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1.
Nat Commun ; 11(1): 4450, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895379

RESUMO

Hollow multishelled structures (HoMSs), with relatively isolated cavities and hierarchal pores in the shells, are structurally similar to cells. Functionally inspired by the different transmission forms in living cells, we studied the mass transport process in HoMSs in detail. In the present work, after introducing the antibacterial agent methylisothiazolinone (MIT) as model molecules into HoMSs, we discover three sequential release stages, i.e., burst release, sustained release and stimulus-responsive release, in one system. The triple-shelled structure can provide a long sterility period in a bacteria-rich environment that is nearly 8 times longer than that of the pure antimicrobial agent under the same conditions. More importantly, the HoMS system provides a smart responsive release mechanism that can be triggered by environmental changes. All these advantages could be attributed to chemical diffusion- and physical barrier-driven temporally-spatially ordered drug release, providing a route for the design of intelligent nanomaterials.


Assuntos
Antibacterianos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/química , Antibacterianos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microesferas , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
2.
Nat Commun ; 11(1): 4504, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908131

RESUMO

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.


Assuntos
Microambiente Celular/imunologia , Sistemas de Liberação de Medicamentos/instrumentação , Fator de Crescimento Neural/administração & dosagem , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/terapia , Tecidos Suporte , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interleucina-4/administração & dosagem , Lipossomos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Fator de Crescimento Neural/farmacocinética , Regeneração Nervosa/imunologia , Ratos , Recuperação de Função Fisiológica/imunologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Traumatismos da Medula Espinal/imunologia
3.
J Pharmacol Sci ; 144(1): 9-15, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586692

RESUMO

Since 2015 slow-release oral morphine (SROM) is approved for opioid substitution treatment (OST) in Germany. The SROMOS study (efficacy and tolerability of slow-release oral morphine in opioid substitution treatment) evaluates the efficacy and safety of SROM in routine care. This article describes the switching process from racemic methadone, levomethadone and buprenorphine to SROM. Between July 2016 and November 2017 180 patients in 23 study centers in Germany were included in the prospective, non-interventional, naturalistic observational study. Patients were already in OST and switched from a previous medication to SROM. The switching process was analyzed during a period of fourteen days. Data were available for 169 participants. The switching process had a different progression depending on premedication and pre dosage. On the fourteenth day of SROM treatment patients switched from racemic methadone took an average dosage of 922.2 mg/day, from levomethadone 801.0 mg/day and from buprenorphine 626.7 mg/day. Average conversion ratio racemic methadone to SROM was 1:11.8, levomethadone to SROM 1:17.4 and buprenorphine to SROM 1:58.0. This study provides the first data on the switching process from buprenorphine to SROM. Average dose ratio racemic methadone to SROM on the fourteenth day of treatment was considerably higher than recommended in the prescribing information.


Assuntos
Buprenorfina/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Substituição de Medicamentos/métodos , Metadona/administração & dosagem , Morfina/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
5.
AAPS PharmSciTech ; 21(4): 126, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382992

RESUMO

Orally dissolving films (ODFs) have received much attention as potential oral drug delivery systems for paediatric and geriatric patients, particularly those suffering from dysphagia. With their unique properties and advantages, the technology offers improved patient compliance and wider acceptability, eliminates the fear of choking, enables ease of administration and offers dosing convenience, without the requirement of water. However, adequate drug loading remains a challenge. The aim of this study was to mechanistically design and evaluate fast and extended release ODF formulations with high drug loading capacity, displaying good physicochemical and mechanical properties, as a potential dosage form for paediatric and geriatric use employing a slightly soluble model drug-ibuprofen. Different polymers (0.6-10% HPMC, 0.6-1.5% guar gum), plasticisers (0.1-0.5% glycerine, 0.1% sorbitol) and processing conditions (40-60°C drying temperatures, 8-16 h drying times) were investigated to produce films using the solvent casting method. Molecular compatibility was assessed using TGA, XRD and FTIR whereas film topography was assessed using SEM. Maximum ibuprofen load in single films was 20.7 mg/film (54.4%) and released 100% drug content in 5 min, while triple layered ibuprofen-loaded films contained 62.2 mg/film and released 100% drug release in 1 h. The ODFs demonstrated good disintegration time using low volume artificial saliva media and high dosage from uniformity. This study provides a mechanistic insight to the design and evaluation of fast and extended release ODFs with high drug loading, suitable for administration to paediatric and geriatric patients.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ibuprofeno/química , Ibuprofeno/metabolismo , Administração Oral , Idoso , Criança , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Geriatria , Humanos , Ibuprofeno/administração & dosagem , Pediatria , Solubilidade , Difração de Raios X/métodos
6.
J Pharmacokinet Pharmacodyn ; 47(3): 189-198, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32435882

