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Apricoxib, A COX-2 inhibitor.

July 29, 2014 3:52 am / 1 Comment on Apricoxib, A COX-2 inhibitor.

APRICOXIB

A COX-2 inhibitor.

MF; C19H20N2O3S

Mol wt: 356.439

CAS: 197904-84-0

CS-701; TG01, R-109339, TG-01 ,TP-1001
TP-2001, Capoxigem, Kymena, UNII-5X5HB3VZ3Z,

Benzenesulfonamide, 4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]-;

4-[2-(4-Ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide

4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide .

PHASE 2 http://clinicaltrials.gov/search/intervention=Apricoxib

Daiichi Sankyo (innovator)Daiichi Sankyo Co Ltd,

Current developer: Tragara Pharmaceuticals, Inc.

Apricoxib is an orally bioavailable nonsteroidal anti-inflammatory agent (NSAID) with potential antiangiogenic and antineoplastic activities. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis.

Chemical structure for apricoxib

R-109339 is a cyclooxygenase-2 (COX-2) inhibitor currently in phase II clinical development at Tragara Pharmaceuticals for the oral treatment of non-small cell lung cancer (NSCLC) and for the treatment of inflammation. Additional phase II clinical trials are ongoing in combination with gemcitabine and erlotinib for the treatment of pancreas cancer. The company had been evaluating R-109339 for the treatment of colorectal cancer, but development for this indication was discontinued for undisclosed reasons. Daiichi Sankyo and Tragara Pharmaceuticals had been conducting phase II clinical trials with the drug candidate for the oral treatment of arthritis and for the treatment of breast cancer, respectively; however, no recent development for this indication has been reported.

COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. In addition to several other functions, prostaglandins act as messenger molecules in the process of inflammation. The compound is also designed to act against a well-defined cancer pathway that affects several routes of cancer pathogenesis. In preclinical cancer models, R-109339 demonstrated superiority to compounds with similar mechanisms of action and potential for use in combination with cisplatin. Furthermore, the compound demonstrated the ability to inhibit the cachexia and weight loss seen in mouse tumor models.

Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma, and Recamp et al.

The original synthetic route is outlined below. Though the initial two steps were accomplished with decent yields, the final step of pyrrolidine formation followed by dehydration and dehydrocyanation produced only 3% of 1 as a brown powder. The yield in the last step of the synthesis of the 2-(4-methoxyphenyl) analog, 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, was 6%, indicating that this synthesis route is problematic.

14 Kimura T, Noguchi Y, Nakao A, Suzuki K, Ushiyama S, Kawara A, Miyamoto M. 799823. EP. 1997:A1.

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Synthesis

Bioorg Med Chem Lett. Oct 15, 2011; 21(20): 6071–6073.

Published online Aug 19, 2011. doi: 10.1016/j.bmcl.2011.08.050

SEE AT

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310163/

An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalysed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulphanilamide. This method provided multi-gram access of aprocoxib in good yield. Apricoxib exhibited potency equal to celecoxib at inhibition of prostaglandin E₂ synthesis in two inflammatory breast cancer cell lines.

We envisioned that 7 could be prepared by ozonolysis of homoallylic ketone (8) (Route B). A recent development in the synthesis of homoallylic ketones by Dorr et al. via copper-catalyzed cascade addition of alkenylmagnesium bromide to an ester a²⁴ was examined. Treatment of commercially available methyl 4-ethoxybenzoate with 1-propenylmagnesium bromide (4.0 equiv) in presence of CuCN (0.6 equiv) resulted in 95% yield of desired ketone8 after silica gel chromatography, along with a minor amount of unreacted ester).b²⁵

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Efficient synthesis of apricoxib (1):

The product was a mixture of cis/trans R/S stereoisomers, as detected in the ¹H NMR spectrum, and was used directly in the next step without separation. Ozone was bubbled through a solution of 8 in MeOH/CH₂Cl₂ at −78°C, until all starting materials were consumed. The ozonide was then reduced to aldehyde 7 by treatment with Me₂S overnight. Removal of volatiles and subsequent addition and evaporation of toluene gave the crude 1,4-dicarbonyl compound 7 which was sufficiently pure for the following condensation step. The ¹H NMR signal at 9.78 ppm of the crude product confirmed the formation of the aldehyde. No attempt was made to characterize the enantiomeric ratio of 7 since the dehydration/aromatization reaction of the next step removes the chirality of the product. Treatment of 7 with sulfanilamide in 40% acetic acid-acetonitrile at 70°C for three hours resulted in a brown product. Purification by silica gel flash chromatography yielded 71% of pure 1 as a white solid.c²⁶

a24. Dorr AA, Lubell WD. Can J Chem. 2007;85:1006.

b25. Synthesis of 1-(4-ethoxy-phenyl)-3-methyl-hex-4-en-1-one (8): To a stirred suspension of CuCN (1.8 g, 20.0 mmol) in 50 mL of dry THF at −78°C under argon, a solution of 1-propenylmagnesium bromide (133.2 mmol, 265 mL of 0.5 M solution in THF) was added dropwise. The slurry was stirred for an additional 30 min and then a solution of methyl 4-ethoxybenzoate (6.0 g, 33.3 mmol) in 60 mL of dry THF was added slowly. The stirred reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with ice cold saturated aqueous NaH₂PO₄ (100mL) and the mixture was extracted with ether (4 × 100 mL). The combined ether extracts were washed with brine (2 × 100mL), dried (MgSO₄), filtered, and evaporated to dryness. The crude homoallylic ketone was purified by silica gel flash chromatography using a gradient of ethyl acetate in hexane as the eluent to give 8 (7.4 g, 95%) as a colorless oil. ¹H NMR (CDCl₃, 300.0 MHz) δ 1.04–1.07 (m, 3H), 1.44 (t, J = 6.9 Hz, 3H), 1.6–1.64 (m, 3H), 2.8–2.96 (m, 2.5H), 3.2 (m, 0.5H), 4.1 (q, J = 6.9 Hz, 2H), 5.25 (m, 0.5 H), 5.34–5.46 (m, 1.5H), 6.92 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H). ¹³C NMR (CDCl₃, 75.0 MHz) δ 12.9, 14.6, 17.9, 20.4, 21.0, 28.4, 33.0, 45.4, 45.5, 63.7, 114.1, 123.1, 123.4, 130.2, 130.3, 135.5, 136.0, 141.9, 162.7, 198.1. M+H Calcd: 233.1542; Found, 233.2482.

