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BACKGROUND: Nearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the search for effective antiviral agents continues, we aimed to review data on the potential of repurposing antiparasitic drugs against viruses in general, with an emphasis on coronaviruses. METHODS: We performed a review by screening in vitro and in vivo studies that assessed the antiviral activity of several antiparasitic agents: chloroquine, hydroxychloroquine (HCQ), mefloquine, artemisinins, ivermectin, nitazoxanide (NTZ), niclosamide, atovaquone and albendazole. RESULTS: For HCQ and chloroquine we found ample in vitro evidence of antiviral activity. Cohort studies that assessed the use of HCQ for COVID-19 reported conflicting results, but randomized controlled trials (RCTs) demonstrated no effect on mortality rates and no substantial clinical benefits of HCQ used either for prevention or treatment of COVID-19. We found two clinical studies of artemisinins and two studies of NTZ for treatment of viruses other than COVID-19, all of which showed mixed results. Ivermectin was evaluated in one RCT and few observational studies, demonstrating conflicting results. As the level of evidence of these data is low, the efficacy of ivermectin against COVID-19 remains to be proven. For chloroquine, HCQ, mefloquine, artemisinins, ivermectin, NTZ and niclosamide, we found in vitro studies showing some effects against a wide array of viruses. We found no relevant studies for atovaquone and albendazole. CONCLUSIONS: As the search for an effective drug active against SARS-CoV-2 continues, we argue that pre-clinical research of possible antiviral effects of compounds that could have antiviral activity should be conducted. Clinical studies should be conducted when sufficient in vitro evidence exists, and drugs should be introduced into widespread clinical use only after being rigorously tested in RCTs. Such a search may prove beneficial in this pandemic or in outbreaks yet to come.
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Antiparasitarios/farmacología , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos , Hidroxicloroquina/farmacología , Ivermectina/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antiparasitarios/uso terapéutico , COVID-19/epidemiología , Humanos , Hidroxicloroquina/uso terapéutico , Ivermectina/uso terapéutico , Pandemias , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Encapsulated local anesthetics extend postoperative analgesic effect following site-directed nerve injection; potentially reducing postoperative complications. Our study aim was to investigate efficacy of our improved extended duration formulation - 15% bupivacaine in poly(DL-lactic acid co castor oil) 3:7 synthesized by ring opening polymerization. In vitro, around 70% of bupivacaine was released from the p(DLLA-CO) 3:7 after 10 days. A single injection of the optimal formulation of 15% bupivacaine-polymer or plain (0.5%) bupivacaine (control), was injected via a 22G needle beside the sciatic nerve of Sprague-Dawley rats under anesthesia; followed (in some animals) by a 1cm longitudinal incision through the skin and fascia of the paw area. Behavioral tests for sensory and motor block assessment were done using Hargreave's hot plate score, von Frey filaments and rearing count. The 15% bupivacaine formulation significantly prolonged sensory block duration up to at least 48 h. Following surgery, motor block was observed for 48 h following administration of bupivacaine-polymer formulation and rearing was reduced (returning to baseline after 48 h). No significant differences in mechanical nociceptive response were observed. The optimized bupivacaine-polymer formulation prolonged duration of local anesthesia effect in our animal model up to at least 48 h.
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Anestésicos Locales/farmacología , Bupivacaína/farmacología , Umbral del Dolor/efectos de los fármacos , Dolor Postoperatorio/prevención & control , Nervio Ciático/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Animales , Conducta Animal/efectos de los fármacos , Bupivacaína/administración & dosificación , Bupivacaína/química , Aceite de Ricino/análogos & derivados , Aceite de Ricino/química , Química Farmacéutica , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Dolor Postoperatorio/etiología , Dolor Postoperatorio/fisiopatología , Poliésteres/química , Ratas Sprague-Dawley , Nervio Ciático/fisiopatología , Nervio Ciático/cirugía , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
Leukemic cells are hard-to-transfect cell lines. Many transfection reagents which can provide high gene transfer efficiency in common adherent cell lines are not effective to transfect established blood cell lines or primary leukemic cells. This study aims to examine a new class of cationic polymer non-viral vector, PEGylated-dextran-spermine (PEG-D-SPM), to determine its ability to transfect the leukemic cells. Here, the optimal conditions of the complex preparation (PEG-D-SPM/plasmid DNA (pDNA)) were examined. Different weight-mixing (w/w) ratios of PEG-D-SPM/pDNA complex were prepared to obtain an ideal mixing ratio to protect encapsulated pDNA from DNase degradation and to determine the optimal transfection efficiency of the complex. Strong complexation between polymer and pDNA in agarose gel electrophoresis and protection of pDNA from DNase were detected at ratios from 25 to 15. Highest gene expression was detected at w/w ratio of 18 in HL60 and K562 cells. However, gene expression from both leukemic cell lines was lower than the control MCF-7 cells. The cytotoxicity of PEG-D-SPM/pDNA complex at the most optimal mixing ratios was tested in HL60 and K562 cells using MTS assay and the results showed that the PEG-D-SPM/pDNA complex had no cytotoxic effect on these cell lines. Spherical shape and nano-nature of PEG-D-SPM/pDNA complex at ratio 18 was observed using transmission electron microscopy. As PEG-D-SPM showed modest transfection efficiency in the leukemic cell lines, we conclude that further work is needed to improve the delivery efficiency of the PEG-D-SPM.
