Loco-regional administration of anticancer agents : isolated lung perfusion with doxorubicin hypoxic abdominal stop-flow perfusion with gemcitabine

SUMMARY Regional drug delivery is an approach designed to improve the selectivity of anticancer chemotherapy. The advantage of regional treatments lies in increasing the drug concentration in the affected organ, while the rest of the organism is spared, thus improving efficacy and limiting treatment toxicity. The goal of this thesis was to assess the distribution throughout the body and the disposition (pharmacokinetics) of two anticancer agents, doxorubicin and gemcitabine, administered by two different regional administration modalities: isolated lung perfusion (ILP) for pulmonary metastases from soft tissue sarcomas and abdominal stop-flow hypoxic perfusion for advanced pancreatic cancers, respectively. For this purpose, two high-performance liquid chromatography methods were developed and validated. The first enabled the determination of doxorubicin in four different biological matrices: serum, reconstituted effluent, tissues with low levels of doxorubicin and tissues with high levels of doxorubicin. The second allows the analysis of gemcitabine and its principal metabolite dFdU in plasma. The administration of doxorubicin by ILP was studied in three preclinical studies (one on pigs and two on rats). It was first shown that, regardless of the administration mode, doxorubicin was not homogeneously distributed throughout the lung and that some regions remained out of reach. Secondly, it was demonstrated that doxorubicin did not adequately reach the tumours despite very high levels found in the lung. Finally, an attempt to enhance the doxorubicin tumoural uptake by pharmacologic modulation using two P-glycoprotein inhibitors, cyclosporin and valspodar, was unsuccessful. The last part of this work involves the administration of gemcitabine by abdominal stop-flow as a part of a phase I clinical trial in patients with advanced pancreatic disease or resistant malignant ascites. The study has demonstrated that the regional exposure to gemcitabine was increased while the exposure of the entire organism was similar to standard intravenous administrations. From a toxicological perspective, the procedure was rather well tolerated. However, even if no clinical response is expected from a phase I study, no hints of clinical responses were unfortunately observed. In conclusion, even if loco-regional therapies may afford the pharmacological advantage of increasing anticancer drug levels at the tumour site, further studies of these investigational treatment modalities are warranted to ascertain whether they can provide a significant improvement of the cancer therapy for patients, in terms of treatment tolerability, improved responses and survival rates. RÉSUMÉ L'administration locorégionale d'agents anticancéreux est une approche destinée à augmenter la sélectivité du traitement. L'avantage des traitements régionaux repose sur le fait que la concentration du médicament cytostatique est augmentée dans l'organe où est localisée la tumeur, alors que le reste de l'organisme est épargné, améliorant ainsi en théorie l'efficacité du traitement et en limitant sa toxicité. Le but de ce travail de thèse avait pour objectif de préciser, la pharmacocinétique au sein de l'organisme de deux agents anticancéreux, la doxorubicine et la gemcitabine, administrés par deux types de perfusions loco-régionales: la perfusion isolée du poumon (ILP) pour les métastases pulmonaires de sarcomes des tissus mous, et la perfusion hypoxique (stop-flow) abdominale pour les cancers avancés du pancréas. Dans cette optique, deux méthodes de chromatographie liquide à haute performance ont été développées et validées. La première permet le dosage de la doxorubicine dans quatre milieux biologiques: le sérum, l'effluent reconstitué, ainsi que des tissus contenant des concentrations faibles et élevées en doxorubicine. La seconde méthode permet le dosage dans le plasma de la gemcitabine et de son principal métabolite, le dFdU. L'administration de doxorubicine par ILP a été étudiée dans trois études précliniques (une chez le porc et deux chez le rat). Il a été montré, dans un premier temps, que la doxorubicine n'était pas distribuée de façon homogène au sein du poumon, quel que soit son mode d'administration. Dans un deuxième temps, il a été démontré que le médicament n'atteignait pas les tumeurs de façon adéquate, malgré des concentrations très élevées au sein du tissu pulmonaire. Finalement, une tentative d'augmenter la pénétration tumorale de la doxorubicine par une modulation pharmacologique de la P-glycoprotéine en utilisant la cyclosporine et le valspodar n'a pas abouti. La dernière partie de ce travail concernait l'administration de gemcitabine par stop-flow abdominal dans le cadre d'une étude clinique de phase I menée auprès de patients atteints de cancers avancés du pancréas ou d'ascites malignes réfractaires. Cette étude a démontré que l'exposition régionale à la gemcitabine était augmentée, alors que l'exposition de l'organisme était similaire à une administration de dose standard par voie intraveineuse. D'un point de vue toxicologique la procédure fut relativement bien tolérée. Cependant, même s'il n'est pas attendu de réponses cliniques dans une étude de phase I, aucun signe de réponse au traitement n'a pu être malheureusement observé. En conclusion, même si les thérapies loco-régionales présentent -en théorie- l'avantage pharmacologique d'augmenter les taux du médicaments anticancéreux sur le site de la tumeur, d'autres études précliniques et cliniques sont nécessaires pour démontrer que ces nouvelles modalités de traitement, de nature investigationelle à présent, apportent une réelle amélioration pour la prise en charge des patients cancéreux, en terme de tolérance au traitement et de l'augmentation des taux de réponses et de survie.

