Plant-made drug reverses breathing paralysis

July 8, 2013

Paralytic drugs like succinylcholine are often used during surgery or when critically ill patients require endotracheal intubation. But if the drug is not swiftly cleared from the patient’s system, the results can be deadly.

In a new study, Tsafrir Mor, a researcher at Arizona State University’s Biodesign Institute and assistant professor in the School of Life Sciences, shows that the plant-produced recombinant human enzyme butyrylcholinesterase (BChE) can rapidly reverse paralysis of the airways – or apnea – caused by succinylcholine. Download Full Image

The results, recently reported in the journal PLOS ONE, suggest an expanded role for trauma techniques, like rapid sequence intubation, as well as other methods involving the use of succinylcholine, particularly in the pre-hospital arena, where a speedy intervention can mean the difference between life and death. Given the variety and frequency of conditions involving failed airways, a means of reversing succinylcholine-induced apnea may have profound implications.

“BChE is a promiscuous enzyme that can function as an effective, safe and versatile bioscavenger, but its use has been hampered by its availability,” Mor says. “Plants expressing recombinant human BChE may provide the answer for this limitation.”

The new findings build on earlier work by Mor’s group, which demonstrated the potential for plant-made BChE to reverse the effects of organophosphate poisons, including pesticides and weaponized nerve agents. Possibilities also exist for reversing the effects of acute cocaine overdose or using plant-derived BChE as a cocaine prophylactic, dampening the drug’s euphoric effects and thereby discouraging use.

Succinylcholine is a neuromuscular blocking agent, commonly used in conjunction with a sedative during anesthesia or to allow intubation to be carried out on an emergency basis. Succinylcholine is the drug of choice for such procedures due to the rapid onset and short duration of its effects, as it is rapidly cleared by the patient’s serum BChE.

In certain patients however, clearance can be dangerously prolonged, leading to succinylcholine-induced apnea that can last several hours. The phenomenon has been recognized since the 1950s and may occur as a result of genetic factors or as an acquired condition. In either case, it is generally the result of a deficiency in the serum enzyme BChE.

Because of concerns regarding patient sensitivity to succinylcholine, use of the drug as an anesthetic in pre-hospital situations has been controversial. Lacking hospital resources to deal with patients exhibiting butyrylcholinesterase deficiency, first responders are often reluctant to undertake the risks involved in emergency endotracheal intubation. Currently, cases of post-succinylcholine apnea are typically managed in hospital settings through supportive care, due to a lack of safe, effective and plentiful reversing agents.

About one in 1800 administrations of succinylcholine result in prolonged apnea. Around 65 percent of these cases result from decreased hydrolysis of succinylcholine by BChE and its variants. Inability to hydrolyze succinylcholine can have a hereditary basis, with some patients carrying an abnormal variant of one or more genes responsible for succinylcholine hydrolysis. Depending on the particular mutation, these individuals can experience periods of apnea ranging from around two hours for those carrying one copy of the non-functional allele, to three to four hours or more for those carrying two copies.

Additionally, BChE deficiency can be acquired as a result of conditions including cirrhosis, burns, liver cancer or malnutrition, or as a side effect of some commonly prescribed drugs, including oral contraceptives. The authors of the current study note that the ability to reverse hereditary or acquired apnea could significantly improve the safety margin for succinylcholine, rapidly restoring normal breathing to an affected patient.

Rapidly and safely reversing succinylcholine-induced apnea may open new possibilities for respiratory management, including new devices or medications for acute trauma situations. Such strategies could be particularly useful in cases of upper airway obstruction, where neuromuscular blockage carries a risk of airway collapse and suffocation.

Although missing or nonfunctional serum BChE could potentially be replaced using blood products, including stabilized serum, fresh frozen plasma or purified enzyme, such treatment carries the risk of blood-borne pathogens and prions as well as more common complications associated with transfusion. Mor notes that purification of the enzyme for various applications would necessitate dedicating the entire annual U.S. blood supply to produce a sufficient number of doses.

The solution underlined in the new study involves producing recombinant butyrylcholinesterase in transgenic tobacco plants. The plants are modified to synthesize the BChE enzyme in their leaves. In a series of experiments involving both mice and guinea pigs, Mor demonstrates the ability of plant-derived BChE to reverse post-succinylcholine apnea. The method can be rapidly scaled up to provide a significant stockpile of the apnea-reversing agent, without the costs and attendant risks associated with purifying butyrylcholinesterase from blood products.

Further work by Mor and his colleagues will explore issues of pharmacokinetics, safety and efficacy.

