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1.
Folia Morphol (Warsz) ; 80(4): 1027-1031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33124034

RESUMO

During educational dissection of cadavers, we encountered anatomical variability of the left phrenic nerve (PN). In this cadaver, nerve fibres from C3 and C4 descended and crossed behind the transverse cervical artery (TCA), a branch of the thyrocervical trunk, at the level of the anterior scalene muscle. On the other hand, nerve fibres from C5 descended obliquely above the TCA and then joined the fibres from C3-C4 on the medial side of the anterior scalene muscle to form the PN. To our knowledge, the encircling of the TCA by the left PN in the neck has not yet been reported and may pose a potential risk for nerve compression during movement of the neck. We discuss several types of anatomical variants of the PN and the associated risk during thorax and neck dissection procedures.


Assuntos
Pescoço , Nervo Frênico , Cadáver , Dissecação , Humanos , Nervo Frênico/anatomia & histologia , Artéria Subclávia
2.
Osteoporos Int ; 32(5): 939-949, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33128075

RESUMO

Low phase angle, a non-invasive bioimpedance marker, is associated with elevated odds of dysmobility syndrome and its components. Phase angle (estimated cutoffs: < 4.8° in men; < 4.5° in women) can be used to detect dysmobility syndrome in community-dwelling older adults as a simple, integrative screening tool. INTRODUCTION: Dysmobility syndrome uses a score-based approach to predict fracture risk that incorporates the concepts of osteoporosis, sarcopenia, and obesity. Low phase angle (PhA), a simple, non-invasive bioelectrical impedance marker, was associated with low lean mass, high fat mass, and poor muscle function. We aimed to investigate the association between PhA and dysmobility syndrome, with the exploration of the diagnostic cutoffs. METHODS: In a community-dwelling Korean older adult cohort, dysmobility syndrome was defined as the presence of ≥ 3 of the following components: osteoporosis, low lean mass, falls in the preceding year, low grip strength, high fat mass, and poor timed up and go performance. RESULTS: Among the 1825 participants (mean age 71.6, women 66.7%), subjects were classified into sex-stratified PhA tertiles. The prevalence of dysmobility syndrome increased from the highest PhA tertile group to the lowest (15.50 to 2.45% in men; 33.41 to 12.25% in women, P for trend < 0.001). The mean PhA values decreased as the dysmobility score increased (5.33° to 4.65° in men; 4.76° to 4.39° in women, P for trend < 0.001). Low PhA (cutoff: < 4.8° in men; < 4.5° in women) was associated with twofold elevated odds of dysmobility syndrome after adjusting for age, sex, and conventional risk factors. Low PhA improved the identification of individuals with dysmobility syndrome when added to the conventional risk model (area under the curve, 0.73 to 0.75, P = 0.002). CONCLUSION: Low PhA was associated with dysmobility syndrome and its components, independent of age, sex, body mass index, nutritional status, and inflammation.


Assuntos
Osteoporose , Sarcopenia , Idoso , Feminino , Humanos , Vida Independente , Masculino , Osteoporose/diagnóstico , Osteoporose/epidemiologia , República da Coreia/epidemiologia , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Síndrome
3.
BJOG ; 124(2): 314-320, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27342222

