HU star researchers take Kaye Prizes for innovation

The Jerusalem Post

A new method for lowering blood pressure with a compound that synthesizes a cannabis (hashish or marijuana) plant component has been developed by a Hebrew University doctoral student in pharmacology.

For his work on the cardiovascular activity of cannabinoids (chemical compounds derived from cannabis), Yehoshua Maor has been named one of the winners of this year's Kaye Innovation Awards, to be presented on Tuesday during the university's 69th annual board of governors meetings.

The Kaye Innovation Awards, established by British pharmaceutical industrialist Isaac Kaye, have been given annually since 1994 to encourage HU faculty, staff and students to develop innovative methods and inventions with good commercial potential to benefit the university and society.

Not all patients respond well to conventional hypertension drugs. But the cannabis plant, through its chemical compounds, has been shown to have a beneficial, hypotensive effect. But a drawback in the therapeutic use of cannabinoids has been the undesirable psychotropic properties such as hallucinatory effects. Attempts to separate the hypotensive action from their psychotropic properties have been only partially successful until now.

Working under the supervision of Prof. Raphael Mechoulam at the HU School of Pharmacy, Maor - a native of Brazil who immigrated to Israel in 1998 - has created a synthetic version of a minor cannabis constituent named cannabigerol, which is devoid of psychotropic activity. In laboratory experiments with rats, in collaboration with Prof. Michal Horowitz, it was found that this novel compound reduced blood pressure when administered in relatively low doses. Additional testing also showed that the compound also brought about another beneficial effect - relaxation of the blood vessels. A further beneficial property observed in work carried out with Prof. Ruth Gallily was that the compounds produced an anti-inflammatory response.

Maor says these qualities could be combined to create a valuable new clinical drug with major market potential, especially for diabetic patients suffering from hypertension, since reductions in blood pressure can decrease the risk of diabetes complications and in others with metabolic irregularities.

Meanwhile, former Russian immigrant Elena Khazanov, 34, will also receive a Kaye Prize for developing a novel method for combining two anti-cancer drugs into a single delivery system, thereby dramatically improving treatment efficacy. Khazanov, who arrived here 12 years ago, developed her drug delivery system as a PhD student under the tutelage of Prof. Yechezkel Barenholz of the Hebrew University-Hadassah Medical School's biochemistry department.

Khazanov used an approach called combination therapy, in which two or more agents are introduced within a single delivery unit, with the result that the combination has a better beneficial chemotherapeutic effect than otherwise would be possible. Her work was based on the previous success of HU scientists with the delivery system for an anti-cancer drug, doxorubicin (DXR), which resulted in development of DXR delivery through sterically stabilized liposomes (SSL), which are ball-like fatty molecules.

A highly successful medication based on that research has been manufactured by SEQUUS Pharmaceuticals and is marketed as Doxil. Khazanov aimed to combine DXR with ceramides, a family of fatty molecules found in high concentrations within cell membranes. These act as signaling molecules, triggering programmed cell death in many types of cancer cells. However, the physical and chemical properties of ceramides make them unusable by themselves for therapeutic application in vivo. Her efforts ultimately proved successful in formulating a novel drug delivery system consisting of SSL that contained both DXR and ceramides.

In laboratory tests on mice, the synergism between the two drugs resulted in an improved therapeutic benefit over Doxil alone. The fact that both were delivered by one tiny SSL liposome enables long plasma circulation time and liposome-selective delivery to the tumor site by their introduction into the tumor through pores present in the tumor blood vessels.

Additional trials, including therapeutic efficacy studies in mice bearing different tumors, plus toxicology studies of this new liposome formulation, are continuing to ultimately enable human clinical trials. Patents have been secured through Yissum, HU's technology transfer company, to enable further development of the delivery system.

New, non-invasive therapies for treating diseases such as basal cell carcinoma, viral and microbial deep skin infections and erectile dysfunction are being developed by Prof. Elka Touitou, another Kaye Prize recipient from the pharmacy school. The new approach uses a specially designed, patented topical delivery system known as Ethosome for targeting drugs directly to the disease site. Touitou invented the system with a group of her students and postdoctoral fellows.

Ethosome provides a dermal delivery system that overcomes the natural skin barrier that has prevented anti-cancer drugs applied on the skin from reaching their targets. Drugs encased in Ethosome are able to penetrate even into the deep skin layers where basal carcinoma cells occur, thereby providing a non-invasive alternative to surgical intervention. A number of clinical studies, including a recent one on the use of Ethosomalprostaglandin for treatment of impotence, have shown their efficiency, and the delivery system can be used in cosmetic compounds

New and safer compounds for treatment of epilepsy patients and those suffering from other neural disorders have been developed by Prof. Meir Bialer and Prof. Boris Yagen. Their work at the pharmaceutics, medicinal chemistry and natural products department at the pharmacy school is also being recognized by a Kaye Prize they will share.

They developed a potential alternative for valproic acid (VPA), one of the leading anti-epileptic drugs, which has been used as a central nervous system treatment since 1967, but which also has serious safety drawbacks. Its side effects can cause damage especially to children or women of child-bearing age. Patents have been obtained by Yissum.

The Barenholz Prize for Creativity and Originality in Applied Research will be presented to a 29-year-old HU doctoral student at the pharmacy school, for her work in discovering a way to prevent restenosis - recurrent blocking of coronary arteries after angioplasty (balloon therapy).

The award, named for its donor, cancer researcher Prof. Yehezkel Barenholz, will be presented during the board meetings to Hila Epstein-Barash. In her research, she and her colleagues hypothesized that if the macrophages that accumulate in the area of the angioplastic treatment could be inactivated, the problem could be solved. The problem was how to deliver a cell-specific drug that could achieve this.

In their research they found that this could be accomplished through the use of bisphosphonates - bone-seeking agents used clinically to treat osteoporosis - which have high affinity to calcium and are assimilated into bone tissue by osteoclasts - which are closely related to macrophages. The problem before them was how to reach the targeted area of macrophages in the blood vessels, since the drug alone, due to its chemical makeup, is not able to cross cell membranes.

The researchers subsequently found that by encapsulating the bisphosphonates in liposomes, the drug could be delivered to the macrophages in the blood vessels that had been opened by angioplasty. The scientists found that a single injection of liposomes containing bisphosphonates, soon after angioplasty, significantly prevented restenosis in rat and rabbit models, markedly reducing the thickness of the inner wall of the affected arteries and leaving enough room for the blood to circulate.

Pre-clinical trials are now proceeding in Australia, using this procedure which is non-toxic and presents no side effects.