RESUMEN
BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).(AU)
Asunto(s)
Humanos , Queratosis Actínica/terapia , Rayos Ultravioleta/efectos adversos , Terapia CombinadaRESUMEN
BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).
Asunto(s)
Queratosis Actínica/terapia , Terapia Combinada , Medicina Basada en la Evidencia , Humanos , Queratosis Actínica/diagnóstico , Queratosis Actínica/etiologíaRESUMEN
OBJECTIVES: Cytochrome oxidase (COX) dysfunction is associated with mitochondrial oxidative stress. We determined the association between COX expression, obesity and type 2 diabetes. SUBJECTS/METHODS: COX4I1 and COX10 genes were measured in monocytes of 24 lean controls, 31 glucose-tolerant and 67 diabetic obese patients, and 17 morbidly obese patients before and after bariatric surgery. We investigated the effect of caloric restriction and peroxisome proliferator-activated receptor (PPAR) agonist treatment on Cox in obese diabetic mice, and that of diet-induced insulin resistance in Streptozotocin-treated mice. RESULTS: Low COX4I1 was associated with type 2 diabetes in obese patients, adjusting for age, gender, smoking, interleukin-6 and high-sensitivity C-reactive protein, all related to metabolic syndrome (MetS; odds ratio: 6.1, 95% confidence interval: 2.3-16). In contrast, COX10 was low in glucose-tolerant and diabetic obese patients. In morbidly obese patients, COX4I1 was lower in visceral adipose tissue collected at bariatric surgery. In their monocytes, COX4I1 decreased after bariatric surgery, and low COX4I1 at 4 months was associated with MetS at 7 years. In leptin-deficient obese diabetic mice, Cox4i1 was low in white visceral adipose tissue (n=13; P<0.001) compared with age-matched lean mice (n=10). PPARγ-agonist treatment (n=13), but not caloric restriction (n=11), increased Cox4i1 (P<0.001). Increase in Cox4i1 depended on the increase in glucose transporter 4 (Glut4) expression and insulin sensitivity, independent of the increase in blood adiponectin. In streptozotocin-treated mice (three groups of seven mice, diet-induced insulin resistance decreased Cox4i1 and Glut4 (P<0.001 for both). CONCLUSION: COX4I1 depression is related to insulin resistance and type 2 diabetes in obesity. In peripheral blood monocytes, it may be a diagnostically useful biomarker.
Asunto(s)
Transferasas Alquil y Aril/genética , Diabetes Mellitus Tipo 2/fisiopatología , Complejo IV de Transporte de Electrones/genética , Resistencia a la Insulina/genética , Proteínas de la Membrana/genética , Mitocondrias/patología , Obesidad Mórbida/fisiopatología , Animales , Cirugía Bariátrica , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/genética , Transporte de Electrón , Variación Genética , Humanos , Ratones , Ratones Obesos , Mitocondrias/genética , Obesidad Mórbida/genética , Pérdida de PesoRESUMEN
UNLABELLED: In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitochondrial apoptosis, effector caspase activation downstream of mitochondria or a combination of both predicts patient responses. In a cohort of 20 rectal cancer patients, we performed protein profiling of tumour tissue and employed validated ordinary differential equation-based systems models of apoptosis signalling to calculate the ability of cancer cells to undergo apoptosis. Model outputs were compared to clinical responses. Systems modelling of BCL2-signalling predicted patients in the poor response group (p = 0.0049). Systems modelling also demonstrated that rectal cancers depended on BCL2 rather than B cell lymphoma-extra large (BCL(X)L) or myeloid cell leukemia 1 (MCL1) for survival, suggesting that poor responders may benefit from therapy with selective BCL2 antagonists. Dynamic modelling of effector caspase activation could not stratify patients with poor response and did not further improve predictive power. We deliver a powerful patient stratification tool identifying patients who will likely not benefit from neoadjuvant chemoradiotherapy and should be prioritised for surgical resection or treatment with BCL2 antagonists. KEY MESSAGES: Modelling BCL2-family proteins identifies patients unresponsive to therapy. Caspase activation downstream of mitochondria cannot identify these patients. Rectal tumours of poor responders are BCL2- but not BCL-XL-dependent. DR_MOMP allows clinicians to identify patients who would not benefit from therapy. DR_MOMP is also a useful patient stratification tool for BCL2 antagonists.
