The parasite Entamoeba histolytica attacks and kills human immune cells leading to inflammation of the colon (colitis), after which it ingests the cell remains allowing further invasion of the host tissue. This leads to the death of 100,000 people each year.
In the study, published in PLoS Patho-gen, William Petri, study leader, hypothesized that identifying the molecules involved in corpse ingestion might provide insight into how the ameba leads to colitis in children.
The team identified the protein phagosome-associate transmembrane kinase (PATMK), a member of the TMK family, situated on the surface of the ameba that aids in the ingestion of the immune cell corpses. Using a special technique called RNA interference they were able to inhibit the actions of this kinase, and therefore prevent the ameba from eating the dead cells.
“By blocking this kinase, we have for the first time prevented the ameba from colonizing and invading the gut,” said Petri. “We are a step closer to preventing this disease, which wreaks havoc among children worldwide.”
“Infection and further invasion into the gut require the clearance of dead cells in order to prevent immune recognition of the damaged tissue,” says fellow researcher Douglas Boettner. “PATMK is the first individual member of a large family of proteins to be assigned a function related to the clearance of dying tissue during pathogenesis.”
“This protein may be a pivotal vaccination target because these preliminary studies show that alterations in PATMK function reduces progression of amebiasis in mice,” Boettner added. “A vaccine that ultimately would prevent this amoeba from clearing the damaged host may attract helpful immune cells which may recognize and eliminate this infection.”
This work shows how infection is dependent upon the ameba's consumption of dead cells. By identifying the molecule that controls eating, scientists are one step closer to the ultimate goal of preventing disease caused by this parasite.
Source: Boettner DR, Huston CD, Linford AS et al. Entamoeba histolytica phagocytosis of human erythrocytes involves PATMK, a member of the transmembrane kinase family. PLoS Pathog. 4(1), e8 (2008)
Uncovering the ability of pancreatic cancer cells to evade detection
Researchers are one step closer to understanding how metastatic pancreatic cells evade immune detection.
The ability of metastatic pancreatic cells to hide from the immune system once they have localized to lymph nodes has been a question without answer for some time.
Scientists at the Jefferson's Kimmel Cancer Center in Philadelphia (PA, USA) think they now have, at least, one potential answer: indoleamine-pyrrole 2′3-dioxygenase (IDO). This protein was found to be expressed in higher amounts on pancreatic cancer cells that had spread to lymph nodes compared with those cells in primary tumors that had not metastasized.
IDO is known to induce a resting state in T cells by inhibiting tryptophan production. In addition, the protein also stimulates recruitment of a different subset of T cells, Treg, which are known to considerably dampen immune responses. In this manner, metastatic pancreatic cancer cells in lymph nodes are able to hide from the immune system, thus making it a particularly difficult cancer to treat.
Jonathan Brody, leader of the study, suggests administering IDO inhibitors, already clinically available, to patients with lymph node-positive pancreatic cancer before initiation of any other type of therapy, including surgery. Further studies will, hopefully, confirm the importance of IDO inhibition in sensitizing resistant cancer cells to treatment.
Source: www.jeffersonhospital.org/news/2007/article15657.html
Overprescription of proton pump inhibitors draining UK NHS funds
A recent editorial from the British Medical Journal suggested that at least GB£100 million of the UK National Health Service (NHS) budget, and almost £2 billion worldwide, is being spent unnecessarily on proton pump inhibitors (PPIs) each year.
Proton pump inhibitors are one of the most frequently prescribed classes of drug, as they combine a high level of efficacy with low toxicity. In 2006, expenditure on these drugs was £425 million in England and £7billion globally. However, studies consistently show that PPIs are being overprescribed in both primary and secondary care. Between 25 and 70% of patients taking these drugs have no indication for the prescription claim the study's authors.
Proton pump inhibitors have been a tremendous therapeutic advance and have proved valuable in patients with previously intractable symptoms of gastroesophageal reflux, with its associated complications, and patients at risk of iatrogenic upper gastrointestinal pathology.
The first generic PPI (omeprazole) was introduced in 2002 and now comprises more than four-fifths of all prescriptions for PPIs in the UK. Although effective and less expensive alternative drugs are available, prescriptions for PPIs have superseded those for all other acid-inhibiting agents and now account for over 90% of the NHS drug budget for treating dyspepsia.
The authors suggest that these relatively expensive drugs are being prescribed too eagerly and that GPs fail to take patients off the drugs once they are no longer indicated. “Effective and cheaper alternative drugs are available for many patients. Yet prescriptions for PPIs have superseded those for all other acid-inhibiting agents and now account for over 90% of the NHS drug budget for treating dyspepsia,” they told the British Medical Journal. “Although they are incredibly safe and effective for indigestion, PPIs are being overused. It's a bit like giving morphine for a headache.”
In 2000, the National Institute for Health and Clinical Excellence (NICE) issued its PPI guidance, stating that the NHS could save up to £50 million a year in drug costs in England and Wales by prudent prescribing of these drugs.
