RESUMEN
Controlled release or controlled drug delivery comprises the set of techniques and approaches to improve bioavailability through improved safety and/or efficacy using a carrier material for the molecule of interest. The predictability and tunability of these carriers make them ideal for protection, localization, and sustained presentation of a wide range of therapeutics, including growth factors implicated in cell survival and regeneration. Here we provide a method for encapsulating epidermal growth factor in a degradable polymer matrix for delivery to the cornea. Additional notes are included to demonstrate the wide-ranging capabilities of such methods for other materials, therapeutic agents, and sites of action within the eye.
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Supervivencia Celular , Preparaciones de Acción Retardada , Supervivencia Celular/efectos de los fármacos , Humanos , Regeneración , Factor de Crecimiento Epidérmico/metabolismo , Animales , Córnea/metabolismo , Córnea/citología , Sistemas de Liberación de Medicamentos/métodos , Polímeros/química , Portadores de Fármacos/químicaRESUMEN
Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.
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Liposomas , MicroARNs , Fotoquimioterapia , Fármacos Fotosensibilizantes , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Animales , Humanos , Liposomas/química , MicroARNs/genética , MicroARNs/metabolismo , Fotoquimioterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Femenino , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/patología , Ratones , Aptámeros de Nucleótidos/química , Preparaciones de Acción Retardada/química , Interferencia de ARN , Pez CebraRESUMEN
Background: Switching from methadone to buprenorphine in patients receiving opioid maintenance therapy often requires inpatient care with a gradual tapering of methadone and an opioid-free day with challenging withdrawal symptoms. This case report describes and discusses a gentle outpatient approach without the opioid-free day. Case presentation: A patient with a 15-year history of opioid maintenance therapy reduced his methadone dose from 80 mg to 50 mg due to concurrent use of other sedative substances and a significant risk of overdose. A week-long switch to buprenorphine 16 mg subcutaneous depot formulation was then undertaken using a microinduction approach in the outpatient setting. Interpretation: In line with earlier reports on microinduction, the switch from methadone to buprenorphine was carried out with no opioid withdrawal symptoms or complications. Microinduction offers a smooth and more patient-friendly approach to switching from full opioid agonists to partial agonists. Randomised controlled trials are, however, needed for a systematic evaluation of this method.
Asunto(s)
Atención Ambulatoria , Buprenorfina , Metadona , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides , Humanos , Buprenorfina/administración & dosificación , Buprenorfina/uso terapéutico , Metadona/administración & dosificación , Metadona/uso terapéutico , Masculino , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/rehabilitación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Preparaciones de Acción Retardada , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
Perilla essential oil (PLEO) offers benefits for food preservation and healthcare, yet its instability restricts its applications. In this study, chitosan (CS) and TiO2 used to prepare composite particles. TiO2, after being modified with sodium laurate (SL), was successfully introduced at 0.1 %-3 % into the CS matrix. The resulting CS-SL-TiO2 composite particles can be formed by intertwining and rearranging through intramolecular and intermolecular interactions, and form an O/W interface with stability and viscoelasticity. The Pickering emulsions stabilized by these particles exhibit non-Newtonian pseudoplastic behavior, shear-thinning properties, and slow-release characteristics, along with antibacterial activity. Emulsions with 0.5 % and 1 % CS-SL-TiO2 composites demonstrated superior antibacterial effects against Escherichia coli and Staphylococcus aureus. The study revealed that all emulsions undergo Fickian diffusion and a sustained release of PLEO, with the Ritger-Peppas model best describing this release mechanism. The slow-release behaviors positively correlates with interfacial pressure, composite particle size, composite particle potential, composite contact angle, emulsion particle size and emulsion potential, but negatively correlates with diffusion rate, penetration rate, release kinetics and release rate. The findings lay groundwork for developing slow-release antimicrobial emulsions within polysaccharide matrices, showcasing promise for antimicrobial packaging solutions and enhanced food preservation techniques.
