Tuesday 17 September 2013

Drug therapy: Solamargine and other solasodine rhamnosyl glycosides as anticancer agents





Modern ChemotherapyVol.2 No.2(2013), Article ID:30489,17 pagesDOI:10.4236/mc.2013.22005
Drug therapy: Solamargine and other solasodine rhamnosyl glycosides as anticancer agents
Bill E. Cham
Australasian Institute of Medical Research, Brisbane, Australia; bill.cham@gmail.com
Copyright © 2013 Bill E. Cham. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received 24 February 2013; revised 26 March 2013; accepted 5 April 2013
Keywords: Cancer; Skin Cancer; Solamargine; Solasonine; BEC; Solasodine Rhamnosyl Glycosides; CuradermBEC5; Apoptosis; Antineoplastic; Targeted Therapy
ABSTRACT
In the last century, the discovery of cytotoxic agents was revolutionary for anticancer therapy. These therapies have resulted in better understanding of cancer in general. However, the development of agents that combine efficacy, safety and convenience remains a great challenge. The narrow, if not adverse, therapeutic index of most drugs, the damage not only to cancer cells, but also to normal and healthy tissue and the occurrence of resistance have limited anticancer efficacy. This review presents the development of promising novel cytotoxic solasodine rhamnosyl glycoside drugs that offer not only gains in specificity and efficacy, but also in safety, tolerability, non-resistance and convenience in the treatment of patients with cancer.
1. INTRODUCTION
In the past 100 years our understanding of the biology of cancer has come a long way. We now have a reasonable working knowledge of how tumors initially form, grow and spread. Importantly, substantial information about features distinguishing tumor from normal cells is being accumulated, resulting in major new insights into cancer biology................
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Generic versions of high cholesterol drug Lovaza can be developed, rules judge « New Drug Approvals

Generic versions of high cholesterol drug Lovaza can be developed, rules judge « New Drug Approvals:

'via Blog this'

Scripps Research Institute Scientists Create Extremely Potent and Improved New Derivatives of Successful Anticancer Drug

Dale Boger, PhD, is chair of the Department of Chemistry at The Scripps Research Institute.
LA JOLLA, CA—September 16, 2013—Scientists at The Scripps Research Institute (TSRI) have found a way to make dramatic improvements to the cancer cell-killing power of vinblastine, one of the most successful chemotherapy drugs of the past few decades. The team’s modified versions of vinblastine showed 10 to 200 times greater potency than the clinical drug. Even more significantly, these new compounds overcome the drug resistance that emerges upon treatment relapse, which renders continued or subsequent vinblastine treatment ineffective in some patients.

The TSRI researchers expect that similar modifications will boost the effectiveness of vincristine, a closely related drug that is commonly used against childhood leukemias and Hodgkin’s disease.
http://www.scripps.edu/news/press/2013/20130916boger.html

vincristine



http://www.scripps.edu/news/press/2013/20130916boger.html


vincristine

Sunday 15 September 2013

LEVOCETRIZINE

File:Levocetirizine structure 2.svg
LEVOCETRIZINE
Levocetirizine (as levocetirizine dihydrochloride) is a third-generation non-sedative antihistamine, developed from the second-generation antihistamine cetirizine. Chemically, levocetirizine is the active enantiomer of cetirizine. It is the R-enantiomer of the cetirizine racemate. Levocetirizine works by blocking histamine receptors. It does not prevent the actual release of histamine from mast cells, but prevents it binding to its receptors. This in turn prevents the release of other allergy chemicals and increased blood supply to the area, and provides relief from the typical symptoms of hay fever.
The manufacturers claim it to be more effective with fewer side effects than the second-generation drugs; however, there have been no published studies supporting this assertion, although other studies have concluded it may be more effective.[1]

    History and formulations

    Levocetirizine was first launched in 2001 by Belgian pharmaceutical company UCB. It is sold under the brand name Xyzal/ˈzzæl/ in Australia, Czech Republic, Austria, Finland, France, Ireland, Netherlands, Portugal, Romania, Taiwan, Turkey, United States, South Africa and UK; Xuzal in Mexico; Xusal in Germany; and Xozal in Greece. In Hungary it is marketed by Richter Gedeon under the Zilola brand name.