Since then, the price of omeprazole, which makes up 90% of NHS dyspepsia prescriptions, has decreased as its patent has expired. This means other drug companies can make generic versions of the branded drug for sale at a fraction of the price.
Richard Stevens, chairman of the Primary Care Society for Gastroenterology, said this might now mean it was cost effective to prescribe the drugs more frequently. However, he cautioned: “We do not want patients taking these drugs unnecessarily. Not all patients require acid suppression.”
Although PPIs are safe drugs, they are not without side effects. An increase in the prevalence of pneumonia and Campylobacter enteritis is reported, as well as a doubling of the risk of infection with Clostridium difficile. Acute interstitial nephritis and osteoporosis have also been reported, but such effects are fortunately rare.
A NICE spokeswoman said, “It is always disappointing when our recommendations are not consistently followed. For many patients PPIs should only be used for a short period of time until the underlying cause of the dyspepsia can be identified and treated. We would strongly urge Primary Care Trusts to use the criteria set by NICE for prescribing PPIs so that they can be confident they are targeting resources where they are most likely to offer benefit.”
Source: Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. Br. Med. J. 336(7634), 2 (2008).
Genes may explain high liver cancer rates in men
Research indicates that men tend to be more susceptible to hepatocellular carcinoma (HCC) or liver cancer compared with women, and new research by scientists at MIT (MA, USA) suggests that the difference is in the genes.
“This is the first genome-wide study that helps explain why there is such a gender effect in a cancer of a nonreproductive organ, where you wouldn't expect to see one,” stated Arlin Rogers.
Liver cancer is one of the most common types of cancer worldwide, with males being affected more often than females. In the USA the incidence of liver cancer in men is twice that in women, whereas in other parts of the world (especially Asia) it can be eight- or ten-times more prevalent in men than women. Liver cancer has been shown to be closely associated with hepatitis b HBV infection; other risk factors include HCV, aflatoxin B1 and cirrhosis.
Most of the variation between male and female livers arises at puberty, when exposure to growth hormones at intervals causes male livers to express different genes. This underlies the innate difference between male and female livers, and explains why men and women may respond differently to antibiotics, among other medicines.
Researchers used mice infected with Helicobacter hepaticus to model the hepatic symptoms that characterize human HBV and HCV infection. The infection also causes inflammation and HCC with a male bias in mice. Using microarray analysis, they observed a variety of changes in the expression of sexually dimorphic liver genes in male mice that had developed chronic hepatitis. Some male specific genes were upregulated, others inactivated and some female specific genes were found to be switched on. This erratic gene profile can be called ‘liver-gender disruption’.
The scientists found evidence that suggests that the inflammatory pathways may be involved, making these results of possible relevance to other cancers such as those of the stomach and colon – both of which have been shown to be associated with chronic inflammation and are also more frequent in men.
Source: Rogers AB, Theve EJ, Feng Y et al. Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res. 67(24), 11536–11546 (2007).
Impact of hepatitis B on quality of life
A study due to be published in Value in Health will provide valuable information for comparing new treatment options for chronic hepatitis B (CHB) by estimating preference-based ‘utility weights’ for six increasingly severe health states that occur with chronic infection with the virus. Information was elicited from respondents living in six jurisdictions in the USA, Europe and Asia, that ranged from low to high prevalence of CHB infection.
Over 350 million people worldwide are affected by the CHB virus, with infection causing considerable distress to individuals and costs of treatment resulting in substantial global economic loss. CHB is a condition that results in substantial morbidity and mortality worldwide owing to progressive liver damage.
The impact of CHB on the quality of life of patients has not been well studied to date, and despite the availability of new treatment options, little information is available on how infected and uninfected persons value the impact of health states arising from the CHB virus.
Investigators undertaking economic evaluations of new therapeutic agents require estimates of health-related quality of life. Recent evidence suggests that differences in cultural backgrounds have a quantifiable impact on perceptions of health.
The authors interviewed 534 CHB-infected patients and 600 uninfected respondents, making this one of the largest valuations of health states ever published, for any disease. The results show that CHB and compensated cirrhosis health states have a moderate impact on health-related quality of life, and also indicated that there is a large detrimental effect on quality of life associated with decompensated cirrhosis and hepatocellular carcinoma.
Significant geographic differences were observed among countries, with a greater impact on quality of life seen in Hong Kong and mainland China, which are jurisdictions with a high prevalence of disease. The authors speculate that these findings may be attributable to a greater fear of the social consequences of infection. A practical implication of the intercountry differences is that economic evaluations may benefit from country-specific utility estimates.
Source: Levy AR, Kowdley KV, Iloeje U et al. Theimpact of chronic hepatitis B on quality of life: a multinational study of utilities from infected and uninfected persons. Value Health (2008) (Epubahead of print).