RESUMO

OBJECTIVE: The aim of the study was to investigate whether opportunistic salpingectomy has any deleterious effects on ovarian reserve and increases surgical risk in patients undergoing laparoscopic hysterectomy. DESIGN: A multicentre, randomised controlled trial. SETTING: Three university hospitals in Korea. POPULATION: Sixty-eight patients undergoing laparoscopic hysterectomy for the treatment of symptomatic benign uterine diseases. METHODS: Patients were randomised to undergo either opportunistic salpingectomy (n = 34) or no salpingectomy (n = 34) during laparoscopic hysterectomy. MAIN OUTCOME MEASUREMENTS: The primary and secondary outcome measures were the change of ovarian reserve, determined by the rate of decline in anti-Müllerian hormone (AMH) level from before surgery to 3 months post-surgery and surgical outcomes, respectively. RESULTS: Baseline demographic and clinical characteristics were similar between the two groups. There was also no difference in operative outcomes such as operative time, operative bleeding, or complications between the two groups. In both groups, postoperative AMH levels were significantly lower than preoperative AMH levels (both, P < 0.01). The decline rate in AMH was 12.5% (interquartile range 0.8-60.9%) in the opportunistic salpingectomy group and 10.8% (interquartile range 6.9-27.4%) in the no salpingectomy group, with no significant difference between both groups (P = 0.898). CONCLUSIONS: Opportunistic salpingectomy at the time of laparoscopic hysterectomy did not have any negative effects on ovarian reserve or increased surgical risk. TWEETABLE ABSTRACT: Opportunistic salpingectomy did not have any negative effects on ovarian reserve or increased surgical risk.


Assuntos
Hormônio Antimülleriano/sangue , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Salpingectomia/efeitos adversos , Doenças Uterinas/cirurgia , Adulto , Feminino , Humanos , Histerectomia/métodos , Laparoscopia/métodos , Pessoa de Meia-Idade , Reserva Ovariana/fisiologia , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , República da Coreia , Salpingectomia/métodos , Resultado do Tratamento , Doenças Uterinas/sangue , Doenças Uterinas/fisiopatologia
4.
Eur J Obstet Gynecol Reprod Biol ; 195: 177-181, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26550945

RESUMO

OBJECTIVE: To compare the effectiveness and safety of vasopressin with epinephrine for reducing blood loss during laparoscopic myomectomy. STUDY DESIGN: Sixty patients undergoing laparoscopic myomectomy were allocated at random to receive either dilute vasopressin or epinephrine into the serosal and/or overlying myometrium, and just around the myoma. The surgeon was blinded to the group allocation. Blood loss, duration of surgery, degree of surgical difficulty, postoperative pain scores and complications were compared. RESULTS: Patient characteristics (e.g. age, body mass index, demographic data), number of myomas, and location and size of the largest myoma were similar between the two study groups. There were no differences in operative blood loss, operative time, subjective surgical difficulty or postoperative pain between the two groups. Transient and non-serious increases in systolic and diastolic blood pressure and heart rate following intra-operative intramyometrial and/or perimyometrial injection of the vasoconstrictive agent only occurred in the epinephrine group, but the difference between the groups was not significant (13% vs 0%, p=0.112). No significant postoperative complications were observed in either group. CONCLUSIONS: Injection of dilute epinephrine before laparoscopic myomectomy was comparable to injection of dilute vasopressin in terms of operative blood loss, operative time, subjective surgical difficulty, postoperative pain and complications.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Epinefrina/uso terapêutico , Leiomioma/cirurgia , Neoplasias Primárias Múltiplas/cirurgia , Hemorragia Uterina/prevenção & controle , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Vasoconstritores/uso terapêutico , Vasopressinas/uso terapêutico , Adulto , Feminino , Humanos , Laparoscopia , Pessoa de Meia-Idade
5.
PLoS One ; 10(7): e0132955, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26181329

RESUMO

OBJECTIVES: We aimed to compare tissue-specific expression profiles and biological pathways of RNA from amniocytes and amniotic fluid supernatant (AFS) from second-trimester pregnancies by using transcriptome analysis. Additionally, we wanted to explore whether cell-free RNA from AFS exhibits a unique gene expression signature that more adequately reflects the fetal developmental process than amniocyte RNA. METHODS: Amniotic fluid samples were prospectively collected in the second trimester of pregnancy from euploid fetuses. Total RNA was extracted from amniocytes and AFS and hybridized to Affymetrix GeneChip Human Arrays. Significantly differentially expressed transcripts between amniocytes and AFS were obtained by using Welch's t-test. Unsupervised hierarchical clustering was used to visualize overall expression characteristics and differences in transcripts between AFS and amniocytes. The biological functions of selected genes were analyzed using various online Gene Ontology databases. RESULTS: A total of 3,072 and 15,633 transcripts were detected in the second-trimester AFS and amniocytes, respectively. Hierarchical clustering revealed differential transcript expression between AFS and amniocytes. We found 353 genes that were specifically enriched in the AFS only, and tissue expression analysis showed enrichment of brain-specific genes in the AFS. Biological pathway analysis revealed that AFS-specific transcripts were mainly involved in embryonic development, cardiovascular development, and cellular morphology pathways. CONCLUSION: This study demonstrated differential tissue-specific gene expression profiles and biological pathways between AFS and amniocytes. The results suggested that AFS is the preferred RNA source to investigate potential biomarkers of fetal neurodevelopment.