Asunto(s)
Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias del Recto/metabolismo , Adulto , Anciano , Apoptosis , Quimioradioterapia Adyuvante , Daño del ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Membranas Mitocondriales/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Terapia Neoadyuvante , Neoplasias del Recto/terapia , Transducción de Señal , Resultado del TratamientoRESUMEN
BACKGROUND: Cutaneous Rosai-Dorfman disease is a rare disorder belonging to the spectrum of non-Langerhans cell histiocytoses. It is characterized by dermal and subcutaneous infiltrates of histiocytes as well as accompanying lymphocytes, plasma cells and granulocytes. Because it is so rare, standard therapies have not been established. CASE REPORT: A 27-year-old man showed an excellent response to intralesional corticosteroids after unsuccessful prior treatment with methotrexate, systemic steroids and surgery as well as laser therapy.
Asunto(s)
Corticoesteroides/administración & dosificación , Dermatitis/tratamiento farmacológico , Dermatitis/patología , Histiocitosis Sinusal/tratamiento farmacológico , Histiocitosis Sinusal/patología , Adulto , Humanos , Inyecciones Intralesiones , Masculino , Síndrome , Resultado del TratamientoRESUMEN
Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive-enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKα or its upstream kinases, LKB1 and CaMKKß, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability.
Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Ácido Glutámico/farmacología , Indoles/farmacología , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Cerebelo/citología , Silenciador del Gen , Transportador de Glucosa de Tipo 3/efectos de los fármacos , Transportador de Glucosa de Tipo 3/metabolismo , Ratones , Mitocondrias/metabolismo , Neocórtex/citología , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , RatasRESUMEN
BACKGROUND: The combination of coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging--referred to as multimodal imaging--provides complementary contrast based on molecular vibrations, the structure of various tissue components and endogenous fluorophores, respectively. OBJECTIVES: To present a comprehensive overview of the appearance of human skin in multimodal imaging. METHODS: Multimodal imaging of unstained skin cross-sections of 32 individuals was performed using a laser scanning microscope and picosecond laser pulse for excitation. RESULTS: The epidermis, dermis and subcutis are distinguishable in all three applied modalities, but are unveiled best in multimodal images. While the subcutis is dominated by the CARS signal, predominately SHG and the secondary TPEF signal detect the dermis. In contrast, no SHG signal is detected in the epidermis, whereas CARS and TPEF show equal contributions. Additionally, the appearance of the major skin appendages is described, i.e. the hair follicle, sebaceous and sweat glands, and blood vessels belonging to the vascular system. All four investigated functional units show a characteristic morphochemistry in TPEF and CARS, allowing identification of further subunits, e.g. the major components of the hair follicle, while the SHG signal delineates the localization of the functional units. CONCLUSIONS: Multimodal imaging is a powerful tool to investigate human skin by providing high contrast based on the molecular constitution. It is therefore suggested that multimodal imaging has a high potential in application to dermatological research and clinical diagnostics of various skin alterations.
Asunto(s)
Imagen Multimodal/métodos , Piel/anatomía & histología , Dermis/anatomía & histología , Epidermis/anatomía & histología , Humanos , Rayos Láser , Microscopía Confocal/métodos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Espectrometría Raman/métodosRESUMEN
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.