RESUMO

To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial.


Assuntos
Antivirais/administração & dosagem , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Modelos Biológicos , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Cães , Humanos , Indometacina/farmacocinética , Pandemias , Pneumonia Viral/virologia , Carga Viral/efeitos dos fármacos
8.
Psychopharmacology (Berl) ; 237(8): 2381-2394, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32435818

RESUMO

RATIONALE: Reward-related impairments are common in major depressive disorder (MDD) and may contribute to the loss of interest in pleasurable activities. A novel approach to studying reward-related decision-making are effort-based tasks; however, direct comparisons between delayed-onset and rapid-acting antidepressants (ADs) have not yet been carried out. OBJECTIVES: To investigate the effects of conventional delayed-onset ADs versus rapid-acting ADs, ketamine and scopolamine, on effort-related choice behaviour. METHODS: Female Lister hooded rats were trained in an operant effort for reward task (EfRT) where animals choose between working for a high value-high effort reward and consuming low value-low effort chow. Using a within-subject study design, animals were then tested following acute treatment with different monoaminergic ADs, and the rapid-acting ADs ketamine or scopolamine. RESULTS: Consistent with previous findings, we found choice behaviour was sensitive to dopaminergic manipulations. We observed that pre-feeding altered choice behaviour and that the use of high or low value reward differentially affected behaviour. Monoamine re-uptake inhibitors and rapid-acting ADs resulted in similar, general patterns of reduced motivation without any evidence for specific effects, and we did not observe any clear differences between these classes of antidepressant. CONCLUSIONS: Motivational changes induced by dopaminergic manipulations and pre-feeding differentially affect effort choice behaviour. However, both conventional delayed-onset ADs and ketamine and scopolamine appear to have detrimental effects on motivation in this task at the higher doses tested without any evidence of specificity for effort-related choice behaviour, in contrast to their specificity in tasks which look at more cognitive aspects of reward processing.


Assuntos
Antidepressivos/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Motivação/efeitos dos fármacos , Recompensa , Animais , Comportamento de Escolha/fisiologia , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Preparações de Ação Retardada/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Motivação/fisiologia , Ratos , Fatores de Tempo
9.
Clin Drug Investig ; 40(5): 459-468, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32274654

