Biodegradation characteristics and genomic analysis of a newly isolated indole-degrading strain Pseudomonas aeruginosa Jade-X / Características de biodegradación y análisis genómico de una cepa degradante de indol recientemente aislada Pseudomonas aeruginosa Jade-X

Indole is a typical heterocyclic compound derived from tryptophan widespread in nature. Pseudomonas aeruginosa is one of the most common opportunistic pathogens everywhere in the world. Indole and P. aeruginosa will encounter inevitably; however, the indole transformation process by P. aeruginosa remains unclear. Herein, an indole-degrading strain of P. aeruginosa Jade-X was isolated from activated sludge. Strain Jade-X could degrade 1 mmol/L indole within 48 h with the inoculum size of 1% (v/v). It showed high efficiency in indole degradation under the conditions of 30–42 °C, pH 5.0–9.0, and NaCl concentration less than 2.5%. The complete genome of strain Jade-X was sequenced which was 6508614 bp in length with one chromosome. Bioinformatic analyses showed that strain Jade-X did not contain the indole oxygenase gene. Three cytochrome P450 genes were identified and up-regulated in the indole degradation process by RT-qPCR analysis, while cytochrome P450 inhibitors did not affect the indole degradation process. It suggested that indole oxidation was catalyzed by an unraveled enzyme. An ant gene cluster was identified, among which the anthranilate 1,2-dioxygenase and catechol 1,2-dioxygenase genes were upregulated. An indole-anthranilate-catechol pathway was proposed in indole degradation by strain P. aeruginosa Jade-X. This study enriched our understanding of the indole biodegradation process in P. aeruginosa.(AU)

Exploring the feasibility and safety of ropinirole combined with nerve growth factor for enhancing neurological health in football players

Objective: This study aims to investigate the viability and safety of utilizing ropinirole in combination with nerve growth factor for the management of neurological health in football players.Methods: A total of 92 athletic inpatients diagnosed with Parkinson's disease were enrolled in this study from December 2018 to December 2020. They were randomly divided into two groups: the control group and the research group, each comprising 46 athletic patients. The control group received nerve growth factor treatment, while the research group received a combination of ropinirole and nerve growth factor. Various serum markers, brain nerve factors, quality of life indicators, therapeutic outcomes, and safety profiles were evaluated and compared between the two groups.Results: Following treatment, both groups exhibited a significant increase in superoxide dismutase (SOD) levels compared to baseline, accompanied by substantial reductions in the levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B P65 (NF-κB P65). Moreover, the research group demonstrated significantly higher SOD levels and lower IL-1β, TNF-α, and NF-κB P65 levels compared to the control group (P<0.05). The levels of ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), dopamine (DA), and serotonin (5-HT) significantly increased in both groups post-treatment, with the research group exhibiting notably higher levels of these factors compared to the control group (P<0.05). Assessment of cognitive function (Montreal Cognitive Assessment - MoCA), balance (Berg Balance Scale - BBS), and activities of daily living (ADL) scores revealed significant improvements in both groups after treatment. However, the research group displayed higher MoCA and BBS scores and lower ADL scores than the control group (P<0.05). (AU)

Does preoperative use of silodosin affect the stages of f-urs Procedure? / ¿Afecta el uso de silodosin preoperatorio los pasos de la ureteroscopia flexible?

OBJECTIVES: To evaluate the effect of silodosin on stages of the flexible ureterorenoscopy (F-URS) procedures. METHODS: Between November 2015 and August 2017, a total of 76 patients suffering from 10-30 mm kidney stone were enrolled in this randomized prospective study. Patients were randomly divided into 2 groups for treatment: Group 1 had F-URS with preoperative daily uptake of 8 mg silodosin for 10 days, and group 2 had F-URS without silodosin uptake. None of the patients had preoperative JJ stenting. Stages of the F-URS was defined as entrance to bladder time (ETBT) with a semirigid ureterorenoscope (R-URS), entrance to ureteric orifice time (ETUOT) with R-URS using a guide wire and proceeding 2 cm inside the ureter, application of access sheath time (AAST) using the guide wire advanced through R-URS, F-URS time (FURST) + lithotripsy with laser time (LT), and total operation time (OT). We compared the time of each stage between two groups. RESULTS: There were 38 patients group1 and 2, respectively. There was one ureteral access sheath (UAS) application failure in group 1, and 3 failures in group 2 (p = 0.307). The ETBT, ETUOT, and AAST were significantly short in group 1 than group 2 (p = 0.001,0.007,0.002). CONCLUSIONS: Although preoperative use of silodosin facilitated only an insignificant positive effect on UAS placement failure, it eased the F-URS procedure by reducing the ETBT, ETUOT, and AAST in seconds. More studies are needed to make an exact conclusión