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Regulación Leucémica de la Expresión Génica , Técnicas de Transferencia de Gen , Nanopartículas/química , Polietilenglicoles/farmacología , Espermina/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Genes Reporteros , Células HL-60 , Humanos , Células K562 , Células MCF-7 , Sustancias Macromoleculares/química , Microscopía Electrónica de Transmisión , Nanopartículas/ultraestructura , Tamaño de la Partícula , Plásmidos/química , Plásmidos/genética , Polietilenglicoles/química , Espermina/química , TransfecciónRESUMEN
Systemic toxicity through overdose of local anaesthetic agents is a real concern. By encapsulating local anaesthetics in biodegradable carriers to produce a system for prolonged release, their duration of action can be extended. This encapsulation should also improve the safety profile of the local anaesthetic as it is released at a slower rate. Work with naturally occurring local anaestheticss has also shown promise in the area of reducing systemic and neurotoxicity. Extended duration local anaesthetic formulations in current development or clinical use include liposomes, hydrophobic based polymer particles such as Poly(lactic-co-glycolic acid) microspheres, pasty injectable and solid polymers like Poly(sebacic-co-ricinoleic acid) P(SA:RA) and their combination with synthetic and natural local anaesthetic. Their duration of action, rationale and limitations are reviewed. Direct comparison of the different agents is limited by their chemical properties, the drug doses encapsulated and the details of in vivo models described.
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Anestésicos Locales/administración & dosificación , Química Farmacéutica , Ensayos Clínicos como Asunto , Preparaciones de Acción Retardada , Inyecciones , Ácido Láctico/administración & dosificación , Liposomas , Microesferas , Ácido Poliglicólico/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , PolímerosRESUMEN
IMPORTANCE OF THE FIELD: Pain following surgery is often treated by local anesthetic agents. Duration of the analgesia can be extended safely following administration of encapsulated large doses of local anesthetic agents. AREAS COVERED IN THIS REVIEW: This review considers formulations used for encapsulation of local anesthetic agents for prolonged anesthesia effect. All studies describing encapsulation of a commercial local anesthetic agent for providing prolonged analgesia were considered using the NCBI Medline site. of local anesthetic, prolonged anesthesia, polymers and liposomes were entered in order to retrieve appropriate articles and reviews from 1966 to 2010, with emphasis on the last 10 years. Reference pages were searched manually for other relevant articles. The topics covered include an overview of local anesthetic agents and a review of local anesthetic carrier agents, with emphasis on liposomes and polymer carriers. Articles were limited to the English language. WHAT THE READER WILL GAIN: The current research areas for prolongation of local anesthetic effect are evaluated, along with their limitations. Each topic has been summarized, and the review has attempted to cover all current laboratory and clinical studies in a simple manner that should also be useful for readers without a pharmacology background. The direction of research is promising and exciting, and this review should be a useful up-to-date reference. TAKE HOME MESSAGE: Many formulations including polymer and liposome carriers have facilitated prolonged local anesthetic action for several days, although few clinical studies have been performed. This field promises a safe way to deliver local anesthetics for effect far beyond that of commercially available agents, with potential cost and health benefits for patients suffering chronic or postoperative pain.
