DR ANTHONY MELVIN CRASTO

ORGANIC CHEMISTRY EDUCATION

4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

Chemical structures of Varenicline Tartrate and degradant product (DP-I).........4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

(A) 1H NMR spectrum of DP-I. (B) Proton decoupled 13C NMR spectrum of DP-I.

UHPLC-ToF MS+ of DP-I.

The impurity obtained as pale white crystals. mp 71â73.

RP-UHPLC, tR = 1.8 min (98.5% purity).

MS (ESI, 70 eV): [M + H+] m/z 244.

FT-IR (KBr), v, cmâ1 3371, 3319, 3279, 3173, 3005, 2808, 1696, 1678, 1588, 1406, 1388, 1338, 1305, 1264, 1135, 1067, 873, 790, 680, 569, 485.

1H NMR (400 MHz, DMSO-d6 +D2O, TMS): Î´ 7.2 (s, 2H, H-7,8), 3.1â3.4 (m, 6H, H-11,13,14 & 16),2.3 (m, 1H, H-12), 2.0 (d, 1H, 11.2 Hz, H-12).

13C NMR (100 MHz, DMSO-d6, TMS): Î´ 173.8 (C-2,3), 155.1 (C-5,6), 137.6 (C-9,10), 125.1 (C-7,8), 38.8 (C-11), 37.9 (C-12), 38.8 (C-13), 45.8 (C-14), 48.6 (C-16).

UHPLC ToF MS+: m/z [M + H+].Calcd for C13H13N3O2: 244.1086; found: 244.1082.

Based on the above spectral data, the molecular formula of DP-I is C13H13N3O2 and the corresponding structure was characterized as 4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

 PMC full text: Published online 2012 Mar 20. doi:  10.3797/scipharm.1201-08

Chemical structures of Varenicline Tartrate and degradant product (DP-I).........4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

(A) 1H NMR spectrum of DP-I. (B) Proton decoupled 13C NMR spectrum of DP-I.

UHPLC-ToF MS+ of DP-I.

The impurity obtained as pale white crystals. mp 71â73.

RP-UHPLC, tR = 1.8 min (98.5% purity).

MS (ESI, 70 eV): [M + H+] m/z 244.

FT-IR (KBr), v, cmâ1 3371, 3319, 3279, 3173, 3005, 2808, 1696, 1678, 1588, 1406, 1388, 1338, 1305, 1264, 1135, 1067, 873, 790, 680, 569, 485.

1H NMR (400 MHz, DMSO-d6 +D2O, TMS): Î´ 7.2 (s, 2H, H-7,8), 3.1â3.4 (m, 6H, H-11,13,14 & 16),2.3 (m, 1H, H-12), 2.0 (d, 1H, 11.2 Hz, H-12).

13C NMR (100 MHz, DMSO-d6, TMS): Î´ 173.8 (C-2,3), 155.1 (C-5,6), 137.6 (C-9,10), 125.1 (C-7,8), 38.8 (C-11), 37.9 (C-12), 38.8 (C-13), 45.8 (C-14), 48.6 (C-16).

UHPLC ToF MS+: m/z [M + H+].Calcd for C13H13N3O2: 244.1086; found: 244.1082.

Based on the above spectral data, the molecular formula of DP-I is C13H13N3O2 and the corresponding structure was characterized as 4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

 PMC full text: Published online 2012 Mar 20. doi:  10.3797/scipharm.1201-08

ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride

You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.

The preference for endoâstereochemistry is âobservedâ in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together.

Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:

Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated.

The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated.

The NMR spectrum of  cis-5-norbornene-2,3- endo-dicarboxylic anhydride is given below:

Cis-Norbornene-5,6-endo-dicarboxylic anhydride
Cyclopentadiene was previously prepared through the cracking of dicyclopentadiene and kept under cold conditions.  In a 25 mL Erlenmeyer flask, maleic anhydride (1.02 g, 10.4 mmol) and ethyl acetate (4.0 mL) were combined, swirled, and slightly heated until completely dissolved.  To the mixture, ligroin (4 mL) was added and mixed thoroughly until dissolved.  Finally, cyclopentadiene (1 mL, 11.9 mmol) was added to the mixture and mixed extensively.  The reaction was cooled to room temperature and placed into an ice bath until crystallized.  The crystals were isolated through filtration in a Hirsch funnel.  The product had the following properties: 0.47 g (27.6% yield) mp: 163-164 °C (lit: 164 °C).  1H NMR (CDCl3, 300 MHz) Î´: 6.30 (dd, J=1.8 Hz, 2H), 3.57 (dd, J=7.0 Hz, 2H), 3.45 (m, 2H), 1.78 (dt, J=9.0,1.8 Hz, 1H), 1.59 (m, 1H) ppm.  13C NMR (CDCl3, 75Hz) Î´: 171.3, 135.5, 52.7, 47.1, 46.1 ppm.  IR 2982 (m), 1840 (s), 1767 (s), 1089 (m) cm-1.

Reaction Mechanism The scheme below depicts the concerted mechanism of the Diels-Alder reaction of cyclopentadiene and maleic anhydride to formcis-Norbornene-5,6-endo-dicarboxylic anhydride.

Results and Discussion
When combining the reagents, a cloudy mixture was produced and problems arose in the attempt to completely dissolve the mixture.  After heating for about 10 minutes and magnetically stirring, tiny solids still remained. The undissolved solids were removed form the hot solution by filtration and once they cooled, white crystals began to form. Regarding the specific reaction between cyclopentadiene and maleic anhydride, the endo isomer, the kinetic product, was formed because the experiment was directed under mild conditions.   The exo isomer is the thermodynamic product because it is more stable.3
A total of 0.47 g of the product was collected; a yield of 27.6%. The melting point was in the range of 163-164 °C which indicates the absence of impurities because the known melting point of the product is 164 °C.

The 1H NMR spectrum of the product revealed a peak in the alkene range at 6.30 ppm, H-2 and H-3 (Figure 1).  In addition, it exhibited two peaks at 3.57 and 3.45 ppm because of the proximity of H-1, H-4, H-5, and H-6 to an electronegative atom, oxygen.  Finally, two peaks at 1.78 and 1.59 ppm corresponded to the sp3 hydrogens, Hb and Ha, respectively.  Impurities that appeared included ethyl acetate at 4.03, 2.03, and 1.31 ppm as well as acetone at 2.16 ppm.
Regarding the 13C NMR, a peak appeared at 171.3 ppm, accounting for the presence of two carbonyl functional groups, represented by C-7 and C-8 in Figure 1.  The alkene carbons, C-2 and C-3, exhibited a peak at 135.5 ppm, while the sp3 carbons close to oxygen, C-5 and C-6, displayed a peak at 52.7 ppm.  Finally, peaks at 46.1 and 47.1 ppm accounted for the sp3 carbons, C-1 and C-4, and C-9.  Impurities of ethyl acetate appeared at 46.6, 25.8, and 21.0 ppm accompanied with acetone at 30.9 ppm.
The IR spectrum revealed a peak at 2982 cm-1 representing the C-H stretches.  A peak at 1840 cm-1 accounted for the carbonyl functional group, while a peak at 1767 cm-1 accounted for the alkene bond.  A peak at 1089 cm-1 represented the carbon-oxygen functional group.
In order to distinguish between the two possible isomers, properties such as melting point and spectroscopy data were analyzed.  The exo product possessed a melting point in the range of 140-145 °C which is significantly lower than the endo product.  The observed melting point in this experiment supported the production of the endo isomer.
The 1H NMR spectum exhibited a doublet of doublets at 3.57 ppm for the endo isomer.  The exo isomer would possess a triplet around 3.50 ppm due to the difference in dihedral angle between the hydrogen molecules of H-1 and H-4, and H-5 and H-6 (Figure 1).  A peak at 3.00 ppm would appear in the exo isomer spectra as opposed to a peak at 3.60 ppm as shown in the observed endo product.3 This is because of the interaction and coupling with the H-5 and H-6, as displayed in Figure 1.

Conclusion
Through the Diels-Alder reaction, 27.6% yield of cis-Norbornene-5,6-endo-dicarboxylic anhydride was produced. The distinction of the presence of the endo isomer was proven by analyzing physical properties of both possible isomers.
Martin, J.; Hill, R.; Chem Rev, 196161, 537-562.
2 Pavia, L; Lampman, G; Kriz, G; Engel, R. A Small Scale Approach to Organic Laboratory   Techniques, 2011, 400-409.
3 Myers, K.; Rosark, J. Diels-Alder Synthesis, 2004, 259-265.
http://orgspectroscopyint.blogspot.in/2014/08/cis-norborene-56-endo-dicarboxylic.html

ORGANIC SPECTROSCOPY INTERNATIONAL

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Oleanolic acid spectral data and interpretation

Oleanolic acid

Oleanic acid, Caryophyllin, Astrantiagenin C, Giganteumgenin C, Virgaureagenin B, 3beta-Hydroxyolean-12-en-28-oic acid, OLEANOLIC_ACID
Molecular Formula: C 30H 48O 3
Molecular Weight: 456.70032

Ursolic acid [(3b)-3-Hydroxyurs-12-en-28-oic acid] rarely occurs without its isomer oleanolic acid [(3b)-3-Hydroxyolean-12-en-28-oic acid] They may occur in their free acid form, as shown in Figure 1, or as aglycones for triterpenoid saponins which are comprised of a triterpenoid aglycone linked to one or more sugar moieties. Ursolic and oleanolic acids are similar in pharmacological activity

A pentacyclic triterpene that occurs widely in many PLANTS as the free acid or the aglycone for many SAPONINS. It is biosynthesized from lupane. It can rearrange to the isomer, ursolic acid, or be oxidized to taraxasterol and amyrin.

MS
EIMS m/z (rel. int.) 456 [M]+ (5), 412 (3), 248 (100), 203 (50), 167 (25), 44 (51)

IR KBR
(KBr) 3500, 2950, 2850, 1715; 1H-NMR (250 MHz, pyridine-d5) Î´: 5.49 (1H, s, H-12), 3.47 (1H, t, J = 8.0 Hz, H-3), 3.30 (1H, m, H-18), 1.12 (3H, s, CH3-27), 0.96 (3H, s, CH3-30), 0.91 (3H, s, CH3-25), 0.89 (3H, s, CH3-23), 0.87 (3H, s, CH3-24), 0.75 (3H, s, CH3-26)

1H NMR

 (250 MHz, pyridine-d5)Î´: 5.49 (1H, s, H-12), 3.47 (1H, t, J = 8.0 Hz, H-3), 3.30 (1H, m, H-18), 1.12 (3H, s, CH3-27), 0.96 (3H, s, CH3-30), 0.91 (3H, s, CH3-25), 0.89 (3H, s, CH3-23), 0.87 (3H, s, CH3-24), 0.75 (3H, s, CH3-26)

13 C NMR

 (63 MHz, pyridine-d5) Î´: 180.2 (C-28), 144.8 (C-13), 122.5 (C-12), 78.0 (C-3), 55.7 (C-5), 48.0 (C-9), 46.6 (C-8, 17), 42.1 (C-14), 39.7 (C-4), 39.4 (C-1), 37.3 (C-10), 33.2 (C-7), 32.9 (C-29), 32.4 (C-21), 30.9 (C-20), 28.7 (C-23), 27.2 (C-2), 26.9 (C-15), 26.1 (C-30), 23.7 (C-11), 23.6 (C-16), 18.7 (C-6), 17.4 (C-26), 16.5 (C-24), 15.5 (C-25)
FIG. 4 shows the  1H NMR spectrum of oleanolic acid;
FIG. 5 shows the  13C NMR spectrum of oleanolic acid;
FIG. 6 shows the  13C DEPT NMR spectrum of oleanolic acid;
FIG. 7 shows the  113C HSQC NMR spectrum of oleanolic acid;

see below

EXAMPLE 2 Extraction and Isolation of Oleanolic Acid (9) and Maslinic Acid (10) from Cloves

Syzygium aromaticum dried buds or whole cloves were obtained commercially. The cloves (1.5 kg, whole) of  Syzygium aromaticum were sequentially and exhaustively extracted with hexane and ethyl acetate to give, after solvent removal in vacuo, a hexane extract (68.8 g, 4.9%) and an ethyl acetate extract (34.1 g, 2.3%). A portion of the ethyl acetate extract (10.0 g), was subjected to chromatographic separation on silica gel (60-120 mesh) column (40×5.0 cm). Elution with hexane/ethyl acetate solvent mixtures (8:2â6:4) afforded pure oleanolic acid (9) (4.7 g, 1.06%), a mixture of oleanolic acid (9) and maslinic acid (10) (0.5 g), and pure maslinic acid (10) (0.25 g). The structures of oleanolic acid (9) and maslinic acid (10) (as 2,3-diacetoxyoleanolic acid) were confirmed by spectroscopic data analysis (1D and 2D  1H NMR and  13C NMR experiments) (FIGS. 4-7 and FIGS. 8-10, respectively).

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All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 7 million hits on google, pushing boundaries, one lakh plus connections worldwide, 3 lakh plus VIEWS on this blog in 193 countries

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ARAB MEDICINE- Alyeadah (Teucrium Stocisianum Bois)

Tree Germander (Teucrium fruticans)

This plant is used in folk medicine for treating diarrhea, cough, jaundice and abdominal pain

Medicinal plants are used for the treatment of different diseases in almost all cultures. Teucrium species grow wildly at different geographical locations around the world. Teucrium stocksianum is used in folk medicine for the treatment of diarrhea, cough, jaundice and abdominal pain. Scientific study on Teucrium stocksianum shows that it possesses anthelmintic, cytotoxic and antispasmodic activity. The aim of our present study is to identify the chemical composition and antinociceptive potential of the essential oil extracted from Teucrium stocksianum bioss.

