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Zhang X, Zhang Y, Chen Y, Cheng J, Zhang J, Shang J, Chen Y, Liu Q, An Q, Feng Z. Microbubble-Enhanced Transdermal Drug Delivery Sonoelectric Patch. ACS APPLIED MATERIALS & INTERFACES 2024; 16:49069-49082. [PMID: 39236665 DOI: 10.1021/acsami.4c10049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
Transdermal drug delivery systems are highly appealing as a convenient drug delivery manner applicable to a wide variety of drugs. While most delivery relies on only passive diffusion and suffers low transdermal efficiencies. Ultrasound motivation promotes drug transdermal penetration but still calls for improvement, because only a thin proportion of the ultrasound energy is applied on the drug delivery patch and most ultrasound energy is wasted in deeper portions of biotissues. In this work, we develop a transdermal patch for enhanced drug delivery. The combination of microsized air pockets and the piezoelectric soft structure enable the conversion of an intended proportion of ultrasound energy into electric energy. The intensified drug flow and synergistic ultrasound pressure and electric field function simultaneously to enhance drug transdermal delivery. The delivery efficacy is related to the power of the ultrasound motivation, the size of the microscopic air pockets, and the chemical structure of the drug molecules. The temperature of the patch within the delivery process remains in the safe range, and the mild temperature elevation causes color changes of the thermochromic patch, used to indicate effective ultrasound-patch matching. A model delivery patch for pain release is constructed, and animal experiments indicate that the drug blood concentrations are 100% higher than the delivery using only ultrasound and even more remarkably enhanced when compared to only electric-field-motivated delivery or static delivery without external motivations.
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Affiliation(s)
- Xinyue Zhang
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Yihe Zhang
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Yao Chen
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Jiajun Cheng
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Jiahe Zhang
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Jing Shang
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Yunfan Chen
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Qi Liu
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Qi An
- Engineering Research Center of Ministry of Education for Geological Carbon Storage and Low Carbon Utilization of Resources, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, School of Materials Science and Technology, China University of Geosciences (Beijing), Beijing 100083, People's Republic of China
| | - Zeguo Feng
- Department of Pain, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, People's Republic of China
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Marathe D, Bhuvanashree VS, Mehta CH, T. A, Nayak UY. Low-Frequency Sonophoresis: A Promising Strategy for Enhanced Transdermal Delivery. Adv Pharmacol Pharm Sci 2024; 2024:1247450. [PMID: 38938593 PMCID: PMC11208788 DOI: 10.1155/2024/1247450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/04/2024] [Accepted: 05/13/2024] [Indexed: 06/29/2024] Open
Abstract
Sonophoresis is the most approachable mode of transdermal drug delivery system, wherein low-frequency sonophoresis penetrates the drug molecules into the skin. It is an alternative method for an oral system of drug delivery and hypodermal injections. The cavitation effect is thought to be the main mechanism used in sonophoresis. The cavitation process involves forming a gaseous bubble and its rupture, induced in the coupled medium. Other mechanisms used are thermal effects, convectional effects, and mechanical effects. It mainly applies to transporting hydrophilic drugs, macromolecules, gene delivery, and vaccine delivery. It is also used in carrier-mediated delivery in the form of micelles, liposomes, and dendrimers. Some synergistic effects of sonophoresis, along with some permeation enhancers, such as chemical enhancers, iontophoresis, electroporation, and microneedles, increased the effectiveness of drug penetration. Sonophoresis-mediated ocular drug delivery, nail drug delivery, gene delivery to the brain, sports medicine, and sonothrombolysis are also widely used. In conclusion, while sonophoresis offers promising applications in diverse fields, further research is essential to comprehensively elucidate the biophysical mechanisms governing ultrasound-tissue interactions. Addressing these gaps in understanding will enable the refinement and optimization of sonophoresis-based therapeutic strategies for enhanced clinical efficacy.
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Affiliation(s)
- Divya Marathe
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Vasudeva Sampriya Bhuvanashree
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Chetan Hasmukh Mehta
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Ashwini T.
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Usha Yogendra Nayak
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
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Mahran HG. Shockwave versus ultrasound therapy in the enhancement of Aloe vera in cutaneous wound healing. J Wound Care 2023; 32:cxxxix-cxlv. [PMID: 37405969 DOI: 10.12968/jowc.2023.32.sup7a.cxxxix] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
OBJECTIVE To investigate the healing efficacy of topical Aloe vera enhanced by shockwave or ultrasound therapy on wounds in rats and compare both effects. METHOD A total of 75 male albino rats were randomly divided into equal groups A, B, C, D and E. Under anaesthesia, a wound (6cm2) was created on the back of each rat. Group A received topical Aloe vera under occlusive dressing followed by shockwave therapy with the following parameters: 600 shocks, four pulses/second and 0.11mJ/mm2. Group B received topical Aloe vera under occlusive dressing followed by therapeutic ultrasound with the following parameters: pulsed mode, 2:8 duty cycle, 1MHz and 0.5 W/cm2. Group C received the same treatment as group A but in a reversed sequence-the shockwave therapy followed by the Aloe vera gel. Group D received the same treatment as group B but in a reversed sequence-therapeutic ultrasound followed by the Aloe vera gel. And control group E only received topical Aloe vera under occlusive dressing. Each group received three sessions per week, for two weeks. Wound extent and shrinkage rates were measured at study initiation and at the end of each week. RESULTS There were significant wound reductions in groups A and B compared to C and D, respectively, and in group A compared to group B. CONCLUSION Shockwaves and ultrasound were found to amplify the effect of the Aloe vera on the wound, and there was improved wound healing in the shockwave group A compared to the ultrasound group B.
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Affiliation(s)
- Hesham Galal Mahran
- Department of Physical Therapy for Surgery, Faculty of Physical Therapy, Cairo University, Giza, Egypt
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Yu CC, Shah A, Amiri N, Marcus C, Nayeem MOG, Bhayadia AK, Karami A, Dagdeviren C. A Conformable Ultrasound Patch for Cavitation-Enhanced Transdermal Cosmeceutical Delivery. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2300066. [PMID: 36934314 DOI: 10.1002/adma.202300066] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/06/2023] [Indexed: 06/09/2023]
Abstract
Increased consumer interest in healthy-looking skin demands a safe and effective method to increase transdermal absorption of innovative therapeutic cosmeceuticals. However, permeation of small-molecule drugs is limited by the innate barrier function of the stratum corneum. Here, a conformable ultrasound patch (cUSP) that enhances transdermal transport of niacinamide by inducing intermediate-frequency sonophoresis in the fluid coupling medium between the patch and the skin is reported. The cUSP consists of piezoelectric transducers embedded in a soft elastomer to create localized cavitation pockets (0.8 cm2 , 1 mm deep) over larger areas of conformal contact (20 cm2 ). Multiphysics simulation models, acoustic spectrum analysis, and high-speed videography are used to characterize transducer deflection, acoustic pressure fields, and resulting cavitation bubble dynamics in the coupling medium. The final system demonstrates a 26.2-fold enhancement in niacinamide transport in a porcine model in vitro with a 10 min ultrasound application, demonstrating the suitability of the device for short-exposure, large-area application of sonophoresis for patients and consumers suffering from skin conditions and premature skin aging.
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Affiliation(s)
- Chia-Chen Yu
- Media Lab, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Aastha Shah
- Media Lab, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Nikta Amiri
- Department of Mechanical and Aerospace Engineering, University at Buffalo, Buffalo, NY, 14260, USA
| | - Colin Marcus
- Media Lab, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | | | - Amit Kumar Bhayadia
- Department of Mechanical and Aerospace Engineering, University at Buffalo, Buffalo, NY, 14260, USA
| | - Amin Karami
- Department of Mechanical and Aerospace Engineering, University at Buffalo, Buffalo, NY, 14260, USA
| | - Canan Dagdeviren
- Media Lab, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
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Han W, Liu F, Liu G, Li H, Xu Y, Sun S. Research progress of physical transdermal enhancement techniques in tumor therapy. Chem Commun (Camb) 2023; 59:3339-3359. [PMID: 36815500 DOI: 10.1039/d2cc06219d] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
The advancement and popularity of transdermal drug delivery (TDD) based on the physical transdermal enhancement technique (PTET) has opened a new paradigm for local tumor treatment. The drug can be directly delivered to the tumor site through the skin, thus avoiding the toxic side effects caused by the first-pass effect and achieving high patient compliance. Further development of PTETs has provided many options for antitumor drugs and laid the foundation for future applications of wearable closed-loop targeting drug delivery systems. In this highlight, the different types of PTETs and related mechanisms, and applications of PTET-related tumor detection and therapy are highlighted. According to their type and characteristics, PTETs are categorized as follows: (1) iontophoresis, (2) electroporation, (3) ultrasound, (4) thermal ablation, and (5) microneedles. PTET-related applications in the local treatment of tumors are categorized as follows: (1) melanoma, (2) breast tumor, (3) squamous cell carcinoma, (4) cervical tumor, and (5) others. The challenges and future prospects of existing PTETs are also discussed. This highlight will provide guidance for the design of PTET-based wearable closed-loop targeting drug delivery systems and personalized therapy for tumors.