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Anestésicos Locales/farmacología , Anestésicos Locales/farmacocinética , HumanosRESUMEN
OBJECTIVE: The aim of the present study was to evaluate the in-vitro dissolution and in-vivo pharmacokinetic profile of a novel two-phase modified-release formulation for diltiazem hydrochloride, as a water-soluble drug. MATERIALS AND METHODS: The delivery system consisted of two tablets inserted into a capsule. Both tablets comprised a coated drug core-matrix. The coating of the first tablet was intended to produce a first phase with a relatively fast release profile, while that of the second tablet included a unique controlling membrane designed to achieve a delayed controlled-release profile. Three different formulations were tested for their dissolution profiles both in water media and in buffer with a pH of 6.8. These formulations were also evaluated for their pharmacokinetic profile in healthy volunteers after single administration of a 240 mg dose. Serial venous blood samples were collected over 36 h post administration to measure diltiazem levels by HPLC. In addition the in-vivo /in-vitro correlation (IVIVC) was calculated for these formulations. RESULTS: The in-vitro characteristics of these formulations demonstrated a controlled release profile in both media but with different characteristics, as in Formulation 3 where faster dissolution profile obtained in water but slower one in pH 6.8 buffer. In-vivo the pharmacokinetic profile of these formulations showed that arabinogalactan containing formulations achieved plasma levels which allow a once daily administration. IVIVC calculation demonstrated that dissolution tested in buffer 6.8 media better correlates with the percent absorbed in-vivo and the best results were achieved with the formulation containing the highest amount of polysaccharide in the coating. CONCLUSION: It is concluded that the developed formulations achieved a controlled release profile both in-vitro and in-vivo which are suitable for once-daily administration.
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Bloqueadores de los Canales de Calcio/administración & dosificación , Química Farmacéutica/métodos , Diltiazem/administración & dosificación , Sistemas de Liberación de Medicamentos , Adulto , Área Bajo la Curva , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Cápsulas , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Preparaciones de Acción Retardada , Diltiazem/química , Diltiazem/farmacocinética , Método Doble Ciego , Femenino , Humanos , Masculino , Solubilidad , Espectrofotometría Ultravioleta , Comprimidos , Adulto JovenRESUMEN
We evaluated the biocompatibility of an injectable gelling polymeric device for the controlled release of gentamicin sulfate in the treatment of invasive bacterial infections in bone of male Wister rats. The biodegradable delivery carrier, poly(sebacic-co-ricinoleic-ester-anhydride), designated as p(SA:RA), was injected, with and without gentamicin, into the tibial canal. Rats were killed 3 weeks later. The tibiae were processed histologically, leaving the injectable polymer in situ. The local tissue reaction to the polymer with or without antibiotic consisted mainly of mild reactive fibroplasia/fibrosis and mild to moderate increased reactive bone formation. At this stage, no evidence for any active inflammatory response to the polymer was seen. Thus, the injection of p(SA:RA) was well tolerated and did not induce any signs of a progressive inflammatory reaction.
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Portadores de Fármacos/efectos adversos , Ensayo de Materiales/métodos , Osteomielitis/tratamiento farmacológico , Polímeros/efectos adversos , Animales , Antibacterianos/química , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Preparaciones de Acción Retardada , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Inflamación/inducido químicamente , Inyecciones , Masculino , Osteomielitis/microbiología , Osteomielitis/patología , Polímeros/administración & dosificación , Polímeros/química , Ratas , Ratas WistarRESUMEN
Nonbiodegradable polymer coating based on N-(2-carboxyethyl)pyrrole (PPA) and butyl ester of PPA (BuOPy) were successfully electrodeposited on a stainless steel stent surface using cyclic voltammetry. Chemical composition of the coating was examined by X-ray photoelectron spectroscopy. Polymer stability was examined by immersing the coated stent into 1:1 solution of fetal calf serum:seline solution up to 1 year and implantation subcutaneously in mouse for 1 week. Morphology changes were then recorded by scanning electron microscopy. Paclitaxel loading was carried out by immersion into drug solution and its release was detected by HPLC. The results show that thin (single micrometers), uniform coating with various morphology and hydrophobicity can be created by electrochemical deposition. The polymer did not show significant histopathological or morphological changes in vitro and in vivo. The surface properties allow loading appropriate amounts of paclitaxel and release it slowly up to a month.
