Principles of Instrumental Analysis by Skoog, Holler & Crouch

Principles of Instrumental Analysis by Skoog, Holler & Crouch

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Principles of Instrumental Analysis

Details of Book: Principles of Instrumental Analysis
Book: Principles of Instrumental Analysis
Authors: Douglas A. Skoog, F. James Holler, Stanley R. Crouch
ISBN-10: 0495012017
ISBN-13: 978-0495012016
Publisher: Brooks Cole
Publication Date: December 6, 2006
Edition: 6th edition

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Cipla introduces new pain free screening technology for early detection of breast cancer in India

Cipla introduces new pain free screening technology for early detection of breast cancer in India

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Cipla, one of the leading pharmaceutical companies from India, announces the launch of a breakthrough screening technology in India today called the ‘No Touch Breast Scan (NTBS); ' the first-ever painless, non-invasive and radiation-free breast scanning technique for detecting breast cancer at an early stage. Dr. Shekhar Kulkarni, Consultant Breast Cancer Surgeon, Magnolia Breast Surgery Clinic, Pune said, “Breast cancer is rising rapidly among urban women and is now the most common cancer in cities such as Mumbai and Delhi . Unfortunately most cancers are diagnosed when the disease is advanced leading to low chances of cure. Although Mammography has been available for years it is not used that widely. There are many reasons for it such as lack of awareness, pain and discomfort during the procedure and a concern about repeated exposure to radiation. Welcoming the introduction of NTBS in India , Dr. Rakesh Sinha, Consultant Gynaecologist Surgeon, BEAMS Hospital , Mumbai said, “The No-Touch Breast scan is a painless option for women who wish to get themselves regularly screened. It is of particular use in younger women who have dense breasts and mammography is inconclusive. If a woman shows changes on the NTBS then she is sent for further investigation which includes mammography, sonography etc. At BEAMS Mumbai, of the 41 patients who have undergone the NTBS test, only 1 had to be referred for mammography.” 

Thermal imaging has been approved by the FDA several years ago for early diagnosis of breast cancer. With improvements in digital camera technology during the last few years, thermal imaging is fast gaining acceptance. Developed by UE Life Sciences Inc, the ‘No Touch Breast Scan' is the World's first fully computerized ‘thermal imaging technology' with dual IR cameras which can find thermal changes at less than 0.08 deg. C. The NTBS using infrared imaging creates a sophisticated heat-map of the breast without using any radiation. Breast cancer is associated with increased formation of new blood vessels and these show up as 'hot spots' which could indicate a cancerous growth. 

At Dr Kulkarni's Magnolia Beauty and Clinic in Pune, the NTBS test was taken by about 165 women and only 12 of them needed further investigation. Mrs. Ambike, an asymptomatic woman who has untaken the NTBS test said, “I had taken a mammography test earlier but it was quite traumatic. With this totally touch-free and quick NTBS test, I would not defer my annual check-up anymore.”

The ‘No-Touch Breast Scan' would be exclusively marketed by Cipla across diagnostic centres and hospitals in India . It has already been installed at BEAMS Hospital , Mumbai and Indore and Magnolia Beauty and Clinic, Pune and would be extended by Cipla on a requirement-basis to over 20 more diagnostic centres or hospitals across India . Addressing the press, Dr. Jaideep Gogtay, Medical Director Cipla said , “Cipla has been working in the area of cancer by manufacturing drugs for the last 20 years but this is for the first time we have taken a step towards focusing on early diagnosis of breast cancer.

There are 3 NTBS machines available in the US , UK , Turkey and Kazakhstan , but women in India would have greater access to this landmark technology and have more control over their breast health.”

The cost of per NTBS test would range between Rs 800 – 1000, depending on the pricing determined individually by the hospitals and centres. 

About Cipla:

Cipla laid foundations for the Indian pharmaceutical industry back in 1935 with the vision to make India self-reliant in healthcare. Over the years Cipla has emerged as one of the most respected names not just in India but worldwide. Its state of the art R&D centre has given the country and the world many firsts. This includes the revolutionary AIDS cocktail for less than a dollar a day. With over 40 manufacturing units across the country, Cipla manufactures over 1200 products in 80 therapies.

