Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: A randomized controlled trial and experimental animal model of pneumonitis.

INTRODUCTION: Epidemiological studies have reported an association between exposures to ambient air pollution and respiratory diseases, including chronic obstructive pulmonary disease (COPD). Pneumonitis is a critical driving factor of COPD and exposure to air pollutants (e.g., acrolein) is associated with increased incidence of pneumonitis. OBJECTIVES: Currently available anti-inflammatory therapies provide little benefit against respiratory diseases. To this end, we investigated the preventive role of curcumin against air pollutant-associated pneumonitis and its underlying mechanism. METHODS: A total of 40 subjects was recruited from Chengdu, China which is among the top three cities in terms of respiratory mortality related to air pollution. The participants were randomly provided either placebo or curcumin supplements for 2 weeks and blood samples were collected at the baseline and at the end of the intervention to monitor systemic markers. In our follow up mechanistic study, C57BL/6 mice (n = 40) were randomly allocated into 4 groups: Control group (saline + no acrolein), Curcumin only group (curcumin + no acrolein), Acrolein only group (saline + acrolein), and Acrolein + Curcumin group (curcumin + acrolein). Curcumin was orally administered at 100 mg/kg body weight once a day for 10 days, and then the mice were subjected to nasal instillation of acrolein (5 mg/kg body weight). Twelve hours after single acrolein exposure, all mice were euthanized. RESULTS: Curcumin supplementation, with no noticeable adverse responses, reduced circulating pro-inflammatory cytokines in association with clinical pneumonitis as positive predictive while improving those of anti-inflammatory cytokines. In the pre-clinical study, curcumin reduced pneumonitis manifestations by suppression of intrinsic and extrinsic apoptotic signaling, which is attributed to enhanced redox sensing of Nrf2 and thus sensitized synthesis and restoration of GSH, at least in part, through curcumin-Keap1 conjugation. CONCLUSIONS: Our study collectively suggests that curcumin could provide an effective preventive measure against air pollutant-enhanced pneumonitis and thus COPD.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Introduction).

BACKGROUND: The field of new biological agents is increasing exponentially over the past years, thus making prevention and management of associated infectious complications a challenge for nonspecialized clinicians. AIMS: The present consensus document is an initiative of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) aimed at analysing, from an infectious diseases perspective, the safety of targeted and biological therapies. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The document is structured in sections according to the targeted site of action of each drug class: proinflammatory cytokines; interleukins, immunoglobulins and other soluble immune mediators; cell surface receptors and associated signaling pathways; intracellular signaling pathways; lymphoma and leukaemia cells surface antigens; and other targeted therapies. A common outline is followed for each agent: summary of mechanism of action, approved indications and common off-label uses; expected impact on the host's susceptibility to infection; available clinical evidence (i.e. pivotal clinical trials, postmarketing studies, case series and case reports); and suggested prevention and risk minimization strategies. The methodologic and practical difficulties of assessing the specific risk posed by a given agent are also discussed. IMPLICATIONS: This ESGICH consensus document constitutes not only a comprehensive overview of the molecular rationale and clinical experience on the risk of infection associated with approved targeted therapies but also an attempt to propose a series of recommendations with the purpose of guiding physicians from different disciplines into this emerging framework.

Biological Therapies of Immunologic Diseases: Strategies for Immunologic Interventions.

The immune system possesses a vast number of potential targets for therapeutic intervention. Although therapies for many pathways have been pursued, only few have yielded significant success. Hindrances in altering biologic pathways include the potential for unwanted downstream effects, ineffectiveness owing to biological redundancy, recognition of a therapeutic molecule as foreign by the body's innate immune system, and the risks of subsequent malignancy and/or autoimmunity. This article covers currently available biotherapeutic agent classes as well as potential direction for future therapy.

Circadian Rhythm in Cytokines Administration.

In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.

