Is poor Research the Cause of the Declining productivity of the pharmaceutical Industry An Industry in need of a Paradigm shift

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Jul 212013

picked up from a japanes site

創薬パラダイム・シフト：プロセス重視からサイエンス重視へ転換せよ

Sams-Dodd F. Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift.

Drug discovery today. 2012;00(00):1–7.

Available at:http://linkinghub.elsevier.com/retrieve/pii/S1359644612003674

過去２０年の創薬パラダイムであるターゲットベースの創薬は、何千億円の投資の割にはそれほど効果的ではなかったと言われている。なぜこれほどまでに機能しなかったのか？ここでは従来の手法の失敗確率の高い理由を知り、生産性向上のための創薬手法の転換を提案する。たとえば、ターゲット選定の段階で、多くの研究者は選択的な化合物を目指そうとするが、癌のキナーゼ研究を見てもわかるように、薬効を示すのはマルチのターゲットによって複数のシグナルを同時に作用する事に発揮する場合も多い。また、製薬企業では薬効につながる明確なMOAを必要とする傾向にあるが、実際には精神疾患の薬剤のようにMOAが十分に説明できずに使,,,,,,,,,,,,,,,,,,see below a translation

Available at: http:// linkinghub.elsevier.com/retrieve/pii/S1359644612003674

It is said that drug discovery of target-based drug discovery is a paradigm of the past 20 years, was not very effective in what percent of one hundred billion yen of investment. Why did not work so much? You know why a high failure probability of the conventional method, we propose the transformation of drug discovery techniques to improve productivity in this case.

For example, at the stage of target selection, many researchers trying to aim at compounds selective, but as can be seen from kinase cancer research, and shows a medicinal action at the same time a plurality of signals by the target multi- If you want to demonstrate to that you often. Further, it tends to require a clear MOA leading to efficacy in pharmaceutical companies, but the MOA is used to not be fully described as drug mental illness often actually in practice. Movement of proteins in vivo actually that it is not so simple many MOA to be described coherently At first glance also, also, may be used instead of different views depending on the specifications of interpretation in practice.

If you prove that it is selective for off-target of 100 kinds about the compound that is optimized in a single mechanism, if there is action on targets unknown other, it is that there is a clinically significant after we In some cases, it can be seen. Next is to evaluate and to build the flow of screening MOA and target Once you have decided, but it is also not necessarily the one that bridges the screening and clinical actually.

Case of cancer cells, and so extrapolate clinical efficacy in inhibition of proliferation activity, but are those far removed from the actual in vivo in most cases, the process itself is continuously evaluated by routine work ends as a waste of time not money. If you choose to use compound somehow, animal disease model is not possible to accurately predict clinical outcome. Uncertainties like this a lot, theme 97% never fail downright non-clinical. Rather than biology and disease clearly, feeling had focused on the process is undeniable drug discovery paradigm of current. Important thing originally, is to to centered on principles and appropriate science focused on disease in clinical, it is to re-build process on it.

Reorganization research and development are important, it is not able to change the nature of the disease where you have reorganized matter. Therefore, it is a secondary or if the organization. The new research paradigms consider the process to focus on the disease, it is necessary to apply the three principles. One of them is the process of science-based.Science is made up by systematic law, which is evidenced by the accumulation of observation and experiment without prejudice. It’s that you have to often is that is do we need to note here, discussions would begin while not to suspect the hypothesis and doctrine that are major premise.

For example, the earth if the major premise that it is a flat, what’s there in the flat world of another fall from the tip of the flat earth?Question that will come out. However, if you can dispel the assumption by the belief that there is no basis to recognize the shape of the earth, it is possible to pursue science in the right direction in a totally different perspective. This same is true for drug discovery research. For example, if a certain phenomenon is to work, it would no longer consider the direction of the other.

Cause of schizophrenia may be mentioned a theory that based on the excess dopamine hyperactivity as an example.May develop the symptoms of schizophrenia-like D amphetamine is allowed to release dopamine, this concept is the basis that it has a D2 antagonism dopamine psychotropic drugs many. However, it is said, not the D amphetamine contraindicated, psychotropic drugs long-term treatment is also lead to enhanced dopamine system schizophrenia many patients. However, the fact that you have these, never to be little consideration on the grounds that would be go against the doctrine of dopamine hypothesis. In other words, the doctrine would be to blind us to the alternative hypothesis essentially.

