An analgesic molecule discovered in its natural state in Africa

A team of researchers led by Michel De Waard, Inserm Research Director at the Grenoble Institute of Neurosciences  (Inserm, University Joseph Fourier, CNRS), has discovered that an African medicinal plant produces large quantities of molecules with analgesic properties. Even more surprising, analysis show that the molecule is identical to Tramadol, a wholly synthetic medication that is used world-wide as a painkiller. According to the research team, this is the first time ever that a synthetic medication produced by the pharmaceutical industry has been discovered in strong concentrations in a natural source. This unexpected discovery had just been published in the chemical journal’ “Angewandte Chemie.

Nauclea latifolia (also know as the pin cushion tree) is a small shrub that is widely abundant throughout Sub-Saharan Africa. In traditional medicine, in particular in Cameroon, this plant is used to treat different pathologies including epilepsy, fevers, malaria and pain.

In order to identify the presence and the type of potential active substances in this plant, Michel De Waard, Inserm Research Director, organised joint scientific research with the Grenoble Institute of Neurosciences (Inserm unit 836 UJF/CEA/CHU), the Department of Molecular Pharmacological Chemistry (UMR UJF/CNRS 5063, Pr Ahcène Boumendjel) and the University of Buea (Dr. Germain Sotoing Taiwe).

Thanks to this work, the researchers were able to isolate and determine the properties of the component in the plant that was responsible for the presumed analgesic effects, by analysing part of the root bark. And to everyone’s surprise, they found that this component was already commercially available under the name: Tramadol.

The biggest surprise in this study was the fact that this molecule was a known one. “It was identical to Tramadol, a synthetic medication developed in the seventies and often used to treat pain”, explained Michel De Waard, Inserm research director. This medication is used world-wide, because although it is a derivative of morphine, it has less side effects than morphine, in particular addiction problems.

Tramadol1 is in fact a simplified form of morphine that has conserved the elements needed to produce analgesic effects.

structure tramadol vs morphine

crédit : Structure of Tramadol versus structure of morphine

In order to confirm their results, the researchers tested different processes with the aim of proving that the substance discovered was of natural origin. Their analyses were confirmed by three independent laboratories that had received different samples at different times of the year.

“All results converge and confirm the presence of Tramadol in the root bark of Nauclea latifolia. On the other hand, no trace of this molecule was detected in the aerial part of the shrub (leaves, trunk or branches)“, explained the researcher.

Finally, in order to exclude the possibility of accidental contamination of the samples by synthetic Tramadol, the researchers took samples from inside the roots themselves and thus confirmed the presence of the molecule.

From a quantitative point of view, the concentration of Tramadol in the dried bark extracts was measured at 0.4% and 3.9%. These are extremely high levels of active substance.

In addition to the unprecedented aspect of this discovery (the first ever potentially exploitable case where a hitherto synthetically produced medication has been discovered in a natural form and in high quantities), this major result opens up prospects for local populations, giving them access to a source of cheap treatment and validating the concepts of traditional medicines (as decoctions made from barks and roots).

There are over 10 different varieties of this shrub in Africa, so we can envisage repeating the tests in order to determine which varieties contain Tramadol”, concludes Michel De Waard.

This study can also be used to provide a warning as to the risks of drug dependency linked to over-consumption of the roots of this plant. Tramadol is listed as an opiate product, just like morphine from which it is derived.

plant de citronnier


1 No medication is without risks and they all have potentially harmful side effects. It is impossible to predict with any certainty the effects of treatment by any medication. All medication products have both beneficial effects, but also a risk of being harmful. We can reduce this risk as far as possible by ensuring that the prescribed medication is of the correct quality, is safe, efficient, administered to the people who need it, at the right doses and at the right times. Source: WHO

Dwarfism: a new development to restore bone growth

Achondroplasia is the most common form of dwarfism, affecting roughly one child in every 15,000 births[1]. Inserm researcher Elvire Gouze, and her associates from the Mediterranean Centre for Molecular Medicine in Nice (Inserm Unit 106), have succeeded in restoring bone growth in mice suffering from this developmental pathology. The proof-of-concept created by the researchers is for a therapy based on injecting a particularly promising human growth factor, which restores the growth process in long bones. Its results include a reduced mortality rate in the treated mice, with no complications associated with the disease. No apparent toxicity was observed over the short term.

The results of this research were published in the  Science Translational Medicine review on 18 September.

