Access to Multifunctionalized Benzofurans by Aryl Nickelation of Alkynes: Efficient Synthesis of the Anti-Arrhythmic Drug Amiodarone.

An unconventional nickel-catalyzed reaction was developed for the synthesis of multifunctionalized benzofurans from alkyne-tethered phenolic esters. The transformation involves the generation of a nucleophilic vinyl NiII species by the regioselective syn-aryl nickelation of an alkyne, which then undergoes an intramolecular cyclization with phenol ester to yield highly functionalized 1,1-disubstituted alkenes with 3-benzofuranyl and (hetero)aryl substituents. The methodology can be used for the late-stage benzofuran incorporation of various drug molecules and natural products, such as 2-propylvaleric acid, gemfibrozil, biotin, and lithocholic acid. Furthermore, this arylative cyclization method was successfully applied for the efficient synthesis of the anti-arrhythmic drug amiodarone.

Convergent Synthesis of Dronedarone, an Antiarrhythmic Agent.

We have developed a convergent synthesis of dronedarone, an antiarrhythmic agent. The key steps of the process are the construction of a benzofuran skeleton by iodocyclization and the carbonylative Suzuki-Miyaura cross-coupling for biaryl ketone formation. This synthetic route required only eight steps from 2-amino-4-nitrophenol in 23% overall yield.

Synthesis and characterization of new related substances of the antiarrhythmic drug dronedarone hydrochloride.

Two new potential impurities of antiarrhythmic drug substance Dronedarone Hydrochloride together with debutyldronedarone were detected by LC-MS analysis during process development. A successful synthetic strategy for the synthesis of these potential impurities was developed facilitating the access to new impurity reference standards. Their synthesis and characterization are discussed in detail. The availability of these impurity standards allowed cost reduction through the increase of process control.

OPTIMIZATION OF THE PREPARATION OF KOLLIDON SR-BASED AMIODARONE HYDROCHLORIDE TABLETS WITH SUSTAINED RELEASE.

AIM: The formulation of sustained release tablets of AMD-HCl using KOLLIDON SR as matrix-forming agent. Chitosan, a natural polysaccharide with superior hydrating and absorbing properties was used in the formulation stage to optimize the release characteristics of those matrix tablets. MATERIAL AND METHODS: Nine formulations of sustained release matrix tablets of AMD x HCl (200 mg/tablet) were prepared through direct compression. The concentrations of matrix forming agents were included as independent variables of a type 2(3) mixed factorial plan in order to develop formulations of AMD-HCl with optimal release characteristics. The dependent variables of that plan were the amount of AMD released from the tablets studied by using in vitro dissolution testing. The test was carried out in the paddle apparatus II for 12 hours in two pH media that were relevant to oral delivery: 2 hours at pH 1.2 and 10 hours at pH 6.8. The released AMD-HCl was quantitatively determined through a validated HPLC method. RESULTS: The increase in KOL concentration leads to a decrease in AMD release rate at both pH values. The use of CHT resulted in a decrease of AMD release only at pH 6.8 in formulations with the lowest concentration of KOL. CONCLUSIONS: The retarding effect on the release of AMD-HCl in the tablets developed in this study was directly proportional to the KOL concentration in the formulation.

Eventos cardíacos decorrentes da infusão contínua de cloridrato de amiodarona: implicações para o enfermeiro / Cardiac events originated from the continuous infusion of amiodarone hydrochloride: consequences for the nurse

