Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
1.
Surg Technol Int ; 432023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37972544

RESUMO

Failed back surgery syndrome (FBSS) is a complication of spinal surgery that results in severe and disabling back/leg pain. Epiduroscopy is a percutaneous minimally invasive surgical technique used in the treatment of lumbar radicular pain that enables both direct visualization of epidural adhesions in patients with FBSS and the mechanical release of fibrotic scars in the epidural space. Although the use of a balloon catheter during epiduroscopy can usually remove adhesions between the dura and the vertebrae, in the thickest areas of fibrosis, the use of a catheter with a molecular quantum resonance radiofrequency generator may resect hard epidural fibrotic obstructions. The aim of this study was to evaluate the efficacy and safety of this radiofrequency catheter in the treatment of severe epidural fibrotic scars. Ninety-three patients with FBSS were enrolled in this study. In 49 cases, a thick area of fibrosis was visualized during epiduroscopy and the use of a balloon catheter could not remove the fibrotic scars. In all of these cases, we used a molecular quantum resonance radiofrequency catheter to remove dense fibrotic areas. Intraoperatively during epiduroscopy, we could directly visualize lysis of the fibrotic scars. Immediately after the procedure and at 1-month and 6-month follow-up, the patients reported significant pain reduction. Pain reduction and patient satisfaction were also reported at 12 months in all but 5 cases. This study found a clinically relevant reduction of pain at 1 and 6 months after epiduroscopy in patients with FBSS. The use of a radiofrequency catheter is safe and effective in resection of hard and thick epidural scars.

2.
Org Biomol Chem ; 21(4): 743-747, 2023 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-36601663

RESUMO

Cationic, monolayer-protected gold nanoparticles provide a multivalent charged surface and a hydrophobic monolayer that synergistically contribute to the binding of phosphatidylinositol (3,4,5)-trisphosphate, a relevant biomarker. The observed dissociation constant is in the picomolar region, providing the possibility of using these gold nanoparticles for the selective extraction of this molecule from biological fluids.


Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Interações Hidrofóbicas e Hidrofílicas
3.
J Clin Med ; 11(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36556040

RESUMO

Introduction: Radiation exposure is a frequent drawback of spinal surgery, even if X-ray guidance plays a pivotal role in improving the accuracy and safety of spinal procedures. Consequently, radiation protection is essential to reduce potential negative biological effects. The aim of this study was to evaluate patients' radiation exposure, the radiation dose emission during fluoroscopy-guided ozone chemonucleolysis (OCN), and the potential role of patient characteristics. Methods: The radiation dose emission reports were retrospectively evaluated in patients who underwent single-level OCN for lumbar disc herniation. A generalized linear model (GLM) with a gamma distribution and log link function was used to assess the association between radiation emission and patients' characteristics such as age, sex, BMI, level of disc herniation, disc height, and site of disc herniation. Results: Two hundred and forty OCN cases were analyzed. A safe and low level of radiation exposure was registered during OCN. The median fluoroscopy time for OCN was 26.3 (19.4−35.9) seconds, the median radiation emission dose was 19.3 (13.2−27.3) mGy, and he median kerma area product (KAP) was 0.46 (0.33−0.68) mGy ⋅ m2. The resulting KAP values were highly dependent on patient variables. In particular, sex, obesity, and residual disc height < 50% significantly increased the measured KAP, while levels of disc herniations other than L5-S1 reduced the KAP values. Conclusions: The radiation exposure during OCN is low and quite similar to a simple discography. However, patient characteristics are significantly related to radiation exposure and should be carefully evaluated before planning OCN.

4.
PLoS One ; 16(7): e0254550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34255793

RESUMO

BACKGROUND: COVID-19 pandemic has rapidly required a high demand of hospitalization and an increased number of intensive care units (ICUs) admission. Therefore, it became mandatory to develop prognostic models to evaluate critical COVID-19 patients. MATERIALS AND METHODS: We retrospectively evaluate a cohort of consecutive COVID-19 critically ill patients admitted to ICU with a confirmed diagnosis of SARS-CoV-2 pneumonia. A multivariable Cox regression model including demographic, clinical and laboratory findings was developed to assess the predictive value of these variables. Internal validation was performed using the bootstrap resampling technique. The model's discriminatory ability was assessed with Harrell's C-statistic and the goodness-of-fit was evaluated with calibration plot. RESULTS: 242 patients were included [median age, 64 years (56-71 IQR), 196 (81%) males]. Hypertension was the most common comorbidity (46.7%), followed by diabetes (15.3%) and heart disease (14.5%). Eighty-five patients (35.1%) died within 28 days after ICU admission and the median time from ICU admission to death was 11 days (IQR 6-18). In multivariable model after internal validation, age, obesity, procaltitonin, SOFA score and PaO2/FiO2 resulted as independent predictors of 28-day mortality. The C-statistic of the model showed a very good discriminatory capacity (0.82). CONCLUSIONS: We present the results of a multivariable prediction model for mortality of critically ill COVID-19 patients admitted to ICU. After adjustment for other factors, age, obesity, procalcitonin, SOFA and PaO2/FiO2 were independently associated with 28-day mortality in critically ill COVID-19 patients. The calibration plot revealed good agreements between the observed and expected probability of death.


