RESUMO
The antidepressants trazodone and nefazodone were approved some 4 and 3 decades ago, respectively. Their action is thought to be mediated, at least in part, by inhibition of the serotonin transporter [SERT/solute carrier (SLC)-6A4]. Surprisingly, their mode of action on SERT has not been characterized. Here, we show that, similar to the chemically related drug vilazodone, trazodone and nefazodone are allosteric ligands: trazodone and nefazodone inhibit uptake by and transport-associated currents through SERT in a mixed-competitive and noncompetitive manner, respectively. Contrary to noribogaine and its congeners, all three compounds preferentially interact with the Na+-bound outward-facing state of SERT. Nevertheless, they act as pharmacochaperones and rescue the folding-deficient variant SERT-P601A/G602A. The vast majority of disease-associated point mutations of SLC6 family members impair folding of the encoded transporter proteins. Our findings indicate that their folding defect can be remedied by targeting allosteric sites on SLC6 transporters. SIGNIFICANCE STATEMENT: The serotonin transporter is a member of the solute carrier-6 family and is the target of numerous antidepressants. Trazodone and nefazodone have long been used as antidepressants. Here, this study shows that their inhibition of the serotonin transporter digressed from the competitive mode seen with other antidepressants. Trazodone and nefazodone rescued a folding-deficient variant of the serotonin transporter. This finding demonstrates that folding defects of mutated solute carrier-6 family members can also be corrected by allosteric ligands.
Assuntos
Antidepressivos , Piperazinas , Proteínas da Membrana Plasmática de Transporte de Serotonina , Trazodona , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Trazodona/farmacologia , Trazodona/metabolismo , Humanos , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Piperazinas/farmacologia , Piperazinas/metabolismo , Regulação Alostérica/efeitos dos fármacos , Células HEK293 , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Triazóis/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Cloridrato de Vilazodona/farmacologia , Cloridrato de Vilazodona/metabolismoRESUMO
The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective ß-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Hemodinâmica/efeitos dos fármacos , Morfolinas/farmacocinética , Propanolaminas/farmacocinética , Ureia/análogos & derivados , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Adulto , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , República Tcheca , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Propanolaminas/administração & dosagem , Propanolaminas/efeitos adversos , Estudos Prospectivos , Equivalência Terapêutica , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/farmacocinética , População Branca , Adulto JovemRESUMO
Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective ß-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hours, 20 µg/kg BW/min for 2 hours, 40 µg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Ureia/análogos & derivados , População Branca , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Estudos Prospectivos , Ureia/administração & dosagem , Ureia/farmacocinéticaRESUMO
PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective ß1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Morfolinas/administração & dosagem , Propanolaminas/administração & dosagem , Ureia/análogos & derivados , População Branca , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Morfolinas/farmacocinética , Morfolinas/farmacologia , Propanolaminas/farmacocinética , Propanolaminas/farmacologia , Estudos Prospectivos , Ureia/administração & dosagem , Ureia/farmacocinética , Ureia/farmacologia , Adulto JovemRESUMO
BACKGROUND: Alcoholism is a chronic and potentially fatal disease. One of the therapeutic options is pharmacotherapy with the opioid antagonist naltrexone in combination with psychotherapy. OBJECTIVES: The objective of this review was to compare the clinical effectiveness of naltrexone (50 mg/day) versus that of a placebo in alcohol-dependent patients receiving psychotherapy. METHODS: The clinical effectiveness of the treatment was assessed in accordance with the principles of systematic review, as outlined in the Cochrane Collaboration guidelines (Cochrane Reviewer's Handbook) and the guidelines of the Polish Agency for Health Technology Assessment (AHTAPol). RESULTS: Statistical significances in favor of the treatment modality were found in both the percentage of patients maintaining total abstinence and the percentage of relapsed patients. CONCLUSION: The analysis herein demonstrates that for short (12-16 weeks) period of treatment, a combination of naltrexone administration and psychotherapy results in high clinical efficacy with a safety profile comparable to that of the placebo in the treatment of alcohol-dependent patients. The side effects of naltrexone treatment are usually mild and transient.
Assuntos
Alcoolismo/terapia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Psicoterapia/métodos , Terapia Combinada , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
We investigated the hemodynamic effects of 2 short-acting ß1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 µg/kg/min esmolol or 10 µg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of ß-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of ß-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for ß-blockers, whereas the blood pressure effects are likely due to direct and indirect ß-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.
