RESUMEN
A rising number of cases of misuse and abuse of propylhexedrine (Benzedrex), an over-the-counter nasal decongestant, have been documented. Misuse of this drug can lead to serious and potentially fatal cardiac and psychiatric adverse effects.
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Descongestionantes Nasales/efectos adversos , Propilaminas/efectos adversos , Humanos , Descongestionantes Nasales/administración & dosificación , Medicamentos sin Prescripción/efectos adversos , Propilaminas/administración & dosificación , Propilaminas/farmacologíaRESUMEN
The management of Parkinson's disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single-center, randomized, double-blind, placebo-controlled phase I, and first-in-human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well-tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose-dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single-ascending-dose and multiple-ascending-dose parts indicated dose- and time-independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well-tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice-daily use in patients.
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Antagonistas de Dopamina/administración & dosificación , Éteres Fenílicos/administración & dosificación , Propilaminas/administración & dosificación , Receptores de Dopamina D3/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Disponibilidad Biológica , Antagonistas de Dopamina/efectos adversos , Antagonistas de Dopamina/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Ayuno/metabolismo , Interacciones Alimento-Droga , Semivida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Éteres Fenílicos/efectos adversos , Éteres Fenílicos/farmacocinética , Propilaminas/efectos adversos , Propilaminas/farmacocinética , Adulto JovenRESUMEN
Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double-blind, placebo-controlled single- and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.
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Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Propilaminas/administración & dosificación , Propilaminas/sangre , Adulto , China/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía/métodos , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Canales KATP/metabolismo , Síndrome de QT Prolongado/sangre , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/epidemiología , Masculino , Propilaminas/efectos adversosRESUMEN
The prevalence of periodontal disease poses a significant global health burden. Treatments for these diseases, primarily focused on removal and eradication of dental plaque biofilms, are challenging due to limited access to periodontal pockets where these oral pathogens reside. Herein, we report on the development and characterization of nitric oxide (NO)-releasing carboxymethylcellulose (CMC) derivatives and evaluate their in vitro bactericidal efficacy against planktonic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, two prominent periodontopathogens. Bactericidal exposure assays revealed that three of the synthesized NO-releasing polymers were capable of reducing bacterial viability of both species by 99.9% in 2 hr at concentrations of 4 mg ml-1 or lower, reflecting NO's potent and rapid bactericidal action. The NO-releasing CMCs elicited minimal toxicity to human gingival fibroblasts at their bactericidal concentrations following 24-hr exposure.
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Aggregatibacter actinomycetemcomitans/efectos de los fármacos , Antibacterianos/farmacología , Compuestos Azo/farmacología , Carboximetilcelulosa de Sodio , Etanolaminas/farmacología , Óxido Nítrico/farmacología , Enfermedades Periodontales/microbiología , Poliaminas/farmacología , Porphyromonas gingivalis/efectos de los fármacos , Propilaminas/farmacología , Antibacterianos/administración & dosificación , Compuestos Azo/administración & dosificación , Compuestos Azo/química , Biopolímeros , Línea Celular , Diaminas/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Etanolaminas/administración & dosificación , Etanolaminas/química , Fibroblastos/efectos de los fármacos , Encía/citología , Humanos , Estructura Molecular , Óxido Nítrico/administración & dosificación , Óxido Nítrico/toxicidad , Poliaminas/administración & dosificación , Poliaminas/química , Propilaminas/administración & dosificación , Propilaminas/química , Especificidad de la Especie , ViscosidadRESUMEN
Tacrolimus (TAC), a potent immunosuppressive macrolide, has been investigated for ocular diseases due to promising results in the treatment of anterior and posterior segments eye diseases. Mesoporous and functionalized silica nanoparticles show potential as TAC delivery platforms owing to their interesting characteristic as large surface area, uniform pore size distribution, high pore volume, and excellent biocompatibility. The purpose of this study was to incorporate TAC in functionalized silica nanoparticles with 3-aminopropyltriethoxysilane (MSNAPTES) and investigate the safety and biocompatibility of the systems. The MSNAPTES and MSNAPTES TAC nanoparticles were characterized. The in vitro cytotoxicity of MSNAPTES and MSNAPTES load with TAC (MSNAPTES-TAC) in retinal pigment epithelial cells (ARPE-19) was determined, chorioallantoic membrane (CAM) assay model was used to investigate the in vivo biocompatibility, and safety of intravitreal injection was evaluated using clinical examination (assessment of intraocular pressure and indirect fundus ophthalmoscopy), electroretinographic (ERG) and histologic studies in rats' eyes. The elemental analysis (CHN), thermogravimetric (TGA), photon correlation spectroscopy and Fourier transform infrared (FTIR) analysis confirmed the presence of functionalized agent and TAC in the MSNAPTES nanoparticles. TAC loading was estimated at 7% for the MSNAPTES TAC nanoparticles. MSNAPTES and MSNAPTES TAC did not present in vitro cytotoxicity. The drug delivery systems showed good biocompatibility on CAM. No retinal abnormalities, vitreous hemorrhage, neovascularization, retinal detachment, and optic nerve atrophy were observed during the in vivo study. Follow-up ERGs showed no changes in the function of the retina cells after 15 days of intravitreal injection, and histopathologic observations support these findings. In conclusion, MSNAPTES TAC was successfully synthesized, and physicochemical analyses confirmed the presence of TAC in the nanoparticles. In vitro and in vivo studies indicated that MSNAPTES TAC was safe to intravitreal administration. Taking into account the enormous potential of MSNAPTES to carry TAC, this platform could be a promising strategy for TAC ocular drug delivery in the treatment of eye diseases.
