RESUMEN
Vinpocetine (VIN) is a herbal supplement extracted from the periwinkle plant. It is a multi-action agent, which is used to treat various neurological disorders such as Alzheimer's and Parkinson's disease. Vinpocetine has also anti-inflammatory, analgesic, antioxidant property and treats various thinking and memory problems. Currently, vinpocetine is also available in the market as a dietary supplement to enhance cognition and memory. This profile explains the physicochemical properties, methods of preparation, content of related impurities and different spectroscopical behavior of vinpocetine. It also discusses the reported methods of analysis of the drug, which include Compendial Methods, Electrochemical Methods, Spectrophotometric Methods and Chromatographic Methods of analysis. Furthermore, this profile explains the stability of the drug subjected to stress conditions of acid, alkaline and photolytic degradation. In addition, the clinical applications of the drug, its uses, side effects, dosing information, pharmacokinetics and mechanism of action are also discussed.
Asunto(s)
Alcaloides de la Vinca , Antioxidantes , Suplementos Dietéticos , Humanos , Trastornos de la Memoria/tratamiento farmacológico , Alcaloides de la Vinca/análisis , Alcaloides de la Vinca/farmacología , Alcaloides de la Vinca/uso terapéuticoRESUMEN
K-Ras is one of the most important oncogenes in human oncogenesis. K-Ras transfection of normal rat fibroblasts induces phenotypic change from flat to round morphology. Then, we screened compounds inducing flat morphology in K-Ras transformed fibroblasts from microbial culture filtrates and plant extracts. As a result, the alkaloid conophylline was isolated from the leaves of Ervatamia microphylla collected in Thailand. Conophylline induced flat morphology and inhibited cellular invasion in K-Ras-transformed normal rat kidney (K-Ras-NRK) cells. It also inhibited the growth of the K-Ras-NRK tumor in mice. Cancer-associated fibroblasts are now considered to activate cancer growth. Conophylline was found to suppress secretions of various inflammatory cytokines by pancreatic cancer-associated fibroblasts. Moreover, when combined with gemcitabine, it inhibited the growth of pancreatic cancer growth in mice. Conophylline is orally active. Thus, the plant-derived alkaloid conophylline inhibited cancer growth directly and indirectly, and it shows promise as a new anticancer agent.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Alcaloides de la Vinca , Animales , Genes ras , Ratones , Hojas de la Planta/química , Ratas , Tabernaemontana/química , Alcaloides de la Vinca/farmacologíaRESUMEN
AIM: Vinpocetine (Vin) has long been used as a medicine to treat cerebrovascular disorders and as a dietary supplement to improve cognitive functions. Previous studies have revealed that the transcription factor nuclear factor kappa B (NF-κB) activity plays an important role in osteogenic differentiation of mesenchymal stem cells (MSC). Vin inhibits NF-κB-dependent inflammatory responses; however, the effect of Vin on the osteogenic differentiation of MSCs has not been reported. In this study, we aimed to the investigate effect of Vin on the osteogenic differentiation of rat bone marrow-derived MSCs (BMSCs). METHODS: We treated BMSCs with clinical plasma (0.17 µM) or higher concentrations (5 and 20 µM) of Vin with no significant effect on the cell viability. Alizarin Red S and alkaline phosphatase (ALP) stainings were used to evaluate mineralizations on days 14 and 21. Moreover, expressions of target genes were detected using qRT-PCR analysis. RESULTS: Osteogenic differentiation of BMSCs did not significantly change with Vin's clinical plasma concentration, but significantly decreased with higher concentrations. Calcium mineralization, ALP staining and mRNA gene expressions of Runx2 and ALP were decreased significantly with high concentrations of Vin, paticularly on day 21. CONCLUSION: Our in vitro findings suggest that clinically relevant concentration of Vin seems safe to use in elderly patients with respect to osteoporosis. On the other hand, Vin at high concentrations appears to be harmful to bone homeostasis.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Alcaloides de la Vinca/sangre , Alcaloides de la Vinca/farmacología , Fosfatasa Alcalina/metabolismo , Animales , Células de la Médula Ósea/efectos de los fármacos , Calcificación Fisiológica/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/biosíntesis , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/efectos de los fármacos , RatasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The leaf of Sarcocephalus latifolius is known to be used traditionally by the Fulanis in Nigeria to deworm animals. As helminthosis remains a major constraint to profitable livestock production worldwide, a precarious situation aggravated by the advent of resistant parasites, the discovery of new anthelmintics is a priority, necessitating exploration of