Detection of erythropoiesis-stimulating agents in human anti-doping control: past, present and future.

Stimulation of erythropoiesis is one of the most efficient ways of doping. This type of doping is advantageous for aerobic physical exercise and of particular interest to endurance athletes. Erythropoiesis, which takes place in bone marrow, is under the control of EPO, a hormone secreted primarily by the kidneys when the arterial oxygen tension decreases. In certain pathological disorders, such as chronic renal failure, the production of EPO is insufficient and results in anemia. The pharmaceutical industry has, thus, been very interested in developing drugs that stimulate erythropoiesis. With this aim, various strategies have been, and continue to be, envisaged, giving rise to an expanding range of drugs that are good candidates for doping. Anti-doping control has had to deal with this situation by developing appropriate methods for their detection. This article presents an overview of both the drugs and the corresponding methods of detection, and thus follows a roughly chronological order.

Que faire des nouveaux anti-épileptiques [Clinical utilization of new anti-epileptic agents].

Since the beginning of the 1990's, a dozen of new anti-epileptic drugs have been on the market or will be soon. This article reviews the daily clinical utilisation of new anti-epileptic drugs. It considers, without being complete, the current opinions and tendencies. The new anti-epileptic substances are generally as efficient as conventional medications. However, they are better tolerated and are more easily used in combination with conventional anti-epileptic drugs. Polytherapy is certainly the form of treatment, which is used in the most cases of resistant epilepsies. The surgical treatment can be used in only a very limited number of cases. The objective of treatment is the complete control of seizures, with minimum secondary effects. Though this objective is rarely reached, the NAE significantly improves the quality of life of patients suffering from severe epilepsy. The utilisation of NAE is not without risk. Increase in the frequency and severity of seizures may occur; we should remember that severe adverse effects appeared in the post-marketing period of the use of Vigabatrine and Felbamate. Therefore, we must remain vigilant in the clinical use of the anti-epileptic drugs.

Redox dysregulation and oxidative stress in schizophrenia: genetic and functional anomalies of glutathione synthesis in patients and experimental models involving GABA interneurons and NMDA receptors

Objective: Converging evidence speak in favor of an abnormal susceptibility to oxidative stress in schizophrenia. A decreased level of glutathione (GSH), the principal non-protein antioxidant and redox regulator, was observed both in cerebrospinal-fluid and prefrontal cortex of schizophrenia patients (Do et al., 2000). Results: Schizophrenia patients have an abnormal GSH synthesis most likely of genetic origin: Two independent case-control studies showed a significant association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease-associated genotypes correlated with a decrease in GCLC protein expression, GCL activity and GSH content. Such a redox dysregulation during development could underlie the structural and functional anomalies in connectivity: In experimental models, GSH deficit induced anomalies similar to those observed in patients. (a) morphology: In animal models with GSH deficit during the development we observed in prefrontal cortex a decreased dendritic spines density in pyramidal cells and an abnormal development of parvalbumine (but not of calretinine) immunoreactive GABA interneurones in anterior cingulate cortex. (b) physiology: GSH depletion in hippocampal slices induces NMDA receptors hypofunction and an impairment of long term potentiation. In addition, GSH deficit affected the modulation of dopamine on NMDA-induced Ca 2+ response in cultured cortical neurons. While dopamine enhanced NMDA responses in control neurons, it depressed NMDA responses in GSH-depleted neurons. Antagonist of D2-, but not D1-receptors, prevented this depression, a mechanism contributing to the efficacy of antipsychotics. The redox sensitive ryanodine receptors and L-type calcium channels underlie these observations. (c) cognition: Developing rats with low [GSH] and high dopamine lead deficit in olfactory integration and in object recognition which appears earlier in males that females, in analogy to the delay of the psychosis onset between man and woman. Conclusion: These clinical and experimental evidence, combined with the favorable outcome of a clinical trial with N-Acetyl Cysteine, a GSH precursor, on both the negative symptoms (Berk et al., submitted) and the mismatch negativity in an auditory oddball paradigm supported the proposal that a GSH synthesis impairment of genetic origin represent, among other factors, one major risk factor in schizophrenia.

Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents : a role for long-term prevention of infective endocarditis in humans?

BACKGROUND: Infective endocarditis (IE) mostly occurs after spontaneous low-grade bacteremia. Thus, IE cannot be prevented by circumstantial antibiotic prophylaxis. Platelet activation following bacterial-fibrinogen interaction or thrombin-mediated fibrinogen-fibrin polymerization is a critical step in vegetation formation. We tested the efficacy of antiplatelet and antithrombin to prevent experimental IE. METHODS: A rat model of experimental IE following prolonged low-grade bacteremia mimicking smoldering bacteremia in humans was used. Prophylaxis with antiplatelets (aspirin, ticlopidine [alone or in combination], eptifibatide, or abciximab) or anticoagulants (antithrombin dabigatran etexilate or anti-vitamin K acenocoumarol) was started 2 days before inoculation with Streptococcus gordonii or Staphylococcus aureus. Valve infection was assessed 24 hours later. RESULTS: Aspirin plus ticlopidine, as well as abciximab, protected 45%-88% of animals against S. gordonii and S. aureus IE (P < .05). Dabigatran etexilate protected 75% of rats against IE due to S. aureus (P < .005) but failed to protect against S. gordonii (<30% protection). Acenocoumarol was ineffective. CONCLUSIONS: Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.

The interior designer : Can the physiological agents of homeostasis create the appearance of design in nature?

Review of the book: The Tinkerer's Accomplice: How Design Emerges From Life Itself by J. Scott TurnerHarvard University Press: 2007. 304 pp.

Allergo-immunologie. 2. Faut-il se méfier des agents biologiques [Allergy-immunology. Do we have to be afraid of biological agents?].

Biologicals are now fully part of our daily therapeutic strategies. However, even if their high specificity seems to induce less risk compared to older or classical immunosuppressive drugs, there are not harmless especially regarding infectious but also immunological and allergic issues. Recent attempts to better characterize the different types of reactions to biologicals should be reported, allowing us better understanding of the risk to maintain these therapies or defining how to improve the methods to use them.

A Structural Analysis of the Health Expenditures and Portfolio Choices of Retired Agents

Richer and healthier agents tend to hold riskier portfolios and spend proportionally less on health expenditures. Potential explanations include health and wealth effects on preferences, expected longevity or disposable total wealth. Using HRS data, we perform a structural estimation of a dynamic model of consumption, portfolio and health expenditure choices with recursive utility, as well as health-dependent income and mortality risk. Our estimates of the deep parameters highlight the importance of health capital, mortality risk control, convex health and mortality adjustment costs and binding liquidity constraints to rationalize the stylized facts. They also provide new perspectives on expected longevity and on the values of life and health.

The expressions of GABA and glutannate transporters are altered in the spared nerve injury model of neuropathic pain in the rat

Neuropathic pain is a common form of chronic pain, and is unsuccessfully alleviated by usual medications. Mounting evidence strongly point at non-neuronal glial cells in the spinal cord as key actors behind the persistence of pain. In particular, a change in the astrocytic capacity to regulate extracellular concentrations of neurotransmitters might account for the strengthened spinal nociceptive neurotransmission. Therefore, we investigated whether spinal expressions of GABA (GAT) and glutamate (EAAT) transporters were affected in the spared nerve injury (SNI) rat model of neuropathic pain. SNI was induced in male Sprague-Dawley rats by a unilateral section of tibial and common peroneal branches of the sciatic nerve, leaving the sural branch untouched. Western-blot analysis was performed to study the expression of GAT-1 and GAT-3 as well as EAAT-1 and EAAT-2, the main astrocytic GABA and glutamate transporters respectively. Seven days post-surgery, a significant increase in GAT-1, GAT-3 and EAAT-1 expressions is detected in both ipsilateral and contralateral sides of lumbar spinal cord in comparison to sham animals. No change in EAAT-2 signal could be detected. Furthermore, the astrocytic reaction parallels the glutamate and GABA transporters changes as we found an increased GFAP expression compared to the sham condition, in both spinal sides. Together, our results indicate that modifications in GABA and glutamate transport may occur along with SNI-associated painful neuropathy and identify spinal neurotransmitter reuptake machinery as a putative pharmacological target in neuropathic pain.

