Researchers try new approaches to preventing HIV

Tablets, insertable rings and dissolving films can effectively deliver drugs to help protect women and perhaps men from infection with the AIDS virus, researchers reported on Monday.

They also found evidence that using such an approach -- called a microbicide -- may help overcome some of the risks of drug resistance that can come with taking pills to prevent infection.

Here are some of the findings from the International Microbicides Conference being held in Pittsburgh:

* A flexible ring designed for use in the vagina can continually deliver two AIDS drugs for up to a month. Andrew Loxley of Bethlehem, Pennsylvania-based Particle Sciences, Inc., and colleagues lab tested a vaginal ring that time-released dapivirine, a drug made by Johnson & Johnson's Tibotec Inc and licensed to the International Partnership for Microbicides, and the entry inhibitor maraviroc sold by Pfizer under the brand name Selzentry. It has not been tested in people yet.

* A vaginal tablet worked in similar fashion, time-releasing maraviroc and another experimental HIV drug called DS003, licensed to the International Partnership for Microbicides by Bristol-Myers Squibb, Sanjay Garg of the University of Auckland in New Zealand told the conference. The tablet uses a polymer designed to attach to the moist lining inside the vagina.

* A third approach uses a film, Anthony Ham of ImQuest BioSciences of Frederick, Maryland reported. ImQuest is testing the HIV drug IQP-0528 in a film smaller and thinner than a stick of gum, similar to a mouthwash strip.

* Susan Schader of McGill University in Montreal, Canada, and colleagues said tests of these and other HIV drugs used as microbicides showed that drug resistance emerged only if HIV was in the lab dish first -- which suggests people would only develop drug-resistant infections by using microbicides when they were already infected.

* The AIDS virus infects more than 33 million people globally and it has killed 25 million, according to the United Nations AIDS agency UNAIDS. Globally, more than half of those with HIV are women, most infected by husbands or steady partners and many of whom who are unable to insist on use of a condom.

* AIDS experts have long been searching for a microbicide -- a cream, gel or vaginal ring that women or men could use as a chemical shield to protect themselves from sexual transmission of the deadly and incurable virus.

* Microbicides using HIV drugs would represent a large new market for the companies that make the drugs, which are now used only to treat infection.

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New Data on Two Nano-Scale Delivery Platforms

Celator Pharmaceuticals today announced data from animal studies demonstrating the superior bone marrow uptake of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection, its lead clinical-stage program, as well as the enhanced circulation kinetics and efficacy of its preclinical hydrophobic docetaxel prodrug nanoparticle (HDPN) formulation were presented at the 101st Annual Meeting of the American Association for Cancer Research in Washington, DC.

"This research continues to expand our understanding of the activity and potential clinical benefits of improved cancer therapeutics based on our proprietary technologies; the CombiPlex® platform and the nanoparticle prodrug delivery platform," said Scott Jackson, chief executive officer of Celator Pharmaceuticals. "The work done with CPX-351 helps explain the encouraging anti-leukemic activity we are seeing in Phase 2 clinical studies and the results seen with HDPN contributed to this product being selected for study by the NCI's Nanotechnology Characterization Laboratory."

In the first presentation, researchers reported on the circulation characteristics and anti-tumor activity of HDPN in mice bearing HT-29 human colorectal tumor xenografts. Two nanoparticle preparations of the docetaxel pro-drug demonstrated significantly greater plasma half-lives than docetaxel formulated in polysorbate 80, the detergent drug solubilizer used in the marketed product Taxotere®. Furthermore, when administered at either their respective maximum tolerated doses or at equimolar doses to free docetaxel, the two HDPN preparations produced greater antitumor activity, as measured by tumor growth delay, than the free docetaxel. These results confirmed that the proprietary HDPN approach -- encapsulating hydrophobic docetaxel prodrugs in block co-polymer nanoparticles -- produces prolonged circulation kinetics and enhanced therapeutic activity. HDPN is currently undergoing comprehensive pre-clinical evaluation at the National Cancer Institute's (NCI) Nanotechnology Characterization Laboratory to support an eventual investigational new drug (IND) filing with the U.S. Food and Drug Administration.