Assuntos
COVID-19/mortalidade , Mortalidade/tendências , COVID-19/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Cardiopatias/epidemiologia , Humanos , Hipertensão/epidemiologia , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Obesidade/epidemiologia
5.
Surg Technol Int ; 38: 491-495, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33999402

RESUMO

Peripheral nerve stimulation (PNS) electrodes are used to treat intractable painful conditions involving peripheral nerves. Methods for performing PNS continue to evolve, from open surgical to minimally invasive placement of electrodes. A PNS system consisting of subcutaneously implanted leads with an integrated anchor and electrodes, and an external pulse generator to produce peripheral neuromodulation, is now available for use in the clinical setting. This novel system allows either surgical or percutaneous lead positioning, and avoids the use of long leads or extensions crossing the joints, which are exposed to mechanical stress and damage. To identify methods for successfully inserting these electrodes, we investigated if a cadaver model could be an effective educational tool for teaching PNS electrode placement using ultrasound guidance. Six cadavers were studied in an attempt to find an ideal approach for ultrasound-guided electrode placement into the upper and lower extremities and cervical spine, and to describe the unique anatomy of the peripheral nerves relative to percutaneous stimulation-electrode placement. The use of cadaveric model simulations offers opportunities to practice percutaneous placement of PNS electrodes under stress-free conditions without patient discomfort, to acquire skill and confidence in performing these surgical approaches. Ultrasound-guided percutaneous placement of PNS electrodes should be learned in a simulation laboratory before such placement is performed in actual patients.


Assuntos
Estimulação Elétrica Nervosa Transcutânea , Cadáver , Eletrodos , Humanos , Nervos Periféricos/diagnóstico por imagem , Ultrassonografia de Intervenção
7.
Pain Pract ; 21(6): 653-661, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33721371

RESUMO

OBJECTIVES: The aim of this study was to retrospectively investigate factors predicting a successful outcome after ozone chemonucleolysis (OCN) in patients with radicular pain and poor response to conservative treatments. METHODS: Univariable and multivariable logistic regression analysis was used to identify the predictors of good outcome after OCN. Good outcome was defined as 33% Oswestry Disability Index (ODI) reduction (model 1) or 13-point ODI improvement (model 2) at 1 month after OCN. RESULTS: Two hundred seventy-three patients were analyzed. A significant pain reduction (pre-operative Numerical Rating Scale [NRS] 6.7 ± 1.5, postoperative NRS 2.6 ± 2.2, P < 0.0001) and ODI improvement (pre-operative ODI 39 ± 13.7, postoperative ODI 21.4 ± 13.8, P < 0.0001) was obtained 1 month after OCN. Pain duration (< 1 year), type of disk herniation based on Michigan State University classification (MSU), stages of disk degeneration revealed by discogram and absence of foraminal stenosis (bony or ligament flavum hypertrophy) appeared as predictors of successful outcome. Age, gender, previous spine surgery, level site of disk herniation, presence of uncontained lumbar disk herniation, and vertebral Modic changes were not statistically associated with the outcome. Both the models showed a good accuracy (model 1, area under the curve [AUC] = 0.84 ± 0.027, 95% confidence interval [CI] = 0.79 to 0.89; model 2, AUC = 0.86 ± 0.024, 95% CI = 0.81 to 0.91). CONCLUSIONS: OCN is an effective treatment for radicular pain due to disk herniation. Pain duration (< 1 year), MSU disk herniation type (1A, 1B, 1C, 2A, and 2B), disk degeneration grade 2, and absence of foraminal stenosis are all associated with the successful outcome and should be carefully evaluated before OCN.