Teucrium is a genus of perennial plants in the family Lamiaceae. The name is believed to refer to King Teucer of Troy. Members of the genus are commonly known as germanders. These species are herbs, shrubs or subshrubs. They are most common in Mediterranean climates.

An unusual feature of this genus compared with other members of Lamiaceae is that the flowers completely lack the upper lip of thecorolla, although it is somewhat reduced also in other genera (Ajuga among them).

Several species are used as food plants by the larvae of some Lepidoptera species including the Coleophora case-bearersColeophora auricella and Coleophora chamaedriella. The latter is only known from Wall Germander (T. chamaedrys).

Teucrium species are rich in essential oils. They are valued as ornamental plants and a pollen source, and some species have culinary and/or medical value.

ARAB MEDICINE- KHAT

 Catha edulis

Khat (Catha edulis) is a flowering plant native to the Horn of Africa and the Arabian Peninsula. Among communities from these areas, khat chewing has a long history as a social custom dating back thousands of years.

Khat contains a monoamine alkaloid called cathinone, an amphetamine-like stimulant, which is said to cause excitement, loss of appetite and euphoria. In 1980, the World Health Organization (WHO) classified it as a drug of abuse that can produce mild to moderatepsychological dependence (less than tobacco or alcohol), although the WHO does not consider khat to be seriously addictive. The plant has been targeted by anti-drug organizations such as the DEA.It is a controlled substance in some countries, such as the United States, Canada and Germany, while its production, sale and consumption are legal in other nations, including Djibouti, Ethiopia, Somalia and Yemen.

Man chewing khat in Sanaâa, Yemen, January 2009

Khat is a slow-growing shrub or tree that grows to between 1.4 m and 3.1 m tall, depending on region and rainfall. It has evergreenleaves 5â10 cm long and 1â4 cm broad. The flowers are produced on short axillary cymes 4â8 cm long. Each flower is small, with five white petals. The fruit is an oblong three-valved capsule containing 1â3 seeds. The seeds are samaras

Allegedly according to some sources, but disputed by others, khatâs exact place of origin is uncertain.One argument is that it was first grown in Ethiopia,with the explorer Sir Richard Burton suggesting that the plant was later introduced to Yemen from Ethiopia in the 15th century. He specifically mentions the eastern city of Harar as the birthplace of the plant.

However, amongst communities in the Horn of Africa (Djibouti, Eritrea, Ethiopia, Somalia) and the Arabian Peninsula, khat chewing has a long history as a social custom dating back thousands of years.

The Ancient Egyptians considered the khat plant a divine food, which was capable of releasing humanityâs divinity. The Egyptians used the plant for more than its stimulating effects; they used it for transcending into âapotheosisâ, with the intent of making the user god-like.

The earliest known documented description of khat is found in the Kitab al-Saidala fi al-Tibb ÙØªØ§Ø¨ Ø§ÙØµÙØ¯ÙØ© ÙÙ Ø§ÙØ·Ø¨, an 11th century work onpharmacy and materia medica written by AbÅ« RayhÄn al-BÄ«rÅ«nÄ«, a Persian scientist and biologist. Unaware of its origins, al-BÄ«rÅ«nÄ« wrote that khat is:

a commodity from Turkestan. It is sour to taste and slenderly made in the manner of  batan-alu. But  khat is reddish with a slight blackish tinge. It is believed that  batan-alu is red, coolant, relieves biliousness, and is a refrigerant for the stomach and the liver.

In 1854, Malay writer Abdullah bin Abdul Kadir noted that the custom of chewing khat was prevalent in Al Hudaydah in Yemen

You observed a new peculiarity in this city â everyone chewed leaves as goats chew the cud. There is a type of leaf, rather wide and about two fingers in length, which is widely sold, as people would consume these leaves just as they are; unlike betel leaves, which need certain condiments to go with them, these leaves were just stuffed fully into the mouth and munched. Thus when people gathered around, the remnants from these leaves would pile up in front of them. When they spat, their saliva was green. I then queried them on this matter: âWhat benefits are there to be gained from eating these leaves?â To which they replied, âNone whatsoever, itâs just another expense for us as weâve grown accustomed to itâ. Those who consume these leaves have to eat lots of ghee and honey, for they would fall ill otherwise. The leaves are known as  Kad.â

khat contains Cathinone ,

or benzoylethanamine (marketed as hagigat in Israel), is amonoamine alkaloid found in the shrub Catha edulis (khat) and is chemically similar toephedrine, cathine and other amphetamines. Cathinone induces the release of dopaminefrom striatal preparations that are prelabelled either with dopamine or its precursors. It is probably the main contributor to the stimulant effect of Catha edulis. Cathinone differs from many other amphetamines in that it has a ketone functional group. Other amphetamines that share this structure include the antidepressant bupropion and the stimulantmethcathinone, among others.

Internationally, cathinone is a Schedule I drug under the Convention on Psychotropic Substances. Circa 1993, the DEA added cathinone to the Controlled Substances Actâs Schedule I.

The sale of khat is legal in some jurisdictions, but illegal in others â see Khat (Regulation). Synthetic cathinone is also often used as the key ingredient of recreational drug mixes commonly known as âbath saltsâ in the United States.

Cathinone is structurally related tomethcathinone, in much the same way asamphetamine is related to methamphetamine. Cathinone differs from amphetamine by possessing a ketone oxygen atom (C=O) on the Î² (beta) position of the side chain. The corresponding alcohol compound cathine is a less powerful stimulant. The biophysiological conversion from cathinone to cathine is to blame for the depotentiation of khat leaves over time. Fresh leaves have a greater ratio of cathinone to cathine than dried ones, therefore having more psychoactive effects.

Cathinone can be extracted from Catha edulis, or synthesized from Î±-bromopropiophenone(which is easily made from propiophenone).

Pfizer, GSK form productivity pact with Singaporeâs A*Star

Pfizer, GlaxoSmithKline and engineering giant Siemens have signed on as founding members of a new consortium set up by Singaporeâs Agency for Science, Technology and Research (A*Star) to address challenges such as costs, regulatory compliance and processes to bring drugs from trials to markets.

The Agency for Science, Technology and Research (AbbreviationA*STARChinese: æ°å å¡ç§æç ç©¶å±) is a statutory board under the Ministry of Trade and Industry of Singapore. The Agency was established in 1991 to foster scientific research and talent for a knowledge-based Singapore.

Established in 1991 as the former National Science and Technology Board (NSTB), A*STAR was established with the primary mission to raise the level of science and technology in Singapore.[1]

The current chairman of A*STAR is Mr. Lim Chuan Poh. He was formerly the Permanent Secretary (Education) and the Chief of Defence Force. Mr Lim took over the reins of A*STAR from Mr. Philip Yeo, who later became Chairman of SPRING Singapore, on 1 April 2007.[2]

The scientific leadership includes Tan Chorh Chuan, George RaddaSydney BrennerDavid Lane, Charles Zukoski and used to include Prof Low Teck Seng. Prof Low Teck Seng left A*Star on 19 July 2012 to join the National Research Foundation of the Prime Ministerâs Office.

A*STAR Entities

The agency is made up of:

• The Biomedical Research Council (BMRC) â Oversees public sector research activities in the biomedical sciences
• The Science and Engineering Research Council (SERC) â Oversees public sector research activities in the physical sciences & engineering
• The A*STAR Joint Council (A*JC) â Promotes and supports interdisciplinary collaborations between biomedical sciences, and physical sciences & engineering
• Exploit Technologies Pte Ltd (ETPL) â Manages the intellectual property created by research institutes in Singapore, and facilitates technology transfer to industry
• The Corporate Group â Supports the rest of the organisation with finance, human resources, legal and other services

The agency oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and six consortia & centre, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.

A*STAR supports Singaporeâs key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.

Research Institutes & Units

Biomedical Research Council

The Biomedical Research Council (BMRC) oversees 7 research institutes and several other research units that focus on both basic as well as translational and clinical research to support the key industry clusters in Biomedical Sciencespharmaceuticals, medical technology, biotechnology and healthcare services.

Having established a strong foundation in basic biomedical research capabilities, there is now an added focus on translating new knowledge and technologies created at the âbenchesâ into new clinical applications for diagnosis and treatment that can one day be delivered at the âbedsidesâ of our hospitals and disease centres.

The research institutes and units under BMRC are:

The BMRC Research Institutes focus on building up core biomedical capabilities in the areas of bioprocessing; chemical synthesis; genomics and proteomics; molecular and cell biology; bioengineering and nanotechnology and computational biology. In addition, the Institute of Medical Biology (IMB) and Singapore Institute for Clinical Sciences (SICS) focus on translational and clinical research.

Science and Engineering Council

A*STARâs Science and Engineering Research Council (SERC) promotes public sector research and development in the physical sciences & engineering.

SERC manages seven research institutes and several state-of-the art centres and facilities with core competencies in a wide range of fields including communications, data storage, materials, chemicals, computational sciences, microelectronics, advanced manufacturing and metrology to tackle global technological challenges and create future industries from its headquarters at Fusionopolis, Singaporeâs iconic hub for science and technology research.

The research institutes and units under SERC are:

The seamless integration of the research institutes is key to addressing industry needs, which may span multiple disciplines. To this end, SERCâs broad range of capabilities are in a unique position to develop new technologies in areas such as automotives, aerospace, energy, electronic healthcare and medical technology, nanotechnology, photonics, sensors and sensor networks.

In July 2012, it was announced that A*STAR collaborates with Chinese language internet search provider Baidu to open a joint laboratory, called the Baidu-I2R Research Centre (BIRC), which aims to develop language processing technologies.[3]

Scholarships

Each year, the Agency gives out a number of scholarships and awards to young and aspiring scientists. These awards are meant to help Singapore achieve its goal of becoming a research hub by nurturing home-grown PhDs to serve both in the public sector and in industry. In 2008, a total of 101 scholarships were awarded to Bachelor of Science and PhD students who were to embark on their studies in overseas universities.[4] The administration of these awards are governed by the A*Star Graduate Academy, some of which are listed below:

• National Science Scholarship (BS)
• National Science Scholarship (PhD)
• Singapore International Graduate Award (SINGA)
• Singapore International Pre-Graduate Award (SIPGA)
• A*Star International Fellowship

www.a-star.edu.sg

Pfizer, GSK form productivity pact with Singaporeâs A*Star

Pfizer, GlaxoSmithKline and engineering giant Siemens have signed on as founding members of a new consortium set up by Singaporeâs Agency for Science, Technology and Research (A*Star) to address challenges such as costs, regulatory compliance and processes to bring drugs from trials to markets.

The Agency for Science, Technology and Research (AbbreviationA*STARChinese: æ°å å¡ç§æç ç©¶å±) is a statutory board under the Ministry of Trade and Industry of Singapore. The Agency was established in 1991 to foster scientific research and talent for a knowledge-based Singapore.

Established in 1991 as the former National Science and Technology Board (NSTB), A*STAR was established with the primary mission to raise the level of science and technology in Singapore.[1]

The current chairman of A*STAR is Mr. Lim Chuan Poh. He was formerly the Permanent Secretary (Education) and the Chief of Defence Force. Mr Lim took over the reins of A*STAR from Mr. Philip Yeo, who later became Chairman of SPRING Singapore, on 1 April 2007.[2]

The scientific leadership includes Tan Chorh Chuan, George RaddaSydney BrennerDavid Lane, Charles Zukoski and used to include Prof Low Teck Seng. Prof Low Teck Seng left A*Star on 19 July 2012 to join the National Research Foundation of the Prime Ministerâs Office.

A*STAR Entities

The agency is made up of:

• The Biomedical Research Council (BMRC) â Oversees public sector research activities in the biomedical sciences
• The Science and Engineering Research Council (SERC) â Oversees public sector research activities in the physical sciences & engineering
• The A*STAR Joint Council (A*JC) â Promotes and supports interdisciplinary collaborations between biomedical sciences, and physical sciences & engineering
• Exploit Technologies Pte Ltd (ETPL) â Manages the intellectual property created by research institutes in Singapore, and facilitates technology transfer to industry
• The Corporate Group â Supports the rest of the organisation with finance, human resources, legal and other services

The agency oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and six consortia & centre, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.

A*STAR supports Singaporeâs key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.

Research Institutes & Units

Biomedical Research Council

The Biomedical Research Council (BMRC) oversees 7 research institutes and several other research units that focus on both basic as well as translational and clinical research to support the key industry clusters in Biomedical Sciencespharmaceuticals, medical technology, biotechnology and healthcare services.

Having established a strong foundation in basic biomedical research capabilities, there is now an added focus on translating new knowledge and technologies created at the âbenchesâ into new clinical applications for diagnosis and treatment that can one day be delivered at the âbedsidesâ of our hospitals and disease centres.

The research institutes and units under BMRC are:

The BMRC Research Institutes focus on building up core biomedical capabilities in the areas of bioprocessing; chemical synthesis; genomics and proteomics; molecular and cell biology; bioengineering and nanotechnology and computational biology. In addition, the Institute of Medical Biology (IMB) and Singapore Institute for Clinical Sciences (SICS) focus on translational and clinical research.

Science and Engineering Council

A*STARâs Science and Engineering Research Council (SERC) promotes public sector research and development in the physical sciences & engineering.

SERC manages seven research institutes and several state-of-the art centres and facilities with core competencies in a wide range of fields including communications, data storage, materials, chemicals, computational sciences, microelectronics, advanced manufacturing and metrology to tackle global technological challenges and create future industries from its headquarters at Fusionopolis, Singaporeâs iconic hub for science and technology research.

