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2.
Acta Med Port ; 32(6): 453-458, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31292027

RESUMO

INTRODUCTION: Skin and skin structure infections are an increasing cause of hospitalization. Although mortality is relatively low, skin and skin structure infections are associated with prolonged hospital length of stay and high costs. Oxazolidinones have been suggested as a tool to treat infected patients in the ambulatory setting in order to decrease hospital length of stay. We wanted to address the evidence associated with the use of oxazolidinones in the treatment of skin and skin structure infections. MATERIAL AND METHODS: In this observational retrospective study we analyzed the anonymized diagnosis related group coded information from the Portuguese database for hospital admissions, that included all adult patients with a diagnosis of oxazolidinone use and a SSSI, discharged between 2010 and 2015. RESULTS: During the study period, a total of 5518 patients had a diagnosis of oxazolidinone treatment. We selected 483 of those who were also diagnosed with a skin and skin structure infections. Their mean age was 64.9 years and 62.7% were male. The median hospital length of stay was 27 days (Inter quartile range 13 - 56) and the mortality rate was 12.6%. The prevalence of secondary anemia and of thrombocytopenia in the whole group treated with oxazolidinones was 2.5% and 3%, respectively. DISCUSSION: Despite the high bioavailability of oxazolidinones, we were not able to find evidence that its use was associated with a decrease of mortality or hospital length of stay (due to early discharge) of patients with skin and skin structure infections. CONCLUSION: In this study we were not able to find evidence that oxazolidinones had any clinically significant benefit. A structured approach, including antibiotics with favorable pharmacokinetic and safety profile as well as a carefully planned ambulatory follow up may be needed.


Assuntos
Anti-Infecciosos/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Oxazolidinonas/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/estatística & dados numéricos , Anemia/induzido quimicamente , Anemia/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Portugal/epidemiologia , Estudos Retrospectivos , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/mortalidade , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia
3.
Drug Deliv ; 26(1): 689-699, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31274014

RESUMO

Enhancement of zolmitriptan bioavailability through development of micronized zolmitriptan pressurized metered dose inhaler (MDI) as an alternative to its traditional drug delivery systems. A reversed phase HPLC method for zolmitriptan determination was developed and evaluated. Micronized zolmitriptan MDI formulations were prepared using two different propellants. The prepared formulations were evaluated for mean shot weight, drug content, and leakage rate in addition to in-vitro deposition using next generation impactor where mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle dose, fine particle fraction (FPF), emitted dose (ED), and dispersibility were determined. The selected formulation was evaluated for in-vivo bronchial absorption in rats. The physicochemical characters of the prepared formulations were found to be dependent mainly on the vapor pressure of the used propellant. MDI formulation prepared with HFA 134a propellant was found to have the lowest MMAD (3.47 ± 0.65) with GSD of 2.3 ± 0.4. It also had the highest FPF (41.9), ED (89.26 ± 2.35) with dispersibility of 46.9%. This formulation, when applied to rats, resulted in faster Tmax (27 ± 5 min) with higher Cmax (1236 ± 116 ng/mL) and AUC(0-12) (3375 ± 482 ng/mL·h) over the oral tablet. Its relative bioavailability was 72.7% which was 1.25 times higher than the oral tablet relative bioavailability. Zolmitriptan MDI formulation was developed using micronized zolmitriptan powder without further modification or particle engineering. The developed formulation using HFA 134a propellant could be favorable alternative, with enhanced bioavailability, to zolmitriptan oral tablet for acute migraine treatment.


Assuntos
Inaladores Dosimetrados , Transtornos de Enxaqueca/tratamento farmacológico , Oxazolidinonas/administração & dosagem , Triptaminas/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Excipientes , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/farmacologia , Inaladores Dosimetrados/microbiologia , Oxazolidinonas/farmacocinética , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Tamanho da Partícula , Ratos , Triptaminas/farmacocinética , Triptaminas/farmacologia , Triptaminas/uso terapêutico
4.
Chem Biol Interact ; 308: 120-129, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129132