Asunto(s)
Algoritmos , Neoplasias Encefálicas/metabolismo , Caspasas/metabolismo , Glioblastoma/metabolismo , Adulto , Anciano , Antineoplásicos Alquilantes/toxicidad , Proteínas Reguladoras de la Apoptosis , Factor Apoptótico 1 Activador de Proteasas/metabolismo , Neoplasias Encefálicas/patología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Supervivencia Celular/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/toxicidad , Supervivencia sin Enfermedad , Femenino , Glioblastoma/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/metabolismo , Temozolomida , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
The development of malignancies during therapy with biologics has been discussed controversially. A patient with extensive pityriasis rubra pilaris failed to respond to standard therapeutic approaches. While receiving immunomodulatory therapy, lastly with ustekinumab, the patient developed a CD30(+) anaplastic large cell lymphoma.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Inmunosupresores/efectos adversos , Linfoma Anaplásico de Células Grandes/inducido químicamente , Linfoma Anaplásico de Células Grandes/diagnóstico , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , UstekinumabRESUMEN
Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the pro-apoptotic BH3-only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single-cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feed-forward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK-mediated Bim expression and apoptosis during transient or physiological bioenergetic stress.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Núcleo Celular/metabolismo , Células Cultivadas , Regulación hacia Abajo , Proteína Forkhead Box O3 , Glucosa/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Neuronas/citología , Neuronas/metabolismo , Fosforilación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factor de Transcripción AP-1/metabolismoRESUMEN
Mitochondrial outer membrane permeabilisation (MOMP) during apoptosis is triggered by the activation and oligomerisation of Bax and Bak, but a quantification of these processes in individual cells has not yet been performed. Single-cell imaging of Bax translocation and oligomerisation in Bax-deficient DU-145 cells expressing CFP-Bax and YFP-Bax revealed that both processes started only minutes before or concomitantly with MOMP, with the majority of Bax translocation and oligomerisation occurring downstream of MOMP. Quantification of YFP-Bax concentrations at mitochondria revealed an increase of only 1.8 + or - 1.5% at MOMP onset. This was increased to 11.2 + or - 3.6% in bak-silenced cells. These data suggested that Bax activation exceeded by far the quantities required for MOMP induction, and that minimal Bax or Bak activation may be sufficient to trigger rapid pore formation. In a cellular automaton modelling approach that incorporated the quantities and movement probabilities of Bax and its inhibitors, activators and enablers in the mitochondrial membrane, we could re-model rapid pore formation kinetics at submaximal Bax activation.
Asunto(s)
Membranas Mitocondriales/metabolismo , Modelos Biológicos , Proteína X Asociada a bcl-2/metabolismo , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/fisiología , Transferencia Resonante de Energía de Fluorescencia , Humanos , Proteínas Luminiscentes/genética , Masculino , Microscopía Confocal , Neoplasias de la Próstata , ARN Interferente Pequeño , Transducción de Señal/fisiología , Biología de Sistemas , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/genéticaRESUMEN
Individual cells within a population undergo apoptosis at distinct, apparently random time points. By analyzing cellular mitotic history, we identified that sibling HeLa cell pairs, in contrast to random cell pairs, underwent apoptosis synchronously. This allowed us to use high-speed cellular imaging to investigate mitochondrial outer membrane permeabilization (MOMP), a highly coordinated, rapid process during apoptosis, at a temporal resolution approximately 100 times higher than possible previously. We obtained new functional and mechanistic insight into the process of MOMP: We were able to determine the kinetics of pore formation in the outer mitochondrial membrane from the initiation phase of cytochrome-c-GFP redistribution, and showed differential pore formation kinetics in response to intrinsic or extrinsic apoptotic stimuli (staurosporine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)). We also detected that the onset of mitochondrial permeabilization frequently proceeded as a wave through the cytosol, and that the frequency of wave occurrence in response to TRAIL was reduced by inhibition of protein kinase CK2. Computational analysis by a partial differential equation model suggested that the spread of permeabilization signals could sufficiently be explained by diffusion-adsorption velocities of locally generated permeabilization inducers. Taken together, our study yielded the first comprehensive analysis of clonal cell-to-cell variability in apoptosis execution and allowed to visualize and explain the dynamics of MOMP in cells undergoing apoptosis.
Asunto(s)
Apoptosis/fisiología , Permeabilidad de la Membrana Celular/fisiología , Membranas Mitocondriales/metabolismo , Apoptosis/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Estructuras de la Membrana Celular/efectos de los fármacos , Estructuras de la Membrana Celular/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Células HeLa , Humanos , Cinética , Microscopía , Membranas Mitocondriales/efectos de los fármacos , Modelos Biológicos , Estaurosporina/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.