OBJETIVOS: Evaluar el efecto de la silodosina en las etapas de los procedimientos de ureterorrenoscopia flexible (F-URS). MÉTODOS: Entre noviembre de 2015 y agosto de 2017, un total de 76 pacientes con cálculos renales de 10-30 mm se inscribieron en este estudio prospectivo aleatorizado. Los pacientes se dividieron aleatoriamente en 2 grupos para el tratamiento: el grupo 1 tenía F-URS con captación diaria preoperatoria de 8 mg de silodosina durante 10 días, y el grupo 2 tenía F-URS sin captación de silodosina. Ninguno de los pacientes tenía stent JJ preoperatorio. Las etapas del F-URS se definieron como entrada al tiempo de la vejiga (ETBT) con un ureterorrenoscopio semirrígido (R-URS), entrada al tiempo del orificio ureteral (ETUOT) con R-URS usando una guía y 2 cm dentro del uréter. Aplicación del tiempo de vaina de acceso (AAST) utilizando el cable de guía avanzado a través de R-URS, tiempo de F-URS (FURST) + litotricia con tiempo de láser (LT) y tiempo total de operación (OT). Comparamos el tiempo de cada etapa entre dos grupos. RESULTADOS: Hubo 38 pacientes grupo 1 y 2, respectivamente. Hubo una falla en la aplicación de la cubierta de acceso ureteral (UAS) en el grupo 1 y 3 fallas en el grupo 2 (p = 0,307). ETBT, ETUOT y AAST fueron significativamente cortos en el grupo 1 que en el grupo 2 (p = 0,001, 0,007, 0,002). CONCLUSIONES: Aunque el uso preoperatorio de silodosina facilitó solo un efecto positivo insignificante en la falla de colocación de UAS, alivió el procedimiento de F-URS al reducir el ETBT, ETUOT y AAST en segundos. Se necesitan más estudios para llegar a una conclusión exacta

Experiencia con silodosina en la "vida real" (estudio SIRE) / Experience with silodosin in "real life" (SiRE study)

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Effects of cyclopiazonic acid and dexamethasone on serotonin-induced calcium responses in vascular smooth muscle cells

We previously observed that sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) blockade by cyclopiazonic acid (CPA) significantly potentiates serotonin (5-hydroxytryptamine (5-HT))-induced vascular contractions. Furthermore, 5-HT receptor antagonist methysergide partially inhibited CPA-potentiated 5-HT contractions. In the present study, we further investigated whether SERCA inhibition potentiates 5-HT-induced Ca2+ responses along with attenuating the receptor antagonism by store-operated Ca2+ (SOC) entry and protein kinase C (PKC)-mediated mechanisms. The effects of dexamethasone that was previously shown to induce SOC entry and enhance 5-HT responses were also tested. For this purpose, intracellular Ca2+ levels were monitored in A7r5 embryonic rat vascular smooth muscle cells by spectrofluorometry using the fluorescent indicator fura-2. The results showed that CPA, although not dexamethasone, significantly potentiated 5-HT-induced Ca2+ elevations. Ketanserin partially decreased 5-HT-induced and CPA-potentiated Ca2+ elevations whereas both PKC inhibitor D-sphingosine and SOC entry blocker 2-aminoethoxydiphenyl borate (2-APB) abolished the remaining responses. The data suggests that diminished antagonistic effect on 5-HT-induced Ca2+ elevations in the presence of SERCA inhibition is induced by SOC entry and PKC activation (AU)

