Issue 34

Contents

Declaratory Judgment Action
Malaria Drug from Chinese Herb
New Trypanosomiasis in India
Bacteria Make Medicine For You
Small Molecule of Diabetes
Phenylpropanolamine
Pfizer's Problems
Buckyball's in Cancer Therapy
Algal Gel for HIV Prevention
Joining Forces against Diabetes 
A new generation of medicinal products

Management Lessons from India

Malaria Drug from Chinese Herb
A Chinese called the Artemisia annua is widely regarded by medical experts as the best cure for malaria. In Luofushan in China's southern Guangdong province, the shrub with fern-like leaves first found its way into Chinese medical annals more than 1,600 years ago.   Ge Hong (283-363 AD) first wrote about it in his Book of Emergency Medicine when he served as a Taoist priest in this mountainous region.  Artemisinin is the malaria-fighting compound extracted from the shrub and is used to treat the disease, which causes fever, vomiting, body aches, diarrhea, anemia, loss of concentration, delirium, convulsions, coma and eventually, death.  Children and pregnant women deteriorate especially rapidly because of their weak immune systems, and the very young can die within 24 hours of the onset of symptoms if they are not treated.

New Trypanosomiasis in India
A farmer in India, from the village of Shivani (district of Chandrapur) 140 km from Nagpur in the central State of Maharashtra, has recently been identified as the first confirmed case of human trypanosomiasis recorded in that country. Human trypanosomiases are endemic in Africa and South America : respectively sleeping sickness caused by the parasites Trypanosoma brucei gambiense or T. b. rhodiense, and Chagas disease induced by T. cruzi. In other regions of the world such as India, only animals were up to now known to be infected by certain trypanosomes, which are not pathogenic for humans. The patient, who had been suffering for several months from recurring bouts of fever, had very high blood parasite count, equal or greater than 106 parasites/ml of blood. Parasitological, serological and molecular analyses confirmed this result. It is the world’s first formally identified case of human trypanosomiasis caused by T. evansi. This trypanosome, which was first identified in 1881 India, in the Punjab, in the horse and Bactrian camel, usually causes a disease called “surra “ in bovines and camel species. Although cases of human carriers of animal trypanosomiases were recorded during that century in India, Sri Lanka and Malaysia, these have either never been formally demonstrated or were only very short-lasting infections.

Bacteria Make Medicine For You
Professor Carding has modified one of the trillions of bacteria in the human gut so that it will produce human growth factors which help repair the layer of cells lining the colon, so reducing inflammation caused by IBD. But he's also adapted the bacteria so it only activates in the presence of a plant sugar called xylan that is found in tree bark. Xylan is naturally present in food in low concentrations, so by taking it in higher quantities, a patient will be able to produce their own medicine as and when they need it. The discovery has been patented – and is being developed further with support from the University's technology transfer partner, Techtran Group Ltd – part of the IP Group plc – and the Medical Research Council. The technique has been shown to work in vitro, but the researchers will be testing the treatment over the next twelve months in preparation for clinical trials.

Small Molecule of Diabetes
Liao and his colleagues at University of CA, Riverside screened a library of more than 48,000 natural and synthetic compounds, they identified a molecule, Boc5, which mimics glucagon-like peptide1 in the blood leading to increases in insulin secretion in laboratory cultured rat pancreatic cells when exposed to high glucose levels. The molecule also worked when administered by injection and orally in experiments with laboratory mice.  Thus Boc5 behaved as full GLP1 mimic, both in the test tube and in the laboratory mice, the researchers reported in an article that appeared in the Jan. 16 edition of the Proceedings of the National Academies of Science titled “A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.” The molecule also lowered appetite and promoted weight loss in mice.

 

Phenylpropanolamine
Taking small, doses of cold remedies containing phenylpropanolamine (PPA) appears to increase the risk of hemorrhagic stroke in women, Korean researchers report. Association between diet pills containing large doses of PPA and brain hemorrhage was already proven, the new study reveals that even smaller doses of PPA in cold remedies can increase the risk of hemorrhagic stroke. Neurology, January 9, 2007

Pfizer's Problems
The U.S. Food and Drug Administration (FDA) announced that Barr Pharmaceuticals, Inc (and its subsidiary PLIVA) has received final approval for an Abbreviated New Drug Application (ANDA) to manufacture and market Azithromycin for Injection, 500 mg vial, the generic version of Pfizer Labs' ZITHROMAX(R) IV (azithromycin for injection). The Company intends to launch its product during the first quarter of 2007.  Azithromycin for Injection is indicated for the treatment in patients who require intravenous therapy for infections caused by susceptible strains of the designated microorganisms in: 1) Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, or Streptococcus pneumoniae; and 2) Pelvic inflammatory disease due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis. An antimicrobial agent with anaerobic activity should be administered in combination with ZITHROMAX if appropriate.
The Company's Azithromycin for Injection, 500 mg vial will compete in a market that had total U.S. sales of approximately $75 million, based on IMS data for the 12-month period ending November 2006.

Higher doses of Viagra (sildenafil) may impair the ability to smell, which is possibly related to an increase in nasal congestion, German researchers report in The Journal of Urology.

Cancer Nurses may Become Infertile
In a study of oncology nurses, skin contact with chemotherapy drugs seemed to increase the time needed to conceive and to also raise the risk of premature delivery, according to a report in the journal Epidemiology.  Even very low (skin exposure to chemotherapy drugs) can cause an elevated risk of a prolonged time to pregnancy, premature delivery, or a low birth weight, even when gloves are worn during work.

Buckyball's in Cancer Therapy
Scientists at Rice University and pediatric specialists at Baylor College of Medicine have discovered a new way to use Rice's famed buckyball nanoparticles as passkeys that allows drugs to enter cancer cells.  The research appears in the Jan. 21 issue of the journal Organic and Biomolecular Chemistry.