RESUMO

A preclinical study using DEN-induced HCC rat model was attempted to evaluate the antitumor potential of zolmitriptan (ZOL). The molecular insights were investigated using ELISA, qRT-PCR and Western blot techniques. The result confirmed that the HCC condition was developed in response to lower expressions of caspase 3 and 9 which, in turn, was due to the upstream regulation of iNOS, Bcl-xl and Bcl-2, and downstream regulation of eNOS, BAX, BAD and Cyt C. The treatment with ZOL caused the significant activation of caspase mediated apoptotic signals that could be responsible for its anti-HCC potential. Later, 1H NMR based serum metabolomics study confirmed that ZOL restored the perturbed metabolites associated with DEN-induced HCC. The antineoplastic potential of ZOL was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Oxazolidinonas/farmacologia , Triptaminas/farmacologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Citocinas/análise , Modelos Animais de Doenças , Glutationa/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxazolidinonas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Triptaminas/uso terapêutico , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Dtsch Med Wochenschr ; 144(8): 553-560, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30986864

RESUMO

Enterococci with special resistance patterns (mainly vancomycin-resistant enterococci) play an important role in everyday clinical practice. Rising resistance rates to linezolid, daptomycin or tigecycline are also increasingly reported. Therapeutically, linezolid and daptomycin are the most important substances mainly in infections due to vancomycin-resistant enterococci. Several systematic meta-analyses of bloodstream infections showed discrepant results in the comparison of mortality of linezolid and daptomycin-treated bacteraemias. The containment of enterococci with special resistance patterns is currently receiving great attention. The key hygienic issue in all recommendations for dealing with multidrug-resistant enterococci can be summarized very simply: current scientific evidence is often inconsistent and studies that have clearly tested a single intervention for efficacy are lacking. The present work gives an insight into the current epidemiology and therapeutic strategies. Furthermore, the recently published German KRINKO recommendations are presented.


Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Antibacterianos/uso terapêutico , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Farmacorresistência Bacteriana , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/prevenção & controle , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Lipoglicopeptídeos/farmacologia , Lipoglicopeptídeos/uso terapêutico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Tigeciclina/farmacologia , Tigeciclina/uso terapêutico , Resistência a Vancomicina
6.
Value Health ; 22(3): 293-302, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30832967

RESUMO

BACKGROUND: Migraine is a common, chronic, disabling headache disorder. Triptans, used as an acute treatment for migraine, are available via prescription in Australia. An Australian Therapeutic Goods Administration (TGA) committee rejected reclassifying sumatriptan and zolmitriptan from prescription medicine to pharmacist-only between 2005 and 2009, largely on the basis of concerns about patient risk. Nevertheless, pharmacist-only triptans may reduce migraine duration and free up healthcare resources. OBJECTIVES: To estimate the cost-effectiveness of reclassifying triptans from prescription-only to pharmacist-only in Australia. METHODS: The study design included decision-analytic modeling combining data from various sources. Behavior before and after reclassification was estimated using medical practitioner and patient surveys and also administrative data. Health outcomes included migraine frequency and duration as well as adverse events (AEs) discussed by the TGA committee. Efficacy and AEs were estimated using randomized controlled trials and observational studies. RESULTS: Reclassifying triptans will reduce migraine duration but increase AEs. This will result in 337 quality-adjusted life-years gained at an increased cost of A$5.9 million over 10 years for all Australian adults older than 15 years (19.6 million). The incremental cost-effectiveness ratio was estimated to be A$17 412/quality-adjusted life-year gained. CONCLUSIONS: The incremental cost-effectiveness ratio is likely to be considered cost-effective by Australian decision makers. Serotonin syndrome, a key concern of the TGA committee, had little impact on the results. Further research is needed regarding pharmacist-only triptan use by migraineurs currently using over-the-counter medicines and by nonmigraineurs, the efficacy of triptans, and the risk of cardiovascular and cerebrovascular AEs and chronic headaches with triptans.


Assuntos
Análise Custo-Benefício/métodos , Controle de Medicamentos e Entorpecentes/métodos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/economia , Oxazolidinonas/classificação , Sumatriptana/classificação , Triptaminas/classificação , Austrália/epidemiologia , Análise Custo-Benefício/tendências , Controle de Medicamentos e Entorpecentes/economia , Clínicos Gerais/economia , Humanos , Transtornos de Enxaqueca/epidemiologia , Medicamentos sem Prescrição/classificação , Medicamentos sem Prescrição/economia , Medicamentos sem Prescrição/uso terapêutico , Oxazolidinonas/economia , Oxazolidinonas/uso terapêutico , Farmacêuticos/economia , Medicamentos sob Prescrição/classificação , Medicamentos sob Prescrição/economia , Medicamentos sob Prescrição/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/classificação , Agonistas do Receptor 5-HT1 de Serotonina/economia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Sumatriptana/economia , Sumatriptana/uso terapêutico , Triptaminas/economia , Triptaminas/uso terapêutico
7.
Indian J Tuberc ; 66(1): 12-19, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30797268