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Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Materiales Biocompatibles Revestidos , Paclitaxel/química , Paclitaxel/metabolismo , Acero Inoxidable/química , Stents , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/metabolismo , Sistemas de Liberación de Medicamentos , Electroquímica , Ésteres/química , Femenino , Ensayo de Materiales , Ratones , Estructura Molecular , Paclitaxel/administración & dosificación , Polímeros/química , Polímeros/metabolismo , Pirroles/química , Propiedades de SuperficieRESUMEN
OBJECTIVE: Deximune soft-gelatin capsules (Dexcel Ltd., Hadera, Israel), the test preparation and Sandimmun Neoral (Novartis Inc., Basel, Switzerland), the reference preparation, are two cyclosporine (CyA) formulations widely used after stem cells and solid organ transplantation. A post-marketing, retrospective, parallel, comparative, multicenter survey study in transplant patients receiving these two formulations after transplantation was carried out in order to compare the toxicity profile and bioavailability. MATERIALS AND METHODS: The study was conducted in the five main leading transplantation centers in Israel and included 174 patients. A total of 1-3 CyA serum levels at different periods after transplantation were measured in each subject and the bioavailability, efficacy and toxicity profile were assessed. The blood concentrations were compared using a statistical model after adjustment for type of transplantation, dose and time after transplantation as confounding factors. RESULTS: No distinct differences were observed between the two CyA formulations. Using model-derived least squares means (LSM) of the CyA blood levels and adjusting for relevant confounding factors, no significant difference could be found between the blood levels of the test and reference formulations. Most of the side effects were mild and transient with both formulations, whereas 23% of the patients reported serious adverse events (mainly hypertension, 15%). 20% of the patients developed infectious complications during the therapy. CONCLUSIONS: Deximune administration is safe. The toxicity profile of the product, incidence and type of side effects and bioavailability are similar to those of Sandimmun Neoral.
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Ciclosporina/efectos adversos , Ciclosporina/farmacocinética , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Trasplante de Órganos , Trasplante de Células Madre , Adolescente , Adulto , Disponibilidad Biológica , Cápsulas , Niño , Preescolar , Ciclosporina/sangre , Monitoreo de Drogas , Femenino , Gelatina , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/sangre , Lactante , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: To evaluate the efficiency of the dexamethasone phosphate penetration into the rabbit eye after transcorneal and transscleral iontophoresis using a drug loaded hydrogel assembled on a portable iontophoretic Mini Ion device. METHODS: lontophoresis of dexamethasone phosphate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel sponges and portable iontophoretic device. Corneal iontophoretic administration was performed with electric current of 1 mAmp for 1, 2, and 4 min. In the control group, the dexamethasone was applied in drops into the conjunctival sac. Transconjunctival and transscleral iontophoresis were performed in the pars plana area, through the conjunctiva or directly on the sclera. Dexamethasone concentrations were assayed using HPLC method. To study the anatomical changes after iontophoresis application, histological examinations of corneas excised 5 minutes and 8 hours after the procedure were performed. RESULTS: Dexamethasone levels in the rabbits' corneas after a single transcorneal iontophoresis were up to 38 times higher compared to those obtained after topical eye drops instillation. High drug concentrations were obtained in the retina and sclera 4 hours after transscleral iontophoresis as well. There were no statistically significant differences in the drug concentration after transscleral and tranconjunctival iontophoresis. Histological examination of the corneas after the iontophoresis showed only discrete reversible changes of the epithelium and the stroma. CONCLUSION: A short, low-current, non-invasive iontophoretic treatment using the dexamethasone-loaded hydrogels has a potential clinical value in increasing the drug's penetration into the anterior and posterior segment of the eye.
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Dexametasona/análogos & derivados , Ojo/metabolismo , Iontoforesis , Animales , Córnea/metabolismo , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Conejos , Esclerótica/metabolismoRESUMEN
OBJECTIVE: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. RESULTS: For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. CONCLUSIONS: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.