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Antibacterianos , Quitosano , Emulsiones , Escherichia coli , Staphylococcus aureus , Titanio , Agua , Quitosano/química , Quitosano/farmacología , Titanio/química , Antibacterianos/química , Antibacterianos/farmacología , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Agua/química , Aceites Volátiles/química , Aceites Volátiles/farmacología , Tamaño de la Partícula , Preparaciones de Acción Retardada/química , Aceites de Plantas/química , Aceites de Plantas/farmacología , Pruebas de Sensibilidad Microbiana , Liberación de FármacosRESUMEN
Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of µ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and µ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.
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Ansia , Preparaciones de Acción Retardada , Giro del Cíngulo , Imagen por Resonancia Magnética , Naltrexona , Antagonistas de Narcóticos , Plasticidad Neuronal , Trastornos Relacionados con Opioides , Tomografía de Emisión de Positrones , Corteza Prefrontal , Humanos , Naltrexona/farmacología , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Masculino , Adulto , Femenino , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Antagonistas de Narcóticos/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/diagnóstico por imagen , Plasticidad Neuronal/efectos de los fármacos , Estudios Longitudinales , Ansia/efectos de los fármacos , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/efectos de los fármacos , Persona de Mediana Edad , Receptores Opioides mu/efectos de los fármacos , Fentanilo/administración & dosificación , Fentanilo/análogos & derivadosRESUMEN
Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming an intratumoral sustained drug release depot that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues, consequently generating systemic anticancer immunoreactivity. CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-ß inhibitor in preclinical tumor models in female mice.
Asunto(s)
Preparaciones de Acción Retardada , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Factor de Crecimiento Transformador beta , Microambiente Tumoral , Animales , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/antagonistas & inhibidores , Femenino , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/antagonistas & inhibidores , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Glicoproteínas de MembranaRESUMEN
Core-shell nanostructures are powerful platforms for the development of novel nanoscale drug delivery systems with sustained drug release profiles. Coaxial electrospinning is facile and convenient for creating medicated core-shell nanostructures with elaborate designs with which the sustained-release behaviors of drug molecules can be intentionally adjusted. With resveratrol (RES) as a model for a poorly water-soluble drug and cellulose acetate (CA) and PVP as polymeric carriers, a brand-new electrospun core-shell nanostructure was fabricated in this study. The guest RES and the host CA molecules were designed to have a reverse gradient distribution within the core-shell nanostructures. Scanning electron microscope and transmission electron microscope evaluations verified that these nanofibers had linear morphologies, without beads or spindles, and an obvious core-shell double-chamber structure. The X-ray diffraction patterns and Fourier transform infrared spectroscopic results indicated that the involved components were highly compatible and presented in an amorphous molecular distribution state. In vitro dissolution tests verified that the new core-shell structures were able to prevent the initial burst release, extend the continuous-release time period, and reduce the negative tailing-off release effect, thus ensuring a better sustained-release profile than the traditional blended drug-loaded nanofibers. The mechanism underlying the influence of the new core-shell structure with an RES/CA reverse gradient distribution on the behaviors of RES release is proposed. Based on this proof-of-concept demonstration, a series of advanced functional nanomaterials can be similarly developed based on the gradient distributions of functional molecules within electrospun multi-chamber nanostructures.