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Nanopartículas/química , Dióxido de Silicio/química , Tacrolimus/administración & dosificación , Administración Intravesical , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Porosidad , Propilaminas/administración & dosificación , Propilaminas/química , Propilaminas/farmacología , Ratas , Silanos/administración & dosificación , Silanos/química , Silanos/farmacología , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/farmacología , Tacrolimus/química , Tacrolimus/farmacologíaRESUMEN
Infection of orthopedic implants is a growing clinical challenge to manage due to the proliferation of drug-resistant bacterial strains. In this study, we aimed to investigate whether the treatment of implants with ceragenin-90 (CSA-90), a synthetic compound based on endogenous antibacterial peptides, could prevent infection in a novel rat model of periprosthetic joint infection (PJI) challenged with either local or systemic Staphylococcus aureus. A novel preclinical model of PJI was created using press-fit porous titanium implants in the distal femur of male Wistar rats. Sterile implants were pre-treated with 500 µg CSA-90 in saline. S. aureus was applied either directly at the time of surgery or administered via tail vein injection immediately afterward. Animals were monitored daily for clinical and radiographic evidence of infection for a total of 6 weeks. Post-study microbiological, radiographic, and histological analysis were performed to determine the incidence of PJI and assess osseointegration. CSA-90 treated groups demonstrated a reduced rate of PJI as confirmed by deep tissue swab culture at the time of cull compared with untreated groups with both local (33% vs 100%; P = .009) and systemic (10% vs 90%; P < .0001) S. aureus inoculation. Median survival time also increased from 8 to 17 days and from 8 to 42 days, respectively. In conclusion, this study describes a novel preclinical model of local and hematogenous PJI using a porous metal implant. CSA-90 reduced the incidence of PJI in this model supporting its further development as an antimicrobial coating for orthopedic implants.
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Artritis Infecciosa/prevención & control , Pregnanos/administración & dosificación , Propilaminas/administración & dosificación , Infecciones Relacionadas con Prótesis/prevención & control , Infecciones Estafilocócicas/prevención & control , Animales , Artritis Infecciosa/etiología , Resorción Ósea/diagnóstico por imagen , Masculino , Oseointegración/efectos de los fármacos , Flebotomía/efectos adversos , Infecciones Relacionadas con Prótesis/etiología , Ratas Wistar , Staphylococcus aureus/aislamiento & purificación , Microtomografía por Rayos XRESUMEN
The present study describes synthesis of amino-decorated mesoporous silica nanoparticles (MSNs) for sustained delivery and enhanced bioavailability of sofosbuvir. Sofosbuvir is active against hepatitis C virus and pharmaceutically classified as class III drug according to biopharmaceutics classification system (BCS). MSNs were synthesized using modified sol-gel method and the surface was decorated with amino functionalization. Drug loaded MSNs were also grafted with polyvinyl alcohol in order to compare it with the amino-decorated MSNs for sustained drug release. The prepared MSNs were extensively characterized and the optimized formulation was toxicologically and pharmacokinetically evaluated. The functionalized MSNs of 196 nm size entrapped 29.13% sofosbuvir in the pores, which was also confirmed by the decrease in surface area, pore volume and pore size. The drug-loaded amino-decorated MSNs revealed an improved thermal stability as confirmed by thermal analysis. Amino-decorated MSNs exhibited Fickian diffusion controlled sofosbuvir release as compared with non-functionalized and PVA grafted MSNs. Amino-decorated MSNs were deemed safe to use in Sprague-Dawley rats after 14-days exposure as confirmed by the toxicological studies. More interestingly, we achieved a 2-fold higher bioavailability of sofosbuvir in Sprague-Dawley rats in comparison with sofosbuvir alone, and the Tmax was delayed 3-times indicating a sustained release of sofosbuvir.