This same is true with respect to Alzheimer’s.When the doctrine of a certain hypothesis is treated as the principles, facts that go against the doctrine is ignored, hypothesis another is neglected, progress of science’s delayed in order to look away from the truth. Hypothesis became a doctrine becomes absolute only and is deified as the Bible. Fact defeat the hypothesis that even came out after another, the cause interpreted as another factor, never wake up until push forward until you collapse in clinical late as a result. Hypothesis that build on doctrine the wrong does not lead only in the wrong direction all.

Simply because I admit to know that the earth is a sphere, a new way of science he is cut open. In addition, reductionism approach dominant also should be noted in the discussion of science. Element has a plurality of by influencing the complex in vivo, originally, it is not possible to understand the living body to focus on a single element. For example, to understand the engine of the car, there is a need to disconnect the engine from the mirror and the door, however, they are not able to understand the engine itself and accidentally disconnect without knowing the function of important and bolts cylinder engine. Multi-target has been spotlighted in the drug synergy effect by the action of more than one is because the expected effect even insufficient for single target. That it kept asking the research many times, to re-examine the design of the experiment is important in decision-making, but is in surprisingly poor. Schizophrenia negative symptoms model of phencyclidine-induced and model of cerebral infarction has become a problem much that there is no reproducibility by the lab.

In the process of science-based, it will continue to refine while obtaining conclusive evidence to do the practice and discussion is important. Clinical success rate is low, it sifted the hypothesis as much as possible in the process of advancing the research, better should remain. The second principle is that the customers know. Be patient with the customer for the pharmaceutical companies. It is not possible to produce products that are competitive by knowing the limit disease, condition, existing drugs. Even on the researchers know the needs of the patient, taking into closer contact with the doctor is important. Principles of the third, is to understand the risks. The acceptable risk, it is not what we deal with the risk, that is, whether to undertake the corresponding risk, the only pass to avoid the discussion if not. First of all drug discovery are those difficult, many programs to fail in the mid-way is typical for the pharmaceutical companies.

However, it should be avoided risk, such as notice and a predictable if you even care, because he turn away the failure of such a future, because it should not be happening that failure waiting to happen after we some. A few years ago, pharmaceutical companies some had considered mGluR5 antagonists as an anti-anxiety drug. This MOA was expected as much anti-anxiety drug, but the side effects of psychotic disorders such as hallucinations and delusions has been concern on the other hand. However, was never to be fully verified until the compound drop in its side effects in Phase 1 this concern. Many pharmaceutical companies are in was not able to deal with known risks.

Any pharmaceutical company, and the last would complete the study because of the common “because other companies are doing” and, nobody did not want to press the stop button. Pharmaceutical companies had been wiped out by the results of the problem banzai charge of pharmaceutical companies which can be called reckless risk-taking took place waiting to happen in clinical trials. To avoid this situation, the practice of the process of due diligence scientific is the essential. Inspection with no bias due to opposition support and opinion is carried out in this process. And verified by experiment hypothesis that there is sufficient scientific reason to support (1) project, if you can dispel the uncertain surface with a (2) simple additional experiments, and (3) key in this process it is determined Uruka about, you can reduce the risk of later on in (4) checkpoint. Researchers lament “factor of the disease is too complex” and the “because there is no way of doing the other”, the researchers would start the research been sticking to the one target.

However, you should know that a little time, to discuss the clinical symptoms of the disease, you only need to discuss the screening method of Japan before, and there is also a problem that can be resolved

Venomous drugs from spiders

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Jul 192013

Spiders are nature’s pest controllers. These eight-legged, web-forming arachnid predators are equipped with two venom glands full of valuable chemicals designed to kill insect prey. Such compounds, from small organic molecules to complex structures such as acylpolyamines, neuropeptides and enzymes, are precious ligands that target several biological receptors. Since insect receptors are not substantially different from those of humans and other mammals, the majority of the molecules contained in spider venom could also target human receptors.

Spider

The potential medical uses of spider venoms are largely due to their selectivity and affinity for ion channels.

The potential medical uses of spider venoms are largely due to their selectivity and affinity for ion channels [proteins that allow ions to cross cell membranes] and other receptors. This makes them suitable for studying cell function and for designing therapeutic drugs. As an example, the venom of the theraphosid Grammostola spatulata from South America contains a peptide, GsMtx-4, that blocks stretch-activated ion channels. These channels are sensitive to muscle contraction and blood pressure and play an important role in coordinating a heartbeat. Potentially, GsMtx-4 could be used to prevent atrial fibrillation after a heart attack and to treat cardiac patients.