Efeito da suplementação com castanha-do-brasil (Bertholletia excelsa H. B. K) como fonte de selênio sobre os marcadores de estresse oxidativo, citocinas inflamatórias e sua relação com o polimorfismo Pro198Leu no gene da glutationa peroxidase 1 em pacientes com artrite reumatoide / Effect of Brazil-nut supplementation (Bertholletia excelsa HBK) as a source of selenium on markers of oxidative stress, inflammatory cytokines and their relationship with the polymorphism Pro198Leu of glutathione peroxidase-1 gene in patients with rh

A artrite reumatoide (AR) é uma doença inflamatória crônica, caracterizada por inflamação das articulações e se manifesta por inchaço e incapacidade funcional das mesmas. A patologia da doença envolve a produção excessiva de radicais livres pelos neutrófilos ativados, podendo induzir à peroxidação lipídica nas membranas celulares o que leva ao aumento da inflamação. Nesse sentido, o selênio (principal fonte é a castanha-do-brasil) é um importante fator por diminuir a atividade dos hidroperóxidos por meio da ação da enzima antioxidante glutationa peroxidase (GPx). No entanto, estudos que avaliem a associação do estado nutricional relativo ao selênio em pacientes com AR com os biomarcadores do estresse oxidativo e de inflamação são escassos na literatura. Desse modo, a avaliação do efeito potencial in vivo da suplementação com castanha-do-brasil, como fonte de selênio, sobre os parâmetros descritos anteriormente e sua relação com o polimorfismo Pro198Leu no gene da GPx1, em pacientes com artrite reumatoide (AR), vêm a suprir essa lacuna. Inicialmente foi realizada a caracterização da castanha-do-brasil quanto à composição de macronutrientes e teor de selênio. O estudo em pacientes com artrite reumatoide foi de natureza longitudinal. Foram avaliados 46 pacientes com AR, com idade média de 55,2 ± 10,9 anos, atendidos no Setor de Reumatologia da Universidade Federal de São Paulo. O estudo foi dividido em duas fases: antes (T0) e após a suplementação (T1) com 1 nóz de castanha-do-brasil. Foi realizada a avaliação da composição corporal e do consumo alimentar. Além disso, foram avaliados parâmetros bioquímicos relativos ao status de selênio por espectrofotometria de absorção atômica por geração de hidretos; atividades da GPx e SOD com uso de kits comerciais; concentração da GPx1 por kits comerciais, sua expressão gênica (qRT-PCR) e genotipagem do Pro198Leu no referido gene por PCR em tempo real; determinação de 8-isoprostanos por kit comercial, assim como níveis circulantes de fibrinogênio, proteína C reativa, IL-6, IL-10, TNF-α, IL-1ß, IL-2, VCAM, ICAM, PAI-1 e sE-selectina pelo ensaio ELISA. O genótipo selvagem (Pro/Pro) foi observado em 57,63% das participantes; 35,59% para as heterozigotas para o alelo variante (Pro/Leu) e 6,78% apresentaram os dois alelos variantes. As pacientes com artrite reumatoide apresentaram baixa ingestão de selênio e, após a intervenção, o consumo aumentou significantemente. Em relação ao status de selênio, houve um aumento em sua concentração no plasma e eritrócitos após o período de intervenção com castanha-do-brasil, assim como na atividade da GPx, na concentração da GPx1 e em sua expressão gênica. Níveis urinários reduzidos de 8-isoprostano e nenhuma alteração quanto à capacidade antioxidante total plasmática e quanto aos marcadores inflamatórios foram observados após o período de intervenção. Por outro lado, houve um aumento nas concentrações séricas das moléculas de adesão celulares. Portanto, pode-se concluir que a suplementação com castanha-do-brasil mostrou-se efetiva em melhorar o estado nutricional relativo ao selênio dos pacientes e os marcadores de estresse oxidativo, todavia a ingestão de 350 µgSe/dia não foi suficiente para promover uma melhora do quadro inflamatório. Além disso, a presença do polimorfismo Pro198Leu modificou as respostas dos indivíduos CT e TT em relação à suplementação, sendo inferior à dos indivíduos CC