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Affiliation(s)
- Weiqiang Han
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Fengyu Liu
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No. 2 Linggong Road, Ganjingzi District, Dalian 116023, P. R. China.
| | - Guoxin Liu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Hongjuan Li
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Yongqian Xu
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Shiguo Sun
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
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Fiedorova K, Augustynek M, Kubicek J, Kudrna P, Bibbo D. Review of present method of glucose from human blood and body fluids assessment. Biosens Bioelectron 2022; 211:114348. [DOI: 10.1016/j.bios.2022.114348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 03/22/2022] [Accepted: 05/05/2022] [Indexed: 12/15/2022]
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Yang FA, Chen HL, Peng CW, Liou TH, Escorpizo R, Chen HC. A systematic review and meta-analysis of the effect of phonophoresis on patients with knee osteoarthritis. Sci Rep 2022; 12:12877. [PMID: 35896559 PMCID: PMC9329477 DOI: 10.1038/s41598-022-16084-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 07/04/2022] [Indexed: 11/08/2022] Open
Abstract
This systematic review and meta-analysis investigated the effect of phonophoresis when various gel types were used. Medline (using PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were used to search for relevant studies from the date of their inception to June 28, 2021. We included studies that were randomized controlled trials (RCTs), included patients with a diagnosis of knee osteoarthritis, included treatment with either phonophoresis or therapeutic ultrasound with placebo gel, and reported clinical and functional outcomes. Continuous variables are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Statistical analysis was performed using RevMan 5.3 software. We initially retrieved 2176 studies and finally analyzed nine RCTs including 423 patients. The intervention group significantly outperformed the control group in pain scores with NSAID gel (SMD = - 0.53, 95% CI [- 1.02, - 0.05], I2 = 73%) and in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) function score with corticosteroid gel (SMD = - 0.96, 95% CI [- 1.47, - 0.44], I2 = 20%). Phonophoresis alleviated pain and improved functional performance. Because of some limitations of this study, additional high-quality, large-scale RCTs are required to confirm the benefits.
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Affiliation(s)
- Fu-An Yang
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hung-Lun Chen
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Wei Peng
- School of Gerontology Health Management, College of Nursing, Taipei Medical University, Taipei, Taiwan
- School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - Tsan-Hon Liou
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, No. 291 Zhongzheng Road, Zhonghe District, New Taipei City, 235, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Reuben Escorpizo
- Department of Rehabilitation and Movement Science, College of Nursing and Health Sciences, University of Vermont, Burlington, VT, USA
- Swiss Paraplegic Research, Nottwil, Switzerland
| | - Hung-Chou Chen
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, No. 291 Zhongzheng Road, Zhonghe District, New Taipei City, 235, Taiwan.
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Center for Evidence-Based Health Care, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
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Kalave S, Chatterjee B, Shah P, Misra A. Transdermal Delivery of Macromolecules Using Nano Lipid Carriers. Curr Pharm Des 2021; 27:4330-4340. [PMID: 34414868 DOI: 10.2174/1381612827666210820095330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/28/2021] [Indexed: 11/22/2022]
Abstract
Skin being the largest external organ, offers an appealing procedure for transdermal drug delivery, so the drug needs to reach above the outermost layer of the skin, i.e., stratum corneum. Small molecular drug entities obeying the Lipinski rule, i.e., drugs having a molecular weight less than 500 Da, high lipophilicity, and optimum polarity, are favored enough to be used on the skin as therapeutics. Skin's barrier properties prevent the transport of macromolecules at pre-determined therapeutic rates. Notable advancements in macromolecules' transdermal delivery have occurred in recent years. Scientists have opted for liposomes, the use of electroporation, low-frequency ultrasound techniques, etc. Some of these have shown better delivery of macromolecules at clinically beneficial rates. These physical technologies involve complex mechanisms, which may irreversibly incur skin damage. Majorly, two types of lipid-based formulations, including Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), are widely investigated as transdermal delivery systems. In this review, the concepts, mechanisms, and applications of nanostructured lipid carriers used to transport macromolecules via transdermal routes are thoroughly reviewed and presented along with their clinical perspective.
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Affiliation(s)
- Sana Kalave
- SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai, India
| | - Bappaditya Chatterjee
- SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai, India
| | - Parth Shah
- SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai, India
| | - Ambikanandan Misra
- SVKM's NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai, India
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Caligiore D, Montedori F, Buscaglione S, Capirchio A. Increasing Serotonin to Reduce Parkinsonian Tremor. Front Syst Neurosci 2021; 15:682990. [PMID: 34354572 PMCID: PMC8331097 DOI: 10.3389/fnsys.2021.682990] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/21/2021] [Indexed: 01/07/2023] Open
Abstract
While current dopamine-based drugs seem to be effective for most Parkinson's disease (PD) motor dysfunctions, they produce variable responsiveness for resting tremor. This lack of consistency could be explained by considering recent evidence suggesting that PD resting tremor can be divided into different partially overlapping phenotypes based on the dopamine response. These phenotypes may be associated with different pathophysiological mechanisms produced by a cortical-subcortical network involving even non-dopaminergic areas traditionally not directly related to PD. In this study, we propose a bio-constrained computational model to study the neural mechanisms underlying a possible type of PD tremor: the one mainly involving the serotoninergic system. The simulations run with the model demonstrate that a physiological serotonin increase can partially recover dopamine levels at the early stages of the disease before the manifestation of overt tremor. This result suggests that monitoring serotonin concentration changes could be critical for early diagnosis. The simulations also show the effectiveness of a new pharmacological treatment for tremor that acts on serotonin to recover dopamine levels. This latter result has been validated by reproducing existing data collected with human patients.
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Affiliation(s)
- Daniele Caligiore
- Computational and Translational Neuroscience Laboratory, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
| | - Francesco Montedori
- Computational and Translational Neuroscience Laboratory, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
| | - Silvia Buscaglione
- Neurophysiology and Neuroengineering of Human-Technology Interaction Research Unit (NeXT), Campus Bio-Medico University, Rome, Italy
| | - Adriano Capirchio
- Computational and Translational Neuroscience Laboratory, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
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Zhai H, Zhang C, Ou H, Chen M. Transdermal delivery of heparin using low-frequency sonophoresis in combination with sponge spicules for venous thrombosis treatment. Biomater Sci 2021; 9:5612-5625. [PMID: 34254062 DOI: 10.1039/d1bm00703c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This study reports that the use of low-frequency sonophoresis (LFS) in combination with sponge Haliclona sp. spicules (SHS), referred to as cSoSp (combined Sonophoresis and Spicules), can enhance the transdermal drug delivery in a synergistic manner. The topical application of cSoSp in vitro significantly enhanced the skin absorption of Fluorescent-Dextrans (4000 Da, FD-4K), a model drug of low-molecular-weight heparin (LMWH). The utilization of cSoSp dramatically increased the transdermal flux of FD-4K (188.6 ± 93.7 ng cm-2 h-1) compared to LFS (5.8 ± 3.1 ng cm-2 h-1) and SHS (3.2 ± 1.2 ng cm-2 h-1) among others. The mechanism of action of cSoSp could be attributed to the synergism between plenty of long-lasting nano-channels created by SHS and the disorders of SC lipids made by shock waves of LFS, which improves the homogeneity of the cavitation effects. Furthermore, LMWH (3000 Da) was transdermally delivered by using cSoSp to treat both superficial venous thrombosis (SVT) and deep venous thrombosis (DVT) in the marginal ear vein of rabbits with a good therapeutic effect. Furthermore, skin irritation and toxicity studies using guinea pigs indicated that cSoSp was nonirritating without any morphological changes in the keratinocytes. cSoSp offers a promising strategy to enhance the transdermal delivery of hydrophilic macromolecules such as heparin.
