Codeine accumulation and elimination in larvae, pupae, and imago of the blowfly Lucilia sericata and effects on its development.

The aim of this study was to evaluate the reliability of insect larvae as samples for toxicological investigations. For this purpose, larvae of Lucilia sericata were reared on samples of minced pig liver treated with different concentrations of codeine: therapeutic, toxic, and potentially lethal doses. Codeine was detected in all tested larvae, confirming the reliability of these specimens for qualitative toxicology analysis. Furthermore, concentrations measured in larvae were correlated with levels in liver tissue. These observations bring new elements regarding the potential use of opiates concentrations in larvae for estimation of drug levels in human tissues. Morphine and norcodeine, two codeine metabolites, have been also detected at different concentrations depending on the concentration of codeine in pig liver and depending on the substance itself. The effects of codeine on the development of L. sericata were also investigated. Results showed that a 29-h interval bias on the evaluation of the larval stage duration calculated from the larvae weight has to be considered if codeine was present in the larvae substrate. Similarly, a 21-h interval bias on the total duration of development, from egg to imago, has to be considered if codeine was present in the larvae substrate.

Nouvelles armes thérapeutiques contre le mélanome de stade IV [New therapeutic weapons in stage IV melanoma].

The treatment of stage IV melanoma has been revolutionized over the last years with the development of immunotherapies that, for the first time, have shown a significant benefit in overall survival, as well as with extremely effective targeted therapies, that also led to improved survival. These results are the fruits of an important translational research effort that allowed a rational approach with a very fast clinical development. The treatment of metastatic melanoma is, therefore, an illustration of the new paradigms of modern molecular research in oncology. In this review, we will present the various agents that have made the proof of their clinical benefit, as well as the scientific discoveries that allowed their development. Some of the remaining questions will be touched upon with the ongoing clinical trials. Inclusion of patients in these studies remains the top priority to improve on the clinical care.

Biases on the administered parenteral doses of an experimental drug during phase I clinical trials

Introduction: The pharmaceutical aspects of drug administration in clinical trials receive poor consideration compared with the important attention devoted to the analytical and mathematical aspects of biological sample exploitation. During PK calculations, many researchers merely use for dose the nominal amount declared, overlooking the noticeable biases that may result in the assessment of PK parameters. The aim of this work was to evaluate the biases related to doses injected of a biosimilar drug in 2 Phase I clinical trials. Patients (or Materials) and Methods: In trial A, 12 healthy volunteers received different doses of a biosimilar of interferon beta-1a by either subcutaneous (SC) or intravenous (IV) injection. The doses were prepared by partially emptying 0.5-mL syringes supplied by the manufacturer (drop count procedure). In trial B, 12 healthy volunteers received 3 different formulations of the drug by IV injection (biosimilar without albumin [HSA], biosimilar with HSA and original brand [Rebif®]) and 2 different formulations as multiple SC injections (biosimilar HSA-free and original brand). In both trials, the actual dose administered was calculated as: D = C·V - losses. The product titer C was assessed by ELISA. The volume administered IV was assessed by weighting. Losses were evaluated by in vitro experiments. Finally, the binding of 125I-interferon to HSA was evaluated by counting the free and HSA complexed molecule fractions separated by gel filtration. Results: Interferon was not significantly adsorbed onto the lines used for its IV administration. In trial A, the titer was very close to the one declared (96 ± 7%). In trial B, it differed significantly (156 ± 10% for biosimilar with/without HSA and 123 ± 5% for original formulation). In trial A, the dose actually administered showed a large variability. The real injected volume could be biased up to 75% compared with the theoretical volume (for the lower dose administered [ie, 0.03 mL]). This was mainly attributed to a partial re-aspiration of the drug solution before withdrawing the syringe needle. A strict procedure was therefore applied in trial B to avoid these inaccuracies. Finally, in trial B, 125I-Interferon beta-1a binding to HSA appeared time dependent and slow, reaching 50% after 16-hour incubation, which is close to steady state reported for the comparator Rebif®. Conclusion: These practical examples (especially biases on actual titer and volume injected) illustrate that actual dose assessment deserves attention to ensure accuracy for estimates of clearance and distribution volume in the scientific literature and for registration purposes, especially for bioequivalence studies.

Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases.

Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.