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, manifested by swelling and joint impairment. These pathology involves excessive free radicals production by activated neutrophils leading to lipid peroxidation in cell membranes and increased inflammation. Accordingly, selenium (Brazil-nut as main source) is an important factor reducing hydroperoxides through the improvement of glutathione peroxidase (GPx) activity. However, studies evaluating their association with oxidative stress biomarkers and inflammation in RA patients are scarce. Thus, the assessment of the in vivo potential Brazil nut supplementation on the parameters described above and its relationship to the polymorphism Pro198Leu in GPx1 gene in patients with rheumatoid arthritis, come to fill this gap. First of all, we analysed macronutrients and selenium content in Brazil nut. This is a longitudinal study with 46 RA patients attending rheumatologic treatment at Federal University of São Paulo and whose mean age were 55.2 ± 10.9 years. The present study was carried out by two phases, before and after one Brazil ingestion. We evaluated selenium status by spectrophotometry absorption with hydride generation; body composition, SOD, GPx activites, GPx1 concentration and 8- isoprostane levels, using commercial Kits; gene expression by RT-PCR and genotyping using real time PCR. Besides, inflamatory biomarkers were performed (fibrinogen, C reactive protein, IL-6, IL-10, TNF-α, IL-1ß, IL-2, VCAM, ICAM, PAI-1 e sE-selectin by ELISA. The wild genotype (Pro/Pro) was observed in 57.63% of the participants, 35.59% were heterozygote for variant allele (Pro/Leu) and 6.78% had two variant alleles. Patients with rheumatoid arthritis had low selenium intake and after the intervention, consumption of this element increased significantly. Selenium status increased significantely after Brazil nut ingestion, as well as GPx activity, GPx1concentration and its gene expression. Reduced urinary levels of 8-isoprostane and no change for total plasma antioxidant capacity and markers for inflammation were observed after the intervention period. On the other hand, there was an increase in serum concentrations of cell adhesion molecules. Therefore, it can be concluded that Brazil-nut supplementation proved to be effective in improving selenium status and markers of oxidative stress in RA patients, however ingestion of 350 µgSe/day wasn't enough to ameliorate inflammation. Besides, the presence of Pro198Leu polymorphisms interfere in supllementation response in CT and TT groups, being less responsive than CC ones

Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines.

The flavonoid vitexin (1) is a flavone C-glycoside (apigenin-8-C-ß-D-glucopyranoside) present in several medicinal and other plants. Plant extracts containing 1 are reported to possess antinociceptive, anti-inflammatory, and antioxidant activities. However, the only evidence that 1 exhibits antinociceptive activity was demonstrated in the acetic acid-induced writhing model. Therefore, the analgesic effects and mechanisms of 1 were evaluated. In the present investigation, intraperitoneal treatment with 1 dose-dependently inhibited acetic acid-induced writhing. Furthermore, treatment with 1 also inhibited pain-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), capsaicin (an agonist of transient receptor potential vanilloid 1, TRPV1), and both phases of the formalin test. It was also observed that inhibition of carrageenan-, capsaicin-, and chronic CFA-induced mechanical and thermal hyperalgesia occurred. Regarding the antinociceptive mechanisms of 1, it prevented the decrease of reduced glutathione levels, ferric-reducing ability potential, and free-radical scavenger ability, inhibited the production of hyperalgesic cytokines such as TNF-α, IL-1ß, IL-6, and IL-33, and up-regulated the levels of the anti-hyperalgesic cytokine IL-10. These results demonstrate that 1 exhibits an analgesic effect in a variety of inflammatory pain models by targeting TRPV1 and oxidative stress and by modulating cytokine production.

Similar biological medicinal products currently licensed in the European union--overview of non-clinical study programs.

In the EU, a regulatory framework has been established which defines general conditions for marketing authorisation approval of similar biological medicinal products (SBMPs). In addition, the framework provides product-class specific recommendations for non-clinical evaluation of specific SBMPs containing as active substance recombinant somatropin, granulocyte-colony stimulating factor (G-CSF), erythropoietin, interferon alpha, insulin or low molecular weight heparins. During the last years, a number of SBMPs have been succesfully licensed in the EU. This article summarizes the non-clinical evaluations performed for these medicinal products and provides a comparison with the current requests for non-clinical evaluation as laid down in the respective EU regulatory guidelines.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.

α 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic ß-cells.

α1-antitrypsin (AAT) is a serine protease inhibitor, which recently has been shown to prevent type 1 diabetes (T1D) development, to prolong islet allograft survival and to inhibit ß-cell apoptosis in vivo. It has also been reported that T1D patients have significantly lower plasma concentrations of AAT suggesting the potential role of AAT in the pathogenesis of T1D. We have investigated whether plasma-purified AAT can affect ß-cell function in vitro. INS-1E cells or primary rat pancreatic islets were used to study the effect of AAT on insulin secretion after glucose, glucagon-like peptide-1 (GLP-1) and forskolin stimulation and on cytokine-mediated apoptosis. The secreted insulin and total cyclic AMP (cAMP) were determined using radioimmunoassay and apoptosis was evaluated by propidium iodide staining followed by FACS analysis. We found that AAT increases insulin secretion in a glucose-dependent manner, potentiates the effect of GLP-1 and forskolin and neutralizes the inhibitory effect of clonidine on insulin secretion. The effect of AAT on insulin secretion was accompanied by an increase in cAMP levels. In addition, AAT protected INS-1E cells from cytokine-induced apoptosis. Our findings show that AAT stimulates insulin secretion and protects ß-cells against cytokine-induced apoptosis, and these effects of AAT seem to be mediated through the cAMP pathway. In view of these novel findings we suggest that AAT may represent a novel anti-inflammatory compound to protect ß-cells under the immunological attack in T1D but also therapeutic strategy to potentiate insulin secretion in type 2 diabetes (T2D).

