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1.
Phytochemistry ; 173: 112296, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32087436

RESUMO

The first phytochemical examination of extracts from leaves and stem bark of Palicourea luxurians (Rusby) Borhidi yielded two undescribed and one known alstrostine derivative together with the oxindole alkaloid javaniside as well as with 5α-carboxystrictosidine. Additionally, five iridoids and four secologanin derived isolation artifacts have been isolated. Lack of strictosidine and its follow-up metabolization products suggested that the Pictet-Spenglerase in P. luxurians does barely or not catalyze the formation of strictosidine. Against this background the biosynthesis of javaniside and 5α-carboxystrictosidine is discussed with regard to possible reaction mechanisms. Similarly, P. luxurians used an independent biosynthetic pathway to produce alstrostine type structures from secologanin and tryptamine in a 2:1 ratio. The structure of isoalstrostine A, which was isolated for the first time, allowed the refinement of a previously reported pathway to the alstrostine type carbon skeleton as well as to some follow-up metabolization products. In spite of various biosynthetic pathways incorporating secologanin to gain different types of tryptophan- and tryptamine-iridoid alkaloids, P. luxurians accumulates this compound as well a couple of further metabolized iridoids deriving from loganin and secologanin.


Assuntos
Alcaloides , Rubiaceae , Alcaloides de Triptamina e Secologanina , Glucosídeos Iridoides , Iridoides , Triptaminas , Triptofano , Alcaloides de Vinca
2.
Xenobiotica ; 50(5): 580-587, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31424307

RESUMO

The effect of different doses of borneol on the pharmacokinetics of vinpocetine after intraocular administration in the rat plasma and the brain was investigated.Intraocular administration of vinpocetine (3 mg/kg) was performed, in combination with different doses (0, 5, 10, and 20 mg/kg) of borneol. Intravenous administration of vinpocetine was used as a control (1 mg/kg). The concentrations of vinpocetine in the rat plasma and the brain were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Using the non-compartmental models with the DSA 2.0 software, the main pharmacokinetics parameters and the brain-targeting effect evaluated.In comparison with intravenous administration, after intraocular administration of vinpocetine alone, the absolute bioavailability (F) of vinpocetine was 43.82% for the plasma, and the drug target index (DTI) was 1.05 for the brain. After intraocular administration of vinpocetine combined with different doses of borneol, the relative bioavailability (Fr) of vinpocetine in the plasma was increased by 130.46-182.90%. The relative bioavailability (Fr) of vinpocetine in the brain was improved (147.19-225.36%). The DTI was 1.12, 1.18, and 1.21 for 5, 10, and 20 mg/kg of borneol, respectively.Compared with the intraocular administration of vinpocetine alone, the co-administration of different doses of borneol resulted in an obvious brain targeting effect.


Assuntos
Canfanos/metabolismo , Alcaloides de Vinca/farmacocinética , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Injeções Intraoculares , Plasma/metabolismo , Ratos
3.
Epilepsia ; 60(12): 2459-2465, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31755996

RESUMO

OBJECTIVE: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation. METHODS: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation. RESULTS: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention. SIGNIFICANCE: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.


Assuntos
Síndrome de Lennox Gastaut/tratamento farmacológico , Síndrome de Lennox Gastaut/genética , Mutação/genética , Medicina de Precisão/métodos , Receptores de GABA-A/genética , Alcaloides de Vinca/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Células HEK293 , Humanos , Síndrome de Lennox Gastaut/diagnóstico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Alcaloides de Vinca/farmacologia , Ácido gama-Aminobutírico/farmacologia
4.
J Peripher Nerv Syst ; 24 Suppl 2: S63-S73, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31647152

RESUMO

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.


Assuntos
Antineoplásicos/efeitos adversos , Furanos/efeitos adversos , Cetonas/efeitos adversos , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Talidomida/efeitos adversos , Alcaloides de Vinca/efeitos adversos , Estudos de Coortes , Humanos , Imunossupressores/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/terapia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/terapia
5.
Compr Psychiatry ; 94: 152122, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31473552