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Ciclosporina , Inmunosupresores , Administración Oral , Adulto , Área Bajo la Curva , Cápsulas , Estudios Cruzados , Ciclosporina/administración & dosificación , Ciclosporina/química , Ciclosporina/farmacocinética , Gelatina , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/química , Inmunosupresores/farmacocinética , Masculino , Tasa de Depuración Metabólica , Solubilidad , Equivalencia TerapéuticaRESUMEN
In this study, we compared two systems which can be applied for transfection in vitro and in vivo: polyplexes based on the polymer dextran-spermine (D-SPM) and lipoplexes based on 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol. The carriers differ in (1) solubility in aqueous media, (2) source of the positive charges (quaternary amines for DOTAP and primary plus secondary amines for D-SPM), (3) electrostatics, i.e., for lipid and polymer, respectively: zeta-potential (81.0 and 48.1 mV), surface potential (180 and 92 mV), and surface pH (10.47 and 8.97), and (4) charge distribution (ordered versus non-ordered). The stability of the complex upon interaction with serum proteins was studied by means of fluorescence resonance energy transfer (FRET) between rhodamine-labeled cationic carriers and fluorescein-labeled DNA. Addition of serum increases the lipid-DNA average distance and decreases the polymer-DNA distance. However, FRET efficiency indicates that serum proteins do not induce a major DNA dissociation for either polyplexes or lipoplexes. Comparing the biodistribution of rhodamine-labeled complexes and the transgene expression after intravenous (i.v.), intramuscular (i.m.), and intranasal (i.n.) administration, we found that local administration of lipoplexes resulted in the lipoplexes remaining at the site of injection, whereas the polyplexes showed systemic distribution, accompanied by transgene expression in lungs and liver. It is suggested that the high water-solubility of the polymer combined with its lower positive charge (compared to DOTAP), which makes its association with the cells at the site of injection weaker, enables the polymer to reach and transfect distant organs through the blood stream. Using chemically modified D-SPM, we demonstrated the importance of high density of positive charges and a sufficient level of secondary amines for achieving efficient transgene expression in vivo.
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Colesterol/metabolismo , Dextranos/metabolismo , Ácidos Grasos Monoinsaturados/metabolismo , Liposomas/metabolismo , Compuestos de Amonio Cuaternario/metabolismo , Espermina/metabolismo , Administración por Inhalación , Animales , Colesterol/administración & dosificación , Colesterol/química , ADN/química , Dextranos/administración & dosificación , Dextranos/química , Ácidos Grasos Monoinsaturados/administración & dosificación , Ácidos Grasos Monoinsaturados/química , Femenino , Fluoresceína , Transferencia Resonante de Energía de Fluorescencia , Colorantes Fluorescentes , Técnicas de Transferencia de Gen , Concentración de Iones de Hidrógeno , Inyecciones Intramusculares , Inyecciones Intravenosas , Liposomas/química , Liposomas/farmacocinética , Hígado/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Plásmidos , Compuestos de Amonio Cuaternario/administración & dosificación , Compuestos de Amonio Cuaternario/química , Rodaminas , Solubilidad , Organismos Libres de Patógenos Específicos , Espermina/administración & dosificación , Espermina/química , Electricidad Estática , Distribución Tisular , Transgenes , Agua/químicaRESUMEN
Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.
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Antineoplásicos/administración & dosificación , Permeabilidad Capilar , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Polímeros/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Química Farmacéutica , Ensayos Clínicos como Asunto , Diseño de Fármacos , Endocitosis , Humanos , Hidrólisis , Estructura Molecular , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Polímeros/química , SolubilidadRESUMEN
Pharmaceutical grade D,L-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis. MTX loaded microspheres showed the encapsulation efficiency of 44-64% and were in the size range of 40-60 microm. These were used to study the release profile of the encapsulated drug. The release was found to be affected by the pH and buffer concentration of the release medium which was in turn revealed by solubility studies of MTX. The overall study demonstrates significance of drug as well as polymer properties on release. Biocompatibility of polymer was evaluated by injecting microspheres subcutaneously into Sprague-Dawley (SD) rat and no local histopathological abnormalities were found.
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Materiales Biocompatibles/síntesis química , Ácidos Decanoicos/química , Ácidos Dicarboxílicos/química , Portadores de Fármacos , Ácido Láctico/química , Metotrexato/química , Polímeros/síntesis química , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/efectos adversos , Tampones (Química) , Química Farmacéutica , Ácidos Decanoicos/administración & dosificación , Ácidos Decanoicos/efectos adversos , Ácidos Dicarboxílicos/administración & dosificación , Ácidos Dicarboxílicos/efectos adversos , Composición de Medicamentos , Femenino , Concentración de Iones de Hidrógeno , Inflamación/inducido químicamente , Inflamación/patología , Inyecciones Subcutáneas , Cinética , Ácido Láctico/administración & dosificación , Ácido Láctico/efectos adversos , Microesferas , Tamaño de la Partícula , Polímeros/administración & dosificación , Polímeros/efectos adversos , Ratas , Ratas Sprague-Dawley , Solubilidad , Factores de TiempoRESUMEN
The aim of this study was to evaluate the use of solid hydrogel as a probe for the drug delivery to the rabbit eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylenglycol dimethacrylate (EGDMA) were prepared to form solid hydrogels. The concentrations of gentamicin sulfate in different segments of rabbit eye after transconjunctival and transscleral iontophoresis were also studied. For iontophoresis we used a portable Mini Ion device (designed at Hebrew University of Jerusalem) and applied a current from 0 mA to 1.5 mA for pre-set period from 30 to 120 seconds and after application the concentrations of gentamicin in cornea were assayed. The rabbits in control group were treated with fortified gentamicin eye-drops (concentration 1.4 %). The highest concentration of gentamicin sulfate was reached after iontophoresis with current intensity of 1.5 mA applied for 60 s. High gentamicin concentration were found in the retina and in the sclera four hours after transscleral iontophoresis, the lowest concentration was obtained in vitreous. The delivery of gentamicin to the eye via iontophoresis with solid HEMA/EGDMA hydrogels seems to be promising method achieving high concentrations of the drug in the eye tissue.