medicinal plants for their anthelmintic principles. AIM OF THE STUDY: To identify and characterise compounds with anthelmintic activity from the leaf of Sarcocephalus latifolius. MATERIALS AND METHODS: Powdered S. latifolius leaves were extracted by successive maceration with n-hexane, chloroform and acetone. The dried extracts were evaluated for anthelmintic activity against Haemonchus placei adult worms, and the most active extract was subjected to bioassay-guided chromatographic separations. The isolated compounds were evaluated for cytotoxicity against the mammalian HeLa and MC3T3-E1 cell lines, using alamar blue and CellTitreGloTM to quantify cell viability. LC50 values were computed from the in vitro anthelmintic activity data by fitting to a non-linear regression equation (variable slope). Isolated compounds were characterized using spectroscopic and mass spectrometric analyses. RESULTS: Anthelmintic activity LC50 values for n-hexane, chloroform and acetone extracts were 47.85, 35.76 and 5.72 (mg/mL), respectively. Chromatographic separation of acetone extract afforded two bioactive epimers, identified as vincosamide (LC50 14.7â¯mg/mL) and strictosamide (LC50 12.8â¯mg/mL). Cytotoxicity evaluation showed that, below 200⯵g/mL (400⯵M), neither compound was toxic to the HeLa or MC3T3-E1 cells. CONCLUSION: Vincosamide and strictosamide could serve as novel scaffolds for the development of anthelmintic derivatives with improved potency and helminth selectivity.
Asunto(s)
Antihelmínticos/farmacología , Alcaloides Indólicos/farmacología , Rubiaceae/química , Alcaloides de la Vinca/farmacología , Células 3T3 , Animales , Antihelmínticos/aislamiento & purificación , Antihelmínticos/toxicidad , Haemonchus/efectos de los fármacos , Células HeLa , Humanos , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/toxicidad , Dosificación Letal Mediana , Ratones , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Hojas de la Planta , Alcaloides de la Vinca/aislamiento & purificación , Alcaloides de la Vinca/toxicidadRESUMEN
Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.
Asunto(s)
Antineoplásicos/farmacología , Reactivos de Enlaces Cruzados/farmacología , ADN/química , Neoplasias Endometriales/tratamiento farmacológico , Receptores de Folato Anclados a GPI/química , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Alquilantes/química , Animales , Bovinos , Cisplatino/administración & dosificación , Perros , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacología , Humanos , Concentración 50 Inhibidora , Células KB , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Paclitaxel/administración & dosificación , Ratas , Alcaloides de la Vinca/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Síndrome de Lennox-Gastaut/tratamiento farmacológico , Síndrome de Lennox-Gastaut/genética , Mutación/genética , Medicina de Precisión/métodos , Receptores de GABA-A/genética , Alcaloides de la Vinca/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Electroencefalografía/métodos , Femenino , Células HEK293 , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Alcaloides de la Vinca/farmacología , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.
Asunto(s)
Síndrome Metabólico/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fitoterapia , Alcaloides de la Vinca/farmacología , Alcaloides de la Vinca/uso terapéutico , Animales , Autofagia/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Fibrosis , Humanos , Islotes Pancreáticos/patología , Ratones , Terapia Molecular Dirigida , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Hojas de la Planta/química , Tabernaemontana/química , Alcaloides de la Vinca/aislamiento & purificaciónRESUMEN
Roots and rhizomes of Vinca herbacea Waldst. et Kit, were collected during early flowering and fruiting. Ð henophases biologically active substances I and II were obtained by liquid-liquid extraction. Dominant alkaloids: tabersonin, reserpine, maidine, norfluorocurarin and copsinin were obtained after the dispertion in citrare-phosfhate buffer and subsequent TLC. Accelerated restitution of granulocytopoiesis was observed in mice during both irradiation and myelotoxic drug-induced acute leucopenia. Increase in total WBC over 200% was observed after treatment by substance I in drug-induced leucopenia model (fivefold oral administration) and over 130% after treatment by substance I in irradiate mice (fivefold intraperitoneal administration). Morphological and anatomical structures of the underground organs of V. herbacea have been studied. The main microstructural characteristics are revealed - Rhizomes are characterized by coutinized epidermis, lamellar collenchyma, fibers and the texture of the vascular system of a monocyclic structure. The root system shows the whole cortex, the endoderm with Kaspar spots; the outer, radially continuous phloem tissue is located in the conducting system and distinguishes the cylindrical xylem tissue with annular and spiral-circular blood vessels.