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Antioxidant components of selected indigenous edible mushrooms of the obsolete order Aphyllophorales / Compuestos antioxidantes en setas autóctonas comestibles del antiguo orden Aphyllophorales

Background: Species of phylum Basidiomycota are of greatinterestin many studies as a source of valuable biological compounds. Aims: To estimate the levels of antioxidant compounds (phenolic acids, indole compounds and sterols) in edible species of Aphyllophorales (sensu lato): Hydnum repandum L. and Sparassis crispa (Wulf.) Fr. Methods: A reversed-phase high performance liquid chromatography (RP-HPLC) method was used for the quantitative and qualitative analyses of antioxidant components (phenolic acids, indole compounds, and sterols). Results: Analysis of phenolic acids revealed that 8 out of the 10 analyzed compounds were present. The quantitatively predominant in Hydnum repandum was protocatechuic acid (75.23 mg/100 g DW), and in Sparassis crispa it was p-hydroxybenzoic acid (43.92 mg/100 g DW). In turn, analysis of indole compounds identified 5 out ofthe 12 analyzed compounds: indole, melatonin, serotonin, tryptamine, and l-tryptophan. Moreover, ergosterol was also identified and quantitatively determined (150.37 mg/100 g DW) in Sparassis crispa extracts. Conclusions: The data presented in this paper confirm the significant potential of chemical components with recognized antioxidant activity. The species can be considered as an alternative source of phenolic acids and ergosterol (AU)

Antecedentes: Los hongos del filo Basidiomycota son de gran interés en diversas investigaciones por ser una fuente de compuestos biológicos valiosos. Objetivos: Determinar los niveles de compuestos antioxidantes (ácidos fenólicos, compuestos de indol y esteroles) en las especies comestibles de Aphyllophorales (sensu lato) Hydnum repandum L. y Sparassis crispa (Wulf.) Fr. Métodos: El método RP-HPLC se empleó en el análisis cuantitativo y cualitativo de los siguientes componentes con actividad antioxidante: ácidos fenólicos, compuestos de indol y esteroles. Resultados: El análisis de los ácidos fenólicos reveló que 8 de los 10 compuestos analizados estaban presentes. El ácido cuantitativamente predominante en Hydnum repandum era el ácido protocatéquico (75,23 mg/100 g DW) y en Sparassis crispa el ácido p-hidroxibenzoico (43,92 mg/100 g DW). A su vez, el análisis de compuestos de indol identificó 5 de los 12 compuestos en estudio: indol, melatonina, serotonina, triptamina y l-triptófano. Por otra parte, en los extractos de Sparassis crispa se determinó también cuantitativamente la presencia de ergosterol (150,37 mg/100 g DW). Conclusiones: Los datos presentados en este trabajo confirman el gran potencial de los componentes químicos con actividad antioxidante reconocida. Las especies pueden ser consideradas como una fuente alternativa de ácidos fenólicos y ergosterol (AU)

Suplementos dietéticos como tratamiento en el cáncer cervicouterino; revisión sistemática / Dietary supplements as a treatment for cervical cancer; a systemic review

Introducción: En el cáncer cervicouterino (CaCu) y neoplasias intraepiteliales cervicales (NIC) se requiere de una cuidadosa selección de terapias convencionales y complementarias, la inclusión de suplementos dietéticos dentro de ellas marcaría la pauta dentro de los tratamientos. Sin embargo, no se tiene algún reporte de qué tipo de suplementos pudieran ser utilizados para brindar una mejor respuesta ante la enfermedad por estas pacientes. Objetivo: En la presente revisión se analizan los ensayos clínicos de los últimos 20 años que evaluaron suplementos dietéticos en esta población, con el objetivo de dar a conocer cuáles de ellos son viables para ser administrados. Metodología: Se realizó una búsqueda de ensayos clínicos que utilizaron algún suplemento dietario en mujeres con CaCu y algún grado de NIC analizando en ellos el modo de utilización del suplemento; el tratamiento convencional; si existe una deficiencia del nutriente ó compuesto a evaluar; las características de la población, del ensayo clínico y del suplemento; así como la dosis y los efectos esperados. Resultados: Veinte fueron en total el número de estudios analizados. Los artículos fueron clasificados según la naturaleza del suplemento: Retinoides, vitamina E, probióticos, indoles, multivitamínico, ácido fólico y selenio. Conclusión: Para el tratamiento de CaCu y NIC resultaron efectivos algunos de los suplementos encontrados en esta revisión, sin embargo su efecto dependerá de diferentes factores propios de la enfermedad. Debido a esto, es necesario el manejo correcto de los suplementos dietéticos para poder ser utilizados eficientemente como tratamiento complementario en esta población (AU)