RESUMO

Tuberculosis (TB) being the leading infectious killer in the domain wherein globally, almost 20% of all TB strains are resistant to at least 1 major TB drug and there's a growing incidence of multi-drug resistance tuberculosis (MDR-TB). Looking at the current scenario and challenges the existing strategies fall back in terms of treatment of TB. So, to overcome this new, stronger, improved TB drug pipeline and a new standard for the development of novel anti-TB drugs are required in order to make more drug-resistant and efficient drug which also lower the duration period of the treatment of the TB. This review article aims to highlight the recent developments in the anti-tuberculosis agents, those are currently in the clinical development stage.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Diarilquinolinas/uso terapêutico , Desenvolvimento de Medicamentos , Quimioterapia Combinada , Etambutol/uso terapêutico , Etilenodiaminas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Macrolídeos/uso terapêutico , Adesão à Medicação , Nitroimidazóis/uso terapêutico , Oxazolidinonas/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico
8.
Eur J Pharm Sci ; 130: 21-26, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639401

RESUMO

The pharmacotherapeutic management of seizure disorders with currently available medications is not optimal due to side effects and failure of some patients to respond to all available medications. As such there is the need to develop new antiseizure drugs by looking at new chemical classes of compounds. We recently screened, in vitro, a new class of compounds, the oxazolidinones, for actions in the brain that may indicate potential for antiseizure activity. A few compounds were identified with such a potential. Here we tested whether one of these lead compounds, PH192, will exhibit in vivo antiseizure activity using chemically- and electrically- induced seizures models in mice and rats. Out of 5 compounds tested, all of them had minimal neurotoxicological effects in mice, with PH192 being the best, with comparable efficacy (ED50) and toxicity (TD50) to only levetiracetam. Intraperitoneal (IP) pretreatment with PH192 produced a dose-dependent protection of mice from seizures induced using the 6 Hz stimulation protocol with an estimated ED50 of 34.5 mg/kg in mice and about 90 mg/kg in rats and a neurotoxic dose >500 mg/kg in mice, yielding a calculated neuro (protective) index of >14.7. When pretreated with 100 mg/kg PH192 for 30 min, about 75% of mice were protected from 6 Hz-induced seizures. When rats were pretreated for 30 min with PH192, 66.6% of rats were protected from seizures induced using the 6 Hz stimulation protocol while 83.3% were protected using the maximal electroshock (MES) stimulation protocol. Pentylenetetrazole (PTZ) injection at 50, and 100 mg/kg produced stage 5 seizures in all rats. Thirty minutes IP pretreatment of rats with 100 mg/kg PH192 protected 80% of rats from the PTZ-induced seizures, a level of protection similar to that obtained with a reference antiepileptic drug (AED) phenytoin (40 mg/kg), that is used clinically for the treatment of various seizure disorders. The results of these studies indicate that PH192 protects against both chemically- and electrically-induced seizures with little central nervous system side effects. This suggests that the oxazolidinone pharmacophore has potential for discovering new antiepileptic drugs with possibly minimal central side effects.


Assuntos
Anticonvulsivantes/uso terapêutico , Oxazolidinonas/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Oxazolidinonas/química , Pentilenotetrazol/toxicidade , Ratos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
9.
Microb Drug Resist ; 25(6): 938-943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30694735