c26. Synthesis of Apricoxib (1): Homoallylic ketone (8) (5.0 g, 21.53 mmol) in 180 mL of CH₂Cl₂/MeOH (1:5) was treated with ozone bubbles at −78°C until a blue coloration persisted. The solution was purged with argon, 8.0 mL of dimethylsulphide (21.5 mmol) was added, and the reaction mixture then warmed slowly to rt overnight. The solvent was evaporated under vacuum to give 7 which was then diluted with 100 mL of 40 % acetic acid in acetonitrile, (v/v) and sulphanilamide (4.0 g, 23.2 mmol) was added. The mixture was refluxed until complete consumption of 1,4-dicarbonyl compound was detected by TLC (ca 3 h). After cooling to room temperature, the product was concentrated under vacuum and diluted with 250 mL of ethyl acetate. The organic layer then washed with saturated Na₂CO₃ solution (3 × 50 mL) followed by brine (1 × 50 mL), dried (MgSO₄), and evaporated to dryness. The crude brown material was purified by silica gel flash chromatography using a gradient of EtOAc in hexane to give apricoxib as white solid (5.5 g, 15.43 mmol, 71%).

m.p. 161–163°C (lit. 135–139°C¹⁴).

¹H NMR (CDCl₃, 300.0 MHz) δ 1.32 (t, J = 6.9 Hz, 3H), 2.1 (s, 3H), 3.92 (q, J = 6.9 Hz, 2H), 4.95 (s, 2H), 6.14 (m, 1H), 6.63 (m, 1H), 6.69 (d, J = 6.6 Hz, 2H), 6.94 (d, J = 6.6 Hz, 2H), 7.13 (d, J = 6.6 Hz, 2H), 7.74 (d, J= 6.6 Hz, 2H).

¹³C NMR (CDCl₃, 75.0 MHz) δ 11.7, 14.8, 63.4, 82.4, 113.2, 114.4, 121.0, 121.1, 124.9, 125.2, 127.4, 129.7, 133.6, 138.7, 144.2, 158.0

M+H Calcd: 357.1273; Found, 357.1252.

01

Click here to view.^{(2.1M, pdf) DOWNLOAD TO GET NMR , 13C, COSY}

Supplementary Material

¹H, ¹³C, and COSY NMR spectra of compounds 1 and 8.

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SYNTHESIS

synthesis

In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,Ndiisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib

Intermediate (V) can also be prepared by reaction of 1-(4- ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitroderivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).In an alternativestrategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishesN-(4-ethoxybenzylidene)-

4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α- amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib

reference for above

Drugs of the Future 2011, 36(7): 503-509
Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617.
Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078
Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives,their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858.

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Golden Root (Rhodiola rosea)…….a queen of adaptogenic herbs

July 28, 2014 11:27 am / Leave a comment

Golden Root (Rhodiola rosea) – Also called Arctic Root or Roseroot, golden root is considered a queen of adaptogenic herbs. As one blogger puts it, “[Golden root] allows us to regulate our immune, physiological and neurological responses to stress, allowing us to survive not only rough environmental/weather challenges, but also to adapt and adjust our often neurotic mental habits and crazy social/political climates as well.

”The Russians use it to improve physical stamina and adapt to environmental stress. In Siberia, people still say, “Those who drink Rhodiola tea will live more than 100 years old.” The extract possesses positive mood enhancing and anti-stress properties with no detectable levels of toxicity. Golden root works by enhancing the body’s ability to make serotonin, dopamine, and other neurotransmitters that aid in happiness and stress-reduction.

Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron’s rod, arctic root, king’s crown, lignum rhodium, orpin rose) is a perennial flowering plant in the family Crassulaceae. It grows in cold regions of the world, including much of the Arctic, the mountains ofCentral Asia, scattered in eastern North America from Baffin Island to the mountains of North Carolina, and mountainous parts of Europe, such as the Alps, Pyrenees, and Carpathian Mountains, Scandinavia, Iceland, Great Britain and Ireland. It grows on sea cliffs and on mountains^[2] at altitudes up to 2280 meters.^[where?]^{[citation needed]} Several shoots grow from the same thick root. Shoots may reach 5 to 35 cm in height. R. rosea is dioecious – having separate female and male plants.

History

The first time that R. rosea is described was from Dioscorides in De Materia Medica.

Uses

Plant

Some studies have found support for it having antidepressant effects.^[3]^[4] It is not approved by the U.S. Food and Drug Administration (FDA) to cure, treat, or prevent any disease. In fact, the FDA has forcibly removed some products containing R. rosea from the market due to disputed claims that it treats cancer, anxiety, influenza, the common cold, bacterial infections, and migraines.^[5]

R. rosea may be effective for improving mood and alleviating depression. Pilot studies on human subjects^[6]^[7]^[8] showed it improves physical and mental performance, and may reduce fatigue.

In Russia and Scandinavia, R. rosea has been used for centuries to cope with the cold Siberianclimate and stressful life.^{[citation needed]}^[9]^[10] Such effects were provided with evidence in laboratory models of stress using the nematode C. elegans,^[11] and in rats in which Rhodiola effectively prevented stress-induced changes in appetite, physical activity, weight gain and the estrus cycle.^[12]

The plant has been used in traditional Chinese medicine, where it is called hóng jǐng tiān (红景天). The medicine can be used to prevent altitude sickness.^{[citation needed]}

The aerial portion is consumed as food in some parts of the world, sometimes added to salads.^[13]

Phytochemicals and potential health effects

Withering flower

Scientists have identified about 140 chemical compounds in the subterranean portions of R. rosea.^[14] Rhodiola roots contain phenols,rosavin, rosin, rosarin, organic acids, terpenoids, phenolcarbonic acids and their derivatives, flavonoids, anthraquinones, and alkaloids.