The second presentation described results of a biodistribution comparison of CPX-351 to empty liposomes in a human leukemia xenograft model. The plasma clearance of both CPX-351 and the empty liposomes was similar in both leukemic and non-leukemic mice and both formulations had similar organ distribution profiles. However, accumulation of CPX-351 in bone marrow was 20 to 50 percent higher than that of the empty liposomes in cancer-free mice and 75 percent higher in leukemic mice after the first injection. CPX-351 accumulation increased an additional 20 percent with subsequent injections. The researchers concluded that the presence of encapsulated cytarabine:daunorubicin in CPX-351 markedly augmented marrow uptake and/or retention of the liposomes, a benefit that along with the prolonged circulation made possible by liposomal encapsulation itself, helps increase the exposure of tumor cells to the two active drugs at the synergistic ratio.

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A New Way to Inhale, Not Inject, Insulin

People with diabetes often inject themselves with insulin at mealtime to help control their blood sugar levels. But a new, palm-size device may let them discretely inhale a dose of insulin instead of using a needle.

A small inhaler and insulin powder created by the MannKind Corporation, a drug developer in Valencia, Calif., are before the Food and Drug Administration for marketing approval.

The insulin powder, called Afresa, is inhaled into the lungs, dissolves there and then travels into the bloodstream, says Matthew J. Pfeffer, chief financial officer at MannKind.

Using insulin or other drugs to control blood sugar helps diabetics avoid serious complications, including heart disease, kidney failure, blindness and nerve damage.

The use of insulin in an inhaled form is not new. It was introduced by Pfizer with a product called Exubera in 2006. But the inhaler used with Exubera was large and awkward, some critics contended, which may have been a reason the product didn’t become popular. It was withdrawn less than two years after federal approval.

But MannKind may have better prospects because of its smaller inhaler and fast-acting insulin. Mr. Pfeffer says the MannKind inhaler fits neatly in one hand, and a second-generation versions the company is using in clinical trials is even smaller, the size of a whistle.

Patients put insulin doses — pre-packaged in cartridges — into the inhaler and turn the mouthpiece to release the insulin. The inhaler uses no electricity or compressed gas. “The patient’s breathing action does the job,” Mr. Pfeffer said. “The airflow through the cartridge allows the powder to be inhaled.”

The system now before the F.D.A. is for adults with Type 1 diabetes, which often begins in childhood, and Type 2 diabetes, which typically occurs when people are older.

Simos Simeonidis, a senior biotechnology analyst at the New York investment bank Rodman & Renshaw, who wrote a report on MannKind, said he expected its system to be available next year, if the F.D.A. approved. (Dr. Simeonidis has no stock in MannKind, but Rodman & Renshaw has provided investment banking services for it.)

Leonid Poretsky, chief of endocrinology at Beth Israel Medical Center in New York and director of the Gerald J. Friedman Diabetes Institute there, said that the MannKind system will face many problems even if it is approved.

“Injections today are essentially painless,” he said of the short, thin needles that are commonly used to inject insulin. And you don’t necesssarily “have to draw from a bottle into a syringe. Injections work so well that the advantages of a new route like this are unclear.”

Dr. Poretsky was also concerned about using the lungs to transport drugs. “It’s possible for people to stay on insulin for decades,” he said. “The whole issue of exposing the lungs to insulin for a long period of time has to be examined carefully.”

Dr. Gerald Bernstein, a New York-based endocrinologist who is a former president of the American Diabetes Association, agreed that the long-term use of inhalable insulin might carry risks for some patients. Dr Bernstein is vice president of the Generex Biotechnology Corporation, which is developing an insulin delivered through the lining of the mouth.

“It’s counterintuitive to use the fragile cells of the alveoli,” the tiny air sacs within the lungs, “to get insulin to the bloodstream,” he said. “The lungs were developed to transport gases, not proteins.”

Mr. Pfeffer of MannKind said that the company’s clinical data included no signs of damage to lungs.

Dr. David M. Nathan , a professor of medicine at Harvard Medical School and director of the Massachusetts General Hospital Diabetes Center, said that even if safety issues were addressed, there could be other long-term problems with Afresa. He questioned whether MannKind’s inhalable product could achieve the same level of blood sugar control as that obtained with injections or insulin pumps.

“Insulin inhalers are tricky to use,” he said. “The amount you breathe in can be variable.” But he acknowledged that injections aren’t perfect and that many people would prefer to get their insulin in a more convenient way.

Mr. Pfeffer said trials by MannKind had shown a high consistency in doses by patients using the inhalers.

