Redox dysregulation, neurodevelopment, and schizophrenia.

In schizophrenia, a developmental redox dysregulation constitutes one 'hub' on which converge genetic impairments of glutathione synthesis and environmental vulnerability factors generating oxidative stress. Their timing at critical periods of neurodevelopment could play a decisive role in inducing impairment of neural connectivity and synchronization as observed in schizophrenia. In experimental models, such redox dysregulation induces anomalies strikingly similar to those observed in patients. This is mediated by hypoactive NMDA receptors, impairment of fast-spiking parvalbumin GABA interneurons and deficit in myelination. A treatment restoring the redox balance without side effects yields improvements of negative symptoms in chronic patients. Novel interventions based on these mechanisms if applied in early phases of the disease hold great therapeutic promise.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.

Agonistes de neurotrofines com a teràpia neuroprotectora per la Esclerosi Múltiple

Les neurotrofines son factors tròfics que poden induir la supervivencia, la diferenciació i el creixement de les neurones i aquesta és la principal raó per la qual les estudiem en el context de les malalties neurológiques. Les propietats nombrades son crucials per a la cerca d’efectes funcionals pel que fa a tractaments de malalties neurológiques. Avui en dia. donada la seva activitat neuroprotectora, s’ha intentat l’administració extena de neurotrofines com una terapia per diverses enfermetats cerebrals, pero fins ara han tingut poc o cap resultat donada la inhabilitat d’aquestes molècules per creuar la barrera hematoencefàlica i pels seus efectes secondaris, com ara el dolor neuroilogic. Per això, l’aplicació de petites molècules similars a les neurotrofines es considerada com unapossible sol•lució com un possible tractament neuroprotector amb el cervell com a diana. L’objectiu principal d’aquest projecte és testar l’eficacia d’un compost replicant de la neurotrofina pel tractament de algunes enfermetats neurològiques i per a estudiar el mecanisme d’acció d’aquesta molècula. Els resultats obtinguts fins al moment mostren que hem desenvolupat e identificat un compost replicant de la neurotrofina (G79) que manté la seva capacitat com a factor de creixement nerviós (NGF) en un assaig funcional d’NGF (diferenciació i tests de supervivència). A més a més, hem obtingut una proba de concepte per a la eficacia d’aquest compost com un agent terapèutic en diversos models in vivo e in vitro d’Esclerosi Múltiple, glaucoma, enfermetat de Parkinson y Esclerosi Lateral Amiotrófica. En conclusió, els resultats obtinguts durant aquests dos anys suggereixen que la molècula replicant d’NGF G79 és un bon candidat per a ser desenvolutat com a part d’una estratégica terapeutica la diferenciació neuronal, promou la supervivència, activa la fosforilització de TrkA i TrkB, vies de senyalització específiques de la neurotrofina. Aquesta molècula ademés pot creuar la barrera hematoencefàlica per vies de transport actiu, millora el score clínic en animals infectats per Encefalomielitis Autoinmune Experimental, protegeix les cèlules gangliars retinals en el model in vivo de Glaucoma, promou la supervivència de les cèlules en els models in vitro de l’enfermetat de Parkinson i en ELA. En resum, els nostres resultats sugereixen que les molècules replicants de neurotrofina poden desenvoluparse com part d’una estratègia terapéutica neuroprotectora.

Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis.

BACKGROUND AND STUDY AIMS: Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn's disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model. METHODS: The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm (2); delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4 (+) T cells, percentage of apoptotic CD4 (+) T cells, body weight, and systemic side effects were evaluated. RESULTS: LDPDT improved the MEIC ( P = 0.011) and the histological score ( P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 ( P = 0.042), interleukin-17 ( P = 0.029), and interferon-gamma ( P = 0.014), decreased the number of mucosal CD4 (+) T cells, and increased the percentage of apoptotic CD4 (+) T cells compared with the disease control group. No local or systemic side effects occurred. CONCLUSION: LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4 (+) T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.

Cytokine targeting in tumors using a bispecific antibody directed against carcinoembryonic antigen and tumor necrosis factor alpha.