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Antivirales , Portadores de Fármacos , Nanopartículas , Propilaminas , Silanos , Dióxido de Silicio , Sofosbuvir , Animales , Antivirales/administración & dosificación , Antivirales/química , Antivirales/farmacocinética , Antivirales/toxicidad , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/toxicidad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Células Hep G2 , Humanos , Masculino , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/toxicidad , Alcohol Polivinílico/química , Porosidad , Propilaminas/administración & dosificación , Propilaminas/química , Propilaminas/farmacocinética , Propilaminas/toxicidad , Ratas Sprague-Dawley , Silanos/administración & dosificación , Silanos/química , Silanos/farmacocinética , Silanos/toxicidad , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/toxicidad , Sofosbuvir/administración & dosificación , Sofosbuvir/química , Sofosbuvir/farmacocinética , Sofosbuvir/toxicidadRESUMEN
Here, we have developed a facile fluorometric system for the detection of adenosine triphosphate (ATP) by a rolling circle amplification (RCA) based on proximity ligation mediated amplification, and simultaneously achieved the release of the anticancer drug doxorubicin (DOX) through the mesoporous silicon system. Once the ATP molecule is present, the linker DNA will be released from the graphene oxide (GO) surface and hybridized to the template DNA of the GO surface joining with ligation enzyme. RCA reaction is followed by the addition of the phi29 DNA polymerase. The product of RCA reaction contains a base fragment complementary to the signal DNA, allowing the fluorescent oligonucleotide probe to be released from the GO surface and fluorescence is recovered. The strong fluorescence signal realized the sensitive detection of ATP. Gate DNA were modified to the surface of the mesoporous silica (MSN) by electrostatic attraction to encapsulate DOX. After the above-mentioned RCA process, its result that long DNA chain containing a base fragment complementary to gate DNA, would be hybridized to the gate DNA strand on the surface of MSN, which opened the MSN hole and released the drug DOX into cell for HeLa cell therapy. And the specificity to folate receptor overexpressed on cell surface was satisfactory which would be beneficial for cancer therapy.
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Adenosina Trifosfato/análisis , Técnicas de Amplificación de Ácido Nucleico/métodos , Adenosina Trifosfato/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , ADN/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/administración & dosificación , Ácido Fólico/química , Grafito/administración & dosificación , Grafito/química , Células HeLa , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/química , Óxidos/administración & dosificación , Óxidos/química , Propilaminas/administración & dosificación , Propilaminas/química , Silanos/administración & dosificación , Silanos/química , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/químicaRESUMEN
Stress-induced disturbance of the hypothalamic-pituitary-adrenal (HPA) axis is strongly implicated in incidence of mood disorders. A heightened neuroinflammatory response and oxidative stress play a fundamental role in the dysfunction of the HPA axis. We have previously demonstrated that iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could prevent oxidative injury and neuroinflammation against multiple stimuli-induced brain injury. The present study was to demonstrate the impacts of Ipt in stress-induced HPA axis disorder and depressive behavior. We employed 2 stress paradigms: 8 weeks of continuous restraint stress (chronic restraint stress, CRS) and 2h of restraint stress (acute restraint stress, ARS), to mimic both chronic stress and severe acute stress. Prolonged (4 weeks) and short-term (a single injection) Ipt treatment was administered 30min before each stress paradigm. We found that HPA axis was altered after stress, with different responses to CRS (lower ACTH and CORT, higher AVP, but normal CRH) and ARS (higher CRH, ACTH and CORT, but normal AVP). Both prolonged and short-term Ipt treatment normalized stress-induced HPA axis disorders and abnormal behaviors in mice. CRS and ARS up-regulated mRNA levels of inflammation-related molecules (TNFα, IL-1ß, IL-6 and TLR4) and oxidative stress molecules (gp91phox, iNOS and Nrf2) in the mouse hypothalamus. Double immunofluorescence showed CRS and ARS increased microglia activation (CD11b and TNFα) and oxidative stress in neurons (NeuN and gp91phox), which were alleviated by Ipt. Therefore, the present study reveals that Ipt could prevent against stress-induced HPA axis disorders and depressive behavior by alleviating inflammation and oxidative stress in the hypothalamus.