LIPID BOUND Like related peptide toxins, GsMTx4 has a highly hydrophobic face (green). The cysteines that make up the protein’s core are colored yellow, and positive and negative residues are shown in blue and red, respectively.
NATURE ©2004

“Peptides make up a substantial part of spider venom and modulate ionic currents across calcium, sodium or potassium ion channels.”

Peptides make up a substantial part of spider venom, and modulate ionic currents across Ca²⁺, Na⁺, or K⁺ ion channels. Some spider peptides can discriminate between ion channel subtypes and several will inhibit peripheral neurons, the nerve cells that are associated with supplying sensation to the skin and skeletal muscles. Spider toxins that block the neuronal Ca²⁺ ion channel could prove important for the treatment of chronic pain.

A special group of the spider peptides have a mixed hydrophilic-hydrophobic nature – they are amphipathic. These form -helical structures that insert into cell membranes to form pores, resulting in loss of cell function. Although most of these peptides will destroy red blood cells, they could potentially be used in topical applications, such as antibacterial coatings for medical implants, in inhibiting the growth of oral bacteria associated with tooth decay and early plaque formation and in treating skin infections.

Venom peptides contain a common basic structure called a ‘cysteine knot,’ a tangle of protein chains and disulfide bridges that gives them an excellent molecular stability. Also, the small organic components of spider venom, such as organic acids, amines, nucleic acids and amino acids, are thought to stabilise the mixture and enhance the delivery and effectiveness of the peptides.

“The acylpolyamines represent the vast majority of the molecules in the mixture. These have been shown to suppress epileptic activity in brain tissue.”

Of all the venom components, the acylpolyamines represent the vast majority of the molecules in the mixture. These have been shown to suppress epileptic activity in brain tissue. They can also act as pain-killers, by blocking capsaicin receptor channels, non-selective cation channels in sensory neurons that respond to pain-causing stimuli. Moreover, brain damage caused by restricted blood flow, for example during a stroke, can be prevented with acylpolyamines. The compounds work by blocking Ca²⁺ voltage-gated ion channels or preventing glutamate release, both of which are implicated in neuronal death.

Finally, enzymes and large protein components of spider venoms are of special medical importance. For example, the neurotoxic protein -latrotoxin, from the black widow spider, causes massive neurotransmitter release. Similarly, an active enzyme in the venom of the brown recluse spider is sphingomyelinase D, which degrades cell membranes and causes painful lesions to develop. Another component of brown recluse spider venom, hyaluronidase, belongs to a family of compounds that have shown medical potential as tumour treatments.

“Most spider species are harmless to humans, so peptides or drug molecules from these spiders are likely to be safe.”

Most spider species are harmless to humans, so peptides or drug molecules from these spiders are likely to be safe. By modifying the molecular surfaces and active sites of peptides and enzymes from spiders, whilst keeping the spider scaffold, it is possible to gain specificity and/or affinity for a given receptor. Therefore, acylpolyamines, peptides and enzymes from spider venoms represent an interesting source of molecules for the design of novel pharmaceutical drugs.

References

Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs

G Estrada, E Villegas and G Corzo, Nat. Prod. Rep., 2007,

DOI: 10.1039/b603083c

Applications of Spider Venom

Interest in potential agricultural and medical uses of spider venom is largely due to its selectivity in species and site of action. Current research centres around exploring the development of pesticides and drugs for treating cardiac patients.

Pesticides

Components in the neurotoxic venom of an Australian funnel-web spider have been found to be specific for insects such as cockroaches, crickets, fruit-flies and the Helicoverpa armigera moth which destroys cotton crops. Targeting specific species prevents the accidental killing of other insects. This selectivity also means that the pesticide is harmless to other organisms so there would be no danger if it entered the food chain. The compounds in venom are environmentally friendly and the development of resistance to a spider venom pesticide would be slow. Traditional chemical pesticides do not tend to be species specific, are toxic to humans in large amounts and insects develop resistance towards them relatively fast so it is easy to see why pesticides based on spider venom are attractive.

Prevention of Atrial Fibrillation

The venom of the Chile Rose tarantula (Grammostola spatulata) from South America contains an active protein, GsMtx-4, which blocks ion channels that are stretch activated. These channels are therefore sensitive to muscle contraction and blood pressure and play an important role in co-ordinating a heartbeat. A heart attack causes these ion channels to open and release chemicals which interfere with the heart rhythm leading to atrial fibrillation. Fibrillation is when the upper heart chambers (the atria) contract rapidly and prevent sufficient blood from entering the lower chambers (the venticles). It is fibrillation which often causes the death of a heart attack victim, not the attack itself so GsMtx-4 could be utilised in a potentially life-saving drug which prevents fibrillation. GsMtx-4 is ineffective on the normal unstretched heart so side effects should be small or even non-existent. The venom from the Chile Rose spider is also harmless to humans which constitutes an extra safety precaution.