The use of tumor necrosis factor alpha (TNFalpha) in cancer therapy is limited by its short circulatory half-life and its severe systemic side effects. To overcome these limitations, we evaluated the capability of a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and human TNFalpha to target this cytokine in tumors. A BAb was constructed by coupling the Fab' fragments from an anti-CEA monoclonal antibody (MAb) to the Fab' fragments from an anti-TNFalpha MAb via a stable thioether linkage. The double specificity of the BAb for CEA and TNFalpha was demonstrated using a BIAcoreTM two-step analysis. The affinity constants of the BAb for CEA immobilized on a sensor chip and for soluble TNFalpha added to the CEA-BAb complex were as high as those of the parental MAbs (1.7 x 10(9) M-1 and 6.6 x 10(8) M-1, respectively). The radiolabeled 125I-labeled BAb retained high immunoreactivity with both CEA and TNFalpha immobilized on a solid phase. In nude mice xenografted with the human colorectal carcinoma T380, the 125I-labeled BAb showed a tumor localization and biodistribution comparable to that of 131I-labeled anti-CEA parental F(ab')2 with 25-30% of the injected dose (ID)/g tumor at 24 h and 20% ID/g tumor at 48 h. To target TNFalpha to the tumor, a two-step i.v. injection protocol was used first, in which a variable dose of 125I-labeled BAb was injected, followed 24 or 48 h later by a constant dose of 131I-labeled TNFalpha (1 microg). Mice pretreated with 3 microg of BAb and sacrificed 2, 4, 6, or 8 h after the injection of TNFalpha showed a 1.5- to 2-fold increased concentration of 131I-labeled TNFalpha in the tumor as compared to control mice, which received TNFalpha alone. With a higher dose of BAb (25 microg), mice showed a better targeting of TNFalpha with a 3.2-fold increased concentration of 131I-labeled TNFalpha in the tumor: 9.3% versus 2.9% ID/g in control mice 6 h after TNFa injection. In a one-step injection protocol using a premixed BAb-TNFalpha preparation, similar results were obtained 6 h postinjection (3.5-fold increased TNFalpha tumor concentration). A longer retention time of TNFalpha was observed leading to an 8.1-fold increased concentration of TNFalpha in the tumor 14 h postinjection (4.4 versus 0.5% ID/g tumor for BAb-treated and control mice, respectively). These results show that our BAb is able, first, to localize in a human colon carcinoma and, there, to immunoabsorb the i.v.-injected TNFalpha, leading to its increased concentration at the tumor site.

Développement de l'irrigation et évolution des régimes fonciers dans la région de Gaya (Niger)