Asunto(s)
Alcaloides de la Vinca/análisis , Vinca/química , Animales , Citostáticos/toxicidad , Femenino , Georgia (República) , Leucopenia/sangre , Leucopenia/tratamiento farmacológico , Leucopenia/etiología , Masculino , Ratones , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Raíces de Plantas/química , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/etiología , Rizoma/química , Pruebas de Toxicidad Aguda , Alcaloides de la Vinca/farmacología , Alcaloides de la Vinca/toxicidadRESUMEN
α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Fosfodiesterasa I/antagonistas & inhibidores , Agregación Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Animales , Línea Celular , Dipiridamol/farmacología , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Agregación Patológica de Proteínas/tratamiento farmacológico , Alcaloides de la Vinca/farmacología , alfa-Sinucleína/antagonistas & inhibidoresRESUMEN
The aim of present study was to develop VIN-loaded mPEG-PLA nanoparticle systems. The VIN mPEG-PLA nanoparticles were prepared using an emulsion solvent evaporation method, and studied their particle size, morphology, encapsulation efficiency and drug-loading coefficient. Moreover, the nanoparticles were evaluated on the drug release behaviors in vitro and bioavailability in vivo. The results show that the spherical nanoparticles obtained were negatively charged with a zeta potential of about -23.4 mV and characterized â¼110 nm with a narrow size distribution. The encapsulation efficiency and drug loading of prepared NPs were 76.4 ± 6.3 and 9.2 ± 2.2% (n=5), respectively. The in vitro release showed that the percent of accumulated dissolution of VIN NPs in phosphate-buffered saline 6.8 over 24 h was <80%, which was almost 100% of VIN in commercial injections. The in vivo study indicated that systemic absorption of VIN was significantly enhanced by incorporating into mPEG-PLA NPs compared with VIN injection (2.87-fold in AUC0-t). The results suggested that the form of VIN in mPEG-PLA NPs could enter the body circulation to perform sustained release in vitro and in vivo.
Asunto(s)
Nanopartículas/química , Poliésteres , Polietilenglicoles , Alcaloides de la Vinca , Animales , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Evaluación Preclínica de Medicamentos , Masculino , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Ratas , Ratas Wistar , Alcaloides de la Vinca/química , Alcaloides de la Vinca/farmacocinética , Alcaloides de la Vinca/farmacologíaRESUMEN
BACKGROUND: Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated. MATERIALS AND METHODS: Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor α (TNF-α), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured. RESULTS: CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-α, and apoptosis compared to CP alone. CONCLUSION: CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP.
Asunto(s)
Antioxidantes/farmacología , Cloropirifos/toxicidad , Contaminantes Ambientales/toxicidad , Linfocitos/efectos de los fármacos , Melatonina/farmacología , Ubiquinona/análogos & derivados , Alcaloides de la Vinca/farmacología , Antioxidantes/metabolismo , Técnicas de Cultivo de Célula , Células Cultivadas , Radicales Libres/metabolismo , Humanos , Linfocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ubiquinona/farmacologíaRESUMEN
In the present study, the effects of the two classical anti-epileptic drugs, carbamazepine and valproic acid, and the non-classical anti-seizure drug vinpocetine were investigated on the expression of the pro-inflammatory cytokines IL-1ß and TNF-α in the hippocampus of rats by PCR or western blot after the administration of one or seven doses. Next, the effects of the anti-seizure drugs were investigated on the rise in cytokine expression induced by lipopolysaccharides (LPS) inoculation in vivo. To validate our methods, the changes induced by the pro-convulsive agents 4-aminopyridine, pentylenetetrazole and pilocarpine were also tested. Finally, the effect of the anti-seizure drugs on seizures and on the concomitant rise in pro-inflammatory cytokine expression induced by 4-aminopyridine was explored. Results show that vinpocetine and carbamazepine reduced the expression of IL-1ß and TNF-α from basal conditions, and the increase in both pro-inflammatory cytokines induced by LPS. In contrast, valproic acid failed to reduce both the expression of the cytokines from basal conditions and the rise in IL-1ß and TNF-α expression induced by LPS. Tonic-clonic seizures induced either by 4-aminopyridine, pentylenetetrazole or pilocarpine increased the expression of IL-1ß and TNF-α markedly. 4-aminopyridine-induced changes were reduced by all the tested anti-seizure drugs, although valproic acid was less effective. We conclude that the anti-seizure drugs, vinpocetine and carbamazepine, whose mechanisms of action involve a decrease in ion channels permeability, also reduce cerebral inflammation. The mechanism of action of anti-seizure drugs like vinpocetine and carbamazepine involves a decrease in Na(+) channels permeability. We here propose that this mechanism of action also involves a decrease in cerebral inflammation.