Richard Harth

Science writer, Biodesign Institute at ASU


Phoenix-area foreclosure saga ending

July 8, 2013

The Phoenix-area housing market has finally hit “normal, historical levels” for those going into foreclosure. After years of severe foreclosure trouble, a new report from the W. P. Carey School of Business at Arizona State University reveals that good news, and more for Maricopa and Pinal counties, as of May:

• The median single-family-home price rose again to $185,000; up about 26 percent from May of last year. Mike Orr Download Full Image

• The final chapter of the foreclosure crisis is wrapping up in Phoenix, as foreclosure starts – homeowners receiving notice their lenders may foreclose in 90 days – finally hit normal, historical levels in May.

• On the negative side, the chronic shortage of area homes available for sale continues to be an issue and could last for years.

Phoenix-area home prices hit a low point in September 2011 and have risen dramatically since then. The median single-family-home price reached $185,000 this May, up from $147,000 last May. That’s a boost of 25.9 percent. Realtors will note the average price per square foot went up 22 percent at the same time. The median townhouse/condo price went up about 27.1 percent.

“Between this January and May alone, the average price per square foot rose about 13 percent for area single-family homes,” says the report’s author, Mike Orr, director of the Center for Real Estate Theory and Practice at the W. P. Carey School of Business. “However, the upward pricing pressure should disappear during the summer. I expect the prices to resume their strong upward direction in the fall, once temperatures drop below 100 degrees and snowbirds return.”

Rising prices don’t appear to be dampening the housing recovery in the Phoenix area at this point. In fact, home-and-condo sales activity went up 6.6 percent between April and May. May is the second month in a row where activity increased from the same time during the prior year, reversing a long negative trend. Even the luxury market is gaining, with more sales in May than in any other single month over the past six years.

“There has been much talk of rising interest rates and the negative effect this might have on demand,” says Orr. “The sudden and recent increase in rates has certainly reduced the motivation to refinance existing home loans. However, it is almost certainly increasing buyers’ determination to purchase homes now, rather than later, when rates may go even higher.”

Orr adds he sees early signs some lenders may react to higher interest rates by easing up their rules, allowing more people to buy homes. He also believes prospective buyers may simply settle for purchasing smaller, more affordable houses than they originally wanted in order to manage the higher interest payments.

At the same time, the wave of foreclosures triggered by the housing crisis appears to be ending in the Phoenix area. Completed foreclosures on single-family homes and townhome/condos in May were down 53 percent from last May. Foreclosure starts went down an incredible 67 percent in the same period. Given population growth, this means the area finally hit its normal, historical level of foreclosure starts this May.

“Foreclosure starts dropped 15 percent just between April and May alone,” says Orr. “Foreclosure levels are now far below the peak levels of March 2009, and the number of pending foreclosures is below the level from the first quarter of 2002. We expect these numbers to continue to fall over the next several years due to the very tight underwriting standards in place.”

Without cheap foreclosures coming into the market – and with ordinary homeowners reluctant to sell because they’re either locked in by negative equity or waiting for prices to keep rising – the Phoenix-area housing market continues to struggle with a chronic shortage of homes available for sale that may last for years. The number of active single-family listings without an existing contract was just over 11,000 as of June 1. That’s down 0.4 percent since May 1, and 83 percent of the available homes are priced above $150,000, creating a problem for those looking in the lower price range. At least the shortage has improved somewhat from last year, when supply was dropping at a rate of 6 percent per month.

“The chronic shortage applies to both homes for purchase and homes for lease,” Orr explains. “The average time for a leased home to be on the market is down to about one month. With this fast turnover and relatively low vacancy rates, it’s perhaps surprising that single-family and condo rents have only very modestly increased.”

New-home builders don’t appear too anxious to help meet the demand. They are trying to make sure they don’t overbuild like they did before the housing crisis, and they want to keep prices moving up. Current new-home sales rates are less than a third of what would normally be needed to keep up with local population growth. As a result, Orr says the combined population of Maricopa and Pinal counties grew 2.9 percent from 2010 to 2012, but the number of owned and leased dwelling units only grew by 1 percent.

Lastly, institutional investors continue to lose interest in the Phoenix area. Their buying spree that began in 2011 is in a downward trend. The percentage of the area’s total single-family-home and condo sales carried out by investors is down from 39.7 in July 2012 to 27.3 percent this May. Most investor transactions are actually going to so-called “mom and pop” purchasers. Orr says they own roughly 96 percent of the area’s rental-home inventory.

Orr’s full report, including statistics, charts and a breakdown by different areas of the Valley, can be viewed at A podcast with more analysis from Orr is also available from knowWPCarey, the business school’s online resource and newsletter, at