Assuntos
Líquido Amniótico/metabolismo , Feto/metabolismo , RNA/genética , Transcriptoma , Adulto , Amniocentese , Líquido Amniótico/química , Células Cultivadas , Feminino , Feto/citologia , Perfilação da Expressão Gênica , Humanos , Anotação de Sequência Molecular , Família Multigênica , Neurogênese/genética , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Segundo Trimestre da Gravidez , RNA/metabolismo
6.
Gene Ther ; 19(12): 1159-65, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22170343

RESUMO

Current gene therapies are predominantly based on a handful of viral vectors. The limited choice of delivery vectors has been one of the stumbling blocks to the advancement of gene therapy. Therefore, the development of novel recombinant vectors should facilitate the application of gene therapies. In this study, we examined coxsackievirus B3 (CVB3) as a novel recombinant vector for the delivery and expression of a foreign gene in vitro and in vivo. A recombinant CVB3 complementary DNA was constructed by inserting a gene encoding human fibroblast growth factor 2 (FGF2). The recombinant virus (CVB3-FGF2) efficiently expressed FGF2 in HeLa cells and human cardiomyocytes in vitro and in mouse hindlimbs in vivo. The injection of the recombinant virus into mice with ischemic hindlimbs protected the hindlimbs from ischemic necrosis. CVB3-FGF2 injection significantly improved the blood flow in the ischemic limbs for over 3 weeks compared with that in the phosphate-buffered saline- or CVB3-injected controls, suggesting that FGF2 expressed from CVB3-FGF2 is functional and therapeutically effective. The virulence of CVB3 was also drastically attenuated in the recombinant virus. Thus, CVB3 can be modified to express a functional foreign protein, supporting its use as a novel viral vector for gene therapy.


Assuntos
Enterovirus Humano B/genética , Fator 2 de Crescimento de Fibroblastos/genética , Terapia Genética , Vetores Genéticos , Animais , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células HeLa , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/terapia , Camundongos , Miócitos Cardíacos/metabolismo , Fluxo Sanguíneo Regional , Virulência
8.
Bioorg Med Chem Lett ; 11(8): 1045-7, 2001 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-11327585

RESUMO

A series of arylhydantoin derivatives modeled after the antiandrogen RU 58841 was generated to identify potential candidates for development as androgen receptor (AR) radioligands. Side-chain modified derivatives of RU 58841, suitable for labeling with either carbon-11 or radiohalogens (fluorine-18, iodine-123), were synthesized and tested for their AR binding affinities. The N-(iodopropenyl) derivative 13 (Ki = 13 nM) is a potential candidate for development as a radioiodinated AR ligand.


Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/metabolismo , Animais , Sítios de Ligação/fisiologia , Isótopos de Carbono/química , Flúor/química , Hidantoínas/síntese química , Hidantoínas/metabolismo , Imidazóis/metabolismo , Nitrilas/metabolismo , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade
9.
J Korean Med Sci ; 15(1): 111-4, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10719821