Asunto(s)
Anticonvulsivantes/farmacología , Carbamazepina/farmacología , Hipocampo/metabolismo , Interleucina-1beta/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis , Ácido Valproico/farmacología , Alcaloides de la Vinca/farmacología , 4-Aminopiridina/antagonistas & inhibidores , 4-Aminopiridina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Western Blotting , Convulsivantes/farmacología , ADN Complementario/biosíntesis , ADN Complementario/genética , Epilepsia Tónico-Clónica/inducido químicamente , Epilepsia Tónico-Clónica/fisiopatología , Hipocampo/efectos de los fármacos , Interleucina-1beta/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Reacción en Cadena de la Polimerasa , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Vintafolide (EC145) is a novel folate-conjugated vinca alkaloid (desacetylvinblastine hydrazide; DAVBLH) that binds with high affinity to the folate receptor (FR), expressed in a majority of epithelial ovarian cancers. In preclinical studies, vintafolide had significant antiproliferative activity and tolerability. Phase I studies demonstrated an acceptable safety profile, with constipation being the dose-limiting toxicity. A Phase II study of vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with platinum-resistant ovarian cancer showed a statistically significant improvement in progression-free survival with combination therapy. (99m)Tc-etarfolatide, a diagnostic radiopharmaceutical, determines FR status, which allows determination of those patients most likely to benefit from treatment with vintafolide. A Phase III study evaluating vintafolide plus PLD versus PLD alone in patients with platinum-resistant ovarian cancer is currently underway.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácido Fólico/análogos & derivados , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Alcaloides de la Vinca/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Epitelial de Ovario , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Femenino , Ácido Fólico/química , Ácido Fólico/farmacología , Ácido Fólico/uso terapéutico , Humanos , Terapia Molecular Dirigida , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Ováricas/diagnóstico , Resultado del Tratamiento , Alcaloides de la Vinca/química , Alcaloides de la Vinca/farmacologíaRESUMEN
In our study, the binding affinities of selected natural products towards PfTrxR, PfGR, human TrxR and human GR were determined using a mass spectrometry based ligand binding assay. The in vitro antimalarial activity and cytotoxicity of these ligands were also determined. Catharanthine, 11-(OH)-coronaridine, hernagine, vobasine and hispolone displayed antiplasmodial activity against PfK1 (IC50 = 0.996-3.63 microg/mL).