O objeto de estudo são os eventos cardíacos resultantes da infusão contínua de cloridrato de amiodarona em pacientes que evoluíram com fibrilação atrial em pós-operatório de cirurgia cardíaca. Os objetivos foram descrever as características dos pacientes que receberam infusão contínua de cloridrato de amidoarona, apresentar a prevalência de bradicardia e hipotensão encontrada nos pacientes que receberam infusão contínua de cloridrato de amiodarona e discutir as implicações dos achados para a prática dos enfermeiros a partir da prevalência encontrada de bradicardia e hipotensão decorrente da infusão contínua desta substância. Trata-se de um estudo transversal, retrospectivo, documental, por meio de análise de prontuários e avaliação quantitativa dos mesmos. Desenvolvida em uma unidade de pós-operatório de cirurgia cardíaca em um hospital universitário pertencente à rede sentinela no município do Rio de Janeiro. Foi considerado hipotensão em presença de PAS menor que 90 mmHg e bradicardia em presença de frequência cardíaca menor que 60 bpm. As variáveis que caracterizavam a população do estudo e as aferições de pressão arterial e frequência cardíaca foram transcritas para um instrumento de coleta de dados dos anos de 2010 e 2011, gerando 1782 horas de infusão contínua de cloridrato de amiodarona em 27 pacientes cirúrgicos (10,50%). Tratou-se de uma população predominantemente feminina, com idade a cima de 60 anos, período de internação superior a uma semana, apresentava hipertensão arterial prévia (59,26%), era portadora de fibrilação atrial (55,56%) e o diagnóstico cirúrgico de revascularização do miocárdio com circulação extracorpórea foi predominante (70,37%). Os dados mostram que 85,19% dos pacientes eram portadores de pelo menos um fator de risco, 70,37% apresentavam dois fatores de risco e 55,55% apresentavam três fatores de risco para desenvolver fibrilação atrial no pós-operatório de cirurgia cardíaca...

The subject-matter of the following study is the cardiac events that are consequences from the continuous infusion of amiodarone hydrochloride into patients that developed atrial fibrillation in a postoperative care from a cardiac surgery. The aims of the study are: to describe the characteristics of the patients that received continuous infusion of amiodarone hydrochloride; to present the prevalence of bradycardia and hypotension in the patients that received continuous infusion of amiodarone hydrochloride; and to discuss the implications of the findings for the practice of nurses from the prevalence of bradycardia and hypotension that stemmed from the continuous infusion of amiodarone hydrochloride. This is a cross-sectional, retrospective, documentary study through the analysis and quantitative evaluation of medical records. It was developed in a cardiac surgery postoperative unit in a university hospital that belongs to the Rede Sentinela in the City of Rio de Janeiro. Hypotension was defined as the presence of a systemic arterial blood pressure (ABP) lower than 90 mmHg and bradycardia as the presence of a heart rate below 60 bpm. The variables that characterized the population of the study and the measuring of arterial blood pressure and heart rate were transcribed into a data collection instrument through the years 2010 and 2011, creating 1782 hours of continuous infusion of amiodarone hydrochloride into 27 surgical patients (10,50%). The population of the study was mainly composed of women over 60 years old, with an admission over a week period, they showed pre-existing arterial hypertension (58,26%) and have atrial fibrillation (55,56%) and the surgical diagnosis of myocardium revascularization with extracorporeal circulation was predominant (70,37%)...

Effect of deuteration on the metabolism and clearance of some pharmacologically active compounds--synthesis and in vitro metabolism of deuterated derivatives of dronedadrone.

The synthesis and in vitro metabolism studies of a family of specifically deuterated derivatives of dronedarone are described. Metabolic stability and clearance of the parent compound are not sensitive to deuterium substitution, irrespective of the position of the heavy label.

Novel amiodarone-doxorubicin cocktail liposomes enhance doxorubicin retention and cytotoxicity in DU145 human prostate carcinoma cells.

We have developed novel cocktail liposomes bearing doxorubicin in their hydrophilic cores, and amiodarone, a potent multidrug resistance inhibitor, in their lipid bilayers. The efficacy of these liposomes was studied in DU145 human prostate carcinoma cells. Intracellular calcein retention, which is inversely proportional to multidrug resistance activity, significantly increased following cell incubation with amiodarone loaded liposomes. Fluorescence confocal microscopy on cells incubated with the cocktail liposomes revealed enhanced intranuclear doxorubicin accumulation. Two liposomal drug concentration combinations were employed to assess the differential cytotoxicity of the cocktail liposomes, doxorubicin (1.4 microM)-amiodarone (15 microM) and doxorubicin 3 (microM)-amiodarone (45 microM), and two incubation times, 5 and 19 h. Cell toxicity was determined by XTT assays at 24, 48, and 72 h following incubation and was significantly enhanced for incubation with the cocktail liposomes. On the whole, we believe that these liposomes will greatly contribute to the cancer chemotherapy arena.