RESUMO

Fibrosing cholestatic hepatitis is an aggressive and usually fatal form of viral hepatitis in immunosuppressed patients. We report three cases of fibrosing cholestatic hepatitis in various clinical situations. Case 1 was a 50-year-old man who underwent a liver transplant for hepatitis B virus (HBV)-associated liver cirrhosis. Two and a half years after the transplant, he complained of fever and jaundice, and liver enzymes were slightly elevated. Serum HBsAg was positive. Case 2 was a 30-year-old man in an immunosuppressed state after chemotherapy for acute lymphoblastic leukemia. He was a HBV carrier. Liver enzymes and total bilirubin were markedly elevated. Case 3 was a 50-year-old man who underwent renal transplantation as a known HBV carrier. One year after the transplant, jaundice developed abruptly, but liver enzymes were not significantly elevated. Microscopically lobules were markedly disarrayed, showing ballooning degeneration of hepatocytes, prominent pericellular fibrosis, and marked canalicular or intracytoplasmic cholestasis. Portal inflammation was mild, but interphase activity was definite and cholangiolar proliferation was prominent. Hepatocytes were diffusely positive for HBsAg and HBcAg in various patterns. Patients died of liver failure within 1 to 3 months after liver biopsy in spite of anti-viral treatment.


Assuntos
Colestase Intra-Hepática/etiologia , Hepatite B/complicações , Adulto , Colestase Intra-Hepática/imunologia , Colestase Intra-Hepática/virologia , Fibrose , Humanos , Terapia de Imunossupressão/efeitos adversos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade
10.
Neuroreport ; 10(3): 443-7, 1999 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-10208569

RESUMO

Little is known about the molecular organization and functions of the postsynaptic density (PSD), a cytoskeletal specialization on the postsynaptic membrane. In an attempt to elucidate the protein composition of PSD, we have sequenced a 35 kDa protein of the rat forebrain PSD fraction. Amino acid sequence information of the tryptic peptides and immunoblot analyses revealed that the protein is a voltage-dependent anion channel 1 (VDAC1). VDAC1 was enriched in the PSD fraction and was partially soluble in 1% n-octyl glucoside (NOG) or Triton X-100. Our data indicate that VDAC1, which is originally found in the outer mitochondrial membrane, is also present in the central nervous system (CNS) synapses in association with the PSD 'core'.


Assuntos
Frações Subcelulares/metabolismo , Sinapses/metabolismo , Sequência de Aminoácidos/genética , Animais , Cromatografia Líquida de Alta Pressão , Immunoblotting , Porinas/química , Porinas/genética , Porinas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Sinapses/ultraestrutura , Canal de Ânion 1 Dependente de Voltagem , Canais de Ânion Dependentes de Voltagem
11.
Mol Cells ; 7(1): 64-71, 1997 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-9085267

RESUMO

We carried out quantitative analyses of the developmental expression, subcellular localization of the N-methyl-D-aspartate receptor subunit 2A (NR2A) and 2B (NR2B), and tyrosine phosphorylation of NR2B. Immunoblot analyses showed that NR2A was not detected during the embryonic period and the first postnatal week but its expression reached 63.90% of adult at P14 and continued to increase until the fourth week, reaching a maximum at P30 (110% of adult). The NR2B was detected from as early as E14 (2.65% of adult) and its expression was transiently elevated at birth (43.73% of adult), decreasing for the first postnatal week, and then increased again rapidly in the second week (105.45% of adult at P14) with a maximum at P30 (123.34% of adult). There were 2.26 +/- 0.40-fold more NR2B than NR2A proteins in the forebrain PSD fractions, and NR2A and NR2B were enriched 2.75 +/- 0.35 and 4.65 +/- 0.25 fold, respectively, in the synaptosome, and 13.75 +/- 0.80 and 16.04 +/- 0.25-fold, respectively, in the PSD fraction from brain homogenate. The tyrosine phosphorylation of NR2B reached an adult level at around birth declining in the first postnatal week but recovered to the adult level by the end of the second week, while the amount of the protein itself increased 2.28-fold after birth, indicating that only a fraction of the proteins are phosphorylated in vivo. Our results indicate that expression and tyrosine phosphorylation of NR2B might be important for NMDA receptor functions in embryonic and early postnatal development.