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Affiliation(s)
- Haojie Zhai
- Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China.
| | - Chi Zhang
- Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China.
| | - Huilong Ou
- Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China.
| | - Ming Chen
- Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen 361102, China. and State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, Xiamen University, Xiamen 361102, China and Shenzhen Research Institute of Xiamen University, Shenzhen 518000, China
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11
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Phadke A, Amin P. A Recent Update on Drug Delivery Systems for Pain Management. J Pain Palliat Care Pharmacother 2021; 35:175-214. [PMID: 34157247 DOI: 10.1080/15360288.2021.1925386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Pain remains a global health challenge affecting approximately 1.5 billion people worldwide. Pain has been an implicit variable in the equation of human life for many centuries considering different types and the magnitude of pain. Therefore, developing an efficacious drug delivery system for pain management remains an open challenge for researchers in the field of medicine. Lack of therapeutic efficacy still persists, despite high throughput studies in the field of pain management. Research scientists have been exploiting different alternatives to curb the adverse side effects of pain medications or attempting a more substantial approach to minimize the prevalence of pain. Various drug delivery systems have been developed such as nanoparticles, microparticles to curb adverse side effects of pain medications or minimize the prevalence of pain. This literature review firstly provides a brief introduction of pain as a sensation and its pharmacological interventions. Second, it highlights the most recent studies in the pharmaceutical field for pain management and serves as a strong base for future developments. Herein, we have classified drug delivery systems based on their sizes such as nano, micro, and macro systems, and for each of the reviewed systems, design, formulation strategies, and drug release performance has been discussed.
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Uddin SMZ, Komatsu DE, Motyka T, Petterson S. Low-Intensity Continuous Ultrasound Therapies—A Systematic Review of Current State-of-the-Art and Future Perspectives. J Clin Med 2021; 10:2698. [PMID: 34207333 PMCID: PMC8235587 DOI: 10.3390/jcm10122698] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 01/02/2023] Open
Abstract
Therapeutic ultrasound has been studied for over seven decades for different medical applications. The versatility of ultrasound applications are highly dependent on the frequency, intensity, duration, duty cycle, power, wavelength, and form. In this review article, we will focus on low-intensity continuous ultrasound (LICUS). LICUS has been well-studied for numerous clinical disorders, including tissue regeneration, pain management, neuromodulation, thrombosis, and cancer treatment. PubMed and Google Scholar databases were used to conduct a comprehensive review of all research studying the application of LICUS in pre-clinical and clinical studies. The review includes articles that specify intensity and duty cycle (continuous). Any studies that did not identify these parameters or used high-intensity and pulsed ultrasound were not included in the review. The literature review shows the vast implication of LICUS in many medical fields at the pre-clinical and clinical levels. Its applications depend on variables such as frequency, intensity, duration, and type of medical disorder. Overall, these studies show that LICUS has significant promise, but conflicting data remain regarding the parameters used, and further studies are required to fully realize the potential benefits of LICUS.
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Affiliation(s)
- Sardar M. Z. Uddin
- Department of Orthopaedics and Rehabilitation, Stony Brook University, Stony Brook, NY 11794, USA;
| | - David E. Komatsu
- Department of Orthopaedics and Rehabilitation, Stony Brook University, Stony Brook, NY 11794, USA;
| | - Thomas Motyka
- Department of Osteopathic Manipulative Medicine, Campbell University, Buies Creek, NC 27506, USA;
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Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Transl Res 2021; 12:758-791. [PMID: 33474709 PMCID: PMC7817074 DOI: 10.1007/s13346-021-00909-6] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2021] [Indexed: 12/11/2022]
Abstract
Transdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. These methods include drug/vehicle interactions, vesicles and particles, stratum corneum modification, energy-driven methods and stratum corneum bypassing techniques. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. Microneedle technology platforms have proven themselves to be more versatile than other transdermal systems with opportunities for intradermal delivery of drugs/biotherapeutics and therapeutic drug monitoring. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems.
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Papadopoulos ES, Mani R. The Role of Ultrasound Therapy in the Management of Musculoskeletal Soft Tissue Pain. INT J LOW EXTR WOUND 2020; 19:350-358. [DOI: 10.1177/1534734620948343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ultrasound is an invaluable physical modality widely used for diagnosis and therapy in humans and animals. It is noninvasive, atraumatic, and may be used repeatedly. As a therapeutic tool, ultrasound has been in use for some 6 decades. Therapeutic ultrasound (TUS) is used for the treatment of musculoskeletal disorders, including acute soft tissue injuries, overuse syndromes, as well as chronic orthopedic and rheumatologic conditions. The aim of this review was to investigate the clinical effectiveness of TUS in musculoskeletal acute and chronic pain, mainly through the control of inflammation and the promotion of soft tissue injury healing. Based on the evidence presented, TUS is clinically effective in some musculoskeletal soft tissue pain conditions, but due to conflicting results in some studies, no specific positive recommendations can be made, nor does it permit exclusion of TUS from clinical practice. In phonophoresis, TUS plays a significant role, without reported adverse effects. There is scope for improving the evidence base with better designed studies.
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Affiliation(s)
| | - Raj Mani
- Shanghai Jiao Tong University, Shanghai, China
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Vahdatpour B, Taheri P, Abasi F. Extracorporeal Shock Wave Therapy for Lateral Epicondylitis, Lonely or in Combination with Topical Corticosteroid; Which Approach is Superior? Galen Med J 2020; 9:e1791. [PMID: 34466592 PMCID: PMC8343590 DOI: 10.31661/gmj.v9i0.1791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 12/24/2019] [Accepted: 01/12/2020] [Indexed: 11/16/2022] Open
Abstract
Background Lateral epicondylitis (LE) is a common musculoskeletal disorder. Although varieties of modalities have been proposed for its treatment, the outcomes are uncertain, and the responses would diminish early by the time passage. The current study was aimed to assess the efficacy of extracorporeal shock wave therapy (ESWT) merely and in combination with topical corticosteroid for the treatment of LE. Materials and Methods In the current double-blinded randomized clinical trial, 70 patients with the diagnosis of LE were randomly allocated to two intervention groups of ESWT merely (control group) (n=35) or ESWT plus topical corticosteroid (intervention group) (n=35). The ESWT was performed weekly for three weeks. Topical clobetasol was utilized within 30 minutes before ESWT for the intervention group, while Vaseline gel was used in a similar pattern for controls. Pain based on a visual analog scale (VAS), handgrip strength (HGS) and the Patient-Rated Tennis Elbow Evaluation (PRTEE) were assessed for the patients before the intervention, following the intervention cessation, and within two months post-intervention. Results Statistically significant improvement was found following both interventions in terms of pain, HGS, and function (P-value<0.001 for all), while the comparison of the two interventions, ESWT, merely versus in combination with topical clobetasol, revealed insignificant difference (P-value>0.05). Conclusion The findings of our study are in favor of ESWT use either merely or in combination with topical steroids for the treatment of LE, while the comparison of the two techniques revealed insignificant differences.