Primate testing of TGN1412: right target, wrong cell.

The failure of toxicity studies in non-human primates to predict the cytokine release syndrome during a first-in-man study of the CD28-specific monoclonal antibody TGN1412 has remained unexplained so far. In this issue of the BJP, work from the NIBSC first identifies the effector memory subset of human T-lymphocytes as the most likely source of the pro-inflammatory cytokines released during the study, and goes on to show that in cynomolgus monkeys, this subset lacks CD28, the target molecule of TGN1412. We discuss the implications for the TGN1412 catastrophe and for preclinical evaluation of biologicals in animal models in general.

Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.

Do the results of the new trials change the standard treatment of metastatic renal cell cancer?

With the emergence of novel angiogenesis inhibitors, we are moving to a new era for patients with metastasized renal cell carcinoma. Since the results achieved reflect more a modification of the natural course of the disease than a cure, past achievements should not be neglected. Low-risk patients with clear cell histology, especially those with pulmonary metastasis only, should still be offered cytokine therapy. For intermediate-risk patients sunitinib is the treatment of choice. For high-risk patients, temsirolimus has to date provided the most convincing data, its availability is however limited. Data with sorafenib and sunitinib in the high-risk group are still anecdotal. The toxicity profiles of these 2 drugs are different and might particularly relate to patients with known cardiovascular co-morbidity. No sufficient data are available regarding sequential use. After cytokine failure, sorafinib is the treatment of choice. Patients should preferably be treated within clinical trials to answer unaddressed questions. It is well known that the strict entry criteria used within the clinical studies were applied very flexibly when drugs have been approved. These aspects require a careful follow-up to ascertain optimal use and to prevent misuse. Finally, the costs of prolonged treatment will be enormous, and only meaningful survival advantages will convince the health authorities to make these new treatments available for all patients.

Cortex cinnamomi extract prevents streptozotocin- and cytokine-induced beta-cell damage by inhibiting NF-kappaB.

AIM: To clarify the mechanism underlying the anti-diabetic activities of cortex cinnamomi extract (CCE). METHODS: To induce in vivo diabetes, mice were injected with streptozotocin (STZ) via a tail vein (100 mg STZ/kg body weight). To determine the effects of CCE, mice were administered CCE twice daily for 7 d by oral gavage starting 1 wk before the STZ injection. Blood glucose and plasma insulin concentration were measured as an index of diabetes. Also, to induce cytotoxicity of RINm5F cells, we treated with cytokines (IL-1beta (2.0 ng/mL) and IFN-gamma (100 U/mL)). Cell viability and nitric oxide production were measured colorimetrically. Inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined by RT-PCR and Western blotting, respectively. The activation of NF-kappaB was assayed by using gel mobility shift assays of nuclear extracts. RESULTS: Treatment of mice with STZ resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of STZ were completely prevented when mice were pretreated with CCE. The inhibitory effect of CCE on STZ-induced hyperglycemia was mediated through the suppression of iNOS expression. In rat insulinoma RINm5F cells, CCE completely protected against interleukin-1beta and interferon-gamma-mediated cytotoxicity. Moreover, RINm5F cells incubated with CCE showed significant reductions in interleukin-1beta and interferon-gamma-induced nitric oxide production and in iNOS mRNA and protein expression, and these findings correlated well with in vivo observations. CONCLUSION: The molecular mechanism by which CCE inhibits iNOS gene expression appears to involve the inhibition of NF-kappaB activation. These results reveal the possible therapeutic value of CCE for the prevention of diabetes mellitus progression.

Cytokines as mediators of depression: what can we learn from animal studies?

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.

Cytokines and major depression.

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Urgosedin inhibits hypotension, hypoglycemia, and pro-inflammatory mediators induced by lipopolysaccharide.

