scholarly journals Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness

2020 ◽  
Vol 10 (4) ◽  
pp. 242
Author(s):  
Giulia Di Prima ◽  
Giuseppina Campisi ◽  
Viviana De Caro
Keyword(s):  
Buccal Mucosa ◽  
Therapeutic Strategy ◽  
Therapeutic Response ◽  
Ex Vivo ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Promising Candidate ◽  
Steady State Condition ◽  
Drug Pharmacokinetic ◽  
Drug Flux

Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient’s needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h−1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient’s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials.

scholarly journals Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 508
Author(s):  
Sara Silva ◽  
António J. Almeida ◽  
Nuno Vale
Keyword(s):  
Side Effects ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Pharmacokinetic Profile ◽  
The Elderly ◽  
Motor Symptoms ◽  
Administration Routes ◽  
Pharmaceutical Therapy ◽  
Drug Pharmacokinetic ◽  
The Brain

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

Potency and preclinical evidence of synergy of oral azole drugs and miltefosine in an ex vivo model of Leishmania (Viannia) panamensis infection

2021 ◽  
Author(s):  
Olga Lucía Fernández ◽  
Mariana Rosales-Chilama ◽  
Natali Quintero ◽  
Bruno L. Travi ◽  
Dawn M. Wetzel ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Ex Vivo ◽  
Synergistic Activity ◽  
Ex Vivo Model ◽  
Clinical Strains ◽  
Frequent Use ◽  
Drug Concentrations ◽  
Resistant Lines ◽  
Potential Synergy ◽  
Sensitive Line

Failure of treatment of cutaneous leishmaniasis with antimonial drugs and miltefosine is frequent. Use of oral combination therapy represents an attractive strategy to increase efficacy of treatment and reduce the risk of drug resistance. We evaluated the potency of posaconazole, itraconazole, voriconazole and fluconazole, and the potential synergy of those demonstrating the highest potency, in combination with miltefosine (HePC), against infection with Leishmania (Viannia) panamensis . Synergistic activity was determined by isobolograms and calculation of Fractional Inhibitory Concentration Index (FICI), based on parasite quantification using an ex vivo model of human PBMCs infected with a luciferase-transfected, antimony and miltefosine sensitive line of L. panamensis . The drug combination and concentrations that displayed synergy were then evaluated for anti-leishmanial effect in 10 clinical strains of L. panamensis by qRT-PCR of Leishmania 7SLRNA. High potency was substantiated for posaconazole and itraconazole against sensitive as well as HePC and antimony resistant lines of L. panamensis , whereas fluconazole and voriconazole displayed low potency. HePC combined with posaconazole (Poz) demonstrated evidence of synergy at free drug concentrations achieved in plasma during treatment (2 μM HePC + 4 μM Poz). FICI, based on 70% and 90% reduction of infection, was 0.5 for the sensitive line. Combination of 2 μM HePC + 4 μM Poz effected significantly greater reduction of infection by clinical strains of L. panamensis than individual drugs. Orally administrable miltefosine/posaconazole combinations demonstrated synergistic anti-leishmanial capacity ex vivo against L. panamensis , supporting their potential as a novel therapeutic strategy to improve efficacy, and effectiveness of treatment.

scholarly journals Development of the First Aliphatic 18F-Labeled Tetrazine Suitable for Pretargeted PET Imaging – Expanding the Bioorthogonal Tool Box

2021 ◽  
Author(s):  
Umberto Maria Battisti ◽  
Klas Bratteby ◽  
Jesper Tranekjær Jørgensen ◽  
Lars Hvass ◽  
Vladimir Shalgunov ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Blocking Effect ◽  
Structure Property ◽  
Promising Candidate ◽  
Bioorthogonal Reaction ◽  
Radiation Burden ◽  
Small Structure ◽  
Radiochemical Yields ◽  
State Of Art

<p>Pretargeting imaging of nanomedicines have attracted considerable interest in nuclear medicine since it has the potential to increase imaging contrast while simultaneously reducing radiation burden to healthy tissue. Currently, the tetrazine ligation is the fastest bioorthogonal reaction available for this strategy and consequently, the state-of-art choice for <i>in vivo</i>chemistry. We have recently identified key properties for tetrazines to be applied in pretargeting. We have also developed a method to <sup>18</sup>F-label highly reactive tetrazines using an aliphatic nucleophilic substitution strategy.<a> In this study, we combined this knowledge and developed an <sup>18</sup>F-labeled tetrazine for pretargeted imaging. In order to develop this ligand, a small structure-property study was carried out. The most promising compound - with respect to reactivity, hydrophilicity and <i>ex vivo</i> blocking effect - was selected for labeling and subsequent PET <i>in vivo</i> imaging. Radiolabeling was achieved in satisfying radiochemical yields, molar activities as well as in high radiochemical purities. The tracer </a><a>displayed favorable pharmacokinetics and remarkable target-to-background ratios in pretargeted experiments - already one hour post injection.</a> We believe that the developed pretargeting imaging agent is a promising candidate for translation into clinical studies.</p>

scholarly journals Optimal H2O2 preconditioning to improve BMSCs’ engraftment  in wounds healing