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Affiliation(s)
- Babak Vahdatpour
- Department of Physical Therapy and Rehabilitation, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parisa Taheri
- Department of Physical Therapy and Rehabilitation, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Abasi
- Department of Physical Therapy and Rehabilitation, Isfahan University of Medical Sciences, Isfahan, Iran
- Correspondence to: Fatemeh Abasi, Department Physical therapy and Rehabilitation, Isfahan University of Medical Sciences, Isfahan, Iran Telephone Number: +989376445992 Email Address:
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Guillot AJ, Cordeiro AS, Donnelly RF, Montesinos MC, Garrigues TM, Melero A. Microneedle-Based Delivery: An Overview of Current Applications and Trends. Pharmaceutics 2020; 12:pharmaceutics12060569. [PMID: 32575392 PMCID: PMC7355570 DOI: 10.3390/pharmaceutics12060569] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/13/2020] [Accepted: 06/16/2020] [Indexed: 12/18/2022] Open
Abstract
Microneedle arrays (MNA) are considered as one of the most promising resources to achieve systemic effects by transdermal delivery of drugs. They are designed as a minimally invasive, painless system which can bypass the stratum corneum, overcoming the potential drawbacks of subcutaneous injections and other transdermal delivery systems such as chemical enhancers, nano and microparticles, or physical treatments. As a trendy field in pharmaceutical and biomedical research, its applications are constantly evolving, even though they are based on very well-established techniques. The number of molecules administered by MNA are also increasing, with insulin and vaccines administration being the most investigated. Furthermore, MNA are being used to deliver cells and applied in other organs and tissues like the eyes and buccal mucosae. This review intends to offer a general overview of the current state of MNA research, focusing on the strategies, applications, and types of molecules delivered recently by these systems. In addition, some information about the materials and manufacturing processes is presented and safety data is discussed.
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Affiliation(s)
- Antonio José Guillot
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Avda. Vincent Andrés Estellés s/n, 46100 Burjassot, Spain; (A.J.G.); (A.M.)
| | - Ana Sara Cordeiro
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK; (A.S.C.); (R.F.D.)
| | - Ryan F. Donnelly
- School of Pharmacy, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK; (A.S.C.); (R.F.D.)
| | - M. Carmen Montesinos
- Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Avda. Vincent Andrés Estellés s/n, 46100 Burjassot, Spain
- Center of Molecular Recognition and Technological Development (IDM), 46100 Burjassot, Spain
- Correspondence: (M.C.M.); (T.M.G.)
| | - Teresa M. Garrigues
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Avda. Vincent Andrés Estellés s/n, 46100 Burjassot, Spain; (A.J.G.); (A.M.)
- Correspondence: (M.C.M.); (T.M.G.)
| | - Ana Melero
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Avda. Vincent Andrés Estellés s/n, 46100 Burjassot, Spain; (A.J.G.); (A.M.)
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Alarjah MA. Effect of Ultrasound Intensity and Mode on Piroxicam Transport Across Three-Dimensional Skin Equivalent Epiderm™. ACTA ACUST UNITED AC 2020; 14:75-83. [PMID: 32106808 DOI: 10.2174/1872211314666200227115014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 02/03/2020] [Accepted: 02/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Transdermal drug delivery has many advantages compared to other routes. However, the barrier function of the stratum corneum limits the use of the skin as an administrative route for medications. Different methods were investigated to alter the barrier function of the stratum corneum and it was found that applying different ultrasound waves could enhance the skin's permeability. OBJECTIVE The aim of this work is to study the effect of ultrasonic waves on the alteration of skin natural barrier function, to improve the permeability of the skin to Piroxicam using three-dimension skin (EpiDermTM) as a skin model for the investigation. METHOD The effect of ultrasound at 1 MHz and 20 kHz on the permeation of Piroxicam across the three-dimensional skin equivalent using a Franz diffusion cell, was evaluated and the concentration of Piroxicam in the receiving compartment was determined using liquid chromatography method. RESULTS The permeation of Piroxicam enhanced by 199% when therapeutic ultrasound at 1 MHz frequency was used. Significant permeation enhancement was also found upon utilizing low frequency sonophoresis at 20 kHz (427%) with no apparent damage to the membrane. CONCLUSION Sonophoresis has a positive effect on enhancing skin permeability. The enhancement level was largely dependent on the sonication factors; frequency, intensity and length of treatment. Multiple mechanisms of action might be involved in permeation improvement of the piroxicam molecule. Those mechanisms are largely dependent on the ultrasonic conditions.
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Affiliation(s)
- Mohammed A Alarjah
- Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Alqura University, 2373, Al Awali, Makkah 24381 8073, P.O. Box: 715, Saudi Arabia
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Altan L, Kasapoğlu Aksoy M, Kösegil Öztürk E. Efficacy of diclofenac & thiocolchioside gel phonophoresis comparison with ultrasound therapy on acute low back pain; a prospective, double-blind, randomized clinical study. ULTRASONICS 2019; 91:201-205. [PMID: 30139568 DOI: 10.1016/j.ultras.2018.08.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 06/29/2018] [Accepted: 08/12/2018] [Indexed: 06/08/2023]
Abstract
PURPOSE To investigate the effect of Phonophoresis (PP) with the combination of nonsteroidal anti-inflammatory drugs (NSAID's) and myorelaxant versus routine Ultrasound (US) treatment with non-therapeutic gel on the patients with acute low back pain (ABP). METHODS Sixty patients with ABP were randomly assigned into 2 groups. In Group 1 (n = 30) US was applied using diclofenac + Thiocolchicoside gel for 10 min and for a total of 10 sessions. In Group 2 (n = 30) the same US protocol was applied with the same setting and timing with Group 1 using US gel that does not contain any pharmaceutical ingredient. Evaluation parameters were Visual numeric scale (VNS), Oswestry Disability Index (ODI), and Shober test. RESULTS Comparison of the results obtained from the two groups before treatment and at second (W2) and sixth weeks (W6) posttreatment showed significant improvement in all parameters in both groups (p < 0.05). Comparison of the groups showed significantly superior improvement in Group 1 for ODI while there was no difference in other parameters at W2. At W6, there was significantly superior improvement in all parameters (p < 0.05) except for Shober test in Group1. CONCLUSION Our results showed that PP treatment is superior than conventional US therapy at short term in ABP patients.
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Affiliation(s)
- L Altan
- Uludağ University Medicine Faculty, Department of Physical Medicine and Rehabilitation, Turkey; University of Health Sciences Bursa Yüksek Ihtisas Training and Research Hospital, Department of Physical Medicine and Rehabilitation, Turkey
| | - M Kasapoğlu Aksoy
- University of Health Sciences Bursa Yüksek Ihtisas Training and Research Hospital, Department of Physical Medicine and Rehabilitation, Turkey.
| | - E Kösegil Öztürk
- University of Health Sciences Bursa Yüksek Ihtisas Training and Research Hospital, Department of Physical Medicine and Rehabilitation, Turkey
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Abstract
The transdermal transport of pharmaceuticals possesses various advantageous properties over conventional drug administration techniques such as oral delivery and hypodermic injections. However, the stratum corneum persists as the main barrier, which impedes percutaneous transport. The ultrasound-based transdermal delivery of therapeutics is one of the techniques that are being investigated to overcome this obstacle. This review outlines the background information pertaining to sonophoresis and then discusses the individual sections of sonophoretic research. These areas include the sonophoretic application of various drugs, dual-frequency sonophoresis, synergistic combinations of transdermal drug delivery techniques, and the use of nanosized carriers in ultrasound-based transdermal delivery. The various challenges associated with sonophoretic drug delivery and trends of future research are also highlighted.
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Affiliation(s)
| | - Boon Mian Teo
- School of Chemistry, Monash University, Clayton, VIC 3800, Australia,
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Vahdatpour B, Mokhtarian A, Raeissadat SA, Dehghan F, Nasr N, Mazaheri M. Enhancement of the Effectiveness of Extracorporeal Shock Wave Therapy with Topical Corticosteroid in Treatment of Chronic Plantar Fasciitis: A Randomized Control Clinical Trial. Adv Biomed Res 2018; 7:62. [PMID: 29862211 PMCID: PMC5952528 DOI: 10.4103/abr.abr_40_17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Chronic recalcitrant plantar fasciitis is a disabling condition. We presumed if shock wave could increase the permeability of skin and facilitate penetration of topical corticosteroid through the skin; the combinational therapeutic effect would be stronger than using shock wave alone. The study purpose was to utilize the synergistic effect of shock wave and topical corticosteroid in treatment of plantar fasciitis. MATERIALS AND METHODS Patients in both groups (n = 40) received four sessions of shock wave with the same protocol at weekly intervals. At 30 min before each session, we used an occlusive dressing of topical clobetasol for the intervention group and Vaseline oil for the control group. Pain severity was assessed with visual analog scale (VAS) and modified Roles and Maudsley score (RMS) at baseline and 1 month and 3 months after intervention. Plantar fascia (PF) thickness was measured with ultrasonography at baseline and 3 months after intervention. RESULTS One month after intervention, VAS morning showed significant improvement in intervention group (P = 0.006) and RMS showed better improvement in intervention group (P = 0.026). There was no significant difference between the two groups after 3 months in RMS or VAS score. PF thickness was decreased significantly in both groups, but it was not significant between the two groups (P = 0.292). CONCLUSIONS This combinational therapy yielded earlier pain reduction and functional improvement than using shock wave alone; topical corticosteroid could enhance the effectiveness of shockwave in short-term in the treatment of recalcitrant plantar fasciitis.