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Depresión/tratamiento farmacológico , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Canales KATP/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Propilaminas/administración & dosificación , Estrés Psicológico , Animales , Depresión/metabolismo , Depresión/prevención & control , Encefalitis/tratamiento farmacológico , Encefalitis/metabolismo , Encefalitis/prevención & control , Sistema Hipotálamo-Hipofisario/metabolismo , Canales KATP/agonistas , Masculino , Ratones Endogámicos C57BL , Sistema Hipófiso-Suprarrenal/metabolismoRESUMEN
The delivery of large cargos of diameter above 15nm for biomedical applications has proved challenging since it requires biocompatible, stably-loaded, and biodegradable nanomaterials. In this study, we describe the design of biodegradable silica-iron oxide hybrid nanovectors with large mesopores for large protein delivery in cancer cells. The mesopores of the nanomaterials spanned from 20 to 60nm in diameter and post-functionalization allowed the electrostatic immobilization of large proteins (e.g. mTFP-Ferritin, ~534kDa). Half of the content of the nanovectors was based with iron oxide nanophases which allowed the rapid biodegradation of the carrier in fetal bovine serum and a magnetic responsiveness. The nanovectors released large protein cargos in aqueous solution under acidic pH or magnetic stimuli. The delivery of large proteins was then autonomously achieved in cancer cells via the silica-iron oxide nanovectors, which is thus a promising for biomedical applications.
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Sistemas de Liberación de Medicamentos , Compuestos Férricos , Ferritinas , Proteínas Fluorescentes Verdes , Nanocompuestos , Dióxido de Silicio , Compuestos Férricos/administración & dosificación , Compuestos Férricos/química , Ferritinas/administración & dosificación , Ferritinas/química , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/química , Proteínas Fluorescentes Verdes/administración & dosificación , Proteínas Fluorescentes Verdes/química , Células HeLa , Humanos , Fenómenos Magnéticos , Nanocompuestos/administración & dosificación , Nanocompuestos/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Porosidad , Propilaminas/administración & dosificación , Propilaminas/química , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/químicaRESUMEN
Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1 mT, 10 Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects.
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Muerte Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Nanocables/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Humanos , Magnetismo/métodos , Propilaminas/administración & dosificación , Albúmina Sérica Bovina/administración & dosificación , Silanos/administración & dosificaciónRESUMEN
Although 5-(2-aminopropyl)benzofuran (5-APB) and 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (phenazepam) are being used as recreational drugs, research on their dependence liability or mechanisms of action is lacking. The present study aimed to evaluate the behavioral effects and dependence liability of these drugs using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques were used to assess the substance-induced alterations in synaptosome-released dopamine. While both of the tested substances elicited increases in conditioned place preference and dopamine, neither of them facilitated self-administration, suggesting that 5-APB and phenazepam have rewarding effects, rather than reinforcing effects.
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Benzodiazepinas/administración & dosificación , Benzofuranos/administración & dosificación , Encéfalo/metabolismo , Drogas de Diseño/administración & dosificación , Dopamina/biosíntesis , Propilaminas/administración & dosificación , Trastornos Relacionados con Sustancias/metabolismo , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
AIM: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. METHODS: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. RESULTS: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. CONCLUSION: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.
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Analgésicos no Narcóticos/uso terapéutico , Benzodioxoles/uso terapéutico , Fibromialgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Propilaminas/uso terapéutico , Neuropatía Ciática/tratamiento farmacológico , Inhibidores de Captación de Serotonina y Norepinefrina/uso terapéutico , Analgésicos no Narcóticos/administración & dosificación , Animales , Benzodioxoles/administración & dosificación , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos , Estructura Molecular , Dimensión del Dolor , Propilaminas/administración & dosificación , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificaciónRESUMEN
BACKGROUND: Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. METHODS: This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. RESULTS: In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). CONCLUSION: This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.