RESUMO

BACKGROUND AND OBJECTIVE: Long-acting injectable antipsychotics (LAIs) have been widely studied in schizophrenia and evidence suggests that they could be also used for the treatment of bipolar and schizoaffective disorders. Nonetheless, there are no studies evaluating their role in other psychiatric disorders. We aimed to evaluate the use of the newest monthly and 3-monthly LAIs-aripiprazole once monthly, paliperidone 1- and 3-monthly (PP1M, PP3M)-against the 2-weekly LAIs, using the following clinical outcomes: (1) the number of hospital re-admissions, (2) the number of documented suicidal behaviors/attempts, and (3) the use of concomitant treatments, including benzodiazepines, oral antipsychotics, and biperiden. METHODS: A total of 431 patients were included who were treated with the corresponding LAI over at least 12 months and were previously diagnosed with a psychiatric disorder. Statistical analyses were performed using an ANCOVA model, Student's t test, and the Pearson's r test. RESULTS: Our results showed significantly decreased re-admissions using PP3M versus the bi-weekly LAIs and aripiprazole once monthly, while no significant differences were found in suicidal behavior. Furthermore, we found a significantly lower intake of benzodiazepines in PP1M and PP3M groups versus the bi-weekly and aripiprazole once-monthly groups. In addition, patients treated with PP1M and PP3M used a significantly lower dose of haloperidol equivalents versus the bi-weekly LAIs group. Finally, significantly higher doses of biperiden were used by the bi-weekly LAIs group. CONCLUSION: In conclusion, paliperidone LAIs reduced hospital re-admissions and, as aripiprazole once monthly, lowered concomitant psychiatric medication versus the bi-weekly LAIs. Further research and analysis of subgroups are needed; however, these findings might be useful for clinicians.


Assuntos
Antipsicóticos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Prescrições de Medicamentos , Saúde Mental , Adulto , Feminino , Humanos , Masculino , Readmissão do Paciente , Esquizofrenia/tratamento farmacológico , Espanha
10.
Lancet ; 395(10232): 1259-1267, 2020 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-32171422

RESUMO

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.


Assuntos
Úlcera de Buruli/tratamento farmacológico , Claritromicina/administração & dosagem , Rifampina/administração & dosagem , Estreptomicina/administração & dosagem , Administração Oral , Adolescente , Adulto , Antibacterianos , Benin , Criança , Claritromicina/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Quimioterapia Combinada , Feminino , Gana , Humanos , Masculino , Rifampina/efeitos adversos , Estreptomicina/efeitos adversos , Cicatrização/efeitos dos fármacos , Adulto Jovem
11.
PLoS One ; 15(3): e0227784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160196

RESUMO

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2-3 times per day, for 4-8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.


Assuntos
Portadores de Fármacos/química , Empiema Pleural/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Empiema Pleural/patologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrina/metabolismo , Fibrinolíticos/farmacocinética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Hidrogéis/química , Hidrogéis/toxicidade , Poloxâmero/química , Poloxâmero/toxicidade , Temperatura , Fatores de Tempo , Testes de Toxicidade , Ativador de Plasminogênio Tipo Uroquinase/farmacocinética
12.
Stroke ; 51(4): 1142-1149, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32138631

RESUMO

Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.


Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Microesferas , Nimodipina/administração & dosagem , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/tratamento farmacológico , Administração Oral , Idoso , Preparações de Ação Retardada/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
13.
Fertil Steril ; 113(4): 828-835, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32147182

RESUMO

OBJECTIVE: To evaluate the effects of gonadotropin-releasing hormone agonists (GnRH-a) on fertility in women with mild endometriosis who are undergoing in vitro fertilization and embryo transfer (IVF-ET) procedures. DESIGN: Prospective, randomized, controlled trial. SETTING: Three tertiary university hospitals. PATIENT(S): Four hundred infertile women with mild endometriosis, documented with laparoscopy, undergoing IVF and 200 women with tubal factor infertility. INTERVENTION(S): Administration of GnRH-a for 3 months before an IVF attempt (group A, n = 200) or IVF without GnRH-a (group B, n = 200). MAIN OUTCOME MEASURE(S): Follicular fluid (FF) levels of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8, and IL-1 receptor antagonist; fertilization rate (FR), implantation rate (IR), quality of embryos, and clinical pregnancy rate (PR). RESULT(S): Women who received GnRH-a had a statistically significantly reduced concentration of FF cytokines compared with women who did not receive this regimen. Women in group B had a reduced FR (61.7; 95% CI, 59.20-64.20) compared with the women in group A (72.7; 95% CI, 70.50-74.90) and compared with the women with tubal factor infertility (74.7; 95% CI, 72.00-77.24). The embryo quality, IR, and clinical PR showed no statistically significant improvement in the women of group A compared with group B. CONCLUSION(S): Women who received GnRH-a for 3 months had a lower concentration of FF cytokines. These women had also a higher FR than the women who did not receive GnRH-a. However, the IR, embryo quality, and clinical PR showed no statistically significant difference when comparing the two groups. CLINICALTRIALS. GOV ID: NCT01269125.


