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Sonawane K, Dixit H, Thota N, Mistry T, Balavenkatasubramanian J. "Knowing It Before Blocking It," the ABCD of the Peripheral Nerves: Part B (Nerve Injury Types, Mechanisms, and Pathogenesis). Cureus 2023; 15:e43143. [PMID: 37692583 PMCID: PMC10484240 DOI: 10.7759/cureus.43143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 09/12/2023] Open
Abstract
Selander emphatically said, "Handle these nerves with care," and those words still echo, conveying a loud and clear message that, however rare, peripheral nerve injury (PNI) remains a perturbing possibility that cannot be ignored. The unprecedented nerve injuries associated with peripheral nerve blocks (PNBs) can be most tormenting for the unfortunate patient and a nightmare for the anesthetist. Possible justifications for the seemingly infrequent occurrences of PNB-related PNIs include a lack of documentation/reporting, improper aftercare, or associated legal implications. Although they make up only a small portion of medicolegal claims, they are sometimes difficult to defend. The most common allegations are attributed to insufficient informed consent; preventable damage to a nerve(s); delay in diagnosis, referral, or treatment; misdiagnosis, and inappropriate treatment and follow-up care. Also, sufficient prospective studies or randomized trials have not been conducted, as exploring such nerve injuries (PNB-related) in living patients or volunteers may be impractical or unethical. Understanding the pathophysiology of various types of nerve injury is vital to dealing with them further. Processes like degeneration, regeneration, remyelination, and reinnervation can influence the findings of electrophysiological studies. Events occurring in such a process and their impact during the assessment determine the prognosis and the need for further interventions. This educational review describes various types of PNB-related nerve injuries and their associated pathophysiology.
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Affiliation(s)
- Kartik Sonawane
- Anesthesiology, Ganga Medical Centre and Hospitals, Coimbatore, IND
| | - Hrudini Dixit
- Anesthesiology, Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, IND
| | - Navya Thota
- Anesthesiology, Ganga Medical Centre and Hospitals, Coimbatore, IND
| | - Tuhin Mistry
- Anesthesiology, Ganga Medical Centre and Hospitals, Coimbatore, IND
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Oliveira JD, Rodrigues da Silva GH, de Moura LD, Göethel G, Papini JZB, Casadei BR, Ribeiro LNDM, Cabeça LF, Garcia SC, Martinez EF, Tofoli GR, de Paula E. DoE development of ionic gradient liposomes: A successful approach to improve encapsulation, prolong anesthesia and decrease the toxicity of etidocaine. Int J Pharm 2023; 634:122672. [PMID: 36738810 DOI: 10.1016/j.ijpharm.2023.122672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 01/19/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023]
Abstract
Etidocaine (EDC) is a long-acting local anesthetic of the aminoamide family whose use was discontinued in 2008 for alleged toxicity issues. Ionic gradient liposomes (IGL) are nanostructured carriers for which an inner/outer gradient of ions increases drug upload. This work describes IGLEDC, a formulation optimized by Design of Experiments, composed of hydrogenated soy phosphatidylcholine:cholesterol:EDC, and characterized by DLS, NTA, TEM/Cryo-TEM, DSC and 1H NMR. The optimized IGL showed significant encapsulation efficiency (41 %), good shelf stability (180 days) and evidence of EDC interaction with the lipid bilayer (as seen by DSC and 1H NMR results) that confirms its membrane permeation. In vitro (release kinetics and cytotoxicity) tests showed that the encapsulation of EDC into the IGL promoted sustained release for 24 h and decreased by 50 % the intrinsic toxicity of EDC to Schwann cells. In vivo IGLEDC decreased the toxicity of EDC to Caenorhabditis elegans by 25 % and extended its anesthetic effect by one hour, after infiltrative administration, at clinically used (0.5 %) concentration, in rats. Thus, this novel drug delivery system is a promise for the possible reintroduction of EDC in clinics, aiming at the control of operative and postoperative pain.
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Affiliation(s)
- Juliana Damasceno Oliveira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, SP, Brazil
| | | | - Ludmila David de Moura
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, SP, Brazil
| | - Gabriela Göethel
- Toxicology Laboratory, Pharmacy Faculty, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Juliana Z B Papini
- São Leopoldo Mandic Institute and Research Center, Campinas-São Paulo, Brazil
| | | | | | - Luis Fernando Cabeça
- Department of Chemistry, Federal Technological University of Parana, Londrina, PR, Brazil
| | - Solange Cristina Garcia
- Toxicology Laboratory, Pharmacy Faculty, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | | | | | - Eneida de Paula
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, SP, Brazil.
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Markova L, Cvetko E, Ugwoke CK, Horvat S, Umek N, Stopar Pintarič T. The Influence of Diabetic Peripheral Neuropathy on the Duration of Sciatic Nerve Block with 1.3% Liposomal Bupivacaine and 0.25% Bupivacaine Hydrochloride in a Mouse Model. Pharmaceutics 2022; 14:pharmaceutics14091824. [PMID: 36145571 PMCID: PMC9502724 DOI: 10.3390/pharmaceutics14091824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/05/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
Little is known regarding the pharmacological properties of extended-release local anesthetics in the setting of diabetic peripheral neuropathy. We investigated and compared the duration of sciatic nerve block following administration of clinically relevant concentrations of liposomal bupivacaine (LB) and bupivacaine hydrochloride (BH) in diabetic mice with peripheral neuropathy. In this prospective, randomized, and double-blind study, twenty-four female C57BL/6J-OlaHsd mice were assigned to a streptozotocin-induced type 1 diabetes group and a control group without diabetes. The presence of peripheral neuropathy was established by assessing the duration of thermal latency of the plantar and tail-flick tests, following which both groups were subdivided into two subgroups in which 35 mg/kg of 1.31% LB and 7 mg/kg of 0.25% BH were respectively administered for sciatic nerve block. The average sensory block duration with BH was 106 min and 117.1 min in the control and diabetic groups, respectively. With LB, the average sensory block duration was 118 min in the control mice, while in mice with diabetic peripheral neuropathy, the average block duration was significantly longer and above the 270 min limit set in our study. Accordingly, sensory block duration was longer with LB compared to BH, and diabetic peripheral neuropathy significantly increased sciatic nerve block duration with LB.