Since the mid 90's, international actors as well as governmental actors have raised their interest into the development of irrigation's potential that is still largely unexploited in Niger. It seems all the more interesting as it could answer the needs of a fast growing population (3.3% per year). However, if everyone agrees on the need to development this system, the current implementation triggers questions on the process itself and its side effects. National and international policies on this matter were build upon an historical process through colonial, post-colonial and then the late 1980's neoliberal structures, leading to a business model that reveals a discrepancy between the state logic and the farming one. This business model asks for a high capacity of mobilization of resources unachievable for many, especially when they want to address small-scale irrigation (area -2ha). This research aims at exploring the linkage between the small-scale irrigation and the evolution of land tenure systems. The empirical analysis raise three main questions that concern the issue of secure land rights through the modern law, the commoditization of land and land access for the producers. The department of Gaya has a large potential of accessible water resources that allowed an extensive production of fruits and vegetables since the 1980's. These productions were developed at first by the local farmers, but the high value added engendered then attracted external players as well, such as civil servants and merchants. The World Bank supported this momentum through the development of a business type project. Unfortunately, it reached mostly the new external players and local elites rather than the small farmers, notably due to the high illiteracy rate among farmers. In terms of land tenure analysis, the project excluded all farmers cultivating land on a loan or lease agreement and all those for whom it was difficult to obtain a title of ownership. However, this new interest for small-scale irrigation exerted by the project and the new players triggered the commoditization of land. As a matter of fact, the demographic constraints and the fragmentation of the familial land ownership led to a more individual production system, where the customary relation to land tenure is weakened or even overcome. This makes it easier for the new players who need to settle their small-scale irrigation projects to purchase land. When there are only few areas available for selling, the. purchasing processes are undermining the farmers with insecure rights. If the withdrawal of lands is supposed to be smoothened by social measures, such as replacement of the land and primary offers to purchase the land, those measures are often not attractive. The proposed land of replacement is frequently too far away located or lesser fertile to be of any use and the economic capacity of purchasing is too little, eventually leading the farmers to leave their terroirs. Those in charge of the application of the Rural Code have succeeding in answering the need of written secured land tenure, but have difficulty to meet the challenge of doing the same to secure rights for farmers with loans or lease agreements. The small-scale irrigation could bring an answer for their financial needs to buy the land, but it would require mobilizing resources to invest or an easier access to supportive projects. The economic benefice from small-scale irrigation is now widely recognized, but we have to take also into account the risks of marginalization of part of the small farmers. For a more widely spread exploitation of small-scale irrigation, the mechanism of land regulation as well as the process to access the financial and technical support of projects must be revised in order to reach more small farmers. Développement de l'irrigation et évolution des régimes fonciers dans la région de Gaya (Niger) - Le secteur de l'irrigation a bénéficié d'un regain d'intérêt de la part des acteurs internationaux du développement et de l'Etat nigérien depuis le milieu des années 1990. Cet intérêt est à la hauteur du potentiel en terres irrigables (300Ό00 ha environ) du pays, largement sous-exploité alors que les besoins alimentaires sont grandissants, la population augmentant de 3.3% par an. Si le diagnostic est correct, les stratégies mises en oeuvre en matière d'irrigation posent question. Les interventions, aussi bien publiques qu'internationales, reposent sur un modèle entrepreneurial qui parachève une longue trajectoire historique. Initiée par l'Etat colonial, poursuivie par l'Etat post-colonial et transformé par les politiques néolibérales des années 1980, elle se caractérise par un hiatus constant entre logiques étatiques et logiques paysannes. En matière de petite irrigation privée (surfaces < 1-2 ha, technologies à faible coût), ce modèle présuppose une mobilisation de ressources (économiques, sociales, éducationnelles et foncières) inégalement réparties au sein de la population rurale. Cette recherche s'est intéressée à expliciter les liens qui existent entre le développement de la petite irrigation privée et l'évolution des régimes fonciers. Les trois questionnements qui ont guidé l'analyse empirique portent sur la sécurisation foncière, les dynamiques de marchandisation de la terre et l'accès à la terre pour tous les producteurs. Le Département de Gaya dispose d'un potentiel très important en ressources hydriques, facilement mobilisables. Les productions maraîchères et fruitières ont connu un essor très important à partir des années 1980. Initialement pratiquées par les cultivateurs, elles ont progressivement attiré l'attention d'acteurs externes au monde rural (fonctionnaires, commerçants), du fait de leur haute valeur ajoutée. La Banque mondiale a fortement soutenu cette dynamique à travers un projet à vocation entrepreneuriale, qui s'est pourtant révélé hors de portée de la majorité des petits paysans et a principalement bénéficié à ces acteurs extra-ruraux ainsi qu'à certaines élites locales. Au plan foncier, il a en particulier exclu tous les emprunteurs des terres, qui ne sont pas à même de produire des documents écrits confirmant leurs droits sur la terre. Ce projet, et plus largement l'intérêt que les acteurs extra-ruraux portent à la petite irrigation, ont contribué à alimenter la marchandisation de la terre. Sans ancrage familial dans les terroirs villageois, ces acteurs sont obligés d'acheter la terre pour faire de l'irrigation. Leur demande vient s'inscrire dans un contexte général où la pression démographique et le morcellement successif des capitaux fonciers familiaux ont progressivement individualisé la relation entre les producteurs et la terre, au point d'affaiblir ou de faire tomber les interdits coutumiers en matière de vente. Dans les espaces disposant de faibles réserves foncières, les ventes se font principalement au détriment des acteurs qui, comme les emprunteurs, disposent de droits fonciers peu stables et sécurisés. Si le retrait de la terre est socialement encadré (terre en remplacement, possibilité d'acheter la terre qui va être vendue), il pose également des contraintes agronomiques (sols de moindre qualité) et économiques (nécessité de disposer des liquidités pour racheter la terre) qui peuvent, en dernier ratio, obligent les acteurs concernés à quitter les terroirs. Les instances du Code rural, qui ont su apporter des réponses satisfaisantes à la demande de sécurisation foncière par l'établissement de documents écrits, rencontrent aujourd'hui de grandes difficultés à en faire de même pour les droits de prêt. Dans ce contexte, l'irrigation peut apporter les sommes nécessaires à l'achat des terres. Encore faut-il que ces emprunteurs disposent des ressources financières propres pour la développer ou qu'ils puissent y avoir accès grâce à l'appui d'un projet. Si l'intérêt économique de la petite irrigation privée est indiscutable, les risques de marginalisation d'une partie de producteurs ruraux qu'elle peut produire sont bien réels. Pour en faire une activité accessible au plus grand nombre, il faut revoir les mécanismes de régulation foncière, ainsi que les montages techniques et financiers qui supportent le développement de ce secteur d'activité très prometteur.