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Antibacterianos/administración & dosificación , Portadores de Fármacos , Ojo , Gentamicinas/administración & dosificación , Hidrogel de Polietilenoglicol-Dimetacrilato , Iontoforesis , Animales , Antibacterianos/farmacocinética , Córnea/metabolismo , Gentamicinas/farmacocinética , Metacrilatos , ConejosRESUMEN
The clinical treatment of leishmaniasis is based on a limited number of drugs, which are associated with adverse effects and have already induced resistance. Amphotericin B (AmB), a polyene antibiotic produced by Streptomyces sp, is the only anti-leishmanial drug which has not induced clinical resistance since its discovery in 1956. The limiting factor in the use of AmB is its toxic effects, mainly nephrotoxicity. The maximal dose of AmB for human use is 1.5 mg/kg which sometimes is not sufficient for cure. The mode of action of AmB is associated with its toxicity: it selectively binds to parasite membrane ergosterol but also, to a lesser extent, to human cholesterol. Apart from this mechanism, AmB has immunomodulatory effects, some of them are deleterious. Reduction of the toxic effects by using lipid formulations allows the infusion of higher doses of AmB. Unfortunately, these formulations are relatively expensive and therefore out of reach for patients in need, in the endemic areas. All the existing formulations are given parenterally, which has obvious disadvantages; most important is the need for hospitalization or multiple visits in the clinic. The current efforts to improve AmB are directed at the production of AmB aggregates in liquid solutions, encapsulation with lipid components, and solubilization by binding to soluble polymers. The expected improved treatment resulting from use of the new formulations is based on better pharmacokinetics, reduced toxicity originating from slow release, targeting to the infected organ and an altered pattern of immune responses (related to AmB). Of particular importance are the attempts to produce derivatives for oral treatment, which will decrease costs of hospitalization and improve applicability for children and the elderly population.
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Anfotericina B/uso terapéutico , Antiprotozoarios/uso terapéutico , Leishmaniasis/tratamiento farmacológico , Anfotericina B/efectos adversos , Anfotericina B/farmacocinética , Animales , Antiprotozoarios/efectos adversos , Antiprotozoarios/farmacocinética , Química Farmacéutica , Humanos , Ratones , SolubilidadRESUMEN
Heparin is a biogenic anionic charged sulfated polysaccharide that has a range of desired activities including inhibition of tumor metastasis and inhibition of restenosis. However, its clinical use is limited to treating blood-clotting disorders. Anionic macromolecules called heparinoids have been investigated with the objective of developing heparin-like molecules with reduced anti-coagulant activity and selective anti-metastasis and anti-restenosis activity. This mini-review summarizes the synthesis and biological activity of the main synthetic heparinoids reported in the past three decades.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Heparinoides/farmacología , Aminoácidos/química , Aminoácidos/farmacología , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Antineoplásicos/química , Reestenosis Coronaria/tratamiento farmacológico , Reestenosis Coronaria/prevención & control , Inhibidores Enzimáticos/química , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/antagonistas & inhibidores , Heparina/química , Heparina/farmacología , Heparinoides/química , Heparitina Sulfato/metabolismo , Humanos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/prevención & controlRESUMEN
Many drugs that are administered in an unmodified form by conventional systemic routes fail to reach target organs in an effective concentration, or are not effective over a length of time due to a facile metabolism. Various types of targeting delivery systems and devices have been tried over a long period of time to overcome these problems. Targeted delivery or localized drug delivery offers an advantage of reduced body burden and systemic toxicity of the drugs, especially useful for highly toxic drugs like anticancer agents. Local drug delivery via polymer is a simple approach and hypothesized to avoid the above stated problems. Polyanhydrides are a unique class of polymer for drug delivery because some of them demonstrate a near zero order drug release and relatively rapid biodegradation in vivo. Further, the release rate of polyanhydride fabricated device can be altered over a thousand fold by simple changes in the polymer backbone. Hence, these are one of the best-suited polymers for drug delivery, with biodegradability and biocompatibility. The review focuses on the advantages of polyanhydride carriers in localized drug delivery along with their degradability behavior, toxicological profile and role in various disease conditions.