Prevention of Brain Damage

Oxygen deprivation caused by events such as stroke or excessive smoke inhalation can result in nerve cell damage in the brain. Glutamate is a neurotransmitter in the human brain and large amounts of it are released by these damaged neurons causing the death of neighbouring nerve cells. The Holena curta funnel-web spider produces a venom containing the active ingredient HF-7 which blocks receptors on the nerve cell membranes and prevents glutamate production. A drug developed using this compound could therefore limit brain damage for stroke victims.

Sugammadex sodium-agent for reversal ofneuromuscular blockade by the agent rocuronium in general anaesthesia

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Jul 192013

Sugammadex sodium

Sugammadex (designation Org 25969, tradename Bridion) is an agent for reversal ofneuromuscular blockade by the agent rocuronium in general anaesthesia. It is the firstselective relaxant binding agent (SRBA) and was discovered at the Newhouse research site in Scotland. These scientists who discovered Sugammadex worked for the pharmaceutical company, Organon. Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

On January 3, 2008, Schering-Plough submitted a New Drug Application to the US Food and Drug Administration for sugammadex, but the FDA rejected the application on August 2008. It was approved for use in the European Union on July 29, 2008.

Sugammadex incapsulating a molecule of rocuronium

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at theneuromuscular junction.

Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientationSugammadex also has some affinity for other aminosteroid neuromuscular blocking agents such as vecuronium and pancuronium. Though sugammadex’s affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade. Vecuronium is approximately seven times more potent than rocuronium and overall requires fewer molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium. Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.

A Cochrane systematic review on sugammadex has been recently published by Abrishami et al. This review article included 18 randomized controlled trials on the efficacy and safety of sugammadex. The trials included a total of 1321 patients. The review concluded that “sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations”.

Cancer drug PAC-1 tested in pet dogs is now bound for human trials

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Jul 182013

pac 1

Cancer drug tested in pet dogs is now bound for human trials
Medical Xpress
If PAC-1 (pack one) makes it through the U.S. Food and Drug Administration’s Investigational New Drug review, the first human (Phase I) clinical trial of the drug will begin in mid-2014. The investor, who wishes to … Procaspase-3 has long been an …

read all at

http://medicalxpress.com/news/2013-07-cancer-drug-pet-dogs-bound.html

www.ncbi.nlm.nih.gov/pmc/articles/PMC3113694/ this gives srtucture of pac-1

http://medicalxpress.com/partners/university-of-illinois-at-urbana-champaign/

A cell undergoing apoptosis. The dying cell blebs apart and sends signals to thephagocytes, which are part of the immune system, to engulf it.

PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 has shown good results in mouse models and is being further evaluated for use in humans. In 2010 a published study showed PAC-1 to be safe to research dogs, and a second study published later that same year reported that a PAC-1 derivative (called S-PAC-1) was well tolerated in a small Phase I Clinical Trial of pet dogs with lymphoma. Even at low doses of S-PAC-1, tumors regressed in 1/6 dogs, and the disease was stabilized (no additional tumor growth) in 3/6 dogs.

PAC-1 (pronounced “pack one”) was discovered in Paul Hergenrother’s labs at theUniversity of Illinois at Urbana-Champaign during a process that screened many chemicals for anti-tumor potential. This molecule, when delivered to cancer cells, signals the cells to self-destruct by activating an “executioner” protein, procaspase-3. Then, the activated executioner protein begins a cascade of events that destroys the machinery of the cell.

This cascade of events is named apoptosis. Apoptosis is self-induced in cells to combat infections or DNA damage. For instance, when a cell in one’s body is infected with a bacterium or virus, it will self-destruct to take away the resources needed by the virus to proliferate. Apoptosis is also found to help in embryo development (destroying the webbing in between an embryo’s fingers to separate the fingers) and the regular replenishment of cells that are constantly being used up or destroyed (cells that line the intestinal tract), also called homeostasis.

A cell undergoing apoptosis. The dying cell blebs apart and sends signals to thephagocytes, which are part of the immune system, to engulf it.

The problem lies when one part of the apoptosis pathway is broken. Normally, the balance between cell division and apoptosis is rigorously regulated to keep the integrity of organs and tissues. Examples of broken apoptosis pathways occur in many cancers. If old lung cells cannot self-destruct to make room for new lung cells, a large mass of cells form and a tumor is made.