The research institutes and units under SERC are:

The seamless integration of the research institutes is key to addressing industry needs, which may span multiple disciplines. To this end, SERCâs broad range of capabilities are in a unique position to develop new technologies in areas such as automotives, aerospace, energy, electronic healthcare and medical technology, nanotechnology, photonics, sensors and sensor networks.

In July 2012, it was announced that A*STAR collaborates with Chinese language internet search provider Baidu to open a joint laboratory, called the Baidu-I2R Research Centre (BIRC), which aims to develop language processing technologies.[3]

Scholarships

Each year, the Agency gives out a number of scholarships and awards to young and aspiring scientists. These awards are meant to help Singapore achieve its goal of becoming a research hub by nurturing home-grown PhDs to serve both in the public sector and in industry. In 2008, a total of 101 scholarships were awarded to Bachelor of Science and PhD students who were to embark on their studies in overseas universities.[4] The administration of these awards are governed by the A*Star Graduate Academy, some of which are listed below:

• National Science Scholarship (BS)
• National Science Scholarship (PhD)
• Singapore International Graduate Award (SINGA)
• Singapore International Pre-Graduate Award (SIPGA)
• A*Star International Fellowship

PLASTIC SURGERY-Breast Lift Surgery-mastopexy

Breast lift, or mastopexy, surgery raises and firms the breasts by removing excess skin and tightening the surrounding tissue to reshape and support the new breast contour.

Breast lift procedure steps

What happens during breast lift surgery? Your mastopexy surgery can be achieved through a variety of incision patterns and techniques. The appropriate technique for you will be determined based on:

• Breast size and shape
• The size and position of your areolas
• The degree of breast sagging
• Skin quality and elasticity as well as the amount of extra skin

Step 1 â Anesthesia

Medications are administered for your comfort during breast lift surgery. The choices include intravenous sedation and general anesthesia. Your doctor will recommend the best choice for you.

Step 2 â The incision

There are three common incision patterns:

Around the areola, . note-pics deleted

Around the areola and vertically down from the areola to the breast crease

Around the areola, vertically down from the breast crease and horizontally along the breast crease

Step 3 â Reshaping your breasts

After your doctor makes the incisions:

• The underlying breast tissue is lifted and reshaped to improve breast contour and firmness.
• The nipple and areola are repositioned to a natural, more youthful height.
• If necessary, enlarged areolas are reduced by excising skin at the perimeter.
• Excess breast skin is removed to compensate for a loss of elasticity.

Step 4 â Closing the incisions

After your breasts are reshaped and excess skin is removed, the remaining skin is tightened as the incisions are closed.

Some incision lines resulting from breast lifts are concealed in the natural breast contours; however, others are visible on the breast surface. Incision lines are permanent, but in most cases will fade and significantly improve over time.

Sutures are layered deep within the breast tissue to create and support the newly shaped breasts. Sutures, skin adhesives and/or surgical tape may be used to close the skin.

Step 5 â See the results

The results of your breast lift surgery are immediately visible. Over time, post-surgical swelling will resolve and incision lines will fade.

Satisfaction with your new image should continue to grow as you recover and realize the fulfillment of your goal for breasts which have been restored to a more youthful and uplifted position.

FDA Approves Pediatric Indication for Astellasâ Mycamine (micafungin sodium) for Injection

micafungin sodium

• C56-H70-N9-O23-S.Na

1292.265

Fujisawa (Originator), Merck & Co. (Codevelopment)

Antifungal Agents, ANTIINFECTIVE THERAPY, 1,3-beta-Glucan Synthase Inhibitors, Echinocandins

Launched-2002

{5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(1R)-2-carbamoyl-1-hydroxyethyl]-11,20,21,25-tetrahydroxy-15-[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[(4-{5-[4-(pentyloxy)phenyl]-1,2-oxazol-3-yl}benzene)amido]-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxyphenyl}oxidanesulfonic acid

June 24, 2013 , Astellas Pharma US, Inc. (âAstellasâ), a U.S. subsidiary of Tokyo-based Astellas Pharma Inc. (Tokyo: 4503), announced that the U.S. Food and Drug Administration (FDA) has approved its Supplemental New Drug Application (sNDA) for the use of MYCAMINE® (micafungin sodium) for injection by intravenous infusion for the treatment of pediatric patients four months and older with candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, esophageal candidiasis, and prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplants (HSCT).

Micafungin (trade name Mycamine) is an echinocandin antifungal drug developed by Astellas Pharma. It inhibits the production ofbeta-1,3-glucan, an essential component of fungal cell walls. Micafungin is administered intravenously. It received final approval from the U.S. Food and Drug Administration on March 16, 2005, and gained approval in the European Union on April 25, 2008.

Micafungin is indicated for the treatment of candidemia, acute disseminated candidiasisCandida peritonitisabscesses andesophageal candidiasis. Since January 23, 2008, micafungin has been approved for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation (HSCT).

Micafungin works by way of concentration-dependent inhibition of 1,3-beta-D-glucan synthase resulting in reduced formation of 1,3-beta-D-glucan, which is an essential polysaccharide comprising one-third of the majority of Candida spp. cell walls. This decreased glucan production leads to osmotic instability and thus cellular lysis

• Micafungin sodium, FK-463, Mycamine, Funguard,208538-73-2

• The synthesis of FK-463 can be performed as follows: The enzymatic deacylation of FR-901379 with Streptomyces anulatas No. 4811, S. anulatas No. 8703, Streptomyces strain No. 6907 or A. utahensis IFO13244 gives the deacylated lipopeptide FR-179642 (1), which is then reacylated with 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole 3-oxide (VI) by means of dimethylaminopyridine (DMAP) in DMF. The acylating compound (VI) can be obtained as follows: The cyclization of 4-pentyloxyphenylacetylene (I) with 4-(hydroxyiminomethyl)benzoic acid methyl ester (II) by means of triethylamine in hot THF gives 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in hot THF/water yielding the corresponding free acid (IV). Finally, this compound is condensed with 1-hydroxybenzotriazole (V) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDMCA) in dichloromethane.

Fromtling, R.A.; Castr, Drugs Fut 1998, 23, 12, 1273

The synthesis of FK-463 can be performed as follows: The enzymatic deacylation of FR-901379 with Streptomyces anulatas No. 4811, S. anulatas No. 8703, Streptomyces strain No. 6907 or A. utahensis IFO13244 gives the deacylated lipopeptide FR-179642 (1), which is then reacylated with 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole 3-oxide (VI) by means of dimethylaminopyridine (DMAP) in DMF. The acylating compound (VI) can be obtained as follows: The cyclization of 4-pentyloxyphenylacetylene (I) with 4-(hydroxyiminomethyl)benzoic acid methyl ester (II) by means of triethylamine in hot THF gives 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in hot THF/water yielding the corresponding free acid (IV). Finally, this compound is condensed with 1-hydroxybenzotriazole (V) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDMCD) in dichloromethane.
• 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego)1998,:Abst F-145

Date rape drug sensor

gamma-butyrolactone

The first fluorescent sensor for known date rape drug gamma-butyrolactone (GBL) has been developed in Singapore. It emits orange fluorescence in alcoholic drinks containing GBL when irradiated with a green laser.

Gamma-butyrolactone (GBL) is a readily available industrial solvent that is often used as a date rape drug. There are several detection kits that can show if a drink has been spiked with drugs like gamma-hydroxybutyric acid (GHB) and ketamine but there are no commercially available sensors to detect GBL.

Fernando Patolsky and Michael Ioffe of Tel Aviv University developed a sensor that, when dipped into a drink, will instantly detect the presence of a drug such as GHB, ketamine, or Rohypnol.

Ketamine

Predatory drugs or date rape drugs are responsible for the creation of the most dangerous and pathologic environment that exists around drug use and drug abuse. Predatory drugs are a general class of drug that are primarily used to ârender the victim incapable of resisting sexual advancesâ. (U.S. DEA)

This statement does not imply that the drug makes a person desire sexual activity, but quite the opposite. Predatory drugs leave the victim helpless, possibly unconscious, but certainly without any memory of a crime being committed against him/her. It can not be emphasized enough that giving someone a predatory drug is not only morally reprehensible it is also a serious criminal act. Illicit use of date rape drugs involve some of the most pathologic criminals who are involved with our justice system.

Street Names: Special K, K, Roofi, Sleepy
Misspellings: Ketamene, Ketimane, Rohipnol, Rophinol

What is Date Rape Drug Addiction?

So called date rape drugs are also found at rave parties, clubs, college parties, and even in high school social environments. They are potent drugs that can cause serious health problems, developmental problems, overdose and death. To further complicate the effects of these drugs, many are produced in illegal labs. Illicit production of drugs means there is no quality control standards. The lack of quality control standards can greatly diminish the purity of the drugs and leaves the user vulnerable to harsh chemicals and possibly overdose. Most of the chemicals found in date rape drugs are not intended for human consumption.

The number of drugs that are considered predatory drugs is increasing. To date, the most commonly used are:

• GHB â GBHâs chemical name is gama hydroxybutyrate and is currently a
DEA

schedule 1 drug that has central nervous system depressant effects.

• GBL/1 â GBL is a pro-drug of GHB and produces the same effects.
• 4-BD â The chemical name of 4-BD is 1,4-Butanediol and is used industrially as a solvent. When taken recreationally, it produces the same effects as GHB.
• Ketamine â Ketamine, or special K, as it is known on the streets, is a type of anesthetic known as a dissociative anesthetic and is approved for human and veterinarian use. When taken recreationally, it produces euphoria and hallucinations.
• Rohypnol â The generic name of Rohypnol is flunitrazepam and it is marketed as a potent hypnotic, sedative, and it produces amnesia. It is in the class of drugs known as benzodiazepines.

Some of these drugs are made from industrial strength floor cleansers, lye, and Dranno and can cause brain damage.

Signs and Symptoms Date Rape Drugs Addiction

The regular use of drugs such as GHB/GBL used to lower inhibitions can create significant side effects. The most common side effects produced by the recreational use of date rape drugs are:

• Psychosis and severe agitation requiring self-protection procedures and sedation
• Mild tachycardia (increased heart rate) and hypertension
• Neurologic effects, including prolonged delirium
• Hallucinations
• Diaphoresis (profuse sweating), nausea, and vomiting
• Overdose, coma, and death

Because of the memory loss associated with these drugs, the user can be prone to use again and again without memory of severe side effects. Once used regularly, date rate drugs could also lead to serious withdrawal symptoms. These withdrawal symptoms will require medical attention and medication.

Beyond the physical dependence an emotional dependence can quickly develop. Once regular use begins an addict can experience personality changes which may result in aggressive behavior, a disregard for authority, a disregard for personal safety, risky sexual behavior, a loss of boundaries, financial difficulties, problems at school or work, a change in friends, and the loss of interest in normal activities.

No one plans on becoming an addict but the power of drugs on the brainâs functioning, accompanied by the alterations in the neuroreceptors, drives the addiction process. It is not about choice or desire once the bodyâs systems have been affected. Date rape drugs or predatory drugs are extraordinarily powerful both in their addictive qualities and the serious, negative, health consequences that accompany regular use.

Numerous small gallstones made up largely of cholesterol.

gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder but may distally pass into other parts of the biliary tract such as the cystic ductcommon bile ductpancreatic duct, or theampulla of Vater. Rarely, in cases of severe inflammation, gallstones may erode through the gallbladder into adherent bowel potentially causing an obstruction termed gallstone ileus.

Presence of gallstones in the gallbladder may lead to acute cholecystitis,[2] an inflammatory condition characterized by retention of bile in the gallbladder and often secondary infection by intestinal microorganisms, predominantly Escherichia coli, Klebsiella, Enterobacter, and Bacteroides species.Presence of gallstones in other parts of the biliary tract can cause obstruction of the bile ducts, which can lead to serious conditions such as ascending cholangitis or pancreatitis. Either of these two conditions can be life-threatening and are therefore considered to be medical emergencies

Symptoms

Gallstones may be asymptomatic, even for years. These gallstones are called âsilent stonesâ and do not require treatment.Symptoms commonly begin to appear once the stones reach a certain size (>8 mm). A characteristic symptom of gallstones is a âgallstone attackâ, in which a person may experience intense pain in the upper-right side of the abdomen, often accompanied by nausea and vomiting, that steadily increases for approximately 30 minutes to several hours. A patient may also experience referred pain between the shoulder blades or below the right shoulder. These symptoms may resemble those of a âkidney stone attackâ. Often, attacks occur after a particularly fatty meal and almost always happen at night, and after drink.

A positive Murphyâs sign is a common finding on physical examination.

Causes

Gallstone risk increases for females (especially before menopause) and for people near or above 40 years; the condition is more prevalent among both North and South Amerindians and among those of European descent than among other ethnicities. A lack ofmelatonin could significantly contribute to gallbladder stones, as melatonin inhibits cholesterol secretion from the gallbladder, enhances the conversion of cholesterol to bile, and is an antioxidant, which is able to reduce oxidative stress to the gallbladder.Researchers believe that gallstones may be caused by a combination of factors, including inherited body chemistry, body weight, gallbladder motility (movement), and perhaps diet. The absence of such risk factors does not, however, preclude the formation of gallstones.