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Affiliation(s)
- Liljana Markova
- Department of Anaesthesiology and Surgical Intensive Therapy, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Erika Cvetko
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Chiedozie Kenneth Ugwoke
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Simon Horvat
- Department of Animal Science, Biotechnology and Immunology, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domžale, Slovenia
| | - Nejc Umek
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
- Correspondence:
| | - Tatjana Stopar Pintarič
- Department of Anaesthesiology and Surgical Intensive Therapy, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
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Suo M, Zhao X, Yu G, Zhang W. Lidocaine loaded nanostructured lipid carriers for prolonged local anesthesia: in vitro and in vivo studies. J DISPER SCI TECHNOL 2022. [DOI: 10.1080/01932691.2020.1844739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Meng Suo
- Department of Anesthesiology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Xu Zhao
- Department of Anesthesiology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Guanling Yu
- IVF laboratory, Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
| | - Wenjia Zhang
- Department of Anesthesiology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
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Freitas de Lima F, da Silva BB, Oliveira JD, de Moura LD, Rodrigues da Silva GH, Fernandes PCL, Souza RIC, Dos Santos AC, de Paula E. Prolonged anesthesia and decreased toxicity of enantiomeric-excess bupivacaine loaded in ionic gradient liposomes. Int J Pharm 2021; 606:120944. [PMID: 34324985 DOI: 10.1016/j.ijpharm.2021.120944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 11/26/2022]
Abstract
Bupivacaine is the most employed local anesthetic in surgical procedures, worldwide. Its systemic toxicity has directed the synthesis of the less toxic, S(-) enantiomer. This work describes a formulation of ionic gradient liposomes (IGL) containing S75BVC, an enantiomeric excess mixture of 75% S(-) and 25% R(+) bupivacaine. IGL prepared with 250 mM (NH4)2SO4 in the inner aqueous core of phosphatidylcholine and cholesterol (3:2 mol%) vesicles plus 0.5% S75BVC showed average sizes of 312.5 ± 4.5 nm, low polydispersity (PDI < 0.18), negative zeta potentials (-14.2 ± 0.2 mV) and were stable for 360 days. The encapsulation efficiency achieved with IGLS75BVC (%EE = 38.6%) was higher than with IGL prepared with racemic bupivacaine (IGLRBVC, %EE = 28.3%). TEM images revealed spherical vesicles and µDSC analysis provided evidence on the interaction of the anesthetic with the lipid bilayer. Then, in vitro - release kinetics and cytotoxicity- and in vivo - toxic effects in Zebrafish and biochemical/histopathological analysis plus analgesia in Wistar rats - tests were performed. IGLS75BVC exhibited negligible toxicity against Schwann cells and Zebrafish larvae, and it did not affect biochemical markers or the morphology of rat tissues (heart, brain, cerebellum, sciatic nerve). The in vitro release of S75BVC from IGL was extended from 4 to 24 h, justifying the prolonged anesthetic effect measured in rats (~9 h). The advantages of IGLS75BVC formulation over IGLRBVC and plain bupivacaine formulations (prolonged anesthesia, preferential sensorial blockade, and no toxicity) confirm its potential for clinical use in surgical anesthesia.
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Affiliation(s)
- Fernando Freitas de Lima
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil
| | - Bianca Brandão da Silva
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil
| | - Juliana Damasceno Oliveira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil
| | - Ludmilla David de Moura
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil
| | | | | | | | | | - Eneida de Paula
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil.
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Li W, Zhang G, Wei X. Lidocaine-loaded reduced graphene oxide hydrogel for prolongation of effects of local anesthesia: In vitro and in vivo analyses. J Biomater Appl 2021; 35:1034-1042. [PMID: 33487069 DOI: 10.1177/0885328220988462] [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] [Indexed: 01/01/2023]
Abstract
Lidocaine is widely used as a local anesthetic for alleviation of post-operative pain and for management of acute and chronic painful conditions. Although several approaches are currently used to prolong the duration of action, an effective strategy to achieve neural blockage for several hours remains to be identified. In this study, a lidocaine-loaded Pluronic® F68-reduced graphene oxide hydrogel was developed to achieve sustained release of lidocaine. Fourier transform infrared spectroscopy, X-ray diffraction, and Raman spectroscopy confirmed the synthesis of Pluronic® F68-reduced graphene oxide. Transmission electron microscopy showed wrinkled, flat nanosheets with micelles attached. The developed hydrogel showed desirable pH, viscosity, adhesiveness, hardness, and cohesiveness for topical application. The ex vivo release study demonstrated the ability of the Pluronic® F68-reduced graphene oxide hydrogel to prolong release up to 10 h, owing to the strong π-π interactions between the graphene oxide and the lidocaine. In comparison with a commercial lidocaine ointment, the developed graphene oxide hydrogel showed sustained anesthetic effect in the radiant heat tail flick test and sciatic nerve block model. Thus, this study demonstrates the potential of using Pluronic® F68-reduced graphene oxide nanocarriers to realize prolonged effects of local anesthesia for effective pain management.
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Affiliation(s)
- Weifan Li
- Department of Anesthesiology, Jinan Second People's Hospital, Jinan, China
| | - Guangqi Zhang
- Department of Anesthesiology, Jinan Second People's Hospital, Jinan, China
| | - Xiaoxia Wei
- Department of Anesthesiology, Jinan Second People's Hospital, Jinan, China
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Safety and efficacy concerns of modern strategies of local anesthetics delivery. 3 Biotech 2020; 10:333. [PMID: 32656066 DOI: 10.1007/s13205-020-02309-y] [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: 05/12/2020] [Accepted: 06/18/2020] [Indexed: 10/23/2022] Open
Abstract
In the last few decades, several formulations have evolved to realize better efficacy of administered anesthesia. These innovative formulations have facilitated surgeons to perform operations under purely local anesthesia, which provides extra protection and comfort to patients. Ease of delivery of local anesthesia is the need of the current generation, because some of the standard procedures are performed without the use of any sedative agent. Therefore, we are presenting here the various approaches of administration of local anesthetics by the surgeons. To construct a comprehensive report on various methods of anesthesia, we followed a systematic literature search of bibliographic databases of published articles recently in the international journals and publishers of repute. A comprehensive study of several reports of the field indicates that there are significant progresses towards developing novel formulations of anesthesia drugs as well as strategies of delivery. Among formulations, nanoparticle-based delivery approaches, including polymeric, liposomal, and micellar structures, have offered the much needed efficacy with low toxicity. Therefore, several of such techniques are at various stages of clinical trials. Nanotechnology-based delivery approaches have significantly emerged in recent past due to the low systemic toxicity and better efficacy of the nonconventional local anesthetics. The other methods of local anesthesia delivery such as transdermal, magnetophoresis, electrophoresis, and iontophoresis are frequently used due to them being minimally invasive and locally effective. Therefore, the combination of the nanotechnological methods with above mentioned techniques would significantly enhance the overall process of local anesthesia delivery and efficacy.