Assuntos
Endometriose/terapia , Fertilização In Vitro/métodos , Fertilização In Vitro/tendências , Hormônio Liberador de Gonadotropina/agonistas , Leuprolida/administração & dosagem , Taxa de Gravidez/tendências , Adulto , Preparações de Ação Retardada/administração & dosagem , Esquema de Medicação , Endometriose/diagnóstico , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Humanos , Gravidez , Estudos Prospectivos , Fatores de Tempo
14.
Nature ; 579(7799): 421-426, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188939

RESUMO

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1-5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Neoplasias Mamárias Experimentais/imunologia , Piroptose/imunologia , Animais , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Preparações de Ação Retardada/farmacocinética , Feminino , Proteínas de Fluorescência Verde/administração & dosagem , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/farmacocinética , Células HeLa , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/farmacocinética , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas/administração & dosagem , Proteínas/química , Proteínas/metabolismo , Proteínas/farmacocinética , Silanos/administração & dosagem , Silanos/química , Silanos/metabolismo , Silanos/farmacocinética , Linfócitos T/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/química , Trastuzumab/metabolismo , Trastuzumab/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Curr Pain Headache Rep ; 24(3): 6, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32002676

RESUMO

PURPOSE OF REVIEW: Acute postoperative pain reduction is a major target against the opioid crisis. While opioids have traditionally been the mainstay for postoperative analgesia, current practice has focused on a multimodal approach to pain control, including ultrasound-guided blocks with longer acting local anesthetic agents. RECENT FINDINGS: Non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, are an important class of medications utilized to manage pain in the perioperative period. An additional treatment used in perioperative or postoperative pain relief is Exparel, a bupivacaine (sodium channel blocker) liposomal injectable suspension with a 3-4-day duration of action. The long-acting mechanism and formulation of Exparel consistently has demonstrated decreased opioid use and pain scores in patients undergoing many different surgical procedures. A concern is that pH negatively alters the efficacy of bupivacaine, as in cases of inflamed tissue and acidic fluid pH. For this reason, a combination medication with both meloxicam and bupivacaine has been developed, which normalizes pH and has anti-inflammatory and anti-pain conduction properties. Clinical studies demonstrate that this combination agent can be extremely beneficial in treating postoperative pain. This manuscript summarizes the newest developments with regard to liposomal bupivacaine and the non-steroidal meloxicam, their roles in effective treatment of postoperative pain, contraindications, special considerations of using these medications, and future considerations. HTX-011 pairs up a new extended-release formulation of the local anesthetic bupivacaine with meloxicam, a well-established non-steroidal anti-inflammatory drug (NSAID).


Assuntos
Anestésicos Locais/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Bupivacaína/administração & dosagem , Meloxicam/administração & dosagem , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Preparações de Ação Retardada/administração & dosagem , Quimioterapia Combinada/métodos , Humanos , Lipossomos
16.
Adv Ther ; 37(3): 1188-1202, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020565