Elvire Gouze

Sophie Garcia and Elvire Gouze in Inserm Unit 1065 “Centre méditerranéen de médecine moléculaire” in Nice

Achondroplasia is a rare genetic disease characterized by abnormal bone development. The related growth failure affects bones in the upper and lower limbs, and some bones in the skull; people suffering from it are short, reaching no more than an average of 135 cm in adulthood. In the most severe cases, deformation of the skull and vertebrae may result in neurological and/or orthopaedic complications. This pathology is caused by mutations in the FGFR3 (Fibroblast growth factor 3) gene.  The protein produced by this gene is a receptor known for its role in bone growth regulation. Normally, growth can only occur through a subtle mechanism during which the FGF growth factor bonds with the FGFR3 receptor and then separates from it. In the case of achondroplasia, the receptor/growth factor pair is disturbed and prevents the bone from growing in a constant manner.

A new strategy to restore bone growth

In this study, researchers from Inserm and the Université de Nice Sophia Antipolis have found a way to prevent constant protein activation. They implemented a new strategy, which consists of using a decoy – functional soluble human FGFR3 receptors – that is injected in mice afflicted with the disease, thus restoring the equilibrium required between bone growth activation and inhibition.

The solution containing soluble FGFR3 receptors was injected into growing mice suffering from dwarfism twice a week over a three-week period.  The additional normal receptors made it possible for the growth factor to bond and separate normally, thus restoring bone growth. Mutated mice then grew normally and reached the average adult size. Once the therapy had stopped, the researchers then monitored the mice over an eight month period to check there were no signs of therapy toxicity. During this monitoring, the researchers observed that an increased pelvis size enables reproduction with litters identical to disease-free mice.

“Rather surprisingly, our strategy prevents the most severe complications observed in mice (reduced mortality rate, respiratory problems, etc.). This could lead us to believe that injection-based therapy could replace surgery for children suffering from this disease” explains Elvire Gouze, Inserm researcher.

Preventing the development of achondroplasia

Today, there are no proven therapies to prevent the development of the disease, even if some (such as growth hormone injections or surgical limb-lengthening) have undergone trials without any convincing results.

“The product that we tested has major advantages compared with those tested in other ongoing trials: its lifetime in the body is sufficiently long, meaning daily injections are not necessary. We think that our approach could be effective when treating children with achondroplasia and possibly other forms of dwarfism” underlines the researcher, who is the main author of the study.

The researchers will now endeavour to verify that there are no long-term toxic effects. Before undertaking clinical studies in human patients, they must also identify the minimum dose at which the therapy is effective and when it becomes toxic. Another area to be explored is to determine whether it is possible to begin the therapy later, thereby increasing the number of patients who could benefit from this treatment.

[1] Source: Orphanet Achondroplasie

Cystic fibrosis : new compounds display strong therapeutic potential

Cystic fibrosis is a lethal genetic disorder that in France affects one child per 4,500 births. An international team led by scientists at the Institut Fédératif de Recherche Necker-Enfants Malades (CNRS/Inserm/Université Paris Descartes), led by Aleksander Edelman, has recently discovered two new compounds that could be used to treat patients carrying the most common mutation. By means of virtual screening and experiments on mice and human cells in culture, the scientists were able to screen 200,000 compounds and selected two that allowed the causal mutated protein to express itself and fulfill its function. These findings were recently published online inEMBO Molecular Medicine.

Cystic fibrosis is a genetic disorder that affects the epithelia[2] of numerous organs, and particularly those in the lungs, pancreas and intestine. In the lungs, this takes the form of insufficient epithelial hydration, resulting in excess mucus in the bronchi. This mucus retains pathogenic agents and favors the onset of chronic infections and inflammatory conditions that are ultimately fatal to the sufferer.

The disease is caused by mutations in the gene coding for a protein called CFTR (cystic fibrosis transmembrane conductance regulator). This protein, which is essential to ensure the passage of water through an epithelium, is an ion channel that allows chloride ions to pass through cell membranes. To date, about 2,000 gene mutations that cause the disease have been determined, but 70% of cases of cystic fibrosis are due to a single mutation called ΔF508. And it is this mutation that is targeted by the recently-discovered compounds.

The scientists used computer techniques to screen 200,000 compounds, looking for those that might interact with a specific zone in the abnormal protein, and found about a dozen potentially active molecules. Using these 12 compounds, they then performed in-vitro tests on human cell cultures and in-vivo experiments on mice showing this mutation. They were thus able to observe that two of these compounds allowed the mutated ΔF508-CFTR protein to be trafficked to the membrane and fulfill its role.