    In India, levocetirizine is marketed by GlaxoSmithKline under the brand name Vozet and Xyzal. On May 25, 2007, theUnited States Food and Drug Administration approved Xyzal, where it is co-marketed by Sanofi-Aventis. Torrent Pharma launched UVNIL in rural market of India. It is also available as LEZYNCET 5 mg tablets through Unichem in India. In India, generic name of Lev-Cit 5 mg is manufactured by VIP Pharmaceuticals. Also marketed in India by Croslands (Ranbaxy Laboratories Ltd.) under the brand name Teczine. In Brazil it is marketed under the brand name 'Zyxem' by Farmalab. It is marketed in Egypt by BORG Pharma under the brand name 'Xaltec'Allear by western pharmaceuticals and levcet by marcryl.
    In Pakistan levocetirizine was first launched in liquid formulation by Novartis Consumer Health Division by the name of T-Day Syrup. It is available as 5 mg-strength tablets and a 0.5 mg/mL oral solution. In Pakistan levocetirizine is available in liquid formulation as well with the name of OCITRA and T-Day 2.5 mg/5 mL. In Bangladesh levocetirizine is available in 5 mg tablet & 2.5 mg/5 mL oral liquid formulation with the brand name of Alcet marketed by Healthcare Pharmaceuticals and Seasonix marketed by Incepta Pharmaceuticals. In Nepal levocetirizine is available in 5 mg tablet with brand name ofCurin manufactured by Beximco Pharma.[2]

    Side effectsl

    levocetirizine is called a non-sedating antihistamine as it does not enter the brain in significant amounts, and is therefore unlikely to cause drowsiness. However, some people may experience some slight sleepiness, headache, mouth dryness,lightheadedness, vision problems (mainly blurred vision), palpitations and fatigue.[3]

    Research

    latest research shows levocetirizine reduces asthma attacks by 70% in children.[4]

    Availability]

    The drug is currently available by prescription in the United States. Although the drug was only authorized by the FDA on 25 May 2007, it was already available in most European countries. Like many new drugs it entered the market at a higher price than currently available third and second generation antihistamines. In India, one form of the drug is available as Crohist MK tablets and syrup, a formulation of levocetirizine hydrochloride and montelukast. In India, Crohist MK is a Schedule 'H' drug and may only be prescribed by a registered medical practitioner. In Finland, the drug is sold over-the-counter.
    Different brands (ActavisGlenmarkUCB) Levocetirizine tablets and oral solution.


    1. ^ Grant, JA; Riethuisen, JM; Moulaert, B; DeVos, C; Gamalero, C.; Descalzi, D.; Folli, C.; Passalacqua, G. et al. (2002-02). "A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects.". Ann Allergy Asthma Immunol 88 (2): 190–197. doi:10.1016/S1081-1206(10)61995-3PMID 11868924.
    2. ^ http://www.beximco-pharma.com/allergic-disorders/147-curin.html
    3. ^ XOZAL technical specifications booklet.
    4. ^ Pasquali, M; Baiardini, I; Rogkakou, A; Riccio, AM; Gamalero, C; Descalzi, D; Folli, C; Passalacqua, G et al. (2006-09)."Levocetirizine in persistent allergic rhinitis and asthma: effects on symptoms, quality of life and inflammatory parameters.".Clinical & Experimental Allergy 36 (9): 1161–7. doi:10.1111/j.1365-2222.2006.02548.xPMID 16961716.


