RESUMO
Tranexamic acid is an antifibrinolytic drug used widely to prevent bleeding. Its use in reducing bleeding during total knee arthroplasty surgery is well proven but there is no final consensus regarding the regimen. The purpose of our study was to compare the effectiveness of intravenous and intra-articular regimen of tranexamic acid during the total knee arthroplasty surgery. A total of 40 patients were received three doses of intravenous tranexamic acid during total knee arthroplasty surgery. Intra-articular tranexamic acid was used in 40 patients during the surgery. We concluded that intra-articular tranexamic acid is equally effective as three dose intravenous regimen in reducing blood loss during total knee arthroplasty surgery.
Assuntos
Antifibrinolíticos/administração & dosagem , Artroplastia do Joelho/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Hemorragia Pós-Operatória/prevenção & controle , Ácido Tranexâmico/administração & dosagem , Idoso , Transfusão de Sangue , Feminino , Hemoglobinas/metabolismo , Humanos , Injeções Intra-Articulares , Injeções Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.
Assuntos
Doença de Parkinson , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Encéfalo/metabolismo , Mutação , Canais Iônicos/metabolismoRESUMO
BACKGROUND: Closed multiple metacarpal fractures are considered highly unstable and are more prone to poor functional outcome. The authors assess the functional outcome of mini fragment plate fixation in closed ipsilateral multiple metacarpal fractures. PATIENTS AND METHODS: In 21 patients with closed ipsilateral multiple metacarpal fractures treated with open reduction and internal fixation using mini fragment plate, functional outcome was assessed using the American Society for Surgery of the Hand (ASSH) Total Active Flexion (TAF) score and the Disabilities of the Arm, Shoulder, and Hand (DASH) scoring system. RESULTS: Union rate of 100% was achieved. Functional outcome was excellent in 85.71% (18 of 21) and good in 9% (2 of 21) of patients. Average DASH score was 8.47 (range 1-26). Five cases of infection (two deep, three superficial) were reported, which subsided with dressings and antibiotics. CONCLUSIONS: Plate fixation is a good option for treating closed ipsilateral multiple metacarpal fractures, providing rigid fixation for early mobilization and good functional outcome.
Assuntos
Placas Ósseas , Parafusos Ósseos , Fixação Interna de Fraturas/instrumentação , Consolidação da Fratura , Fraturas Fechadas/cirurgia , Ossos Metacarpais/lesões , Fraturas do Rádio/cirurgia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Fraturas Fechadas/diagnóstico por imagem , Fraturas Fechadas/fisiopatologia , Humanos , Masculino , Ossos Metacarpais/cirurgia , Pessoa de Meia-Idade , Miniaturização , Estudos Prospectivos , Desenho de Prótese , Radiografia , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.
Assuntos
Doença de Parkinson , Ratos , Humanos , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/tratamento farmacológico , Indazóis/farmacologia , Indazóis/uso terapêutico , Leucócitos Mononucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Encéfalo/metabolismo , Trifosfato de AdenosinaRESUMO
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.
Assuntos
Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacologia , Encéfalo/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Antiparkinsonianos/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.
RESUMO
A tug-of-war between the mammalian host and bacterial pathogen for nutrients, including first-row transition metals (e.g. Mn, Fe, Zn), occurs during infection. Here we present recent advances about three metal-chelating metabolites that bacterial pathogens deploy when invading the host: staphylopine, staphyloferrin B, and enterobactin. These highlights provide new insights into the mechanisms of bacterial metal acquisition and regulation, as well as the contributions of host-defense proteins during the human innate immune response. The studies also underscore that the chemical composition of the microenvironment at an infection site can influence bacterial pathogenesis and the innate immune system.
Assuntos
Bactérias/metabolismo , Infecções Bacterianas/metabolismo , Quelantes/metabolismo , Homeostase , Interações Hospedeiro-Patógeno , Metais/metabolismo , HumanosRESUMO
We synthesized a library of 48 analogs of the Mycobacterium tuberculosis cell growth inhibitor SQ109 in which the ethylene diamine linker was replaced by oxa-, thia- or heterocyclic species, and in some cases, the adamantyl group was replaced by a 1,2-carborane or the N-geranyl group by another hydrophobic species. Compounds were tested against Mycobacterium tuberculosis (H37Rv and/or Erdman), Mycobacterium smegmatis, Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae, Trypanosoma brucei and two human cell lines (human embryonic kidney, HEK293T, and the hepatocellular carcinoma, HepG2). Most potent activity was found against T. brucei, the causative agent of human African trypanosomiasis, and involved targeting of the mitochondrial membrane potential with 15 SQ109 analogs being more active than was SQ109 in cell growth inhibition, having IC50 values as low as 12 nM (5.5 ng/mL) and a selectivity index of ~300.
RESUMO
We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.
Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Descoberta de Drogas , Proteínas de Membrana Transportadoras/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Feminino , Fungos/efeitos dos fármacos , Humanos , Células MCF-7 , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Modelos Moleculares , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Células Tumorais CultivadasRESUMO
We synthesized 30 lipophilic bisphosphonates and tested them in malaria parasite killing (targeting parasite geranylgeranyl diphosphate synthase, GGPPS) as well in human γδ T cell activation (targeting human farnesyl diphosphate synthase, FPPS). Similar patterns of activity were seen in inhibiting human FPPS and Plasmodium GGPPS, with short to medium chain-length species having most activity. In cells, shorter chain-length species had low activity, due to poor membrane permeability, and longer chain length species were poor enzyme inhibitors. Optimal activity was thus seen with ~C10 side-chains, which have the best combination of enzyme inhibition and cell penetration. We also solved the crystal structure of one potent inhibitor, bound to FPPS. The results are of interest since they suggest the possibility of a combined chemo/immuno-therapeutic approach to anti-malarial development in which both direct parasite killing as well as γδ T cell activation can be achieved with a single compound.