If all goes well at the F.D.A., Mr. Pfeffer says he thinks that MannKind will eventually go to market with the smaller dispenser now in trials. “The expectation,” he said, “is that we will launch with the whistle-sized inhaler” — which, by the way, was given the internal company name “Dreamboat” by its design team.

“Perhaps we’ll consider a different name, though,” he said.

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Swallowed capsule falls short for colon cancer test

A swallowed capsule that takes pictures of the colon as it passes through misses too many pre-cancerous lesions and is not ready to replace more traditional colonoscopies, Belgian researchers reported on Wednesday.

The Given Imaging PillCam, containing tiny video cameras at each end of a 3 cm-long (1.2-inch) capsule, detects some colon tumors and polyps but missed five of the 19 tumors found in patients who were also checked with a colonoscopy, the researchers reported in the New England Journal of Medicine,.

The PillCam technique, actively marketed in Europe but still considered experimental in the United States, also missed more than one quarter of polyps and pre-cancerous lesions, known as adenomas, that were larger than 6 millimeters (0.23 inch).

"Since the size of colorectal lesions is a predictor of the development of cancer, the relatively lower sensitivity of capsule endoscopy for the detection of large adenomas is cause for concern," Dr. Michael Bretthauer of Oslo University Hospital in Norway wrote in a commentary on the study.

Doctors are looking for an easier way to screen for colorectal cancer, the third leading cause of cancer deaths in the United States and an important cause globally.

The best method, a colonoscopy, uses a lit tube inserted into the colon. But preparing for the test can be uncomfortable and the procedure requires anesthesia or sedation. In rare cases, the colon may be punctured. Only about half of the people who should get one actually do.

Dr. Andre Van Gossum of Erasme University Hospital in Brussels and colleagues tested the Israel-based Given's PillCam in 320 people.

The capsule did well at finding small abnormalities, so it may work well in combination with a a so-called virtual colonoscopy, which uses a computer enhanced X-ray called a CT scan, Van Gossum said.

The PillCam for the colon "is probably not ready to be recommended as a screening procedure. But the results are quite encouraging," Van Gossum said in a telephone interview.

Given, which also makes a PillCam for the small intestine, paid for the study.

The capsule examination costs about the same as a colonoscopy. But if suspicious polyps are found, a colonoscopy is still needed to remove them.

"With the capsule's relatively low sensitivity for the detection of colorectal lesions, its requirement for more extensive bowel-cleansing regimens as compared with colonoscopy and CT colonography, and its high cost, colon capsule endoscopy cannot be recommended at this time," Bretthauer wrote.

The capsule takes pictures for three minutes after being swallowed, providing images of the esophagus and stomach. Then it turns itself off for 105 minutes to preserve the battery while is passes through most of the small intestine on its way to the large bowel.

It generally took as little as four minutes and as long as eight hours for it to pass through the colon, although in one patient it stayed in the body for nearly a month.

Van Gossum said he did not think the findings are a setback for the capsule technique and hopes the technology will improve.

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Chemo revolution: A dramatic new approach to fighting cancer is set to transform survival rates

No one in their right mind would want to take chemotherapy drugs for any longer than the absolute minimum. Or would they?

Traditional chemotherapy is usually gruelling because in poisoning the fast-growing cancer cells it also poisons all the body's other fast-growing cells, such as hair follicles and those lining the stomach. So the tumour shrinks, but your hair falls out and you feel incredibly ill.

That's why everyone wants to undergo chemotherapy for the shortest time possible to get the job done.

As a result, treatment tends to follow a 'boom and bust' pattern - you get chemotherapy for a short while until the cancer has shrunk or gone into remission and then it stops and you hope it doesn't come back. If it does, treatment starts again.

But a new approach to treating cancer involves giving drugs for much longer than usual.

Chemotherapy becomes a kind of everyday maintenance therapy, effectively treating cancer as a chronic disease.

Lung cancer patients, who in general have short survival times, are set to benefit most from this development.
This form of cancer kills more people in Britain than any other - 30,000 a year - and the survival rate is poor. Only 6 per cent of patients are still alive five years after diagnosis.

However, a trial reported last month found that giving lung cancer patients a more targeted drug for longer than usual increased survival times. The scientists running the trial declared it a major breakthrough.

'This will change how we treat cancer,' said Dr Chandra Belani, deputy director of the Penn State Hershey Cancer Institute in the U.S.