RESUMO

BACKGROUND: Schizophrenia is a mental disorder characterized by hyperlocomotion, cognitive symptoms, and social withdrawal. Brain-derived neurotrophic factor (BDNF) and postsynaptic density (PSD)-95 are related to schizophrenia-like deficits via regulating the synaptic ultrastructure, and play a role in drug therapy. Vinpocetine is a nootropic phosphodiesterase-1 (PDE-1) inhibitor that can reverse ketamine-induced schizophrenia-like deficits by increasing BDNF expression. However, the effects of vinpocetine on alleviating schizophrenia-like deficits via reversing the synaptic ultrastructure by regulating BDNF-related PSD-95 have not been sufficiently studied. METHODS: In this study, the schizophrenic model was built using ketamine (30 mg/kg) for 14 consecutive days. The effect of vinpocetine on reversing schizophrenia-like behaviors was examined via behavioral testing followed by treatment with certain doses of vinpocetine (20 mg/kg, i.p.). The BDNF and PSD-95 levels in the posterior cingulate cortex (PCC) were measured using biochemical assessments. In addition, the synaptic ultrastructure was observed using transmission electron microscopy (TEM). RESULTS: Ketamine induced drastic schizophrenia-like behaviors, lower protein levels of BDNF and PSD-95, and a change in the synaptic ultrastructure in the PCC. After treatment, the vinpocetine revealed a marked amendment in schizophrenia-like behaviors induced by ketamine, including higher locomotor behavior, lower cognitive behavior, and social withdrawal defects. Vinpocetine could increase the PSD-95 protein level by up-regulating the expression of BDNF. In addition, the synaptic ultrastructure was changed after vinpocetine administration, including a reduction in the thickness and curvature of the synaptic interface, as well as an increase in synaptic cleft width in the PCC. CONCLUSION: Vinpocetine can reverse the synaptic ultrastructure by regulating BDNF-related PSD-95 to alleviate schizophrenia-like deficits induced by ketamine in rats.


Assuntos
Proteína 4 Homóloga a Disks-Large/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Esquizofrenia/tratamento farmacológico , Sinapses/ultraestrutura , Alcaloides de Vinca/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Ketamina , Masculino , Ratos , Esquizofrenia/induzido quimicamente
6.
Neurochem Res ; 44(10): 2435-2447, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31535355

RESUMO

Vinpocetine is considered as neuroprotectant drug and used for treatment of brain ischemia and cognitive deficiencies for decades. A number of enzymes, channels and receptors can bind vinpocetine, however the mechanisms of many effects' are still not clear. The present study investigated the effects of vinpocetine from the mitochondrial bioenergetic aspects. In primary brain capillary endothelial cells the purinergic receptor-stimulated mitochondrial Ca2+ uptake and efflux were studied. Vinpocetine exerted a partial inhibition on the mitochondrial calcium efflux. In rodent brain synaptosomes vinpocetine (30 µM) inhibited respiration in uncoupler stimulated synaptosomes and decreased H2O2 release from the nerve terminals in resting and in complex I inhibited conditions, respectively. In isolated rat brain mitochondria using either complex I or complex II substrates leak respiration was stimulated, but ADP-induced respiration was inhibited by vinpocetine. The stimulation of oxidation was associated with a small extent of membrane depolarization. Mitochondrial H2O2 production was inhibited by vinpocetine under all conditions investigated. The most pronounced effects were detected with the complex II substrate succinate. Vinpocetine also mitigated both Ca2+-induced mitochondrial Ca2+-release and Ca2+-induced mitochondrial swelling. It lowered the rate of mitochondrial ATP synthesis, while increasing ATPase activity. These results indicate more than a single mitochondrial target of this vinca alkaloid. The relevance of the affected mitochondrial mechanisms in the anti ischemic effect of vinpocetine is discussed.


Assuntos
Encéfalo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Alcaloides de Vinca/farmacologia , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Células Endoteliais/metabolismo , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos Wistar , Sinaptossomos/metabolismo
7.
Bol Med Hosp Infant Mex ; 76(5): 215-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536041

RESUMO

Background: Extended-release vinpocetine is effective to control focal onset epileptic seizures with a low rate of adverse events. A clinical study was performed to evaluate the efficacy and tolerability of vinpocetine as an adjuvant treatment in patients with this condition. Methods: A double-blind clinical study of parallel groups was conducted, in which 87 patients with a diagnosis of focal epilepsy treated with one to three antiepileptic drugs were recruited. Patients were randomized to receive vinpocetine (n = 41) or placebo (n = 46) adjuvant to their treatment. Patients entered the baseline phase (4 weeks), the titration phase (4 weeks) and the evaluation phase (8 weeks), maintaining stable doses of vinpocetine and their respective antiepileptic drug treatment. Results: Vinpocetine was more effective than placebo in reducing seizures at the end of the evaluation phase (p < 0.0001). Sixty-nine percent of the vinpocetine-treated patients had a 50% reduction in seizures compared to 13% of placebo-treated patients. No significant differences in the presence of adverse effects in patients treated with vinpocetine compared to those treated with placebo were observed. The most frequent adverse events observed with vinpocetine were headache (7.9%) and diplopia (5.2%). Conclusions: As an adjuvant treatment, vinpocetine (2 mg/kg/day) effectively reduced the frequency of epileptic seizures and proved to be well tolerated. Vinpocetine has a wide safety profile and well-known adverse events, which are transient and with no sequelae.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsias Parciais/tratamento farmacológico , Alcaloides de Vinca/administração & dosagem , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Criança , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Alcaloides de Vinca/efeitos adversos , Adulto Jovem
8.
Int J Nanomedicine ; 14: 5555-5567, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413562