Assuntos
Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Encéfalo/embriologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Desenvolvimento Embrionário e Fetal , Feminino , Fosforilação , Gravidez , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Frações Subcelulares/metabolismo , Sinapses/metabolismo , Tirosina/metabolismo
12.
Mol Cells ; 7(6): 749-54, 1997 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-9509416

RESUMO

Quantitative immunoblot analyses were carried out to study the distribution of N-methyl-D-aspartate (NMDA) receptor subunit 2A and 2B (NR2A and NR2B, respectively) at the protein level in the adult rat brain. Highest levels of NR2A were detected in cerebral cortex and hippocampus, followed at more or less similar levels (about 36-72% of cerebral cortex) by striatum, thalamus, olfactory bulb, superior and inferior colliculi, and cerebellum. The lowest levels were detected in midbrain and lower brain stem (30-31% of cerebral cortex). The NR2B was more dramatic in differential distribution than the NR2A. Highest levels of NR2B were found in telencephalic (olfactory bulb, cerebral cortex, hippocampus, and striatum) and thalamic regions, and expression in superior and inferior colliculi, midbrain, lower brain stem, and cerebellum were significantly lower (4-25% of cerebral cortex). Interestingly, NR2B proteins were barely detectable in the cerebellum. When the postsynaptic density (PSD) fractions were compared, the amount of NR2B in the cerebellar PSD fraction was only 1.8% of that present in the cerebral PSD fraction where the subunit is highly enriched. Immunoblot analyses with a phosphotyrosine-specific antibody showed that the molecular sizes of major phosphotyrosine-containing proteins in forebrain and hindbrain are 180 and 45 kDa, respectively. The regional distribution of the 180 kDa major phosphotyrosine protein was very similar to that of NR2B, and the protein could be immunoprecipitated by NR2B antibody. Our data shows that NR2A and NR2B subunits are differentially distributed in the brain in an overlapping manner, and that the major phosphotyrosine-containing protein of 180 kDa in forebrain is the NR2B.


Assuntos
Encéfalo/citologia , Receptores de N-Metil-D-Aspartato/análise , Animais , Immunoblotting , Fosfoproteínas/análise , Fosforilação , Fosfotirosina/análise , Fosfotirosina/imunologia , Ratos , Ratos Sprague-Dawley
13.
J Med Chem ; 39(17): 3331-42, 1996 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-8765517

RESUMO

UNLABELLED: Alzheimer's disease is characterized by progressive cerebral cholinergic neuronal degeneration. Radiotracer analogs of benzovesamicol, which bind with high affinity to the vesamicol receptor located on the uptake transporter of acetylcholine storage vesicles, may provide an in vivo marker of cholinergic neuronal integrity. Five positional isomers of racemic iodobenzovesamicol (4'-, 5-, 6-, 7-, and 8-IBVM) were synthesized, exchange-labeled with iodine-125, and evaluated as possible in vivo markers for central cholinergic neurons. Only two isomers, 5-IBVM (5) and 6-IBVM (10), gave distribution patterns in mouse brain consistent with cholinergic innervation: striatum >> hippocampus > or = cortex > hypothalamus >> cerebellum. The 24-h tissue-to-cerebellum concentration ratios for 5-IBVM (5) were 3-4-fold higher for striatum, cortex, and hippocampus than the respective ratios for 6-IBVM (10). Neither 8-IBVM (16) nor 4'-IBVM (17) exhibited selective retention in any of the brain regions examined. In the heart, only 5-IBVM (5) exhibited an atria-to-ventricles concentration ratio consistent with high peripheral cholinergic neuronal selectivity. The 7-IBVM (14) isomer exhibited an anomalous brain distribution pattern, marked by high and prolonged retention in the five brain regions, most notably the cerebellum. This isomer was screened for binding in a series of 26 different biological assays; 7-IBVM (14) exhibited affinity only for the delta-receptor with an IC50 of approximately 30 nM. Drug-blocking studies suggested that brain retention of 7-IBVM (14) reflects high-affinity binding to both vesamicol and delta-receptors. Competitive binding studies using rat cortical homogenates gave IC50 values for binding to the vesamicol receptor of 2.5 nM for 5-IBVM (5), 4.8 nM for 6-IBVM (10), and 3.5 nM for 7-IBVM (14). Ex vivo autoradiography of rat brain after injection of (-)-5-[125I]IBVM ((-)-[125I]5) clearly delineated small cholinergic-rich areas such as basolateral amygdala, interpeduncular nucleus, and facial nuclei. Except for cortex, regional brain levels of (-)-5-[123I]IBVM ((-)-[123I]5) at 4 h exhibited a linear correlation (r2 = 0.99) with endogenous levels of choline acetyltransferase. CONCLUSION: Vesamicol receptor mapping of cholinergic nerve terminals in murine brain can be achieved with 5-IBVM (5) and less robustly with 6-IBVM (10), whereas the brain localization of 7-IBVM (14) reflects high-affinity binding to both vesamicol and delta-receptors.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Fármacos Neuromusculares Despolarizantes/metabolismo , Neurônios/fisiologia , Piperidinas/metabolismo , Receptores Colinérgicos/análise , Tetra-Hidronaftalenos/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Autorradiografia , Ligação Competitiva , Encéfalo/citologia , Encéfalo/metabolismo , Feminino , Cobaias , Humanos , Radioisótopos do Iodo , Isomerismo , Camundongos , Camundongos Endogâmicos , Fármacos Neuromusculares Despolarizantes/síntese química , Neurônios/citologia , Neurônios/metabolismo , Especificidade de Órgãos , Piperidinas/síntese química , Ratos , Ratos Sprague-Dawley , Tetra-Hidronaftalenos/síntese química
14.
Nucl Med Biol ; 23(5): 611-6, 1996 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8905825

