RESUMO
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3-30â¯mg/kg po for 7â¯days. The effects at 30â¯mg/kg are comparable to that of PF-04457845 (10â¯mg/kg) and Tramadol (40â¯mg/kg).
Assuntos
Amidoidrolases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Neuralgia/tratamento farmacológico , Amidoidrolases/metabolismo , Animais , Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Neuralgia/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
Assuntos
Antagonistas do Receptor A1 de Adenosina/química , Antagonistas do Receptor A1 de Adenosina/farmacologia , Hipoxantinas/química , Hipoxantinas/farmacologia , Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida , Desenho de Fármacos , Células HEK293 , Humanos , Hipoxantinas/síntese química , Hipoxantinas/farmacocinética , Masculino , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
AIM: To compare dentinal microcrack formation whilst using Ni-Ti hand K-files, ProTaper hand and rotary files and the WaveOne reciprocating file. METHODOLOGY: One hundred and fifty mandibular first molars were selected. Thirty teeth were left unprepared and served as controls, and the remaining 120 teeth were divided into four groups. Ni-Ti hand K-files, ProTaper hand files, ProTaper rotary files and WaveOne Primary reciprocating files were used to prepare the mesial canals. Roots were then sectioned 3, 6 and 9 mm from the apex, and the cut surface was observed under scanning electron microscope (SEM) and checked for the presence of dentinal microcracks. RESULTS: The control and Ni-Ti hand K-files groups were not associated with microcracks. In roots prepared with ProTaper hand files, ProTaper rotary files and WaveOne Primary reciprocating files, dentinal microcracks were present. There was a significant difference between control/Ni-Ti hand K-files group and ProTaper hand files/ProTaper rotary files/WaveOne Primary reciprocating file group (P < 0.001) with ProTaper rotary files producing the most microcracks. No significant difference was observed between teeth prepared with ProTaper hand files and WaveOne Primary reciprocating files. CONCLUSION: ProTaper rotary files were associated with significantly more microcracks than ProTaper hand files and WaveOne Primary reciprocating files. Ni-Ti hand K-files did not produce microcracks at any levels inside the root canals.
Assuntos
Cavidade Pulpar , Humanos , Microscopia Eletrônica de VarreduraRESUMO
BACKGROUND: The aim of this article was to verify the utility of nasogastric (NG) tube in primary anterior cervical surgeries. Palpating and identifying the NG tube introduced during induction is one of the ways of preventing esophageal injuries during surgery. It may also be used as a conduit for postoperative feeding. However, the use of NG tube is not without complications. Esophageal perforation is one of them, with an incidence of 0.3%. MATERIALS AND METHODS: A retrospective observational study was performed of patients who underwent a primary anterior cervical spine surgery from January 2007 to July 2017 by a single surgeon. The indications were degenerative, trauma, infection, and neoplasia. NG tube was avoided in all cases. The patients were followed for 6 months. RESULTS: Our study included 356 patients (201 males and 155 females), with a mean age of 43.6 years (18-92 years) and a mean follow-up of 6 months. We had only one case of esophageal perforation (0.28%) attributed to a traumatic burst fracture. CONCLUSIONS: This study indicates that the use of a NG tube in primary anterior cervical spine surgery can be avoided. Comprehensive knowledge of anatomy and meticulous dissection may avoid the disastrous complication of esophageal rupture. This way the discomfort and complications associated with NG tube can be avoided.
RESUMO
The aim of this study was to describe a new experimental animal model for simultaneous measurement of carbachol-induced increase in intravesical pressure and salivary secretion in rabbits. Further, we also compared the in vivo potency and urinary bladder versus salivary gland selectivity profiles of Oxybutynin, Tolterodine, Solifenacin and Darifenacin. The intravesical pressure and salivary secretion were evoked by intra-arterial injection of carbachol (1.5 microg/kg). The carbachol-induced increase in intravesical pressure and salivation was simultaneously recorded before and after increasing doses of test drugs administered intravenously. The basal mean changes in intravesical pressure and salivation subsequent to carbachol administration were in the range of 6.7-7.5 mm Hg and 0.5-0.7 g respectively. Repeated administration of vehicle did not elicit any appreciable changes in intravesical pressure and salivary secretion to carbachol administration from the basal values till 3 h. All the test drugs exhibited a dose-dependent inhibition of carbachol-induced increase in intravesical pressure and salivary secretion. Darifenacin demonstrated a greater potency compared to other muscarinic receptor antagonists for inhibiting carbachol-induced increase in intravesical pressure. It also exhibited functional selectivity for the urinary bladder versus salivary gland. In contrast, Oxybutynin was functionally more selective in inhibiting carbachol-induced increase in salivary secretion. The observed urinary bladder versus salivary selectivity values were 0.6+/-0.2, 1.1+/-0.2, 1.7+/-0.5, and 2.3+/-0.5 for Oxybutynin, Tolterodine, Solifenacin and Darifenacin respectively. These results suggest that the functional selectivity of muscarinic receptor antagonists between urinary bladder and salivary glands can be readily detected in this model. Thus rabbits may represent a useful animal model for evaluating putative bladder selective muscarinic receptor antagonists for the treatment of overactive bladder.
Assuntos
Antagonistas Colinérgicos/farmacologia , Glândulas Salivares/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Anestesia , Animais , Compostos Benzidrílicos/farmacologia , Benzofuranos/farmacologia , Carbacol/administração & dosagem , Carbacol/farmacologia , Cresóis/farmacologia , Injeções Intra-Arteriais , Masculino , Ácidos Mandélicos/farmacologia , Fenilpropanolamina/farmacologia , Pressão , Pirrolidinas/farmacologia , Quinuclidinas/farmacologia , Coelhos , Glândulas Salivares/metabolismo , Succinato de Solifenacina , Tetra-Hidroisoquinolinas/farmacologia , Tartarato de Tolterodina , Bexiga Urinária/fisiologiaRESUMO
Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Benzotiazóis/farmacologia , Cicloexanóis/farmacologia , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Administração Oral , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Levodopa/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).
RESUMO
Intermittent claudication (IC) is defined by leg muscle pain, cramping and fatigue brought on by ambulation/exercise; relieved on rest; and caused by inadequate blood supply and is the primary symptom of peripheral arterial disease (PAD). PAD has a detrimental effect on the quality of life. PAD is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. IC is an extremely important marker of atheroma. Up to 60% patients with IC have significant underlying coronary and/or carotid disease and 40% of all patients suffering from IC die or suffer a stroke within 5 years of presentation. The therapeutic intervention of IC essentially aims at providing symptomatic relief and reducing the systemic cardiovascular complications. Although exercise therapy is one of the most efficacious conservative treatments for claudication, the pharmacotherapeutic goals can be best achieved through an increase in the walking capacity to improve quality of life and a decrease in rates of amputation. In the development of treatment for IC, an aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with IC are considered. In the next 2 years, the results of major trials of drugs that stabilize and regress atherosclerosis such as statins and angiotensin converting enzyme inhibitors, and anti-platelet agents, recombinant growth factors and immune modulators will be available for IC. Levocarnitine (l-carnitine) and a derivative, propionyl levocarnitine, are emerging agents that increase the pain-free walking and improve the quality of life in IC patients by working at the metabolism and exercise performance of ischemic muscles. This article provides a comprehensive review of the pathophysiology involved, diagnosis of IC and existing and emerging pharmacotherapies with rationale for their use in its treatment.