RESUMO

Tedizolid activity was compared with other agents with oral and intravenous formulations against community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Tedizolid (MIC50/90, 0.12/0.12 mg/L; 100.0% susceptible) was the most potent agent tested against CA-MRSA and subsets from adult and pediatric patients. Tedizolid minimum inhibitory concentrations (MICs) were twofold to fourfold lower than daptomycin (MIC50/90, 0.25/0.5 mg/L; 99.9-100% susceptible) and fourfold to eightfold lower than linezolid (MIC50/90, 1/1 mg/L; 100.0% susceptible), ceftaroline (MIC50/90, 0.5-1/1 mg/L; 96.6-98.8% susceptible), and vancomycin (MIC50/90, 0.5-1/1 mg/L; 100.0% susceptible) against CA-MRSA and subsets. Clindamycin resistance rates among CA-MRSA from pediatric and adult patients were 18.3-19.1% (13.4-14.2% constitutive, 4.9-6.4% inducible) and 36.2-37.6% (29.8-30.1% constitutive, 6.4-7.5% inducible), respectively. Tetracycline (90.4-96.4% susceptible) and trimethoprim-sulfamethoxazole (96.2-100.0% susceptible) were active against CA-MRSA or subsets, whereas erythromycin (83.8-89.4% nonsusceptible) and levofloxacin (50.2-70.8% nonsusceptible) had limited activities. Tedizolid had MIC50/90 values of 0.12/0.12 mg/L against CA-MRSA showing clindamycin constitutive-resistance and recovered from adult or pediatric patients. Tedizolid had potent activities against CA-MRSA, regardless of clindamycin phenotype or patient population. Tedizolid may be considered for the treatment of ABSSSI in adults. Further studies are warranted for the clinical development in the pediatric population.


Assuntos
Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Meticilina/uso terapêutico , Oxazolidinonas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Tetrazóis/uso terapêutico , Adolescente , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Infecções Estafilocócicas/microbiologia , Estados Unidos
10.
Cardiol Rev ; 27(5): 242-248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30601160

RESUMO

Cholesterol metabolism and transport has been a major focus in cardiovascular disease risk modification over the past several decades. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been the most commonly used agents, with the greatest benefit in reducing both the primary and secondary risks of cardiovascular disease. However, heart disease remains the leading cause of death in both men and women in the United States. Further investigation and intervention are required to further reduce the risk for cardiovascular disease and cardiovascular-related deaths. This review will focus on high-density lipoprotein metabolism and transport, looking particularly at cholesteryl ester transfer protein (CETP) inhibitors. While studies of the other CETP inhibitors in its class have not shown a significant improvement in the prevention of primary or secondary cardiovascular risk, anacetrapib, the fourth and latest of the CETP inhibitors to be investigated, may be more promising.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/uso terapêutico , Feminino , Humanos , Lipoproteínas HDL/metabolismo , Masculino
11.
Transl Stroke Res ; 10(1): 104-111, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29476447

RESUMO

The sole FDA-approved drug treatment for ischemic stroke is tissue-type plasminogen activator (tPA). However, upregulation of JNK mitogen-activated protein kinase (MAPK) and endothelin 1 (ET-1) by tPA after stroke contributes to impaired cerebrovascular autoregulation. Wild-type (wt) tPA can bind to the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA receptors (NMDA-Rs), exacerbating vasoconstriction. Elevations in IL-6, a marker of inflammation that accompanies stroke, are reported to be an adverse prognostic factor. We hypothesized that IL-6 released into CSF after stroke by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contribute to impairment of cerebrovascular autoregulation and increased histopathology. Results show that IL-6 was increased post stroke in pigs, which was increased further by wt-tPA. Co-administration of the IL-6 antagonist LMT-28 with wt-tPA prevented impairment of cerebrovascular autoregulation and necrosis of hippocampal cells. wt-tPA co-administered with the JNK inhibitor SP 600125 and the ET-1 antagonist BQ 123 blocked stroke-induced elevation of IL-6. Co-administration of LMT-28 with wt-tPA blocked the augmentation of JNK and ET-1 post stroke. In conclusion, IL-6 released after stroke, which is enhanced by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebrovascular autoregulation and increases histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and upregulation of IL-6 may improve the benefit/risk ratio compared to wt-tPA in treatment of stroke.


Assuntos
Córtex Cerebral/fisiopatologia , Hipocampo/patologia , Homeostase/fisiologia , Interleucina-6/metabolismo , Acidente Vascular Cerebral , Animais , Antracenos/uso terapêutico , Modelos Animais de Doenças , Endotelina-1 , Necrose/etiologia , Oxazolidinonas/uso terapêutico , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato , Transdução de Sinais , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Suínos , Ativador de Plasminogênio Tecidual/uso terapêutico , Regulação para Cima
12.
Drug Metab Dispos ; 47(3): 227-233, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567880

RESUMO

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Gotículas Lipídicas/metabolismo , Oxazolidinonas/farmacologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Linhagem Celular , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Meia-Vida , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazolidinonas/administração & dosagem , Oxazolidinonas/uso terapêutico , Poloxâmero/farmacologia , Distribuição Tecidual/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-30559131

RESUMO

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.