RESUMO

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods:  Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.


Assuntos
Géis/administração & dosagem , Micelas , Temperatura , Alcaloides de Vinca/administração & dosagem , Vitamina E/química , Administração Intranasal , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Bovinos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Masculino , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Alcaloides de Vinca/sangue , Alcaloides de Vinca/farmacocinética
9.
Support Care Cancer ; 27(10): 3729-3737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363906

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.


Assuntos
Antineoplásicos/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Bortezomib/efeitos adversos , Predisposição Genética para Doença/genética , Humanos , Taxoides/efeitos adversos , Alcaloides de Vinca/efeitos adversos
10.
Metab Eng ; 55: 76-84, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31226348

RESUMO

Monoterpene indole alkaloids (MIAs) from plants encompass a broad class of structurally complex and medicinally valuable natural products. MIAs are biologically derived from the universal precursor strictosidine. Although the strictosidine biosynthetic pathway has been identified and reconstituted, extensive work is required to optimize production of strictosidine and its precursors in yeast. In this study, we engineered a fully integrated and plasmid-free yeast strain with enhanced production of the monoterpene precursor geraniol. The geraniol biosynthetic pathway was targeted to the mitochondria to protect the GPP pool from consumption by the cytosolic ergosterol pathway. The mitochondrial geraniol producer showed a 6-fold increase in geraniol production compared to cytosolic producing strains. We further engineered the monoterpene-producing strain to synthesize the next intermediates in the strictosidine pathway: 8-hydroxygeraniol and nepetalactol. Integration of geraniol hydroxylase (G8H) from Catharanthus roseus led to essentially quantitative conversion of geraniol to 8-hydroxygeraniol at a titer of 227 mg/L in a fed-batch fermentation. Further introduction of geraniol oxidoreductase (GOR) and iridoid synthase (ISY) from C. roseus and tuning of the relative expression levels resulted in the first de novo nepetalactol production. The strategies developed in this work can facilitate future strain engineering for yeast production of later intermediates in the strictosidine biosynthetic pathway.


Assuntos
Engenharia Metabólica , Microrganismos Geneticamente Modificados , Mitocôndrias , Monoterpenos/metabolismo , Saccharomyces cerevisiae , Alcaloides de Vinca/biossíntese , Catharanthus/enzimologia , Catharanthus/genética , Microrganismos Geneticamente Modificados/genética , Microrganismos Geneticamente Modificados/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
11.
EBioMedicine ; 45: 447-455, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31204276

RESUMO

BACKGROUND: The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. METHODS: Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. FINDINGS: Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ±â€¯0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE. INTERPRETATION: The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. FUND: This study was funded by an mRACE Erasmus MC grant.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Inibidores da Fosfodiesterase 5/administração & dosagem , Pré-Eclâmpsia/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Adulto , GMP Cíclico/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Feminino , Humanos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Inibidores da Fosfodiesterase 5/metabolismo , Placenta/efeitos dos fármacos , Placenta/patologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro/genética , Citrato de Sildenafila/metabolismo , Vasodilatação/efeitos dos fármacos , Alcaloides de Vinca/administração & dosagem , Alcaloides de Vinca/metabolismo
12.
Life Sci ; 229: 21-35, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31063734

