Corneal Anesthesia With Site 1 Sodium Channel Blockers and Dexmedetomidine

McAlvin, J. Brian; Zhan, Changyou; Dohlman, Jenny C.; Kolovou, Paraskevi E.; Salvador-Culla, Borja; Kohane, Daniel S.

doi:10.1167/iovs.15-16591

Cited by 21 publications

(22 citation statements)

References 42 publications

(70 reference statements)

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“…DMED is known to prolong the effects of local anesthetics, both conventional [26–28] and site 1 sodium channel blockers [9]. One type of potential mechanism for this prolongation is analgesic effects mediated by α 2 -adrenergic agonism or blockade of hyperpolarization-activated cation currents [29, 30].…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of TTX can be greatly enhanced by co-administration with a variety of compounds [6, 7]; the α 2 -adrenergic agonist dexmedetomidine (DMED) is one such compound [8]. Its enhancement of the activity of TTX may be due to local vasoconstriction, which would maintain a high local concentration of drug, but other mechanisms are possible [9]. Here we have hypothesized that if TTX could be released against a background of release of DMED, each quantity of released TTX would be more effective, allowing lower irradiances – releasing less TTX – to achieve a given therapeutic effect.…”

Section: Introductionmentioning

confidence: 99%

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Multiply repeatable and adjustable on-demand phototriggered local anesthesia

Rwei¹,

Zhan

Wang

et al. 2017

Journal of Controlled Release

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A phototriggerable system whereby patients could repeatedly and non-invasively control the timing and dosage of local anesthesia according to their needs would be beneficial for perioperative pain and perhaps obviate the need for oral narcotics. However, clinical application of phototriggerable systems have been limited by concerns over phototoxicity of lasers and limited tissue penetration of light. To address these limitations, we increased the devices’ effective sensitivity to light by co-delivering a second compound, dexmedetomidine, that potentiates the effect of delivered local anesthetics. The concurrent release of dexmedetomidine enhanced the efficacy of released local anesthetics, greatly increasing the number of triggerable nerve blocks (up to nine triggerable events upon a single injection) and reducing the irradiance needed to induce nerve block by 94%. The intensity and duration of on-demand analgesia could be adjusted by varying the intensity and duration of irradiance, which could not only be delivered by lasers, but also by light-emitting diodes, which are less expensive, safer, and more portable.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiply repeatable and adjustable on-demand phototriggered local anesthesia

Rwei¹,

Zhan

Wang

et al. 2017

Journal of Controlled Release

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“…The intensity and duration of nerve block from any given release event could be extended by the codelivery of drugs that enhance the effectiveness of site 1 sodium-channel blockers, including amino-amide and amino-ester ("conventional") local anesthetics (6,50,53), vasoconstrictors (50,53), and dexmedetomidine (54). The basal release of TTX from the liposomes could be slowed by designing vesicles that can revert to their original state and maintain their physical integrity after irradiation, allowing further triggered events.…”

Section: J/cmmentioning

confidence: 99%

Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes

Rwei

Lee

Zhan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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127

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Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.pain | site 1 sodium-channel blocker | photosensitizer | light | near infrared

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“…To further enhance the number and duration of ultrasound-triggerable nerve blocks, we co-administered dexmedetomidine-loaded liposomes (Lipo-DMED, see Figure S8 for cryo-TEM image, see Methods for synthesis) with Lipo-PPIX-TTX at a 1:2 (Lipo-DMED: Lipo-PPIX-TTX) mass ratio. Dexmedetomidine, an α 2 -adrenergic agonists, prolongs the local anesthetic effects of TTX 28 Lipo-PPIX-TTX + Lipo-DMED caused an initial nerve block of 34.5 ± 5.0 h ( Figure 5 , Table S2 ). Repeated insonation (3 W/cm 2 , 1 MHz, 10 min) after the return to ≤ 4 s latency triggered three separate consecutive nerve blocks with durations of 1.8 ± 1.2 h, 0.9 ± 0.3 h, and 0.5 ± 0.3 h respectively ( Figure 5a , Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Ultrasound-triggered local anaesthesia

et al. 2017

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On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve block in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve block to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produces reactive oxygen species that react with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. We also show repeatable ultrasound-triggered nerve blocks in vivo, with nerve-block duration depending on the extent and intensity of insonation. We did not detect any systemic toxicity, and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the managing of relatively localized pain states, and potentially minimize opioid use.

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Corneal Anesthesia With Site 1 Sodium Channel Blockers and Dexmedetomidine

Abstract: Coadministration of S1SCBs with dexmedetomidine provided prolonged corneal anesthesia without delaying corneal wound healing. Such formulations may be useful for the management of acute surgical and nonsurgical corneal pain.

Cited by 21 publications

References 42 publications

Multiply repeatable and adjustable on-demand phototriggered local anesthesia

Multiply repeatable and adjustable on-demand phototriggered local anesthesia

Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes

Ultrasound-triggered local anaesthesia

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