RESUMO

INTRODUCTION: Prolonged-release oxycodone/naloxone (OXN PR), combining an opioid analgesic with selective blockade of enteric µ-opioid receptors, provided effective analgesia and improved bowel function in patients with moderate-to-severe pain and opioid-induced constipation in clinical trials predominantly conducted in Western countries. This double-blind randomized controlled trial investigated OXN PR (N = 116) versus prolonged-release oxycodone (OXY PR, N = 115) for 8 weeks at doses up to 50 mg/day in patients with moderate-to-severe, chronic, non-malignant musculoskeletal pain and opioid-induced constipation recruited in China. METHODS: A total of 234 patients at least 18 years of age with non-malignant musculoskeletal pain for more than 4 weeks that was moderate-to-severe in intensity and required round-the-clock opioid therapy were randomized (1:1) to OXN PR or OXY PR. The primary endpoint was bowel function using the Bowel Function Index (BFI). Secondary endpoints included safety, Brief Pain Inventory-Short Form (BPI-SF), use of analgesic and laxative rescue medication, and health-related quality of life (EQ-5D). RESULTS: While BFI scores were comparable at baseline, at week 8 improvements were greater with OXN PR vs OXY PR (least squares mean [LSM] difference (95% CI) - 9.1 (- 14.0, - 4.2); P < 0.001. From weeks 2 to 8, mean BFI scores were in the range of normal bowel function (≤ 28.8) with OXN PR but were in the range of constipation (> 28.8) at all timepoints with OXY PR. Analgesia with OXN PR was similar and non-inferior to OXY PR on the basis of modified BPI-SF average 24-h pain scores at week 8: LSM difference (95% CI) - 0.3 (- 0.5, - 0.1); P < 0.001. The most frequent treatment-related AEs were nausea (OXN PR 5% vs OXY PR 6%) and dizziness (4% vs 4%). CONCLUSION: OXN PR provided clinically meaningful improvements in bowel function and effective analgesia in Chinese patients with moderate-to-severe musculoskeletal pain and pre-existing opioid-induced constipation. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01918098.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Naloxona/uso terapêutico , Constipação Induzida por Opioides/prevenção & controle , Oxicodona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Analgésicos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , China , Preparações de Ação Retardada/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Laxantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Naloxona/administração & dosagem , Naloxona/efeitos adversos , Oxicodona/administração & dosagem , Oxicodona/efeitos adversos , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Qualidade de Vida
17.
Drug Dev Ind Pharm ; 46(2): 264-271, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32000536

RESUMO

Topical drug delivery for local anesthetics has been an interesting area of research for formulators considering the resistance and barrier properties of skin and high clearance rate of drugs like prilocaine and lidocaine (duration of action < 2.5 h). In this study, efforts have been made to sustain the release of prilocaine and lidocaine by using depot microemulsion system. Drug loaded microemulsions were formulated using Capmul MCM, Pluronic F127, polyethylene glycol 200 (PEG 200) and water from pseudo-ternary diagrams. The Smix at 1:4 ratio showed larger microemulsion area in comparison to 1:2 ratio. The ex-vivo studies indicate sustained release of prilocaine and lidocaine from the microemulsion up to 8 h, in comparison to 4 h with ointments. Skin irritation study on rabbits confirmed the safety of drug loaded microemulsions for local drug delivery. The improved ex vivo data is reflected in the in vivo studies, were radiant heat tail-flick test and sciatic nerve model showed prolong duration of action for both prilocaine and lidocaine microemulsions in comparison to ointment. The in vitro and in vivo efficacy of prilocaine and lidocaine was non-significant. The improved efficacy was due to high penetration of microemulsion and depot effect due to local precipitation (destabilization of microemulsion) of drug in the skin layer. The sustained local anesthetic effect is highly desirable for the treatment of skin irritation due to skin burns and pre- and post-operative pain.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Emulsões/química , Lidocaína/administração & dosagem , Lidocaína/química , Prilocaína/administração & dosagem , Prilocaína/química , Administração Cutânea , Anestésicos Locais/administração & dosagem , Anestésicos Locais/química , Animais , Química Farmacêutica/métodos , Diglicerídeos/química , Sistemas de Liberação de Medicamentos/métodos , Cabras , Monoglicerídeos/química , Poloxâmero/química , Polietilenoglicóis/química , Coelhos , Ratos , Ratos Wistar , Pele/metabolismo , Absorção Cutânea
18.
Molecules ; 25(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046113