Asunto(s)
Celulosa , Preparaciones de Acción Retardada , Portadores de Fármacos , Liberación de Fármacos , Nanofibras , Resveratrol , Nanofibras/química , Preparaciones de Acción Retardada/química , Resveratrol/química , Resveratrol/administración & dosificación , Celulosa/química , Celulosa/análogos & derivados , Portadores de Fármacos/química , Polímeros/química , Espectroscopía Infrarroja por Transformada de Fourier , Sistemas de Liberación de Medicamentos/métodos , Difracción de Rayos XRESUMEN
BACKGROUND: Incarceration provides an opportunity for health interventions, including opioid use disorder (OUD) treatment and prevention of opioid-related overdoses post-release. All FDA-approved forms of medication for OUD (MOUD) treatment were mandated in several Massachusetts jails in 2019, with some jails offering extended-release buprenorphine (XR-Bup). Little is known about patient perspectives on and experiences with XR-Bup in carceral settings. METHODS: We conducted semi-structured interviews in 2022 with community-dwelling people who received MOUD during a recent incarceration in a Massachusetts jail. We asked participants about their experiences with and perspectives on XR-Bup while in jail. Qualitative data were double-coded deductively and reviewed inductively to identify emergent themes, which were structured using the Theoretical Framework of Acceptability (TFA). RESULTS: Participants (n = 38) had a mean age of 41.5 years, were 86% male, 84% White, 24% Hispanic, and 95% continued to receive MOUD at the time of their interview, including 11% receiving XR-Bup. Participants who viewed XR-Bup favorably appreciated avoiding the taste of sublingual buprenorphine; avoiding procedural difficulties and indignities associated with daily dosing in carceral settings (e.g., mouth checks, stigmatizing treatment from correctional staff); avoiding daily reminders of their addiction; experiencing less withdrawal; having extra time for other activities, such as work; and reduction of diversion of MOUD within the jail setting. Participants who viewed XR-Bup less favorably preferred to maintain their daily dosing routine; liked daily time out of their housing unit; wanted to know what was "going into my body everyday"; and feared needles and adverse events. Participants also reported that jail clinicians used XR-Bup for patients who were previously caught diverting sublingual buprenorphine, suggesting limited patient participation in decision-making around XR-Bup initiation in some jails. CONCLUSION: People who received MOUD in Massachusetts jails had both favorable and unfavorable views and experiences with XR-Bup. Understanding these preferences can inform protocols in jails that are considering implementation of XR-Bup treatment.
Asunto(s)
Buprenorfina , Preparaciones de Acción Retardada , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides , Investigación Cualitativa , Humanos , Buprenorfina/administración & dosificación , Buprenorfina/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos/métodos , Massachusetts , Cárceles Locales , Prisioneros , Entrevistas como Asunto , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéuticoRESUMEN
Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites. This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting. An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA. PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA. Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment.
Asunto(s)
Antipsicóticos , Aripiprazol , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Aripiprazol/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Masculino , Femenino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangre , Antipsicóticos/uso terapéutico , Persona de Mediana Edad , Polimorfismo Genético/genética , Quinolonas/farmacocinética , Quinolonas/sangre , Adulto Joven , Piperazinas/farmacocinética , Piperazinas/sangre , Anciano , Preparaciones de Acción Retardada/farmacocinéticaRESUMEN
BACKGROUND: Ongoing psychiatric follow-up and medication adherence improve outcomes for patients with psychotic disorders. Due to COVID-19, outpatient care may have been disrupted, impacting healthcare utilization. METHODS: A retrospective population-wide study was conducted for adults in Manitoba, Canada. Medication adherence and healthcare utilization were examined from 2019 to 2021. The presence of a diagnosed psychotic disorder was identified in the five years before the index date in each year. The LAI and clozapine cohorts consisted of those who received at least two prescriptions in each year 180 days before the March 20th index date. The change in adherence was measured using the average Medication Possession Ratio. Healthcare utilization rates were compared using Generalized Estimating Equation models. RESULTS: There were no significant differences between LAI and clozapine discontinuation rates before and during the pandemic. In the LAI cohort, general practitioner visits decreased significantly (-3.5 %, p = 0.039) across four quarters of 2021 versus 2019. All-cause hospitalizations decreased by 16.8 % in 2020 versus 2019 (p = 0.0055), while psychiatric hospitalizations decreased by 18.7 % across four quarters in 2020 (p = 0.0052) and 13.7 % in 2021 (p = 0.0425), versus 2019 in the LAI cohort. There was a significant transition to virtual care during the first wave of COVID-19 (71 % in clozapine, 51 % in LAI cohorts). Trends in total outpatient visits and non-psychiatric hospitalizations remained stable. CONCLUSION: COVID-19 had no substantial impact on LAI and clozapine discontinuation rates for patients previously adherent. Outpatient care remained stable, with a significant proportion of visits being done virtually at the outset of the pandemic.
