RESUMO
Studies of the choroid plexus lag behind those of the more widely known blood-brain barrier, despite a much longer history. This review has two overall aims. The first is to outline long-standing areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second aim is to review research over the past 10 years where the focus has shifted to the idea that there are choroid plexuses located in each of the brain's ventricles that make specific contributions to brain development and function through molecules they generate for delivery via the CSF. These factors appear to be particularly important for aspects of normal brain growth. Most research carried out during the twentieth century dealt with the choroid plexus, a brain barrier interface making critical contributions to the composition and stability of the brain's internal environment throughout life. More recent research in the twenty-first century has shown the importance of choroid plexus-generated CSF in neurogenesis, influence of sex and other hormones on choroid plexus function, and choroid plexus involvement in circadian rhythms and sleep. The advancement of technologies to facilitate delivery of brain-specific therapies via the CSF to treat neurological disorders is a rapidly growing area of research. Conversely, understanding the basic mechanisms and implications of how maternal drug exposure during pregnancy impacts the developing brain represents another key area of research.
Assuntos
Barreira Hematoencefálica , Plexo Corióideo , Humanos , Barreira Hematoencefálica/fisiologia , Encéfalo , Transporte Biológico/fisiologia , Ventrículos CerebraisRESUMO
BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.
Assuntos
Dissulfiram , Neoplasias Pulmonares , Metaloproteinase 2 da Matriz , Nanopartículas , Neovascularização Patológica , Neoplasias de Mama Triplo Negativas , Dissulfiram/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Metaloproteinase 2 da Matriz/metabolismo , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Nanopartículas/química , Neovascularização Patológica/tratamento farmacológico , Camundongos Endogâmicos BALB C , Camundongos Nus , Reposicionamento de Medicamentos , Ondas Ultrassônicas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.
Assuntos
Chlorella , Portadores de Fármacos , Fotossíntese , Animais , Camundongos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Terapia Combinada , Fotoquimioterapia/métodos , Neoplasias/terapia , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Sistemas de Liberação de Medicamentos/métodos , Verde de Indocianina/farmacocinética , Verde de Indocianina/química , FemininoRESUMO
To explore the efficacy of ultrasound drugs in the treatment of hemiplegia after stroke. The evaluation included clinical symptoms and signs, the Stroke Scale, activities of daily living, sensory disorder Fugl-Meyer and Lindmark, electromyography sensory nerve amplitude, and conduction velocity indexes in both groups. There was no significant difference in the improved Fugl-Meyer and Lindmark score between treatment (26.97 ± 2.78) and the control group (27.45 ± 3.1) (t = 14.528, P = 0.593). After treatment, the observation group (37.10 ± 4.2) was significantly different from the control group (34.76 ± 4.36) (t = 11.259, P = 0.005) and (t = 10.15 ± 1.69), (40.87 ± 6.58) (t = 7.943,9.538, P = 0.564,0.826). After treatment, the observation group the Stroke Scale (4.27 ± 0.57), activities of daily living score (76.15 ± 12.38) and the control group (5.36 ± 0.89), (58.41 ± 9.69) (t = 16.274,5.379, P = 0.035,0.000) after treatment and F wave and M wave. The cure rate of the observation group was 77.50% (31/40), which was significantly better than that of the control group, 47.50% (19/40), with a significant difference (χ2 = 11.724,P = 0.000). After comparison, the total response rate of the observed group reached 92.500% (37 / 40), which was significantly higher than the 80.00% (32 / 40) of the control group. This difference was statistically significant (χ 2 = 9.458, P = 0.015). This therapy closely links the theoretical knowledge of modern medicine with the theoretical knowledge of traditional Chinese medicine, and uses the meridian theory to give full play to the unique advantages of traditional Chinese medicine.