Introduction: Cervical cancer and cervical intraepithelial neoplasia (CIN) require a careful selection of conventional and complementary therapies. The inclusion of dietary supplements within the aforementioned treatments set the tone within treatments. However, there are no reports of what kind of supplements could be used to provide a better response to the disease in these patients. Objective: In this review, we analyze clinical trials of the past 20 years that evaluated dietary supplements on this population, with the objective to raise awareness on which of them are viable to be administered. Methods: We performed a search for clinical trials that used a dietary supplement in women with cervical cancer and some degree of NIC analyzing them how to use the supplement, the conventional treatment, deficiency of the nutrient or compound to be evaluated, the characteristics of the population, the clinical trial and the supplement, as well as dosage and their effects. Results: Twenty were in total the number of studies reviewed. The articles were classified according to the nature of the supplement: Retinoids, vitamin E, probiotics, indoles, multivitamin, folic acid and selenium. Conclusion: Some supplements were found to be effective in the treatment of cervical cancer and CIN. However, their effect depends on specific factors of the disease. The correct management of dietary supplements is an effective aid to help the patient with cancer and therefore, it is important to define what complementary therapies can be used for this population (AU)

Cost-effectiveness evaluation of sunitinib as first-line targeted therapy for metastatic renal cell carcinoma in Spain

INTRODUCTION Sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, delays disease progression, with a median overall survival (OS) of more than 2 years, improves quality of life and is becoming the first-line standard of care for metastatic renal carcinoma (mRCC). PURPOSE To assess the economic value of sunitinib as fi rst-line therapy in mRCC within the Spanish healthcare system. METHODS An adapted Markov model with a 10-year time horizon was used to analyse the cost effectiveness of sunitinib vs. sorafenib (SFN) and bevacizumab/interferon-α (BEV/IFN) as first-line mRCC therapy from the Spanish third-party payer perspective. Progression-free survival (PFS) and OS data from sunitinib, SFN and BEV/IFN pivotal trials were extrapolated to project survival and costs in 6-week cycles. Results, in progression-free life-years (PFLY), life years (LY) and quality-adjusted life-years (QALY) gained, expressed as incremental cost-effectiveness ratios (ICER) with costs and benefits discounted annually at 3%, were obtained using deterministic and probabilistic analyses. RESULTS Sunitinib was more effective and less costly than both SFN (gains of 0.52 PFLY, 0.16 LY, 0.17 QALY) and BEV/IFN (gains of 0.19 PFLY, 0.23 LY, 0.16 QALY) with average cost savings/patients of €1,124 and €23,218, respectively. Using a willingness-to-pay (WTP) threshold of €50,000/QALY, sunitinib achieved an incremental net benefit (INB) of €9,717 and €31,211 compared with SFN and BEV/IFN, respectively. At this WTP, the probability of sunitinib providing the highest INB was 75%. CONCLUSION Our analysis suggests that sunitinib is a costeffective alternative to other targeted therapies as first-line mRCC therapy in the Spanish healthcare setting (AU)

Tyrosine kinase inhibitors in treating soft tissue sarcomas: sunitinib in non-GIST sarcomas

Sarcomas are uncommon malignancies that represent more than 50 different tumor types. Surgery remains the mainstay of treating localised disease. Anthracycline and ifosfamide-based chemotherapy is an option for advanced disease; however, effective treatment of advanced soft tissue sarcoma remains a challenge. Advances in understanding the genetic nature of cancer have led to the development of new treatment options for sarcoma. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic properties and promising activity in the treatment of GIST refractory to imatinib, however in either soft tissue sarcoma, experience with sunitinib is under development in different clinical trials. In this review we offer the experience with this small molecular target in non-GIST sarcomas (AU)

