Health Canada has approved two GlaxoSmithKline (GSK) drugs, Tafinlar(TM) (dabrafenib mesilate) and Mekinist(TM) (trametinib), for patients with unresectable or metastatic melanoma. Dabrafenib mesylate, which is a BRAF-inhibitor, is indicated as a monotherapy oral treatment for unresectable melanoma or metastatic melanoma in adult …http://www.gsk.ca/english/html/media-centre/2013-07-24.html
Iron oxide nanoparticles precisely direct stem cells to damage tissues, thereby increasing their therapeutic potential
http://www.chemistryviews.org/details/news/5039301/Iron_Oxide_Nanoparticles_Show_the_Way.html
The discovery of a gene’s function in E. coli and other bacteria might lead to a probiotic to prevent calcium-oxalate urinary stones, the most common type of kidney stone. Human cells can’t metabolize oxalate and high concentrations can result in painful blockages of the urinary tract.
http://www.precisionnutrition.com/all-about-kidney-stones
selumetinib
Array Biopharma To Report Top-line Results From ARRY-502 Asthma Trial
Sacramento Bee
AstraZeneca began a pivotal trial with selumetinib (an Array-invented drug) in patients with thyroid cancer in May 2013 and expects to begin a Phase 3 trial in patients with non-small cell lung cancer during the second half of 2013. Three other Array …
http://www.sacbee.com/2013/07/22/5586413/array-biopharma-to-report-top.html
Selumetinib (AZD6244) is a drug being investigated for the treatment of various types of cancer, for example non-small cell lung cancer (NSCLC).
The gene BRAF is part of the MAPK/ERK pathway, a chain of proteins in cells that communicates input from growth factors. Activating mutations in the BRAF gene, primarily V600E (meaning that the amino acid valine in position 600 is replaced by glutamic acid), are associated with lower survival rates in patients with papillary thyroid cancer. Another type of mutation that leads to undue activation of this pathway occurs in the gene KRAS and is found in NSCLC. A possibility of reducing the activity of the MAPK/ERK pathway is to block the enzyme MAPK kinase (MEK), immediately downstream of BRAF, with the drug selumetinib. More specifically, selumetinib blocks the subtypes MEK1 and MEK2 of this enzyme.[1]
KRAS mutations appear in 20 to 30% of NSCLC cases and about 40% of colorectal cancer.[1]
A Phase II clinical trial about selumetinib in NSCLC has been completed in September 2011;[3] one about cancers with BRAF mutations is ongoing as of June 2012[update].[4]
|displayauthors= suggested (help) edit|displayauthors= suggested (help) editmore info…………………………………….
AZD-6244 (Selumetinib) is an orally-available, aminobenzimidazole-based, allosteric inhibitor of MEK1 kinase with an IC50 of 14 nM. [1] IC50 concentrations of
In cellular growth assays, AZD-6244 was more potent in cell lines containing activating B-Raf and Ras mutations, with IC50 values ranging from 59 to 473 nM. In HT-29 and Malme-3M cell studies, AZD-6244 was found to induce G1-S cell cycle arrest, inducing apoptosis after a 2-day incubation period. [1] In Colo-205 xenografts, AZD6244 induced increased levels of cleaved caspase-3, indicating apoptosis. [2]
In diffuse large B-cell lymphoma (DLBCL) lines, nanomolar concentration of AZD-6244 effectively downregulated MEK/ERK target substrates, including c-Myc, Mcl-1, and Bcl-2. [3]
Technical information:
| Chemical Formula: | C17H15BrClFN4O3 | |
| CAS #: | 606143-52-6 | |
| Molecular Weight: | 457.68 | |
| Appearance: | White | |
| Chemical Name: | 6-(4-bromo-2-chlorophenylamino)-7-fluoro-N-(2-hydroxyethoxy)-3-methyl-3H-benzo[d]imidazole-5-carboxamide | |
| Solubility: | Up to 100 mM in DMSO | |
| Synonyms: | AZD-6244, AZD 6244, AZD6244, Selumetinib, Selumetinib sulfate, NSC-748727, ARRY-142886 |
Reference:
| 1. | Yeh et al., Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin. Cancer Res. 2007, 13, 1576-1583 Pubmed ID: 17332304 |
| 2. | Davies et al., AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther. 2007, 6, 2209-2219. Pubmed ID: 17699718 |
| 3. | Bhalla et al., The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma. Blood, 2011, 118(4), 1052-1061. Pubmed ID: 21628402 |
A compound is being investigated as a Type II diabetes treatment by Lexicon Pharmaceuticals, although it is in an early stage of development
LX4211
A compound is being investigated as a Type II diabetes treatment by Lexicon Pharmaceuticals, although it is in an early stage of development.