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Zhao Z, Lian Y, Zhu Y, Ye H, Liu M, Li J. Depot lidocaine-loaded microemulsion for prolonged local anesthesia: Different efficacy model studies. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2019.101404] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Mosqueira M, Aykut G, Fink RHA. Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes. BMC Anesthesiol 2020; 20:10. [PMID: 31914932 PMCID: PMC6947945 DOI: 10.1186/s12871-019-0926-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022] Open
Abstract
Background The potential mechanism of mepivacaine’s myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level. Therefore, we evaluated mepivacaine’s effects on Ca2+ transient in isolated adult mouse cardiomyocytes. Methods Single ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10 μM fluorescent Ca2+ indicator Fluo-4-AM to record intracellular Ca2+ transients upon electrical stimulation. The mepivacaine effects at half-maximal inhibitory concentration (IC50) was determined on calibrated cardiomyocytes’ Ca2+ transients by non-parametric statistical analyses on biophysical parameters. Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 were used to test a possible mechanism to explain mepivacaine-induced Ca2+ transients’ reduction. Results A significant inhibition at mepivacaine’s IC50 (50 μM) on Ca2+ transients was measured in biophysical parameters such as peak (control: 528.6 ± 73.61 nM vs mepivacaine: 130.9 ± 15.63 nM; p < 0.05), peak area (control: 401.7 ± 63.09 nM*s vs mepivacaine: 72.14 ± 10.46 nM*s; p < 0.05), slope (control: 7699 ± 1110 nM/s vs mepivacaine: 1686 ± 226.6 nM/s; p < 0.05), time to peak (control: 107.9 ± 8.967 ms vs mepivacaine: 83.61 ± 7.650 ms; p < 0.05) and D50 (control: 457.1 ± 47.16 ms vs mepivacaine: 284.5 ± 22.71 ms; p < 0.05). Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 showed a significant increase in the baseline of [Ca2+] and arrhythmic activity upon electrical stimulation. Conclusion At cellular level, mepivacaine blocks Na+ channels, enhancing the reverse mode activity of NCX, leading to a significant reduction of Ca2+ transients. These results suggest a new mechanism for the mepivacaine-reduction contractility effect.
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Affiliation(s)
- Matias Mosqueira
- Cardio-Ventilatory Muscle Physiology Laboratory, Institute of Physiology and Pathophysiology, Heidelberg University Hospital, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
| | - Güçlü Aykut
- Cardio-Ventilatory Muscle Physiology Laboratory, Institute of Physiology and Pathophysiology, Heidelberg University Hospital, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany
| | - Rainer H A Fink
- Cardio-Ventilatory Muscle Physiology Laboratory, Institute of Physiology and Pathophysiology, Heidelberg University Hospital, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany
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Nascimento Vieira AL, Franz-Montan M, Cabeça LF, de Paula E. Anaesthetic benefits of a ternary drug delivery system (Ropivacaine-in-Cyclodextrin-in-Liposomes): in-vitro and in-vivo evaluation. ACTA ACUST UNITED AC 2019; 72:396-408. [PMID: 31859378 DOI: 10.1111/jphp.13211] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/16/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVES To evaluate whether a ternary system composed of hydroxypropyl-β-cyclodextrin (HP-βCD) further encapsulated into egg phosphatidylcholine liposomes (LUV) could prolong the action and reduce the toxicity of ropivacaine (RVC). METHODS Dynamic light scattering and NMR were used to characterize the inclusion complex (RVC : HP-βCD), liposomal (RVC : LUV) and ternary (LUV : RVC : HP-βCD) systems containing 0.25% RVC. Their encapsulation efficiency, release kinetics, in-vitro cytotoxicity and in-vivo anaesthetic effect (paw-withdraw tests in mice) were also evaluated. KEY FINDINGS 1 : 1 RVC : HP-βCD inclusion complex was encapsulated in liposomes (220.2 ± 20.3 nm size, polydispersity <0.25, zeta potentials = -31.7 ± 1.4 mV). NMR (diffusion-ordered spectroscopy (DOSY)) revealed stronger anaesthetic binding to LUV : RVC : HP-βCD (Ka = 342 m-1 ) than to RVC : HP-βCD (Ka = 128 m-1 ) or liposomal formulation (Ka = 22 m-1 ). The formulations promoted in-vitro sustained drug release and partially reverted the cytotoxicity of RVC against 3T3 fibroblasts in the profile: LUV : RVC : HP-βCD ≥ RVC : HP-βCD > RVC : LUV. Accordingly, in-vivo sensory block of free RVC (180 min) was prolonged ca. 1.7 times with the ternary system and RVC : HP-βCD (300 min) and 1.3 times with RVC : LUV (240 min). CONCLUSIONS These results confirm the suitability of this double-carrier system in clinical practice, to decrease the toxicity and prolong the anaesthesia time evoked by RVC.
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Affiliation(s)
- Ana Laís Nascimento Vieira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas - Unicamp, Campinas, Brazil
| | - Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas - Unicamp, Piracicaba, Brazil
| | - Luís Fernando Cabeça
- Department of Chemistry, Federal Technological University of Paraná, Londrina, Brazil
| | - Eneida de Paula
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas - Unicamp, Campinas, Brazil
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de Almeida ACP, Pinto LMA, Alves GP, Ribeiro LNDM, Santana MHA, Cereda CMS, Fraceto LF, de Paula E. Liposomal-based lidocaine formulation for the improvement of infiltrative buccal anaesthesia. J Liposome Res 2018; 29:66-72. [PMID: 29969062 DOI: 10.1080/08982104.2018.1483947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study describes the encapsulation of the local anaesthetic lidocaine (LDC) in large unilamellar liposomes (LUV) prepared in a scalable procedure, with hydrogenated soybean phosphatidylcholine, cholesterol and mannitol. Structural properties of the liposomes were assessed by dynamic light scattering, nanoparticle tracking analysis and transmission electron microscopy. A modified, two-compartment Franz-cell system was used to evaluate the release kinetics of LDC from the liposomes. The in vivo anaesthetic effect of liposomal LDC 2% (LUVLDC) was compared to LDC 2% solution without (LDCPLAIN) or with the vasoconstrictor epinephrine (1:100 000) (LDCVASO), in rat infraorbital nerve blockade model. The structural characterization revealed liposomes with spherical shape, average size distribution of 250 nm and low polydispersity even after LDC incorporation. Zeta potential laid around -30 mV and the number of suspended liposomal particles was in the range of 1012 vesicles/mL. Also the addition of cryoprotectant (mannitol) did not provoke structural changes in liposomes properties. In vitro release profile of LDC from LUV fits well with a biexponential model, in which the LDC encapsulated (EE% = 24%) was responsible for an increase of 67% in the release time in relation to LDCPLAIN (p < 0.05). Also, the liposomal formulation prolonged the sensorial nervous blockade duration (∼70 min), in comparison with LDCPLAIN (45 min), but less than LDCVASO (130 min). In this context, this study showed that the liposomal formulations prepared by scalable procedure were suitable to promote longer and safer buccal anaesthesia, avoiding side effects of the use of vasoconstrictors.