No clear relationship has been proved between diet and gallstone formation; however, low-fiber and high-cholesterol diets have been suggested as contributing to gallstone formation. Other nutritional factors that may increase risk of gallstones include rapid weight loss; constipation; eating fewer meals per day; and low intake of the nutrients folate, magnesium, calcium, and vitamin C. On the other hand, wine and whole-grained bread may decrease the risk of gallstones. Pigment gallstones are most commonly seen in the developing world. Risk factors for pigment stones include hemolytic anemias (such as sickle-cell disease and hereditary spherocytosis), cirrhosis, and biliary tract infections. People with erythropoietic protoporphyria (EPP) are at increased risk to develop gallstones. Additionally, prolonged use of proton pump inhibitors has been shown to decrease gallbladder function, potentially leading to gallstone formation

Diet is the fundamental part in the treatment of gall bladder disorders. In cases of acute gall-bladder inflammation, the patient should fast for two or three days, until the acute condition clears. Nothing but water should be taken during the fast. After the fast, the patient should take carrot, beet, grape fruit, lemon and grape juice for a few days. The diet should contain a sufficient amount of lacto-vegetarian, consisting of raw and cooked vegetables, vegetable juices, and a moderate amount of fruit and seeds. Yogurt, cottage cheese and a tablespoon of olive oil twice a day should also be taken.

All meats, eggs, animal fats and processed and denatured fats as well as fried foods should be avoided. The diet should also keep out refined carbohydrates, particularly sugar, sugar products, alcohol, soft drinks, cakes, puddings, ice-cream, coffee and citrus fruits. The patient should eat small meals at regular intervals, rather than three large meals.

Treatment

Medical

Cholesterol gallstones can sometimes be dissolved by oral ursodeoxycholic acid, but it may be necessary for the patient to take this medication for up to two years. Gallstones may recur, however, once the drug is stopped. Obstruction of the common bile duct with gallstones can sometimes be relieved by endoscopic retrograde sphincterotomy (ERS) following endoscopic retrograde cholangiopancreatography (ERCP). Gallstones can be broken up using a procedure called extracorporeal shock wave lithotripsy(often simply called âlithotripsyâ), which is a method of concentrating ultrasonic shock waves onto the stones to break them into tiny pieces. They are then passed safely in the feces. However, this form of treatment is suitable only when there is a small number of gallstones.

Surgical

Cholecystectomy (gallbladder removal) has a 99% chance of eliminating the recurrence of cholelithiasis. Surgery is only indicated in symptomatic patients. The lack of a gallbladder may have no negative consequences in many people. However, there is a portion of the population â between 10 and 15% â who develop a condition called postcholecystectomy syndrome which may cause gastrointestinal distress and persistent pain in the upper-right abdomen, as well as a 10% risk of developing chronic diarrhea.

There are two surgical options for cholecystectomy:

• Open cholecystectomy is performed via an abdomenal incision (laparotomy) below the lower right ribs. Recovery typically requires 3â5 days of hospitalization, with a return to normal diet a week after release and to normal activity several weeks after release.
• Laparoscopic cholecystectomy, introduced in the 1980s, is performed via three to four small puncture holes for a camera and instruments. Post-operative care typically includes a same-day release or a one night hospital stay, followed by a few days of home rest and pain medication.[7] Laparoscopic cholecystectomy patients can, in general, resume normal diet and light activity a week after release, with some decreased energy level and minor residual pain continuing for a month or two. Studies have shown that this procedure is as effective as the more invasive open cholecystectomy, provided the stones are accurately located by cholangiogram prior to the procedure so that they can all be removed.
A New Alternative Surgical Technique

A new surgical technique is available to remove Gallstones without excision of gallbladder. This technique is available in China.

Alternative medicine

A regimen called a âgallbladder flushâ or âliver flushâ is a popular remedy in alternative medicine.In this treatment, often self-administered, the patient drinks four glasses of pure apple juice (not cider) and eats five apples (or applesauce) per day for five days, then fasts briefly, takes magnesium, and then drinks large quantities of lemon juice mixed with olive oil before bed. The next morning, they painlessly pass a number of green and brown pebbles purported to be stones flushed from the biliary system. Apples are a source of pectin, which has been shown to sequester bile and facilitate its elimination in the stool.

A brief communication in The Lancet presents a case report of such a treatment where the patient released many soft stones. According to the letter, âAt the university hospital the stones were recognized as fatty stonesâ. In another case report, a patient with ultrasonography-confirmed gallstones drank olive oil and lemon juice, suffered diarrhea and intense abdominal pain, and released several gallstones. After that treatment, the gallbladder was empty, as confirmed by ultrasonography.

On the other hand, a couple of case reports challenge whether the stones retrieved from the stool after the âgallbladder flushâ really come from the gallbladder. A New Zealand hospital analyzed stones from a typical gallbladder flush and found them to be composed of fatty acids similar to those in olive oil, with no detectable cholesterol or bile salts, demonstrating that they are little more than hardened olive oil. Despite the gallbladder flush, the patient still required surgical removal of multiple true gallstones. A similar case report in The Lancet,accompanied by a simple chemical experiment, concludes that the observed stones from a typical gallbladder flush actually are a consequence of the flush: they form in the stomach under the action of digestive enzymes on the mix of olive oil and lemon.

Finally, drinking an infusion of âChanca Piedraâ, or âBreak Stonesâ (Phyllanthus niruri), a plant that is native to the Amazon, has long been used in South American traditional medicine to maintain kidney, liver, and gallbladder health and to treat gallstones and kidney stones and jaundice.

Other patients have anecdotally reported that symptoms can be temporarily reduced by drinking several glasses of water when experiencing gallstone pain. There is no known evidence backing this claim, and this approach will not eliminate the gallstones or improve the patientâs condition in the long term

Treatment involves removing the stone using ERCP. Typically, the gallbladder is then removed, an operation called cholecystectomy, to prevent a future occurrence of common bile duct obstruction or other complications

FOODS TO AVOID

YOGA

Regular applications of hot and cold fomentations to the abdomen improve the circulation of the liver and gall-bladder. They also stimulate concentrations of the gall-bladder, thereby improving the flow of bile. A cold hip bath improves the general abdominal tone. The pain of gall-stone colic can be relieved by the application of hot packs or fomentation to the upper abdominal area. A warm water enema at body temperature will help eliminate faecal accumulations if the patient is constipated. Exercise is necessary as physical inactivity can lead to lazy gall-bladder type indigestion which may eventually result in the formation of stones. Yogic asanas which are beneficial in toning up the liver and gall-bladder are: sarvangasanapaschimottanasanasalabhasanadhanurasana andbhujangasana.

TIPS

Gugulipid, an Extract of Ayurveda Medicine Plant Commiphora Mukul as a Potent Agent for Cancer Chemoprevention and Cancer Chemotherapy

E-Guggulsterone

Z-Guggulsterone

Citation: Xiao M, Xiao D (2012) Gugulipid, an Extract of Ayurveda Medicine Plant Commiphora Mukul as a Potent Agent for Cancer Chemoprevention and Cancer Chemotherapy. Med chem 2:e105.
doi:10.4172/2161-0444.1000e105

Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA

Gugulipid (GL), an extract of Commiphora mukul, has been safely used for thousands of years in the Indian Ayurveda medicine practice for the treatment of different ailments and has been used recently in many clinical trials that focused on its cholesterol-lowering effect. GL has recently been paid great attention for its cancer chemopreventive and chemotherapeutic potential. Z- and E-Guggulsterone have been identified as the major active components of GL. Studies have shown that GL as well as Guggulsterones can inhibit cancer growth in vitro and in vivo and lead to prevention of cancer initiation, promotion and progression. Although the action mechanisms of GL are not completely understood, GL has been revealed as a multitargeted cancer chemopreventive and chemotherapeutic agent. The increased understanding of the anti-cancer activity of GL and its molecular targets would allow us to improve its efficacies in different types of human cancers by single and/or combination strategies.

Gugulipid (GL, guggul, guggal, or gugul lipid) is the ethyl acetate extract of gum guggul resin (raw material) that is harvested directly from the Commiphora mukul tree (family name: Burseraceae; synonyms: Hook, Bandari, Balsamodendron mukul, and Commiphora Wightii). GL is a highly valued botanical medicine. As aforementioned, GL has been safely used for thousands of years in the Indian Ayurvedic medicine for the treatment of different ailments, including lipid disorders, rheumatoid arthritis, ulcers, osteoarthritis, bone fractures, epilepsy and obesity . In 1986, GL was granted approval in India for marketing as a lipid lowering drug (Indian Pharmacopeia 2007: pgs. 2038-2040). Several products of standardized formulations of Commiphora mukul are already in human use as cholesterollowering agents .

The Z- and E-forms of guggulsterone (Gug, 4,17(20)-pregnadie-3, 16-dione) have been identified as major active components of GL . GL and its active component z-Gug have been used in many clinical trials that focused on its cholesterol-lowering effect . Numerous studies continue to support that many edible phytochemicals have cancer chemopreventive and chemotherapeutic potential .

These finding motivated the investigation of the cancer chemopreventive and chemotherapeutic potential of GL and its active components.Guggulsterone is a plant steroid found in the resin of the guggul plant, Commiphora mukul. Guggulsterone can exist as either of two stereoisomers, E-guggulsterone and Z-guggulsterone. In humans, it acts as an antagonist of the farnesoid X receptor, which was once believed to result in decreased cholesterol synthesis in the liver.

Several studies have been published that indicate no overall reduction in total cholesterol occurs using various dosages of guggulsterone, and levels of low-density lipoprotein ("bad cholesterol") increased in many people.[1][2] Nevertheless, guggulsterone is an ingredient in many nutritional supplements.

Identifiers
CAS number 95975-55-6 (E/Z) , 39025-24-6 (E) , 39025-23-5 (Z)
1. Szapary, PO; Wolfe, ML; Bloedon, LT; Cucchiara, AJ; Dermarderosian, AH; Cirigliano, MD; Rader, DJ (2003). "Guggulipid Ineffective for Lowering Cholesterol". JAMA290 (6): 765â772. doi:10.1001/jama.290.6.765PMID12915429.
2. Sahni, S; Hepfinger, CA; Sauer, KA (2005). "Guggulipid Use in Hyperlipidemia". Am J Health-Syst Pharm62 (16): 1690â1692. doi:10.2146/ajhp040580PMID16085931.

Scheme 1. Stereoselective synthesis of E-guggulsterone (1) from 4-androsten-3,17-dione (5). (i) CH(OEt)3p-TSA, THF/EtOH, quantitative; (ii) EtPPh3Br, t-BuOK, THF, reflux; (iii) HCl, THF, 95% from 6; (iv) SeO2t-BuO2H, 90%; (v) (COCl)2, DMSO, Et3N, CH2Cl2, 85%

Tiny Capsule Effectively Kills Cancer Cells

A diagram of the synthesis of degradable nanocapsules into cell nuclei to induce apoptosis, or programmed cell death, in cancer cells. The nanocapsules degrade harmlessly in normal cells. (Credit: Courtesy of UCLA Engineering)

Devising a method for more precise and less invasive treatment of cancer tumors, scientists have developed a degradable nanoscale shell to carry proteins to cancer cells and stunt the growth of tumors without damaging healthy cells.

A tiny capsule invented at a UCLA lab could go a long way toward improving cancer treatment.

Devising a method for more precise and less invasive treatment of cancer tumors, a team led by researchers from the UCLA Henry Samueli School of Engineering and Applied Science has developed a degradable nanoscale shell to carry proteins to cancer cells and stunt the growth of tumors without damaging healthy cells.

In a new study, published online Feb. 1 in the peer-reviewed journal Nano Today, a group led by Yi Tang, a professor of chemical and biomolecular engineering and a member of the California NanoSystems Institute at UCLA, reports developing tiny shells composed of a water-soluble polymer that safely deliver a protein complex to the nucleus of cancer cells to induce their death. The shells, which at about 100 nanometers are roughly half the size of the smallest bacterium, degrade harmlessly in non-cancerous cells.

The process does not present the risk of genetic mutation posed by gene therapies for cancer, or the risk to healthy cells caused by chemotherapy, which does not effectively discriminate between healthy and cancerous cells, Tang said.

"This approach is potentially a new way to treat cancer," said Tang. "It is a difficult problem to deliver the protein if we don't use this vehicle. This is a unique way to treat cancer cells and leave healthy cells untouched."

The cell-destroying material, apoptin, is a protein complex derived from an anemia virus in birds. This protein cargo accumulates in the nucleus of cancer cells and signals to the cell to undergo programmed self-destruction.

The polymer shells are developed under mild physiological conditions so as not to alter the chemical structure of the proteins or cause them to clump, preserving their effectiveness on the cancer cells.

Tests done on human breast cancer cell lines in laboratory mice showed significant reduction in tumor growth.

"Delivering a large protein complex such as apoptin to the innermost compartment of tumor cells was a challenge, but the reversible polymer encapsulation strategy was very effective in protecting and escorting the cargo in its functional form," said Muxun Zhao, lead author of the research and a graduate student in chemical and biomolecular engineering at UCLA.

Tang's group continues to research ways of more precisely targeting tumors, prolonging the circulation time of the capsules and delivering other highly sought-after proteins to cancer cells.

The research team also included former UCLA Engineering student Zhen Gu, now an assistant professor in the joint biomedical engineering department at the University of North Carolina at Chapel Hill and North Carolina State University, and University of Southern California researchers including graduate student Biliang Hu, postdoctoral scholar Kye-Il Joo and associate professor Pin Wang.

LM11A-31, New drug can help paralyzed people walk again

LM11A-31, C12 H25 N3 O2, Pentanamide, 2-amino-3-methyl-N-[2-(4-morpholinyl)ethyl]- WO 2010102212 TO LONGO FRANK, PUB 10.09.2010 THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

Scientists have developed a pill which they claim could help paralyzed people walk again.