RESUMO

The in vivo behavior of (-)-[11C]phenylephrine (PHEN) is compared with the structurally similar but monoamine oxidase (MAO)-resistant analog (-)-[11C]-m-hydroxyephedrine (HED), which is an established heart neuronal marker. The chiral synthesis of PHEN has been achieved by direct methylation of (-)-m-octopamine with either 11CH3I or CF3SO311CH3. These synthetic methods produced PHEN with a specific activity ranging from 500-1000 Ci/mmol, in a radiochemical yield of > 50% (EOS) and with an enantiomeric purity of 94-96%. Biodistribution studies indicate the initial uptake of PHEN in rat heart is approximately half that of HED. Following PHEN injection, radioactivity egresses from the rat heart rapidly, with 50% washout occurring from 5 to 60 min. HED washout over this interval was less than 20%. The heart neuronal selectivity determined by desipramine blockade of the amine neuronal transporter was 75-77% compared to 92-95% for HED. Ring-labeled (-)-[3H]phenylephrine gave tissue-to-blood concentration ratios and heart clearance times very similar to PHEN. Rats pretreated with the MAO A inhibitor clorgyline showed higher levels of activity in the heart at 15 and 60 min. Tandem PET studies with PHEN and HED in the closed-chest dog provided excellent heart images with both tracers.


Assuntos
Radioisótopos de Carbono , Coração/diagnóstico por imagem , Fenilefrina/farmacocinética , Animais , Clorgilina/farmacologia , Cães , Feminino , Coração/efeitos dos fármacos , Indicadores e Reagentes , Marcação por Isótopo/métodos , Miocárdio/metabolismo , Fenilefrina/síntese química , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual , Tomografia Computadorizada de Emissão
15.
J Med Chem ; 38(14): 2663-71, 1995 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-7629805