The chemical composition of the essential oil from R. rosea root growing in different countries varies. For example, rosavin, rosarin and rosin at their highest concentration according to many tests can be found only in R. rosea of Russian origin; the main component of the essential oil from Rhodiola growing in Bulgaria are geraniol and myrtenol; in China the main components are geraniol and 1-octanol; and in India the main component is phenylethilic alcohol. Cinnamic alcohol was discovered only in the sample from Bulgaria.^[15]

R. rosea contains a variety of compounds that may contribute to its effects,^[16] including the class of rosavins that includes rosavin, rosarin, and rosin. Several studies have suggested that the most active components are likely to be rhodioloside and tyrosol,^[17] with other components being inactive when administered alone, but showing synergistic effects when a fixed combination of rhodioloside, rosavin, rosarin and rosin was used.^[18] Authentication, as well as potency, of R. rosea crude material and standardized extracts thereof are carried out with validated high-performance liquid chromatography analyses to verify the content of the marker constituents salidroside, rosarin, rosavin, rosin and rosiridin.^[19]

Although rosavin, rosarin, rosin and salidroside (and sometimes p-tyrosol, rhodioniside, rhodiolin and rosiridin) are among suspected active ingredients of R. rosea, these compounds are mostly polyphenols. There is no evidence that these chemicals have any physiological effect in humans that could prevent or reduce risk of disease.^[20]

Although these phytochemicals are typically mentioned as specific to Rhodiola extracts, there are many other constituent phenolic antioxidants, including proanthocyanidins,quercetin, gallic acid, chlorogenic acid and kaempferol.^[21]^[22]

Dried R. rosea root

Animal tests have suggested a variety of beneficial effects for R. rosea extracts,^[23] and there is some scientific evidence for its efficacy as a treatment for depression and fatigue ^[6]^[7]^[24]^[25] in humans.

Scientific evidence

R. rosea extract exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects^[6]^[7]^[24] and burnout patients with fatigue syndrome.^[25] Rhodiola significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration.^[25] A 2007 clinical trial from Armenia showed significant effect for a Rhodiola extract in doses of 340–680 mg per day in male and female patients from 18 to 70 years old with mild to moderate depression. No side effects were demonstrated at these doses.^[3] One study found inhibition of MAO-A and MAO-B.^[26] Studies on whether Rhodiola improves physical performance have been inconclusive, with some studies showing some benefit,^[27] while others show no significant difference.^[28]

Two systematic reviews on R. rosea extracts concluded that the research evidence is contradictory, and definite conclusions over its efficacy to relieve mental and physical fatigue are hampered by the lack of rigorously-designed, well-controlled randomized control trials ^[29]

In clinical medical trials on people R. rosea extract has a positive effect on sensitive and fading skin improving overall skin condition.^[30]^{[full citation needed]}

R. rosea promotes the release of norepinephrine from rat pineal corpus cavernosum smooth muscle cell and artery endothelium cell, which was correlated with its effect of resisting senility.^[31] R. rosea extract has been found to increase the life span of fruit fly (Drosophila) by 24% independently of dietary restriction.^[32]