Asunto(s)
Portadores de Fármacos/química , Polianhídridos/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Sistemas de Liberación de Medicamentos , Humanos , Polianhídridos/toxicidadRESUMEN
Recently, a novel cationic polymer, dextran-spermine (D-SPM) was developed for gene delivery. An efficient transfection was obtained using this polycation for a variety of genes and cell lines in serum-free or serum-poor medium. However, transfection using the water-soluble D-SPM-based polyplexes decreased with increasing serum concentration in cell culture in a concentration-dependent manner, reaching 95% inhibition at 50% serum in the cell growth medium. In order to overcome this obstacle, oleyl derivatives of D-SPM (which form micelles in aqueous phase) were synthesized at 1, 10, and 20 mol% of oleyl moiety to polymer epsilon-NH2 to form N-oleyl-D-SPM (ODS). Polyplexes based on ODS transfected well in medium containing 50% serum. Comparison with polyplexes based on well-established polymers (branched and linear polyethyleneimine) and with DOTAP/Cholesterol lipoplexes showed that regarding beta-galactosidase transgene expression level and cytotoxicity in tissue culture, the D-SPM and ODS compare well with the above polyplexes and lipoplexes. Intracellular trafficking using FITC-labeled ODS and Rhodamine-labeled pGeneGrip plasmid cloned with hBMP2 monitored by confocal microscopy revealed that during the transfection process the fluorescent-labeled polymer concentrates in the Golgi apparatus and around the nucleus, while the cell cytoplasm was free of fluorescent particles, suggesting that the polyplexes move in the cell toward the nucleus by vesicular transport through the cytoplasm and not by a random diffusion. We found that the plasmids penetrate the cell nucleus without the polymer. Preliminary results in zebra fish and mice demonstrate the potential of ODS to serve as an efficient nonviral vector for in vivo transfection.
Asunto(s)
Terapia Genética/métodos , Plásmidos/administración & dosificación , Transfección/métodos , Animales , Cationes , Técnicas de Cultivo de Célula , Línea Celular , Núcleo Celular/metabolismo , Medios de Cultivo , Medio de Cultivo Libre de Suero , Citoplasma/metabolismo , Dextranos , Ácidos Grasos Monoinsaturados , Femenino , Citometría de Flujo , Expresión Génica , Aparato de Golgi/metabolismo , Humanos , Inyecciones , Luciferasas/genética , Ratones , Ratones Endogámicos C3H , Micelas , Microscopía Confocal , Células 3T3 NIH , Polietileneimina , Polímeros , Compuestos de Amonio Cuaternario , Espermina , Transgenes , Pez CebraRESUMEN
Nucleic acid delivery has many applications in basic science, biotechnology, agriculture, and medicine. One of the main applications is DNA or RNA delivery for gene therapy purposes. Gene therapy, an approach for treatment or prevention of diseases associated with defective gene expression, involves the insertion of a therapeutic gene into cells, followed by expression and production of the required proteins. This approach enables replacement of damaged genes or expression inhibition of undesired genes. Following two decades of research, there are two major methods for delivery of genes. The first method, considered the dominant approach, utilizes viral vectors and is generally an efficient tool of transfection. Attempts, however, to resolve drawbacks related with viral vectors (e.g., high risk of mutagenicity, immunogenicity, low production yield, limited gene size, etc.), led to the development of an alternative method, which makes use of non-viral vectors. This review describes non-viral gene delivery vectors, termed "self-assembled" systems, and are based on cationic molecules, which form spontaneous complexes with negatively charged nucleic acids. It introduces the most important cationic polymers used for gene delivery. A transition from in vitro to in vivo gene delivery is also presented, with an emphasis on the obstacles to achieve successful transfection in vivo.