In many cases, the apoptotic pathway is disrupted because procaspase-3, the executioner protein, cannot be activated by the cell. This is analogous to an executioner who does not have orders to kill. Without the orders, the condemned will not die. The same analogy can be made with procaspase-3. Without activated procaspase-3, the apoptotic cascade will not occur and the cell will not destroy itself no matter how necessary it may be. PAC-1 acts a replacement order that works and bypasses the lawyers, court orders, and governor’s calls. It will activate procaspase-3 indiscriminately.

How PAC-1 affects the apoptotic process

In cells, the executioner protein, caspase-3, is stored in its inactive form, procaspase-3. This way, the cell can quickly undergo apoptosis by activating the protein that is already there. This inactive form is called a zymogen. Procaspase-3 is known to be inhibited by low levels of zinc. PAC-1 activates procaspase-3 by chelating zinc, thus relieving the zinc-mediated inhibition. This allows procaspase-3 to be an active enzyme, and it can then cleave another molecule of procaspase-3 to active caspase-3. Caspase-3 can further activate other molecules of procaspase-3 in the cell, causing an exponential increase in caspase-3 concentration. PAC-1 facilitates this process and causes the cell to undergo apoptosis quickly.^[1]

Unfortunately, a selectivity problem arises because procaspase-3 is present in most cells of the body. However, it has been shown that in many cancers, including certain neuroblastomas, lymphomas, leukemias, melanomas, and liver cancers, procaspase-3 is present in higher concentrations.^[1] For instance, lung cancer cells can have over 1000 times more procaspase-3 than normal cells.^[1] Therefore, by controlling the dosage, one can achieve selectivity between normal and cancerous cells.

Thus far, PAC-1 seems promising as a new anti-tumor drug. It is synthetically available and a few mouse trials have been performed with moderate success. PAC-1 is the first of many small molecules to directly influence the apoptotic machinery of cells.

References

Putt KS, Chen GW, Pearson JM, Sandhorst JS, Hoagland MS, Kwon JT, Hwang SK, Jin H, Churchwell MI, Cho MH, Doerge DR, Helferich WG, Hergenrother PJ. (2006). “Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat. Chem. Biol”. Nature chemical biology 2 (10): 543–50. doi:10.1038/nchembio814. PMID 16936720.

Peterson, Q. P.; Goode, D. R.; West, D. C.; Ramsey, K. N.; Lee, J. J.; Hergenrother, P. J. “PAC-1 Activates Procaspase-3 in vitro Through Relief of Zinc-Mediated Inhibition” J. Mol. Biol. 2009, 388, 144-158.
Peterson, Q. P.; Hsu, D. C.; Goode, D. R.; Novotny, C. J.; Totten, R. K. Hergenrother, P. J.; “Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of PAC-1, and its Cellular Co-Localization with Caspase-3” J. Med. Chem. 2009, 52, 5721-5731.
Lucas, P. W.; Schmit, J. M.; Peterson, Q. P.; West, D. C.; Hsu, D. C.; Novotny, C. J.; Dirikoul, L.; Deorge, D. R.; Garrett, L. D.; Hergenrother, P. J., Fan, T. M. “Pharmacokinetics and Derivation of an Anticancer Dosing Regimen for PAC-1, a Preferential Small Molecule Activator of Procaspase-3, in Healthy Dogs” Invest. New Drugs. 2010, in press published on web May 25, 2010.

Peterson, Q. P.; Hsu, D. C.; Novotny, C. J.; West, D. C.; Kim, D.; Schmit, J. M.; Dirikolu, L.; Hergenrother, P. J.; Fan, T. M. “Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3-Activating Compound” Cancer Res. 2010, 70, 7232-7241

METRONIDAZOLE

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Jul 172013



Metronidazole (INN) /(Flagyl, and others) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal. It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection. It is marketed in the U.S.A. by Pfizer and globally by Sanofi under the trade name Flagyl, and is also sold under other brand names. Metronidazole was developed in 1960. Metronidazole is used also as a gel preparation in the treatment of the dermatologicalconditions such as rosacea (Rozex and MetroGel by Galderma) and fungating tumours(Anabact, Cambridge Healthcare Supplies).

Metronidazole (INN) /(Flagyl, and others) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal. It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection. It is marketed in the U.S.A. by Pfizer and globally by Sanofi under the trade name Flagyl, and is also sold under other brand names. Metronidazole was developed in 1960.