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Affiliation(s)
- Ana Cláudia Pedreira de Almeida
- a Department of Biochemistry and Tissue Biology, Institute of Biology , University of Campinas-UNICAMP , Campinas , Brazil.,b Faculty of Odontology , Federal University of Alfenas - UNIFAL , Alfenas , Brazil
| | | | - Giuliana Piovesan Alves
- c Department of Chemistry , Federal University of Lavras , Lavras , Brazil.,d Cristália Produtos Químicos e Farmacêuticos Ltda , Itapira , Brazil
| | - Lígia Nunes de Morais Ribeiro
- a Department of Biochemistry and Tissue Biology, Institute of Biology , University of Campinas-UNICAMP , Campinas , Brazil
| | | | - Cíntia Maria Saia Cereda
- a Department of Biochemistry and Tissue Biology, Institute of Biology , University of Campinas-UNICAMP , Campinas , Brazil
| | | | - Eneida de Paula
- a Department of Biochemistry and Tissue Biology, Institute of Biology , University of Campinas-UNICAMP , Campinas , Brazil
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Emelife PI, Eng MR, Menard BL, Myers AS, Cornett EM, Urman RD, Kaye AD. Adjunct medications for peripheral and neuraxial anesthesia. Best Pract Res Clin Anaesthesiol 2018; 32:83-99. [PMID: 30322466 DOI: 10.1016/j.bpa.2018.06.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Regional and neuraxial anesthesia can provide a safer perioperative experience, greater satisfaction, reduced opioid consumption, and reduction of pain, while minimizing side effects. Ultrasound technology has aided clinicians in depositing local anesthetic medication in precise proximity to targeted peripheral nerves. There are a plethora of adjuvants that have been utilized to prolong local anesthetic actions and enhance effects in peripheral nerve blocks. This manuscript describes the current state of the use of adjuncts, e.g., dexmedetomidine, dexamethasone, clonidine, epinephrine, etc., in regional anesthesia. Additionally, evidence behind dosing and block prolongation is summarized along with patient outcomes, adverse effects, and future directions.
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Affiliation(s)
- Patrick Ifesinachi Emelife
- Department of Anesthesiology, LSU Health Sciences Center, Room 653, 1542 Tulane Ave., New Orleans, LA, 70112, USA.
| | - Matthew R Eng
- Department of Anesthesiology, LSU Health Sciences Center, Room 656, 1542 Tulane Ave., New Orleans, LA, 70112, USA.
| | - Bethany L Menard
- Department of Anesthesiology, LSU Health Sciences Center, Room 656, 1542 Tulane Ave., New Orleans, LA, 70112, USA.
| | - Andrew S Myers
- LSU Health Sciences Center, 433 Bolivar St., New Orleans, LA, 70112, USA.
| | - Elyse M Cornett
- Department of Anesthesiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA.
| | - Richard D Urman
- Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA.
| | - Alan D Kaye
- Department of Anesthesiology, LSU Health Sciences Center, Room 653, 1542 Tulane Ave., New Orleans, LA, 70112, USA.
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Swain A, Nag DS, Sahu S, Samaddar DP. Adjuvants to local anesthetics: Current understanding and future trends. World J Clin Cases 2017; 5:307-323. [PMID: 28868303 PMCID: PMC5561500 DOI: 10.12998/wjcc.v5.i8.307] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 05/03/2017] [Accepted: 05/19/2017] [Indexed: 02/05/2023] Open
Abstract
Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans).
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Akkari AC, Papini JZB, Garcia GK, Franco MKD, Cavalcanti LP, Gasperini A, Alkschbirs MI, Yokaichyia F, de Paula E, Tófoli GR, de Araujo DR. Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 68:299-307. [DOI: 10.1016/j.msec.2016.05.088] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 04/06/2016] [Accepted: 05/20/2016] [Indexed: 11/28/2022]
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Zorzetto L, Brambilla P, Marcello E, Bloise N, De Gregori M, Cobianchi L, Peloso A, Allegri M, Visai L, Petrini P. From micro- to nanostructured implantable device for local anesthetic delivery. Int J Nanomedicine 2016; 11:2695-709. [PMID: 27354799 PMCID: PMC4907738 DOI: 10.2147/ijn.s99028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release.