Assuntos
Terapia por Acupuntura , Acidente Vascular Cerebral , Humanos , Atividades Cotidianas , Hemiplegia/tratamento farmacológico , Hemiplegia/etiologia , Preparações de Ação Retardada , Resultado do Tratamento , Acidente Vascular Cerebral/tratamento farmacológico , TecnologiaRESUMO
The cycloserine concentrations in plasma and bone that were collected during operations on 28 osteoarticular tuberculosis (TB) patients treated daily with a 500-mg cycloserine-containing regimen were determined. The median concentrations in plasma and bone were 16.29 µg/mL (interquartile range [IQR], 6.47 µg/mL) and 24.33 µg/g (IQR, 14.68 µg/g), respectively. The median bone/plasma penetration ratio was 0.76 (range, 0.33 to 1.98). Cycloserine could effectively penetrate bone and acquire concentrations comparable to those in plasma, which favors its usage in osteoarticular TB treatment.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Osteoarticular , Antituberculosos/uso terapêutico , China , Ciclosserina/uso terapêutico , Humanos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Osteoarticular/tratamento farmacológicoRESUMO
The analytical technology of Raman spectroscopy has an almost 100-year history. During this period, many modifications and developments happened in the method like discovery of laser, improvements in optical elements and sensitivity of spectrometer and also more advanced light detection systems. Many types of the innovative techniques appeared (e.g. Transmittance Raman spectroscopy, Coherent Raman Scattering microscopy, Surface-Enhanced Raman scattering and Confocal Raman spectroscopy/microscopy). This review article gives a short description about these different Raman techniques and their possible applications. Then, a short statistical part is coming about the appearance of Raman spectroscopy in the scientific literature from the beginnings to these days. The third part of the paper shows the main application options of the technique (especially confocal Raman spectroscopy) in skin research, including skin composition analysis, drug penetration monitoring and analysis, diagnostic utilizations in dermatology and cosmeto-scientific applications. At the end, the possible role of artificial intelligence in Raman data analysis and the regulatory aspect of these techniques in dermatology are briefly summarized. For the future of Raman Spectroscopy, increasing clinical relevance and in vivo applications can be predicted with spreading of non-destructive methods and appearance with the most advanced instruments with rapid analysis time.
Assuntos
Inteligência Artificial , Análise Espectral Raman , Microscopia Confocal/métodos , Pele/metabolismo , Absorção Cutânea , Análise Espectral Raman/métodosRESUMO
Various metal oxide nanomaterials have been widely used as carriers to prepare pH-sensitive nanomedicines to respond to the acidic tumor microenvironment promoting antitumor efficiency. Herein, we used zinc oxide nanoparticles (ZnO NPs) as metal oxide nanomaterial coated with low-molecular-weight heparin (LMHP) and doxorubicin (DOX) complex (LMHP-DOX) to prepare ZnO-LD NPs for controllable pH-triggered DOX release on the targeted site. Our results indicated that the released DOX from ZnO-LD NPs was pH-sensitive. The oxygen produced by ZnO-LD NPs in H2O2 solution was observed in in vitro experiment. The ZnO-LD NPs entered into both PC-3M and 4T1 tumor cells via clathrin-mediated endocytosis and micropinocytosis pathway. The intracellular reactive oxygen species (ROS) generated by ZnO-LD NPs could significantly increase the caspase 3/7 level, leading to tumor cell apoptosis. The in vitro and in vivo antitumor activity was confirmed in PC-3M and 4T1 cell lines or tumor-bearing mice models. The in vivo and in vitro tumor images via second-order nonlinearity of ZnO-LD NPs indicated that ZnO-LD NPs could penetrate deep into the tumor tissues. Therefore, the ZnO-LD NPs developed in our study could provide an efficient approach for the preparation of pH-sensitive nano delivery systems suitable for tumor therapy and imaging.
Assuntos
Nanopartículas , Neoplasias , Óxido de Zinco , Camundongos , Animais , Heparina de Baixo Peso Molecular/farmacologia , Peróxido de Hidrogênio , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Microambiente TumoralRESUMO
Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Candida albicans Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however, robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multiday FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.