Renal failure after high-dose methotrexate in a child homozygous for MTHFR C677T polymorphism

We report the case of an 11-year-old female treated for mediastinal T-cell lymphoma who presented renal failure following the second cycle of high-dose methotrexate (HDMTX). Because of life threatening plasma methotrexate (MTX) levels, carboxypeptidase G2 (CPDG2) was administered resulting in a dramatic decrease within 1 hr. The patient recovered from renal failure and no other side effects were observed. Homozygosity for the methylentetrahydrofolate reductase (MTHFR) C677T polymorphism diagnosed by molecular genetic analysis was the only explanation for this toxicity.

Propranolol in infantile haemangioma: simplifying pretreatment monitoring.

BACKGROUND: Infantile haemangiomas (IHs) are very common vascular tumours. Propranolol is at present the first-line treatment for problematic and complicated haemangioma. In accordance with a Swiss protocol, children are monitored for 2 days at the start of the treatment to detect possible side effects of this drug. Our study advocates a simplification of the pretreatment monitoring process. METHODS: All children with a problematic and complicated haemangioma treated with propranolol between September 2009 and September 2012 were included in the study. All patients were hospitalised under constant nurse supervision for 48 hours at the start of the treatment and subjected to cardiac and blood measurements. The dosage of propranolol was 1 mg/kg/day on the first day and 2 mg/kg/day from the second day. Demographic data, clinical features, treatment outcome and complications were analysed. RESULTS: Twenty-nine infants were included in our study. Of these, 86.2% responded immediately to the treatment. There were no severe adverse reactions. Six patients presented transient side effects such as bradycardia, hypotension after the first dose and hypoglycaemia later. No side effects occurred after the second dose. Treatment was never interrupted. CONCLUSION: Propranolol (a β-blocker) is a safe treatment for problematic IH. Side effects may occur after the first dose. A strict 48 hour monitoring in hospital is expensive and may be unnecessary as long as the contraindications for the drug are respected.

Randomized controlled trial of olanzapine or chlorpromazine as addition to lithium in the treatment of a first manic episode with psychotic features: an 8-week, flexible dose, single-blind trial

Background: Association of mood stabiliser and antipsychotic medication is indicated in psychotic mania, but specific guidelines for the treatment of a first episode of psychotic mania are needed. Aims: To compare safety and efficacy profiles of chlorpromazine and olanzapine augmentation of lithium treatment in a first episode of psychotic mania. Methods: A total of 83 patients were randomised to either lithium + chlorpromazine or lithium + olanzapine in an 8-week trial. Data was collected on side effects, vital signs and weight modifications, as well as on clinical variables. Results: There were no differences in the safety profiles of both medications, but patients in the olanzapine group were significantly more likely to have reached mania remission criteria after 8 weeks. Mixed effects models repeated measures analysis of variance showed that patients in the olanzapine group reached mania remission significantly earlier than those in the chlorpromazine group. Conclusions: These results suggest that while olanzapine and chlorpromazine have a similar safety profile in a cohort of patients with first episode of psychotic mania, the former has a greater efficacy on manic symptoms. On this basis, it may be a better choice for such conditions.