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Affiliation(s)
- Babak Vahdatpour
- From the Department of Physical Medicine and Rehabilitation, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arghavan Mokhtarian
- From the Department of Physical Medicine and Rehabilitation, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Ahmad Raeissadat
- Physical Medicine and Rehabilitation Research Center, School of Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farnaz Dehghan
- From the Department of Physical Medicine and Rehabilitation, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nafiseh Nasr
- Department of Radiology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Mazaheri
- From the Department of Physical Medicine and Rehabilitation, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Goyal AK, Singh R, Chauhan G, Rath G. Non-invasive systemic drug delivery through mucosal routes. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:539-551. [DOI: 10.1080/21691401.2018.1463230] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Amit K. Goyal
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, India
| | - Ranjit Singh
- Department of Pharmaceutics, Shobhit University, Meerut, India
| | - Gaurav Chauhan
- Centre for Nanosciences, Indian Institute of Technology Kanpur, Kanpur, India
- Instituto Tecnologico y de Estudios Superiores de Monterrey, Sensors and Devices Research Group, School of Engineering and Sciences, Monterrey, Mexico
| | - Goutam Rath
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, India
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Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis. Pharmaceutics 2017; 9:pharmaceutics9030029. [PMID: 28817072 PMCID: PMC5620570 DOI: 10.3390/pharmaceutics9030029] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/11/2017] [Accepted: 08/14/2017] [Indexed: 11/17/2022] Open
Abstract
To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)–MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)–MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)–MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)–MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN–MN)—in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid—and intradermal injection of ALN. These findings indicate that ALN(TIP)–MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation.
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Collins DS, Kourtis LC, Thyagarajapuram NR, Sirkar R, Kapur S, Harrison MW, Bryan DJ, Jones GB, Wright JM. Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mechanochemical Drivers. Pharm Res 2017; 34:2000-2011. [PMID: 28707164 PMCID: PMC5579144 DOI: 10.1007/s11095-017-2229-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 07/07/2017] [Indexed: 01/09/2023]
Abstract
The subcutaneous route offers myriad benefits for the administration of biotherapeutics in both acute and chronic diseases, including convenience, cost effectiveness and the potential for automation through closed-loop systems. Recent advances in parenteral administration devices and the use of additives which enhance drug dispersion have generated substantial additional interest in IV to SQ switching studies. Designing pre-clinical and clinical studies using SQ mediated delivery however requires deep understanding of complex inter-related physiologies and transport pathways governing the interstitial matrix, vascular system and lymphatic channels. This expert review will highlight key structural features which contribute to transport and biodistribution in the subcutaneous space and also assess the impact of drug formulations. Based on the rapidly growing interest in the SQ delivery route, a number of potential areas for future development are highlighted, which are likely to allow continued evolution and innovation in this important area.
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Affiliation(s)
- D S Collins
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - L C Kourtis
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - N R Thyagarajapuram
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - R Sirkar
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - S Kapur
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - M W Harrison
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
| | - D J Bryan
- Division of Plastic and Reconstructive Surgery, Lahey Hospital and Medical Center, Burlington, Massachusetts, 01805, USA
| | - G B Jones
- Clinical & Translational Science Institute, Tufts University Medical Center, 800 Washington St, Boston, Massachusetts, 02111, USA.
| | - J M Wright
- Eli Lilly Innovation Center, 450 Kendall Street, Cambridge, Massachusetts, 02142, USA
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Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis. Future Sci OA 2016; 2:FSO110. [PMID: 28031953 PMCID: PMC5137950 DOI: 10.4155/fsoa-2016-0003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/09/2016] [Indexed: 12/30/2022] Open
Abstract
AIMS Osteoarthritis is the most degenerative joint disease. The aim was to investigate the effects of ultrasound using mineral water or aqua sonic gel on severity of knee pain, measured by the visual analog scale and the Western Ontario and McMaster Universities Arthritis Index (WOMAC). MATERIALS AND METHODS Thirty women with bilateral osteoarthritis of the knee were assigned to two groups: ultrasound with mineral water (group 1, n = 15) or with aqua sonic gel (group 2, n = 15). Both groups underwent 4 weeks intervention, three per week. The participants were assessed using the visual analog scale and the WOMAC. Tests were performed before and after interventions. RESULTS Both groups had significantly reduced pain and improved WOMAC compared with preintervention values. DISCUSSION The ultrasound with mineral water group had more pronounced improvement at p-value < 0.001. CONCLUSION Ultrasound with mineral water is preferable in treatment of knee OA.
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Zhao J, Wang Q, Wu J, Shi X, Qi Q, Zheng H, Lang S, Yang L, Zhang D. Therapeutic effects of low-frequency phonophoresis with a Chinese herbal medicine versus sodium diclofenac for treatment of knee osteoarthritis:
a double-blind, randomized, placebo-controlled clinical trial. J TRADIT CHIN MED 2016; 36:613-7. [PMID: 29933529 DOI: 10.1016/s0254-6272(16)30080-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To evaluate the therapeutic effects of low-frequency phonophoresis with a Chinese herbal
medicine (CHM) compared with sodium diclofenac (SD) for knee osteoarthritis (KOA). METHODS In this double-blind, randomized, placebo-controlled trial, 100 KOA patients were assigned
randomly to a placebo group, a CHM group, or SD group. Low-frequency phonophoresis was
used to improve the efficiency of drug delivery. Pain at rest [using a visual analog scale (VAS)], pain
on movement (VAS), and range of motion (degrees) in the three groups were evaluated using
the Western Ontario and McMaster Universities Osteoarthritis Index (WOMACAI) scores. Safety assessments
comprised emergency adverse events, as well as laboratory tests of blood biochemistry, creatinine,
blood urea nitrogen, alanine aminotransferase and aspartate aminotransferase. RESULTS Significant improvements were found after treatment in all outcome measures except stiffness
and range of motion in patients in the CHMP group and SDP group (P < 0.05). No significant differences
in all outcome measures were found between the CHMP group and SDP group. CONCLUSION CHMP and SDP can show good therapeutic effects for KOA in terms of relieving pain
and improving physical function.
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Kathuria H, Li H, Pan J, Lim SH, Kochhar JS, Wu C, Kang L. Large Size Microneedle Patch to Deliver Lidocaine through Skin. Pharm Res 2016; 33:2653-67. [DOI: 10.1007/s11095-016-1991-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/30/2016] [Indexed: 01/15/2023]
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Abstract
Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development.
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Affiliation(s)
- Rima B Shah
- Department of Pharmacology, GMERS Medial College, Gandhinagar, Gujarat, India
| | - Manhar Patel
- Brain Research and Intervention Center, University of Illinois, Chicago, USA
| | - David M Maahs
- Barbara Davis Center for Diabetes, University of Colorado, Denver, USA
| | - Viral N Shah
- Barbara Davis Center for Diabetes, University of Colorado, Denver, USA
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Pires-de-Campos MSM, De Almeida J, Wolf-Nunes V, Souza-Francesconi E, Grassi-Kassisse DM. Ultrasound associated with caffeine increases basal and beta-adrenoceptor response in adipocytes isolated from subcutaneous adipose tissue in pigs. J COSMET LASER THER 2016; 18:116-23. [PMID: 26821226 DOI: 10.3109/14764172.2015.1063659] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND The topical use of caffeine has been indicated for the lipodystrophies treatment as it promotes increased lipolysis. Ultrasound (US) is often used in cutaneous diseases, esthetic conditions, and as a skin permeation enhancer. OBJECTIVE We investigate the lipolytic response of adipocytes isolated from subcutaneous adipose pigs tissue subjected to treatment with topical application of phonophoresis associated with caffeine. METHOD We treated dorsal regions of pigs (Landrace × Large White, 35 days, 15 kg, n = 6) daily for 15 days with gel, gel + US [3 MHz, continuous, 0.2 Wcm(2), 1 min/cm(2), in total 2 min], gel + caffeine (5%w/w), and gel + caffeine + US. We used a fifth untreated region as control. Twenty-four hours after the last application, we isolated the adipocytes of each treated area and quantified the basal and stimulated lipolytic responses to isoprenaline. The results, in μmol glycerol/10(6)cells/60 min, were analyzed with analysis of variance or ANOVA followed by Newman-Keuls test. The value of p < 0.05 was indicative of statistical difference. RESULTS Only the adipocytes isolated from the area treated with caffeine + US showed increased basal lipolysis (0.76 ± 0.26; p = 0.0276) and maximal isoprenaline stimulation (0.38 ± 0.15, p = 0.0029) compared with the other areas. CONCLUSION The results demonstrate that increased lipolysis of caffeine + US is due to an increase in basal and beta-adrenoceptor response by caffeine, and caffeine's effect is local, avoiding unwanted effects.