Assuntos
Antifúngicos , Candidíase Invasiva , Animais , Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Equinocandinas , Micafungina , Camundongos , Testes de Sensibilidade MicrobianaRESUMO
Larger clinical trial enrollments and a greater understanding of biological heterogeneity have led to improved survival rates for children diagnosed with brain tumors in the last 50 years. However, reducing long-term morbidities and improving survival rates of high-risk tumors remain major challenges. Chemotherapy can reduce tumor burden, but effective drug penetration at the tumor site is limited by barriers in the route of drug administration and within the tumor microenvironment. Bioavailability of drugs is impeded by the blood-brain barrier, plasma protein binding, and structural components by the tumor including the matrix and vasculature contributing to increased interstitial fluid pressure, hypoxia, and acidity. Designing drug delivery systems to circumvent these barriers could lead to improved drug penetration at the tumor site and reduce adverse systemic side effects. In this review, we expand on how systemic and local barriers limit drug penetration and present potential methods to enhance drug penetration in pediatric brain tumors.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Disponibilidade Biológica , Barreira Hematoencefálica/fisiologia , Neoplasias Encefálicas/mortalidade , Humanos , Taxa de Sobrevida , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). RESULTS: Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10- 15 g, 0.07 × 10- 15 g, and 1.3 × 10- 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. CONCLUSIONS: The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.
Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Metabolismo dos Lipídeos , Mesoporfirinas/metabolismo , Fotoquimioterapia/métodos , Carcinoma , Técnicas de Cocultura , Matriz Extracelular , Vesículas Extracelulares , Células HT29 , Humanos , Lipídeos , Lipossomos , Nanopartículas , Fármacos Fotossensibilizantes/uso terapêutico , Esferoides Celulares , Microambiente TumoralRESUMO
Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.
Assuntos
Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Glicosídeos/uso terapêutico , Triterpenos/uso terapêutico , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Feminino , Microdissecção e Captura a Laser , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em TandemRESUMO
BACKGROUND: High-intensity ultrasound (HIUS) has been increasingly investigated as a possible tool in the treatment of multiple tumor entities. However, there is only little knowledge on the effect of HIUS on the peritoneum. This preliminary study aims to investigate HIUS' potential for altering the peritoneal surface and potentially improving current treatments for peritoneal metastases. For this purpose, HIUS' qualitative and quantitative structural effects on the peritoneal tissue were analyzed by means of light, fluorescence and electron microscopy. METHODS: Proportional sections were cut from the fresh postmortem swine peritoneum. Peritoneal surfaces were covered with a 6 mm thick liquid film of 0.9% NaCl. HIUS was applied in all tissue samples for 0 (control), 30, 60, 120 and 300 s. Peritoneal tissues were analyzed using light-, fluorescence and electron microscopy to detect possible structural changes within the tissues. RESULTS: Following HIUS, a superficial disruption of peritoneal tissue was visible in light microscopy, which amplified with increased time of HIUS' application. Fluorescence microscopy showed both peritoneal and subperitoneal disruption with tissue gaps. Electron microscopy revealed structural filamentation of the peritoneal surface. CONCLUSION: Our data indicate that HIUS causes a wide range of effects on the peritoneal tissue, including the formation of small ruptures in both peritoneal and subperitoneal tissues. However, according to our findings, these disruptions are limited to a microscopical level. Further studies are required to evaluate whether HIUS application can benefit current therapeutic regimens on peritoneal metastases and possibly enhance the efficacy of intraperitoneal chemotherapy.
Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Peritônio , Animais , Microscopia , Microscopia Eletrônica , Microscopia de Fluorescência , Peritônio/lesões , Cloreto de Sódio , Sonicação/métodos , Sus scrofa , Fatores de TempoRESUMO
Due to the abnormal tumor vasculature and dense stroma, there is limited tumor perfusion in the immunosuppressive tumor microenvironment (TME). In order to reshape tumor blood vessels and enhance the penetration of anticancer drugs into the tumor tissue, an anionic liposome nanosystem with a "sandwich" structure was prepared. The chemotherapeutic agent topotecan (TPT) was encapsulated in the lipid hydrophilic layer, and the sensitizer indocyanine green (ICG) was loaded into the hydrophobic layer. In addition, the positively charged vascular normalization drug erlotinib (ERL) was adsorbed to the outermost layer of the microenvironment. The nanosystem showed superior tumor permeability invitro/in vivo experiments compared with the ERL-treated group. The nanosystem entered the tumor through normalization of blood vessels after the action of ERL. Ultrasound treatment improves the vascular permeability, allowing the nanoparticles to penetrate blood vessels and reach tumor cells. Finally, in addition to cytotoxic effects, TPT can also down-regulate the expression of HIF-1α and so prolong the vascular normalization time. These experimental results showed that the nanosystem effectively improves the tumor microenvironment. This work indicates the great potential of vascular normalization combined with sonodynamic therapy and chemotherapy to enhance efficiency.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Nanopartículas/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Topotecan/farmacologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH- dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV-vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Nanopartículas/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Células MCF-7 , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológicoRESUMO
α-Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (ßCDs), particularly with the native ßCD and/or its derivative 2,6-dimethyl-ß-CD (DMßCD) is a promising technique. Although there have been several reports on the adsorption of ßCDs on the lipid bilayer, the release of the MGS/ßCDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different ßCDs (ßCD and DMßCD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free ßCDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two ßCDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DMßCD molecules potentially permeated into the deeper region of the interior membrane, whereas ßCD only adsorbed at the outer membrane surface. The interaction between secondary rim of ßCD and the 1-palmitoeyl-2-oleoyl-glycero-3-phosphocholine (POPC) phosphate groups showed the highest number of hydrogen bonds (up to 14) corresponding to the favorable location of ßCD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for ßCD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DMßCD adsorption. The release profile of MGS from the ßCDs pocket across the lipid bilayer exhibited two energy minima along the reaction coordinate associated with the permeation of the MGS molecule into the deeper region of the POPC membrane.
Assuntos
Desenho de Fármacos , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Xantonas/administração & dosagem , Xantonas/química , beta-Ciclodextrinas/análise , Adsorção , Portadores de Fármacos , Ligação de Hidrogênio , Lipídeos/química , Permeabilidade , Fosfatidilcolinas/química , Solubilidade , Eletricidade EstáticaRESUMO
Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono (Debio 1452, AFN-1252), a novel antibiotic in development which targets the staphylococcal enoyl-acyl carrier protein reductase (FabI) and exhibits selective potent antibacterial activity against staphylococcal species, including methicillin-resistant Staphylococcus aureus As part of clinical development in bone and joint infections, a distribution study in bone was performed in 17 patients who underwent elective hip replacement surgery. Patients received 3 doses of 240 mg afabicin orally (every 12 h) at various time points before surgery. Afabicin desphosphono concentrations were measured by liquid chromatography-tandem mass spectrometry in plasma, cortical bone, cancellous bone, bone marrow, soft tissue, and synovial fluid collected during surgery at 2, 4, 6, or 12 h after the third afabicin dose. The study showed good penetration of afabicin desphosphono into bone tissues, with mean area under the curve ratios for cortical bone-, cancellous bone-, bone marrow-, soft tissue-, and synovial fluid-to-total plasma concentrations of 0.21, 0.40, 0.32, 0.35, and 0.61, respectively. When accounting for the free fraction in plasma (2%) and synovial fluid (9.4%), the mean ratio was 2.88, which is indicative of excellent penetration and which showed that the afabicin desphosphono concentration was beyond the MIC90 of S. aureus over the complete dosing interval. These findings, along with preclinical efficacy data, clinical efficacy data for skin and soft tissue staphylococcal infection, the availability of both intravenous and oral formulations, and potential advantages over broad-spectrum antibiotics for the treatment of staphylococcal bone or joint infections, support the clinical development of afabicin for bone and joint infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02726438.).
Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Infecções Relacionadas à Prótese/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Artroplastia de Quadril , Osso e Ossos/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Osteomielite/prevenção & controle , Pironas/farmacocinética , Pironas/uso terapêuticoRESUMO
In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens" to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.