Immunosuppresseurs: usages systémiques et neurologiques [Systemic and neurological uses of immunosuppressive agents].

Involvement of the central or peripheral nervous system, frequently present in systemic inflammatory immune disorders, has to be considered a severe threat and requires aggressive immunosuppressive treatment to achieve rapid remission. This is usually obtained with high-dose systemic corticosteroids combined with cyclophosphamide. Once remission is obtained, immunosuppressive agents with a more favorable safety profile are needed to exert a corticosteroid-sparing effect and minimize adverse events. New therapeutic approaches are currently developed to treat autoimmune diseases, mostly linked to the definition of new indications for biological agents such as TNF-alpha antagonists and rituximab.

Disease activity in rheumatoid arthritis patients at initiation of biologic agents and 1 year of treatment: results from the Swiss SCQM registry.

OBJECTIVE: In Switzerland, the prescription of biologic antirheumatic agents in rheumatoid arthritis (RA) patients is not limited by stringent requirements from health authorities. The goals of this study were to: determine the characteristics of the Swiss patients at the initiation of biologics, compare them with other countries and evaluate whether different disease activity levels at initiation of therapy, resulting from distinct access to these treatment, influence their effectiveness. METHODS: This is a retrospective cohort study of RA patients followed in the Swiss register (SCQM-RA). Two thousand and sixty patients treated with biologics were retrieved. We present the disease characteristics and the patients' demographic data, at initiation and some effectiveness data after 1 year of treatment. RESULTS: Two thousand and sixty patients treated with biologics were retrieved. At initiation of treatment, the mean disease activity DAS (SD): 4.4 (1.4), number of previous antirheumatic treatments: 1.1, functional status HAQ: 1.1 (0.7) and median duration of illness: 5.5 years were significantly lower than in other published registries. The mean DAS: 3.3 (1.4) 1 year after initiation of therapy also appears lower than in other countries. Additionally, patients treated more recently (after 2005) had a significantly higher improvement in mean DAS. CONCLUSIONS: Data from the Swiss RA registry demonstrate that biologics are prescribed at a lower level of disease activity and after fewer prior DMARD failures than in most other countries, a practice that seems to correlate with overall lower absolute levels of disease activity and better patient outcomes after 1 year of treatment.

Novel Agents Targeting the IGF-1R/PI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma.

The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for cancer cell proliferation and is known to be frequently altered and activated in neoplasia, including embryonal tumors. Based on the high frequency of alterations, targeting components of the PI3K signaling pathway is considered to be a promising therapeutic approach for cancer treatment. Here, we have investigated the potential of targeting the axis of the insulin-like growth factor-1 receptor (IGF-1R) and PI3K signaling in two common cancers of childhood: neuroblastoma, the most common extracranial tumor in children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastoma cells with R1507, a specific humanized monoclonal antibody against the IGF-1R, we could observe cell line-specific responses and in some cases a strong decrease in cell proliferation. In contrast, targeting the PI3K p110α with the specific inhibitor PIK75 resulted in broad anti-proliferative effects in a panel of neuro- and medulloblastoma cell lines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumor cells after treatment with PIK75 or R1507. Together, our studies demonstrate the potential of targeting the IGF-1R/PI3K signaling axis in embryonal tumors. Hopefully, this knowledge will contribute to the development of urgently required new targeted therapies for embryonal tumors.

Agents and intermediaries

Managing Football is the first book to directly respond to the rapid managerial, commercial and global development of the sport and offers a thorough analysis of how the football industry can meet the challenges that flow from these developments. Expertly edited by two well known specialists in football business management, it draws together the work of a world-class contributor team to form a comprehensive analysis of the most important issues facing the managers of football businesses across the world. The cutting edge analysis examines all the important business challenges in the football industry and the management of football businesses and covers all of the key football markets including England, Spain, France, Italy, Germany, Australia, North America, China, South Africa, South Korea, the Netherlands & Belgium, and Mexico. Managing Football is simply a must-read for anyone studying or working in football business management and is set to be an important landmark in this rapidly moving and globally expansive field.