Duración prolongada de anestesia local con toxicidad mínima
Prolonged duration local anesthesia with minimal toxicity.
Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS.
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, USA.
Erratum in Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4264.
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7125-30. doi: 10.1073/pnas.0900598106. Epub 2009 Apr 13.
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.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678453/pdf/zpq7125.pdf
Una visión general de la neurotoxina marina, saxitoxina: la genética, dianas moleculares, métodos de detección y funciones ecológicas
An overview on the marine neurotoxin, saxitoxin: genetics, molecular targets, methods of detection and ecological functions.
Cusick KD, Sayler GS.
The University of Tennessee Center for Environmental Biotechnology, Knoxville, TN 37996, USA. kdaumer@utk.edu
Mar Drugs. 2013 Mar 27;11(4):991-1018. doi: 10.3390/md11040991.
Abstract
Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin's ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxinresearch are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705384/pdf/marinedrugs-11-00991.pdf
Bloqueo nervioso prolongado retrasa el inicio de dolor neuropático
Prolonged nerve blockade delays the onset of neuropathic pain.
Shankarappa SA, Tsui JH, Kim KN, Reznor G, Dohlman JC, Langer R, Kohane DS.
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Erratum in Proc Natl Acad Sci U S A. 2013 May 7;110(19):7958.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17555-60. doi: 10.1073/pnas.1214634109. Epub 2012 Oct 8.
Abstract
Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ~1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491532/pdf/pnas.201214634.pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
Prolonged duration local anesthesia with minimal toxicity.
Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS.
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, USA.
Erratum in Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4264.
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7125-30. doi: 10.1073/pnas.0900598106. Epub 2009 Apr 13.
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.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678453/pdf/zpq7125.pdf
Una visión general de la neurotoxina marina, saxitoxina: la genética, dianas moleculares, métodos de detección y funciones ecológicas
An overview on the marine neurotoxin, saxitoxin: genetics, molecular targets, methods of detection and ecological functions.
Cusick KD, Sayler GS.
The University of Tennessee Center for Environmental Biotechnology, Knoxville, TN 37996, USA. kdaumer@utk.edu
Mar Drugs. 2013 Mar 27;11(4):991-1018. doi: 10.3390/md11040991.
Abstract
Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin's ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxinresearch are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705384/pdf/marinedrugs-11-00991.pdf
Bloqueo nervioso prolongado retrasa el inicio de dolor neuropático
Prolonged nerve blockade delays the onset of neuropathic pain.
Shankarappa SA, Tsui JH, Kim KN, Reznor G, Dohlman JC, Langer R, Kohane DS.
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Erratum in Proc Natl Acad Sci U S A. 2013 May 7;110(19):7958.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17555-60. doi: 10.1073/pnas.1214634109. Epub 2012 Oct 8.
Abstract
Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ~1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491532/pdf/pnas.201214634.pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
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