Produtividade de milho na presença de doses de N e de inoculação de Herbaspirillum seropedicae

Resumo: O objetivo deste trabalho foi avaliar o efeito de nitrogênio e da inoculação de Herbaspirillum seropedicae sobre a produtividade de milho (Zea mays) e os teores de nutrientes nos grãos. Os híbridos simples BRS 1030 e BRS 1060 receberam inoculação da estirpe BR 11417, na presença ou não de doses de adubação nitrogenada, em Argissolo Vermelho-Amarelo distrófico, durante os períodos de entressafra (plantio em maio de 2012) e safra (plantio em outubro de 2012). Em cada época, os seguintes tratamentos foram avaliados: controle absoluto, sem adubação nitrogenada nem inoculação; controle com inoculação; doses de 50 e 100 kg ha-1 de N, sem inoculação; e dose de 50 kg ha-1 de N mais inoculação. BRS 1030 produziu 1.157 kg ha-1 a mais de grãos que BRS 1060, na análise conjunta dos dois cultivos. Para o primeiro genótipo, a dose de 50 kg ha-1 de N, com inoculação, incrementou em 2% a produtividade na entressafra e em 4,5% na safra. A inoculação de H. seropedicae, estirpe BR 11417, favorece o acúmulo de P nos grãos, mas tem efeito positivo sobre a produtividade somente em combinação com doses de N mineral, o que indica que seu efeito é mais destacado na promoção do crescimento do milho do que na fixação biológica de N.

Therapeutic concepts in adult and paediatric eosinophilic oesophagitis.

Eosinophilic oesophagitis (EoE) was first described in the early 1990s. Although initially reported to be a rare entity, EoE has rapidly become a regularly diagnosed disease with a prevalence of approximately 1 in 2,000 individuals in the USA and Europe. The disease is characterized by a combination of oesophageal dysfunction and predominant eosinophilic infiltration of the oesophageal tissue. At diagnosis, other diseases that can be associated with oesophageal eosinophilic infiltration must be ruled out. Children with EoE present with a wide variety of symptoms, whereas adults mostly present with dysphagia for solid food and chest pain. Histologic features of EoE resemble those of T-helper type 2 inflammation. Endoscopy should be carried out to establish the diagnosis, but endoscopic abnormalities are not pathognomonic for EoE and the examination might not show histologic abnormality. Treatment modalities for EoE include drugs (corticosteroids, PPIs, antiallergic and biologic agents), hypoallergenic diets and oesophageal dilatation for strictures that are unresponsive to medical therapy. Unresolved eosinophilic inflammation leads to the formation of oesophageal strictures, which probably increase the risk of food bolus impactions. To date, long-term strategies for the therapeutic management of this chronic inflammatory disease remain poorly defined.

Radiation doses in computed tomography: pitfalls in comparing CT to chest X-ray

Rapid response to : Madan M Rehani and Manorma Berry Radiation doses in computed tomography BMJ 2000; 320: 593-594

Nouvelles approches therapeutiques de l'hypertension arterielle. [New therapeutic approaches to arterial hypertension]

Today two largely new approaches are available for the treatment of clinical hypertension. First, captopril, an orally active angiotensin converting enzyme inhibitor, makes possible chronic blockade of the renin-angiotensin system. This compound, given alone or in combination with a diuretic, normalizes the blood pressure of most hypertensive patients. Unfortunately, because captopril may induce serious adverse effects the use of this inhibitor must be restricted to patients with high blood pressure refractory to conventional antihypertensive drugs. Second, compounds such as verapamil and nifedipine are capable of producing a marked vasodilating effect by inhibiting the entry of calcium into the vascular smooth muscle cells. However, the role of calcium channel blockers in the treatment of hypertensive disease awaits more precise definition.

Therapeutisches Drug-Monitoring in der Psychiatrie : Kurze Zusammenfassung des neuen Konsensuspapiers der Arbeitsgruppe TDM der AGNP [Therapeutic drug monitoring in psychiatry : A brief summary of the new consensus paper by the task force on TDM of the AGNP].

In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries.

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients.

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.

Crescimento de porta-enxertos de citros em tubetes influenciados por doses de N

Este trabalho teve como objetivo avaliar os efeitos de doses de N (0; 400; 800; 1.600; 3.200 e 4.800 mg/dm³ de N no substrato) sobre o crescimento de porta-enxertos de citros cultivados em tubetes. Os porta-enxertos limoeiros-'Cravo' e 'Volkameriano' mostraram maior crescimento, sendo que as tangerineiras-'Cleópatra' e 'Sunki' apresentaram crescimento intermediário, e o híbrido 'Tangelo-Orlando' exibiu crescimento inferior. A adição de doses crescentes de N, utilizando-se do fertilizante uréia em cobertura, promoveu acréscimos nos teores de N-total na matéria seca da parte aérea destes porta-enxertos e aumento no crescimento dos porta-enxertos. Aos 120 dias após a semeadura, o limoeiro-'Cravo' apresentou altura máxima de 13,3 cm quando adubado com 1.240 mg/dm³ de N no substrato, sendo que o limoeiro-'Volkameriano' apresentou altura máxima de 12,3 cm adubado com 1.417 mg/dm³ de N no substrato. A tangerineira-'Cleópatra' apresentou altura máxima estimada de 12,0 cm quando adubada com 1.170 mg/dm³ de N no substrato, sendo que a tangerineira-'Sunki' apresentou altura de 10,1 cm adubada com 1.145 mg/dm³ de N no substrato, aos 120 dias após a semeadura. O híbrido 'Tangelo-Orlando' exibiu altura máxima de 9,1cm quando foi aplicada a dose de 1.117 mg/dm³ de N no substrato, aos 120 dias após a semeadura.

