Subcutaneous antiemitics

The subcutaneous administration of granisetron, an antiemetic pharmaceutical drug (suitable for control of vomiting), achieves similar blood concentrations to those administered intravenously. This was the conclusion of clinical tests undertaken by specialists at the University Hospital of Navarra, the results of which have been published in The Oncologist.

The efficacy of granisetron, when administered orally or intravenously, has already been shown, but never studied when given subcutaneously. The research shows that granisetron, administered subcutaneously, behaves in a similar manner as when injected intravenously.

The advantage of the subcutaneous method is the ease of treatment for nonhospitalised patients. Intravenous administration can be problematic as it requires specialised care; while administering orally may involve the patient vomiting. This form of medication is also useful for healthcare personnel such as the emergency services.



Beta blocker receptor

More than 40 years after beta blockers were first used clinically, scientists can finally get a close-up look at the drugs’ molecular target – the b2-adrenergic receptor. The work is particularly exciting because it offers the first glimpse into an important, but scientifically elusive family of human proteins called G proteincoupled receptors (GPCRs).

Because GPCRs control critical bodily functions, several of our senses, and the action of about half of today’s pharmaceuticals, the research promises not only to speed the discovery of new and improved drugs, but also to broaden our understanding of human health and disease.

Published online in the 25 October 2007 issue of Science Express, the research was supported by two major initiatives of the US National Institutes of Health – the Roadmap and the Protein Structure Initiative (PSI), which is led by the National Institute of General Medical Sciences. Additional funding came from the National Institute of Neurological Disorders and Stroke.

The work represents a technical tour de force that required the scientists to devise several new techniques. Many of the difficulties arose because the receptor is a membrane protein – one of the trickiest molecules to capture in three-dimensional detail. The only other known GPCR structure comes from a cow and was determined in 2000.

“Because of their role in so many medically important processes and the great challenges they present for detailed study, membrane proteins have been one focus of the NIH Roadmap for Medical Research,” said NIH director Elias A. Zerhouni, MD.

“The determination of this structure is an exciting example of the rewards of the Roadmap investment.” After considerable efforts with the protein in a natural form, the researchers, led by Raymond Stevens of The Scripps Research Institute and Brian Kobilka of Stanford University, turned to protein engineering.

To overcome problems with the protein’s floppiness, they replaced part of the protein with another, stiffer molecule, essentially clamping the protein into place so they could work with it more easily. They also utilised several new methods to minimise the amount of the protein needed for detailed structural studies.

“This is an absolutely remarkable advance,” said Jeremy M. Berg, PhD, director of NIGMS. “Many laboratories around the world are trying to reveal the secrets of these proteins and this new structure takes this field to a new level.”



Anti-fibrinolytics

The amount of blood loss that occurs during major complex surgery is limited by the body’s ability to form blood clots. These close off small vessels and prevent more blood leaking out of the patient’s circulatory system. One problem is that the body also has mechanisms that break down blood clots.

An article in the October 2007 issue of the Cochrane Review concludes that drugs that slow down the rate at which these blood clots are dissolved, called anti-fibrinolytics, can significantly reduce blood loss, particularly during cardiac surgery, and reduce the need for reoperation because of continued bleeding.

One of the effective drugs, tranexamic acid, is quite cheap and is likely to be cost effective, particularly in cardiac surgery.

The big question is whether the benefits of treatment with these drugs are offset by adverse effects, in particular thrombosis leading to an excess risk of heart attack and stroke.

This has been a particular concern with aprotinin and some studies that did not use randomisation found an increased risk of these complications with this drug. However, this Cochrane Review of randomised controlled trials found no increase in the risk of thrombosis with aprotinin or tranexamic acid.

“Our review of over 200 clinical trials found that using anti-fibrinolytic drugs during surgery reduced bleeding and reduced the need for transfusions of red blood cells. Importantly they did not appear to increase the risk of serious adverse effects,” says lead researcher Professor David Henry, of the University of Newcastle, Waratah, Australia.

“This is an extremely important finding,” says Professor Mike Clarke, director of the UK Cochrane Centre. “It shows very strongly that anti-fibrinolytics, which are cheap, can dramatically reduce the need for blood transfusion. Blood is scarce, expensive and transfusions can be dangerous, so this is likely to be a very important finding globally.”