    xyzal_structure.png
    Figure 1-The chemical structure of Xyzal

    BACKGROUND
    Cetirizine, chemically [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid is an antihistamine non-sedating type histamine H1-receptor antagonist, indicated for relief of symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and related diseases.
    Figure US20110184174A1-20110728-C00003
    U.S. Pat. No. 4,525,358 and its equivalent EP 58146 disclose cetirizine and its pharmaceutically acceptable salts. The process for the synthesis of cetirizine comprises condensation of 1-[(4-chlorophenyl)-phenylmethyl]piperazine with 2-chloroethoxy acetamide to obtain 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy acetamide which on hydrolysis gives cetirizine.
    It was found later that the pharmacological activity resides primarily in (R)-isomer or (−) form known as levocetirizine. GB 2225321 describes a process for the preparation of the dextro and levorotatory isomers of cetirizine comprising hydrolysis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazynyl]-ethoxy acetonitrile.
    Figure US20110184174A1-20110728-C00004
    (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine is a very important intermediate in the synthesis of levocetirizine. U.S. Pat. No. 5,478,941 discloses a process for the synthesis of (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine involving hydrolyzing 1-[(4-chlorophenyl)-phenylmethyl]-4-(4-methylphenyl)sulfonyl piperazine with hydrobromic acid in the presence of 4-hydroxybenzoic acid.
    Figure US20110184174A1-20110728-C00005
    The alternative routes of synthesis of (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine disclosed in the prior art involve the use of bis chloro ethylamine which is carcinogenic in nature.
    Levocetirizine is a highly-potent non-sedating anti-allergic agent. Hence, there are continuous attempts to develop new processes for the synthesis of levocetirizine and its intermediates. The present invention describes a new process for the preparation of the key intermediate (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine.
    Levorotatory [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, also known by the generic name of levocetirizine, has proven useful as a therapeutic agent for the treatment of allergic disease.
    Levocetirizine and its salts including its dihydrochloride are known and are effective in the treatment of allergies, including but not limited to, chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. Levocetirizine belongs to the second generation of H1 histamine receptor antagonists, which are believed to offer significant advantages over first generation compounds. Studies have shown that levocetirizine provides safe and effective symptomatic relief of seasonal allergies. Levocetirizine is used also for treating chronic idiopathic urticaria.
    GB 2,225,321 describes a process for the preparation of cetirizine in the levorotatory form, dextrorotatory form or a mixture thereof comprising the hydrolysis of enantiomerically pure [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetonitrile. Hydrolysis takes place in aqueous, alcoholic or aqueous-alcoholic medium by a base or by an acid; the acid thus obtained is converted to its dihydrochloride. Optically active starting material 1-[(4-chlorophenyl)phenylmethyl]piperazine is obtained by resolution of the corresponding racemic compound, preferably by conversion to its diastereoisomeric salt with tartaric acid. The yield of resolution is rather low, namely only 12.7%. The obtained optically active intermediate is further converted with chloroethoxyacetonitrile in 69% yield.
    EP 0 617 028 and EP 0 955 295 disclose a process for the preparation of optically active 1-[(4-chlorophenyl)phenylmethyl]piperazine and its conversion to cetirizine in the levorotatory form or dextrorotatory form or to derivative thereof. The process for the preparation is shown in the following scheme:
    Figure US08049011-20111101-C00001
    The drawback of the disclosed reaction is that it requires protection of N,N-bis(2-haloethyl)amine, and consequently deprotection of the intermediate obtained.
    Preparation of Cetirizine in its Levorotatory Form Proceeds in most known syntheses from enantiomerically pure 1-[(4-chlorophenyl)phenylmethyl]piperazine. Consequently it appears to be very desirable to provide new routes to prepare the enantiomers thereof with improved optical purity and good yields.
    Polymorphic form I of crystalline levorotatory dihydrochloride salt of cetirizine and amorphous form thereof are disclosed in WO 2004/050647 and WO 2004/065360. Crystalline form is prepared by crystallization from ketone-containing solvent, such as acetone, methyl ethyl ketone, dimethylketone, 2-pentanone and mixtures thereof. Amorphous form was prepared by solvent evaporation.
    There still exists a need for an efficient synthesis of levocetirizine, new intermediates used in the process, suitable for large-scale production.
    Synthesis of Xyzal:
    Figure 2 displays the synthesis of Cetirizine (Zyrtec). Levocetirizine, the R-enantiomer of cetirizine, is then formed from pyroglutamate salts in a synthesis that does not have attainable details.



    REAL_ceterizine_synthesis.png
    (Figure 2)

    The synthesis of Cetrizine begins by reducing molecule 33 with a catecholborane. This reaction yields molecule 34, which is then treated with tetraflouroboric acid and reacted with an amine, compound 35. In order to remove the chromium group, the compound is refluxed in pyridine and undergoes an acid hydrolysis. This results in a yield of cetrizine.