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Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Alcoholes Bencílicos/administración & dosificación , Clorobencenos/administración & dosificación , Pulmón/efectos de los fármacos , Antagonistas Muscarínicos/administración & dosificación , Fenetilaminas/administración & dosificación , Propilaminas/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinuclidinas/administración & dosificación , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Anciano , Alcoholes Bencílicos/efectos adversos , Clorobencenos/efectos adversos , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Volumen Espiratorio Forzado , Estado de Salud , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Antagonistas Muscarínicos/efectos adversos , Fenetilaminas/efectos adversos , Propilaminas/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quinuclidinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Espirometría , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Capacidad VitalRESUMEN
Bioabsorbable magnesium alloys are becoming prominent as temporary functional implants, as they avoid the risks generated by permanent metallic implants such as persistent inflammation and late restenosis. Nevertheless, the overfast corrosion of Mg alloys under physiological conditions hinders their wider application as medical implant materials. Here we investigate a simple one-step process to introduce a cross-linked 3-amino-propyltrimethoxysilane (APTES) silane physical barrier layer on the surface of Mg-Zn-Y-Nd alloys prior to electrostatic spraying with rapamycin-eluting poly(lactic-co-glycolic acid) (PLGA) layer. Surface microstructure was characterized by scanning electron microscope and Fourier transform infrared spectroscopy. Nanoscratch test verified the superior adhesion strength of PLGA coating in the group pretreated with APTES. Electrochemical tests combined with long-term immersion results suggested that the preferable in vitro anticorrosion behavior could be achieved by dense APTES barrier. Cell morphology and proliferation data demonstrated that APTES pretreated group resulted in remarkably preferable compatibility for both human umbilical vein endothelial cells and vascular smooth muscle cells. On the basis of excellent in vitro mechenical property, the animal study on the APTES pretreated Mg-Zn-Y-Nd stent implanted into porcine coronary arteries confirmed benign tissue compatibility as well as re-endothelialization without thrombogenesis or in-stent restenosis at six-month followup.
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Aleaciones/administración & dosificación , Aleaciones/química , Stents Liberadores de Fármacos , Propilaminas/administración & dosificación , Propilaminas/química , Silanos/administración & dosificación , Silanos/química , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Línea Celular , Células Endoteliales de la Vena Umbilical Humana , Humanos , Roedores , Porcinos , Porcinos EnanosRESUMEN
Solomon Tesfaye speaks to Nick Ward, Commissioning Editor: Solomon Tesfaye, MB ChB, MD, FRCP, speaks about PL37; the first orally administered dual inhibitor of enkephalinases and its potential role in the treatment of painful diabetic neuropathy. Solomon Tesfaye is a Consultant Physician/Endocrinologist at Sheffield Teaching Hospitals and Honorary Professor of Diabetic Medicine at the University of Sheffield. His research projects include the epidemiology, risk factors, pathogenesis, CNS involvement and treatment of diabetic neuropathy and neuropathic pain. He was awarded the Prestigious Camillo Golgi Prize of the European Association for the Study of Diabetes (EASD) in 2014 for major scientific contributions in diabetic neuropathy. He has had international leadership roles including chairmanship of the International Expert Group on Diabetic Neuropathy, and of NEURODIAB (2006-2009). He is also a member of the Science and Research Committee of Diabetes UK; a review panel member for the MRC, a Board Member of the Global Quantitative Sensation Testing Society; a member of the Advisory Council of the Neuropathy Trust; and Secretary of International Insulin Foundation. He has served as a member of the MRC, JDRF, NIDDK and UK NIHR scientific review panels and as a member of a Diabetes and Neuropathic Pain Review Group for NICE.
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Neuropatías Diabéticas/tratamiento farmacológico , Disulfuros/uso terapéutico , Neprilisina/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Propilaminas/uso terapéutico , Administración Oral , Investigación Biomédica/tendencias , Ensayos Clínicos como Asunto , Neuropatías Diabéticas/complicaciones , Disulfuros/administración & dosificación , Humanos , Masculino , Dolor/etiología , Propilaminas/administración & dosificación , Resultado del TratamientoRESUMEN
A suitable aerosol droplet size and formulation output rate is essential for the therapy of lung diseases under application of nebulizers. The current study investigated the potential of amine-modified poly(vinyl alcohol)s as excipients for inhalation delivery. A change of conductivity (effective at <0.1mg/ml) and viscosity (effective at >0.1mg/ml) of samples that were supplemented with charge-modified polymers had a significant influence on the generated droplet size (shift from ~8 to ~4 µm) and formulation throughput rate (shift from ~0.2 to ~1.0 g/min), where polymers with a higher amine density (and molecular weight) showed an elevated activity. Biocompatibility assessment of polymers in A549 cells and an isolated lung model resulted in cell lysis and lung edema formation dependent on the type (degree of amine substitution) and dose of polymer applied. Suitable compositions and concentrations of amine-modified poly(vinyl alcohol)s were identified with respect to an optimized nebulizer performance and acceptable biocompatibility. Charge-modified polymers represent novel excipients with potential to improve inhalation therapy.