The new drug allowed mice with no movement in their lower limbs to walk with 'well-coordinated steps' and even to replicate swimming motions, researchers said.

The experimental drug, called LM11A-31, was developed by Professor Frank Longo, of Stanford University, California.

The researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42 day experimental period, the 'Daily Mail' reported.

In tests, the experimental medication did not increase pain in the mice and showed no toxic effects on the animals.

It also efficiently crossed the blood brain barrier, which protects the central nervous system from potentially harmful chemicals carried around in the rest of the bloodstream.

An injury to the spinal cord stops the brain controlling the body and this is the first time an oral drug has been shown to provide an effective therapy.

"This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model," Professor Sung Ok Yoon, of Ohio State University, Columbus, said.

"So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement," Yoon said.

The small molecule in the study was tested for its ability to prevent the death of cells called oligodendrocytes.

These cells surround and protect axons, long projections of a nerve cell, by wrapping them in a myelin sheath that protect the fibres.

In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon's lab previously found p75 is linked to the death of these specialised cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

"Because we know oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons," she said.

Full Text - Journal of Neuroscience

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death  in Journal of neuroscience, 26(20): 5288-5300; doi: 10.1523/âJNEUROSCI.3547-05.2006 by SM Massa - 2006 - Cited by 51 - Related articles
17 May 2006 â At 5 nm, LM11A-24 and -31 inhibit TUNEL staining to a degree ... We further prioritized LM11A-31, because preliminary studies

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

2010 slide presentation re p75 (e.g. LM11A-31) by PharmatrophiX's ...

investorvillage.com/smbd.asp?mb=160&mn=440341...

3 Nov 2010 â 2010 slide presentation re p75 (e.g. LM11A-31) by PharmatrophiX's founder. Longo is PharmatrophiX's founder.

The experimental drug was developed by Prof Frank Longo from Stanford University

Prof Frank Longo from Stanford University publications

Patents

1 US2013005731  (A1) â 2013-01-03

2 WO2011150347  (A2) â 2011-12-01

3 US2011230479  (A1) â 2011-09-22

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Bedaquiline(Sirturo, TMC207 or R207910) FDA approves 1st new tuberculosis drug in 40 years

(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol, cas no 654653-81-3

Bedaquiline

FDA approves 1st new tuberculosis drug in 40 years
The Food and Drug Administration on Monday approved a Johnson & Johnson tuberculosis drug that is the first new medicine to fight the deadly infection in more than four decades.

Bedaquiline (also known as SirturoTMC207 or R207910) is an diarylquinoline anti-tuberculosis drug, which was discovered by a team led by the Belgian Koen Andries atJanssen Pharmaceutica.[1] It was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting Late-Breaker Session, after the drug had been in development for over seven years,[2] and a trial of 47 patients showed that it is effective in the treatment of M. tuberculosis.[3] It is the first new medicine to fight the infection in more than forty years.[4][5] Sirturo is the first medicine specifically designed for treating multi-drug-resistant tuberculosis â an increasingly common form of the disease that cannot be treated with at least two of the four primary antibiotics used to treat tuberculosis. The standard drugs used to fight the disease were developed in the 1950s and 1960s.

1. de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). "A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910". Proteins 67 (4): 971â80.doi:10.1002/prot.21376.PMID 17387738.
2. Protopopova M, Bogatcheva E, Nikonenko B, Hundert S, Einck L, Nacy CA (May 2007). "In search of new cures for tuberculosis"Med Chem 3 (3): 301â16.doi:10.2174/157340607780620626.PMID 17504204.
3. Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF (June 2009). "The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis". N. Engl. J. Med. 360 (23): 2397â2405.doi:10.1056/NEJMoa0808427.PMID 19494215.
4.  "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. Retrieved 31 December 2012.
5. "F.D.A. Approves New Tuberculosis Drug". New York Times. Retrieved 31 December 2012.
6.  "Sirturo". RxWiki. Retrieved 2 January 2013.
7. Matteelli A, Carvalho AC, Dooley KE, Kritski A (June 2010). "TMC207: the first compound of a new class of potent anti-tuberculosis drugs"Future Microbiol5 (6): 849â58. doi:10.2217/fmb.10.50.PMC 2921705PMID 20521931.
8. Walker, Joseph; Tadena, Nathalie (December 31, 2012). "J&J Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Retrieved 2013-01-01.
9. Edney, Anna (December 31, 2012)."J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg. Retrieved 2013-01-01.
10. http://news.msn.com/science-technology/fda-approves-1st-new-tuberculosis-drug-in-40-years-1?
11. Kotz J (June 2005). "Targeting tuberculosis". Nature Chemical Biology.doi:10.1038/nchembio002.

FDA approves 1st new tuberculosis drug in 40 years

The Food and Drug Administration on Monday approved a Johnson & Johnson tuberculosis drug that is the first new medicine to fight the deadly infection in more than four decades.
The agency approved J&J's pill, Sirturo, for use with older drugs to fight a hard-to-treat strain of tuberculosis that has not responded to other medications. However, the agency cautioned that the drug carries risks of potentially deadly heart problems and should be prescribed carefully by doctors.
Roughly one-third of the world's population is estimated to be infected with the bacteria causing tuberculosis. The disease is rare in the U.S., but kills about 1.4 million people a year worldwide. Of those, about 150,000 succumb to the increasingly common drug-resistant forms of the disease. About 60 percent of all cases are concentrated in China, India, Russia and Eastern Europe.
Sirturo, known chemically as bedaquiline, is the first medicine specifically designed for treating multidrug-resistant tuberculosis. That's a form of the disease that cannot be treated with at least two of the four primary antibiotics used for tuberculosis.
The standard drugs used to fight the disease were developed in the 1950s and 1960s.
"The antibiotics used to treat it have been around for at least 40 years and so the bacterium has become more and more resistant to what we have," said Chrispin Kambili, global medical affairs leader for J&J's Janssen division.
The drug carries a boxed warning indicating that it can interfere with the heart's electrical activity, potentially leading to fatal heart rhythms.
"Sirturo provides much-needed treatment for patients who have don't have other therapeutic options available," said Edward Cox, director of the FDA's antibacterial drugs office. "However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don't have other treatment options."
Nine patients taking Sirturo died in company testing compared with two patients taking a placebo. Five of the deaths in the Sirturo group seemed to be related to tuberculosis, but no explanation was apparent for the remaining four.
Despite the deaths, the FDA approved the drug under its accelerated approval program, which allows the agency to clear innovative drugs based on promising preliminary results.
Last week, the consumer advocacy group Public Citizen criticized that approach, noting the drug's outstanding safety issues.
"The fact that bedaquiline is part of a new class of drug means that an increased level of scrutiny should be required for its approval," the group states. "But the FDA had not yet answered concerns related to unexplained increases in toxicity and death in patients getting the drug."

The FDA said it approved the drug based on two mid-stage studies enrolling 440 patients taking Sirturo. Both studies were designed to measure how long it takes patients to be free of tuberculosis.
Results from the first trial showed most patients taking Sirturo plus older drugs were cured after 83 days, compared with 125 days for those taking a placebo plus older drugs. The second study showed most Sirturo patients were cured after 57 days.

Enolate oxidation by sulfonyloxaziridines

Enolates can be oxidized by sulfonyloxaziridines.[1][2] The enolate reacts by nucleophilic displacement at the electron deficient oxygen of the oxaziridine ring.

This reaction type is extended to asymmetric synthesis by the use of chiral oxaziridines derived from camphor (camphorsulfonyl oxaziridine). Each isomer gives exclusive access to one of the two possible enantiomers. This modification is applied in the Holton Taxol total synthesis.

In the enolate oxidation of the cyclopentaenone below [3] with either camphor enantiomer the trans isomer is obtained because access for the hydroxyl group in the cis position is limited. The use of the standard oxaziridine did not result in an acyloin.

References

1. Synthesis of .alpha.-hydroxycarbonyl compounds (acyloins): direct oxidation of enolates using 2 sulfonyloxaziridines Franklin A. Davis, Lal C. Vishwakarma, Joanne G. Billmers, John Finn J. Org. Chem.1984; 49(17); 3241-3243. Abstract
2. Asymmetric Oxidation of Ester and Amide Enolates Using New (Camphorylsulfony1)oxaziridines Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986, 51, 2402. Abstract
3. An Electrochemical Approach to the Guanacastepenes Chambers C. Hughes, Aubry K. Miller, and Dirk Trauner ORGANIC LETTERS 2005 Vol. 7, No. 16 3425-3428 Article

Ionic liquid pretreatment of lignocellulosic biomass with ionic liquidâwater mixtures

A. Brandt, M. J. Ray, T. Q. To, D. J. Leak, R. J. Murphy and T. Welton,
Green Chem., 2011, 13, 2489  http://dx.doi.org/10.1039/c1gc15374a

Ground lignocellulosic biomass (Miscanthus giganteus, pine (Pinus sylvestris) and willow (Salix viminalis)) was pretreated with ionic liquidâwater mixtures of 1-butyl-3-methylimidazolium methyl sulfate and 1-butyl-3-methylimidazolium hydrogen sulfate. A solid fraction enriched in cellulose was recovered, which was subjected to enzymatic hydrolysis. Up to 90% of the glucose and 25% of the hemicellulose contained in the original biomass were released by the combined ionic liquid pretreatment and the enzymatic hydrolysis. After the pretreatment, the ionic liquid liquor contained the majority of the lignin and the hemicellulose. The lignin portion was partially precipitated from the liquor upon dilution with water. The amount of hemicellulose monomers in the ionic liquid liquor and their conversion into furfurals was also examined. The performance of ionic liquidâwater mixtures containing 1,3-dialkylimidazolium ionic liquids with acetate, methanesulfonate, trifluoromethanesulfonate and chloride anions was investigated. The applicability of the ionic liquid 1-butylimidazolium hydrogensulfate for lignocellulose pretreatment was also examined. It was found that ionic liquid liquors containing methyl sulfate, hydrogen sulfate and methanesulfonate anions were most effective in terms of lignin/cellulose fractionation and enhancement of cellulose digestibility.

Hydrolysis of 1-ethyl-3-methylimidazolium methyl sulfate; 1-Ethyl-3-methylimidazolium hydrogen sulfate

Chemicals Used

1-Ethyl-3-methylimidazolium methyl sulfate
Distilled Water
Concentrated Sulfuric Acid
Activated Charcoal

Procedure

1-Ethyl-3-methylimidazolium methyl sulfate (57.5 g, 258 mmol) was diluted with deionized water (5 ml) in an open-topped three-necked round-bottomed flask fitted with dropping funnel and thermometer. Sulphuric acid (2 drops) was added. The solution was heated at 175 oC for 3 h with vigorous stirring, allowing water and generated methanol to boil off. Deionized water was dispensed dropwise from the dropping funnel, in order to maintain the temperature of 175 oC. The solution was allowed to cool to room temperature, deionized water (50 ml) and activated charcoal were added, and the slurry was stirred at 50 oC overnight. The slurry was filtered through silica gel, and the water was removed by rotary evaporation. The product was dried under high vacuum to yield 1-ethyl-3-methylimidazolium hydrogen sulfate (53.0 g, 98%) as a colourless highly-viscous liquid.
.

The progress of the reacion was monitored by the disappearance of the methyl peak from the methyl sulfate anion, on the 1H NMR spectrum.

Data

1H NMR (400 MHz, DMSO-d6): Î´ 9.13 (1H, s), 7.78 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J = 7 Hz), 3.84 (3H, s), 1.41 (3H, t, J = 7 Hz).

13C { 1H} NMR (100 MHz, DMSO-d6): Î´ 136.4, 123.6, 122.0, 44.1, 35.7, 15.2.

m/z (Fab+): 111 (100%) [C 2C 1im] +, 83 (80%) [1-Methylimidazole-H] +.

m/z (Fab-): 97 (100%) [HSO 4] -.

Protection and deprotection chemistry catalyzed by zirconium oxychloride octahydrate (ZrOCl2Â·8H2O)

An efficient, chemoselective, convenient, and straightforward methodology has been developed for the protection of C=O group of aldehydes/ketones as C=N moiety of hydrazones catalyzed by ZrOCl2·8H2O (10 mol%) in acetonitrile and the same catalyst in methanol oxidatively cleaves C=N moiety of hydrazones to provide parent carbonyl compounds in high yields. The reactions have been performed in aerobic condition. The catalyst is inexpensive, readily available, easy to handle, insensitive to air and moisture, easily recoverable and can be reused and importantly less toxic.

Typical procedure for the protection of carbonyl compounds 1 into hydrazones 2 using ZrOCl2·8H2O vide Scheme 1

In an oven-dried round-bottomed flask (50 mL), benzaldehyde (1 mmol), hydrazine hydrate (1 mmol), and ZrOCl 2·8H 2O (10 mol%) were taken and acetonitrile (5 mL) was added to it. The reaction mixture was refluxed for required time under aerobic condition. After the completion of the reaction (monitored by TLC), the reaction system was allowed to cool to room temperature, acetonitrile was removed in a rotary evaporator and then extracted with ethyl acetate (3×10 mL), washed with water and brine, dried over Na 2SO 4, concentrated in a rotary evaporator and subjected to column chromatography to furnish the pure product (Yield 93%). Finally, the product was recrystalized from ethanol to afford the purest product, which was identified by IR,  1H,  13C-NMR, mass, mp, and compared with authentic sample.