Diabetes prediction

New data from a study now in its 34th year shows that the development of Type 2 diabetes in adults can be predicted in childhood.

The Cincinnati Children's Hospital Medical Center study, which has followed a group of children and adults since 1973, demonstrates that metabolic syndrome in childhood is strongly associated with Type 2 diabetes in adulthood, particularly for African-American men and women.

Metabolic syndrome is a constellation of any three of the following factors: high blood pressure, high triglycerides, high body mass, high blood glucose and low HDL cholesterol – often referred to as “good” cholesterol. The study is published in the online edition of the Journal of Pediatrics.

“Paediatricians and family physicians should evaluate children and adolescents for metabolic syndrome and whether there is a family history of diabetes,” says John Morrison, PhD, a researcher at Cincinnati Children’s and the study’s lead author.

“We need to identify in childhood those who are at risk of adult metabolic syndrome and Type 2 diabetes to prevent these outcomes.” The study is a follow-up of former student participants in the National Heart, Lung and Blood Institute Lipid Research Clinics Princeton Prevalence Study (LRC), which began in 1973, and in the Princeton Follow-up Study (PFS), which took place between 2000 and 2004.

The PFS was a 25-30 year follow-up of students and parents who participated in the Cincinnati clinic of the LRC. The LRC in Cincinnati was a multistage survey of lipids and other cardiovascular disease risk factors.



Blood clots & sport

According to a study published in Journal of Thrombosis and Haemostasis, regular participation in sports reduces the risk of developing blood clots by 39% in women and 22% in men. Researchers from Leiden University Medical Center in the Netherlands evaluated 7,860 people aged 18- 70.

Patients who had suffered their first blood clot in a leg vein or lung artery were compared with control subjects who had never experienced blood clots.

31% of the patients and 40% of the control group participated in sports on a regular basis.

Overall figures for both sexes showed that participating in sports at least once per week, regardless of the type of sport or its intensity, reduced the risk of developing a blood clot in a lung artery by 46% and a blood clot in a leg vein by 24%.

“Women were shown to be even more likely to reap the benefits of regular sporting activities than men,” says FR Rosendaal, co-author of the study. “When we excluded women who were pregnant or receiving oral contraceptive or hormone replacement therapy – all possible causes of blood clots – the risk for women was reduced by 55%.”

The authors note that, while strenuous activity is known to increase the risk of blood clot development in the elderly, regular exercise is also shown to greatly benefit the heart, and that the net effect of elderly sports participation may be positive.

The findings also show that people who did not participate in sports were more than four-times as likely to develop a blood clot if they were obese (with a body mass index of 30 or greater) than lean (with a body mass index of less than 25).

“When we looked at the results, we found that, overall, the mere fact that people took part in a sporting activity at least once a week was enough to lower their risk of blood clots,” say the authors.



Tumour discovery

Scientists studying how immune cells are regulated in healthy individuals, have made a key discovery in understanding why tumours may go undetected by the immune system and remain untreated by the body’s own natural defences.

The findings, published online 19 November 2007 by the Proceedings of the National Academy of Sciences, could lead to new treatments for tumours. Under normal circumstances, the immune system creates sustained inflammation around a dangerous pathogen or injury which tells the body that there is a problem.

However, in the case of tumours, certain cellular mechanisms counteract inflammation which can cause the tumour to go undetected, making it even harder for the body to expel. The researchers at King’s College London discovered that regulatory T cells can reverse the role of a key immune cell called a macrophage which is normally involved in causing inflammation.

Regulatory T cells regulate the immune system to stop it over-responding to every external stimulus and only deal with genuinely harmful pathogens or injuries. The research shows that they can achieve this by encouraging macrophages to instead dampen down the inflammatory response that is automatically induced by all possible threats to the body, even those that turn out to be harmless.

Dr Leonie Taams, research leader explains: “We hope to be able to use this new knowledge about the relationship between regulatory T cells and macrophages to find more effective treatments for tumours.

Interestingly, we also hope to use the same knowledge to achieve the opposite result and block chronic inflammation such as that which occurs in rheumatoid arthritis.”