With a turnover of over US $ 1 billion, Cipla serves doctors and patients in over 183 countries. It has earned a name for maintaining one global standard across all its products and services. Cipla continues to support, improve and save millions of lives with its high-quality drugs and innovative devices. ( www.cipla.com )

Treating Cancer with Light

Treating Cancer with Light

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New LED Device May Help Advance Photodynamic Therapy for Skin Cancer. Scientists at the University of California, Irvine (UC Irvine), believe so. They're exploring new ways to image cancerous lesions using LEDs that might advance a technique for treating cancer called photodynamic therapy (PDT) -- work that they will describe at the Optical Society’s (OSA) 94th annual meeting, Frontiers in Optics (FiO) 2010  at the Rochester Riverside Convention Center in Rochester, N.Y., from Oct. 24-28.

In PDT, photosensitizing chemicals that absorb light are injected into a tumor, which is then exposed to light. The chemicals generate oxygen radicals from the light energy, destroying the cancer cells. PDT is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of esophageal and lung cancer.

Rolf Saager, who works in the lab of Anthony Durkin at the Beckman Laser Institute at UC Irvine in collaboration with Kristen Kelly, M.D., and Modulated Imaging Inc., believes that PDT could also be used to treat skin cancer. But one obstacle to this application is the lack of a detailed imaging technique to target and monitor the effectiveness of PDT.

Exploiting a technique known as spatial frequency domain imaging, the team has designed a new device with an array of five different colors of LEDs that illuminates skin with distinct intensity patterns. These patterns can change depending on the structure of the tissue and the pigments in the skin. With appropriate models of light propagation, the resulting images reveal the biochemistry of the tissue.

"Through this imaging modality, it is now possible to assess how the therapeutic light will travel throughout the affected tissue, quantify the drug present within the lesion and monitor its efficacy during treatment," says Saager.

To evaluate this spatial frequency domain imaging system, the scientists imaged a small population of skin cancers prior to treatment to characterize the variability among subjects and within the lesions themselves. The process took 5-10 seconds and produced images with a resolution of 30 microns, revealing spatially resolved maps of the optical properties of the lesions, tissue oxygenation and quantitative distribution of the photosensitizing drug.

Saager and colleagues hope that this imaging technique will provide a better map for targeting and optimizing photodynamic therapy for basal cell carcinoma, the most common type of skin cancer. The next step for their ongoing experiment will be to enable the therapeutic aspects of the instrument and monitor the tissue dynamics during PDT treatment regimens.

he talk, "A LED Based Spatial Frequency Domain Imaging System for Optimization of Photodynamic Therapy of Basal Cell Carcinoma (BCC)" is at 2 p.m. Tuesday, Oct. 26.

About the Meeting

Frontiers in Optics 2010 is OSA’s 94th Annual Meeting and is being held together with Laser Science XXVI, the annual meeting of the American Physical Society (APS) Division of Laser Science (DLS). The two meetings unite the OSA and APS communities for five days of quality, cutting-edge presentations, fascinating invited speakers and a variety of special events spanning a broad range of topics in physics, biology and chemistry. FiO 2010 will also offer a number of Short Courses designed to increase participants’ knowledge of a specific subject while offering the experience of insightful teachers. An exhibit floor featuring leading optics companies will further enhance the meeting.

About OSA

Uniting more than 106,000 professionals from 134 countries, the Optical Society (OSA) brings together the global optics community through its programs and initiatives. Since 1916 OSA has worked to advance the common interests of the field, providing educational resources to the scientists, engineers and business leaders who work in the field by promoting the science of light and the advanced technologies made possible by optics and photonics. OSA publications, events, technical groups and programs foster optics knowledge and scientific collaboration among all those with an interest in optics and photonics. For more information, visit www.osa.org.

NICE recommends new drug to treat blood clots

NICE recommends new drug to treat blood clots

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Venous thromboembolism (VTE) is the term used to describe a condition in which a blood clot (a thrombus) forms in a vein and then dislodges to travel in the blood (an embolus). A venous thrombus most commonly occurs in the deep veins of the legs or pelvis; this is called deep vein thrombosis (DVT). Blood flow through the affected vein can be limited by the clot, and it can cause swelling and pain in the leg. If the thrombus dislodges and travels to the lungs, this can lead to a potentially fatal pulmonary embolism (PE) when the clot blocks the blood supply to the lungs. Other complications of DVT include post-thrombotic syndrome, a chronic disorder that may include symptoms such as pain, heaviness, swelling, cramps, itching or tingling, increased skin pigmentation and ulceration in the affected limb.