Efeito de doses de NPK sobre os teores de nutrientes nas folhas e no solo, e na produtividade do maracujazeiro amarelo

Objetivou-se avaliar a influência das adubações com nitrogênio, fósforo e potássio nos teores de nutrientes das folhas do maracujazeiro amarelo (Passiflora edulis f. flavicarpa Deg.) e em propriedades químicas do solo, tendo em vista maximizar a produtividade e otimizar a prática da adubação. O experimento foi conduzido no período de maio/96 a abril/98, em Latossolo Amarelo do Município de Cruz das Almas (BA). Empregou-se o delineamento experimental de blocos casualizados, em esquema fatorial fracionado ½ de 4³, com dois blocos incompletos, avaliando-se quatro doses de N (0, 100, 200 e 300 kg ha-1 ano-1), de P2O5 (0, 80, 160 e 240 kg ha-1 ano-1) e de K2O (100, 300, 500 e 700 kg ha-1 ano-1). Amostragens de solo e folhas foram realizadas aos 12 e 24 meses após o plantio, bem como foi avaliada a produtividade no primeiro e no segundo ano. A adubação nitrogenada não influenciou os teores de N na folha, mas diminuiu os de boro e reduziu o pH do solo no segundo ano de cultivo. A adubação fosfatada aumentou, em média, apenas 12% os teores de P nas folhas e 35 vezes no solo. A adubação potássica elevou os teores do nutriente nas folhas do maracujazeiro, e no solo a valores acima do nível ótimo. A produtividade máxima de 22,1 t ha-1, em dois anos de cultivo, foi obtida com a aplicação de 244 kg de N, 72 kg de P2O5 e 285 kg ha-1 de K2O.

Fertirrigação com diferentes doses de NPK e seus efeitos sobre a produção e qualidade de frutos de laranja (Citrus sinensis O.) 'Valência'

O experimento foi realizado na Fazenda Três Irmãos, no município de Pratânia, Estado de São Paulo, com o objetivo de estudar o efeito da fertirrigação com diferentes doses de NPK aplicadas por meio de um sistema de irrigação por microaspersão na cultura da laranja em comparação com a adubação convencional irrigada e não irrigada. A avaliação dos efeitos da irrigação e da fertirrigação na cultura foi feita com base na produção e qualidade dos frutos colhidos, na análise de solo da camada de 0-20 cm e na análise de folhas. Os tratamentos não influenciaram significativamente a produtividade de acordo com a análise estatística realizada, embora se tenha observado uma tendência de maior produtividade nos tratamentos de fertirrigação para uma mesma dose. A análise de qualidade dos frutos não mostrou diferenças significativas entre os tratamentos. Os teores de alguns dos elementos obtidos na análise de solo apresentaram diferenças significativas proporcionadas pela irrigação e/ou modo de aplicação dos fertilizantes à cultura. A análise de folhas diferiu quanto aos teores de Ca, Mg e K.

Resposta de eixos embrionários de cupuaçu (Theobroma grandiflorum Schum.) à concentração de sais, doses de sacarose e renovação do meio de cultivo

Foram estudados os efeitos da concentração de sais, doses de sacarose e freqüência de renovação do meio de cultura para o desenvolvimento de eixos embrionários de cupuaçu (Theobroma grandiflorum Schum.). Testaram-se 2 concentrações de sais MS (100 e 50%), 2 níveis de sacarose (1,5 e 3%) e 3 freqüências de renovação dos meios (sem renovação, renovação aos 30 e aos 60 dias), com os meios acrescidos de ANA (0,5 mg/L) e BAP (0,3 mg/L.), semi-solidificados com ágar 0,7% e pH 5,7. Observou-se que a utilização do meio MS na concentração de sais completa, com a adição de 3% de sacarose e renovações do meio em intervalos de 30 dias, apresentou melhor desenvolvimento dos eixos embrionários.