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Antipsicóticos , COVID-19 , Clozapina , Cumplimiento de la Medicación , Aceptación de la Atención de Salud , Trastornos Psicóticos , Humanos , Masculino , Femenino , COVID-19/epidemiología , Clozapina/uso terapéutico , Clozapina/administración & dosificación , Cumplimiento de la Medicación/estadística & datos numéricos , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/epidemiología , Manitoba/epidemiología , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Aceptación de la Atención de Salud/estadística & datos numéricos , Preparaciones de Acción Retardada , Hospitalización/estadística & datos numéricos , Anciano , Adulto JovenRESUMEN
Neovascular ocular diseases are among the most common causes of preventable or treatable vision loss. Their management involves lifelong, intravitreal injections of anti-vascular endothelial growth factor (VEGF) therapeutics to inhibit neovascularization, the key pathological step in these diseases. Anti-VEGF products approved for ocular administration are expensive biological agents with limited stability and short half-life. Additionally, their therapeutic advantages are hindered by high treatment resistance, poor patient compliance and the need for frequent, invasive administration. Herein, we used electrospinning to develop a unique, non-porous, PLGA implant for the ocular delivery of siponimod to improve ocular neovascular disease management. Siponimod is an FDA-approved drug for multiple sclerosis with a novel indication as a potential ocular angiogenesis inhibitor. The electrospinning conditions were optimised to produce a microfibrous, PLGA matte that was cut and rolled into the desired implant size. Physical characterisation techniques (Raman, PXRD, DSC and FTIR) indicated siponimod was distributed uniformly within the electrospun fibres as a stabilised, amorphous, solid dispersion with a character modifying drug-polymer interaction. Siponimod dispersion and drug-polymer interactions contributed to the formation of smooth fibres, with reduced porous structures. The apparent reduced porosity, coupled with the drug's hydrophobic dispersion, afforded resistance to water penetration. This led to a slow, controlled, Higuchi-type drug diffusion, with â¼30% of the siponimod load released over 90 days. The released drug inhibited human retinal microvascular endothelial cell migration and did not affect the cells' metabolic activity at different time points. The electrospun implant was physically stable after incubation under stress conditions for three months. This novel siponimod intravitreal implant broadens the therapeutic possibilities for neovascular ocular diseases, representing a potential alternative to biological, anti-VEGF treatments due to lower financial and stability burdens. Additionally, siponimod interaction with PLGA provides a unique opportunity to sustain the drug release from the electrospun fibres, thereby reducing the frequency of intravitreal injection and improving patient adherence.
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Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Humanos , Porosidad , Liberación de Fármacos , Preparaciones de Acción Retardada/química , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Azetidinas , Compuestos de BenciloRESUMEN
Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC-MS/MS in 30 study participants-20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L-and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.
Asunto(s)
Úlcera de Buruli , Claritromicina , Preparaciones de Acción Retardada , Mycobacterium ulcerans , Rifampin , Humanos , Claritromicina/farmacocinética , Claritromicina/administración & dosificación , Masculino , Femenino , Adulto , Rifampin/farmacocinética , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Persona de Mediana Edad , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/microbiología , Mycobacterium ulcerans/efectos de los fármacos , Preparaciones de Acción Retardada/farmacocinética , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano , Adulto Joven , Área Bajo la Curva , Espectrometría de Masas en TándemRESUMEN
We aimed to investigate the chemical and physical properties of nano silver fluoride sustained release orthodontic elastomerics (NSF-RE) and determine their antimicrobial and antibiofilm formation activities against Streptococcus mutans. Orthodontic elastomerics were dip-coated with NSF solution in ethyl cellulose (EC) and polyethylene glycol 6000 (PEG). The studied groups included NSF (no EC/PEG), NSF-E (EC), NSF-EP1 (EC:PEG, 4:1), and NSF-EP2 (EC:PEG, 2:1). The cumulative release of silver nanoparticles (AgNPs) and fluoride, along with the compatibility of the tensile force with orthodontic brackets, was evaluated. The antimicrobial activity was evaluated using an agar diffusion test. The inhibition of biofilm formation was evaluated using colony-forming units (CFUs), biofilm thickness, and the live/dead cell ratio. NSF-RE containing EC sustained the release of AgNPs and fluoride for > 7 days. Tensile forces were not significantly different among the groups. The inhibition zone was 2.64- and 1.31-fold larger with NSF-EP2 than that with NSF and NSF-E, respectively. NSF-EP2 was the most effective in inhibiting biofilm formation with significant reductions in CFUs, biofilm thickness, and live/dead cell ratio by 57, 86, and 96%, respectively, as compared to those in the control group. Overall, sustained release of AgNPs and fluoride by NSF-RE provides antimicrobial and antibiofilm effects against S. mutans.