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Affiliation(s)
- Laura Zorzetto
- Department of Chemistry, Materials and Chemical Engineering 'G. Natta', Politecnico di Milano, Milan, Italy
| | - Paola Brambilla
- Department of Chemistry, Materials and Chemical Engineering 'G. Natta', Politecnico di Milano, Milan, Italy
| | - Elena Marcello
- Department of Chemistry, Materials and Chemical Engineering 'G. Natta', Politecnico di Milano, Milan, Italy
| | - Nora Bloise
- Department of Molecular Medicine, Centre for Health Technologies (CHT), INSTM UdR of Pavia, University of Pavia, Pavia, Italy
| | - Manuela De Gregori
- Pain Therapy Service, IRCCS Foundation Policlinico San Matteo Pavia, Pavia, Italy
| | - Lorenzo Cobianchi
- General Surgery Department, IRCCS Foundation Policlinico San Matteo, Pavia, Italy; Departments of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Andrea Peloso
- General Surgery Department, IRCCS Foundation Policlinico San Matteo, Pavia, Italy; Departments of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Massimo Allegri
- Department of Surgical Sciences, University of Parma, Parma, Italy
| | - Livia Visai
- Department of Molecular Medicine, Centre for Health Technologies (CHT), INSTM UdR of Pavia, University of Pavia, Pavia, Italy; Department of Occupational Medicine, Toxicology and Environmental Risks, S. Maugeri Foundation, IRCCS, Lab of Nanotechnology, Pavia, Italy
| | - Paola Petrini
- Department of Chemistry, Materials and Chemical Engineering 'G. Natta', Politecnico di Milano, Milan, Italy
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Cereda CMS, Guilherme VA, Alkschbirs MI, de Brito Junior RB, Tofoli GR, Franz-Montan M, de Araujo DR, de Paula E. Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model. J Liposome Res 2016; 27:74-82. [DOI: 10.3109/08982104.2016.1160924] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Cintia Maria Saia Cereda
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, São Paulo, Brazil,
| | - Viviane Aparecida Guilherme
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, São Paulo, Brazil,
| | - Melissa Inger Alkschbirs
- Department of Physical Chemistry, Institute of Chemistry, State University of Campinas, Campinas, São Paulo, Brazil,
| | - Rui Barbosa de Brito Junior
- Department of Molecular Biology, São Leopoldo Mandic Dental Research Institute, Campinas, São Paulo, Brazil,
| | - Giovana Radomille Tofoli
- Department of Molecular Biology, São Leopoldo Mandic Dental Research Institute, Campinas, São Paulo, Brazil,
| | - Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, São Paulo, Brazil, and
| | | | - Eneida de Paula
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, São Paulo, Brazil,
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Ferreira LEN, Muniz BV, dos Santos CP, Volpato MC, de Paula E, Groppo FC. Comparison of liposomal and 2-hydroxypropyl-β-cyclodextrin–lidocaine on cell viability and inflammatory response in human keratinocytes and gingival fibroblasts. J Pharm Pharmacol 2016; 68:791-802. [DOI: 10.1111/jphp.12552] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 02/29/2016] [Indexed: 01/27/2023]
Abstract
Abstract
Objectives
The aim of this study was to observe the effect multilamellar liposomes (MLV) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in the in-vitro effects of lidocaine in cell viability, pro-inflammatory cytokines and prostaglandin E2 release of both human keratinocytes (HaCaT) and gingival fibroblasts (HGF) cells.
Methods
HaCaT and HGF cells were exposed to lidocaine 100–1 μm in plain, MLV and HP-β-CD formulations for 6 h or 24 h. The formulation effects in cell viability were measured by XTT assay and by fluorescent labelling. Cytokines (IL-8, IL-6 and TNF-α) and PGE2 release were quantified by ELISA.
Key findings
MLV and HP-β-CD formulations did not affect the HaCaT viability, which was significantly decreased by plain lidocaine after 24 h of exposure. Both drug carriers increased all cytokines released by HGF after 24-h exposure, and none of the carriers was able to reduce the PGE2 release induced by lidocaine.
Conclusion
The effect of drug carrier in the lidocaine effects was dependent on the cell type, concentration and time of exposure. MLV and HP-β-CD showed benefits in improving cell viability; however, both of them showed a tendency to increase cytokine release when compared to the plain solution.
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Affiliation(s)
- Luiz Eduardo Nunes Ferreira
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
| | - Bruno Vilela Muniz
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
| | - Cleiton Pita dos Santos
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
| | - Maria Cristina Volpato
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
| | - Eneida de Paula
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
| | - Francisco Carlos Groppo
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Piracicaba, São Paulo, Brazil
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Silva CMGD, Fraceto LF, Franz-Montan M, Couto VM, Casadei BR, Cereda CMS, de Paula E. Development of egg PC/cholesterol/α-tocopherol liposomes with ionic gradients to deliver ropivacaine. J Liposome Res 2015; 26:1-10. [DOI: 10.3109/08982104.2015.1022555] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Ulery BD, Kan HM, Williams BA, Narasimhan B, Lo KWH, Nair LS, Laurencin CT. Facile fabrication of polyanhydride/anesthetic nanoparticles with tunable release kinetics. Adv Healthc Mater 2014; 3:843-7. [PMID: 24376136 DOI: 10.1002/adhm.201300521] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/02/2013] [Indexed: 02/06/2023]
Abstract
This work illustrates a two-step strategy for the fabrication of polymer/drug nanoparticles. Utilizing solvent/non-solvent precipitation and gaseous basification, composite nanoparticles with 0-100% drug loadings are fabricated. Drug release kinetics are dictated by nanoparticle composition allowing future tuning for therapeutic applications.
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Affiliation(s)
- Bret D Ulery
- Institute for Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
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de Paula E, Cereda CMS, Fraceto LF, de Araújo DR, Franz-Montan M, Tofoli GR, Ranali J, Volpato MC, Groppo FC. Micro and nanosystems for delivering local anesthetics. Expert Opin Drug Deliv 2012; 9:1505-24. [DOI: 10.1517/17425247.2012.738664] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Weiniger CF, Golovanevski L, Domb AJ, Ickowicz D. Extended release formulations for local anaesthetic agents. Anaesthesia 2012; 67:906-16. [PMID: 22607613 DOI: 10.1111/j.1365-2044.2012.07168.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Systemic toxicity through overdose of local anaesthetic agents is a real concern. By encapsulating local anaesthetics in biodegradable carriers to produce a system for prolonged release, their duration of action can be extended. This encapsulation should also improve the safety profile of the local anaesthetic as it is released at a slower rate. Work with naturally occurring local anaestheticss has also shown promise in the area of reducing systemic and neurotoxicity. Extended duration local anaesthetic formulations in current development or clinical use include liposomes, hydrophobic based polymer particles such as Poly(lactic-co-glycolic acid) microspheres, pasty injectable and solid polymers like Poly(sebacic-co-ricinoleic acid) P(SA:RA) and their combination with synthetic and natural local anaesthetic. Their duration of action, rationale and limitations are reviewed. Direct comparison of the different agents is limited by their chemical properties, the drug doses encapsulated and the details of in vivo models described.
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Affiliation(s)
- C F Weiniger
- Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Centre, Jerusalem, Israel.
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Tofoli GR, Cereda CMS, Araújo DR, Franz-Montan M, Groppo FC, Quaglio D, Pedrazzoli Junior J, Calafatti SA, Barros FAP, de Paula E. Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers. J Pharm Pharmacol 2011; 64:397-403. [DOI: 10.1111/j.2042-7158.2011.01425.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Abstract
Objectives
The pharmacokinetics of commercial and liposome-encapsulated mepivacaine (MVC) injected intra-orally in healthy volunteers was studied.