RESUMO

A series of substituted 5-tert-butyl-2-phenyl-1,3-dithianes and 5-tert-butyl-2-phenyl-1,1,3,3-tetraoxo-1,3-dithianes was synthesized as ligands for the GABAA receptor complex-associated neuronal chloride ion channels. The in vitro binding affinities of these compounds for the GABA-gated chloride ion channel were determined by their ability to compete with [3H]TBOB for binding to rat brain slices. Of the eight compounds tested, trans-5-tert-butyl-2-(4-cyanophenyl)-2-methyl-1,1,3,3-tetraoxo+ ++-1,3-dithiane, 9b, trans-5-tert-butyl-2-(4-fluorophenyl)-1,1,3,3-tetraoxo-1,3-dithian e, 10, and trans-5-tert-butyl-2-(4-iodophenyl)-2-methyl-1,1,3,3-tetraoxo-1,3- dithiane, 11, showed moderately high binding affinities (Ki = 41, 180, and 105 nM, respectively). Four radioligand candidates from this series, 5-tert-butyl-2-(4-cyanophenyl)-2-[11C]methyl-1,3-dithiane, [11C]6, 5-tert-butyl-2-(4-[18F]fluorophenyl)-1,3-dithiane, [18F]7, 5-tert-butyl-2-(4-[18F]-fluorophenyl)-1,1,3,3-tetraoxo-1,3- dithiane, [18F]10, and 5-tert-butyl-2-(4-[125I]iodophenyl)-2-methyl-1,1,3,3- tetraoxo-1,3-dithiane, [125I]11, have been successfully prepared for evaluation as in vivo imaging agents useful for positron emission tomography and single photon emission computed tomography. Preliminary in vivo studies indicate significant uptake into mouse brain for [18F]7, [18F]10, and [125I]11.


Assuntos
Canais de Cloreto/antagonistas & inibidores , Compostos Heterocíclicos/síntese química , Receptores de GABA-A/fisiologia , Sulfonas/síntese química , Animais , Encéfalo/efeitos dos fármacos , Isótopos de Carbono , Feminino , Flúor , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Técnicas In Vitro , Radioisótopos do Iodo , Ativação do Canal Iônico/fisiologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Sulfonas/química , Sulfonas/farmacologia
16.
J Med Chem ; 38(5): 810-5, 1995 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-7877146

RESUMO

This work explores the biomimetic potential of [18F]fluorine for hydroxy substitution in beta-phenethanolamines as a possible strategy for developing radiotracers for in vivo imaging. Stereospecific syntheses of the two model compounds (1R,2S)-1-[18F]fluoro-1-deoxyephedrine ([18F]FDE) and (1S,2S)-1-[18F]fluoro-1-deoxypseudoephedrine ([18F]FDP) were achieved in high radiochemical yield (62%, decay corrected) and high specific activity (> 2500 Ci/mmol) by reaction of [18F]fluoride ion with the appropriate chiral cyclic sulfamidate precursor. Both tracers exhibited good stability toward metabolic defluorination in vivo. High, homogeneous brain uptake (approximately 8% of injected dose) was observed after intravenous injection in mice similar to that reported for the structurally related analog [11C]methamphetamine. The 1R,2S isomer (FDE) showed a 3-fold higher concentration of radioactivity in whole brain as compared to the 1S,2S isomer (FDP). These results suggest possible employment of this strategy for chiral radiolabeling of biologically important phenethanolamines and catecholamines.


Assuntos
Aminas Biogênicas/química , Aminas Biogênicas/síntese química , Radioisótopos de Flúor , Marcação por Isótopo/métodos , Animais , Desenho de Fármacos , Feminino , Metanfetamina/análogos & derivados , Metanfetamina/síntese química , Metanfetamina/farmacocinética , Camundongos , Estereoisomerismo , Distribuição Tecidual
17.
J Chromatogr A ; 667(1-2): 183-9, 1994 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-8025628

RESUMO

The direct optical resolution of the vesicular acetylcholine uptake inhibitors vesamicol and benzovesamicol and nine benzovesamicol analogues were performed by HPLC on a commercially available cellulose tris(3,5-di-methylphenyl carbamate) chiral stationary phase. Separation of each enantiomeric pair was optimized with respect to solvent strength and flow-rate, using mobile phase mixtures of hexane-2-propanol-diethylamine. The method has been successfully applied to the analysis of the optical purity of benzovesamicol intermediates and products, including (-)-5-[123I]iodobenzovesamicol which is currently undergoing clinical evaluation as a tracer for mapping central cholinergic neurons, and the purification of both antipodes of (+/-)-7-[125I]iodobenzovesamicol.