Assuntos
Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Mycobacterium ulcerans/efeitos dos fármacos , Oxazolidinonas/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Claritromicina/uso terapêutico , Modelos Animais de Doenças , Feminino , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Oxazolidinonas/efeitos adversos , Rifampina/uso terapêutico , Tetrazóis/efeitos adversos
14.
Orthopedics ; 41(6): 323-328, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452066

RESUMO

As a result of the increasing numbers of joint replacement surgeries and other implant-associated procedures performed, the incidences of periprosthetic joint infections and osteomyelitis are on the rise. Antibiotic resistance to gram-positive species, which are mostly isolated from such infections, is a significant obstacle in clinical practice. Promising clinical outcomes have been reported with the use of novel antibiotics for patients with periprosthetic joint infections and osteomyelitis. Further research is necessary for the establishment of these novel antibiotic therapies in routine clinical practice. [Orthopedics. 2018; 41(6):323-328.].


Assuntos
Antibacterianos/uso terapêutico , Osteomielite/tratamento farmacológico , Infecções Relacionadas à Prótese/tratamento farmacológico , Artroplastia de Substituição/efeitos adversos , Cefalosporinas/uso terapêutico , Quimioterapia Combinada , Glicopeptídeos/uso terapêutico , Humanos , Lipopeptídeos/uso terapêutico , Osteomielite/microbiologia , Oxazolidinonas/uso terapêutico , Infecções Relacionadas à Prótese/microbiologia
15.
Clin Infect Dis ; 67(suppl_3): S342-S348, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30496456

RESUMO

Background: Children are often neglected during early development of antituberculosis agents, and most receive treatment after it is first tested in adults. However, very young children have tuberculosis that differs in many respects from adult cavitary pneumonia and could have different toxicity profiles to drugs. Linezolid is effective against intracellular tuberculosis, a common manifestation in young children. However, linezolid has considerable toxicity due to inhibition of mitochondrial enzymes. Tedizolid could be a replacement if it shows equal efficacy and reduced toxicity. Methods: We performed tedizolid dose-effect studies in the hollow fiber system model of intracellular tuberculosis. We measured linezolid concentrations, colony-forming units (CFU), time-to-positivity, and monocyte viability and performed RNA sequencing on infected cells collected from repetitive sampling of each system. We also compared efficacy of tedizolid vs linezolid and vs tedizolid-moxifloxacin combination. Results: There was no downregulation of mitochondrial enzyme genes, with a tedizolid 0-24 hour area under the concentration-time curve (AUC0-24) of up to 90 mg*h/L. Instead, high exposures led to increased mitochondrial gene expression and monocyte survival. The AUC0-24 to minimum inhibitory concentration ratio associated with 80% of maximal bacterial kill (EC80) was 184 by CFU/mL (r2 = 0.96) and 189 by time-to-positivity (r2 = 0.99). Tedizolid EC80 killed 4.0 log10 CFU/mL higher than linezolid EC80. The tedizolid-moxifloxacin combination had a bacterial burden elimination rate constant of 0.27 ± 0.05 per day. Conclusions: Tedizolid demonstrated better efficacy than linezolid, without the mitochondrial toxicity gene or cytotoxicity signatures encountered with linezolid. Tedizolid-moxifloxacin combination had a high bacterial elimination rate.


Assuntos
Antibacterianos/farmacocinética , Moxifloxacina/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazolidinonas/farmacocinética , Tetrazóis/farmacocinética , Tuberculose/tratamento farmacológico , Antibacterianos/uso terapêutico , Criança , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina/uso terapêutico , Oxazolidinonas/uso terapêutico , Tetrazóis/uso terapêutico , Tuberculose/microbiologia
16.
Pak J Pharm Sci ; 31(5(Supplementary)): 2179-2184, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30393230

RESUMO

Major depressive disorder (MDD) is the leading cause of memory impairment in general population. The serotonin hypothesis provides a target model for the treatment of depression and depression-associated memory loss. 5-HT-1B receptor is suggested as a potential candidate in the pathophysiology of depressive illness. Dysfunction of 5-HT-1B receptors has been observed previously in depressive patients. Zolmitriptan, 5-HT-1B agonist is clinically recommended for the treatment of migraine. However, in present study this drug was tested as a potential treatment for depression and associated memory loss by altering the serotonergic function at receptor level. Rats (n=24) were equally divided into unstressed and stressed groups. Depression was induced by 19 days of restraint stress for 4 h which was followed by forced swim test and pattern separation test to assess depressive symptoms and memory impairment, respectively. The initial sign of depression-associated memory loss involves impaired pattern separation which is regarded as pseudodementia. In this study stressed rats showed depression- and pseudodementia-like symptoms. After the induction of depression, rats were treated with zolmitriptan at a dose of 0.3 mg/kg which resulted in a significant attenuation of depression and depression-associated memory impairment. Results are discussed with reference to the modulation of function of 5-HT-1B receptor following the administration of exogenous agonist.