One of the highlights of this work was that the scientists were able to describe the mechanism of action of these two compounds. In itself, and despite its mutation, the ΔF508-CFTR protein may satisfactorily fulfill its function. The problem is that once it is synthesized, it is recognized as being abnormal by keratin 8, another protein which favors its degradation, thus preventing ΔF508-CFTR from reaching the cell membrane. The compounds discovered by the scientists inhibit the interaction between keratin 8 and ΔF508-CFTR so that the protein can be deployed appropriately and fulfill its role as an ion channel. The scientists think that for potential therapeutic purposes, the two molecules they have discovered could be associated with “potentiating” compounds that would enhance the activity of ΔF508-CFTR.

The scientists now want to determine whether these two compounds do indeed cause a reduction in the susceptibility to infection of cystic fibrosis mice models. They also hope to start clinical trials in cystic fibrosis patients in the coming years.

(French) : Journée mondiale de la maladie d’Alzheimer

FIBRO-TARGETS – Europe banks on cardiac fibrosis as a therapeutic target in heart failure

The European Union commits funds to the FIBRO-TARGETS (Targeting cardiac fibrosis for heart failure treatment) research consortium, to be coordinated by Inserm over a four-year period. The objective of the project is to determine the underliying mechanisms in myocardial interstitial fibrosis contributing to the development of heart failure. Unravelling the mechanisms of cardiac fibrosis will lead to the discovery of therapeutic target candidates for various cardiac diseases. FIBRO-TARGETS brings together eleven European expert teams from six different countries both from public research institutes and European biotechs. This is the second EU funding in heart failure for Inserm; the first one was launched last February: HOMAGE (for Heart OMics in AGEing – which aims to validate specific biomarkers of heart failure).
All 11 partners convened in Amsterdam on September 3rd,  for the kickoff of the FIBRO-TARGETS project.

Centre d'Investigation Clinique Plurithématique (CIC-P) Pierre D

© Inserm / P. Delapierre

Beyond and in addition to a diseased heart muscle, myocardial interstitial fibrosis (MIF) is one of the key mechanisms of cardiac remodelling. Cardiac fibrosis contributes to cardiac tissue stiffness. It results from the excessive accumulation of proteins that make up the extracellular matrix. As a consequence, diastolic and systolic cardiac functions are altered which, over time, results in symptomatic heart failure (HF), with breathlessness, fluid congestion, oedema and fatigue.

Heart failure is a serious disease since it is often irreversible. It is estimated that more than 6.5 million people suffer from heart failure in Europe.

 It is the leading cause of hospitalization for patients over the age of 65. The incidence is increasing at an alarming rate because of an aging population and the burden of cardiovascular risk factors (diabetes, obesity and high blood pressure). Early interventions targeting key mechanisms, including myocardial interstitial fibrosis, could slow down progression to heart failure.

Using the large amount of data amassed by the FIBRO-TARGETS consortium, myocardial interstitial fibrosis was identified as a major therapeutic target for the prevention and treatment of heart failure. The FIBRO-TARGETS project therefore aims to accurately identify the main mechanisms involved in MIF and to define therapeutic approaches that target these mechanisms. Cardiac fibroblasts (specific cells in cardiac muscle) make up between 60 – 70 % of all cardiac cells and are the main source of the extracellular matrix proteins responsible for fibrosis. Since these mechanisms have been identified, direct intervention can be performed on fibroblast proliferation and on the composition of extracellular matrix using molecules with potential therapeutic benefits: preventing, repairing or slowing down cardiac remodelling.

“In addition, until now, the only means of quantifying fibrosis was a biopsy, an invasive and inaccurate method used to estimate the total degree of cardiac fibrosis. Over the last ten years, cardiac imaging has allowed to perform accurate anatomic and functional assessments of the myocardium (the muscular tissue of the heart).

Relevant to this project, it is also possible to describe mechanistic phenotypes, including myocardial interstitial fibrosis, using circulating biomarkers”

explains Professor Faiez Zannad, researcher at Inserm unit U1116, Centre d’Investigation Clinique P. Drouin Inserm 9501 in Nancy, and coordinator of the FIBRO-TARGETS and HOMAGE projects.

The FIBRO-TARGETS project objectives are first to confirm the main biological mechanisms involved in myocardial interstitial fibrosis. The next step will be to experimentally validate new molecules and targeted therapeutic strategies that aim to improve the quality of the cellular matrix and limit myocardial interstitial fibrosis. This will allow to propose potential clinical scénarios with the objective to treat heart failure. Finally, the targets could be used as biomarkers to predict, monitor and describe the response to myocardial interstitial fibrosis treatments.

To meet these objectives, the European researchers will undertake experimental physiological and pharmacological studies, as well as molecular biology and pharmaceutical chemistry studies, in an attempt to clarify the mechanisms involved in cardiac interstitial fibrosis using existing in-vitro and in vivo models, and/or models developed during the project. They will also validate the relevance of new therapeutic approaches developed during the project. The second step is a translational research aiming at stratifying patients that are most likely to respond to an anti-fibrotic targeted therapy, eventually leading to a personalized pharmacotherapy. Patients will be classified into groups according to profiles determined using imaging and circulating markers describing the new proposed targets.