R. rosea may enhance the detoxification of many toxic heavy metals.^[33]

References

Jump up^ “Rhodiola rosea – Plants For A Future database report”. http://www.pfaf.org. Retrieved 2008-02-23.
Jump up^ Stace, C.A. (2010). New flora of the British isles (Third ed.). Cambridge, U.K.: Cambridge University Press. p. 138. ISBN 9780521707725.
^ Jump up to:^a ^b Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A (2007). “Clinical trial of Rhodiola rosea L. extract in the treatment of mild to moderate depression”. Nord J Psychiatry 61 (5): 343–8. doi:10.1080/08039480701643290.PMID 17990195.
Jump up^ Dwyer AV, Whitten DL, Hawrelak JA (March 2011). “Herbal medicines, other than St. John’s Wort, in the treatment of depression: a systematic review” (PDF). Altern Med Rev 16 (1): 40–9. PMID 21438645.
Jump up^ See for example, Letter, dated April 21, 2005, Food and Drug Administration
^ Jump up to:^a ^b ^c Shevtsov VA, Zholus BI, Shervarly VI, et al. (Mar 2003). “A randomized trial of two different doses of Rhodiola rosea extract versus placebo and control of capacity for mental work”. Phytomedicine 10 (2–3): 95–105. doi:10.1078/094471103321659780.PMID 12725561.
^ Jump up to:^a ^b ^c Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H (Oct 2000). “Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract with a repeated low-dose regimen on the mental performance of healthy physicians during night duty”. Phytomedicine 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Ha Z, Zhu Y, Zhang X, et al. (Sep 2002). “[The effect of rhodiola and acetazolamide on the sleep architecture and blood oxygen saturation in men living at high altitude]”.Zhonghua Jie He He Hu Xi Za Zhi (in Chinese) 25 (9): 527–30. PMID 12423559.
Jump up^ Azizov, AP; Seĭfulla, RD (May–Jun 1998). “[The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals].”. Eksperimental’naia i klinicheskaia farmakologiia 61 (3): 61–3. PMID 9690082.
Jump up^ Darbinyan, V; Kteyan, A; Panossian, A; Gabrielian, E; Wikman, G; Wagner, H (Oct 2000). “Rhodiola rosea in stress induced fatigue–a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.”. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA (Jun 2008). “Plant adaptogens increase lifespan and stress resistance in C. elegans”.Biogerontology 10 (1): 27–42. doi:10.1007/s10522-008-9151-9. PMID 18536978.
Jump up^ Mattioli L, Funari C, Perfumi M (May 2008). “Effects of Rhodiola rosea L. extract on behavioural and physiological alterations induced by chronic mild stress in female rats”.Journal of Psychopharmacology (Oxford) 23 (2): 130–42.doi:10.1177/0269881108089872. PMID 18515456.
Jump up^ Saratikov A.S. (1974). Golden Root (Rhodiola Rosea) (2nd ed.). Publishing House of Tomsk University. p. 158.
Jump up^ Panossian, A., Wikman, G. (2010). “Rosenroot (Roseroot): Traditional Use, Chemical Composition, Pharmacology, and Clinical Efficacy”. Phytomedicine 17 (5-6): 481–493.doi:10.1016/j.phymed.2010.02.002.
Jump up^ Evstavieva L., Todorova M., Antonova D., Staneva J. (2010). “Chemical composition of the essential oils of Rhodiola rosea L. of three different origins”. Pharmacogn Mag. 6 (24): 256–258.
Jump up^ Kucinskaite A, Briedis V, Savickas A (2004). “[Experimental analysis of therapeutic properties of Rhodiola rosea L. and its possible application in medicine]”. Medicina (Kaunas) (in Lithuanian) 40 (7): 614–9. PMID 15252224.
Jump up^ Mao Y, Li Y, Yao N (Nov 2007). “Simultaneous determination of salidroside and tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-performance liquid chromatography”. J Pharm Biomed Anal 45 (3): 510–5. doi:10.1016/j.jpba.2007.05.031.PMID 17628386.
Jump up^ Panossian A, Nikoyan N, Ohanyan N, et al. (Jan 2008). “Comparative study of Rhodiola preparations on behavioral despair of rats”. Phytomedicine 15 (1–2): 84–91.doi:10.1016/j.phymed.2007.10.003. PMID 18054474.
Jump up^ Ganzera M, Yayla Y, Khan IA (April 2001). “Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography”. Chem. Pharm. Bull. 49 (4): 465–7. doi:10.1248/cpb.49.465.PMID 11310675.
Jump up^ Boudet AM (2007). “Evolution and current status of research in phenolic compounds”.Phytochemistry 68 (22–24): 2722–35. doi:10.1016/j.phytochem.2007.06.012.PMID 17643453.
Jump up^ Yousef GG, Grace MH, Cheng DM, Belolipov IV, Raskin I, Lila MA (Nov 2006). “Comparative phytochemical characterization of three Rhodiola species”. Phytochemistry67 (21): 2380–91. doi:10.1016/j.phytochem.2006.07.026. PMID 16956631.
Jump up^ Liu Q, Liu ZL, Tian X (Feb 2008). “[Phenolic components from Rhodiola dumulosa]”.Zhongguo Zhong Yao Za Zhi (in Chinese) 33 (4): 411–3. PMID 18533499.
Jump up^ Perfumi M, Mattioli L (Jan 2007). “Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice”.Phytother Res 21 (1): 37–43. doi:10.1002/ptr.2013. PMID 17072830.
^ Jump up to:^a ^b Spasov. A.A., Mandrikov, V.B., Mitonova, I.A., 2000b. The effect of Dhodaxonon psycho-physiologic and physical adaptation of students to the academic load. Experimental and Clinical Pharmacology 63 (1), 76-78.
^ Jump up to:^a ^b ^c Olsson E.M.G., von Schéele B., Panossian A.G. (2009). “A randomized double-blind placebo controlled parallel group study of an extract of Rhodiola rosea roots as treatment for patients with stress related fatigue”. Planta medica 75 (2): 105–112.doi:10.1055/s-0028-1088346. PMID 19016404.
Jump up^ van Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, PA.; Hostettmann, K. (Mar 2009). “Monoamine oxidase inhibition by Rhodiola rosea L. roots.”. J Ethnopharmacol122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID 19168123.
Jump up^ De Bock K, Eijnde BO, Ramaekers M, Hespel P (Jun 2004). “Acute Rhodiola rosea intake can improve endurance exercise performance”. Int J Sport Nutr Exerc Metab 14(3): 298–307. PMID 15256690.
Jump up^ Walker TB, Altobelli SA, Caprihan A, Robergs RA (Aug 2007). “Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men”. Metab Clin Exp. 56(8): 1111–7. doi:10.1016/j.metabol.2007.04.004. PMID 17618958.
Jump up^ Ishaque, Sana; Shamseer, Larrisa; Bukutu, Cecilia; Vohra, Sunita. “Rhodiola rosea for physical and mental fatigue: a systematic review”. BMC Complementary and Alternative Medicine 12 (1): 70. doi:10.1186/1472-6882-12-70. PMID 3541197.
Jump up^ Diemant et al., 2008
Jump up^ Effect of Rodiola on level of NO and NOS in cultured rats penile corpus cavernosum smooth muscle cell and artery endothelium cell Kong X., Shi F., Chen Y., Lu H., Yao M., Hu M. Chinese Journal of Andrology 2007 21:10 (6-11)
Jump up^ Schriner, Samuel E.; Lee, Kevin; Truong, Stephanie; Salvadora, Kathyrn T.; Maler, Steven; Nam, Alexander; Lee, Thomas; Jafari, Mahtab; Englert, Christoph (21 May 2013). “Extension of Drosophila Lifespan by Rhodiola rosea through a Mechanism Independent from Dietary Restriction”. PLoS ONE 8 (5): e63886. doi:10.1371/journal.pone.0063886.
Jump up^ Boon-Niermeijer, E.K.; van den Berg, A.; Wikman, G.; Wiegant, F.A.C. “Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis”. Phytomedicine 7 (5): 389–399. doi:10.1016/S0944-7113(00)80060-4.

External links

Media related to Rhodiola rosea at Wikimedia Commons
Whole Health MD, Reference Library
Plants For A Future, Rhodiola rosea Rose Root PFAF
Wilderness Medical Society, Lack of Effect of Rhodiola on Hypoxemia and Oxidative Stress

Tiny amounts of BPA can alter mammary gland development

July 28, 2014 2:09 am / Leave a comment

CLINICALNEWS.ORG

Researchers see BPA effects in monkey mammary glands

Study adds to growing health concerns about common plastic additive

PULLMAN, Wash.—A new study finds that fetal exposure to the plastic additive bisphenol A, or BPA, alters mammary gland development in primates. The finding adds to the evidence that the chemical can be causing health problems in humans and bolsters concerns about it contributing to breast cancer.

“Previous studies in mice have demonstrated that low doses of BPA alter the developing mammary gland and that these subtle changes increase the risk of cancer in the adult,” says Patricia Hunt, a geneticist in Washington State University’s School of Molecular Biosciences. “Some have questioned the relevance of these findings in mice to humans. But finding the same thing in a primate model really hits uncomfortably close to home.”