Assuntos
Dobutamina , Pressão Sanguínea , Estudos Cross-Over , Dobutamina/farmacologia , Humanos , Morfolinas , Propanolaminas , Estudos Prospectivos , Ureia/análogos & derivadosRESUMO
BACKGROUND: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. METHODS: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 µg/kg/min landiolol. RESULTS: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20-60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. CONCLUSION: Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. TRIAL REGISTRATION: Registration number 2010-023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.
Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacocinética , Dobutamina/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/farmacocinética , Ureia/análogos & derivados , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Pressão Sanguínea/fisiologia , Cardiotônicos/administração & dosagem , Estudos Cross-Over , Dobutamina/administração & dosagem , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Frequência Cardíaca/fisiologia , Humanos , Infusões Intravenosas , Masculino , Morfolinas/administração & dosagem , Estudos Prospectivos , Ureia/administração & dosagem , Ureia/farmacocinética , Adulto JovemRESUMO
Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes. Results In the presence of dobutamine, esmolol elimination was substantially faster than without dobutamine, Esmolol infusion reduced dobutamine-induced elevation of HR reversibly whereas the dobutamine-induced systolic blood pressure (SBP) reduction did not recover after the termination of the esmolol infusion. No serious adverse events (AEs) were observed. Conclusions The accelerated elimination of esmolol was likely due to higher cleavage through tissue esterases induced by dobutamine-induced increased tissue passage cycles per time unit. The HR effect was characteristic of a beta-blocker, whereas the blood pressure effect was likely due to a mechanism other than direct beta-blockade. HR remained elevated after the infusion of esmolol and dobutamine, most likely due to persistent blood pressure reduction.
RESUMO
BACKGROUND: Anagrelide hydrochloride is an anti-thrombotic agent indicated for the treatment of essential thrombocythemia (ET). In various previously published clinical trials of 2 branded formulations of anagrelide in patients with ET at high risk for thrombohemorrhagic events, the rates of adverse events and discontinuation were strikingly divergent between brands. Because the formulations and manufacturers differed, the differences in tolerability, as well as platelet counts, might have been related to differences in pharmacokinetic properties between the 2 formulations. OBJECTIVES: The present series of investigations (1) determined the pharmacokinetic profile of anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test and reference formulations of anagrelide; (3) investigated the in vitro release of anagrelide as a marker of intragastric anagrelide release of the test and reference formulations; and (4) compared the platelet-reducing effects of the test and reference formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks. METHODS: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, prospective, singledose study in healthy volunteers, the pharmacokinetic properties (C(max), T(max), and AUC(0-infinity)) of a test formulation of anagrelide were assessed using high-performance liquid chromatography analysis of plasma samples. Based on the results from that study, a single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers was conducted to determine bioequivalence of 2 formulations of anagrelide 2 mg/d (taken as 4 capsules). In vitro dissolution properties of the test or reference formulation containing 0.5 mg anagrelide as the active ingredient were studied in an assay mimicking gastrointestinal release. To test for effects on platelet counts of switching from the reference formulation (previous treatment on stable dose for 3 months) to the test formulation, two 4-week longitudinal trials were conducted: one in patients with ET (in Germany), and one in patients with thrombocythemia associated with chronic myeloproliferative disorders (CMPDs) (in Austria). RESULTS: The pilot pharmacokinetic study of the test formulation in 16 volunteers (10 women, 6 men; mean [SD] age, 20.5 [1.5] years; weight, 69.0 [10.0 kg) suggested that anagrelide was metabolized to 3-hydroxyanagrelide (AUC(0-infinity) 50% compared with anagrelide) and the inactive metabolite 2-amino-5,6-dichloro-,4-dihydroquinazolone. The subsequent bioequivalence study in 24 volunteers (14 women, 10 men; mean [SD] age, 23 [4] years; white, 100%; weight, 67.5 [10.2] kg) found that the test formulation was associated with a significantly lower C(max) (point estimation [PE], 66%; 90% CI, 58%-76%; P < 0.001) and AUC(0-infinity) (PE, 77%; 90% CI, 68%-86%; P = 0.001). T(max) values for anagrelide and 3-hydroxyanagrelide were 1 hour longer with the test formulation compared with the reference formulation. The total number of adverse events with the reference formulation was 46; the test formulation, 29 (P = 0.05). In vitro, anagrelide from the reference formulation was immediately released (89.1% at 5 minutes), whereas there was a delayed release (93.6% at 30 minutes) from the test formulation (P < 0.05). In the last 2 studies, 2 cohorts of white patients (cohort 1, 15 patients with ET; 10 women, 5 men; mean [SD] age, 49.0 [10.7] years [range, 31-66 years]; weight, 73.2 [12.6] kg; cohort 2, 19 patients with thrombocythemia associated with CMPD; 12 women, 7 men; age, 62.6 [12.4] years [range, 38-80 years]; weight, 66.1 [13.3] kg) who had received treatment for > or =3 months with the reference formulation were switched to the same dose of the test formulation and maintained on this dose for 4 weeks. Platelet counts did not change significantly from baseline over 4 weeks and stayed within a predefined margin of 150 x 10(3) cells/microL. CONCLUSIONS: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile differed between the test and reference anagrelide formulations in these healthy volunteers. In patients with ET or thrombocythemia associated with CMPD, platelet counts did not differ significantly from baseline at 4 weeks when subjects were switched from the reference to the test anagrelide formulation.