Metronidazole is used also as a gel preparation in the treatment of the dermatologicalconditions such as rosacea (Rozex and MetroGel by Galderma) and fungating tumours(Anabact, Cambridge Healthcare Supplies).

Synthesis

2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turnalkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3):^[27]^[28]^[29]

27- Ebel, K.; Koehler, H.; Gamer, A. O.; Jäckh, R. (2005), “Imidazole and Derivatives”, Ullmann’s Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH,doi:10.1002/14356007.a13_661
28-Actor, P.; Chow, A. W.; Dutko, F. J.; McKinlay, M. A. (2005), “Chemotherapeutics”, Ullmann’s Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH,doi:10.1002/14356007.a06_173
29-Kraft, M. Ya.; Kochergin, P. M.; Tsyganova, A. M.; Shlikhunova, V. S. (1989). “Synthesis of metronidazole from ethylenediamine”. Pharmaceutical Chemistry Journal 23 (10): 861–863. doi:10.1007/BF00764821.

MORE
Metronidazole (CAS NO.: 443-48-1), with its chemical name of 2-Methyl-5-nitro-1H-Imidazole-1-ethanol, could be produced through the following several reaction routes.1). Preparation method one:
The title compound can also be obtained by alkylation, in different solvents, of 1-(acetoxymethyl)-2-methyl-4-nitroImidazole(I) with either ethylene sulfate (II) or with bis-(2-acetoxyethyl) sulfate (III) -generated from ethyleneglycol diacetate (IV) and either dimethyl sulfate or H₂SO₄ – followed by hydrolysis or alcoholysis treatment.

2). Preparation method two:
2-Methylimidazole (I) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in Ac₂O to produce 2-methyl-4-nitroimidazole (II) . In a variant of this procedure, 2-methylimidazole (I) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. Imidazole (II) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. Alternatively, the alkylation of (II) has been reported by treatment with ethylene oxide (III) under acidic conditions.

Isolation and identification of antibiotic albaflavenone from Dictyophora indusiata

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Jul 162013

Isolation and identification of antibiotic albaflavenone from Dictyophora indusiata

Dictyophora indusiata is a stinkhorn fungus growing in bamboo thickets which has been used as ingredient in Chinese traditional foods for a very long time due to it delicious taste and high nutritional value. It has become a popular ingredient in Chinese cuisine because advances in its cultivation since 1979 have made it cheap and easily available. It has been observed that the broth could stay unspoiled for several days if D. indusiata were added. It has been widely recognised in Chinese folk medicine that D.indusiata has beneficial effects on some diseases, such as cough, inflammation, diarrhoea and bacterial enteritis. The chemical components and antibacterial activity of extracts of D. indusiata have been reported previously, but the components which have antibacterial activity are still unknown.

http://www.sciencereviews2000.co.uk/blog/view/journal-of-chemical-research/58/isolation-and-identification-of-antibiotic-albaflavenone-from-dictyophora-indusiata/544

Top 10 Drug Giants Scramble For A Piece of China

china, Uncategorized Comments Off

Jul 162013

People’s Republic of China

中华人民共和国
Zhōnghuá Rénmín Gònghéguó


	National Emblem

Anthem:

《义勇军进行曲》
Yìyǒngjūn Jìnxíngqǔ (Pinyin)
“March of the Volunteers“

Area controlled by the People’s Republic of China shown in dark green; claimed but uncontrolled regions shown in light green.

With China’s healthcare reform, aging population and growing wealth offsetting concerns over regulatory challenges and intellectual property (IP) protection, the pharmaceutical industry’s center of gravity is shifting east.

There are plenty of opportunities to profit in China. Growth in developed markets, where drug companies make most of their sales, is slowing. The blockbusters of a few years ago are losing patent protection. R.& D. is cheaper in emerging markets like India and China.

China will become the second-biggest pharmaceuticals market in the world by 2020. Most of the top 20 multinational pharmaceutical companies have been expanding their footprint in the research, OTC, distribution, and biotech and are setting up more R&D facilities through various enterprise structures. By investing in China, drug companies like Merck and Novartis are establishing bridgeheads in an important market.

Merck & Co.

Investment: $1.5 billion over 5 years
Themes: Vaccines, diabetes and joint ventures

Merck & Co Inc will establish a new Asian R&D headquarters in Beijing and commit $1.5 billion to research and development in China over the next five years.The No. 2 U.S. drugmaker will eventually employ 600 scientists at its facility, making Merck the latest foreign pharmaceutical company to bolster its presence in China. In addition to research, Merck plans to use its new facility to help it bring existing drugs to the Chinese market. Merck has signed a deal this year with China’s Simcere Pharmaceutical Group (www.simcere.com); aiming to lower costs and allow the company to be in a better position to penetrate the Chinese markets. The company plans to launch new products in China, including medicines for diabetes, infectious diseases and women’s health.