Assuntos
Quimiólise do Disco Intervertebral , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Ozônio , Humanos , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/complicações , Vértebras Lombares/cirurgia , Ozônio/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
8.
Pain Ther ; 10(1): 225-242, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33594594

RESUMO

INTRODUCTION: The present paper focuses on the possible contribution of food compounds to alleviate symptomatic pains. Chronic pain can more easily be linked to anticipatory signals such as thirst and hunger than it is to sensory perceptions as its chronicity makes it fall under the behavioural category rather than it does senses. In fact, pain often negatively affects one's normal feeding behavioural patterns, both directly and indirectly, as it is associated with pain or because of its prostrating effects. NUTRITIONAL COMPOUNDS FOR PAIN: Several nutraceuticals and Foods for Special Medical Purposes (FSMPs) are reported to have significant pain relief efficacy with multiple antioxidant and anti-inflammatory properties. Apart from the aforementioned properties, amino acids, fatty acids, trace elements and vitamins may have a role in the modulation of pain signals to and within the nervous system. CONCLUSION: In our opinion, this review could be of great interest to clinicians, as it offers a complementary perspective in the management of pain. Trials with well-defined patient and symptoms selection and a robust pharmacological design are pivotal points to let these promising compounds become better accepted by the medical community.

9.
Eur J Med Chem ; 183: 111674, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518969

RESUMO

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.


Assuntos
Amidoidrolases/antagonistas & inibidores , Dopamina/metabolismo , Endocanabinoides/metabolismo , Amidoidrolases/metabolismo , Ligação Competitiva , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Pirróis/química , Pirróis/farmacologia
11.
ChemMedChem ; 12(16): 1254-1260, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28426179

RESUMO

This Minireview describes a presentation made at the XXIV National Meeting in Medicinal Chemistry (NMMC) held in Perugia (Italy), September 11-14, 2016. It relates to the discovery of novel templates of the so-called "amino" region of dopamine D3 receptor antagonists. Moving from the early scaffolds, which were modified in the amine portion, this review discusses the variations that led to the discovery of new systems published in 2016, which allowed the identification of compounds endowed with great selectivity over the dopamine D2 receptor and the human ether-à-go-go-related gene (hERG) ion channel. The main efforts in characterizing these compounds were devoted not only to determining their potency and selectivity relative to closely associated targets (e.g., the dopamine D2 receptor), but to ensure a large therapeutic window versus liability points such as hERG. In particular, we present examples of derivatives with selectivities greater than 2000-fold. Furthermore, much focus is devoted to the overall developability of the scaffolds, ensuring that appropriate physicochemical and pharmacokinetic parameters are present in all compounds progressing through the screening cascade.


Assuntos
Antagonistas de Dopamina/química , Receptores de Dopamina D3/metabolismo , Antagonistas de Dopamina/metabolismo , Desenho de Fármacos , Heptanos/química , Heptanos/metabolismo , Humanos , Morfolinas/química , Morfolinas/metabolismo , Ligação Proteica , Pirróis/química , Pirróis/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/antagonistas & inibidores , Relação Estrutura-Atividade
12.
J Med Chem ; 59(18): 8549-76, 2016 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-27564135

RESUMO

A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.


Assuntos
Heptanos/química , Heptanos/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Células CHO , Cricetulus , Cristalografia por Raios X , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
13.
Bioorg Med Chem ; 24(8): 1619-36, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26951894

RESUMO

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.


Assuntos
Pirróis/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
15.
ChemMedChem ; 9(7): 1501-11, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24616267

RESUMO

Cystalysin from Treponema denticola is a pyridoxal 5'-phosphate dependent lyase that catalyzes the formation of pyruvate, ammonia, and sulfide from cysteine. It is a virulence factor in adult periodontitis because its reaction contributes to hemolysis, which sustains the pathogen. Therefore, it was proposed as a potential antimicrobial target. To identify specific inhibitors by structure-based in silico methods, we first validated the crystal structure of cystalysin as a reliable starting point for the design of ligands. By using single-crystal absorption microspectrophotometry, we found that the enzyme in the crystalline state, with respect to that in solution, exhibits: 1) the same absorption spectra for the catalytic intermediates, 2) a close pKa value for the residue controlling the keto enamine ionization, and 3) similar reactivity with glycine, L-serine, L-methionine, and the nonspecific irreversible inhibitor aminoethoxyvinylglycine. Next, we screened in silico a library of 9357 compounds with the Fingerprints for Ligands and Proteins (FLAP) software, by using the three-dimensional structure of cystalysin as a template. From the library, 17 compounds were selected and experimentally evaluated by enzyme assays and spectroscopic methods. Two compounds were found to competitively inhibit recombinant T. denticola cystalysin, with inhibition constant (Ki ) values of 25 and 37 µM. One of them exhibited a minimum inhibitory concentration (MIC) value of 64 µg mL(-1) on Moraxella catarrhalis ATCC 23246, which proves its ability to cross bacterial membranes.


