RESUMO
Botulism is a neuroparalytic disease most commonly caused by foodborne ingestion of neurotoxin types A, B, and E, and is often fatal if untreated. Clinicians should be able to recognize the classic symptoms of botulinum intoxication (12). Owing to its rarity, there are a limited number of studies evaluating the clinical care of patients with wound botulism (10). We present an infected tibial non-union with botulism who underwent a successful radical excision and bone transport. The patient tolerated the procedure well.
Assuntos
Botulismo , Clostridium botulinum , Fraturas da Tíbia , Botulismo/diagnóstico , Botulismo/terapia , Humanos , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgiaRESUMO
The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.
Assuntos
Descoberta de Drogas , Hipertensão Pulmonar/tratamento farmacológico , Receptores de Prostaglandina/agonistas , Animais , Humanos , Hipertensão Pulmonar/induzido quimicamente , Monocrotalina , Agregação Plaquetária/efeitos dos fármacos , Ratos , Receptores de Prostaglandina/metabolismoRESUMO
Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.
RESUMO
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Assuntos
Fármacos Antiobesidade/química , Cicloexilaminas/química , Pirimidinas/química , Quinazolinas/química , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Ingestão de Alimentos , Humanos , Masculino , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Redução de PesoRESUMO
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.
Assuntos
Acetatos/uso terapêutico , Carbamatos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Receptores de Prostaglandina/agonistas , Acetatos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Descoberta de Drogas , Ratos , Relação Estrutura-AtividadeRESUMO
The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.
Assuntos
Quinazolinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Quinazolinas/química , Quinazolinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.
Assuntos
Quinazolinas/química , Quinazolinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Linhagem Celular , Humanos , Relação Estrutura-AtividadeRESUMO
Exposure of the abdominal aorta through the left retroperitoneum is a well-accepted technique. Unfortunately, splenic injury is a complication of this approach that rarely occurs through a mid-line transabdominal incision. In this series we evaluate the occurrence of splenic injury during left retroperitoneal aortic surgery. The records of all patients undergoing abdominal aortic reconstruction via the left retroperitoneal approach were reviewed from 1988 to 2001. Indications included either abdominal aortic aneurysm (AAA) or aortoiliac occlusive disease (AIOD). Thoracoabdominal aneurysms and visceral aortic reconstructions were excluded. Those patients that required splenectomy for splenic injury were stratified and analyzed for demographics, indications for operation, and other complications. Chi-square analysis was used to determine statistical significance. Over the 13-year study period, 2889 aortic reconstructions were performed. These consisted of 1773 elective AAA repairs, 357 ruptured or symptomatic AAA repairs, and 759 aortofemoral bypasses for AIOD. Splenectomies were performed after aortic repair in 21 (0.7%) patients. Breakdown by indication totaled 11/1773 (0.6%) for elective AAA repair, 7/357 (2.0%) for rupture or symptomatic AAA repair, and 3/759 (0.4%) for AIOD ( p < 0.05). Mortality for patients undergoing elective AAA without splenectomy was 1.9% (34/1762) and with splenectomy was 9.1% (1/11), while it was 3.2% (24/756) for AIOD patients without splenectomy and 14% (1/7) for AIOD patients with splenectomy (all p = NS). Splenic injury can occur in elective and emergent aortic reconstructions performed through the left retroperitoneum. The surgeon should be prepared for splenectomy whenever intraperitoneal blood or hemodynamic instability is identified. Evaluation of the spleen prior to flank closure may be prudent.