Photodynamic therapy

Combining light-activated cancer drugs with tumourseeking antibodies could provide a more effective way of treating many cancers, according to new research published online in the International Journal of Cancer.

The study describes how scientists have successfully attached 10 light-activated drug molecules to an antibody which recognises and homes in on the cancerous cells. The researchers have shown that using this method means highly potent drug molecules are delivered to precise cancer targets much more effectively than if they are not attached to the antibody.

Using light-activated drugs to treat cancer is known as photodynamic therapy (PDT). This treatment involves focusing drugs on diseased tissues, and then illuminating the area with a cold laser which sets off a chain reaction in the cancerous tissue, converting oxygen to a highly toxic type of oxygenlike bleach, which destroys cells in the vicinity.

PDT has been shown to be successful in treating head and neck, prostate and skin cancers. However, current PDT is limited by the inefficiency with which the light-activated drugs are able to specifically target tumours. This can mean that the light-activated drugs can circulate in the patient’s body for some time after the treatment, leaving patients light-sensitive and prone to skin damage.

The research team behind the new study think their results show they can solve this problem by ensuring the drugs get straight to the cancerous cells, and do not affect the rest of the body.

Dr Mahendra Deonarain from Imperial College London’s Department of Life Sciences, lead author on the paper, explains: “PDT is a very promising way to treat cancer because it leaves patients with very little cosmetic scarring and there are low chances of drug resistance. We have shown that it’s possible to use tumour-seeking antibodies, like the ones used in drugs like Herceptin and Rituxan, to deliver these potent drugs accurately to the site of the cancer, minimising the risk of healthy tissue getting accidentally damaged in the treatment process, and maximising the number of cancer cells that are destroyed.”

He said the next step was to take the study forward into clinical trials: “We have shown that it’s possible to attach these drug molecules to these targeting antibodies without destroying the useful properties of the antibody itself.

Our initial results are extremely promising and we’re hoping to take this forward into clinical trials in the near future. Our work is expanding the applications of PDT for many cancers and we’re excited about moving towards making targeted PDT a clinical reality.”



Skin rejuvenation

Researchers at the Stanford University School of Medicine have reversed the effects of aging on the skin of mice, at least for a short period, by blocking the action of a single critical protein.

The work could one day be useful in helping older people heal from an injury as quickly as they did when they were younger, said senior author Howard Chang, MD, PhD, assistant professor of dermatology. However, Chang and his colleagues warned their finding will likely be useful in short-term therapies in older people but not as a potential fountain of youth.

The work backs up the theory that aging is the result of specific genetic changes rather than accumulated wear and tear, Chang said. What’s more, those genetic changes can be reversed even late in life. “The implication is that the aging process is plastic and potentially amenable to intervention,” Chang said.

The results are published in the 15 December issue of the journal Genes and Development. The work came about thanks to existing data from experiments using microarrays, which detect the activity of all genes in a cell.

In past experiments, researchers have found a large number of diverse genes that become either more active or less active in older people. Chang and graduate student Adam Adler, the study’s first author, searched through this existing data to see if those age-related genes had anything in common. It turned out that their activity gets dialed up or down with the help of the protein called NF-kappa-B.

Chang said people had long known that NF-kappa- B winds its way into a cell’s nucleus to control which genes were active. What they didn’t know is that many of those genes regulated by the protein have a role in aging. Chang and Adler tested whether blocking the activity of NF-kappa-B in the skin of older mice for two weeks had a youthful effect. “We found a pretty striking reversal to that of the young skin,” Chang said.

First they looked at the genetic changes resulting from blocking NF-kappa-B. After two weeks, the skin of 2-year-old mice had the same genes active as cells in the skin of newborn mice – a striking difference when compared with the skin of a normal 2-year-old mouse. The skin looked more youthful too. It was thicker and more cells appeared to be dividing, much like the skin of a younger mouse.

Chang and Adler caution that their findings aren’t likely to be the source of the long-sought fountain of youth. That’s because they don’t know if the rejuvenating effects of NF-kappa-B are long-lasting. Also, the protein has roles in cancer, the immune system and a range of other functions throughout the body.

Suppressing the protein on a long-term basis could very well result in cancers or other diseases that undermine its otherwise youthful effect. “You might get a longer lifespan but at the expense of something else,” Chang said.