Asunto(s)
Antihipertensivos/farmacocinética , Bloqueadores de los Canales de Calcio/farmacocinética , Nifedipino/análogos & derivados , Absorción , Disponibilidad Biológica , Semivida , Humanos , Riñón/metabolismo , Hígado/metabolismo , Nifedipino/farmacocinéticaRESUMEN
In an open monocentric phase II study, 20 inpatients with hypertension were treated with a single daily dose of nilvadipine for 3 weeks after a 1-week placebo washout phase. The initial dose in all patients was 8 mg/day p.o.; this was doubled to 16 mg once daily if an adequate blood pressure reduction was not achieved after 10 days on 8 mg. The objective of the study was to investigate the effect of this new calcium antagonist on the blood pressure in hypertensive patients. This was done by means of a 24-h blood pressure profile (with measurements at 0.5, 1, 2, 4, 8, 12, and 24 h after administration), and over the complete course of the treatment period (blood pressure measurements each day just before the medication was given). In addition, by determination of the nilvadipine plasma levels on the first, tenth, and last medication day, a possible concentration-efficacy relationship was to be ascertained between plasma concentration of nilvadipine and the observed blood pressure-lowering effect of the drug. Adequate blood pressure reductions were achieved with nilvadipine 8 mg once daily in 13 patients; 7 required a doubling of the dosage to 16 mg/day. Already on the first day of therapy, both the systolic and diastolic blood pressures were significantly reduced compared to those in the placebo phase (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Hipertensión/tratamiento farmacológico , Nifedipino/análogos & derivados , Adulto , Anciano , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/uso terapéutico , Esquema de Medicación , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Nifedipino/administración & dosificación , Nifedipino/farmacocinética , Nifedipino/uso terapéuticoAsunto(s)
Departamentos de Hospitales/legislación & jurisprudencia , Privilegios del Cuerpo Médico/legislación & jurisprudencia , Cuerpo Médico de Hospitales/legislación & jurisprudencia , Rol del Médico , Derivación y Consulta/legislación & jurisprudencia , Rol , Servicio de Cirugía en Hospital/legislación & jurisprudencia , Hospitales de Distrito/legislación & jurisprudencia , Humanos , Garantía de la Calidad de Atención de Salud/legislación & jurisprudencia , SuizaRESUMEN
Droloxifene (DROL) is a new antiestrogen which is used for the treatment of endocrine-responsive breast cancer in humans. As Droloxifene exists in a Z- and E-isomer, we investigated the main pharmacological properties of both isomers. For both compounds the following tests were conducted: affinity for the estrogen receptor (ER); effect on the growth of rat uteri; influence on the growth of the ER + human breast cancer cell line ZR-75; and isomer interconversion in vitro. DROL-(Z) had binding affinity to the cytosolic ER approximately ten times lower than that of DROL-(E). Furthermore, the estrogenic effect of DROL-(Z) in the rat uterus is weak and there is no antiestrogenic activity. The lack of antiestrogenic activity of DROL-(Z) in contrast to DROL-(E) could also be shown in the human breast cancer cells ZR-75. Thus DROL-(Z) is, as far as investigated, without antiestrogenic and estrogenic activities. Of note is the stability of both DROL-isomers. There is no interconversion or metabolism of the parent compounds DROL-(E) and DROL-(Z) in vitro.
Asunto(s)
Antagonistas de Estrógenos/farmacología , Tamoxifeno/análogos & derivados , Animales , Unión Competitiva , División Celular/efectos de los fármacos , Línea Celular , Femenino , Humanos , Isomerismo , Cinética , Tamaño de los Órganos/efectos de los fármacos , ARN Neoplásico/biosíntesis , ARN Neoplásico/efectos de los fármacos , Receptores de Estradiol/efectos de los fármacos , Receptores de Estradiol/metabolismo , Tamoxifeno/farmacología , Útero/anatomía & histología , Útero/efectos de los fármacosRESUMEN
On the basis of biopharmaceutic-pharmacokinetic and galenic aspects a new sustained-release preparation of theophylline according to the "divided-dose" principle was developed. The technological procedure used allows a reproducible manufacture of a stable product with narrow limits of pharmaceutical quality. The bioavailability of the sustained-release pellets in a dose corresponding to 350 mg active principle is examined in comparison to an aqueous solution or retard-tablet formulation on the marked (containing 260 mg drug/dose), respectively, after single or multiple dose administration to 7 healthy volunteers. The relative bioavailability of the new formulation is about 100%. During chronic application the controlled drug delivery from the sustained-release pellets warrants only slight fluctuations of plasma levels by avoiding peak concentrations. Formulations with a dosage of 200, 350 or 500 mg, respectively, allow adaptation of continuous plasma levels in the therapeutic range between 5--20 micrograms/ml according to the therapeutic necessities of a patient.