RESUMO

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder characterized by a progressive decline of cognitive abilities as well as bone loss. Physical and mental activities maintain cognitive functions as well as increase bone mass by inhibiting bone resorption. VIN and CoQ10 are neuroprotective drugs that possess anti-inflammatory and antioxidant properties. AIMS: To study the effect of PH&M on enhancing the neuroprotective role of VIN and CoQ10 combination during induction of AD model in rats besides their role against bone mass loss associated with AD model. MAIN METHODS: Six groups of rats were received saline, AlCl3, and PH&M daily either alone or with a combination of VIN and CoQ10 for 4 weeks. Various biochemical analyses were performed to evaluate the extent of brain damage such as ACHE, ß-secretase, chitinase, Aß, tau protein, and monoamines besides the inflammatory and antioxidant parameters. Serum levels of minerals as well as 25-OHD, PTH, RANKL, and OPG levels were measured to detect the extent of bone impairment. Also, histopathological changes were evaluated in different brain regions and hind paw. KEY FINDINGS: VIN and CoQ10 combination together with PH&M significantly attenuated the neurodegeneration induced by AlCl3 administration through the improvement of AD markers in brain tissue as well as oxidant and inflammatory markers. Bone resorption markers, serum minerals, and PTH levels were also normalized too. SIGNIFICANCE: Neuroprotective drugs together with PH&M have a more protective effect against AD and bone loss rather than PH&M alone.


Assuntos
Doença de Alzheimer/prevenção & controle , Remodelação Óssea/fisiologia , Cognição , Fármacos Neuroprotetores/farmacologia , Natação , Ubiquinona/análogos & derivados , Alcaloides de Vinca/farmacologia , Doença de Alzheimer/metabolismo , Animais , Comportamento Animal , Remodelação Óssea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Terapia Combinada , Masculino , Ratos , Ratos Sprague-Dawley , Ubiquinona/farmacologia , Vitaminas/farmacologia
14.
Drugs ; 79(9): 969-995, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31127530

RESUMO

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.


Assuntos
Antineoplásicos/efeitos adversos , Canabinoides/uso terapêutico , Dor Crônica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neuralgia/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Canabinoides/farmacologia , Dor Crônica/induzido quimicamente , Ensaios Clínicos como Assunto , Humanos , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/efeitos adversos , Taxoides/efeitos adversos , Resultado do Tratamento , Alcaloides de Vinca/efeitos adversos
15.
Mediators Inflamm ; 2019: 6481812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049025

RESUMO

Clinically active drugs for the treatment of acute pain have their prescription limited due to the significant side effects they induce. An increase in reactive oxygen species (ROS) has been linked to several conditions, including inflammation and pain processing. Therefore, new or repurposed drugs with the ability of reducing ROS-triggered responses are promising candidates for analgesic drugs. Vinpocetine is a clinically used nootropic drug with antioxidant, anti-inflammatory, and analgesic properties. However, the effects of vinpocetine have not been investigated in a model with a direct relationship between ROS, inflammation, and pain. Based on that, we aimed to investigate the effects of vinpocetine in a model of superoxide anion-induced pain and inflammation using potassium superoxide (KO2) as a superoxide anion donor to trigger inflammation and pain. In the KO2 model, vinpocetine dose-dependently reduced pain-like behaviors (spontaneous pain and hyperalgesia), paw edema, and neutrophil and mononuclear cell recruitment to the paw skin (assessed by H&E staining, fluorescence, and enzymatic assays) and to the peritoneal cavity. Vinpocetine also restored tissue endogenous antioxidant ability and Nrf2 and Ho-1 mRNA expression and reduced superoxide anion production and gp91phox mRNA expression. We also observed the inhibition of IκBα degradation by vinpocetine, which demonstrates a reduction in the activation of NF-κB explaining the diminished production of IL-33, IL-1ß, and TNF-α. Collectively, our data show that vinpocetine alleviates pain and inflammation induced by KO2, which is a mouse model with a direct role of ROS in triggering pain and other inflammatory phenomena. Thus, the results suggest the repurposing of vinpocetine as an anti-inflammatory and analgesic drug.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Reposicionamento de Medicamentos/métodos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Nootrópicos/uso terapêutico , Superóxidos/toxicidade , Alcaloides de Vinca/uso terapêutico , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/metabolismo , Heme Oxigenase-1 , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Proteínas de Membrana , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
16.
J Neurosurg Sci ; 63(3): 265-269, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31096724

RESUMO

BACKGROUND: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS. METHODS: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status. RESULTS: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group. CONCLUSIONS: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.