Staph protein

Newly described proteins in drug-resistant strains of the Staphylococcus aureus bacterium attract and then destroy protective human white blood cells – a key process ensuring that S. aureus survives and causes severe disease, according to scientists at the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

S. aureus disease is a global public health concern because some strains, including community-associated methicillin resistant S. aureus (CA-MRSA), have developed resistance to existing antibiotics.

The NIAID scientists hope to use this finding to advance development of new therapeutic treatments. In a study published online in Nature Medicine, Michael Otto, PhD, and his colleagues at NIAID’s Rocky Mountain Laboratories (RML) describe how novel members of the phenolsoluble modulin (PSM) protein family help determine disease severity and eliminate immune defense mechanisms against CAMRSA.

“This elegant work helps reveal the complex strategy that S. aureus has developed to evade our normal immune defenses,” says Anthony S Fauci, MD, NIAID director. “Understanding what makes the infections caused by these new strains so severe and developing new drugs to treat them are urgent public health priorities.”



Vasopressin caution

Vasopressin should be used with great caution for the treatment of hypotension in septic shock, according to results from an international research team published in December 2007 in the online open access journal Critical Care.

Their experiments – conducted in pigs – show it can significantly reduce blood flow to vital organs. The peptide hormone vasopressin is being developed as a new therapy for the haemodynamic support of septic shock and vasodilatory shock due to systemic inflammatory response syndrome. Previously, the compound has been shown to increase blood pressure in septic shock that fails to respond to catecholamines.

However, the safety of vasopressin treatment in humans with septic shock is yet to be proven. Now, researchers in Iceland, Switzerland, and the US, have tested the effects of vasopressin on pancreatic, renal, and hepatic perfusion in pigs and discovered that the compound causes severe disturbances in blood flow in these organs.

Dr Vladimir Krejci of the Department of Anesthesiology, Washington University School of Medicine, in St Louis, Missouri, and colleagues investigated the effects of vasopressin on pigs divided into in four groups.

Group S (sepsis) and group SV (sepsis/ vasopressin) were exposed to fecal peritonitis, while Group C and Group V were non-septic controls. The team measured regional blood flow in the hepatic and renal arteries, the portal vein, and the celiac trunk by means of ultrasonic transit time flowmetry.

They found that in septic shock, vasopressin markedly decreased blood flow (by 58%) in the portal vein within an hour, and even after three hours the reduction stood at 45%. Flow was unchanged in the hepatic artery and increased in the celiac trunk, but was unchanged in the liver.

Microcirculatory blood flow in the pancreas also fell considerably and, to a lesser extent, in the kidney. The investigation also revealed that increased urine output does not necessarily reflect increased renal blood flow and so may not be a useful indicator of the effects of a particular treatment.



Yeast infections

A team of internationally renowned scientists has received a grant of £4.6 million (about US$9 million) to fund research which they hope will pave the way for better and more effective anti-fungal drugs. Researchers will make use of ‘systems biology’ – a new approach to life sciences research.

By combining researchers from biological, physical and computational disciplines, this offers a much more powerful and efficient way of studying complex biological problems.

The project will focus on the yeasts Candida albicans and Candida glabrata which live in our bodies and are usually kept in check by our immune systems. But if the yeast is not kept in check it can grow and cause infections such as thrush which is suffered by most women at some point in their lives.

In general, this is easily treated with anti-fungal therapies. However, out-of-control Candida can be life threatening in people with weakened immune systems such as cancer patients and those who have had transplants.

Candida infections are a relatively common cause of bloodstream infections among some patient groups with severe immune deficiencies and about 30- 40% of those cases can be fatal.

Professor Al Brown, chair in Molecular and Cell Biology at the University of Aberdeen and director of the project, said: “This is a tremendously exciting interdisciplinary research project which aims to understand how these medically important fungal pathogens protect themselves against attack from our immune systems.

“Our research should dramatically advance our understanding of these organisms and, in the longer term, this should contribute to the development of more effective antifungal therapies. “The project represents a revolution in the way that we approach biological systems in which organisms are subject to combinations of many different stimuli.

This is the case for most real biological situations, and hence the methods that we develop will be relevant to many other important biological problems.”
 

                                  
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