Assuntos
Transtornos Mieloproliferativos/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Quinazolinas/administração & dosagem , Trombocitose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/métodos , Doença Crônica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/fisiopatologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Contagem de Plaquetas , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Solubilidade , Equivalência Terapêutica , Trombocitose/etiologia , Adulto JovemRESUMO
Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via "danger signals". The recent phase II "GBM-Vax" trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel's effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel's general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up-regulation of the Th1-related immunovariables ELISPOT IFNγ, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNγ and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further - with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers.
Assuntos
Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/fisiologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/fisiologia , Glioblastoma/terapia , Antígenos CD/metabolismo , Compostos de Boro/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Glioblastoma/sangue , Glioblastoma/imunologia , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Estudos Longitudinais , Masculino , Resultado do Tratamento , Regulação para CimaRESUMO
BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Unidades de Terapia Intensiva , Morfolinas/uso terapêutico , Choque Séptico/tratamento farmacológico , Ureia/análogos & derivados , Antagonistas Adrenérgicos beta/efeitos adversos , Antiarrítmicos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos Fase IV como Assunto , Europa (Continente) , Humanos , Morfolinas/efeitos adversos , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Choque Séptico/diagnóstico , Choque Séptico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Ureia/efeitos adversos , Ureia/uso terapêutico , Vasoconstritores/uso terapêuticoRESUMO
Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3â»20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436â»671 versus control: 568 days, 95% CI: 349â»680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.
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BACKGROUND: To date, no data have been reported on the pharmacokinetic and pharmacodynamic properties of landiolol, a fast-acting cardioselective ß1-adrenergic antagonist, in non-Asian subjects. The aim of this study was to compare two landiolol formulations in healthy Caucasian subjects. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in two cross-over periods with 12 healthy subjects (7 women and 5 men) each receiving three doses (0.1, 0.2, and 0.3mg/kg BW) of Onoact® 50 Lyophilized powder (50mg) or Rapibloc® concentrate IV (20mg/2mL) to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the two landiolol formulations. RESULTS: For both formulations, maximum blood concentrations of landiolol were rapidly reached (median tmax 2.3±0.65 and 2.8±1.13min for the high dose of each formulation). The compounds had a short half-life (t1/2=3.2±1.2min and 3.0±1.1min for the low dose of the concentrate formulation and the lyophilized powder, respectively). The results showed no statistically significant differences between both formulations of landiolol for any PK parameters, at study doses. Both formulations dose-dependently and significantly decreased the heart rate values from 62.2bpm at baseline to minimum values of 55-56, 52-53, and 50-52bpm after 0.1, 0.2, and 0.3mg/kg respectively. This bradycardic effect was achieved within 1 to 3min. The decrease in systolic blood pressure (baseline: 107mmHg, minimum values were around 99mmHg) was significant but not dose dependent, and occurred within 3 to 12min. Seven mild to moderate AEs occurred after administration of the concentrate formulation. No SAEs were reported in this study. CONCLUSION: In Caucasians, both landiolol formulations showed similar pharmacokinetic behaviours, displaying very short half-lives (3.0 to 3.6min). In addition, after administration of both formulations, the landiolol-induced heart rate reduction showed fast onset and dose dependence, whilst the decrease of systolic blood pressure occurred more slowly, was less pronounced, and dose independent. In summary, both landiolol formulations delivered comparable plasma concentration profiles and showed good local tolerability. Overall, the pharmacokinetic and pharmacodynamic reactions observed in Caucasians were comparable to those described in Japanese subjects.