Risk factors for VTE include a history of DVT, recent surgery, immobility, active cancer or cancer treatment, age over 60 years, obesity, hormone replacement therapy or oestrogen containing contraceptive therapy and the presence of co-morbidities such as heart disease. It is estimated that there will be over 46,000 cases of acute DVT in England and Wales during 2012, rising to nearly 50,000 by 2016 due in large part to the aging population.

Treatments for VTE include initiation with injectable anticoagulants such as low-molecular-weight heparin or fondaparinux sodium. Treatment is then overlapped with a vitamin-K antagonist, such as warfarin, until effective anticoagulation with the oral agent is achieved.

Rivaroxaban is an orally administered drug that helps to prevent blood from clotting. It does this by stopping a substance called Factor Xa from working. Factor Xa is necessary in the formation of thrombin and fibrin, the key components in blood clot formation. Duration of treatment with rivaroxaban is based on an assessment of the benefit of anticoagulation compared with the risk of bleeding and usually ranges from 3 to 12 months. Some people with ongoing risk factors for recurrence of VTE need ongoing treatment, possibly for many years or lifelong.

Professor Carole Longson, NICE Health Technology Evaluation Centre Director, said: "For many people, using warfarin is difficult because of the need for regular monitoring with blood tests, dosing adjustments, and the need to be careful about their diet because of warfarin’s interaction with certain foods. Because rivaroxaban does not require frequent blood tests to monitor treatment it represents a potential benefit for many people who have had a DVT, particularly those who have risk factors for recurrence of VTE and who therefore need longer term treatment. We are pleased, therefore, to be able to recommend rivaroxaban as a cost-effective option for treating DVT and preventing recurrent VTE in adults."

The guidance is available (from 25 July) on the NICE website at http://guidance.nice.org.uk/TA261

Benefits of statin therapy may extend beyond lowering lipids

Benefits of statin therapy may extend beyond lowering lipids

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People with high cholesterol are at risk of heart attack and stroke because atherosclerotic plaques within their arteries can rupture triggering the formation of a blood clot called an occlusive thrombus that cuts off the blood supply to their heart or brain.

For years, scientists have studied the cause of this abnormal clotting. Now, a study led by researchers from the University of North Carolina at Chapel Hill School of Medicine, has identified a molecular pathway that leads to this abnormal blood clotting and turned it off using a popular class of cholesterol-lowering drugs, statins.

The research was performed using humans, monkeys and mice with highly elevated blood lipid levels. It indicated that elevated levels of oxidized low density lipoprotein (LDL) induces a molecule called "tissue factor" that triggers clotting. The study appears online in the January 3, 2012 issue of the Journal of Clinical Investigation.

"Statins have been shown to have antithrombotic activity in several previous studies. However, I believe our study is the first to elucidate how statins reduce the activation of the blood clotting process independently of their lipid lowering activity, said senior study author Nigel Mackman, PhD, FAHA. Mackman is the John C. Parker Distinguished Professor of Hematology in the Department of Medicine and Director of the UNC McAllister Heart Institute.

Additionally, Mackman noted that statins "only target the 'bad and inducible tissue factor', not the good one used in normal clotting, and therefore should not be associated with the increased bleeding risk that is a typical side effect of anticoagulant drugs currently on the market."

Mackman has spent the last twenty-five years studying tissue factor, the number one initiator of clotting in the body. Tissue factor normally resides outside the blood vessels, only coming into contact with blood after an injury, such as cutting your finger. However, it is expressed at high levels under certain abnormal conditions, such as inside atherosclerotic plaques, and gets turned on in a special subset of blood cells called monocytes. Mackman wondered if this was the cause for the abnormal clotting seen in patients with high cholesterol.

To test his hypothesis, Mackman and his colleagues analyzed humans, monkeys and mice with high cholesterol. They found that all three groups have elevated levels of tissue factor in the circulation. Then the researchers treated the mice and monkeys with simvastatin, a drug widely used to treat high blood cholesterol levels. They showed that simvastatin reduced levels of oxidized low density lipoprotein and circulating tissue factor which normalized coagulation without altering plasma cholesterol levels.

These results suggest that oxidized low density lipoproteins induce tissue factor expression on monocytes and this contributes to formation of an occlusive thrombus after plaque rupture.