Assuntos
Antibacterianos/farmacocinética , Animais , Antibacterianos/uso terapêutico , Humanos , Pulmão/metabolismo , Pulmão/microbiologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/microbiologia , Resultado do TratamentoRESUMO
Isavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis established in mice with chronic granulomatous disease (CGD) (gp91phox-). Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze infected lungs and brain tissues collected 1, 3, 6, and 24 h after a single oral administration of the prodrug at a dose of 256 mg/kg of body weight (corresponding to 122.9 mg/kg of isavuconazole). Drug enrichment within granulomatous lesions was observed in lung tissue at 1 h postdose, although drug levels quickly equilibrated afterwards between lesion and nonlesion areas. A prominent antifungal effect in the infected lung tissue was revealed by histopathological analysis. Isavuconazole also penetrated into the brain with high efficiency. These data further support the value of isavuconazole to treat patients with invasive aspergillosis.
Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Doença Granulomatosa Crônica/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilas/metabolismo , Nitrilas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Triazóis/metabolismo , Triazóis/farmacologia , Administração Oral , Animais , Cromatografia Líquida/métodos , Modelos Animais de Doenças , Doença Granulomatosa Crônica/metabolismo , Infecções Fúngicas Invasivas/metabolismo , Masculino , Camundongos , Pró-Fármacos/farmacologia , Espectrometria de Massas em Tandem/métodos , Distribuição TecidualRESUMO
Systemic chemotherapy is one of the main anticancer treatments used for most kinds of clinically diagnosed tumors. However, the efficacy of these drugs can be hampered by the physical attributes of the tumor tissue, such as tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, tumor metabolic gradients, and non-uniform expression of the cell membrane receptors. This can impede the transport of therapeutic agents to tumor cells in sufficient quantities. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine ways to improve drug delivery on a cell-to-tissue scale (single-cell pharmacology), we developed the microscale pharmacokinetics/pharmacodynamics (microPKPD) modeling framework. Our model is modular and can be adjusted to include only the mathematical equations that are crucial for a biological problem under consideration. This modularity makes the model applicable to a broad range of pharmacological cases. As an illustration, we present two specific applications of the microPKPD methodology that help to identify optimal drug properties. The hypoxia-activated drugs example uses continuous drug concentrations, diffusive-advective transport through the tumor interstitium, and passive transmembrane drug uptake. The targeted therapy example represents drug molecules as discrete particles that move by diffusion and actively bind to cell receptors. The proposed modeling approach takes into account the explicit tumor tissue morphology, its metabolic landscape and/or specific receptor distribution. All these tumor attributes can be assessed from patients' diagnostic biopsies; thus, the proposed methodology can be developed into a tool suitable for personalized medicine, such as neoadjuvant chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Transporte Biológico Ativo , Simulação por Computador , Sistemas de Liberação de Medicamentos , Humanos , Ligantes , Conceitos Matemáticos , Neoplasias/patologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Análise de Célula Única , Análise Espaço-Temporal , Resultado do TratamentoRESUMO
This study was performed to investigate the intrapulmonary penetration of lascufloxacin in humans. Thirty healthy adult male Japanese subjects, allocated into five groups, received lascufloxacin in a single oral dose of 75 mg. Bronchoalveolar lavage and blood sampling were performed simultaneously in each subject at 1, 2, 4, 6, or 24 h after administration, and lascufloxacin concentrations in plasma, epithelial lining fluid, and alveolar macrophages were determined. Lascufloxacin was rapidly distributed to the epithelial lining fluid with a time to maximum drug concentration (Tmax) of 1 h, which was identical to that in plasma. The maximum concentration of drug (Cmax) values in plasma, epithelial lining fluid, and alveolar macrophages were 0.576, 12.3, and 21.8 µg/ml, respectively. The corresponding area under the concentration-time curve from 0 to 24 h (AUC0-24) values were 7.67, 123, and 325 µg · h/ml. The mean drug concentrations in the epithelial lining fluid and alveolar macrophages were much higher than those in plasma at all time points examined, and the average site-to-free plasma concentration ratios fell within the ranges of 57.5 to 86.4 and 71.0 to 217, respectively. Drug levels in epithelial lining fluid and alveolar macrophages exceeded the MIC90 values for common respiratory pathogens. (This study was registered at JAPIC under registration number JapicCTI-142547.).