Assuntos
Cistationina gama-Liase/antagonistas & inibidores , Inibidores Enzimáticos/química , Treponema denticola/enzimologia , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Domínio Catalítico , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Periodontite/tratamento farmacológico , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Treponema denticola/efeitos dos fármacos
16.
Int Immunopharmacol ; 18(1): 169-74, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24287448

RESUMO

Opioid compounds, such as morphine, induce powerful analgesic effects and are extensively used clinically to treat a wide variety of pain. The aim of our study was to evaluate the impact of opioid therapy on phenotype and function peripheral blood NK cells. The patients were referred to three Italian pain therapy centers (Milan, Pavia, Piacenza) for chronic pain in neuropathic or mixed somatic components. The patients were between 18 and 75 years old and were of Caucasian ethnicity. We studied the expression of activating and inhibitory NK receptors to discriminate NK subsets with different CD56 surface expression intensities (CD56(bright) and CD56(dull) NK cells). The flow cytometry analysis of the NK cells was at normal levels in peripheral blood lymphocytes with fewer CD56(bright) compared to the CD56(dull) NK cell subset when compared to blood from drug free donors. Furthermore, the cytolytic activity of in vitro patient NK cells analyzed was not lower, as would be expected from the regular expression of activating NK receptors for both subsets. Taken together, these data indicate that NK cells from opioid treated patients do not show any signs of NK cell immune-suppression.


Assuntos
Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Células Matadoras Naturais/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Morfina/administração & dosagem , Adolescente , Adulto , Idoso , Analgésicos Opioides/efeitos adversos , Antígeno CD56/metabolismo , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Receptores KIR/metabolismo , Adulto Jovem
17.
Expert Opin Ther Pat ; 23(3): 363-81, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23282131

RESUMO

INTRODUCTION: The synthesis and characterization of new highly potent and selective dopamine (DA) D3 receptor antagonists has permitted to characterize the role of the DA D3 receptor in the control of drug-seeking behavior and in the pathophysiology of impulse control disorders and schizophrenia. AREAS COVERED: In the present review, the authors will first describe most recent classes of DA D3 receptor antagonists by reviewing about 43 patent applications during the 2007 - 2012 period; they will then outline the biological rationale in support of the use of selective DA D3 receptor antagonists in the treatment of drug addiction, impulse control disorders and schizophrenia. EXPERT OPINION: The strongest clinical application and potential for selective DA D3 receptor antagonists lies in the reduction of drug-induced incentive motivation, the attenuation of drug's rewarding efficacy and the reduction in reinstatement of drug-seeking behavior triggered either by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior or stress. The selectivity of these antagonists together with reduced lipophilicity (minimizing unspecific binding), increased brain penetration and improved physico-chemical profile are all key factors for clinical efficacy and safety.


Assuntos
Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Antiparkinsonianos/farmacologia , Ensaios Clínicos como Assunto , Cognição/efeitos dos fármacos , Sinais (Psicologia) , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Antagonistas de Dopamina/uso terapêutico , Ejaculação/efeitos dos fármacos , Feminino , Humanos , Nefropatias/prevenção & controle , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiologia , Masculino , Motivação/efeitos dos fármacos , Patentes como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recompensa , Esquizofrenia/tratamento farmacológico , Prevenção Secundária , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia
18.
Neuropsychopharmacology ; 38(2): 302-12, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22968817

RESUMO

Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.


Assuntos
Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Receptores de Dopamina D3/metabolismo , Fumar/tratamento farmacológico , Fumar/metabolismo , Pesquisa Translacional Biomédica/métodos , Adulto , Animais , Células CHO , Cricetinae , Cricetulus , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Papio anubis , Ligação Proteica/fisiologia , Ratos , Receptores de Dopamina D3/antagonistas & inibidores , Abandono do Hábito de Fumar/métodos
19.
Pharm Pat Anal ; 1(4): 469-81, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24236884

RESUMO

Agents interfering with the reuptake of catecholamines and tryptamines are well-known drugs capable of treating serious illnesses, including depression, pain and dependence. Further therapeutic applications and use have been tested and an increase in the variety of the chemical templates has been achieved in the last few years. This review attempts to give an organic overview of molecules capable of simultaneously interfering with the reuptake of all the three major monoamine neurotransmitters (dopamine, norepinephrine/noradrenaline and serotonin).


Assuntos
Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Ciclobutanos/farmacologia , Ciclopropanos/farmacologia , Heptanos/farmacologia , Hexanos/farmacologia , Humanos , Tropanos/farmacologia
20.
Bioorg Med Chem ; 19(11): 3451-61, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21550808

RESUMO

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.


Assuntos
Inibidores da Captação Adrenérgica/química , Inibidores da Captação de Dopamina/química , Heptanos/química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/farmacologia , Heptanos/síntese química , Heptanos/farmacologia , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...