Quality of life transformations before and after kidney transplantation: A prospective qualitative study.

The aim of this IRB-approved study was to analyze prospectively quality of life (QOL) and psychological changes in 30 ESRD patients before and after kidney transplantation (KT). Semi-structured interviews were conducted after inclusion on the waiting list (A). Follow-up interviews were performed 6 months later with patients still awaiting KT (B6, n= 15), and with transplant recipients 6, 12 and 24 months after KT (C6, n=15; C12, n=15; C24, n=14). Qualitative thematic analysis was performed. A: All patients reported loss of freedom, 87% tried to maintain normality; 57% modified medical directives. All mentioned emotional fragility, negative thoughts (43%), and suicidal thoughts (20%) related to loss of QOL from dialysis (D), and professional tension (26%). B6: 40% reported no change compared to baseline, while 60% mentioned increase of illness intrusiveness, 46% D side effects, 40% communication problems, and 33% concerns about the waiting list handling. Fear of emotional breakdown (40%), couple problems (47%), and worsened professional difficulties (20%) were reported. C6: All patients reported recovery of QOL and concerns about acute rejection. 73% were anxious about laboratory results. 93% felt dependent on immunosuppressants (IS), 47% reported difficulties coping with their regimen, and 47% were concerned about side effects; 67% had resumed work, but medical constraints led 40% to professional stigmatization. C12: All enjoyed good QOL. Adherence to IS was mandatory (100%). All were aware of the limited long-term graft survival and 47% anxious about a possible return to D. 60% underlined positive life value; 47% resumed a full time job; 40% were on social security. C24: Good QOL was underlined (86%). Patients stated they would prefer re-TX to resuming D (71%). Post-TX health problems were mentioned (64%); increase of creatinine levels induced fear (36%). 79% complained about side effects. 64% reported changes in life values. This study reveals positive QOL and psychological transformations after KT, which are associated with positive changes related to graft survival and freedom from D. Psychological follow-up should be offered to patients who face relapsing ESRD or post-TX co-morbidities.

Upregulation of vasopressin V1A receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment.

1. The major side effects of the immunosuppressive drug cyclosporin A (CsA) are hypertension and nephrotoxicity. It is likely that both are caused by local vasoconstriction. 2. We have shown previously that 20 h treatment of rat vascular smooth muscle cells (VSMC) with therapeutically relevant CsA concentrations increased the cellular response to [Arg8]vasopressin (AVP) by increasing about 2 fold the number of vasopressin receptors. 3. Displacement experiments using a specific antagonist of the vasopressin V1A receptor (V1AR) showed that the vasopressin binding sites present in VSMC were exclusively receptors of the V1A subtype. 4. Receptor internalization studies revealed that CsA (10(-6) M) did not significantly alter AVP receptor trafficking. 5. V1AR mRNA was increased by CsA, as measured by quantitative polymerase chain reaction. Time-course studies indicated that the increase in mRNA preceded cell surface expression of the receptor, as measured by hormone binding. 6. A direct effect of CsA on the V1AR promoter was investigated using VSMC transfected with a V1AR promoter-luciferase reporter construct. Surprisingly, CsA did not increase, but rather slightly reduced V1AR promoter activity. This effect was independent of the cyclophilin-calcineurin pathway. 7. Measurement of V1AR mRNA decay in the presence of the transcription inhibitor actinomycin D revealed that CsA increased the half-life of V1AR mRNA about 2 fold. 8. In conclusion, CsA increased the response of VSMC to AVP by upregulating V1AR expression through stabilization of its mRNA. This could be a key mechanism in enhanced vascular responsiveness induced by CsA, causing both hypertension and, via renal vasoconstriction, reduced glomerular filtration.