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Affiliation(s)
- Maria Silvia Mariani Pires-de-Campos
- a Laboratory of Stress Study (LABEEST), Department of Structural and Functional Biology , Biology Institute, University of Campinas (UNICAMP) , Campinas , SP , Brazil.,b Physiotherapy, Faculty of Health Sciences (FACIS) University Methodist of Piracicaba (UNIMEP) , Piracicaba , SP , Brazil
| | - Juliana De Almeida
- a Laboratory of Stress Study (LABEEST), Department of Structural and Functional Biology , Biology Institute, University of Campinas (UNICAMP) , Campinas , SP , Brazil
| | - Valéria Wolf-Nunes
- a Laboratory of Stress Study (LABEEST), Department of Structural and Functional Biology , Biology Institute, University of Campinas (UNICAMP) , Campinas , SP , Brazil
| | - Elaine Souza-Francesconi
- a Laboratory of Stress Study (LABEEST), Department of Structural and Functional Biology , Biology Institute, University of Campinas (UNICAMP) , Campinas , SP , Brazil
| | - Dora Maria Grassi-Kassisse
- a Laboratory of Stress Study (LABEEST), Department of Structural and Functional Biology , Biology Institute, University of Campinas (UNICAMP) , Campinas , SP , Brazil
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Walsh L, Ryu J, Bock S, Koval M, Mauro T, Ross R, Desai T. Nanotopography facilitates in vivo transdermal delivery of high molecular weight therapeutics through an integrin-dependent mechanism. NANO LETTERS 2015; 15:2434-41. [PMID: 25790174 PMCID: PMC4478088 DOI: 10.1021/nl504829f] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Transdermal delivery of therapeutics is restricted by narrow limitations on size and hydrophobicity. Nanotopography has been shown to significantly enhance high molecular weight paracellular transport in vitro. Herein, we demonstrate for the first time that nanotopography applied to microneedles significantly enhances transdermal delivery of etanercept, a 150 kD therapeutic, in both rats and rabbits. We further show that this effect is mediated by remodeling of the tight junction proteins initiated via integrin binding to the nanotopography, followed by phosphorylation of myosin light chain (MLC) and activation of the actomyosin complex, which in turn increase paracellular permeability.
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Affiliation(s)
- Laura Walsh
- Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, 1700 Fourth Street, Room 204, San Francisco, California 94158-2330, United States
| | - Jubin Ryu
- Department of Dermatology, University of California-San Francisco, 1701 Divisadero Street, San Francisco, California 94115, United States
| | - Suzanne Bock
- Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Michael Koval
- Division of Pulmonary, Allergy, and Critical Care Medicine and Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Suite 205, Atlanta, Georgia 30322, United States
| | - Theodora Mauro
- Department of Dermatology, University of California-San Francisco, 1701 Divisadero Street, San Francisco, California 94115, United States
- Department of Dermatology, San Francisco Veterans Affairs Hospital, 4150 Clement Street, San Francisco, California 94121, United States
| | - Russell Ross
- Kimberly-Clark Corporation, 8601 Dunwoody Place, Suite 580, Atlanta, Georgia 30350, United States
| | - Tejal Desai
- Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, 1700 Fourth Street, Room 204, San Francisco, California 94158-2330, United States
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Skin cancer and new treatment perspectives: A review. Cancer Lett 2015; 357:8-42. [DOI: 10.1016/j.canlet.2014.11.001] [Citation(s) in RCA: 195] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 10/31/2014] [Accepted: 11/04/2014] [Indexed: 12/25/2022]
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Murugappan SK, Zhou Y. Transsclera Drug Delivery by Pulsed High-Intensity Focused Ultrasound (HIFU): An Ex Vivo Study. Curr Eye Res 2014; 40:1172-80. [PMID: 25380302 DOI: 10.3109/02713683.2014.980006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED PURPOSE/AIM OF STUDY: Drug delivery to the ocular posterior segment is of importance, but it is a challenge in the treatment of irreversible blindness disease, such as age-related macular degeneration. Although some methods (i.e. intraocular injection, sustained release by polymer and iontophoresis) have been applied, some technical drawbacks, such as slow rate and damage to the eye, need to be overcome for wide use. MATERIALS AND METHODS In this study, the feasibility of high-intensity focused ultrasound (HIFU) to enhance the transsclera drug delivery was tested for the first time. One-hundred HIFU pulses with the driving frequency of 1.1 MHz, acoustic power of 105.6 W, pulse duration of 10-50 ms and pulse repetition frequency of 1 Hz were delivered to the fresh ex vivo porcine sclera specimen. RESULTS In comparison to the passive diffusion (control), 50-ms HIFU can increase the penetration depth by 2.0 folds (501.7 ± 126.4 µm versus 252.4 ± 29.2 µm) using bicinchoninic acid assay and Rhodamine 6 G fluorescence intensity by 3.1 folds (22.4 ± 12.3 versus 7.1 ± 4.1) and coverage area by 2.6 folds (40.4 ± 9.1% versus 15.8 ± 2.9%). No morphological changes on the sonicated sclera samples were found using a surface electron microscope. CONCLUSIONS In summary, pulsed-HIFU may be an effective modality in the transsclera drug delivery with a high transporting rate and depth. In vivo studies are necessary to further evaluate its performance, including the drug penetration and its possible side effects.
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Affiliation(s)
- Suresh Kanna Murugappan
- a Division of Engineering Mechanics , School of Mechanical and Aerospace Engineering, Nanyang Technological University , Singapore
| | - Yufeng Zhou
- a Division of Engineering Mechanics , School of Mechanical and Aerospace Engineering, Nanyang Technological University , Singapore
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Nieminen HJ, Salmi A, Karppinen P, Hæggström E, Hacking SA. The potential utility of high-intensity ultrasound to treat osteoarthritis. Osteoarthritis Cartilage 2014; 22:1784-99. [PMID: 25106678 DOI: 10.1016/j.joca.2014.07.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 07/22/2014] [Accepted: 07/29/2014] [Indexed: 02/02/2023]
Abstract
Osteoarthritis (OA) is a widespread musculoskeletal disease that reduces quality of life and for which there is no cure. The treatment of OA is challenging since cartilage impedes the local and systemic delivery of therapeutic compounds (TCs). This review identifies high-intensity ultrasound (HIU) as a non-contact technique to modify articular cartilage and subchondral bone. HIU enables new approaches to overcome challenges associated with drug delivery to cartilage and new non-invasive approaches for the treatment of joint disease. Specifically, HIU has the potential to facilitate targeted drug delivery and release deep within cartilage, to repair soft tissue damage, and to physically alter tissue structures including cartilage and bone. The localized, non-invasive ultrasonic delivery of TCs to articular cartilage and subchondral bone appears to be a promising technique in the immediate future.