Effect of a heterotrimeric G protein α subunit on conidia germination, stress response, and roquefortine C production in Penicillium roqueforti

Heterotrimeric G protein signaling regulates many processes in fungi, such as development, pathogenicity, and secondary metabolite biosynthesis. For example, the Galpha subunit Pga1 from Penicillium chrysogenum regulates conidiation and secondary metabolite production in this fungus. The dominant activating allele, pga1G42R, encoding a constitutively active Pga1 Galpha subunit, was introduced in Penicillium roqueforti by transformation, resulting in a phenotype characterized by low sporulation and slow growth. In this work, the effect of the constitutively active Pga1G42R Galpha subunit on conidial germination, stress tolerance, and roquefortine C production of P. roqueforti was studied. Pga1G42R triggered germination in the absence of a carbon source, in addition to negatively regulating thermal and osmotic stress tolerance. The presence of the Pga1G42R Galpha subunit also had an important effect on roquefortine C biosynthesis, increasing production and maintaining high levels of the mycotoxin throughout a culture period of 30 days. Together, the results suggest that G protein-mediated signaling participates in the regulation of these three processes in P. roqueforti (AU)

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The role of antiangiogenesis therapy: bevacizumab and beyond

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in advanced solid tumours, such breast, colorectal, lung and renal cancer. Clinical data from trials of anti-VEGF agents in this group of tumours are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in those tumour types. Future potential uses of bevacizumab in cancer therapy will be discussed (AU)

Cost-effectiveness analysis of sunitinib in patients with metastatic and/or unresectable gastrointestinal stroma tumours (GIST) after progression or intolerance with imatinib

INTRODUCTION: Sunitinib is a multiselective oral inhibitor of several tyrosine-kinase receptors that has demonstrated its efficacy in patients with metastatic and/or unresectable gastrointestinal stroma tumours (GIST) who were resistant to or intolerant to previous treatment with imatinib. The purpose of this study is to assess the cost-effectiveness of sunitinib vs. best supportive care (BSC) in GIST as a second- line treatment, from the perspective of the Spanish National Health System. MATERIALS AND METHODS: A Markov model was used to assess the cost effectiveness of sunitinib (50 mg/day, 4 weeks "on" and 2 weeks "off") vs. BSC in GIST as a second-line treatment. Transition probabilities between the three health states considered in the model (progression-free survival (PFS), progression and death) were obtained from a clinical trial [Demetri et al. (2006) Lancet 368:1329-1338]. Health resource data (drugs, medical visits, laboratory and radiology tests, palliative care and adverse events) were obtained from an expert panel. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Projected PFS years, life years (LY) and quality of life adjusted years (QALYs) were higher for sunitinib compared with BSC: 0.50 vs. 0.24, 1.59 vs. 0.88 and 1.00 vs. 0.55. Mean costs per patient were 23,259 euros with sunitinib and 1,622 euros with BSC. The incremental cost-effectiveness ratios (ICERs) obtained were: 4,090 euros/month PFS, 30,242 euros/LY and 49,090 euros/QALY gained. The most influential variables for the results were the efficacy and unit cost of sunitinib. CONCLUSIONS: According to the efficiency thresholds for oncology patients in developed countries, sunitinib is considered cost-effective vs. BSC with acceptable costs per LY and QALY gained (AU)

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Angiogénesis neoplásica / Neoplastic angiogenesis

La angiogenésis neoplásica es un proceso esencial en el crecimiento progresivo de las neoplasias, y en la producción de metástasis. La angiogénesis consiste en una serie de complejos pasos consecutivos que conducen en último término al desarrollo de neovasos que aportan sangre a la masa tumoral. El VEGF tiene un papel primordial en la angiogénesis neoplásica, y por tanto es una importante diana en el tratamiento de las neoplasias. Bevacizumab, un anticuerpo monoclonal humano, inhibe el VEGF, y podría mejorar el transporte de la quimioterapia a las masas tumorales. Los inhibidores multi-kinasas (sorafenib y sunitinib) son pequeñas moléculas de administración oral, que inhiben diferentes receptores (esenciales en la angiogénesis neoplásica), como VEGFR o PDGFR. Estos agentes son útiles en el tratamiento del carcinoma de células renales avanzado, y están en investigación en muchos otros tumores