Typical procedure for the deprotection of hydrazones 2 into their parent aldehydes/ketones 1using ZrOCl2·8H2O vide Scheme 1

The benzaldehyde hydrazone (1 mmol) and ZrOCl 2·8H 2O (10 mol%) were taken in an oven-dried round-bottomed flask (50 mL) and methanol (5 mL) was added to it. It was then refluxed for the appropriate time under aerobic condition. After the completion of the reaction (vide TLC), the reaction mixture was allowed to cool to room temperature, methanol was removed in a rotary evaporator and then extracted with ethyl acetate (3×10 mL), washed with water and brine, dried over Na 2SO 4, concentrated in a rotary evaporator and finally performed column chromatography to afford the pure product (Yield 95%). The product was identified by IR,  1H,  13C-NMR, mass, bp and compared with authentic samples.

Protection and deprotection chemistry catalyzed by zirconium oxychloride octahydrate (ZrOCl2·8H2O)

http://www.tandfonline.com/doi/full/10.1080/17518253.2012.677480#tabModule

Green Chemistry Letters and Reviews

Volume 5, Issue 4, 2012

DOI:
10.1080/17518253.2012.677480
Vijay K. Das Subrata Das  &  Ashim J. Thakur

pages 577-586

Department of Chemical Sciences, Tezpur University (A Central University), Tezpur, Napaam, 784028, Assam,  India

Cis Jasmone

Jasmone is a natural organic compound extracted from the volatile portion of the oil fromjasmine flowers. It is a colorless to pale yellow liquid that has the odor of jasmine. Jasmone can exist in two isomeric forms with differing geometry around the pentenyl double bond, cis-jasmone and trans-jasmone. The natural extract contains only the cis form, while synthetic material is often a mixture containing both forms, with the cis form predominating. Both forms have similar odors and chemical properties.

Jasmone is produced within plants by the metabolism of jasmonate, from linolenic acid by the octadecanoid pathway. It can act as either an attractant or a repellent for various insects. Commercially jasmone is used primarily in perfumes and cosmetics.

An attempt to make Z jasmone â an important constituent of many perfumes

In fact one synthesis uses the following as carbon sources:

cis (Z) jasmone ,

cas no 488-10-8, 3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclopent-2-en-1-one

ref-(Can. J. Chem. 1978, Vol 56, p2301)

1    W. Theilheimer. Synthetic Methods of Organic Chemistry. Volume 31, 1977, p. 352
2   Tetrahedron, 39 (24), p. 4127, 1983

Thomas Koch, Katja Bandemer, Wilhelm Boland (1997). "Biosynthesis of cis-Jasmone: a pathway for the inactivation and the disposal of the plant stress hormone jasmonic acid to the gas phase?". Helvetica Chimica Acta 80 (3): 838â850.doi:10.1002/hlca.19970800318.

 Formula: C10H14O CAS#: 488-10-8 MW: 150.22

Boric Acid / Glycerol as an Efficient Catalyst for Synthesis of Thiomorpholine 1,1-Dioxide by Double Michael Addition Reaction in Water

http://www.tandfonline.com/doi/abs/10.1080/00397911.2011.594930

Abstract

Thiomorpholine 1,1-dioxides were prepared with double Michael addition reaction of aromatic amines to divinyl sulfone catalyzed by boric acid / glycerol in water. This catalyst system was also used for the Michael addition reaction of aromatic amines to electron-deficient alkenes. The reaction is simple and green and gives good to excellent yields.

DONEPEZIL

Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor.[1]Its main therapeutic use is in the palliative treatment of mild to moderateAlzheimer's disease.[2] Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the bloodâbrain barrier. Because it has a half-life of about 70 hours, it can be taken once a day.

(RS)-2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one

Donepezil

Synthesis

The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyl lithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane - ethyl acetate (1,2).

Manufacturer Eisai Co., Ltd. (Japan).

References

1. Sugimoto, H., Tsuchiya, Y., Higurashi, K. et al. (Eisai Co., Ltd.) Cyclic amine cpd., its use and pharmaceutical compsns. comprising it. AU 8818216, EP 296560, JP 89079151, US 4895841.

2. Iimura, Y., Mishima, M., Sugimoto, H. Synthesis of 1-benzyl-4-[(5,6-dimethoxy[2-14C]-1-indanon)-2-yl]methylpiperidine hydrochloride (E-2020-14C). J Label Compound Radiopharm 1989, 27(7): 835-9.

1. 1        Birks J, Harvey RJ (2006). Birks, Jacqueline. ed. "Donepezil for dementia due to Alzheimer's disease". Cochrane Database Syst Rev (1): CD001190.doi:10.1002/14651858.CD001190.pub2PMID 16437430.
2. 2       "aricept"The American Society of Health-System Pharmacists. Retrieved 3 April 2011.

OTHER1

OTHER 2

OTHER3

OTHER4

SPECTROSCOPY

MASS

13C NMR

DEPT 90 C13 NMR

DEPT135

IR

1H NMR

COSY 1H NMR

HSQC NMR

HMBC NMR

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

Sertraline hydrochloride

Sertraline hydrochloride (trade names Zoloft and Lustral, among others) is anantidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It was discovered byPfizer. Sertraline is primarily used to treat major depression in adult outpatients as well asobsessiveâcompulsivepanic, and social anxiety disorders in both adults and children

Sertraline

Schematic Representation for Synthesis of Sertraline

Conditions:-

i. Benzene, anhydrous aluminum chloride, dichloromethane,

ii. Diethyl succinate, potassium-t-butoxide, t-butyl alcohol, reflux, 16 h,

iii. 48% aqueous HBr, acetic acid, reflux, 36 h,

iv. Hydrogen gas (1 atm), 5% Pd/c catalyst, ethyl acetate, room temperature, 24 h,

v. a) Thionyl chloride, toluene, reflux, 75 min b) anhydrous aluminum chloride, carbon disulfide, room temperature, 16 h,

vi. Methylamine, tetrahydrofuran, titanium tetrachloride, room temperature, 17 h,

vii. a) Hydrogen gas (1 atm), 10% Pd/c catalyst, tetrahydrofuran, room temperature, 2 h b) Gaseous hydrogen chloride,

viii. Crystallization from methanol and ether,

ix) a) 20% sodium hydroxide, ethyl acetate b) D (-) Mandelic acid, ethanol, resolution

Sertraline

CAS No:- [79617-96-2]

IUPAC Name:- (1S,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine

MW: 306.23

Drug information:- Sertraline is an anti-depressant drug.

â

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

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Ezzat Rafiee et al

Department of Chemistry, Faculty of Science, Razi University, Kermanshah, 67149, Iran

Various 1,3-dicarbonyl compounds reacted readily with benzylic alcohols in the presence of Cs2.5H0.5PW12O40 salt to produce 2-benzylic-1,3-dicarbonyl compounds in high yields. It was found that this catalyst could be completely recovered and reused without loss of its catalytic activities and is thus environmentally conscious especially in solvent-free conditions. The use of this method provides improved modification of the direct benzylation of 1,3-carbonyl compounds in terms of low reaction times, solvent-free conditions, usage of a small amount of the catalyst, and a clean reaction profile. Furthermore, the use of this catalyst is feasible because of its easy preparation, its easy handling, its stability, its easy recovery, its reusability, being environmentally green, its excellent activity, and its selectivity.

Canadian Journal of Chemistry , 2011, 89(12): 1533-1538, 10.1139/v11-134

http://www.nrcresearchpress.com/doi/abs/10.1139/v11-134#.UKY1veR8nrk    copy paste link on browser

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email  or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

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Indigo and Tyrian Purple â From Ancient Natural Dyes to Modern Organic Semiconductors

Article first published online: 5 JUN 2012

DOI: 10.1002/ijch.201100130

Israel Journal of Chemistry, vol 53,6

pages 540â551, June 2012

The world around us is in colour. Humans have used dyes for thousands of years (since before 10,000 BC). The oldest examples are prehistoric cave paintings, which show the already-sophisticated use of carefully-graded colours. What is striking is the lack of blue pigments. Indeed, blue dyes are rare in nature, which is perhaps the reason for associating blue and purple shades with wealth. From the cloth wrapping of mummies and the ancient Israelite sacred pigment Tekhelet to the colours of the uniforms of Napoleonâs soldiers and modern jeans, indigo and Tyrian purple are among the most âhistoricâ structures in organic chemistry (Figure1 , In  recent work, they have focused on natural and nature-inspired materials for organic electronics applications.Organic electronics are proposed for applications ranging from âsmartâ RF-ID packaging tags to electronics embedded in textiles, for instance. This emerging field is motivated by the idea of mass-producing cheap and sustainable electronic devices for display applications, photovoltaic cells, and integrated-circuits and sensors. Future large-scale application of sustainable organic electronics based on biodegradable materials would have a positive impact on the current problem of electronic waste. Our attention to historic dyes has been inspired by the idea of tapping into this massive and highly-developed body of chemical and chemical engineering knowledge to find materials that are potentially useful in electronics.

Figure 1. The molecular structure of indigo (1) and Tyrian purple (2). The numbering scheme shown here is used throughout this paper and in most literature on indigoids from the past sixty years.

We describe the history of indigo dye and its derivative Tyrian purple, from their roles in the ancient world to recent research showing the semiconducting properties of indigoids. Indigoids are natural dyes that have been produced for centuries, and indigo is currently the most produced dye worldwide. Herein we review the history of these materials, their chemistry and physical properties, and their semiconducting characteristics in the solid state. Due to hydrogen bonding and Ï-stacking, indigo and Tyrian purple form highly-ordered crystalline thin films. Such films have been used to fabricate high-performance organic field-effect transistors with ambipolar charge transport, as well as complementary-like circuits. Mobility values were found to be in the range of 10â2â0.4 cm2/Vs. With performance on par with the best available organic semiconductors, indigoids demonstrate the potential of sustainable electronics based on biodegradable and biocompatible materials.

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

A simple and straightforward approach toward selective C=C bond reduction by hydrazine

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Hao Chen, Jianmin Wang, Xuechuan Hong, Hai-Bing Zhou, Chune Dong

Canadian Journal of Chemistry, 2012, 90(9): 758-761, 10.1139/v2012-057

A simple and straightforward method for reducing the C=C double bond with hydrazine is described. A number of representative C=C bonds in various steric and electronic environments were examined. Substituted alkenes can be selectively reduced in EtOH in the presence of hydrazine to give the corresponding products in up to 100% yields.

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution

ANTIALZHEIMER, DONEPEZIL TYPE COMPDS

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Mohamed Ashraf Ali et al

Senile dementia is undesired consequence of progressive aging. Alzheimerâs disease is one form of senile dementia which occurs due to various neuropathological conditions such as senile plaques and neurofibrillary tangles. It is the most widely spread dementias that affects 50% of the population aged 85 years . It is the seventh leading cause of death in the world affecting 5.3 million people. In AD, increasing numbers of nerve cells deteriorate and die along with loss in synapse through which information flows from and to the brain. This leads to cognitive impairment and dementia .

Spiro [2.3â²] oxindolespiro [3.2â³]-5, 6-dimethoxy-indane-1â³-oneindolizine analogue 3a-o described  and a reaction sequence for the preparation is outlined in Scheme 1. In the initial step, 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1- indanone were synthesized by us earlier condensing 5,6-dimethoxy- 1-indanone with appropriate aromatic aldehyde in dilute methanolic sodium hydroxide solution at room temperature, spiro Indolizidinene ring were synthesized via 1,3-dipolar cycloaddition of azomethine ylide generated by the decarboxylative condensation of appropriate isatin and pipecolinic acid with dipolarophiles (5,6-dimethoxy-2-[(E)- 1-phenylmethylidene]-1-indanone) and to get titled compounds in 74- 94% yield after recrystalization with pet ether: ethyl acetate (4:1).

Spiro[2.3â²]oxindolespiro[3.2â³]-5,6-dimethoxy-1â³-indanone-4- (pyridyl)-Indolizine (3a): IR(KBr): 1525, 1690,1724 and 3290 cm-1; 1H NMR (300 MHz, CDCl3): 1.27, 1.47-1.55, (m, 8H, CH2 X4), 2.52-2.62 (d, 2H, CH2), 2.72 (t, 1H, CH), 3.32 (s, 1H, CH), 3.84 (s, 6H, OCH3),7.01- 7.42 (m, 6H, aromatic), 7.42-8.4 (m, 4H, pyridine), 8.48 (s, 1H, NH); Anal. Calcd. for C30H29N3O4: C, 72.71; H, 5.90; N, 8.48%; Found: 72.70; H, 5.88; N, 8.46%; EI-MS m/z 496 (M+1).

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

Titration of Nonstabilized Diazoalkane Solutions by Fluorine NMR

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A new protocol for titrating nonstabilized diazoalkane solutions by quantitative 19F NMR is reported. An excess of 2-fluorobenzoic acid dissolved in CDCl 3 is treated with the diazoalkane solution at a low temperature, immediately forming the corresponding 2-fluorobenzoate ester upon warming. A significant difference in the 19F chemical shift between the ester and acid is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active diazoalkane concentration with high precision.

Titration of Nonstabilized Diazoalkane Solutions by Fluorine NMR

J. Org. Chem., 2012, 77 (2), pp 1181â1185

DOI: 10.1021/jo202214e

view all spectra at
http://pubs.acs.org/doi/suppl/10.1021/jo202214e

all spectra are shown in the link above
DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,email  or call now for sure success formula, amcrasto@gmail.com, 9323115463. you can swim to the shore even if you are drowned in a storm.