Novartis

Investment: $1.25 billion over 5 years
Themes: R&D and APIs

On Nov. 3, 2009, the Swiss pharmaceutical giant Novartis announced it plans to invest $1.25 billion in a pair of Chinese R&D centers over the next five years. Novartis will put $250 million into a new R&D center and manufacturing facility in Changshu, a city near Shanghai, and another $1 billion to add 1,000 researchers at an existing center in Shanghai. Earlier this year, Novartis received regulatory approval in China from the State Food and Drug Administration (SFDA) for Lucentis® (ranibizumab) to treat wet (neovascular) age-related macular degeneration (AMD), and Galvus® (vildagliptin), an oral treatment for patients with type 2 diabetes approved in China as an add-on to metformin, the standard of care.

In 2011 Novartis acquired Chinese pharmaceuticals and vaccines company Zhejiang Tianyuan Bio-Pharmaceutical (www.ty-pharm.com) for $125 millioin, in a move to expand vaccines presence in China

Roche

Investment: $410 million over several years
Themes: R&D and diagnostics

AstraZeneca

Investment: $200 million
Themes: Branded generics and CRO collaboration

UK-based AstraZeneca announced in 2011 a $200 million investment in a new manufacturing facility in Taizhou in Jiangsu province, set to be completed by the end of 2014. The factory will make AstraZeneca’s own branded drugs as well as generic copies of other medicines. Like other international drugmakers, AstraZeneca is pushing hard into emerging markets as it is seeing a string of lucrative patents running out over the next few years, including Nexium, its $5 billion-a-year blockbuster, and Seroquel(patent expired on march, 2012), its best-selling bipolar drug.

In September 2012, AstraZeneca inked a deal with WuXi PharmaTech (www.wuxiapptec.com) to develop and commercialize MEDI5117, a biologic for rheumatoid arthritis and other inflammatory diseases. Last month, AZ inked a multiyear deal with Chinese CRO Pharmaron(www.pharmaron.com). The partnership will target treatments for cancer and cardiovascular, respiratory, gastrointestinal and infectious diseases. AstraZeneca plans to boost efforts to bring new, innovative drugs to China by hiring 1,000 more people–across R&D, operations and commercial–by 2015.

In December 2011, AstraZeneca acquired Chinese generic injectables maker Guangdong BeiKang Pharmaceutical for an undisclosed sum.

Merck Serono

Investment: $200 million over several years
Themes: R&D and CRO collaboration

Merck Serono, a division of the German giant pharmaceutical company Merck (Merck KgaA), invested $200 million to build and run the Beijing R&D hub on the Pharmaron campus in Beijing.

Pfizer

Investment: $145 million
Themes: Branded generics and joint ventures

Pfizer reported this year in a planned joint venture with Chinese drug firm Zhejiang Hisun Pharmaceutical (www.hisunpharm.com) to manufacture and sell off-patent drugs in China and the rest of the world. Hisun’s expertise in the production of active pharmaceutical ingredients (API), and the fact that Chinese law and regulations favor drugs manufactured in China, will all benefit Pfizer. Registered capital is $250 million and new factories are in Fuyang and Zhejiang provinces. Hisun owns a 51% stake in the venture, while Pfizer is entitled to the remaining stake. Hisun-Pfizer Pharmaceuticals aims to employ 1,000 people by next month.An additional 500 people will be hired in 2013.

Novo Nordisk

Investment: $100 million
Themes: Diabetes

The Chinese diabetes drug market will climb to $2.8 billion by 2015 from $642 million in 2009 while the latest study shows one in 10 people in China have diabetes.

The Danish company Novo Nordisk, the world’s biggest maker of insulin, saw its share of synthetic insulin in china dropped from about 70 percent in 2006 to 53 percent last year after Paris-based Sanofi introduced its 24-hour insulin Lantus in 2004. Novo Nordisk will spend $100 million on research in China to preserve its dominance in the world’s largest market to fend off sanofi as it will train 10,500 doctors and experts in diabetes care. Novo has allocated $40 million for building a research facility in Beijing and $60 million on funding studies and adding 200 scientists in China by 2015.

Sanofi

Investment: $90 million
Themes: Diabetes

The French drugmaker Sanofi-Aventis, the world’s fourth-biggest drug maker, will invest $90 million to boost output of the insulin Lantus in China.