LX4211 is not selective for just sodium glucose co-transporter-2, or SGLT-2 – it also inhibits SGLT-1.1 Inhibiting this second transporter, responsible for the absorption of glucose in the intestines, it also results in an increase in the release of glucagon-like peptide-1 (GLP-1), but might be combated by administering the dual inhibitor in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor to prevent it being activated.
– See more at:
http://www.manufacturingchemist.com/technical/article_page/Diabetes__LX4211/88179
Dr Reddy’s Laboratories Ltd new patent on
Preparation of lubiprostone
Jackson, Mark; Dahanukar, Vilas Hareshwar; Joseph, Suju Chuttippari; Eda, Vishnu Vardhana Verma Reddy; Ramdas, Sandip Khobare
US 20130184476, 18-JUL-2013
| IN2011CH2389 | 13-JUL-2011 priority |
NCT01674530, Phase 3
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general info in public domain
Lubiprostone (rINN, marketed under the trade name Amitiza) is a medicationused in the management of chronic idiopathic constipation and irritable bowel syndrome. It was approved by the U.S. Food and Drug Administration (FDA) for this purpose on 31 January 2006.
Lubiprostone is used for the treatment of chronic constipation of unknown cause in adults, as well as irritable bowel syndrome associated with constipation in women.
As of 20 July 2006, Lubiprostone has not been studied in children. There is current research underway to determine the efficacy in postoperative bowel dysfunction, and opioid-induced bowel dysfunction.
Synthesis:Sobrera, L. A.; Castaner, J. (2004). Drugs of the Future 29 (4): 336.
PA 824
The search for a new tuberculosis drug after many decades and first time through a unique model of open drug discovery programme may finally bear fruits in near future, with India all set for the launch of the phase II clinical trial of the drug candidate.
The drug, coming through the Open Source Drug Discovery (OSDD) programme by Council of Scientific and Industrial Research (CSIR), will go for the clinical trials on drug-resistant TB patients in India very soon. The process of filing for permission from the Drug Controller General of India (DCGI) is on and public sector LRS Hospital for Respiratory and Infectious Diseases, New Delhi, has been selected for trials. This phase II trials will involve around 250-300 patients, sources said.
The drug candidate, Pa824, was synthesised in India long ago. After a series of ownership changes, the molecule was licensed to CSIR for further development now.
http://www.pharmabiz.com/NewsDetails.aspx?aid=76568&sid=1
Tuberculosis (TB) is one of the leading infectious diseases in the world, with approximately one-third of the world’s population harboring the causative agent, Mycobacterium tuberculosis (Mtb). Though previously a disease associated with aristocratic societies, TB is now predominantly a third-world disease, particularly affecting Asian communities and sub-Saharan Africa. Mtb isolates are increasingly resistant to drug therapies: multidrug-resistant TB (MDR TB) or more severely, extensively drug-resistant TB (XDR TB). As a consequence of these emerging strains, it is becoming increasingly apparent that novel drugs are necessary to combat Mtb infections.
PA 824 is an experimental anti-tuberculosis drug.[1][2] The bicyclic nitroimidazole like molecule PA-824 has got a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis.Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism.The respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment.[3]PA-824 recently was shown to be safe, well tolerated, and efficacious at doses of 100–200 mg daily in a dose-ranging study among drug-sensitive, sputum smear–positive, adult pulmonary TB patients [4]
QSAR modeling of the nitroimidazole PA-824. Shown are two hydrogen bond acceptors (green), one hydrogen bond donor (purple), and one hydrophobe (aqua). Credit: NIAID
picked up from a japanes site
Available at:
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
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.
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The potential medical uses of spider venoms are largely due to their selectivity and affinity for ion channels.
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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 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.
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. 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
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 (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.
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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”.