Urgosedin is a newly synthesized compound especially with serotonergic and alpha-adrenergic blocking actions. In rat isolated thoracic aorta, urgosedin competitively antagonized norepinephrine-, clonidine-, and serotonin-induced vasocontractions in a concentration-dependent manner. In radioligand binding experiments, urgosedin had significant binding affinities on alpha1/alpha2, 5-HT1A, 5-HT1B and 5-HT2A receptors. Intravenous injection of lipopolysaccharide (LPS) produced a biphasic hypotension in normotensive rats. Although intravenous injection of urgosedin caused minor depressor actions in the normotensive Wistar rat, urgosedin significantly attenuated the secondary prolonged hypotension produced by LPS. The plasma levels of cytokines (IL-1beta, IL-6, TNF-alpha, and IFN-gamma) and hypoglycemia induced by LPS were also reduced by urgosedin. Moreover, the acute survival rates (350 minutes) of endotoxic shock increased from 0% (LPS group) to 100% in the groups pretreated with urgosedin. In RAW264.7 cells, urgosedin inhibited LPS-induced inducible nitric oxide synthase (iNOS) expression. In conclusion, our data suggest that urgosedin was a newly potent serotonergic and mild alpha-adrenergic blocking agent. Its prevention of LPS-induced hypotension and hypoglycemia might partially mediate through its inhibition activities on the iNOS expression and cytokines formation. Urgosedin might be an effective pharmacological agent against LPS-induced hypotension, hypoglycemia, and the formation of pro-inflammatory mediators.

Recent developments in toxic nephropathy.

Toxic nephropathy is an important cause of reversible renal injury if detected early. Renal damage can be due to several different mechanisms affecting different segments of the nephron, renal microvasculature or interstitium. Clinical signs may not be apparent in the early stages and assessment of renal function should include thorough evaluation of glomerular filtration rate, proximal and distal tubular function. A kidney biopsy may be indicated to establish the cause and effect relationship. The presence of comorbid conditions such as older age, diabetes mellitus, hypertension and congestive heart failure have a significant influence on the patient's ability to recover from the toxic effects. A significant degree of drug-induced renal toxicity is only acceptable if the causative agent is used for the curative treatment of an underlying disease but not if the aim is the palliative or supportive therapy. The decision to reduce the dose or to stop the toxic agent must be based on the ultimate goal of therapy and the patient's baseline health status.

[Development of new chronopharmacotherapies based on biological rhythm].

The mammalian circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). Clock genes are the genes that control the circadian rhythms of physiology and behavior. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. However, many drugs are still administered without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The monitoring of rhythmic markers may be useful in choosing the most appropriate time of day for administration of drugs and may increase their therapeutic effects and/or reduce their side effects. On the other hand, several drugs can cause alterations in 24-h rhythms, leading to illness and altered homeostatic regulation. Here, we show the disruptive effect of interferon on the rhythm of locomotor activity, body temperature, and clock gene mRNA expression in the periphery and SCN. The alteration of the clock function, a new concept of adverse effects, can be overcome by devising a dosing schedule that minimizes adverse drug effects on clock function. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best effective and/or tolerated.

Cytokines and anorexia: a brief overview.

Cytokine immunotherapy with interferon-alpha, interleukin-1, interleukin-2, or tumor necrosis factor-alpha is consistently associated with anorexia and other neurologic and neuropsychiatric manifestations. Preclinical and clinical studies have shown that cytokines induce anorexia when administered peripherally or into the brain. Cytokine-induced anorexia involves both peripheral and central nervous system mechanisms. Cytokines modulate gastrointestinal activities, cause metabolic changes, affect the endocrine system, and modulate the normal neurotransmitter/neuropeptide profile of the hypothalamus, all of which can influence eating behavior. The direct effects of interferon-alpha, interleukin-1beta, and tumor necrosis factor-alpha on glucose-sensitive neurons in two specific regions of the hypothalamus could cause profound changes in eating patterns in animals and humans. Cytokine immunotherapy also induces production of a large array of endogenous cytokines, which may act synergistically to cause anorexia, taste aversions, and other neuropsychiatric manifestations. A variety of approaches have been proposed for ameliorating cytokine-induced anorexia. These include dietary supplementation with specific fatty acids, megestrol acetate, and specific neuropeptides or peptide hormones that have the ability to modulate cytokine production or activity.