"Though statin therapy is primarily prescribed to lower cholesterol, some added benefits are its anti-inflammatory and antithrombotic activities," said Mackman. "In terms of drug development, I think we should be trying to better understand the antithrombotic activities of statins so we can develop safer antithrombotic drugs that target the expression of inducible tissue factor."

Nano-Technology: New Hopes in Cancer Treatment

Nano-Technology: New Hopes in Cancer Treatment

Posted in Cancer, Pharmacology

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Cancer has become a foremost cause of death around the world. Cancer is an extremely complex disease to understand because it entails multiple cellular physiological systems such as cell signaling and apoptosis. However the most cancer treatments are limited to chemotherapy, radiation and surgery. Even in these scopes, different drawback plays major role shortcoming its affectivity. 99% of chemotherapy does not reach the cancer cells, US National Cancer Institute (OTIR, 2006). Moreover poor drug delivery and residence at the target sites reach o significant complications including multi drug-resistance. Radiation therapy is also not specific to cancer cells. Most of the normal cells in the body die at 460 C (1080 F) which limited the extent of affectivity of radiation therapy. And most of times surgery is possible if cancer is detected at early stages.

Nanotechnology has the power to offer solutions to these current obstacles in cancer therapies due to its unique size (1-100 nm) and large surface to volume ratios. Currently, lots of research is going on to design novel nanodevices capable of detecting cancer at its earliest stages, pinpointing its location in the body and delivering anti-cancer drugs specifically to malignant cells. According to OTIR:

“The advent of nanotechnology in cancer research couldn’t have come at a more opportune time. The vast knowledge of cancer genomics and proteomics emerging as a result of the Human Genome Project is providing critically important details of how cancer develops which in turn, creates new opportunities to attack the molecular underpinnings of cancer”.

Nano-devices can swift and sensitive detection of cancer retreated molecules enabling the scientists to detect molecular changes even when they occur in minute percentage of cells. Nano-technology will allow diminution of screening tools which means many tests can be run on a single device making screening faster and cost efficient. Scientists have already succeeded to design such modified nano-particles which allows better drug delivery reducing toxicity and decreasing tumor growth rates. Thus nano-particles allows drug delivery only at certain conditions    e.g. pH sensitive allowing drug delivery only at certain pH value, similar to pH value unique in tumor cells. Recently a clinical research showed a significant result reducing tumor growth by 22% without and side-effects due to their high selectivity, where as aqueous solution only had reduced 44%. Furthermore the shelf life of nano-particles carrying drugs are also more than the usual.
Nanotechnology will radically change the way we diagnose, treat and prevent cancer to help meet the goal of eliminating suffering and death from the cancer. It will provide the technical tools which will enable those developing new diagnostics, therapeutics and prevention. With nano-medicine we might be able to stop cancer even before it develops.

Author: Santanu Mahiuddin, B.Pharm, M.Sc. (UK), Quality Control Officer, Novartis Bangladesh Limited.

Sugar to fight against Hospital infections!!

Sugar to fight against Hospital infections!!

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A Carbohydrate found on the surface of one of the most virulent strains of Clostridium Difficile has been synthesized by scientists in Germany.
This piece of research can prove to be an important breakthrough in the Vaccine development programme against the infection.

C.Difficile bacterium

C.Difficile is a species of Gram-positive bacteria of the genus Clostridium that remains in a dormant form (i.e. spores) inside the colon until a person pops an antibiotic pill. The antibiotics in its course of action also destroys the normal gut flora(the good bacteria) leading to an overgrowth of C. difficile, which flourishes under these conditions. This results in the C.difficile getting converted into its active form and producing toxins which damages the gut wall, resulting in bloody diarrhoea and pseudomembraneous colitis.


C.difficile infections are one of the most common Nosocomial infections worldwide and are the leading cause of death in elderly and those with weakened immune system.Peter Seeberger, who led the team that carried out the research at the Max Planck Institute of Colloids and Interfaces, Potsdam was qouted as saying"C. difficile is on the rise in industrialised countries.There is a need for a vaccine but it's a big challenge."


Treatment with antibiotics is not so effective because of increasing resistance and tough nature of bacterial spores..The majority of severe infections are caused by just one hypervirulant strain - type 027.