Neoplastic angiogenesis is an essential process in the progressive growth of neoplasms and the production of metastasis. Angiogenesis consists of a series of linked and sequential steps that ultimately leads to the development of a neovascular blood supply to the tumor mass. VEGF has got an essential role in neoplastic angiogenesis, there fore it is an important target in the treatment of neoplasms. Bevacizumab, a humanized monoclonal antibody, inhibits VEGF, and may also improve the delivery of chemotherapy to the tumor mass. Multi-kinase ihibitors (sorafenib and sunitinib) are orally administered small-molecules, that inhibit different receptors (essentials in the neoplastic angiogenesis), such as the VEGFR or PDGFR. These agents are useful in the treatment of advanced renal-cell carcinoma, and are under investigation in several tumors

Molecular biology of renal cell carcinoma

Recent developments in molecular biology have lead to an increased understanding of the events involved in renal cell carcinoma (RCC) carcinogenesis. In this field, basic molecular pathways important to oncogenic transformation secondary to Von Hippel-Lindau (VHL) tumor suppression gene inactivation, associated to clear-cell RCC, have been elucidated. Loss of function of VHL results in the high-expression of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). New therapies against specific targets in RCC have demonstrated significant clinical activity in patients. These therapeutic approaches are based on the VEGF inhibition by using anti-VEGF monoclonal antibodies (bevacizumab) or multi-kinase inhibitors, that also target PDGF and c-kit tyrosine kinases (sorafenib, sunitinib); or by the inhibition of the mammalian target of rapamycin (mTOR) pathway (temsirolimus). This article reviews current knowledge of molecular pathogenesis of inherited and sporadic RCC (AU)

Ropinirol en el tratamiento de la enfermedad de Parkinson: actualización / Ropinirole in the treatment of Parkinson’s disease: an update

Introducción. El ropinirol es un agonista dopaminérgicono ergótico con alta afinidad por los receptores dopaminérgicos D2,que proporciona una mejoría sintomática de la enfermedad de Parkinson(EP) y retrasa la aparición de las complicaciones motoras. Se diferencia de la primera generación de agonistas dopaminérgicos en que, al carecer de estructura ergolínica, no presenta los efectos secundarios que aparecen con este grupo farmacológico. Desarrollo. Recientes estudios con neuroimagen funcional invocan un posible efecto neuroprotector del fármaco, aunque este aspecto es foco de discusión. Desde hace años, la pregunta de cuándo y cómo debe iniciarse el tratamiento de la EP precoz continúa siendo un motivo de controversia. Los agonistas dopaminérgicos se han utilizado en monoterapia en pacientes con enfermedad de novo con la intención de retrasar el tratamiento con levodopa y, consecuentemente, diferir el comienzo de las complicaciones derivadas de su uso. El ropinirol se ha evaluado en diferentes estudios, tanto en monoterapia como en terapia añadida a la levodopa. Conclusiones. En losmúltiples ensayos clínicos realizados, parece constatado que el ropinirol puede administrarse durante años como tratamiento único dela EP precoz y que reduce notablemente la aparición de discinesias. Dada una relación lineal dosis-respuesta, el fármaco dispone de una amplia 'reserva terapéutica' que permite aumentar la dosis a medida que progresa la enfermedad (AU)