Asunto(s)
Antiprotozoarios/farmacología , Productos Biológicos/farmacología , Glutatión Reductasa/antagonistas & inhibidores , Plasmodium falciparum/enzimología , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Animales , Humanos , Ibogaína/análogos & derivados , Ibogaína/farmacología , Alcaloides Indólicos/farmacología , Concentración 50 Inhibidora , Alcaloides de la Vinca/farmacologíaRESUMEN
CONTEXT: Catharanthus roseus (L.) G. Don (Apocynaceae) is a medicinal plant that produces more than 130 alkaloids, with special attention given to the production of the anti-hypertensive monomeric indole alkaloids, serpentine and ajmalicine, and the antitumor dimeric alkaloids, vinblastine and vincristine. OBJECTIVE: This study evaluated the cytotoxic activity of the indole alkaloid-enriched bioactive extract obtained from suspension cultured-cells of C. roseus elicited with methyl jasmonate (MJ) and cyclodextrins (CDs) in three cell lines: JURKAT E.6 human lymphocytic leukemia, THP-1 human monocytic leukemia and BL 1395 non-tumor human B-cell line. MATERIALS AND METHODS: An indole alkaloid-enriched bioactive extract was obtained from C. roseus cell cultures elicited with MJ and CDs. The indole alkaloids were identified using an HPLC-diode array system coupled to a time-of-flight mass spectrometer using electrospray ionization (ESI) source. The cytotoxic assays were made using the colorimetric assay 2, 3-bis (2-methoxy-4-nitro-5-sulfophenyl)-S-[(phenylamino)carbonyl]-2 tetrazolium hydroxide (XTT). RESULTS: Four indole alkaloids were identified (catharanthine, ajmalicine, tabersonine and lochnericine) but only catharanthine and ajmalicine were quantified. The concentration of the indole alkaloid-enriched bioactive extract that inhibited cell growth by 50% was 211 and 210 ng/mL for the JURKAT E.6 and THP-1 cell lines, respectively. DISCUSSION AND CONCLUSION: The results confirm that the powerful antitumor activity of this indole alkaloid-enriched bioactive extract is not due to the effect of a single compound but depends on the synergistic action of the four compounds identified.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Catharanthus/metabolismo , Alcaloides Indólicos/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/metabolismo , Acetatos/farmacología , Antineoplásicos Fitogénicos/biosíntesis , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Catharanthus/química , Catharanthus/citología , Catharanthus/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Ciclodextrinas/farmacología , Ciclopentanos/farmacología , Descubrimiento de Drogas , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Concentración 50 Inhibidora , Oxilipinas/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/citología , Hojas de la Planta/efectos de los fármacos , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacología , Alcaloides de Triptamina Secologanina/química , Alcaloides de Triptamina Secologanina/metabolismo , Alcaloides de Triptamina Secologanina/farmacología , Espectrometría de Masa por Ionización de Electrospray , Alcaloides de la Vinca/química , Alcaloides de la Vinca/metabolismo , Alcaloides de la Vinca/farmacologíaRESUMEN
Increasing recurrence of mammalian tumors and severe side-effects of chemotherapeutic agents reduce the clinical efficacy of a large variety of anticancer agents that are currently being used. Thus, there is always a constant need to develop alternative or synergistic anticancer drugs with minimal side-effects. One important strategy to develop effective anticancer agents is to study into anticancer agents derived from natural sources. Anticancer agents derived from plants and their derivatives have been proven to be effective for cancer prevention and therapeutics. Vinca alkaloid and their derivatives, alone and in combination with therapeutic agents, have been used for a long time for the treatment of various types of cancers. Polyphenols form one of the most important and extensively used classes of plant-derived therapeutics for cancer prevention or chemotherapy. The present review highlights a plethora of studies focused on the antineoplastic properties of plant-derived chemicals, such as Vinca alkaloid, saponins, and flavonoids.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Productos Biológicos/uso terapéutico , Flavonoides/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Humanos , Extractos Vegetales/uso terapéutico , Saponinas/química , Saponinas/farmacología , Saponinas/uso terapéutico , Alcaloides de la Vinca/química , Alcaloides de la Vinca/farmacología , Alcaloides de la Vinca/uso terapéuticoRESUMEN
Two new water-soluble folate receptor-targeted drug conjugates that contain the highly active doxorubicin derivative N-(5,5-diacetoxybut-1-yl)doxorubicin were designed and evaluated for their biological activity against folate receptor positive tumours. The prodrugs were designed to contain an acid-sensitive hydrazone bond KO019 or in addition a disulphide bond KO013 in order to elucidate the importance of the pre-determined breaking point for their in vitro and in vivo properties. Fluorescence microscopy studies confirmed higher uptake of the prodrugs in folate receptor positive KB cells than in the folate receptor negative A549 lung cancer cells. In subsequent in vivo studies in the folate receptor positive KB xenograft model, KO019 was as active as the free drug but significantly less toxic when dosed at twice the dose of the free drug whereas KO013 showed no anticancer efficacy. As an explanation, we could show by HPLC that the prodrug KO013 that additionally contains a disulphide bond undergoes rapid disulphide exchange in murine plasma in the order of 40% after 5h at 37°C in contrast to KO019 which was essentially stable after a 5h incubation.