To fight this particular strain, Seeberger and his team synthesised the repeating unit of a carbohydrate -pentasaccharide PS-1 - that is only found on the surface of type 027. The linear synthesis involved using one precursor molecule to make four different building blocks, making an efficient process.Their aim is to use PS-1 to create a vaccine to enable the immune system to recognise it, make antibodies against it and mount a response against the infection.

'It is elegant chemistry and shows that if you master the challenges of synthetic carbohydrate chemistry, you can produce something that's medically useful,' says Gerd Wagner, a medicinal chemistry expert at King's College London, UK, who agrees that the research 'opens the door to exploring a vaccine candidate'. 

Seeberger's team was also the first to synthesize PS-2, a carbohydrate found on all strains of C. difficile. He states the possibility of 'combining PS-1 and PS-2 in a single vaccine candidate for better coverage'. His team has begun tests using PS-1 attached to a protein carrier to determine whether animals can create antibodies against it. It will be years before a vaccine is available, he says, but he emphasizes that PS-1 and PS-2 are both promising candidates!!

Vaccine for Brain Tumor: A New Height in Personalized Medicine

Vaccine for Brain Tumor: A New Height in Personalized Medicine

Posted in Articles, brain tumor, clinical trials, heat shock proteins, HSPPC-96, personalized medicine, vaccine

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Developing a Vaccine produced from a patient's one's own tissues has definitely taken Pharmacogenomics-popularly known as "Personalized medicine" to a new height in the present scenario.

The concept of Pharmacogenomics deals with the genetic variation among the masses, and using the genetic data to select the right drugs to treat disease in a given patient. Although at a primary level, this can help the doctors in avoiding pointless treatments and reducing adverse drug reactions in the concerned patients.

Using a patient's own tissues for developing a Vaccine, is in itself a novel strategy employed by Valley Hospital in Ridgewood, N.J, wherein they are offering patients with newly diagnosed glioblastoma multiforme (GBM) (brain tumor) the opportunity to take part in the clinical trials.

The phase II trial, headed by principal investigator and researcherAnthony D'Ambrosio, M.D., director of Valley's neuro-oncology disease management team, is designed to evaluate safety, survival and immune response in patients treated with a heat shock protein peptide-complex vaccine (HSPPC-96) derived from each patient's specific tumor cells.

"Heat shock proteins are believed to play an essential role in helping the immune system to recognize and eradicate diseased cells," said D'Ambrosio.

The Glioblastoma Vaccine study is sponsored by the University of California, San Francisco, and is currently available in limited locations across the country. The study is currently searching for participants who are newly diagnosed, over age 18 and whose tumors have not been excised.

These trials indicate a new era in healthcare with the advent of personalized medicines, for the common good of humanity.

Naming the Antibiotics: Some Intriguing Facts

Naming the Antibiotics: Some Intriguing Facts

Posted in Antibiotics, Articles

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An entertaining and brief but fully documented review of the methods by which discoverers of antibiotics have chosen names for them is given byD. Perlman of the School of Pharmacy, University of Wisconsin. 

Antibiotics named after Organisms: 

Some of the best known, and a total of about 500, have names derived from the organisms producing them, either that of the genus (penicillin, streptomycin, cephalosporins) or of the species (griseofulvin from Penicillium griseofulvum). A few, such as staphylomycin and gramicidin, denote not the source but the organisms susceptible to them.

Antibiotics named after Places:

These antibiotics are named after the geographical sources of the soil where the producing organism was cultivated.

Pimaricin, a useful antifungal antibiotic was named after Pietermaritzburg, near which the soil yielding Streptomyces natalensis was collected.

Nystatin, is the only antibiotic named after the institution in which it was isolated, the laboratories of the New York State Board of Health.

Antibiotics named after people:

1Bacitracin-- Margaret Tracy being the child with a compound fracture from whose wound the producing Bacillus was isolated, where its growth was apparently contributing to overcoming septic infection.

2Helenine, an antibiotic of no clinical value but having an interesting action on some virus infections in mice, was so named by the late R. E. Shope after his wife Helen, because he found the mould producing the antibiotic growing on the cover of a photograph of her which he was carrying while serving in the war in the Pacific.

3saramycetin (a sulphur-containing peptide with systemic antifungal activity) was named  after a mother-in-law.

Antibiotics with Peculiar Names

Public Domain Databases for Medicinal Chemistry

Public Domain Databases for Medicinal Chemistry

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Here's a useful overview of the public-domain medicinal chemistry databases out there. 