Emergent BioSolutions receives recommendation to continue Phase II trial of hepatitis B vaccine
Drug: Hepatitis B virus vaccine
Vaccine/vector: Hepatitis B core antigen + spi-VEC®
Manufacturer: Emergent BioSolutions
Indication: Hepatitis B virus
An independent Safety Monitoring Committee (SMC) has recommended Emergent BioSolutions, Inc. (MD, USA) continue the Phase II clinical trial of its therapeutic vaccine against hepatitis B virus (HBV).
According to the WHO, approximately a third of the world's population is infected by HBV at one point in their life. Adults can recover from HBV infection, while infants usually become chronic carriers. There are between 350 and 400 million chronically infected individuals worldwide and chronic HBV is the leading cause of liver cancer.
Emergent BioSolutions has developed a therapeutic vaccine using a Salmonella-based bacterial vector that carries the hepatitis B core antigen (HBcAg). The company's proprietary vector – spi-VEC – is administered orally and delivers HBcAg to the gut's macrophages, which will trigger immune responses including HBcAg-specific T-cell-mediated immunity. This will, hopefully, help the patients clear HBV and reduce liver damage.
In this clinical trial, 45 patients with chronic HBV infection will be randomized into three groups receiving either the vaccine or placebo. The SMC's recommendation followed the safety data review from the first group of patients who have completed day 70 of the study. The study can now proceed with the two remaining groups of patients.
“We are pleased by the SMC's recommendation and look forward to advancing this critical study of our hepatitis B candidate. Hepatitis B is the tenth leading cause of death worldwide and our commitment to the development of this therapeutic vaccine is squarely in line with our mission – to protect life,” said Daniel Abdun-Nabi, President of Emergent BioSolutions, Inc.
The company anticipates that results from this trial will be available in the first half of 2009, with preliminary safety and efficacy data available at the end of 2008.
Source: www.emergentbiosolutions.com
Tysabri® receives restricted US FDA approval for Crohn'sdisease
Drug: Natalizmab
Tradename: Tysabri®
Manufacturer: Elan Corporation, plc., Dublin, Ireland
Indication: Multiple sclerosis; adult patients with moderate-to-severe Crohn's disease with inflammation or who are nonresponsive to conventional therapy
Tysabri® (natalizmab), currently used in the treatment of multiple sclerosis, has just received US FDA approval for the treatment of adult patients with moderate-to-severe Crohn's disease who have evidence of inflammation and have not responded well to conventional therapy.
In one study, sponsored by Elan of Dublin, one company who produce the drug, 60% of Tysabri patients responded to treatment after 12 weeks of therapy, compared with 44% receiving placebo.
However, Tysabri carries a warning for progressive multifocal leukoencephalopathy, an opportunistic viral infection that affects the brain and can lead to death or severe disability. Accordingly, patients administered the drug must be enrolled in a restricted distribution program called the Crohn's Disease Tysabri Outreach Unified Commitment to Health (CD TOUCH) Prescribing Program.
Crohn's disease is a chronic, inflammatory bowel disease that can cause diarrhea, fever, rectal bleeding, malnutrition, narrowing of the intestinal tract, obstructions, abscesses, cramping and abdominal pain. There is no cure and its cause is unknown. The disease can also lead to abnormal connections (fistulas) leading from the intestine to the skin or internal organs. There are more than 1 million people (male and female) with Crohn's disease worldwide.
“The addition of Tysabri to the treatment options for sufferers of Crohn's disease is important, but one that carries serious risks,” said Daniel Shames, deputy director of the Office for Drug Evaluation III and director of the Division of Gastroenterology Products for the Center for Drug Evaluation and Research. “Healthcare providers must carefully monitor patients for these risks. The CD-TOUCH Prescribing Program will aid the FDA in monitoring this drug through its life cycle.”
Other serious adverse events that have occurred in Tysabri-treated patients include hypersensitivity reactions, such as anaphylaxis and liver injury. Serious opportunistic and other atypical infections have been observed in patients receiving immunosuppressants while on Tysabri, and Tysabri should generally not be used in patients receiving immunosuppressants. Serious herpes infections have also been observed. Common side effects include headache, fatigue, infusion reactions, urinary tract infections, joint and limb pain, and rash.
Due to these risks, patients, prescribers, pharmacies and infusion centers must all be enrolled in CD-TOUCH and agree to comply with the company's strict monitoring guidelines. Additionally, they must participate in an extensive educational program designed to inform people about the risks of Tysabri treatment.
The CD-TOUCH program stipulates that healthcare providers evaluate patients after 3 months of treatment. If no improvement is noted, treatment is discontinued. Concurrent steroid treatment should also be tapered and treatment discontinued if steroids can not be completely ceased.
European regulators have recommended against the use of Tysabri for Crohn's disease. However, a final decision from the European Commission is expected during the first quarter of 2008. The drug will undergo long-term surveillance for its safety.
Source: www.fda.gov