can be tuned by changing the wavelength of the laser or by changing the relative angle between the two laser beams. The real-time control of the periodicity of the lattice is still a challenging task. Because the wavelength of the laser cannot be varied over a large range in real time, the periodicity of the lattice is normally controlled by the relative angle between the laser beams.[4] However, it is difficult to keep the lattice stable while changing the relative angles, since the interference is sensitive to the relative phase between the laser beams. Recently, a novel method of real-time control of the lattice periodicity was demonstrated,[5] in which the center fringe moved less than 2.7 μm while the lattice periodicity was changed from 0.96 to 11.2 μm. Whether this method can keep atoms (or other particles) trapped while changing the lattice periodicity remains to be tested experimentally. Such accordion lattices are useful for controlling ultracold atoms in optical lattices, where small spacing is essential for quantum tunneling, and large spacing enables single-site manipulation and spatially resolved detection.\nBesides trapping cold atoms, optical lattices have been widely used in creating gratings and photonic crystals. They are also useful for sorting microscopic particles,[6] and may be useful for assembling cell arrays. An optical lattice is able to trap an atom because the electric fields of the lasers induce an electric dipole moment in the atom. The interaction between this dipole moment, which is oscillating, and the electric field of the laser modifies the energy of the atom. If the laser frequency is less than a specific electronic transition frequency within an atom, the atoms are pulled towards the regions of maximum laser intensity. However, if the laser frequency is higher than the transition frequency, the atoms are pushed away from the maxima. Either way the atoms can be trapped in the bright or dark regions of the optical lattice, and the strength of the optical potential confining the atoms can be increased by turning up the laser intensity . An optical lattice is simply a set of standing wave lasers. The electric field of these lasers can interact with atoms - the atoms see a potential and therefore congregate in the potential minima. In the case of a typical one-dimensional setup, the wavelength of the opposing lasers is chosen so that the light shift is negative. This means that the potential minima occur at the intensity maxima of the standing wave. Furthermore, the natural beam width can constrain the system to being one-dimensional. \n\nTo keep the atoms from distributing over too large a distance, the lattice is superimposed with an additional trap. This trap is generated by a dipole laser beam focused at the position of the atom cloud. Perpendicular to the beam axis, this creates a Gaussian intensity profile. For small excursions from the trap centre this is a near harmonic trap. Along the beam axis, the trapping frequency is too low, though: atoms could spread out many 100 µm. To close the trap in this direction, a second (and later a third) perpendicular laser beam is focussed onto the atom cloud. \n\nIf one of these laser beams is now collimated after passing through the atom cloud and retro-reflected on a mirror, the intensity and thus the trap-depth at the trap centre is doubled. But now a standing wave forms, with its first node at the surface of the retro-reflecting mirror. The interference pattern extends back to the atom cloud, producing an intensity modulation with a distance of half the laser wavelength between intensity maxima. A 2D or 3D lattice is formed by also retro-reflecting the other laser beams. The standing waves intersect and lattice sites are where all standing waves have an intensity maximum. Consider the oblate traps of one standing wave as parallel planes. Then two perpendicular groups of planes intersecting with each other form an array of cigar-shaped traps in a regular 2D lattice. A third group of parallel planes divides these 2D lattice sites into spherically symmetric traps arranged in a 3D optical lattice.\nS.Nandakumar ,astro genetics dept,uk on behalf of hubble-nasa ?oxford space science coordination\n

January 27, 2009

Poligonal phase convergence and related affined emissions out of such crystallised medicines contributing a cholestrol level decrease due to Linus Paulin polygon symmetry breaking is really is surprising and can be applied well in advance at 58 th year for those who are having the palm print of "heart line breaking the fate line" indicating surprisingly, a preplanned heart attack due to increase in cholestrol levels,as investigated by Oxford astro genetics dn,uk.
Avatar of: Steven Brenner

Steven Brenner

Posts: 14

January 29, 2009

This is quite interesting in that cholesterol trafficking may be involved, especially since one of the biggest Alzheiemr disease risk factors is the Apoe4 gene, which is apparently involved in cholesterol and lipid trafficking, while the Apoe2 gene is protective, reducing the risk for development of Alzheimer. If the Apoe4 gene metabolism, the Apoe4 risky metabolism can be converted to Apoe2 gene metabolism, the protective metabolism, it could lead to a treatment, perhaps a "disease modifying" treatment for Alzheimer's disease.

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