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Mom will teach you NMR

July 26, 2014 11:38 am / Leave a comment

Dedicated to all moms in the world

ETHYL PROPIONATE NMR, carbonyl is dad and oxygen mom, a methyl gets more attention

ORIGINALLY IN http://orgspectroscopyint.blogspot.in/2014/07/ethyl-propionate-nmr-carbonyl-is-dad.html

C=O group is dad

O atom is mom

Carbonyl is dad and oxygen mom hence c labelled methyl has higher chemical shift and gets a little more attention

SEE BELOW

NMR IS EASY

A chemical has Formula: C₅H₁₀O₂

C₅H₁₀O₂
Rule 2, omit O, gives C₅H₁₀
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.

The band at 1740 indicates a carbonyl, probably a saturated aliphatic ester. The bands at 3000-2850 indicate C-H alkane stretches. The bands in the region 1320-1000 could be due to C-O stretch, consistent with an ester.

Structure answer

This is the structure. See if you can assign the peaks on your own.

NMR answer

C has a higher chemical shift than D because it’s closer to a more electron-withdrawing functional group.

Carbonyl is dad and oxygen mom, hence c has higher chemical shift and gets a little more attention in proton nmr

13 C NMR

Mass spectrum

RAMAN

WHAT HAPPENS WHEN A CHLORO IS INTRODUCED

THE INTERPRETATION IS BELOW

remember “a” labelled CH3 appears as a doublet

WHEN THERE IS ONE METHYL

WHEN THERE ONE CH2 SHORT

WHEN MOM HAS ONE MORE CH2

PROPYL PROPIONATE, try this on your own

1H NMR

see interpretation

BIGGER ONE THAN OBOVE

13C NMR

APT

COSY

WILL PASTE INTERPRETATION AFTER ONE WEEK……………….

Natural products from plants protect skin during cancer radiotherapy

July 26, 2014 3:15 am / Leave a comment

CLINICALNEWS.ORG

PUBLIC RELEASE DATE:

24-Jul-2014
Radiotherapy for cancer involves exposing the patient or their tumor more directly to ionizing radiation, such as gamma rays or X-rays. The radiation damages the cancer cells irreparably. Unfortunately, such radiation is also harmful to healthy tissue, particularly the skin over the site of the tumor, which is then at risk of hair loss, dermatological problems and even skin cancer. As such finding ways to protect the overlying skin are keenly sought.

Writing in the International Journal of Low Radiation, Faruck Lukmanul Hakkim of the University of Nizwa, Oman and Nagasaki University, Nagasaki, Japan, and colleagues there and at Macquarie University, New South Wales, Australia, Bharathiar University, India and Konkuk University, South Korea, explain how three ubiquitous and well-studied natural products derived from plants can protect the skin against gamma radiation during radiotherapy.

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Sage Therapeutics receives fast track designation for status epilepticus therapy

July 24, 2014 7:34 am / 1 Comment on Sage Therapeutics receives fast track designation for status epilepticus therapy

SAGE-547

ALLOPREGNANOLONE

Sage Therapeutics (Originator)

Sage Therapeutics

For Epilepsy, status epilepticus

SGE-102; SAGE-547; allopregnanolone; allosteric GABA A receptor modulators (CNS disorders),

Sage Therapeutics receives fast track designation for status epilepticus therapy
Ligand Pharmaceuticals announced that its partner Sage Therapeutics has received fast track designation from the US Food and Drug Administration (FDA) for the Captisol-enabled SAGE-547 to treat status epilepticus.

read at

http://www.pharmaceutical-technology.com/news/newssage-therapeutics-receives-fast-track-designation-for-status-epilepticus-therapy-4324543?WT.mc_id=DN_News

Chemical Name: (3α)-Allopregnanolone

Synonyms: (+)-3α-Hydroxy-5α-pregnan-20-one; (3α,5α)-3-Hydroxypregnan-20-one; 3α,5α-THP; 3α,5α-Tetrahydroprogesterone; 3α-Hydroxy-5α-dihydroprogesterone; 3α-Hydroxy-5α-pregnan-20-one; 3α-Hydroxy-5α-pregnane-20-one; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one; Allopregnan-3α-ol-20-one; Allopregnanolone; Allotetrahydroprogesterone;

CAS Number: 516-54-1

Applications: (3α)-Allopregnanolone acts as a GABAA receptor positive allosteric modulator. (3α)-Allopregnanolone is a metabolite of Progesterone (P755900). (3α)-Allopregnanolone is a neuroactive steroid present in the blood and also the brain.

References: Puja, G. et al.: Neuron, 4, 759 (1990); Belelli, D. et ael. Neurosteroid, 6, 565 (2006); Viapiano, M. et al.: Neurochem. Res., 23, 155 (1998);

Mol. Formula: C21H34O2

Appearance: White Solid

Melting Point: 174-176°C

Mol. Weight: 318.49

SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

In 2014, orphan drug designation was assigned in the U.S for the treatment of status epilepticus. In July 2014, fast track designation was received in the U.S. for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat life-threatening, rare central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has granted fast track designation to the SAGE-547 development program. SAGE-547 is an allosteric modulator of GABAA receptors in development for the treatment of adult patients with refractory status epilepticus who have not responded to standard regimens (super-refractory status epilepticus, or SRSE). SAGE is currently evaluating SAGE-547 in a Phase 1/2 clinical trial for the treatment of SRSE. Preliminary data indicate that the first four patients enrolled in the clinical trial met the key efficacy endpoint, in that each was successfully weaned off his or her anesthetic agent while SAGE-547 was being administered. There have also been no reported drug-related serious adverse events in these four patients to date.

“The fast track designation for SAGE-547 recognizes the significant unmet need that exists in the treatment of super-refractory status epilepticus,” said Jeff Jonas, MD, chief executive officer of SAGE Therapeutics. “The receipt of orphan drug designation earlier this year for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547, and we will continue to work closely with the FDA to advance our lead compound and the additional programs in our pipeline for the treatment of life-threatening CNS disorders.”

Fast track designation is granted by the FDA to facilitate the development and expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

About SAGE-547

SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE.

About Status Epilepticus (SE)

SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.1 We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.