Asunto(s)
Biopelículas , Preparaciones de Acción Retardada , Elastómeros , Nanopartículas del Metal , Compuestos de Plata , Streptococcus mutans , Streptococcus mutans/efectos de los fármacos , Biopelículas/efectos de los fármacos , Compuestos de Plata/farmacología , Compuestos de Plata/química , Nanopartículas del Metal/química , Elastómeros/química , Preparaciones de Acción Retardada/farmacología , Fluoruros/farmacología , Fluoruros/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Sistemas de Liberación de Medicamentos , Plata/química , Plata/farmacología , Pruebas de Sensibilidad Microbiana , Soportes OrtodóncicosRESUMEN
In the modern environment conscious era, there has been a huge demand for the effective green method to fabricate biomaterials for sustained transdermal release of diltiazem hydrochloride to treat hypertension and cardiac failure. In this vein, the present study explores the amination of waste jute sourced nanocellulose (ANC) and its effect as a reinforcing filler to design electrospun polyvinyl alcohol (PVA)/chitosan based polymeric nanofibrous scaffold for drug delivery. The characterization results of FTIR (Fourier Transform Infrared Spectroscopy) confirm the successful chemical modification of nanocellulose (NCC). SEM (Scanning Electron Microscopy) results indicate the morphological modifications in ANC due to grafting. ANC enhances the mechanical properties of scaffold and sustains the release of the loaded drug to 67.89±3.39% as compared to the pure PVA/chitosan scaffold of 92.63±4.63% over a period of 72 h as shown by the results of in-vitro drug release study. Moreover, the incorporation of 0.5 % ANC improves the anti-bacterial activity against both gram-positive (97.4±4.87%, reduction in viable cells count) and gram-negative bacteria (98.5±4.93%, reduction in viable cells count). Further, the skin irritation and MTT assay authenticate the biocompatibility of the developed scaffold. The overall findings hence prove the efficacy of the engineered scaffold as a potential transdermal patch for sustained drug delivery applications.
Asunto(s)
Celulosa , Quitosano , Preparaciones de Acción Retardada , Diltiazem , Liberación de Fármacos , Nanofibras , Alcohol Polivinílico , Quitosano/química , Alcohol Polivinílico/química , Nanofibras/química , Celulosa/química , Diltiazem/química , Diltiazem/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Animales , Espectroscopía Infrarroja por Transformada de Fourier , Portadores de Fármacos/química , Materiales Biocompatibles/química , Andamios del Tejido/químicaRESUMEN
Local anesthesia is essential in dental practices, particularly for managing pain in tooth socket wounds, yet improving drug delivery systems remains a significant challenge. This study explored the physicochemical characteristics of lidocaine hydrochloride (LH) incorporated into a polyelectrolyte complex and poloxamer thermosensitivity hydrogel, assessing its local anesthetic efficacy in mouse models and its onset and duration of action as topical anesthetics in clinical trials. The thermoresponsive hydrogel exhibited a rapid phase transition within 1-3 minutes and demonstrated pseudo-plastic flow behavior. Its release kinetics followed Korsmeyer-Peppas, with 50% of biodegradation occurring over 48 h. In mouse models, certain thermogels showed superior anesthetic effects, with rapid onset and prolonged action, as evidenced by heat tolerance in tail-flick and hot plate models. In clinical trials, the LH-loaded thermoresponsive hydrogel provided rapid numbness onset, with anesthesia (Ton) beginning at an average of 46.5 ± 22.5 seconds and lasting effectively (Teff) for 202.5 ± 41.0 seconds, ranging from 120 to 240 seconds, indicating sustained release. These results highlight the promising properties of these formulations: rapid onset, prolonged duration, mucoadhesion, biodegradability, and high anesthesia effectiveness. This study demonstrates the potential for advancing local anesthesia across various medical fields, emphasizing the synergy between material science and clinical applications to improve patient care and safety.