The FIBRO-TARGETS project results will help resolve one of the 21st century’s major health problems that affects elderly people in particular.

(French) : Les bienfaits d’une nouvelle molécule dans l’angioplastie coronaire

French Cyclists of the Tour de France live 6 years longer that the general population

Circumcision effectively reduces the risk of HIV infection “in real life”

The ANRS-12126 “Bophelo Pele” Project implemented in the township of Orange Farm in South Africa has confirmed the effectiveness of a large-scale program of voluntary medical male circumcision in prevention of heterosexually acquired HIV infection. The follow-up of over 3300 men shows a 57% to 61% reduction in the rate of new HIV infections in circumcised men compared with uncircumcised men. This study, headed by Prof Bertran Auvert and his colleagues, also shows that a circumcision program can be rapidly and effectively implemented in African communities where circumcision is not a social norm. These results, published in PLoS Medicine, argue for accelerated roll-out of voluntary male circumcision programs on the African continent in order to improve prevention of HIV transmission.

Three randomized trials have shown that male circumcision has a protective effect on the risk of HIV infection in men. The first publication dates from 2005 (ANRS-1265 study in South Africa) and its results were subsequently confirmed in Kenya (2007) and Uganda (2007). These studies showed that the risk of circumcised men being infected by HIV was reduced by 50% to 60%. These results led UNAIDS/WHO to recommend in 2007 the circumcision of adult males as a strategy of additional HIV prevention in communities with a high prevalence of HIV and a low prevalence of circumcision.

There remained, however, a need to show that the roll-out of circumcision “in real life” reduces both the incidence (rate of occurrence of new infections) and the prevalence (proportion of people infected in the total population) of HIV infection in men. This had been suggested by preliminary results from the ANRS-12126 “Bophelo Pele” Project of Bertran Auvert and colleagues presented at the International AIDS Society Conference 2011. These results are now confirmed in the PLoS Medicine article, the first scientific publication to show that adult male circumcision “in real life” effectively reduces the risk of HIV infection in men (1).

Between 2007 and 2011, the ANRS-12126 “Bophelo Pele” Project was conducted by Prof Bertran Auvert (UMRS-1018 Inserm, Hôpital Ambroise Paré and Université de Versailles Saint-Quentin) and his colleagues from the National Institute for Communicable Diseases, the Social Sciences Faculty, and Progressus (Johannesburg, South Africa), and from Johns Hopkins University (Baltimore, USA) and the Bichat Hospital (Paris, France). Free, medical circumcision was offered to all male volunteers aged from 15 to 49 years in a population of 110 000 adults in the township of Orange Farm in South Africa. More than 20 000 circumcisions were performed, accompanied by a large information provision and prevention program.

An anonymous questionnaire on sexual practices was administered to 3338 men recruited from the township population who were invited to undergo HIV screening, which included a test to determine, in the event of seropositivity, whether the infection was recent.

The proportion of circumcised men in this sample of 3338 increased from 12% at the start to 53%, and was 58% in the 15- to 29-year-olds. Importantly, sexual behavior, in particular condom use, did not differ between circumcised and uncircumcised men. In contrast, the prevalence and incidence of HIV infection were much reduced in the circumcised men.

The researchers considered that without the voluntary circumcision program, HIV prevalence would have been 19% higher in the study population. This effect is more marked in the 15- to 29-year-olds, in whom the prevalence would have been 28% higher. Also apparent was a decrease in the number of recent infections among the circumcised men. Circumcision was therefore associated with a 57% to 61% reduction in the rate of new infections.

Prof Bertran Auvert considers that “these results are important in two ways. First, they confirm the efficacy of the circumcision practiced on a population scale in reducing HIV transmission appreciably among the men of this population. Second, they show that it is possible to achieve this result in just a few years, including in populations where circumcision is not a common practice.”

The ANRS-12126 Project provides an argument for speeding up the roll-out of voluntary circumcision programs, notably in sub-Saharan Africa, which is home to the vast majority of the 2.2 million people infected by HIV every year worldwide. Prof Jean-François Delfraissy, Director of the ANRS, considers that “given the impact observed in this study on limiting the risk of HIV acquisition in circumcised men, the scale-up of circumcision should more than ever be a public health priority in South and East Africa.”

The ANRS-12126 Project is continuing with the aim of elucidating the effect of circumcision on infection risk reduction in the general population, and in particular among women.