Methods
In this double blind, randomized cross-over study, 15 volunteers received, at four different sessions, 1.8 ml of the following formulations: 2% MVC with 1 : 100 000 epinephrine (MVC2%EPI), 3% MVC (MVC3%), 2% and 3% liposome-encapsulated MVC (MVC2%LUV and MVC3%LUV). Blood samples were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after injections. Liquid chromatography-tandem mass spectrometry was used to quantify plasma MVC concentrations.
Results
Pharmacokinetic analysis showed that the maximum plasma concentration (Cmax) and the areas under the curves (AUC0–360 and AUC0–∞) after MVC2%LUV and MVC2%EPI injections were smaller (P < 0.05) than the equivalent figures for MVC3% and MVC3%LUV. The time to maximum plasma concentration (Tmax) and the half-life of elimination (t½beta) obtained after the treatment with MVC2%LUV, MVC2%EPI, MVC3% and MVC3%LUV presented no statistically significant differences (P > 0.05). Cmax, AUC0–360 and AUC0-∞ after injection of the 2% formulations (MVC2%LUV and MVC2%EPI) did not exhibit statistically significant differences (P > 0.05). The pharmacokinetics of MVC2%LUV were comparable to the pharmacokinetics of MVC2%EPI.
Conclusion
The liposomal formulation of 2% MVC exhibits similar systemic absorption to the local anesthetic with vasoconstrictor.
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Affiliation(s)
| | - Cíntia M S Cereda
- Department of Biochemistry, State University of Campinas, Institute of Biology, Campinas, São Paulo, Brazil
| | | | - Michelle Franz-Montan
- Department of Biochemistry, State University of Campinas, Institute of Biology, Campinas, São Paulo, Brazil
| | - Francisco Carlos Groppo
- Piracicaba Dental School, Department of Physiological Sciences, State University of Campinas, Piracicaba, São Paulo, Brazil
| | - Daiane Quaglio
- CORE, Laboratory of Clinical Analysis, Bragança Paulista, São Paulo, Brazil
| | | | | | | | - Eneida de Paula
- Department of Biochemistry, State University of Campinas, Institute of Biology, Campinas, São Paulo, Brazil
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Study of benznidazole–cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity. J INCL PHENOM MACRO 2011. [DOI: 10.1007/s10847-011-0077-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Poly(Lactide-co-Glycolide) Nanocapsules Containing Benzocaine: Influence of the Composition of the Oily Nucleus on Physico-Chemical Properties and Anesthetic Activity. Pharm Res 2011; 28:1984-94. [DOI: 10.1007/s11095-011-0425-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 03/08/2011] [Indexed: 11/25/2022]
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25
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Grillo R, Pereira ADES, de Melo NFS, Porto RM, Feitosa LO, Tonello PS, Dias Filho NL, Rosa AH, Lima R, Fraceto LF. Controlled release system for ametryn using polymer microspheres: preparation, characterization and release kinetics in water. JOURNAL OF HAZARDOUS MATERIALS 2011; 186:1645-51. [PMID: 21215514 DOI: 10.1016/j.jhazmat.2010.12.044] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 11/25/2010] [Accepted: 12/10/2010] [Indexed: 05/22/2023]
Abstract
The purpose of this work was to develop a modified release system for the herbicide ametryn by encapsulating the active substance in biodegradable polymer microparticles produced using the polymers poly(hydroxybutyrate) (PHB) or poly(hydroxybutyrate-valerate) (PHBV), in order to both improve the herbicidal action and reduce environmental toxicity. PHB or PHBV microparticles containing ametryn were prepared and the efficiencies of herbicide association and loading were evaluated, presenting similar values of approximately 40%. The microparticles were characterized by scanning electron microscopy (SEM), which showed that the average sizes of the PHB and PHBV microparticles were 5.92±0.74 μm and 5.63±0.68 μm, respectively. The ametryn release profile was modified when it was encapsulated in the microparticles, with slower and more sustained release compared to the release profile of pure ametryn. When ametryn was associated with the PHB and PHBV microparticles, the amount of herbicide released in the same period of time was significantly reduced, declining to 75% and 87%, respectively. For both types of microparticle (PHB and PHBV) the release of ametryn was by diffusion processes due to anomalous transport (governed by diffusion and relaxation of the polymer chains), which did not follow Fick's laws of diffusion. The results presented in this paper are promising, in view of the successful encapsulation of ametryn in PHB or PHBV polymer microparticles, and indications that this system may help reduce the impacts caused by the herbicide, making it an environmentally safer alternative.
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Affiliation(s)
- Renato Grillo
- Department of Environmental Engineering, Univ Estadual Paulista, Avenida Três de Março, n° 511, CEP 18087-180 Sorocaba, SP, Brazil
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Weiniger CF, Golovanevski M, Sokolsky-Papkov M, Domb AJ. Review of prolonged local anesthetic action. Expert Opin Drug Deliv 2010; 7:737-52. [PMID: 20408748 DOI: 10.1517/17425241003767383] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
IMPORTANCE OF THE FIELD Pain following surgery is often treated by local anesthetic agents. Duration of the analgesia can be extended safely following administration of encapsulated large doses of local anesthetic agents. AREAS COVERED IN THIS REVIEW This review considers formulations used for encapsulation of local anesthetic agents for prolonged anesthesia effect. All studies describing encapsulation of a commercial local anesthetic agent for providing prolonged analgesia were considered using the NCBI Medline site. of local anesthetic, prolonged anesthesia, polymers and liposomes were entered in order to retrieve appropriate articles and reviews from 1966 to 2010, with emphasis on the last 10 years. Reference pages were searched manually for other relevant articles. The topics covered include an overview of local anesthetic agents and a review of local anesthetic carrier agents, with emphasis on liposomes and polymer carriers. Articles were limited to the English language. WHAT THE READER WILL GAIN The current research areas for prolongation of local anesthetic effect are evaluated, along with their limitations. Each topic has been summarized, and the review has attempted to cover all current laboratory and clinical studies in a simple manner that should also be useful for readers without a pharmacology background. The direction of research is promising and exciting, and this review should be a useful up-to-date reference. TAKE HOME MESSAGE Many formulations including polymer and liposome carriers have facilitated prolonged local anesthetic action for several days, although few clinical studies have been performed. This field promises a safe way to deliver local anesthetics for effect far beyond that of commercially available agents, with potential cost and health benefits for patients suffering chronic or postoperative pain.