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Affiliation(s)
- H J Nieminen
- Department of Physics, University of Helsinki, Finland.
| | - A Salmi
- Department of Physics, University of Helsinki, Finland.
| | - P Karppinen
- Department of Physics, University of Helsinki, Finland.
| | - E Hæggström
- Department of Physics, University of Helsinki, Finland.
| | - S A Hacking
- Department of Orthopaedics, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
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Saleh RH, Ebade AA, Ibrahim M, Tomerek RH. Transplacental transfer and neonatal influences of sonophoretically administered sufentanil versus epidural sufentanil in labor peridural analgesia: A randomized prospective double-blind contemplate. EGYPTIAN JOURNAL OF ANAESTHESIA 2014. [DOI: 10.1016/j.egja.2014.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
| | | | - Mohamed Ibrahim
- Department of Chemical Analysis and Evaluation, Egyptian Petroleum Research Institute , Egypt
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Katsumi H, Quan YS, Kamiyama F, Kusamori K, Sakane T, Yamamoto A. [Development of a novel transdermal delivery system of peptide and protein drugs using microneedle arrays]. YAKUGAKU ZASSHI 2014; 134:63-7. [PMID: 24389619 DOI: 10.1248/yakushi.13-00221-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.
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Levinsen MT. Saturation of shape instabilities in single-bubble sonoluminescence. PHYSICAL REVIEW. E, STATISTICAL, NONLINEAR, AND SOFT MATTER PHYSICS 2014; 90:013026. [PMID: 25122388 DOI: 10.1103/physreve.90.013026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Indexed: 06/03/2023]
Abstract
Excitation of shape instabilities represents one route to bubble death in single-bubble sonoluminescence. This feature is satisfactorily explained by an expansion to first order in the amplitude of a shape distortion in the form of a spherical harmonic. By taking the expansion to second order, it is found that regions of parameter space exist where the exponential growth into bubble disruption is checked and a saturated stable state of shape distortion is possible. Experimental evidence provided by Mie scattering is presented, and a possible connection to simultaneous spatially anisotropic light emission is discussed.
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Lakshmanan S, Gupta GK, Avci P, Chandran R, Sadasivam M, Jorge AES, Hamblin MR. Physical energy for drug delivery; poration, concentration and activation. Adv Drug Deliv Rev 2014; 71:98-114. [PMID: 23751778 DOI: 10.1016/j.addr.2013.05.010] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Revised: 05/15/2013] [Accepted: 05/31/2013] [Indexed: 12/11/2022]
Abstract
Techniques for controlling the rate and duration of drug delivery, while targeting specific locations of the body for treatment, to deliver the cargo (drugs or DNA) to particular parts of the body by what are becoming called "smart drug carriers" have gained increased attention during recent years. Using such smart carriers, researchers have also been investigating a number of physical energy forces including: magnetic fields, ultrasound, electric fields, temperature gradients, photoactivation or photorelease mechanisms, and mechanical forces to enhance drug delivery within the targeted cells or tissues and also to activate the drugs using a similar or a different type of external trigger. This review aims to cover a number of such physical energy modalities. Various advanced techniques such as magnetoporation, electroporation, iontophoresis, sonoporation/mechnoporation, phonophoresis, optoporation and thermoporation will be covered in the review. Special emphasis will be placed on photodynamic therapy owing to the experience of the authors' laboratory in this area, but other types of drug cargo and DNA vectors will also be covered. Photothermal therapy and theranostics will also be discussed.
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40
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Levinsen MT. Concomitance in single bubble sonoluminescence of period doubling in emission and shape distortion. ULTRASONICS 2014; 54:637-643. [PMID: 24074749 DOI: 10.1016/j.ultras.2013.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 08/30/2013] [Accepted: 09/01/2013] [Indexed: 06/02/2023]
Abstract
We report the first direct observation for a single stable sonoluminescing bubble of a shape instability. Furthermore we show that stable saturation of the shape distortion caused by the instability for a certain range of parameters is experimentally possible and furthermore is directly linked to the curious phenomenon of flash by flash period doubling of the sonoluminescent emission as the afterbounce instability causing the shape distortion is always period doubled whenever the emission is & vice versa.
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Affiliation(s)
- Mogens T Levinsen
- BioComplexity Lab, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK-2100 Copenhagen Ø, Denmark.
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Cobo C, Makosch K, Jung R, Kohlmann K, Knopf K. Enhanced Aeromonas salmonicida bacterin uptake and side effects caused by low frequency sonophoresis in rainbow trout (Oncorhynchus mykiss). FISH & SHELLFISH IMMUNOLOGY 2014; 36:444-452. [PMID: 24378683 DOI: 10.1016/j.fsi.2013.12.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 12/12/2013] [Accepted: 12/18/2013] [Indexed: 06/03/2023]
Abstract
Low frequency sonophoresis (LFS) has been recognized as one of the most advanced technologies in transdermal delivery of substances, due to the modification of the stratum corneum lipid bilayer, in focal skin applications in mammals. Based on these findings, LFS has been suggested as a potential technology to be used for enhancement in immersion fish vaccination. In contrast to mammals where LFS is applied to discrete regions of the skin, in fish the whole individual needs to be exposed for practical purposes. The current study evaluated the impact of LFS at 37 kHz on the uptake of an Aeromonas salmonicida bacterin and side effects of the treatment in rainbow trout. Quantitative real time PCR (qPCR) and immunohistochemistry were used to examine the bacterin uptake into skin and gill tissue. Side effects were assessed by behavioural examination, histology and blood serum analysis. The sonication intensity of 171 mW/cm² was enough for increasing skin permeability, but caused heavy erratic swimming and gill haemorrhages. Sonication intensities as low as 105 mW/cm² did not modify skin permeability and enhanced the bacterin uptake into the gill tissue by factor 15 compared to conventional immersion. Following sonication, the gill permeability for the bacterin decreased after 20 min and 120 min by factor 3 and 2, respectively. However, during sonication, erratic swimming of the fish raised some concerns. Further reduction of the sonication intensity to 57 mW/cm² did not induce erratic swimming, and the bacterin uptake into the gill tissue was still increased by factor 3. In addition, a decreasing albumin-globulin ratio in the serum of the rainbow trout within 40 min revealed that LFS leads to an inflammatory response. Consequently, based on both increased bacterin uptake and the inflammatory response, low intensity LFS has the potential to enhance vaccine immunity without significant side effects.
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Affiliation(s)
- Cristóbal Cobo
- Department of Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Müggelseedamm 310, 12587 Berlin, Germany; Faculty of Agriculture and Horticulture, Humboldt University of Berlin, Invaliden Str. 42, 10115 Berlin, Germany.
| | - Katarzyna Makosch
- Department of Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Müggelseedamm 310, 12587 Berlin, Germany
| | - Rainer Jung
- BANDELIN Electronic GmbH & Co. KG, Heinrichstraße 3-4, 12207 Berlin, Germany
| | - Klaus Kohlmann
- Department of Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Müggelseedamm 310, 12587 Berlin, Germany
| | - Klaus Knopf
- Department of Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Müggelseedamm 310, 12587 Berlin, Germany
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Chen M, Zakrewsky M, Gupta V, Anselmo AC, Slee DH, Muraski JA, Mitragotri S. Topical delivery of siRNA into skin using SPACE-peptide carriers. J Control Release 2014; 179:33-41. [PMID: 24434423 DOI: 10.1016/j.jconrel.2014.01.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/04/2014] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
Abstract
Short-interfering RNAs (siRNAs) offer a potential tool for the treatment of skin disorders. However, applications of siRNA for dermatological conditions are limited by their poor permeation across the stratum corneum of the skin and low penetration into the skin's viable cells. In this study, we report the use of SPACE-peptide in combination with a DOTAP-based ethosomal carrier system to enhance skin delivery of siRNA. A DOTAP-based SPACE Ethosomal System significantly enhanced siRNA penetration into porcine skin in vitro by 6.3±1.7-fold (p<0.01) with an approximately 10-fold (p<0.01) increase in epidermis accumulation of siRNA compared to that from an aqueous solution. Penetration of siRNA was also enhanced at the cellular level. Internalization of SPACE-peptide occurred in a concentration dependent manner marked by a shift in intracellular distribution from punctate spots to diffused cytoplasmic staining at a peptide concentration of 10mg/mL. In vitro delivery of GAPDH siRNA by SPACE peptide led to 83.3±3.0% knockdown relative to the control. In vivo experiments performed using female BALB/C mice also confirmed the efficacy of DOTAP-SES in delivering GAPDH-siRNA into skin. Topical application of DOTAP-SES on mice skin resulted in 63.2%±7.7% of GAPDH knockdown, which was significantly higher than that from GAPDH-siRNA PBS (p<0.05). DOTAP-SES formulation reported here may open new opportunities for cutaneous siRNA delivery.