Asunto(s)
Doxorrubicina/análogos & derivados , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/análogos & derivados , Profármacos/farmacología , Pterinas/farmacología , Alcaloides de la Vinca/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Receptores de Folato Anclados a GPI/antagonistas & inhibidores , Ácido Fólico/farmacología , Ratones , Ratones Desnudos , Profármacos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Maternal alcohol use during pregnancy causes a continuum of long-lasting disabilities in the offspring, commonly referred to as fetal alcohol spectrum disorder (FASD). Attention-deficit/hyperactivity disorder (ADHD) is possibly the most common behavioral problem in children with FASD and devising strategies that ameliorate this condition has great clinical relevance. Studies in rodent models of ADHD and FASD suggest that impairments in the cAMP signaling cascade contribute to the hyperactivity phenotype. In this work, we investigated whether the cAMP levels are affected in a long-lasting manner by ethanol exposure during the third trimester equivalent period of human gestation and whether the acute administration of the PDE1 inhibitor vinpocetine ameliorates the ethanol-induced hyperactivity. METHODS: From postnatal day (P) 2 to P8, Swiss mice either received ethanol (5g/kg i.p.) or saline every other day. At P30, the animals either received vinpocetine (20mg/kg or 10mg/kg i.p.) or vehicle 4h before being tested in the open field. After the test, frontal cerebral cortices and hippocampi were dissected and collected for assessment of cAMP levels. RESULTS: Early alcohol exposure significantly increased locomotor activity in the open field and reduced cAMP levels in the hippocampus. The acute treatment of ethanol-exposed animals with 20mg/kg of vinpocetine restored both their locomotor activity and cAMP levels to control levels. CONCLUSIONS: These data lend support to the idea that cAMP signaling system contribute to the hyperactivity induced by developmental alcohol exposure and provide evidence for the potential therapeutic use of vinpocetine in FASD.
Asunto(s)
Consumo de Bebidas Alcohólicas/patología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Alcaloides de la Vinca/farmacología , Consumo de Bebidas Alcohólicas/efectos adversos , Animales , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Depresores del Sistema Nervioso Central/efectos adversos , Depresores del Sistema Nervioso Central/sangre , Depresores del Sistema Nervioso Central/toxicidad , AMP Cíclico/análisis , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Etanol/efectos adversos , Etanol/sangre , Etanol/toxicidad , Femenino , Humanos , Masculino , Ratones , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/uso terapéutico , Embarazo , Complicaciones del Embarazo/inducido químicamente , Método Simple Ciego , Tasa de Supervivencia , Alcaloides de la Vinca/administración & dosificación , Alcaloides de la Vinca/efectos adversos , Alcaloides de la Vinca/uso terapéutico , Aumento de Peso/efectos de los fármacosRESUMEN
The present study investigates the potential of Piracetam and Vinpocetine (nootropic drugs, known to possess neuroprotective properties) in preventing hypoxia-reoxygenation induced oxidative stress in primary hippocampal cell culture. The hippocampal culture was exposed to hypoxia (95% N(2), 5% CO(2)) for 3h and followed by 1h of reoxygenation (21% O(2) and 5% CO(2)) at 37 °C. The primary hippocampal cultures were supplemented with the optimum dose of Piracetam and Vinpocetine, independently, and the cultures were divided into six groups, viz. Control/Normoxia, Hypoxia, Hypoxia+Piracetam, Hypoxia+Vinpocetine, Normoxia + Piracetam and Normoxia+Vinpocetine. The cell-viability assays and biochemical oxidative stress parameters were evaluated for each of the six groups. Administration of 1mM Piracetam or 500 nM Vinpocetine significantly prevents the culture from hypoxia-reoxygenation injury when determined by Neutral Red assay, LDH release and Acetylcholine esterase activity. Results showed that Piracetam and Vinpocetine supplementation significantly prevented the fall of mitochondrial membrane potential, rise in ROS generation and reduction in antioxidant levels associated with the hypoxia-reoxygenation injury. In conclusion, the present study establishes that both Piracetam and Vinpocetine give neuroprotection against hypoxia-reoxygenation injury in primary hippocampal cell culture.