2020 ◽  
Author(s):  
Ling Guo ◽  
Ya Zhang ◽  
Juan Du ◽  
Dan Feng Yuan ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Therapeutic Strategy ◽  
Wound Closure ◽  
Therapeutic Potential ◽  
Caspase 9 ◽  
Promising Candidate ◽  
Optimal Protocol ◽  
Marrow Mesenchymal Stem Cells ◽  
Gsk 3Β ◽  
Migration Capacity

Abstract Background. The transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. However, the poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application. Objective. The optimal protocol for BMSCs preconditioned with H2O2 was investigated, and the therapeutic efficacy of preconditioned BMSCs in wounds was evaluated. Methods. Mouse BMSCs were exposed to various concentrations of H2O2, and their functions were assessed; The H2O2-preconditioned BMSCs were transplanted into mice with full-thickness excisional wounds. Wound analysis was performed to assess the transplantation efficacy. Results. Treatment BMSCs with 50 µM H2O2 for 12 h could enhance their proliferation, migration and survival by maximizing up-regulation the cyclin D1, SDF-1 and its receptors CXCR4/7 expressions, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β. Meanwhile, oxidative stress-induced-BMSCs apoptosis was significantly attenuated by an obviously decreased ratio of Bax/Bcl-2 and cleaved caspase-9/3 expression. After transplantation of BMSCs, the migration of H2O2 preconditioned-BMSCs into the wounds was dramatically increased compared to un-preconditioned-BMSCs, and had an increased microvessel density and wound closure speed. Conclusions. The findings suggested that 50 µM H2O2 pretreated for 12 h is the optimal precondition for the transplantation of BMSC, which gives a considerable insight that this protocol may be served as a promising candidate for improving the therapeutic potential of BMSCs for wound healing.

A comparative ex vivo drug permeation study of beta-blockers through porcine buccal mucosa

2014 ◽  
Vol 468 (1-2) ◽  
pp. 50-54 ◽  
Author(s):  
Sonia Amores ◽  
Jacinto Lauroba ◽  
Ana Calpena ◽  
Helena Colom ◽  
Alvaro Gimeno ◽  
...  
Keyword(s):  
Buccal Mucosa ◽  
Ex Vivo ◽  
Beta Blockers ◽  
Drug Permeation ◽  
Permeation Study

Platelet lysate: a promising candidate in regenerative medicine

2021 ◽  
Vol 16 (1) ◽  
pp. 71-85
Author(s):  
Vafa Meftahpour ◽  
Somaiyeh Malekghasemi ◽  
Amir Baghbanzadeh ◽  
Ali Aghebati-Maleki ◽  
Ramin Pourakbari ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Therapeutic Strategy ◽  
Human Platelet ◽  
Nerve Repair ◽  
Platelet Lysate ◽  
Promising Candidate ◽  
Graft Versus Host ◽  
Tendon Regeneration ◽  
Human Platelet Lysate ◽  
Basal Media

Human platelet lysate has attracted much interest from many researchers as it is growth-factor rich for cell expansion, which is employed as a new therapeutic strategy. Not only are human platelet lysates used for cell therapy, but they are also used for the completion of basal media in mesenchymal stem cell cultures. Due to the presence of a large number of growth factors, platelet lysates have potential roles in wound healing, treatment of ocular graft-versus-host disease, osteoarthritis, Parkinson’s disease, tendon regeneration, infertility, androgenetic alopecia, nerve repair and regenerative tissue, such as bone regeneration. In this review, we summarize that platelet lysates could be valuable candidates for the treatment of a variety of diseases in regenerative medicine.