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Anestésicos Locales , Sistemas de Liberación de Medicamentos , Hidrogeles , Lidocaína , Poloxámero , Lidocaína/administración & dosificación , Lidocaína/química , Animales , Hidrogeles/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Ratones , Poloxámero/química , Sistemas de Liberación de Medicamentos/métodos , Polielectrolitos/química , Masculino , Liberación de Fármacos , Humanos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinéticaRESUMEN
Bacterial vaginosis (BV) is a common vaginal infection affecting millions of women. Vaginal anaerobic dysbiosis occurs whenLactobacillusspp., the dominant flora in healthy vagina is replaced by certain overgrown anaerobes, resulting in unpleasant symptoms such as vaginal discharge and odor. With a high recurrence rate, BV also severely impacts the overall quality of life of childbearing women by inducing preterm delivery and increasing the risks of pelvic inflammatory disease and sexually transmitted infections. Among various BV-associated bacteria,Gardnerella vaginalis(G. vaginalis) has been identified as a primary pathogen since it has been isolated from almost all women carrying BV and exhibits higher virulence potential over other bacteria. When dealing with BV relapse, intravaginal drug delivery systems are superior to conventional oral antibiotic therapies in improving therapeutic efficacy owing to more effective drug dose, reduced drug resistance and minimized side effects such as stomach irritation. Traditional intravaginal drug administration generally involves solids, semi-solids and delivery devices inserted into the vaginal lumen to achieve sustained drug release. However, they are mostly designed for continuous drug release and are not preventative therapies, resulting in severe side effects caused by excess dosing. Stimuli-responsive systems that can release drug only when needed ('on-demand') can help diminish these negative side effects. Hence, we developed a bacteria-responsive liposomal platform for the prevention and treatment of BV. This platform demonstrated sustained drug release in the presence of vaginolysin, a toxin secreted specifically byG. vaginalis. We prepared four liposome formulations and evaluated their responsiveness toG. vaginalis. The results demonstrated that the liposome formulations could achieve cumulative drug release ranging from 46.7% to 51.8% over a 3-5 d period in response toG. vaginalisand hardly any drug release in the presence ofLactobacillus crispatus(L. crispatus), indicating the high specificity of the system. Overall, the bacteria-responsive drug release platform has great potential, since it will be the first time to realize sustained drug release stimulated by a specific pathogen for BV prevention and treatment. This on-demand therapy can potentially provide relief to the millions of women affected by BV.
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Antibacterianos , Gardnerella vaginalis , Vaginosis Bacteriana , Vaginosis Bacteriana/tratamiento farmacológico , Vaginosis Bacteriana/microbiología , Femenino , Humanos , Gardnerella vaginalis/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Administración Intravaginal , Liberación de Fármacos , Liposomas/química , Sistemas de Liberación de Medicamentos/métodos , Preparaciones de Acción Retardada/química , Vagina/microbiologíaRESUMEN
To assess the effect of Long-acting injectable (LAI) antipsychotics in acutely ill patients, we systematically searched major databases for randomized controlled trials (RCTs) comparing LAIs with other LAIs, oral antipsychotics, or placebo in acutely symptomatic adults with schizophrenia-spectrum disorders. Data were analyzed with a random-effects network meta-analysis. Co-primary outcomes were efficacy (mean change in psychopathology rating scales) and acceptability (all-cause discontinuations) at study endpoint. Of 25 RCTs, 19 studies tested second-generation LAIs (SGA-LAIs) and six first-generation LAIs (FGA-LAIs). Due to a disconnected network, FGA-LAIs were analyzed separately, with poor data quality. The SGA-LAIs network included 8,418 individuals (males=63%, mean age=39.3 years). All SGA-LAIs outperformed placebo in reducing acute symptoms at study endpoint (median follow-up=13 weeks). They were more acceptable than placebo with the only exception of olanzapine, for which no differences with placebo emerged. Additionally, we distinguished between different LAI formulations of the same antipsychotic to explore potential pharmacokinetic differences. Most formulations outperformed placebo in the very short-term (2 weeks or less), regardless of the need for initial oral supplementation. SGA-LAIs are evidence-based treatments in acutely ill individuals with schizophrenia-spectrum disorders. Findings support the use of SGA-LAIs to manage psychopathology and improve adherence right from the acute phases of illness.