    Identification of all chirality centers:
    Stereogenic centers are carbon atoms that are bonded to 4 groups. Tetrahedral stereogenic centers are stereogenic centers that are not only bonded to 4 groups but are more importantly bonded to 4 different groups. If a molecule contains 1 tetrahedral stereogenic center it is said to be chiral (nonsuperimposable on its mirror image).If a given compound contains more than 1 stereogenic center it must be further analyzed to determine if it is chiral or achiral(superimosable on its mirror image). The carbon atom bonded to the phenyl groups was found to be a tetrahedral stereogenic center. Therefore,xyzal,which was found to contain only 1 tetrahedral stereogenic center is generally considered a chiral compound because it meets the requirements of chirality and does not have a plane of symmetry that superimposes one half of the molecule on the other and is not super imposable on its mirror image.

    Spectral data for Xyzal (IR and NMR):
    cetirizine_IR.png
    xyzal_nmr.png



    ESCITALOPRAM

    File:Escitalopram structure.svg
    128196-01-0 ESCITALOPRAM
    Escitalopram (also known under various trade names) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition. The similarity between escitalopram and citalopram has led to accusations of “evergreening“, an accusation that Lundbeck has rejected.[1]
    Escitalopram has FDA approval for the treatment of major depressive disorder and generalized anxiety disorder in adults.[2]

    Off-label uses

    Escitalopram is sometimes prescribed off-label for the treatment of other conditions: social anxiety disorder,[3] panic disorder[4]and obsessive-compulsive disorder.[5] There is some evidence favouring escitalopram over the antidepressants citalopram andfluoxetine in the first two weeks of major depression.[6] Concerns of sponsorship bias with the studies are however noted.[6] In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.[7]

    Efficacy

    There is some controversy over selective publishing of SSRI clinical trials.[8] A meta-analysis analyzing published as well as unpublished trials found placebos to be similarly effective to SSRIs in treating mild depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.[9]
    A series of randomized, double-blind trials have found Escitalopram to be more efficacious and have fewer adverse effects than Citalopram.[10][11][12][13] Meta-analysis show a “small” but statistically significant improvement in effect strength [14][15] and some dispute these findings.[16]

    Pharmacology


    Cipralex brand escitalopram 10mg package and tablet sheet
    Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.[42] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[43] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter.[44] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.
    In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.

    History

    Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.[45] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “evergreening[46] (also called “lifecycle management”[47])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of theracemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[48]On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[49]
    In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.[50] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

    Brand names

    Escitalopram is sold under the following brand names:
    • Animaxen (Colombia)
    • Anxiset-E (India)
    • Cipralex
    • Escital (Nigeria)
    • Citalin
    • Citram (Croatia)
    • Ecytara (Slovenia)
    • Elicea
    • Entact (Greece)
    • Escitalopram Actavis (Finland)
    • Escitil (Czech Republic)
    • Esitalo (Australia)
    • Esopram, by Actavis (Iceland)
    • Esto (Israel)
    • Escitalopram Teva (Israel)
    • Exodus (Brazil)
    • Lexam
    • Lexamil (South Africa)
    • Lexapro
    • Losita (Bangladesh)
    • Nexito
    • Reposil (Chile)
    • Selectra (Russia)
    • Selpram (Pakistan)
    • Seroplex
    • Sipralexa (Belgium)

    References

    1. a b c NHS pays millions of pounds more than it needs to for drugsThe Independent. Retrieved 05/10/2011.
    2. ^ “Escitalopram Oxalate”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
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    4. ^ Stahl, SM; Gergel, I; Li, D (2003). “Escitalopram in the treatment of panic disorder: A randomized, double-blind, placebo-controlled trial”. The Journal of clinical psychiatry 64(11): 1322–7. PMID 14658946.
    5. ^ Stein, DJ; Andersen, EW; Tonnoir, B; Fineberg, N (2007). “Escitalopram in obsessive-compulsive disorder: A randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study”. Current medical research and opinion 23 (4): 701–11. doi:10.1185/030079907X178838PMID 17407626.
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    18. ^ Van Gorp, Freek; Whyte, Ian M.; Isbister, Geoffrey K. (2009). “Clinical and ECG Effects of Escitalopram Overdose”Annals of Emergency Medicine 54 (3): 404–8.doi:10.1016/j.annemergmed.2009.04.016PMID 19556032.
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    22. ^ Lexapro prescribing information
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