Algal Gel for HIV Prevention
A type of algae found on the Brazilian coast could hold the key to a powerful new protection for women against HIV.  Brazilian researchers have developed a microbe-killing gel from the algae which they hope will be used to block HIV infection.  In preliminary lab tests they say it proved to be 95% efficient.  The team hopes the gel - one of a new generation of microbicides seen as key to preventing HIV infection in women - will be on the market in seven years. Leading HIV campaigners, including the US philanthropist Bill Gates, have said the key to stopping the AIDS pandemic lies in giving women the power to protect themselves.

Joining Forces against Diabetes
Diabetes is a disease in which the body does not produce or properly use insulin. Insulin is a hormone needed to carry glucose (sugar) from the blood into cells, where it is converted to energy the cells need to perform properly. When insulin is not present or does not function correctly, the result is high levels of glucose in the blood. Over time, high blood glucose levels can lead to complications in the eyes, kidneys, central nervous system or heart.
Type 2 diabetes is the most common form of diabetes, accounting for approximately 90-95 percent of diabetes cases. Having Type 2 diabetes increases the risk of many serious complications, including heart disease or stroke, high blood pressure, amputation (particularly legs), blindness, nerve damage, and kidney failure. The risk of stroke and the rate of deaths due to heart disease are two to four times higher among people with diabetes, while about 65 percent of deaths among people with diabetes are due to heart disease and stroke.
The American Diabetes Association (ADA) estimates that more than 20 million people in the United States, or 7 percent of the population, have diabetes, and that one in three Americans born in 2000 will develop diabetes sometime during their lifetime. There are currently more than 230 million people living with diabetes worldwide. The objective of treating diabetes is to control blood glucose to as normal a level as possible. This can be accomplished by a combination of diet, exercise and medication.

Bristol-Myers Squibb Company (NYSE: BMY - News) and AstraZeneca ("companies") today announced a collaboration to develop and commercialize two investigational compounds being studied for the treatment of Type 2 diabetes. Both compounds were discovered by Bristol-Myers Squibb.  Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently in Phase III development. Upon successful completion of the development program, the companies plan to file for U.S. regulatory approval of saxagliptin during the first half of 2008. Dapagliflozin (previously referred to as BMS-512148), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is currently in Phase IIb development. The collaboration on these compounds is worldwide, except for Japan. Should either party develop additional DPP-4 or SGLT2 compounds, the other company can elect to add those compounds to the collaboration.

A new generation of medicinal products

What is a medicinal product? It is always the result of a subtle marriage between a compound (the active substance which treats a patient) and an appropriate excipient (a neutral substance in which the active substance is incorporated so that it can be absorbed by the body). Thus the necessary tablet, capsule or syrup is obtained. But what would happen if biodegradable materials were used instead of these neutral excipients? This was already possible with some active substances, and can now be applied to many others! The team led by Didier Bourissou in the Laboratory for Fundamental and Applied Heterochemistry (CNRS/University Toulouse 3), has indeed managed to develop a novel synthetic process for these materials which significantly increases their diversity.
Some biodegradable polymers such as polyesters have already been employed as excipients in pharmacology. But this was only possible when they were mixed with certain active substances such as anticancer drugs or growth hormones. And in the field of surgery, the secret of absorbable sutures does indeed reside in the use of these same polyesters. 

What are the principles underlying these "new generation" drugs? The biodegradable excipient containing the active substance can take the form of an implant – a 1 cm-long rod about one millimetre in diameter – which is inserted just under the skin. This procedure is performed by a doctor and only takes a few minutes. The specificity of these polyesters is that they can be hydrolyzed; in other words, broken down by water, which is unlucky for them, as our bodies are full of this substance. Thus the excipient gradually breaks down, over a week, a month or three months, depending on its type, releasing the active substance it contains. Hence the major advantage of the technique: biodegradable excipients enable the controlled administration of sustained-release drugs. This is of considerable benefit in the setting of chronic diseases, as it avoids frequent, repeated intakes of medicines. Another positive point is that this method reduces side effects; by circumventing the digestive tract, the active substance passes directly into the bloodstream. Thus it is also possible to reduce the quantity of drug administered, as there is no longer any need to allow for its partial destruction as it passes through the digestive tract.

In view of these advantages, why can the technique not be extended to a broader range of active substances? Because, until now, we only knew how to make these biodegradable polymers using two monomers (the basic components of polymers), lactide and glycolide. It is rather like making a bead necklace when only green and red beads are available. And in the same way that such a two-coloured necklace would not match all outfits, so the polyesters obtained cannot be combined with just any active substance. Without accounting for the fact that when using these little reactive lactide and glycolide monomers, industrial preparation of the polymers requires lengthy reaction times at high temperatures (e.g. several hours at 140°C-160°C). 

This is where Didier Bourissou's team same up with the idea of changing the recipe and ingredients in order to facilitate access to these polyesters and increase their diversity. Many tests later, they achieved their goal. In collaboration with Isochem, they have developed a new synthetic process for these polymers. This involves new elementary building blocks, the O-carboxy anhydrides, which are much more reactive (i.e. more beads for our necklace), so that the polyesters can be prepared under much less harsh laboratory conditions (e.g. a few minutes at 25°C). And above all, a much wider variety of polymers is available, thus multiplying the chances that an active substance will find its appropriate biodegradable excipient. These promising results have given rise to the filing of two patents.
An unquestioned advance in the daily routine of patients, this technique might also be popular with the major pharmaceutical companies, as it would constitute an added-value for traditional drugs which could be presented in a sustained-release formulation.
http://www.eurekalert.org/pub_releases/2007-01/c-ang011707.php