BindingDB (quantitative binding data to protein targets).

ChEMBL (wide range of med-chem data, overlaps a bit with PubChem).

PubChem (data from NIH Roadmap screen and many others).

PDB (repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids

Binding MOAD (literature-annotated PDB data).

ChemSpider (26 million compounds from hundreds of data sources).

DrugBank (data on 6700 known drugs).

GRAC and IUPHAR-DB (data on GPCRs, ion channels, and nuclear receptors, and ligands for all of these).

PDBbind (more annotated PDB data).

PDSP Ki (data from UNC's psychoactive drug screening program)

SuperTarget (target-compound interaction database).

Therapeutic Targets Database(database of known and possible drug targets).

ZINC (21 million commercially available compounds, organized by class, downloadable in various formats).

Breakthrough Research: Cure for Morphine Addiction found!!

Breakthrough Research: Cure for Morphine Addiction found!!

Posted in Articles, Morphine addiction, opioids, TLR-4 receptor, toll-like receptors. cure for heroin addiction

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In a major breakthrough by a group of Australian scientists, a cure has been found for morphine and heroin addiction which will prove a boon for more than 12 million drug addicts worldwide.(1)

Scientists at the University of Adelaide have identified an immune receptor TLR-4 which is responsible for the drug addiction, and found a way to block this receptor without affecting pain relief.

This discovery can have wide implications as it offers the possibility of using Morphine as a pain reliever without worrying about its addictive properties. The use of morphine and other opioids is currently restricted as it can lead to some harmful effects if addicted to it. 

Morphine and other opioids are known to bind to the opioid receptors in the brain, which results in pain relief and also activation of the "Reward Pathway". This "Reward Pathway" is a result of the release of large quantities of Dopamine in the brain which is the root cause for addiction to opioids.

TLR-4 is a toll-like receptor whose role is to identify  foreign bodies, 
and thus launch an immune attack against harmful pathogens.

The observation that the opioids also bind to the toll-like receptors TLR-4, eventually led the Hutchinson team to the hypothesis, that TLR-4 may act as an amplifier for award when opioids are bound to it. They performed a series of experiments pertaining to the addictive behaviour in rats, by administering a known drug (called plus naloxone- which is known to block TLR-4), and hence blocking the immune receptors. 

Rats given plus-naloxone before receiving morphine did not exhibit behaviour linked to addiction. Their brains also showed a significantlylower release of dopamine than in rats that only received morphine. Using a heat sensitivity test, the team also showed that the rodents given plus-naloxone still experienced pain relief from the morphine, despite lacking signs of addiction.

The idea that the rewarding effect of opioid drugs is potentially mediated by this receptor "flies in the face of current opinion," says Chris Bailey, a pharmacologist from the University of Bath in the UK. "People for hundreds of years have been trying to come up with an opioid analgesic which isn't rewarding," he says.
These findings are particularly interesting, he says, because it's the first time a mechanism has been identified that separates the pain relief and reward responses to opioid drugs. "It has always been seen that the analgesia and the rewarding aspects go hand in hand," he says.

 The National Institutes on Drug Abuse in U.S is further developing the drug to test in clinical trials. As a result, Clinical trials would soon be underway in the coming 2 years, Dr. Hutchinson said.

If the clinical trials were successful, opioid drugs used to relieve pain could potentially be co-formulated with the additional drugs( TLR-4 Blockers) to limit the chance of addiction.

It would also benefit the addicted patients who are admitted in hospital, and require pain relief. Addicted patients require higher doses of the drug, as they are higly tolerant to the drug, so this combination may help in lowering the doses given to the patients.


As bright as it looks, this "potential cure" for morphine addiction can definitely bring a paradigm shift if it passes the clinical trials successively. Hope it happens!!

References: (1) The World Drug Report, 2011 available online at http://www.unodc.org/documents/data-and-analysis/WDR2011/World_Drug_Report_2011_ebook.pdf
(2) for more info on Toll-like receptors, log onto: http://www.sinauer.com/pdf/nsp-immunity-3-10.pdf
(3) for more info on Reward pathways, visit: http://lilt.ilstu.edu/vfdouga/P331/ARTICLES/role%20of%20dopamine%20in%20reward%20and%20pleasure.pdf and http://learn.genetics.utah.edu/content/addiction/drugs/

Pyrogens

Pyrogens

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Pyrogens are Endotoxin, (or)lipopolysaccharide(LPS),is highly toxic to mammalian cells and is one of the most potent  modulators of the immune system.they areproduced from  gram –ve microorganisms.