What's made this approach possible is the latest generation of cancer drugs, which are more targeted and better tolerated by patients. But is this the most effective strategy?

In the normal pattern of treatment, you may be pleased the chemotherapy has stopped, but it could mean the cancer has a chance to regroup and grow again. Yet giving the drug for longer prevents the cancer from returning for longer.

This is an approach already well established for breast and prostate cancer, says Professor Peter Johnson, chief clinician at Cancer Research UK.

'These patients take drugs to block their sex hormones, which can feed the cancer - oestrogen for women, testosterone for men - and that prolongs survival very effectively.'

But it's only since this new generation of drugs has arrived that other patients have been able to benefit.

'The idea is to turn a cancer into a chronic disease that you live with long-term, such as diabetes or heart disease, rather than a death sentence,' says Professor Johnson.

So, in the same way patients are given statins to ward off a second heart attack, cancer patients can be put on drugs to stave off the disease.

The benefits of this approach were confirmed last month in a trial of the lung cancer drug Alimta, which has just been given a licence by the EU regulators.

The patients involved had already had regular chemotherapy, their tumours had shrunk and normally treatment would have stopped there.

But some were then prescribed Alimta, while other took a placebo. Overall, those on the drug survived for just over 13 months, compared with 101/2 months on the placebo (those who had the type of cancer that responds best to the drug lived on average for 151/2 months).

You might think this is not a massive improvement, but because lung cancer is usually spotted so late, it has one of the worst survival rates. So for these patients, any improvement is clearly welcome.

But it is not just lung cancer patients who are set to benefit from these maintenance regimes.

Until recently, survival rates for patients with two other cancers - the blood cancer multiple myeloma and Non-Hodgkin lymphoma, which affects white blood cells - were fairly poor, too.


If you had been getting old-style stop- start chemotherapy for --multiple myeloma, on average you'd survive for three to four years. Recently, a new drug called Revlimid, which patients can take all the time, has almost doubled that.

'As it isn't nearly as toxic as chemotherapy, most patients can keep taking it,' says Eric Low of the charity Myeloma UK.

One American patient, who only wanted to be known as Kevin, said: 'I've been on it for a year and the only problem has been some fatigue and an upset stomach.'

But as Professor Johnson warns, while these drug regimes can certainly be an improvement on traditional treatments, they are far from free of side effects.

Malcolm Cole, a retired computer journalist, found the side effects much more severe than Kevin.

'When I first went on the drug, I was over the moon,' he says. 'It was by far the best treatment I'd had and put my cancer right into remission.'

Unfortunately, he then suffered several side effects within a few weeks.

'I had tremors in my hand and an epileptic fit that may have been connected,' he says.
Despite this, Malcolm does not regret taking the treatment and is continuing with it despite his experience.

The other drug that is making a difference to blood cancers is Rituxan. Taking a maintenance dose of the drug helped patients with non-Hodgkin lymphoma stay in remission for longer.

Another reason these new drug regimes might be more successful is because they are given only to patients who will benefit.

Targeted chemotherapy drugs are not the only maintenance therapy for cancer. A promising new approach works by getting the body's own defences to keep on doing the job instead.

Known as 'therapeutic' vaccines, they could be the next big thing. One given to patients with lung cancer continuously cut the relapse rate by about 25 per cent and had much milder side-effects.

A big trial of the drug, known as Mage 3, is recruiting patients in Britain. But none of these drugs is a magic bullet.

'Alimta, for instance, offers useful gains for lung cancer patients,' says Professor Johnson. 'But it will need more trials to prove it's a breakthrough.'

And there are concerns that maintenance therapy could be a way for the drug companies to boost sales of their very expensive treatments.

Revlimid, which was approved by NICE - the National Institute for Clinical Excellence - in June, costs as much as £40,000 a year; Rituxan is £18,000 a year.

'Of course the companies want their drugs to be used as early as possible and for as long as possible,' says Dr Lawrence Einhorn, oncologist and Distinguished Professor of Medicine at Indiana University School of Medicine.

Deciding who is going to get these drugs in a way that is fair, open and affordable is going to be almost as big a challenge as developing them in the first place.

Source : www.dailymail.co.uk

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New Technique Prevents Major Cause For Heart-related Stroke

Physicians at The Mount Sinai Medical Center were the first in the country to perform a non-surgical procedure using sutures to tie off a left atrial appendage (LAA), which is the source of blood clots leading to stroke in patients with atrial fibrillation (AFib). AFib is the most common sustained heart-rhythm disorder in the United States.