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Nebulizadores y Vaporizadores , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , Propilaminas/química , Propilaminas/farmacología , Animales , Líquido del Lavado Bronquioalveolar/química , Línea Celular Tumoral , Humanos , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Alcohol Polivinílico/administración & dosificación , Propilaminas/administración & dosificación , ConejosRESUMEN
INTRODUCTION: A multicenter retrospective survey of patients poisoned by herbicides containing glyphosate salts in Japan was conducted to identify differences in symptoms and outcome of poisoning. METHODS: Participants were patients who were transported to emergency facilities between October 2006 and March 2014 after consuming herbicides containing glyphosate potassium salt (GlyK(+)) (the K-group) or other glyphosate salts (the O-group). Questionnaires were mailed to 38 emergency facilities that agreed to participate in the study. RESULTS: Serum potassium levels upon arrival were significantly higher (p < 0.01), and abnormal electrocardiogram findings were significantly more common (p < 0.01) in the K-group (n = 55) than in the O-group (n = 62). Conversely, acute lung injury (ALI) including acute respiratory distress syndrome (ARDS) (p = 0.05) and liver injury (LI) (p < 0.01) were significantly more common during hospitalization in the O-group, although no significant differences in the duration of hospital stay (p = 0.92) or outcomes (p = 0.95) were observed between the two groups. DISCUSSION AND CONCLUSION: The ingestion of products containing glyphosate isopropylamine or ammonium salts, and polyoxyethyleneamine (POEA) as a surfactant, can cause severe organ injury. Physicians should note that the ingestion of products containing glyphosate potassium salt and surfactants other than POEA can cause hyperkalemia, potentially leading to fatal arrhythmias or cardiac arrest.
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Glicina/análogos & derivados , Herbicidas/envenenamiento , Intoxicación/patología , Potasio/administración & dosificación , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Relación Dosis-Respuesta a Droga , Femenino , Glicina/administración & dosificación , Glicina/sangre , Glicina/envenenamiento , Herbicidas/administración & dosificación , Humanos , Japón , Masculino , Persona de Mediana Edad , Intoxicación/etiología , Polietilenglicoles/administración & dosificación , Polietilenglicoles/envenenamiento , Potasio/sangre , Propilaminas/administración & dosificación , Propilaminas/envenenamiento , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/patología , Estudios Retrospectivos , Tensoactivos/administración & dosificación , Tensoactivos/envenenamiento , Encuestas y Cuestionarios , Adulto Joven , GlifosatoRESUMEN
Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.
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Inhibidores de Captación Adrenérgica/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Propilaminas/administración & dosificación , Adolescente , Inhibidores de Captación Adrenérgica/farmacocinética , Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Niño , Comorbilidad , Humanos , Propilaminas/farmacocinética , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Treatment of infected open fractures remains a major clinical challenge. In this study, we investigated the novel broad-spectrum antibiotic CSA-90 (cationic steroid antibiotic-90) as an antimicrobial agent. METHODS: CSA-90 was screened in an osteoblast cell culture model for effects on differentiation and mineralization. Local delivery of CSA-90 was then tested alone and in combination with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a mouse ectopic bone formation model (n=40 mice) and in a rat open fracture model inoculated with pathogenic Staphylococcus aureus (n=84 rats). RESULTS: CSA-90 enhanced matrix mineralization in cultured osteoblasts and increased rhBMP-2-induced bone formation in vivo. All animals in which an open fracture had been inoculated with Staphylococcus aureus and not treated with local CSA-90, including those treated with rhBMP-2, had to be culled prior to the experimental end point (six weeks) because of localized osteolysis and deterioration of overall health, whereas CSA-90 prevented establishment of infection in all open fractures in which it was used (p≤0.012). Increased union rates were seen for the fractures treated with rhBMP-2 or with the combination of rhBMP-2 and CSA-90 compared with that observed for the fractures treated with CSA-90 alone (p=0.04). CONCLUSIONS: CSA-90 can promote osteogenesis and be used for prevention of Staphylococcus aureus infection in preclinical models. CLINICAL RELEVANCE: Local delivery of CSA-90 represents a novel strategy for prevention of infection and may have specific benefits in the context of orthopaedic injuries.