Trace amine-associated receptor 1 (TAAR1) is activated by amiodarone metabolites.

Amiodarone (Cordarone, Wyeth-Ayerst Pharmaceuticals) is a clinically available drug used to treat a wide variety of cardiac arrhythmias. We report here the synthesis and characterization of a panel of potential amiodarone metabolites that have significant structural similarity to thyroid hormone and its metabolites the iodothyronamines. Several of these amiodarone derivatives act as specific agonists of the G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR(1)). This result demonstrates a novel molecular target for amiodarone derivatives with potential clinical significance.

Drug evaluation: dronedarone, a novel non-iodinated anti-arrhythmic agent.

sanofi-aventis (formerly Sanofi-Synthelabo) is developing the oral class III anti-arrhythmic agent dronedarone (Multaq) for the potential treatment and prevention of atrial fibrillation. In June 2005, sanofi-aventis submitted EU and US filings for atrial fibrillation. In October 2002, phase I trials for arrhythmia were reported to be ongoing in Japan.

Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives.

Several amiodarone analogues were synthesized varying the 2-substituent on the benzofuran ring and diethylaminoethyl side chain of phenolether by introducing 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole and 1,2,5,6-tetrahydropyridine nitroxides or their amino or hydroxylamino precursors. The new compounds were screened on isolated mitochondria and perfused heart and their toxicity was evaluated on WRL-68 liver cells and H9C2 cardiomyocytes. Most of the newly synthesized derivatives exerted uncoupling effect on the mitochondrial oxidative phosphorilation at higher concentrations, compared to amiodarone and one of the modified amiodarone analogues showed an effect similar to that of amiodarone on the mitochondrial permeability transition and on restoring of mitochondrial high-energy phosphate metabolites in perfused hearts. This amiodarone analogue can be new leading compound among the experimental amiodarone analogues with the same or enhanced efficiency of amiodarone, but with less side effects.

Radiolabeling and biodistribution of amiodarone and desethylamiodarone.

The antiarrhythmic drug amiodarone and its metabolite desethylamiodarone, were radiolabeled with sodium [123I]-iodide in > 98% yield using the exchange labeling method. Biodistribution studies with 123I-amiodarone in mice showed high liver and lung uptake. Heart uptake of 0.98% of the injected dose (id) peaked at 5 min, with clearance seen over 60 min to 0.44% id. 123I-Desethylamiodarone (123I-DEA) showed heart uptake of 0.58% id peaking at 5 min, with slower clearance seen over 60 min to 0.43% id. These results indicate that both agents have poor selectivity as myocardial imaging tracers. Low 123I-DEA brain uptake at 5 min (0.49% id) and rapid washout after 60 min indicate that 123I-desethylamiodarone has limited application as a brain imaging agent.

Aplicacao da catalise de transferencia de fase na avaliacao de rotas alternativas para obtencao industrial da dicicloverina caramifeno e amiodarona / Phase transfer catalysis application in the valuation of the alternatives routes for industrial obtention of the diciclomine, caramiphen and amiodarone

O emprego da catalise de transferencia de fase substituindo uma ou mais etapas da sintese de um farmaco, pode ser um recurso vantajoso sob o ponto de vista tecnologico. Empregando na sintese de importantes farmacos que sao a dicicloverina, caramifeno e amiodarona, a catalise de transferencia de fase revelou-se muito vantajosa na sintese dos dois primeiros. A dicicloverina e o caramifeno tiveram suas rotas de obtencao verticalizadas, com bons resultados e custos bem mais baixos quando comparados com os atualmente adquiridos no exterior. Ficou evidente que a catalise de transferencia de fase pode ser aplicada com sucesso na producao destes e outros farmacos em associacao com tecnicas ja conhecidas com otimos resultados