Sanofi-Aventis SA acquired Chinese pharmaceuticals player BMP Sunstone Corp., the maker of the Hao Wa Wa brand of children’s cough and cold treatments, for $520.6 million in October 2010 to expand in Chinese consumer health-care products. Hao Wa Wa, which means Good Baby, is China’s top pediatric cold brand. BMP Sunstone also makes Kang Fu Te brand hygiene products for women.

Eli Lilly

Investment: $80 million, plus undisclosed R&D spend
Themes: Diabetes and branded generics

Lilly, whose antipsychotic drug Zyprexa lost patent exclusivity in October,increased its investment in China generic-drug maker Novast Laboratories Ltd. by $20 million in June 2012 and expanded their collaboration to enhance Lilly’s efforts to offer branded generic medicines in the country. Lilly originally invested in the Novast roughly five years ago through an US$100 million fund run through its venture-capital arm. Novast Laboratories Ltd. makes generic versions of controlled-release and other pharmaceuticals. The company was founded in 2004 and is based in Nantong. Eli Lilly also opened a diabetes R&D center on May 30 in Shanghai with about 150 scientists and staff hired primarily from China.

GlaxoSmithKline

Investment: ~$63 million
Themes: Vaccines and joint ventures

GlaxoSmithKline acquired the remaining 51 percent equity stake in Chinese joint venture Shenzhen Neptunus Interlong Bio-Technique (www.interlong.com) for $39 millio in June 2011, reiterating its dedication to expanding its vaccines offering in greater China.

A Tale of Twin Cancer Drugs – Sorafenib (Nexavar) and Regorafenib (Stivarga)

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Jul 162013

Bayer’s blockbuster hopeful regorafenib, an oral multi-kinase inhibitor and marketed as Stivarga, was approved by the U.S. Food and Drug Administration (FDA) on September 27, 2012 for the treatment of patients with metastatic colorectal cancer (mCRC).

Regorafenib (aka BAY 73-4506, DAST, Fluoro-Sorafenib) has the same chemical structure as the blockbuster cancer therapy Nexavar marketed jointly by Onyx and Bayer, except for the new cancer drug with the substitution of a single fluorine atom in place of a hydrogen atom.

Germany-based Bayer AG and South San Francisco-based Onyx began working together in 1994, and their collaboration on Nexavar brings Onyx all of its revenue.

Nexavar (sorafenib) approved by US FDA against kidney cancer in 2005 and advanced liver cancer in 2007, sells for about $5,000 a month in the United States. Worldwide sales of the drug grew to $481.1 million in the first six months of 2011.

Onyx Pharmaceuticals filed a lawsuit in May 2009, accusing its partner Bayer of trying to cut it out of the collaboration by developing a drug that was almost identical to the their approved cancer drug Nexavar without informing Onyx so it would not have to make royalty payments to Onyx.

The case is Onyx Pharmaceuticals Inc. vs. Bayer Corp., Case No. 3:09-cv-02145 MHP, U.S. District Court, Northern District of California (San Francisco).

Both companies reached an agreement in 2011 with Bayer paying Onyx a one-time $160 million fee plus a royalty of 20% of future regorafenib sales.

Bayer is developing regorafenib as a treatment for gastrointestinal stromal tumors, which mostly occur in the stomach or small intestine. Bayer has applied for FDA approval of the drug for use in patients who have not been helped by treatment with Novartis AG’s drug Gleevec and Pfizer Inc.’s Sutent.

MAYFIELD CLINIC -TRIALS

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Jul 152013

http://www.mayfieldclinic.com/ClinicalTrials.htm

Belinostat,Melphalan,Apaziquone -Tiny Biotech With Three Cancer Drugs Is More Alluring Takeover Bet Now

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Jul 152013

Belinostat

Melphalan

Apaziquone

Raj Shrotriya, Spectrum’s chairman, president and CEO, likes to be an acquirer, analysts say. To boost the value of Spectrum’s stock, Shrotriya could enter into a merger agreement with a larger pharmaceutical company or acquire another drugmaker with an attractive product. He is confident that as a stand-alone company, Spectrum has the potential of becoming a larfger company with a bigger and diversified presence in the pharmaceutical industry.

Shrotriya says over the next 18 months, he expects Spectrum will be filing three new drug applications with the FDA — for Belinostat, a pan-HDAC inhibitor that could have the potential of becoming a backbone of chemotherapy along with carplatin and paclitaxel; Melphalan, a unique formulation used as a conditioning regimen for bone marrow transplant in certain diseases; and Apaziquone.

http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/