About SAGE Therapeutics

SAGE Therapeutics (NASDAQ: SAGE) is a biopharmaceutical company committed to developing and commercializing novel medicines to treat life-threatening, rare CNS disorders. SAGE’s lead program, SAGE-547, is in clinical development for super-refractory status epilepticus and is the first of several compounds the company is developing in its portfolio of potential seizure medicines. SAGE’s proprietary chemistry platform has generated multiple new compounds that target GABAA and NMDA receptors, which are broadly accepted as impacting many psychiatric and neurological disorders. SAGE Therapeutics is a public company launched in 2010 by an experienced team of R&D leaders, CNS experts and investors. For more information, please visitwww.sagerx.com.

Allopregnanolone

IUPAC name 1-(3-hydroxy-10,13-dimethyl- 2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro- 1H-cyclopenta[a] phenanthren-17-yl)ethanone
Other names 3α,5α-Tetrahydroprogesterone
Identifiers

PubChem	262961
ChemSpider	17216124
ChEMBL	CHEMBL38856
Jmol-3D images	Image 1

Properties
Molecular formula	C₂₁H₃₄O₂
Molar mass	318.49 g/mol

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone), generally abbreviated as ALLO or as 3α,5α-THP, is an endogenous inhibitory pregnane neurosteroid.^[1] It is synthesized from progesterone, and is a potent positive allosteric modulator of the GABA_A receptor.^[1] Allopregnanolone has effects similar to those of other potentiators of the GABA_A receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.^[1]

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions.^[1]

Biosynthesis

The biosynthesis of allopregnanolone starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.^[1]

Depression, anxiety, and sexual dysfunction are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.^[2]

Mechanism

Allopregnanolone acts as a potent positive allosteric modulator of the GABA_A receptor.^[1] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.^[1] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear.^[3]^[4] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,^[5] and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor.^[6] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.^[7]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).^[7] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.^[8] In addition, allopregnanolone has recently been found to be an agonist of the newly-discovered membrane progesterone receptors (mPR), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABA_A receptor.^[9]^[10] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.^[9]^[11] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.^[7]^[12]

Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),^[13] including α₁ subtypes Ca_v1.2 and Ca_v1.3.^[14] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.^[14] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.^[14] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).^[15] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.^[15]

Function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,^[16] prosocial,^[17] antiaggressive,^[18] prosexual,^[17] sedative, pro-sleep,^[19] cognitive and memory-impairing, analgesic,^[20] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.^[1]

Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.^[21]^[22]^[23]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.^[24]^[25]^[26] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.^[24]^[25] This seems to be a common effect of many GABA_A receptor positive allosteric modulators.^[26]^[21] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.^[27]

Therapeutic applications

Allopregnanolone and the other endogenous inhibitory neurosteroids have very short half-lives, and for this reason, have not been pursued for clinical use themselves. Instead, synthetic analogs with improved pharmacokinetic profiles, such as ganaxolone, have been synthesized and are being investigated. However, exogenous progesterone, such as oral micronized progesterone (OMP), reliably elevates allopregnanolone levels in the body with good dose-to-serum level correlations.^[28] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.^[28] As a result, there has been some interest in using OMP to treat catamenial epilepsy,^[29] as well as other menstrual cycle-related and neurosteroid-associated conditions.

……………………………………….

http://www.google.com/patents/WO2006037016A2?cl=en

Materials and Methods

[0181] The materials and methods used for the follwing experiments have been described in Griffin L.D., et al, Nature Medicine 10: 704-711 (2004). This reference is hereby incorporated by reference in its entirety.

Example 1: Allopregnanolone Treatment of Niemann Pick type-C Mice Substantially Reduces Accumulation of the Gangliosides GMl, GM2, and GM3 in the Brain [0182] Mice were given a single injection of allopregnanolone, prepared in 20% βcyclodextrin in phosphate buffered saline, at a concentration of 25 mg/kg. The injection was on day 7 of life (P7, postnatal day 7). Concentrations of gangliosides GMl, GM2, GM3, were measured as well as other lipids such as ceramides and cerebrosides.

…………………………………………….

WO-2014031792 OR EQ

http://www.google.com/patents/US20140057885?cl=en

…………………………………….