Abstract 2056: Blockade of PDGF Receptor Tyrosine Kinase by Ex Vivo Nano-DDS of Imatinib Mesylate into the Vein Suppresses Vein Graft Neointima Formation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Kimura ◽  
Kensuke Egahira ◽  
Hiroyuki Tsujimoto ◽  
Kaori Hara ◽  
Yoshiaki Kawashima ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Vein Graft ◽  
Graft Failure ◽  
Therapeutic Strategy ◽  
Jugular Vein ◽  
Ex Vivo ◽  
Pdgf Receptor ◽  
Neointima Formation ◽  
Vein Graft Failure

Background: Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure due to neointima formation. Platelet-derived growth factor (PDGF), expressed by vascular smooth muscle cells (VSMCs), plays a central role in the pathogenesis of vein graft failure. Therefore, optimal nanotechnology-based drug delivery system (Nano-DDS) of PDGF receptor tyrosine kinase (TK) inhibitor, imatinib mesylate (STI571), can be an innovative therapeutic strategy for clinical application. We have developed such Nano-DDS using bioabsorbable PLGA nanoparticles (NP) for local ex vivo delivery. Hypothesis: Blockade of PDGF receptor TK by Nano-DDS of imatinib suppresses vein graft neointima formation. Methods and Results: [studies in human VSMCs in vitro] Addition of fluorescence (FITC)-encapsulated NP resulted in rapid and stable uptake by 99 % of cells. The Nano-DDS of imatinib prevented PDGF-induced phosphorylation of PDGF receptor TK, and thus normalized the PDGF-induced proliferation. [ ex vivo studies] Incubation of excised rabbit jugular vein and human saphenous vein ex vivo in FITC-encapsulated NP for 30 min resulted in highly efficient intracellular delivery rate (> 90 % cells) into cells of the venous wall. [ in vivo studies in rabbits] The excised jugular vein was treated ex vivo with PBS, imatinib only (100 mM), FITC NP only, or imatinib NP (100 mM) (n=5– 6, each) for 30 min, and then interposed into the carotid artery position of hypercholesterolemic rabbits. Seven and 28 days after ex vivo FITC NP treatment, FITC-positive cells were detected in many cells in the neointima and media (cellular uptake rate: 60 –70 %). Significant neointima was formed 28 days after grafting in PBS group, which was suppressed in imatinib NP group, but not in FITC NP only or imatinib only groups. Imatinib NP also inhibited the appearance of proliferating PCNA-positive cells and increased phosphorylation of PDGF receptor TK, but did not affect monocyte infiltration or endothelial regeneration process. Conclusions: Nano-DDS of imatinib into the excised vein ex vivo was feasible and suppressed vein graft neointima formation in rabbits. Nano-DDS of imatinib may be a clinically promising therapeutic strategy for prevention of vein graft failure.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

scholarly journals Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6702-6713 ◽  
Author(s):  
Yitang Li ◽  
Amit Prasad ◽  
Yonghui Jia ◽  
Saurabh Ghosh Roy ◽  
Fabien Loison ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Ex Vivo ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Granulocyte Transfusion ◽  
Chromosome 10 ◽  
Transfusion Therapy ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Bacteria Killing

Abstract The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)-trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol (3,4,5)-trisphosphate in transfused neutrophils with PTEN inhibitor SF1670, providing a therapeutic strategy for improving the efficacy of granulocyte transfusion.

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

2020 ◽  
Author(s):  
Valentina S. Klaus ◽  
Sonja C. Schriever ◽  
Andreas Peter ◽  
José Manuel Monroy Kuhn ◽  
Martin Irmler ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Hepatic Metabolism ◽  
Omics Data ◽  
Network Integration ◽  
Data Set ◽  
Metabolomics Data ◽  
Different Types ◽  
Hepatic Fat ◽  
Liver Biopsies

ABSTRACTThe steadily increasing amount of newly generated omics data of various types from genomics to metabolomics is a chance and a challenge to systems biology. To fully use its potential, one key is the meaningful integration of different types of omics. We here present a fully unsupervised and versatile correlation-based method, termed Correlation guided Network Integration (CoNI), to integrate multi-omics data into a hypergraph structure that allows for identification of effective regulators. Our approach further unravels single transcripts mapped to specific densely connected metabolic sub-graphs or pathways. By applying our method on transcriptomics and metabolomics data from murine livers under standard chow or high-fat-diet, we isolated eleven genes with a regulatory effect on hepatic metabolism. Subsequent in vitro and ex vivo experiments in human liver cells and human obtained liver biopsies validated seven candidates including INHBE and COBLL1, to alter lipid metabolism and to correlate with diabetes related traits such as overweight, hepatic fat content and insulin resistance (HOMA-IR). Last, we successfully applied our methods to an independent data-set to confirm its versatile and transferable character.

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