Use of Ionic Liquid for the Transformation of Glucose into 5-(Hydroxymethyl)-2-furaldehyde

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Ionic Liquid for the Transformation of Glucose into 5-(Hydroxymethyl)-2-furaldehyde

Coupling of Nanoporous Chromium, Aluminium-Containing Silicates with an Ionic Liquid for the Transformation of Glucose into 5-(Hydroxymethyl)-2-furaldehyde

Molecules 2012, 17(4), 3690-3707; doi: 10.3390/molecules17043690

Lignocellulosic matter is a promising renewable source for the sustainable production of chemicals, materials and fuels which are presently produced essentially from fossil fuels, and is obtainable from agricultural and forestry residues/surpluses, waste streams of biorefineries and municipal paper waste . Lignocellulosic biomass is mainly composed of the carbohydrate polymers, cellulose and hemicelluloses. Cellulose is the most abundant terrestrial biopolymer and consists of chains of D-anhydroglucopyranose residues linked by Î²-1,4-glycosidic bonds which are hydrolysable under acidic reaction conditions to give the monosaccharide, d-glucose (Glu, a hexose). Glu is thus the major building block obtained from carbohydrate biomass, and can be converted into promising platform chemicals such as 5-(hydroxymethyl)-2-furaldehyde (Hmf) with a wide applications profile.

http://www.mdpi.com/1420-3049/17/4/3690/htm

FRUCTOSE TO DIMETHYL FURAN, A BIOFEUL

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New reagents are needed to generate liquid fuels from biomass, but the reagents must serve multiple roles. For the conversion of fructose into the title compound 1, formic acid serves three roles: assists in the isomerization/dehydration, serves as an H2 source for hydrogenation, and helps deoxygenate the alcohol functional groups.

Efficient Production of the Liquid Fuel 2,5-Dimethylfuran from Fructose Using Formic Acid as a Reagent

1. Todsapon Thananatthanachon Dr.,

DOI: 10.1002/anie.201002267

2,5-Dimethylfuran, uses

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2,5-Dimethylfuran serves as a scavenger for singlet oxygen, a property which has been exploited for the determination of singlet oxygen in natural waters. The mechanism involves a Diels-Alder reaction followed by hydrolysis, ultimately leading to diacetylethylene andhydrogen peroxide as products. More recently, furfuryl alcohol has been used for the same purpose.[1]

This compound has also been proposed as an internal standard for NMR spectroscopy. 2,5-Dimethylfuran has singlets in its 1H NMR spectrum at Î´ 2.2 and 5.8; the singlets give reliable integrations, while the positions of the peaks do not interfere with many analytes. The compound also has an appropriate boiling point of 92 °C which prevents evaporative losses, yet is easily removed.[2]

1--------Patrick L. Brezonik. Chemical Kinetics and Process Dynamics in Aquatic Systems. CRC Press, 1994, p. 671.

2---------S. W. Gerritz and A. M. Sefler (2000). "2,5-Dimethylfuran (DMFu): An Internal Standard for the "Traceless" Quantitation of Unknown Samples via 1H NMR". J. Comb. Chem. 2 (1): 39â41.doi:10.1021/cc990041v.

COLD CHAIN

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Cold chain

 A cold chain is a temperature-controlled supply chain. An unbroken cold chain is an uninterrupted series of storage and distribution activities which maintain a given temperature range. It is used to help extend and ensure the shelf life of products such as fresh agricultural produce,[1] seafood, frozen food, photographic film, chemicals and pharmaceutical drugs.[2] Vaccines are temperature controlled until use Slurry ice used to ship sensitive food products Truck with cooling system Iced seafood on display

Cold chains are common in the food and pharmaceutical industries and also some chemical shipments. One common temperature range for a cold chain in pharmaceutical industries is 2 to 8 °C. but the specific temperature (and time at temperature) tolerances depend on the actual product being shipped.

This is important in the supply of vaccines to distant clinics in hot climates served by poorly developed transport networks. Disruption of a cold chain due to war may produce consequences similar to the Smallpox outbreaks in the Philippines during the Spanish-American war.[3]

Traditionally all historical stability data developed for vaccines was based on the temperature range of 2-8 °C. With recent development of biological products by former vaccine developers, biologics has fallen into the same category of storage at 2-8 °C due to the nature of the products and the lack of testing these products at wider storage conditions.

The cold chain distribution process is an extension of the good manufacturing practice (GMP) environment that all drugs and biological products are required to adhere to, enforced by the various health regulatory bodies. As such, the distribution process must be validated to ensure that there is no negative impact to the safety, efficacy or quality of the drug substance. The GMP environment requires that all processes that might impact the safety, efficacy or quality of the drug substance must be validated, including storage and distribution of the drug substance.

Validation

A cold chain can be managed by a quality management system. It should be analyzed, measured, controlled, documented, and validated.

The food industry uses the process of Hazard Analysis and Critical Control Point, HACCP, as a useful tool. Its usage continues into other fields. PDA (Parenteral Drug Association) Technical Report # 39 gives a rough summary of how the cold chain can be validated.

The overall approach to validation of a distribution process is by building more and more qualifications on top of each other to get to a validated state. This is done by executing a Component Qualification on the packaging components. Next, an Operational Qualification that demonstrates the process performs at the operational extremes. The final piece is the Performance Qualification that demonstrates that what happens in the real world is within the limits of what was demonstrated in the Operational Qualification limits.

Think of the validation state in a simple manner like driving a car. One first wants to make sure there are four wheels, they are properly inflated and that the vehicle has gas. That would be like a Component Qualification. Next the car should be operated at its extreme conditions, as fast as possible in the worst weather and then as slow as possible. This is equivalent to the Operational Qualification, operating at the extreme conditions. The final step would be to take the car for a nice long drive like one would normally operate a car. 65 MPH on a nice little road trip, this would be equivalent to the Performance Qualification, the car functions as expected in nominal conditions. One may not operate their car at the extremes, but it sure is good to know that if you did have to operate in those conditions, one would have a high degree of confidence that it is achievable.

Currently there is a misnomer in the industry that three repetitive events equals a successful Validation. In reality, the process monitoring of the distribution process is the only assurance that a process has been successfully Validated. If at any point in time there is an anomaly in the distribution process, that process can no longer be considered Validated, as an anomaly would In-validate that process. Statistically speaking, a process would need at least 30 data points to demonstrate a process is in true control, but that's a separate topic that should be discus in detail.

The PDA's Technical Report states that a Component Qualification is required to demonstrate that a component can be manufactured to the design criteria of that individual component. This was put into the document because the industry did not understand the principles of Validation; all Validation processes were specific to equipment and not auxiliary processes such as shipping/distribution.

Performing thermal testing can also help with validating the cold chain. Certified test labs use environmental chambers to simulate ambient profiles that a package may encounter in the distribution cycle. Thermocouple probes and separate temperature dataloggers measure temperatures within the product load to determine the response of the package to the test conditions. Replicate testing based on a qualification protocols is used to create a final qualification report that can be used to defend the configuration when audited by regulators. It is normally best to have an individual that understands the principles of Validation, when defending such processes to a Federal Regulatory body of any nation.

Cold chains need to be evaluated and controlled:

• Carriers and logistics providers can assist shippers. These providers have the technical ability to link with airlines for real time status, generate web-based export documentation and provide electronic tracking.
• The use of refrigerator trucks, refrigerator cars, reefer ships, reefer containers, and refrigerated warehouses is common.
• Shipment in insulated shipping containers or other specialised packaging.[4]
• Temperature data loggers and RFID tags help monitor the temperature history of the truck, warehouse, etc. and the temperature history of the product being shipped.[5] They also can help determine the remaining shelf life.[6]
• Documentation is critical. Each step of the custody chain needs to follow established protocols and to maintain proper records. Customs delays occur due to inaccurate or incomplete customs paperwork, so basic guidelines for creating a commercial invoice should be followed to ensure the proper verbiage, number of copies, and other details.

During the distribution process one should monitor that process until one builds a sufficient data set that clearly demonstrates the process is in compliance and in a state of control. Each time the process does not conform to the process, the event should be properly documented, investigated and corrected so that the temperature excursion do not occur on future shipments. Thus the process is continually evolving and correcting for anomalies that occur in the process. Eventually the process can evolve into periodic monitoring once sufficient data demonstrates that the process is in a state of control. Any anomaly that occurs once a process is in a state of control will result in the process being invalidated and not in control and result in product withdraw from the market to ensure patient safety.

It is necessary to develop an internal documentation system as well as multi-party communication standards and protocols to transfer or create a central repository or hub to track information across the supply chain. These systems would monitor equipment status, product temperature history, and custody chain, etc. These help ensure that a food, pharmaceutical, or vaccine is safe and effective when reaching its intended consumer.

Notes

1. Kohli, Pawanexh. "Fruits and Vegetables Post-Harvest Care: The Basics" (PDF). Crosstree Techno-visors.
2. Gyesley, S. W. (1991). Total Sysstems Approach to Predict Shelf Life of Packaged Foods. ASTM STP 1113-EB.
3. "Communicable Diseases, Ch. IX Smallpox", Office of Medical History, US Army Medical Department
4. Singh, S. P.; Burgess, Singh (January 2008). "Performance comparison of thermal insulated packaging boxes, bags and refrigerants for single-parcel shipments". Packaging Technology and Science 21 (1): 25â35. doi:10.1002/pts.773.
5. Riva, Marco; Piergiovanni, Schiraldi, Luciano; Schiraldi, Alberto (January 2001). "Performances of time-temperature indicators in the study of temperature exposure of packaged fresh foods". Packaging Technology and Science 14 (1): 1â39. doi:10.1002/pts.521.
6. Meyers, T (June 2007). "RFID Shelf-life Monitoring Helps Resolve Disputes". RFID Journal.

• Protecting Perishable Foods During Transport by Truck, USDA Handbook 669, 1995, [1]
• "Manual on the Management, Maintenance and Use of Blood Cold Chain Equipment", World Health Organization, 2005, ISBN 92-4-154673-5
• Pawanexh Kohli, "Fruits and Vegetables Post-Harvest Care: The Basics", Explains why the cold chain is required for fruits and vegetables.
• Clive, D., "Cold and Chilled Storage Technology", 1997, ISBN 0-7514-0391-1
• EN 12830:1999 Temperature recorders for the transport, storage and distribution of chilled, frozen and deep-frozen/quick-frozen food and ice cream
• Ray Cowland, Developing ISTA Cold Chain Environmental Standards, 2007.
• Sofrigam, A better understanding of the cold chain, 2011. [2]

Chemical oxygen demand

In environmental chemistry, the chemical oxygen demand (COD) test is commonly used to indirectly measure the amount of organic compounds in water. Most applications of COD determine the amount of organic pollutants found in surface water (e.g. lakes and rivers) or wastewater, making COD a useful measure of water quality. It is expressed in milligrams per liter (mg/L also referred to as ppm (parts per million), which indicates the mass of oxygen consumed per liter of solution.

Overview

The basis for the COD test is that nearly all organic compounds can be fully oxidized to carbon dioxide with a strong oxidizing agent under acidic conditions. The amount of oxygen required to oxidize an organic compound to carbon dioxide, ammonia, and water is given by:

$\mbox{C}_n\mbox{H}_a\mbox{O}_b\mbox{N}_c + \left( n + \frac{a}{4} - \frac{b}{2} - \frac{3}{4}c \right)\mbox{O}_2 \rightarrow n\mbox{CO}_2 + \left( \frac{a}{2} - \frac{3}{2}c \right)\mbox{H}_2\mbox{O} + c\mbox{NH}_3$

This expression does not include the oxygen demand caused by the oxidation of ammonia into nitrate. The process of ammonia being converted into nitrate is referred to as nitrification. The following is the correct equation for the oxidation of ammonia into nitrate.

$\mbox{N}\mbox{H}_3 + 2\mbox{O}_2 \rightarrow \mbox{N}\mbox{O}_3^- + \mbox{H}_3\mbox{O}^+$

It is applied after the oxidation due to nitrification if the oxygen demand from nitrification must be known. Dichromate does not oxidize ammonia into nitrate, so this nitrification can be safely ignored in the standard chemical oxygen demand test.

The International Organization for Standardization describes a standard method for measuring chemical oxygen demand in ISO 6060 [1].

History

For many years, the strong oxidizing agent potassium permanganate (KMnO4) was used for measuring chemical oxygen demand. Measurements were called oxygen consumed from permanganate, rather than the oxygen demand of organic substances. Potassium permanganate's effectiveness at oxidizing organic compounds varied widely, and in many cases biochemical oxygen demand (BOD) measurements were often much greater than results from COD measurements. This indicated that potassium permanganate was not able to effectively oxidize all organic compounds in water, rendering it a relatively poor oxidizing agent for determining COD.

Since then, other oxidizing agents such as ceric sulphate, potassium iodate, and potassium dichromate have been used to determine COD. Of these, potassium dichromate (K2Cr2O7) has been shown to be the most effective: it is relatively cheap, easy to purify, and is able to nearly completely oxidize almost all organic compounds.

In these methods, a fixed volume with a known excess amount of the oxidant is added to a sample of the solution being analyzed. After a refluxing digestion step, the initial concentration of organic substances in the sample is calculated from a titrimetric or spectrophotometric determination of the oxidant still remaining in the sample.

Using potassium dichromate

Potassium dichromate is a strong oxidizing agent under acidic conditions. (Acidity is usually achieved by the addition of sulfuric acid.) The reaction of potassium dichromate with organic compounds is given by:

$\mathrm{C_nH_aO_bN_c\ +\ dCr_2O_7^{2-}\ +\ (8d\ +\ c)H^+ \rightarrow nCO_2\ +\ \frac {a + 8d - 3c}{2}H_2O\ +\ cNH_4^+\ + \ 2dCr^{3+}}$

where d = 2n/3 + a/6 - b/3 - c/2. Most commonly, a 0.25 N solution of potassium dichromate is used for COD determination, although for samples with COD below 50 mg/L, a lower concentration of potassium dichromate is preferred.