WO-2013112605

http://www.google.com/patents/WO2013112605A2?cl=en

References

Reddy DS (2010). “Neurosteroids: endogenous role in the human brain and therapeutic potentials”. Prog. Brain Res. 186: 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. PMC 3139029. PMID 21094889.
Römer B, Gass P (December 2010). “Finasteride-induced depression: new insights into possible pathomechanisms”. J Cosmet Dermatol 9 (4): 331–2. doi:10.1111/j.1473-2165.2010.00533.x. PMID 21122055.
Morris KD, Moorefield CN, Amin J (October 1999). “Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids”. Mol. Pharmacol. 56 (4): 752–9. PMID 10496958.
Li W, Jin X, Covey DF, Steinbach JH (October 2007). “Neuroactive steroids and human recombinant rho1 GABAC receptors”. J. Pharmacol. Exp. Ther. 323 (1): 236–47. doi:10.1124/jpet.107.127365. PMID 17636008.
Bullock AE, Clark AL, Grady SR, et al. (June 1997). “Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes”. J. Neurochem. 68 (6): 2412–23. PMID 9166735.
Wetzel CH, Hermann B, Behl C, et al. (September 1998). “Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor”. Mol. Endocrinol. 12 (9): 1441–51. doi:10.1210/mend.12.9.0163. PMID 9731711.
Mellon SH (October 2007). “Neurosteroid regulation of central nervous system development”. Pharmacol. Ther. 116 (1): 107–24. doi:10.1016/j.pharmthera.2007.04.011. PMC 2386997. PMID 17651807.
Rupprecht R, Reul JM, Trapp T, et al. (September 1993). “Progesterone receptor-mediated effects of neuroactive steroids”. Neuron 11 (3): 523–30. PMID 8398145.
Thomas P, Pang Y (2012). “Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells”. Neuroendocrinology 96 (2): 162–71. doi:10.1159/000339822. PMC 3489003. PMID 22687885.
Pang Y, Dong J, Thomas P (January 2013). “Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and {epsilon} (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis”. Endocrinology 154 (1): 283–95. doi:10.1210/en.2012-1772. PMC 3529379. PMID 23161870.
Sleiter N, Pang Y, Park C, et al. (August 2009). “Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release”. Endocrinology 150 (8): 3833–44. doi:10.1210/en.2008-0774. PMC 2717864. PMID 19423765.
Lamba V, Yasuda K, Lamba JK, et al. (September 2004). “PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators”. Toxicol. Appl. Pharmacol. 199 (3): 251–65. doi:10.1016/j.taap.2003.12.027. PMID 15364541.
Hu AQ, Wang ZM, Lan DM, et al. (July 2007). “Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex”. Neuropsychopharmacology 32 (7): 1477–89. doi:10.1038/sj.npp.1301261. PMID 17151597.
Earl DE, Tietz EI (April 2011). “Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors”. J. Pharmacol. Exp. Ther. 337 (1): 301–11. doi:10.1124/jpet.110.178244. PMC 3063747. PMID 21262851.
Keitel V, Görg B, Bidmon HJ, et al. (November 2010). “The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain”. Glia 58 (15): 1794–805. doi:10.1002/glia.21049. PMID 20665558.
Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (July 2002). “The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens”. Eur. J. Neurosci. 16 (1): 169–73. PMID 12153544.
Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”. Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005. PMC 2898141. PMID 19656632.
Pinna G, Costa E, Guidotti A (February 2005). “Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior”. Proc. Natl. Acad. Sci. U.S.A. 102 (6): 2135–40. doi:10.1073/pnas.0409643102. PMC 548579. PMID 15677716.
Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”. Mini Rev Med Chem 12 (11): 1040–8. PMID 23092405.
Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol. 113: 70–8. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490.
Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci. 1007: 42–53. PMID 14993039.
Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”. Epilepsy Behav 13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004. PMID 18346939.
Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5. PMID 21533709.
Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience 191: 46–54. doi:10.1016/j.neuroscience.2011.03.061. PMID 21600269.
Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology 34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003. PMID 19272715.
Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486.
Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology (Berl.) 187 (2): 209–21. doi:10.1007/s00213-006-0417-0. PMID 16724185.
Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas 54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005. PMID 16406399.
Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.

Additional reading

Herd, MB; Belelli, D; Lambert, JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol. Ther. 116(1):20-34. doi:10.1016/j.pharmthera.2007.03.007.

Deoxyribonucleic acid (DNA) synthesis

July 23, 2014 7:02 am / 3 Comments on Deoxyribonucleic acid (DNA) synthesis

Deoxyribonucleic acid (DNA) synthesis is a process by which copies of nucleic acid strands are made. In nature, DNA synthesis takes place in cells by a mechanism known as DNA replication. Using genetic engineering and enzyme chemistry, scientists have developed man-made methods for synthesizing DNA. The most important of these is poly-merase chain reaction (PCR). First developed in the early 1980s, PCR has become a multi-billion dollar industry with the original patent being sold for $300 million dollars.

read all at

http://www.madehow.com/Volume-6/DNA-Synthesis.html

DNA synthesis

From Wikipedia, the free encyclopedia

DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. The term DNA synthesis can refer to any of the following in various contexts:

DNA replication – DNA biosynthesis (in vivo DNA amplification)
Polymerase chain reaction – enzymatic DNA synthesis (in vitro DNA amplification)
Gene synthesis – physically creating artificial gene sequences

DNA replication

In nature, such molecules are created by all living cells through the process of DNA replication, with replication initiator proteins splitting the existing DNA of the cell and making a copy of each split strand, with the copied strands then being joined together with their template strand into a new DNA molecule. Various means also exist to artificially stimulate the replication of naturally occurring DNA, or to create artificial gene sequences.

Polymerase chain reaction

A polymerase chain reaction is a form of enzymatic DNA synthesis in the laboratory, using cycles of repeated heating and cooling of the reaction for DNA melting and enzymatic replication of the DNA.

Gene synthesis

Artificial gene synthesis is the process of synthesizing a gene in vitro without the need for initial template DNA samples. In 2010 J. Craig Venter and his team were the first to use entirely synthesized DNA to create a self-replicating microbe, dubbed Mycoplasma laboratorium.^[1]

Oligonucleotide synthesis

Oligonucleotide synthesis is the chemical synthesis of sequences of nucleic acids. The process has been fully automated since the late 1970s and can be used to form desired genetic sequences as well as for other uses in medicine and molecular biology.

Base pair synthesis

Recent research has demonstrated the possibility of creating new nucleobase pairs in addition to the naturally occurring pairs, A-T (adenine – thymine) and G-C (guanine –cytosine). A third base pair could dramatically expand the number of amino acids that can be encoded by DNA, from the existing 20 amino acids to a theoretically possible 172.^[1]

References

^ Jump up to:^a ^b Fikes, Bradley J. (May 8, 2014). “Life engineered with expanded genetic code”. San Diego Union Tribune. Retrieved 8 May 2014.

Categories:

DNA replication

Pixantrone

July 22, 2014 4:44 am / Leave a comment

Chemical structure for CTK0H5262

Pixantrone

BBR-2778 , CTK0H5262

Pixolti
Pixuvri
UNII-P0R64C4CR9

An immunosuppressant.

144510-96-3 [RN]

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

CTI BioPharma has obtained Israeli Ministry of Health’s approval for Pixuvri (pixantrone), as a monotherapy to treat adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have received up to three previous courses of treatment.

The company also announced that the Dutch Healthcare Authority and the College voor zorgverzekeringen of the Netherlands have approved funding for Pixuvri as an add-on drug for patients who need a third or fourth-line treatment option for aggressive B-cell lymphoma.