Introduction. Ropinirole is a non-ergot dopaminergic agonist with a high affinity for D2 dopaminergic receptors which improves the symptoms of Parkinson’s disease (PD) and delays the appearance of motor complications. It is different to the first generation of dopaminergic agonists in that, because it lacks an ergolinic structure, it does not have the side effects that usually appear with the use of this pharmacological group. Development. Recent functional neuroimaging studies suggest a possible neuroprotector effect of the drug, although this aspect is still under discussion. The question as to when and how early treatment of PD must be started has been a controversial issue for many years now. Dopaminergic agonists have been used in monotherapy in patients with de novo disease with the intention of deferring treatment with levodopa and, inconsequence, postponing the onset of the complications stemming from its use. Ropinirole has been evaluated in different studies both in monotherapy and as adjunctive therapy with levodopa. Conclusions. In the numerous clinical trials that were carried out, it would seem clear that ropinirole can be administered for years as sole early treatment for PD and that it offers a notable reduction in the appearance of dyskinesia's. Given the linear dose-response relation it presents, the drug has a wide 'therapeutic window' that allows the dosage to be increased as the disease progresses (AU)

Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion

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In the absence of progesterone (P), the anti-P at the receptor RU486 reduces basaland GnRH-stimulated LH secretion both in vivo and in vitro, demonstrating theexistence of a ligand-independent activation of progesterone receptor (LIAPR). Theaim of the present study was to determine which component of the intracellular LHsecretory pathway activated by GnRH is responsible for LIAPR. To do this, anteriorpituitary dispersed cells from female rats in proestrus, cultured in the presence of17â-estradiol, were incubated with activators or inhibitors of PKC, cAMP-PKA signallingpathways or intracellular calcium (Ca2+) traffic, in the presence or absence ofRU486. Results showed that RU486 reduced both GnRH- and the PKC activatorPMA-induced LH secretion. In GnRH-stimulated cells incubated with the PKCinhibitor BIS-I or treated with PMA “overnight”, RU486 had no effect on reducedLH secretion, nor on stimulated LH secretion elicited by the Ca2+ ionophore ionomycin.Moreover, when GnRH- or PMA-treated cells were co-incubated with 1 µMof the L-type Ca2+ channel blocker nifedipine or the intracellular Ca2+ chelatorBAPTA-AM, RU486 potentiated the expected inhibition of these drugs on LHsecretion. Activation (forskolin, 8-Br-cAMP) or inhibition (MDL-12,330A) of thecAMP-PKA signalling cascade affected neither the GnRH- and PMA-inducedincrease of LH secretion nor the reduction of LH secretion due to RU486. Takentogether, the data point to the existence of a Ca2+-independent PKC-PR cross-talkmechanism as part of the intracellular signalling of GnRH-stimulated LH secretion

Costes del manejo clínico de los efectos adversos torácicos y del sistema nervioso central asociados al tratamiento de las crisis agudas de migraña con triptanes orales / Management costs of chest and CNS-related adverse events associated with the treatment of acute migraine attacks with oral triptans

Introducción. Aunque los efectos adversos de los triptanes no suelen tener importancia clínica, pueden preocupar al paciente y llevarle a consumir recursos sanitarios. Métodos. Se utilizó un modelo de decisión para representar el comportamiento y manejo de pacientes que experimentan efectos adversos después de tomar triptanes. A partir de datos sobre la incidencia, el comportamiento y manejo de pacientes y los costes unitarios de recursos sanitarios consumidos se calcularon los costes del tratamiento de efectos adversos, así como el factor de coste iatrogénico de los triptanes disponibles en España. Resultados. Entre un 10 y 20 % de los pacientes que sufren efectos adversos torácicos o del sistema nervioso central (SNC) relacionados con la utilización de triptanes acuden a un médico. El coste del manejo de efectos adversos torácicos se estimó en 66,43, 33,09 o 137,01 €, según si el paciente acude a un neurólogo, un médico de atención primaria o a urgencias hospitalarias, respectivamente. Para efectos adversos del SNC el coste se estimó en 52,88, 16,89 o 102,17 €, respectivamente. Sin contar el efecto placebo, el factor iatrogénico resultante varía entre 1 para el almotriptán 12,5 mg y 1,21 para el zolmitriptán 2,5 mg. En términos absolutos, el coste medio por paciente (por encima de placebo) varía entre 0 € para el almotriptán 12,5 mg y 1,17 € para el eletriptán 80 mg. Conclusiones. El manejo de efectos adversos puede añadir al tratamiento con triptanes costes de cierta consideración. Estos costes varían notablemente entre los triptanes debido a las diferencias en la incidencia de los efectos adversos. Los menores costes se obtuvieron para el almotriptán 12,5 mg