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Antipsicóticos , Preparaciones de Acción Retardada , Metaanálisis en Red , Esquizofrenia , Humanos , Antipsicóticos/uso terapéutico , Antipsicóticos/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Adulto , Ensayos Clínicos Controlados Aleatorios como Asunto , Aceptación de la Atención de Salud/estadística & datos numéricosRESUMEN
(-)-Phenserine ("phenserine") and (+)-phenserine (posiphen; buntanetap) are longer-acting enantiomeric analogs of physostigmine with demonstrated promise in the treatment of Alzheimer's and Parkinson's diseases. Both enantiomers have short plasma half-lives, and their pharmacokinetics might be improved through the use of either once or twice-daily administration of an extended-release dosage form. Phenserine was observed to form a colored degradation product in near-neutral and alkaline pH environments, and at pH 7, the half-life of posiphen was determined to be ~ 9 h (40 °C). To limit luminal degradation which would reduce bioavailability, a gastroretentive tablet composed of a polyethylene oxide-xanthan gum matrix was developed. When placed in simulated gastric fluid (pH 1.2), approximately 70% of the phenserine was released over a 12 h period, and no degradants were detected in the release medium. In comparison, a traditional hydrophilic-matrix, extended-release tablet showed measurable amounts of phenserine degradation in a pH 7.2 medium over an 8 h release interval. These results confirm that a gastroretentive tablet can reduce the luminal degradation of phenserine or posiphen by limiting exposure to neutral pH conditions while providing sustained release of the drug over at least 12 h. Additional advantages of the gastroretentive tablet include reduced gastric and intestinal concentrations of the drug resulting from the slower release from the gastroretentive tablet which may also limit the occurrence of the dose-limiting GI side effects previously observed with immediate-release phenserine capsules.
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Preparaciones de Acción Retardada , Comprimidos , Concentración de Iones de Hidrógeno , Preparaciones de Acción Retardada/farmacocinética , Fisostigmina/administración & dosificación , Fisostigmina/farmacocinética , Fisostigmina/análogos & derivados , Fisostigmina/química , Estereoisomerismo , Sistemas de Liberación de Medicamentos/métodos , Disponibilidad Biológica , Semivida , Liberación de FármacosRESUMEN
A 9.4 mg deslorelin slow-release implant was inserted into an adult, healthy billy goat to achieve temporary infertility and a reduction in sexual behavior. The implant was inserted in late autumn. No significant change in testis size was observed over the following 6 weeks. The endocrine function of the testis, which was examined by stimulation with human chorionic gonadotropin, was also unchanged after 6 weeks compared to the initial examination. Histological examination revealed a preserved spermatogenesis.In conclusion, the application of a GnRH analogue implant in the adult male goat has no influence on the investigated parameters - and thus probably also on its fertility.
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Implantes de Medicamentos , Cabras , Hormona Liberadora de Gonadotropina , Pamoato de Triptorelina , Animales , Masculino , Pamoato de Triptorelina/administración & dosificación , Pamoato de Triptorelina/análogos & derivados , Pamoato de Triptorelina/farmacología , Hormona Liberadora de Gonadotropina/administración & dosificación , Testículo/efectos de los fármacos , Preparaciones de Acción Retardada , Espermatogénesis/efectos de los fármacosRESUMEN
The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 µg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 µg/kg, 60 µg/kg, 90 µg/kg, and 120 µg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 µg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 µg/kg and especially at 120 µg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.