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Affiliation(s)
- Carolyn F Weiniger
- Hadassah Hebrew University Medical Center, Department of Anesthesiology and Critical Care Medicine, Jerusalem, POB 12000, Israel.
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Tomoyasu Y, Yasuda T, Maeda S, Higuchi H, Miyawaki T. Liposome-encapsulated midazolam for oral administration. J Liposome Res 2010; 21:166-72. [DOI: 10.3109/08982104.2010.498002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Franz-Montan M, Silva ALR, Fraceto LF, Volpato MC, Paula ED, Ranali J, Groppo FC. Liposomal encapsulation improves the duration of soft tissue anesthesia but does not induce pulpal anesthesia. J Clin Anesth 2010; 22:313-7. [PMID: 20542419 DOI: 10.1016/j.jclinane.2010.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2008] [Revised: 08/11/2009] [Accepted: 03/22/2010] [Indexed: 11/29/2022]
Abstract
STUDY OBJECTIVE To compare the topical and the pulpal anesthesia efficacy of liposomal and plain benzocaine formulations. DESIGN Double-blinded, randomized crossover study. SETTING University ambulatory dental center. PATIENTS 30 ASA physical status I volunteers. INTERVENTIONS Volunteers received, in three different sessions, topical application of liposome-encapsulated 10% benzocaine (LB10), 10% benzocaine gel (B10), and 20% benzocaine gel (B20) in the right maxillary canine mucobuccal fold. MEASUREMENTS Pain associated with the needle insertion was rated by visual analog scale (VAS) and the duration of topical anesthesia was recorded. Pulpal anesthesia was evaluated using an electric pulp tester. MAIN RESULTS VAS values (median, 1st - 3rd quartiles) were 17 cm (11 - 25), 14 cm (3 - 22), and 21 cm (9 - 21) for B10, LB10, and B20, respectively. No differences were noted among the groups (Friedman test; P = 0.58). Soft tissue anesthesia was also not different. The LB10 [10 (8 - 12) min] showed longer soft tissue anesthesia (Friedman test; P < 0.01) than the other agents [B10 = 8 (5 - 10) min, and B20 = 7 (6 - 9) min]. None of the topical benzocaine formulations tested induced pulpal anesthesia. CONCLUSIONS The encapsulation of benzocaine into liposome increased the duration of soft tissue anesthesia. However, it did not induce pulpal anesthesia.
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Affiliation(s)
- Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dentistry School, State University of Campinas - UNICAMP, 13414-903 Piracicaba, São Paulo, Brazil
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Tofoli GR, Cereda CM, Groppo FC, Volpato MC, Franz-Montan M, Ranali J, de Araújo DR, de Paula E. Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers. J Liposome Res 2010; 21:88-94. [DOI: 10.3109/08982104.2010.483596] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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30
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Wiziack Zago PM, Baroni DB, Groppo FC, de Paula E, Ranali J, Volpato MC. Anesthetic efficacy of liposomal prilocaine in maxillary infiltration anesthesia. J Liposome Res 2010; 21:81-7. [DOI: 10.3109/08982101003754393] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Grillo R, de Melo NFS, de Araújo DR, de Paula E, Rosa AH, Fraceto LF. Polymeric alginate nanoparticles containing the local anesthetic bupivacaine. J Drug Target 2010; 18:688-99. [DOI: 10.3109/10611861003649738] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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de Araujo DR, Cereda CMS, Brunetto GB, Vomero VU, Pierucci A, Neto HS, de Oliveira ALR, Fraceto LF, Braga ADFDA, de Paula E. Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine. J Pharm Pharmacol 2010. [DOI: 10.1211/jpp.60.11.0005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Abstract
This study reports an investigation of the pharmacological activity, cytotoxicity and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and α-tocopherol (4:3:0.07, mole%). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVCPLAIN) and liposomal RVC (RVCLUV) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 ± 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P < 0.001) from liposomes. RVCLUV presented reduced cytotoxicity (P < 0.001) when compared with RVCPLAIN. Treatment with RVCLUV increased the duration (P < 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4–1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVCPLAIN. Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVCPLAIN or RVCluv at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVCLUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent.
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Affiliation(s)
- Daniele Ribeiro de Araujo
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Cintia Maria Saia Cereda
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Giovanna Bruschini Brunetto
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Viviane Urbini Vomero
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Amauri Pierucci
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Humberto Santo Neto
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | | | - Leonardo Fernandes Fraceto
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
- Department of Environmental Engineering, State University of São Paulo - UNESP, Sorocaba, SP, Brazil
| | | | - Eneida de Paula
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
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Tofoli GR, Saia Cereda CM, de Araujo DR, Paula ED, Brito Júnior RB, Júnior JP, Meurer E, Proença Barros FA, Groppo FC, Volpato MC, Ranali J. Pharmacokinetic and local toxicity studies of liposome-encapsulated and plain mepivacaine solutions in rats. Drug Deliv 2010; 17:68-76. [DOI: 10.3109/10717540903508995] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS. Prolonged duration local anesthesia with minimal toxicity. Proc Natl Acad Sci U S A 2009; 106:7125-30. [PMID: 19365067 PMCID: PMC2678453 DOI: 10.1073/pnas.0900598106] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2009] [Indexed: 11/18/2022] Open
Abstract
Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague-Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.