In the process of oxidizing the organic substances found in the water sample, potassium dichromate is reduced (since in all redox reactions, one reagent is oxidized and the other is reduced), forming Cr3+. The amount of Cr3+ is determined after oxidization is complete, and is used as an indirect measure of the organic contents of the water sample.

Blanks

Because COD measures the oxygen demand of organic compounds in a sample of water, it is important that no outside organic material be accidentally added to the sample to be measured. To control for this, a so-called blank sample is required in the determination of COD (and BOD -biochemical oxygen demand - for that matter). A blank sample is created by adding all reagents (e.g. acid and oxidizing agent) to a volume of distilled water. COD is measured for both the water and blank samples, and the two are compared. The oxygen demand in the blank sample is subtracted from the COD for the original sample to ensure a true measurement of organic matter.

Measurement of excess

For all organic matter to be completely oxidized, an excess amount of potassium dichromate (or any oxidizing agent) must be present. Once oxidation is complete, the amount of excess potassium dichromate must be measured to ensure that the amount of Cr3+ can be determined with accuracy. To do so, the excess potassium dichromate is titrated with ferrous ammonium sulfate (FAS) until all of the excess oxidizing agent has been reduced to Cr3+. Typically, the oxidation-reduction indicator Ferroin is added during this titration step as well. Once all the excess dichromate has been reduced, the Ferroin indicator changes from blue-green to reddish-brown. The amount of ferrous ammonium sulfate added is equivalent to the amount of excess potassium dichromate added to the original sample. and also we can determine COD by boiling the water sample and we can determine CO2 ratio by the infra-red analyzer

Preparation Ferroin Indicator reagent

A solution of 1.485 g 1,10-phenanthroline monohydrate is added to a solution of 695 mg FeSO4·7H2O in water, and the resulting red solution is diluted to 100 mL.

Calculations

The following formula is used to calculate COD:

$COD = \frac{8000 (b - s)n}{sample\ volume}$

where b is the volume of FAS used in the blank sample, s is the volume of FAS in the original sample, and n is the normality of FAS. If milliliters are used consistently for volume measurements, the result of the COD calculation is given in mg/L.

The COD can also be estimated from the concentration of oxidizable compound in the sample, based on its stoichiometric reaction with oxygen to yield CO2 (assume all C goes to CO2), H2O (assume all H goes to H2O), and NH3 (assume all N goes to NH3), using the following formula:

COD = (C/FW)(RMO)(32)
Where C = Concentration of oxidizable compound in the sample,
FW = Formula weight of the oxidizable compound in the sample,
RMO = Ratio of the # of moles of oxygen to # of moles of oxidizable compound in their reaction to CO 2, water, and ammonia

For example, if a sample has 500 wppm of phenol:

C 6H 5OH + 7O 2 â 6CO 2 + 3H 2O
COD = (500/94)(7)(32) = 1191 wppm

Inorganic interference

Some samples of water contain high levels of oxidizable inorganic materials which may interfere with the determination of COD. Because of its high concentration in most wastewater, chloride is often the most serious source of interference. Its reaction with potassium dichromate follows the equation:

$\mathrm{6Cl^- + Cr_2O_7^{2-} + 14H^+ \rightarrow 3Cl_2 + 2Cr^{3+} + 7H_2O}$

Prior to the addition of other reagents, mercuric sulfate can be added to the sample to eliminate chloride interference.

The following table lists a number of other inorganic substances that may cause interference. The table also lists chemicals that may be used to eliminate such interference, and the compounds formed when the inorganic molecule is eliminated.

Inorganic molecule Eliminated by Elimination forms
Chloride Mercuric sulfate Mercuric chloride complex
Nitrite Sulfamic acid N2 gas
Ferrous iron - -
Sulfides - -

Government regulation

Many governments impose strict regulations regarding the maximum chemical oxygen demand allowed in wastewater before they can be returned to the environment. For example, in Switzerland, a maximum oxygen demand between 200 and 1000 mg/L must be reached before wastewater or industrial water can be returned to the environment [2].

References

• Clair N. Sawyer, Perry L. McCarty, Gene F. Parkin (2003). Chemistry for Environmental Engineering and Science (5th ed.). New York: McGraw-Hill. ISBN 0-07-248066-1.
• Lenore S. Clescerl, Arnold E. Greenberg, Andrew D. Eaton. Standard Methods for Examination of Water & Wastewater (20th ed.). Washington, DC: American Public Health Association. ISBN 0-87553-235-7.

Quality by Design (QbD)

Quality by Design (QbD) is a concept first outlined by well-known quality expert Joseph M. Juran in various publications, most notably Juran on Quality by Design.[1] Juran believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned in the first place.

While Quality by Design principles have been used to advance product and process quality in every industry, and particularly the automotive industry, they have most recently been adopted by the U.S. Food and Drug Administration (FDA) as a vehicle for the transformation of how drugs are discovered, developed, and commercially manufactured.[2][3][4]

Pharmaceutical quality by design

This FDA imperative is best outlined in its report âPharmaceutical Quality for the 21st Century: A Risk-Based Approach.â[5] In the past few years, the Agency has made significant progress in implementing the concepts of "Quality by Design" (QbD) into its pre-market processes. The focus of this concept is that quality should be built into a product with a thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. This is a successor to the "quality by QC" (or "quality after design") approach that the companies have taken up until 1990s.[6] The QbD initiative, which originated from the Office of Biotechnology Products (OBP), attempts to provide guidance on pharmaceutical development to facilitate design of products and processes that maximizes the productâs efficacy and safety profile while enhancing product manufacturability.

Fundamental to this initiative is the understanding of the relationship between the quality attributes of the product (physicochemical and biological properties) and their impact on the safety and efficacy. This requires knowledge of the relationship between structure and biological functions.

QbD activities within FDA

Specifically, the following activities are guiding the overall implementation of QbD:

• In FDAâs Office of New Drug Quality Assessment (ONDQA), a new risk-based pharmaceutical quality assessment system (PQAS) was established based on the application of product and process understanding.
• Implementation of a pilot program to allow manufacturers in the pharmaceutical industry to submit information for a new drug application demonstrating use of QbD principles, product knowledge, and process understanding. In 2006, Merck & Co.âs Januvia became the first product approved based upon such an application.[7]
• Implementation of a Question-based Review (QbR) Process has occurred in CDER's Office of Generic Drugs.
• CDER's Office of Compliance has played an active role in complementing the QbD initiative by optimizing pre-approval inspectional processes to evaluate commercial process feasibility and determining if a state of process control is maintained throughout the lifecycle, in accord with the ICH Q10 lifecycle Quality System.
• Implementation of QbD for a Biologic License Application (BLA) is progressing.

While QbD will provide better design predictions, there is also a strong recognition that industrial scale-up and commercial manufacturing experience provides new and very important knowledge about the process and the raw materials used therein. FDA is aware that knowledge is not static and builds throughout the manufacturing lifecycle. FDA's release of the Process Validation[6] guidance in January 2011 notes the need for companies to continue benefiting from knowledge gained, and continually improve throughout the process lifecycle by making adaptations to assure root causes of manufacturing problems are quickly corrected. This vigilant and nimble approach is explained by FDA to be essential to best protect the consumer (patient).

ICH activities

Working with regulators in the European Union (the European Medicines Agency) and Japan, FDA has been instrumental in furthering Quality by Design objectives through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH guidelines Q8 (on Pharmaceutical Development), Q9 (on Quality Risk Management), and Q10 (on Pharmaceutical Quality System) provide some assistance for manufacturers to implement Quality by Design into their own operations.[8] The ICH Steering Committee meets twice a year to discuss the progress of its efforts. Further details are being developed by industry organizations to assure that Quality Systems objectives are met by application of experience and innovations as process understanding builds throughout the process lifecycle. This practical input should help ensure that quality risk management and knowledge management are used to make necessary lifecycle adaptations that maintain process control and product quality, including evolved controls as well as rapid corrective and preventative action (CAPA) to assure sustainable CGMP compliance.

References

8. Joseph M. Juran, a perspective on past contributions and future impact, Quality and Reliability Engineering International, Vol. 23, pp. 653â663, 2007 by Godfrey, A.B. and Kenett, R.S.

9. Quality by Design Applications in Biosimilar Technological Products, ACQUAL, Accreditation and Quality Assurance, Springer Verlag, Vol. 13, No 12, pp. 681â690, 2008 by Kenett R.S. and Kenett D.A.

Chiloglottone âAustralian orchid uses a single simple diketone to attract wasps that pollinate it

The Australian orchid Chiloglottis trapeziformisâ very existence hinges upon there being some truth to the old adage that love is blind. Unlike other flowers, which lure pollinators with nectar, C. trapeziformis attracts its pollinator, the thynnine wasp Neozeleboria cryptoides, by producing the same pheromone that the insects use to attract the opposite sexâa practice known as sexual deception. Fooled by the pheromone, the male wasp will try to mate with the orchid. But ultimately it leaves the encounter with nothing more than a fine coat of pollen that it carries to its next liaison with a sexually deceptive orchid.

A five-step synthesis of monoalkyl- and 2,5-dialkyl-1,3-cyclohexanediones (1) is described viaa sequence involving sequential Birch reductions and alkylations from the readily accessible and inexpensive starting material, 3,5-dimethoxybenzoic acid. Two approaches were considered in which alkylation at C-2 occurs either prior or subsequent to the proposed reduction. The successful route, in which Birch reduction of a 3-alkyl resorcinol derivative (3) precedes alkylation was applied in the synthesis of chiloglottone 1 (1dc), in 58% overall yield.

(2-ethyl-5-propylcyclohexan-1,3-dione),

Org. Biomol. Chem., 2009, 7, 4296-4300

DOI: 10.1039/B912233H

Identification of the First Alkenyl Chiloglottone Congener

Chiloglottone 4, a plant allomone and insect pheromone, has been identified through synthesis. Field studies have shown it to be the biologically potent floral volatile in the orchid Chiloglottis turfosa attracting the wasp pollinator Neozeleboria sp.

N-allyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-3-nitropropanamide

Procedure

A solution of  POCl3(1.00 mmol, 0.093 mL) inCHCl3 (3.5 mL) was added dropwise to a mixture of

N-allyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-3-nitropropanamide (0.670 mmol, 250 mg) and Et3N (2.68 mmol, 0.373 mL) inCHCl3 (3.5 mL). After 30 min Et3N (1.33 mmol, 0.186 mL)POCl3 (0.499 mmol, 0.0465 mL) inCHCl3 (1.5 mL) were added and the reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere at which point water (20 mL) was added. The crude product was extracted with CH2Cl2 (3 x 15 mL) and dried over anhydrous MgSO4. After evaporation of the organic solvent, the crude product was purified by flash chromatography using silica gel (eluent: ethyl acetate-hexane; 1 : 1) to obtain title compound as a white solid (168 mg, 71% yield,  mp 192-194 °C, Rf= 0.20   (ethyl acetate-hexane; 1 : 1). 50:50 Mixture of diastereoisomers as determined by 1H-NMR integration.

Data

IR-ATR:   3255, 3086, 2936, 2922, 2853, 1660, 1640, 1557 cm-1

1H NMR (400 MHz, DMSO-d6): ppm = 8.27 (1H, d, NH, J= 7.77 Hz), 7.43-7.33 (3H, m, aromatic CH), 7.23-7.20 (2H, m, aromatic CH), 6.29 (0.5H, s, CH-Ar), 6.22 (0.5H, s, CH-Ar), 4.34-4.27 (1H, m), 3.87-3.83 (1H, skew dd, CH2O), 3.81-3.77 (1H, skew t, CH2O), 3.71 (1H, m), 3.65-3.59 (2H, m), 3.57-3.51 (2H, m), 1.80-1.67 (4H, m, cyclohexyl CH2), 1.57-1.54 (1H, m, cyclohexyl CH2), 1.30-1.09 (5H, m, cyclohexyl CH2).

13C NMR (100 MHz, DMSO-d6): ppm = 167.86, 167.81, 166.38, 166.17, 155.47, 155.41, 135.92, 135.70, 128.74, 128.63, 128.60, 128.41, 127.95, 127.86, 70.31, 70.10, 59.76, 58.43, 47.72, 47.17, 46.31, 46.02, 45.84, 32.24, 32.12, 32.08, 32.06, 30.99, 25.11, 24.53, 24.44.

Reference

COLOURED MECHANISMS

Epoxidation

OZONOLYSIS

oxidations

DIELS ALDER RXN

We noted earlier that addition reactions of alkenes often exhibited STEREOSPEFICITY, in that the reagent elements in some cases added syn and in other cases anti to the the plane of the double bond. Both reactants in the Diels-Alder reaction may demonstrate stereoisomerism, and when they do it is found that the relative configurations of the reactants are preserved in the product (the adduct). The following drawing illustrates this fact for the reaction of 1,3-butadiene with (E)-dicyanoethene. The trans relationship of the cyano groups in the dienophile is preserved in the six-membered ring of the adduct. Likewise, if the terminal carbons of the diene bear substituents, their relative configuration will be retained in the adduct. Using the earlier terminology, we could say that bonding to both the diene and the dienophile is syn. An alternative description, however, refers to the planar nature of both reactants and terms the bonding in each case to be suprafacial (i.e. to or from the same face of each plane). This STEREOSPECITY also confirms the synchronous nature of the 1,4-bonding that takes place

NITRILE HYDROLYSIS UNDER ACIDIC CONDITIONS

NITRILE HYDOLYSIS, BASIC CONDITIONS

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