Introduction. Although adverse events of triptans are usually not important from a clinical point of view, they can worry patients and lead them to consume healthcare resources. Methods. A decision analytic model was used to represent the behavior and management of patients who suffered adverse events after taking a triptan. Using data about the incidence of adverse events, the behavior and management of patients, and the unit cost of the healthcare resource consumed, the costs of treating adverse events were calculated, as was the iatrogenic cost factor of the triptans available in Spain. Results. 10 % to 20 % of patients who suffer a chest or CNS-related adverse advent related to triptan use seek medical attention. The management cost of a chest-related event was estimated to be € 66,43, € 33,09, or € 137,01, depending on whether the patient consulted a neurologist, a primary care physician, or a hospital emergency department. For CNS-related events the management cost was estimated to be € 52,88, € 16,89 or € 102,17, respectively. Excluding the placebo effect, the resulting iatrogenic cost factor varied between 1 for almotriptan 12,5 mg and 1,21 for zolmitriptan 2,5 mg. In absolute values, the average cost per patient (above placebo) varied between O € for almotriptan 12,5 mg and € 1,17 for eletriptan 80 mg. Conclusions. The management of adverse events can add substantial costs to a treatment with triptans. These costs vary considerably between triptans due to differences in the incidence of adverse events. Lowest costs were found for almotriptan 12,5 mg

Contribución española al desarrollo clínico de eletriptán: un análisis de los estudios controlados / Spanish contribution to the clinical development of eletriptan: an analysis of controlled studies

Introducción. El eletriptán es un triptán de segunda generación con una potente actividad agonista de los receptores 5-HT1B/1D antimigraña recientemente comercializado. Nuestro objetivo ha sido analizar los resultados específicos de la participación española en los ensayos de fase IIIa y IIIb controlados frente a placebo y compararlos con los resultados en el desarrollo clínico global de eletriptán. Pacientes y métodos. Análisis de los resultados obtenidos en 40 centros españoles (358 pacientes) frente a una muestra global (4.677 pacientes) para la primera crisis de migraña en seis ensayos controlados con eletriptán 40 y 80 mg frente a placebo. El subanálisis español se llevó a cabo para aquellos grupos de tratamiento con más de 50 pacientes, lo que redujo el número final de pacientes españoles a 250.Resultados. La proporción de pacientes con alivio a las 2 h (variable principal) en la muestra española fue de 22, 59 y 67 por ciento para placebo, eletriptán 40 y eletriptán 80 mg, respectivamente. Estos valores fueron significativamente superiores (p < 0,05) al placebo y similares a los de la muestra total. La proporción de pacientes sin dolor a las 2 h en la muestra española fue de 10, 36 y 41 por ciento para placebo, eletriptán 40 y eletriptán 80 mg, respectivamente. Estos valores fueron significativamente superiores a los del placebo (p < 0,05) y entre 15-10 por ciento más elevados que los de la muestra total. La recurrencia en la muestra española fue de 50, 16 y 25 por ciento para placebo, eletriptán 40 y eletriptán 80 mg, respectivamente, y no difirió de la de la muestra total. El alivio mantenido del dolor fue del 46 por ciento tanto con eletriptán 40 como con eletriptán 80, significativo (p < 0,05) frente a placebo (11 por ciento) en la muestra española y sin diferencias frente a la muestra global. Los resultados para otras variables de eficacia como necesidad de medicación de rescate, respuesta funcional a las 2 h, respuesta completa para ausencia de dolor y aceptabilidad siguieron una tendencia similar. El eletriptán fue, en general, bien tolerado. Los efectos adversos fueron de intensidad leve-moderada, transitorios y no se diferenciaron ni en el perfil ni en la proporción al comparar la muestra española con la serie global. Conclusiones. Estos resultados confirman el eletriptán 40 y 80 mg como una excelente opción para el tratamiento sintomático de la migraña en nuestro medio (AU)