The procedure was performed Wednesday by Vivek Y. Reddy, MD, Professor of Medicine and Director of the Cardiac Arrhythmia Service at Mount Sinai Heart, and his colleague, Srinivas R. Dukkipati, MD, Director of Mount Sinai's Experimental Electrophysiology Laboratory. With the patient under general anesthesia, the physicians guided two catheters into the patient's heart to seal the LAA with a pre-tied suture loop. The technique is a safe alternative to drug therapies such as the blood thinner warfarin (Coumadin) that can have serious side effects, as well as open-heart surgery, and more invasive implant surgery.

"People who take Coumadin because of atrial fibrillation include active and otherwise healthy people, as well as elderly people for whom the drug may be contraindicated," said Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Chair of the American/European Guidelines of Atrial Fibrillation.

Drs. Reddy and Dukkipati joined Mount Sinai this month to focus on building the institution's services for heart-rhythm disorders. They had been performing pre-clinical testing of the non-surgical LAA device, and this procedure represents its first application in people in the United States.

"We are very proud of the recruitment of Dr. Reddy and his exceptionally talented team," said Wayne Keathley, President and Chief Operating Officer of The Mount Sinai Hospital. "Their pioneering work has the potential to redirect the field of cardiac rhythm disorders."

"Compared to a lifetime of medication therapy, or other surgical modalities, a one-time, non-surgical procedure to relieve the complications of AFib offers a whole new paradigm," said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Mount Sinai School of Medicine, and Executive Vice President for Academic Affairs, The Mount Sinai Medical Center. "Drs. Reddy and Dukkipati have ushered in a new standard of care for people with this serious cardiac condition."

Approximately 6 million U.S. adults have been diagnosed with AFib, a condition characterized by a rapid and irregular heart beat that can cause serious complications, including stroke and early death. The majority of these patients take warfarin because left untreated, AFib can cause life-threatening blood clots. Approximately 25-30 percent of patients with AFib have contraindications to the drug—such as concerns of falling or imbalance in elderly patients—and, even for the remainder, only about 55-60 percent receive warfarin.

AFib-related deaths have increased over the past two decades and now account for one-quarter of all strokes in the elderly. Those who do take warfarin must rigorously manage the drug's level in their blood. High levels can cause excessive or internal bleeding, even after minor falls, bruises, or cuts. For some, this management regime can mean monthly tests over the course of many years. In eliminating the need to take warfarin, the LAA procedure can reduce the need for frequent medical visits.

"This procedure demonstrates what translational medicine can do for society," said Kenneth L. Davis, MD, President and Chief Executive Officer, The Mount Sinai Medical Center. "Novel therapeutics that can immediately impact health, while minimally impacting the health care system, are our research priority."

"This non-surgical procedure could lead to a permanent means of protecting against stroke in patients with AFib who are ineligible for long-term warfarin anticoagulation therapy," said Dr. Reddy. "The suture delivery system allows us to place a pre-tied suture loop on the outside of the LAA using a pericardial approach, similar to what is used in surgery. But instead of surgery, which can involve spreading the ribcage or cutting through bone to access the LAA, this procedure does not require surgical incisions and is instead performed percutaneously; that is, using needle punctures to introduce catheters to the heart."

In addition to open-heart surgery, which is rarely performed as a stand-alone surgical procedure because of the associated morbidity, non-pharmaceutical treatment options involve occlusion of the LAA via an implant, a technique that is not yet approved by the U.S. Food & Drug Administration (FDA), commented Samin K. Sharma, MD, Director of Mount Sinai's Cardiac Catheterization Laboratory.

The patient, a 78-year-old woman from Miami, presented with a history of stroke and a fall. Her physicians prescribed Coumadin but had difficulty titrating the medication for her. She initially sought an implant but traveled to Mount Sinai for the non-surgical, catheter-based suture delivery system. Following the procedure, the patient is recovering safely and no longer needs to take the drug for stroke prevention. Patients receiving non-invasive procedures usually return to normal activities in about a week.

The procedure—aided by the LARIAT Suture Delivery Device, which was developed by SentreHEART, Inc., and approved by the FDA in May—was performed in a cardiac catheterization laboratory and did not require cardiopulmonary bypass.

Source : www.sciencedaily.com

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