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Affiliation(s)
- Hila Epstein-Barash
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115
- Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Iris Shichor
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115
- Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Albert H. Kwon
- Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Sherwood Hall
- Chemical Contaminants Branch HFS-716, Division of Bioanalytical Chemistry Office of Regulatory Science, U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition, 5100 Paint Branch Parkway, College Park, MD 20740; and
| | - Michael W. Lawlor
- Program in Genomics, Department of Medicine, Children's Hospital Boston, Boston, MA 02115
| | - Robert Langer
- Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Daniel S. Kohane
- Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115
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Cereda CMS, Tófoli GR, de Brito Junior RB, de Jesus MB, Fraceto LF, Groppo FC, de Araujo DR, de Paula E. Stability and local toxicity evaluation of a liposomal prilocaine formulation. J Liposome Res 2009; 18:329-39. [PMID: 18991066 DOI: 10.1080/08923970802500067] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
This study reports a physicochemical stability evaluation of a previously reported liposomal prilocaine (PLC(LUV)) formulation (Cereda et al. J. Pharm. Pharmaceut. Sci. 7:235, 2004) before and after steam sterilization as well as its local toxicity evaluation. Prilocaine (PLC) was encapsulated into extruded unilamellar liposomes (LUVs) composed by egg phosphatidylcholine:cholesterol:alfa-tocopherol (4:3:0.07, mole %). Laser light-scattering analysis (p > 0.05) and thiobarbituric acid reaction (p > 0.05) were used to evaluate the liposomes physical (size) and chemical (oxidation) stability, respectively. The prilocaine chemical stability was followed by (1)H-nuclear magnetic resonance. These tests detected no differences on the physicochemical stability of PLC or PLC(LUV), sterilized or not, up to 30 days after preparation (p > 0.05). Finally, the paw edema test and histological analysis of rat oral mucosa were used to assess the possible inflammatory effects of PLC(LUV). PLC(LUV) did not evoke rat paw edema (p > 0.05), and no significant differences were found in histological analysis, when compared to the control groups (p > 0.05). The present work shows that PLC(LUV) is stable for a 30-day period and did not induce significant inflammatory effects both in the paw edema test and in histological analysis, giving supporting evidence for its safety and possible clinical use in dentistry.
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Affiliation(s)
- Cintia M Saia Cereda
- Department of Biochemistry, Institute of Biology, State University of Campinas, Campinas, São Paulo, Brazil
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Sokolsky-Papkov M, Golovanevski L, Domb AJ, Weiniger CF. Prolonged Local Anesthetic Action Through Slow Release from Poly(Lactic Acid Co Castor Oil). Pharm Res 2008; 26:32-9. [DOI: 10.1007/s11095-008-9699-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2008] [Accepted: 07/25/2008] [Indexed: 10/21/2022]
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de Araujo DR, Tsuneda SS, Cereda CM, Del G.F. Carvalho F, Preté PS, Fernandes SA, Yokaichiya F, Franco MK, Mazzaro I, Fraceto LF, de F.A. Braga A, de Paula E. Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-β-cyclodextrin inclusion complex. Eur J Pharm Sci 2008; 33:60-71. [DOI: 10.1016/j.ejps.2007.09.010] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Revised: 09/11/2007] [Accepted: 09/28/2007] [Indexed: 11/30/2022]
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Hydroxymethylnitrofurazone:dimethyl-beta-cyclodextrin inclusion complex: a physical-chemistry characterization. J Biol Phys 2007; 33:445-53. [PMID: 19669530 DOI: 10.1007/s10867-008-9054-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Accepted: 01/03/2008] [Indexed: 10/22/2022] Open
Abstract
Hydroxymethylnitrofurazone (NFOH) is active against Trypanosoma cruzi; however, its low solubility and high toxicity precludes its current use in treatment of parasitosis. Cyclodextrin can be used as a drug carrier system, as it is able to form inclusion (host-guest) complexes with a wide variety of organic (guest) molecules. Several reports have shown the interesting use of modified beta-cyclodextrins in pharmaceutical formulation, to improve the bioavailability of drugs and to decrease their toxicity. The aim of this work was to characterize inclusion complexes formed between NFOH and dimethyl-beta-cyclodextrin (DM-beta-CD) by complexation/release kinetics and solubility isotherm experiments using ultraviolet (UV)-visible spectrophotometry and by the measurement of the dynamics information obtained from T(1) relaxation times and diffusion (DOSY) experiments using nuclear magnetic resonance (NMR) spectroscopy. The complex was prepared at different NFOH and DM-beta-CD molar ratios. The UV-visible measurements were recorded in a spectrophotometer, and NMR experiments were recorded at 20 degrees C on a NMR spectrometer (Varian Inova) operating at 500 MHz. Longitudinal relaxation times were obtained by the conventional inversion-recovery method and the DOSY experiments were carried out using the BPPSTE sequence. The kinetics of complexation revealed that 30 h is enough for stabilization of the NFOH absorbance in presence of cyclodextrin. Solubility isotherm studies show a favorable complexation and increase in solubility when NFOH interacts with cyclodextrin. The analysis of the NMR-derived diffusion coefficients and T(1) relaxation times shows that in the presence of DM-beta-CD, NFOH decreases its mobility in solution, indicating that this antichagasic compound interacts with the cyclodextrin cavity. The release kinetics assays showed that NFOH changes its release profile when in the presence of cyclodextrin due to complexation. This study was focused on the physicochemical characterization of drug-delivery formulations that may serve as potentially new therapeutic options for the treatment of Chagas' disease.
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Shikanov A, Domb AJ, Weiniger CF. Long acting local anesthetic–polymer formulation to prolong the effect of analgesia. J Control Release 2007; 117:97-103. [PMID: 17137669 DOI: 10.1016/j.jconrel.2006.10.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Revised: 09/06/2006] [Accepted: 10/05/2006] [Indexed: 11/15/2022]
Abstract
Prolonged postoperative analgesia cannot be achieved using single injections of local anesthetic solutions. The study objective was to evaluate the efficacy and toxicity of a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(sebacic-co-ricinoleic acid) for producing motor and sensory block when injected near the sciatic nerve. Bupivacaine was dissolved in poly(fatty ester-anhydride) paste and tested for drug release in vitro and in vivo after injection in mice. The efficacy and toxicity of the polymer-drug combination was determined by injecting the polymer formulation near the sciatic nerve of mice and measure the sensory and motor nerve blockade for 48 h, while monitoring the animal general health and the injection site. Seventy percent of the incorporated drug was released during 1 week in vitro. Single injection of 10% bupivacaine in the polymer caused motor and sensory block that lasted 30 h. Microscopic examination of the injection sites revealed only mild infiltration in three of eight examined tissues with no pathological findings for internal organs were found. In conclusion the polymer poly(sebacic-co-ricinoleic acid) is a safe carrier for prolonged activity of bupivacaine.
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Affiliation(s)
- Ariella Shikanov
- School of Pharmacy, Hadassah Hebrew University Medical Schools, Ein Kerem, Jerusalem, POB 12000, Israel
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Saia Cereda CM, Brunetto GB, de Araújo phd DR, de Paula E. Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration. Can J Anaesth 2006; 53:1092-1097. [DOI: 10.1007/bf03022876] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2006] [Indexed: 11/30/2022] Open
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Local Anesthetics in Lipid-Depot Formulations—Neurotoxicity in Relation to Duration of Effect in a Rat Model. Reg Anesth Pain Med 2006. [DOI: 10.1097/00115550-200609000-00002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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