Assuntos
Depressão/tratamento farmacológico , Depressão/psicologia , Transtornos Autoinduzidos/tratamento farmacológico , Transtornos Autoinduzidos/psicologia , Oxazolidinonas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Triptaminas/uso terapêutico , Animais , Depressão/complicações , Transtornos Autoinduzidos/etiologia , Masculino , Ratos , Ratos Wistar
17.
Atherosclerosis ; 278: 143-146, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30278356

RESUMO

Type 2 diabetes is a causal risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). While treatment with a statin reduces the risk of having an ASCVD event in all people, including those with type-2 diabetes, statin treatment also increases the likelihood of new onset diabetes when given to those with risk factors for developing diabetes. Treatment with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, reduces the risk of having a coronary event over and above that achieved with a statin. However, unlike statins, anacetrapib decreases the risk of developing diabetes. If the reduced risk of new-onset diabetes is confirmed in another CETP inhibitor outcome trial, there will be a case for considering the use of the combination of a statin plus a CETP inhibitor in high ASCVD-risk people who are also at increased risk of developing diabetes.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/complicações , Humanos , Oxazolidinonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
19.
Expert Opin Pharmacother ; 19(13): 1489-1494, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200779

RESUMO

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)is a common pathogen in acute bacterial skin and soft tissue infections (ABSSSIs), nosocomial pneumonia, bacteremia, endocarditis, as well as diabetic foot, bone, and joint infections. Areas covered: This review summarizes the randomized controlled trials that evaluated the clinical efficacy of tedizolid in ABSSSIs, which is currently the only United States Food and Drug Administration-labeled indication for tedizolid. Expert opinion: Tedizolid has several potential advantages over linezolid including once-daily dosing, shorter duration of therapy, and increased tolerability. However, its cost will likely limit its adoption for ABSSSIs with MRSA because other oxazolidinone antibiotics are available in less costly generic versions. Tedizolid is also currently being investigated for its use in other MRSA infections including nosocomial pneumonia as well as diabetic foot, bone, and joint infections and tedizolid's use in these disease states appears more promising. Potential indications for future clinical investigation of tedizolid's efficacy and safety include bacteremia and meningitis.


Assuntos
Antibacterianos/uso terapêutico , Oxazolidinonas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Tetrazóis/uso terapêutico , Humanos , Linezolida/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções dos Tecidos Moles/tratamento farmacológico
20.
Leuk Lymphoma ; 59(12): 2917-2928, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29911936

RESUMO

The Raf-1 kinase inhibitory protein (RKIP) is an important regulatory element in multiple signaling pathways, including MAPK-ERK1/2. We investigated whether targeted disruption of RKIP is a therapeutic option for chronic lymphocytic leukemia (CLL). The RKIP inhibitor locostatin-induced apoptosis of CLL cells, irrespective of poor prognostic indications or treatment history. Locostatin down-regulated MAPK-ERK1/2 and AKT phosphorylation, decreased expression of the chemokine receptor CXCR4 (p = .04) and reduced the migratory capacity of CLL cells toward stroma-derived factor 1α (SDF-1α, p = .02). Immuno-blotting and immuno-precipitation showed that RKIP is constitutively phosphorylated and highly expressed in CLL cells and that the actions of locostatin may be mediated by binding of G-protein receptor kinase-2 (GRK2) to MEK1 and AKT. Collectively, our data suggest that inhibition of RKIP may be effective against CLL, reducing the survival and migratory capacity of the leukemic cells through down-regulation of MAPK-ERK1/2 and AKT-mediated signaling.


Assuntos
Movimento Celular/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Oxazolidinonas/farmacologia , Proteína de Ligação a Fosfatidiletanolamina/antagonistas & inibidores , Receptores CXCR4/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/patologia , Leucócitos Mononucleares , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oxazolidinonas/uso terapêutico , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células
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