Valeur prédictive de la surexpression/ amplification de Her2/neu pour un traitement ciblé du cancer du sein [Predictive value of Her2/neu expression/amplification for the targeted treatment of breast cancer]

Her2/neu is a tyrosine kinase receptor which stimulates cell growth. The receptor is overexpressed in about 20% of breast cancers. Her2/neu expression is an indicator of poor prognosis but also the target of the treatment of breast cancer using humanised anti-Her2/ neu antibodies. Only cancers overexpressing the protein will respond to this therapy, but which has significant (cardiac) side effects and is expensive. It is therefore important to test for the overexpression of the protein on breast cancer cells. This paper discusses how this can be done and ongoing research into new therapeutic options targeting the involved signaling pathways.

Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz.

Objective: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. Methods: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). Results: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R,S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. Conclusions: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART.

Rhumatologie. Une nouvelle option thérapeutique dans la prise en charge de l'inflammation chronique en rhumatologie: les inhibiteurs des janus kinases [A new therapeutical option for chronic inflammation in rheumatology: janus kinases inhibitors (JAK)].

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Smoked cannabis and doping control: looking for the wrong target analyte?

Introduction: Since 2004, cannabis is prohibited by the World Anti-Doping Agency (WADA) for all sports in competition. In the years since then, about half of all positive doping cases in Switzerland have been related to cannabis consumption. In most cases, the athletes plausibly claim to have consumed cannabis several days or even weeks before competition and only for recreational purposes not related to competition. In doping analysis, the target analyte in urine samples is 11-nor-delta-9-tetrahydrocannabinol- 9-carboxylic acid (THC-COOH), the reporting threshold for laboratories is 15 ng/mL. However, the wide detection window of this long-term THC metabolite in urine does not allow a conclusion concerning the time of consumption or the impact on the physical performance. Aim: The purpose of the present pharmacokinetic study on volunteers was to evaluate target analytes with shorter urinary excretion time. Subsequently, urines from athletes tested positive for cannabis should be reanalyzed including these analytes. Methods: In an one-session clinical trial (approved by IRB, Swissmedic, and Federal Office of Public Health), 12 healthy, male volunteers (age 26 ± 3 yrs, BMI 24 ± 2 kg/m2) with cannabis experience (> once/month) smoked a Cannabis cigarette standardized to 70 mg THC/cigarette (Bedrobinol® 7%, Dutch Office for Medicinal Cannabis) following a paced-puffing procedure. Plasma and urine was collected up to 8 h and 11 days, respectively. Total THC, 11-hydroxy-THC (THC-OH), and THC-COOH were determined after enzymatic hydrolyzation followed by SPE and GC/MS-SIM. The limit of quantitation (LOQ) for all analytes was 0.1 ng/mL. Visual analog scales (VAS) and vital functions were used for monitoring psychological and somatic side-effects at every timepoint of specimen collection (up to 480 min). Results: Eight puffs delivered a mean THC dose of 45 mg. Mean plasma levels of total THC, THC-OH and THC-COOH were measured in the range of 0.1-20.9, 0.1-1.8, and 1.8-7.5 ng/mL, respectively. Peak concentrations were observed at 5, 10, and 90 min. Mean urine levels were measured in the range of 0.1-0.7, 0.10-6.2, and 0.1-13.4 ng/mL, respectively. The detection windows were 2-8, 2-96, and 2-120 h. No or only mild effects were observed, such as dry mouth, sedation, and tachycardia. Besides high to very high THC-COOH levels (0-978 ng/mL), THC (0.1-24 ng/mL) and THC-OH (1-234 ng/mL) were found in 90 and 96% of the cannabis-positive urines from athletes. Conclusion: Instead of or in addition to THC-COOH, the pharmacologically active THC and THC-OH should be the target analytes for doping urine analysis. This would allow the estimation of more recent Cannabis consumption, probably influencing performance during competition. Keywords: cannabis, doping, clinical trial, plasma and urine levels, athlete's samples