Assuntos
2-Naftilamina/análogos & derivados , Fenciclidina/análogos & derivados , Piperidinas/isolamento & purificação , Tetra-Hidronaftalenos , 2-Naftilamina/isolamento & purificação , Celulose , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Radioisótopos do Iodo , Fenciclidina/isolamento & purificação , Espectrofotometria Ultravioleta , Estereoisomerismo
18.
Nucl Med Biol ; 21(2): 197-203, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9234283

RESUMO

The diaminodithiol (DADT) ligand has been conjugated to the neuromuscular blocking agent benzovesamicol (BVM) in the 5-position. DADT-BVM 1 was synthesized by coupling of 5-aminomethylbenzovesamicol with a BCA thiolactone reagent. 99mTc radiolabeling of 1 with [99mTc]glucoheptonate gave a 4.7:1 mixture of two 99mTc complexes as determined by HPLC. Biodistribution data of the major [99mTc]-1 complex in CD-1 mice (n = 4-5) showed very little uptake and no regional selectivity in the mouse brain. At all time points examined, the lung and liver showed the highest uptake. For whole brain, the % injected dose values were 0.27, 0.12, 0.04 and 0.01% at t = 1, 5, 30 and 240 min. The major [99mTc]-1 product exhibited a log P = 3.13 +/- 0.06 (SD) with an IC50 = 140-280 nM for the corresponding [99Tc]-1 vs (-)-N-[3H]methyl-5-aminobenzovesamicol. The low brain uptake of [99mTc]-1 vs 5-iodobenzovesamicol is attributed to its higher molecular weight (752) and lower binding affinity.


Assuntos
Compostos de Organotecnécio/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Encéfalo/metabolismo , Estudos de Avaliação como Assunto , Feminino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Compostos de Organotecnécio/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Vísceras/metabolismo
19.
Nucl Med Biol ; 20(8): 929-37, 1993 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8298572

RESUMO

The highly toxic curraremimetic and cholinergic neuron marker (-)-5-iodobenzovesamicol (IBVM) has been labeled with iodine-125 and iodine-123. [125I]IBVM, suitable for animal distribution and ex vivo autoradiographic studies, was synthesized by solid-state exchange; isolated yields were 65-89% with specific activities in the range of 130-200 Ci/mmol. The synthesis of no-carrier-added (-)-5-[125I]IBVM from the corresponding chiral (-)-5-(tri-n-butyltin) derivative using Na125I was evaluated using the oxidants H2O2, peracetic acid and chloramine-T. Both peracetic acid and chloramine-T gave good yields (70-95%). However, when Na123I was utilized, acceptable yields of [123I]IBVM were obtained only with chloramine-T. Use of the latter oxidant did produce 5-chlorobenzovesamicol which was eliminated during HPLC purification. After optimization of the reaction parameters, [123I]IBVM in batch sizes of 10-27 mCi, is routinely obtained with a specific activity of 30-70,000 Ci/mmol, radiochemical purity (> 97%) and chiral purity (> 98%). Isolated radiochemical yields have averaged 71% (N = 40). Distribution analyses of [125I]IBVM and [123I]IBVM in mice 4 h following intravenous administration show essentially equivalent concentrations of the two tracers in the four brain regions sampled. The exceptionally high specific activity of [123I]IBVM has made possible the evaluation of this radiotracer in humans.


Assuntos
Encéfalo/metabolismo , Fibras Colinérgicas/metabolismo , Radioisótopos do Iodo/química , Fenciclidina/análogos & derivados , Piperidinas , Tetra-Hidronaftalenos , Animais , Cloraminas/química , Feminino , Peróxido de Hidrogênio/química , Indicadores e Reagentes/química , Marcação por Isótopo/métodos , Camundongos , Camundongos Endogâmicos , Ácido Peracético/química , Fenciclidina/síntese química , Fenciclidina/farmacocinética , Estereoisomerismo , Distribuição Tecidual , Compostos de Tosil/química
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