Assuntos
Clorpromazina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Prometazina/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso , Aspirina/administração & dosagem , Atorvastatina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Edaravone/administração & dosagem , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/administração & dosagem , Alcaloides de Vinca/administração & dosagem
17.
Life Sci ; 226: 117-129, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981765

RESUMO

AIMS: The study aim was to test the efficacy of a novel created hybrid nanosystem compared to other nanosystems in treatment of scopolamine induced memory impairment. MAIN METHODS: The fabrication and characterization of nanoformulations (microemulsion, liposomes, ethosomes, transfersomes and transethosomes) coencapsulating two cognitive enhancers; piracetam and vinpocetine delivered intranasally, in addition to a novel nanocomposite microemulsion/vesicular nanoformulation was described. KEY FINDINGS: Formulations delivered the drugs across sheep nasal mucosa, with cumulative percentage reaching 29.99% for vinpocetine and 57.78% for piracetam. While the solution form of the drugs was totally ineffective, the selected transethosomal, microemulsion and nanocomposite formulations reversed the scopolamine induced effect on the step through latency of passive avoidance test and the spontaneous alternation behavior in Y maze test, further confirmed by histopathlogical examination. All three nanoformulations significantly decreased the acetylcholinesterase activity and the extent of lipid peroxidation by 32-42%. The nanocomposite formulation was superior to the microemulsion and transethosomal formulations in its anti-inflammatory and antiapoptotic effects, delineated by higher extent of inhibition of COX-2 and caspase 3 expression respectively. SIGNIFICANCE: Results support the hypothesis that the novel microemulsion/vesicular nanocomposite system is a promising neuroprotective modality for intranasal brain targeting which is worthy of exploitation in other brain diseases.


Assuntos
Memória/efeitos dos fármacos , Piracetam/farmacologia , Alcaloides de Vinca/farmacologia , Administração Intranasal , Animais , Encéfalo/efeitos dos fármacos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Nanopartículas/uso terapêutico , Mucosa Nasal/efeitos dos fármacos , Fármacos Neuroprotetores , Piracetam/administração & dosagem , Ratos , Ratos Wistar , Escopolamina/farmacologia , Ovinos , Alcaloides de Vinca/administração & dosagem
18.
Ear Nose Throat J ; 98(5): E30-E31, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30961378

RESUMO

Vinca alkaloids are known to cause bilateral jaw pain that occurs once during the chemotherapy course. We report a patient with first bite syndrome (FBS) during active treatment with chemotherapy. A patient with Hodgkin lymphoma presented with unilateral jaw pain after beginning his chemotherapy regimen. Pain was worse with the first bite of each meal and dissipated over subsequent bites. Workup was negative for any lesions in the parotid, parapharyngeal space, or infratemporal fossa. Pain was timed closely with chemotherapy administration and would improve prior to next cycle. A trial of botulinum chemodenervation failed to completely relieve symptoms. The patient noted resolution of symptoms after the completion of chemotherapy. We report a case of FBS, which may represent the jaw pain seen commonly with administration of vinca alkaloids. There appears to be a correlation between onset and duration of first bite symptoms with chemotherapy administration.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Dor Facial , Doença de Hodgkin , Alcaloides de Vinca , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dor Facial/induzido quimicamente , Dor Facial/diagnóstico , Dor Facial/fisiopatologia , Dor Facial/terapia , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Estadiamento de Neoplasias , Fármacos Neuromusculares/administração & dosagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Resultado do Tratamento , Alcaloides de Vinca/administração & dosagem , Alcaloides de Vinca/efeitos adversos
19.
Drug Dev Ind Pharm ; 45(6): 1017-1028, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30922119

RESUMO

PURPOSE: A series of ß-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated. METHODS: A series of amphiphilic copolymers based on ß-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-ß-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of ß-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated. RESULTS: Around 60 types of ß-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80 × 10-4 to 5.24 × 10-2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded ß-CD-P4 micelles prepared with optimal formulation were about 65 nm, 21.44 ± 0.14%, and 49.05 ± 0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72 h of VP-loaded ß-CD-P4 micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded ß-CD-P4 micelles was 8.98 times higher than that of VP injection. CONCLUSION: The VP-loaded ß-CD-P4 micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the ß-CD-P4 copolymers are an excellent candidate for micelles drug delivery.


Assuntos
Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Polímeros/química , Alcaloides de Vinca/farmacocinética , beta-Ciclodextrinas/química , Animais , Disponibilidade Biológica , Preparações de Ação Retardada/administração & dosagem , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Injeções Intravenosas , Micelas , Ratos , Ratos Sprague-Dawley , Tensoativos/química , Distribuição Tecidual , Alcaloides de Vinca/administração & dosagem
20.
Life Sci ; 222: 245-254, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30858122

RESUMO

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-ß1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Cirrose Hepática/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Masculino , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/uso terapêutico
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