RESUMO

Guanosine- and uridine-rich single-stranded RNA (GU-rich RNA) is an agonist of Toll-like receptor (TLR) 7 and TLR8 and induces strong immune responses. A nanostructured GU-rich RNA/DNA assembly prepared using DNA nanotechnology can be used as an adjuvant capable of improving the biological stability of RNA and promoting efficient RNA delivery to target immune cells. To achieve a sustained supply of GU-rich RNA to immune cells, we developed a GU-rich RNA/DNA hydrogel (RDgel) using nanostructured GU-rich RNA/DNA assembly, from which GU-rich RNA can be released in a sustained manner. A hexapod-like GU-rich RNA/DNA nanostructure, or hexapodRD6, was designed using a 20-mer phosphorothioate-stabilized GU-rich RNA and six phosphodiester DNAs. Two sets of hexapodRD6 were mixed to obtain RDgel. Under serum-containing conditions, GU-rich RNA was gradually released from the RDgel. Fluorescently labeled GU-rich RNA was efficiently taken up by DC2.4 murine dendritic cells and induced a high level of tumor necrosis factor-α release from these cells when it was incorporated into RDgel. These results indicate that the RDgel constructed using DNA nanotechnology can be a useful adjuvant in cancer therapy with sustained RNA release and high immunostimulatory activity.


Assuntos
DNA/imunologia , Preparações de Ação Retardada/administração & dosagem , Hidrogéis/administração & dosagem , Imunidade/efeitos dos fármacos , Glicoproteínas de Membrana/imunologia , RNA/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linhagem Celular , Células Dendríticas/imunologia , Guanosina/imunologia , Camundongos , Nanoestruturas/administração & dosagem , Células RAW 264.7 , Uridina/imunologia
19.
Sci Rep ; 10(1): 1964, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029776

RESUMO

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Trazodona/administração & dosagem , Animais , Antidepressivos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Injeções Intraperitoneais , Lipídeos/química , Masculino , Camundongos , Tamanho da Partícula , Poliésteres/química , Solubilidade , Trazodona/farmacocinética
20.
AAPS PharmSciTech ; 21(2): 58, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912249

RESUMO

The study was aimed to develop a gastro-retentive mucoadhesive sustained release matrix formulation for milnacipran HCl (MCN) by using the design of experiment (DoE). The gastro-retentive swellable mucoadhesive matrix tablets were prepared by modified solvent-based wet granulation through mixing milnacipran (MCN), chitosan low molecular weight (CH-LM), chitosan medium molecular weight (CH-MM), and polycaprolactone (PCL). Optimization of the formulation was carried out via DoE. Formulations were characterized by DSC, FTIR, and in vitro drug release testing. In vitro mucoadhesive studies were performed on rabbit's intestinal mucosa. In vivo drug release studies were performed on dogs. Optimized matrix formulations showed no significant interaction among the polymers and MCN, confirmed by DSC and FTIR, and were characterized as swellable controlled release matrix systems. The optimized formulations MOPT3 and MOPT4 showed significantly improved adhesion time of 12 h on the gastric mucosa. Based on the in vivo analysis, the elimination half-life of MCN was increased that proved the matrix formulation to be sustained release DDS. The Tmax was extended from 2 to 12 ± 1.63 h for MOPT4. Cmax of matrix was reduced to 121.60 ± 9.496 ng/ml as compared to 149.22 ± 9.942 ng/ml of solution. The bioavailability of the matrix formulation was significantly improved as compared to the MCN solution by 272.20 ± 48.11%. The controlled drug release and strong mucoadhesive properties of the gastro-retentive matrix formulations suggested the potential application of the formulations for the extended oral delivery of MCN.


Assuntos
Quitosana/química , Milnaciprano/administração & dosagem , Poliésteres/química , Animais , Preparações de Ação Retardada/administração & dosagem , Cães , Liberação Controlada de Fármacos , Mucosa Gástrica/metabolismo , Masculino , Milnaciprano/química , Coelhos
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