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Affiliation(s)
- Ming Chen
- Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA
| | - Michael Zakrewsky
- Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA
| | - Vivek Gupta
- Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA
| | - Aaron C Anselmo
- Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA
| | - Deborah H Slee
- Convoy Therapeutics, 405 W Cool Drive, Suite 107, Oro Valley 85704, USA
| | - John A Muraski
- Convoy Therapeutics, 405 W Cool Drive, Suite 107, Oro Valley 85704, USA.
| | - Samir Mitragotri
- Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA; Convoy Therapeutics, 405 W Cool Drive, Suite 107, Oro Valley 85704, USA.
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Alassaf A, Aleid A, Frenkel V. In vitro methods for evaluating therapeutic ultrasound exposures: present-day models and future innovations. J Ther Ultrasound 2013; 1:21. [PMID: 25093079 PMCID: PMC4109267 DOI: 10.1186/2050-5736-1-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 09/09/2013] [Indexed: 11/30/2022] Open
Abstract
Although preclinical experiments are ultimately required to evaluate new therapeutic ultrasound exposures and devices prior to clinical trials, in vitro experiments can play an important role in the developmental process. A variety of in vitro methods have been developed, where each of these has demonstrated their utility for various test purposes. These include inert tissue-mimicking phantoms, which can incorporate thermocouples or cells and ex vivo tissue. Cell-based methods have also been used, both in monolayer and suspension. More biologically relevant platforms have also shown utility, such as blood clots and collagen gels. Each of these methods possesses characteristics that are well suited for various well-defined investigative goals. None, however, incorporate all the properties of real tissues, which include a 3D environment and live cells that may be maintained long-term post-treatment. This review is intended to provide an overview of the existing application-specific in vitro methods available to therapeutic ultrasound investigators, highlighting their advantages and limitations. Additional reporting is presented on the exciting and emerging field of 3D biological scaffolds, employing methods and materials adapted from tissue engineering. This type of platform holds much promise for achieving more representative conditions of those found in vivo, especially important for the newest sphere of therapeutic applications, based on molecular changes that may be generated in response to non-destructive exposures.
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Affiliation(s)
- Ahmad Alassaf
- Department of Biomedical Engineering, Catholic University of America, 620 Michigan Ave NE, Washington, DC 20064, USA
| | - Adham Aleid
- Department of Biomedical Engineering, Catholic University of America, 620 Michigan Ave NE, Washington, DC 20064, USA
| | - Victor Frenkel
- Department of Biomedical Engineering, Catholic University of America, 620 Michigan Ave NE, Washington, DC 20064, USA
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Raphael AP, Primiero CA, Ansaldo AB, Keates HL, Soyer HP, Prow TW. Elongate microparticles for enhanced drug delivery to ex vivo and in vivo pig skin. J Control Release 2013; 172:96-104. [PMID: 23933236 DOI: 10.1016/j.jconrel.2013.07.025] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 06/21/2013] [Accepted: 07/30/2013] [Indexed: 11/17/2022]
Abstract
The delivery of therapeutics and cosmaceuticals into and/or through the skin is hindered by epidermal barriers. To overcome the skin's barriers we have developed a novel cutaneous delivery method using high aspect ratio elongate microparticles (EMPs). Using ex vivo and in vivo pig skin we assess the penetration and delivery characteristics of the elongate microparticles. With reflectance confocal microscopy we observed that the elongate microparticles successfully penetrated the epidermis and upper dermis. Delivery was then assessed using two different length populations of EMPs, comparing their delivery profile to topical alone using sodium fluorescein and confocal microscopy. We observed a relatively uniform and continuous delivery profile in the EMP treated area within the upper layers of the skin--up to seven times greater than topical alone. Finally, we delivered two therapeutically relevant compounds (Vitamins A and B3), showing enhanced delivery using the EMPs. To our knowledge this is the first report using high aspect ratio elongate microparticles in this manner for enhanced topical delivery to the skin.
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Affiliation(s)
- Anthony P Raphael
- Dermatology Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane 4102, QLD, Australia
| | - Clare A Primiero
- Dermatology Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane 4102, QLD, Australia
| | - Alexander B Ansaldo
- Dermatology Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane 4102, QLD, Australia
| | - Helen L Keates
- School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton 4343, QLD, Australia
| | - H Peter Soyer
- Dermatology Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane 4102, QLD, Australia
| | - Tarl W Prow
- Dermatology Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane 4102, QLD, Australia.
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Yaturu S. Insulin therapies: Current and future trends at dawn. World J Diabetes 2013; 4:1-7. [PMID: 23493823 PMCID: PMC3596776 DOI: 10.4239/wjd.v4.i1.1] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 10/17/2012] [Accepted: 01/24/2013] [Indexed: 02/05/2023] Open
Abstract
Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future.
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Shah UU, Roberts M, Orlu Gul M, Tuleu C, Beresford MW. Needle-free and microneedle drug delivery in children: A case for disease-modifying antirheumatic drugs (DMARDs). Int J Pharm 2011; 416:1-11. [DOI: 10.1016/j.ijpharm.2011.07.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 06/30/2011] [Accepted: 07/02/2011] [Indexed: 12/22/2022]
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Mason TJ. Therapeutic ultrasound an overview. ULTRASONICS SONOCHEMISTRY 2011; 18:847-852. [PMID: 21316286 DOI: 10.1016/j.ultsonch.2011.01.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Revised: 01/07/2011] [Accepted: 01/10/2011] [Indexed: 05/30/2023]
Abstract
Therapeutic ultrasound is defined as the use of ultrasound for the treatment of diseased or injured organs or bodily structures and is quite distinct from diagnostic ultrasound. There were many early attempts in the past to use ultrasound in therapy for a variety of applications and while some of these have not been pursued others have led on to clinical applications which are now used routinely. Such progress has been made possible by a number of factors including advances in transducer design, more accurate measurement and calibration of acoustic power and careful experiments to determine the precise nature of chemical processes taking place during and following the exposure of tissue to ultrasound. Major advances have been made in some fields where ultrasound is used such as physiotherapy, surgical instruments, chemotherapy, drug delivery and more recently, high intensity focused ultrasound (HIFU). The last of these has seen enormous activity leading to the formation of the International Society of Therapeutic Ultrasound and a number of very well attended regular specialist meetings. In this review some historical perspectives of therapeutic ultrasound and progress in the field since the early 1990's will be presented.
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Affiliation(s)
- Timothy J Mason
- The Sonochemistry Centre at Coventry University, Faculty of Health and Life Sciences, Priory Street, Coventry CV1 5FB, United Kingdom.
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48
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Qureshi IA, Mehler MF. The emerging role of epigenetics in stroke: III. Neural stem cell biology and regenerative medicine. ACTA ACUST UNITED AC 2011; 68:294-302. [PMID: 21403016 DOI: 10.1001/archneurol.2011.6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain.
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Affiliation(s)
- Irfan A Qureshi
- Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Institute for Brain Disorders and Neural Regeneration, Department of Neurology, Rose F. Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Pkwy S, Room 220, Bronx, NY 10461, USA
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Eraso LH, Reilly MP, Sehgal C, Mohler ER. Emerging diagnostic and therapeutic molecular imaging applications in vascular disease. Vasc Med 2011; 16:145-56. [PMID: 21310769 DOI: 10.1177/1358863x10392474] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic ('theragnostic') approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions.This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage inflammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty.
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Affiliation(s)
- Luis H Eraso
- Cardiovascular Division, Vascular Medicine Section, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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Rapoport N, Nam KH, Gupta R, Gao Z, Mohan P, Payne A, Todd N, Liu X, Kim T, Shea J, Scaife C, Parker DL, Jeong EK, Kennedy AM. Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release 2011; 153:4-15. [PMID: 21277919 DOI: 10.1016/j.jconrel.2011.01.022] [Citation(s) in RCA: 306] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Revised: 01/13/2011] [Accepted: 01/19/2011] [Indexed: 01/08/2023]
Abstract
Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.
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Affiliation(s)
- Natalya Rapoport
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
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