COMPOSITION: pyrogens are  is composed of hydrophobic fatty acid and hydrophilic carbohydrate domains

The chemical nature of LPS makes pyrogen removal problematic . LPS is unusually thermostable and fairly insensitive to pH changes.

Both the United States Pharmacopeia and the European Pharmacopoeia specify the rabbit pyrogen test and the Limulus amebocyte lysate

PHYSIOLOGICAL EFFECTS:

1.First,pyrogens elevate the circulating levels of inflammatory cytokines (e.g.,IL-1,IL-6, TNF-_ and IL-8) followed by the clinically relevant events of fever,hypotension, lymphopenia, neutrophilia, and elevated levels of plasma cortisol and acute-phase proteins (e.g., C-reactive protein)

2.Low doses of pyrogens induce inflammatory reactions without any clinicallysignificant symptoms.

3. Moderatedoses of pyrogens induce fever and significant changes in plasma composition.

4. Highdoses of pyrogens can lead to septic shock characterized by cardiovascular dysfunction,including myocardial depression and dilatation, vasodilation, vasoconstriction,endothelium

dysfunction,and organ dysfunction (e.g., kidney, liver, lung, or brain) followed by multiple organ failures and death.

IDENTIFICATION:

Thereare 2 tests for the identification of endotoxins in parenterals

1 LALtest

2.Rabbit fever test

LAL TEST:

                                                        

 LALvials

The rabbit fever test was the standard FDA approved test for endotoxins, until the approval of the LAL test by the FDA in the 1980’s.

THE HORSE SHOE CRAB: LAL reagent is prepared from circulating blood cells of the horse shoe crab(limuluspolyphemus).

Ø     Substituted ffor USP pyrogen test (Rabbitffever test)..

Ø     Single test vial of LAL contains 0.2ml Lyophilized LAL

TEST PROCEDURE:

LAL is an aqueous extract of the blood cells of horseshoecrabs which forms a clot or change in color, depending on the technique, in thepresence of bacterial endotoxin. 

PROCEDURE:

Addition of  Lal reagent to our sample  causes clot formation, if  endotoxins are present.in our sample.

 The main MECHANISM involved in this is

Gram-negative bacterial endotoxin catalyzes the activationof a proenzyme in the Limulus Amebocyte Lysate. The initial rate of activationis determined by the concentration of endotoxin present. The activated enzyme(coagulase) hydrolyzes specific bonds within a clotting protein (coagulogen)also present in Limulus Amebocyte Lysate. Once hydrolyzed, the resultan tcoagulin self-associates and forms a gelatinous clot.

The test sample is compared to a standard series of Control Standard Endotoxin (CSE) dilutions. 

 The endpoint orreaction times of these dilutions are used to calculate the amount of endotoxinpresent in the sample. All tests are performed in at least duplicate. 

A positive control of the sample and negative controlusing non-pyrogenic water are also performed. .

RABBIT FEVER TEST:

The test involvesmeasuring the rise in temperature of rabbits following intravenous injection ofa test solution.

Dose : not to exceed10 ml per kg injected iv with in a period of not more than 10 mins.

Temperature ismeasured by using thermometers or temperature probes, here we measure rectaltemp.of rabbit.

Procedure:

Take 3 healthyrabbits , inject the sample into the ear vein of 3 healthy rabbits of 10 ml perkg of body wt.

 And record the rectal temp. of the rabbit  at 30 min intervals between 1 and 3 hrssubsequent to the inlection.

INTERPRETATION:

 If no rabbit shows an individual rise in temp.of  0.5 0  c. or more and sum of the temp . of therabbits  shows not more than 1.4  0 c. indicates absence of pyrogens in the sample

If any rabbit showsan individual temp. rise of more than 0.5 0  c., continue the test using five otherrabbits, now total 8 rabbits

if not more than 3 of8 rabbits show individual rise in temp. of 0.5 0  c. or more and sum of the 8 individual max temp rises does nt exceed 3.3 0  c.

Indicates absence ofpyrogens and vice versa.