Tel Aviv University faculty of medicine Dr Abraham Avigdor said: “The approval of PIXUVRI in Israel provides patients with aggressive B-cell NHL who have failed second or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side-effects.

read at

http://www.pharmaceutical-technology.com/news/newscti-biopharma-receives-israeli-approval-aggressive-b-cell-non-hodgkins-lymphoma-therapy-4321986?WT.mc_id=DN_News

Pixantrone

IUPAC name 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
Identifiers
CAS number	144510-96-3
PubChem	134019
ChemSpider	118174
KEGG	D05522
ChEMBL	CHEMBL167731
ATC code	L01DB11
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C₁₇H₁₉N₅O₂
Molar mass	325.365 g/mol
Appearance	Blue solid
Pharmacology
Routes of administration	Intravenous
Elimination half-life	9.5–17.5 hours
Excretion	Fecal (main route of excretion) and renal (4–9%)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

Pixantrone dimaleate [USAN]

CAS 144675-97-8

Molecular Formula

C17-H19-N5-O2.2C4-H4-O4

Molecular Weight

441.4417

Benz(g)isoquinoline-5,10-dione, 6,9-bis((2-aminoethyl)amino)-, (2Z)-2-butenedioate (1:2)

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m² administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue.^[1] It acts as a topoisomerase II poison and intercalating agent.^[2]^[3] The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.^[4]

History

Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.^[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.^[1]

Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity^[5] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.^[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho^[5] and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington.^[4]Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori,Milan, and the University of Padua.^[2]^[6]^[4] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.^[5]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone.^[7] A patent application for the injectable preparation was filed in May 2003.^[8]

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.^[9]

Clinical trials

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.^[10] phase III clinical trials of pixantrone have been completed.^[11]^[12] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.

Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.^[1]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.^[13]Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.^[14]

The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.^[15]

Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphomapatients.^[14]

The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma.^[16] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.^[14]

Administration

It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.^[8]^[14]

Regulatory approval

U.S. Food and Drug Administration

The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010^[17]show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.^[18]

European Medicines Agency

On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.^[19] In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.

Research

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.^[20] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production.^[21] Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,^[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.^[23]

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.

J Med Chem1994,37, (6): 828

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

References

Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). “Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone”. Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8. PMID 17285358.
De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F. (1995). “Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives”. Mol Pharmacol. 48 (1): 30–8.PMID 7623772.
Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). “Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent”. Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285. PMC 1920253.PMID 17483512.
Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC, Beggiolin G, Pezzoni G, Menta E, Manzotti C, Oliva A, Spinelli S, Tognella S (1994). “6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations”. J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018. PMID 8145234.
US patent 5587382, Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC, “6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity”, issued 1996-12-24, assigned to Boehringer Mannheim Italia, SpA
Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). “Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II”. Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-Q. PMID 8394077.
Borchmann P, Reiser M (May 2003). “Pixantrone (Novuspharma)”. IDrugs 6 (5): 486–90. PMID 12789604.
EP patent 1503797, Bernareggi A, Livi V, “Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity”, published 2003-11-27, issued 2008-09-29, assigned to Cell Therapeutics Europe S.R.L.
Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”. The New York Times. Retrieved 2010-05-22.
Jump up^ Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
Jump up^ “NCT00088530”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
“NCT00551239”. Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov. 2012-01-31. Retrieved 2012-01-31.
“Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin’s Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy”. Press Release. Retrieved 2012-01-31.
^ Jump up to:^a ^b ^c ^d Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I (September 2006). “EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkin’s lymphoma”. Clin Lymphoma Myeloma 7 (2): 152–4.doi:10.3816/CLM.2006.n.055. PMID 17026830.
Jump up^ “NCT00268853”. A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. ClinicalTrials.gov. Retrieved 2012-01-31.
Jump up^ “NCT00101049”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
Jump up^ Vesely N, Eckhardt SG (2010-03-22). “NDA 022-481 PIXUVRI (pixantrone dimaleate) injection” (pdf). Summary Minutes of the Oncologic Drugs Advisory Committee. United States Food and Drug Administration. Retrieved 2012-01-31.
Jump up^ “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
Jump up^ “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
Jump up^ Gonsette RE, Dubois B (August 2004). “Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity”. J. Neurol. Sci. 223(1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
Jump up^ Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F (November 2005). “Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis”. J. Neuroimmunol. 168 (1-2): 111–7.doi:10.1016/j.jneuroim.2005.07.010. PMID 16120465.
Jump up^ Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F (February 2008). “Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats”. J. Immunol. 180 (4): 2696–703. PMID 18250482.
Jump up^ Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E (April 2009). “CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity”. Electrophoresis 30(8): 1418–29. doi:10.1002/elps.200800377. PMID 19306269.

McLean Hospital study finds herbal extract may curb binge drinking – kudzu

July 22, 2014 1:16 am / 1 Comment on McLean Hospital study finds herbal extract may curb binge drinking – kudzu

CLINICALNEWS.ORG

18 May 2012

Belmont, MA – An extract of the Chinese herb kudzu dramatically reduces drinking and may be useful in the treatment of alcoholism and curbing binge drinking, according to a new study by McLean Hospital and Harvard Medical School researchers.

“Our study is further evidence that components found in kudzu root can reduce alcohol consumption and do so without adverse side effects,” said David Penetar, PhD, of the Behavioral Psychopharmacology Research Laboratory at McLean Hospital, and the lead author of the study. “Further research is needed, but this botanical medication may lead to additional methods to treat alcohol abuse and dependence.”

In the study, published in the current issue of Drug and Alcohol Dependence, researchers in the Behavioral Psychopharmacology Research Laboratory at McLean Hospital looked at one of the major components of the kudzu root—the isoflavone puerarin—to determine whether it would reduce alcohol consumption in a laboratory simulation…

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Component of pizza seasoning herb oregano kills prostate cancer cells – Oregano

July 21, 2014 1:50 am / Leave a comment

CLINICALNEWS.ORG

04 May2012

San Diego, CA — Oregano, the common pizza and pasta seasoning herb, has long been known to possess a variety of beneficial health effects, but a new study by researchers at Long Island University (LIU) indicates that an ingredient of this spice could potentially be used to treat prostate cancer, the second leading cause of cancer death in American men.

Prostate cancer is a type of cancer that starts in the prostate gland and usually occurs in older men. Recent data shows that about 1 in 36 men will die of prostate cancer. Estimated new cases and deaths from this disease condition in the US in 2012 alone are 241,740 and 28,170, respectively. Current treatment options for patients include surgery, radiation therapy, hormone therapy, chemotherapy, and immune therapy. Unfortunately, these are associated with considerable complications and/or severe side effects.

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SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

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