Focused ultrasound enhances the anesthetic effects of topical lidocaine in rats

Abstract

Background High-intensity ultrasound has been used to induce acoustic cavitation in the skin and subsequently enhances skin permeability to deliver hydrophobic topical medications including lidocaine. In contrast, instead of changing skin permeability, pulsed application of low-intensity focused ultrasound (FUS) has shown to non-invasively and temporarily disrupt drug-plasma protein binding, thus has potential to enhance the anesthetic effects of hydrophilic lidocaine hydrochloride through unbinding it from serum/interstitial α1-acid glycoprotein (AAG). Methods FUS, operating at fundamental frequency of 500 kHz, was applied pulse-mode (55-ms pulse duration, 4-Hz pulse repetition frequency) at a spatial-peak pulse-average intensity of 5 W/cm2. In vitro equilibrium dialysis was performed to measure the unbound concentration of lidocaine (lidocaine hydrochloride) from dialysis cassettes, one located at the sonication focus and the other outside the sonication path, all immersed in phosphate-buffered saline solution containing both lidocaine (10 µg/mL) and human AAG (5 mg/mL). In subsequent animal experiments (Sprague-Dawley rats, n = 10), somatosensory evoked potential (SSEP), elicited by electrical stimulations to the unilateral hind leg, was measured under three experimental conditions—applications of FUS to the unilateral thigh area at the site of administered topical lidocaine, FUS only, and lidocaine only. Skin temperature was measured before and after sonication. Passive cavitation detection was also performed during sonication to evaluate the presence of FUS-induced cavitation. Results Sonication increased the unbound lidocaine concentration (8.7 ± 3.3 %) from the dialysis cassette, compared to that measured outside the sonication path (P < 0.001). Application of FUS alone did not alter the SSEP while administration of lidocaine reduced its P23 component (i.e., a positive peak at 23 ms latency). The FUS combined with lidocaine resulted in a further reduction of the P23 component (in a range of 21.8 − 23.4 ms after the electrical stimulations; F(2,27) = 3.2 − 4.0, P < 0.05), indicative of the enhanced anesthetic effect of the lidocaine. Administration of FUS neither induced cavitation nor altered skin conductance or temperature, suggesting that skin permeability was unaffected. Conclusions Unbinding lidocaine from the plasma proteins by exposure to non-thermal low-intensity ultrasound is attributed as the main mechanism behind the observation.

Transcutaneous application of ultrasound enhances the effects of finasteride in a murine model of androgenic alopecia

“…A duty cycle of 22% yielded a spatial peak temporal average acoustic intensity (I SPTA ) of 550 mW/cm 2 . The choice of the acoustic pulsing parameter was based on previous studies that showed unbinding of phenytoin and lidocaine from plasma proteins [ 15 , 16 ]. The mechanical index, rarefaction pressure (P r in MPa)×fundamental frequency (in MHz) -0.5 , indicates the risk of mechanical damage to the tissue, and a value of 1.9 is currently defined as the regulatory limit for most ultrasound imagers [ 23 ].…”

“…Recent investigations have revealed that pulsed application of acoustic pressure waves can unbind pharmacological agents from plasma proteins [ 15 , 16 ]. For example, an anti-epileptic drug, phenytoin, was unbound from albumin by the focal application of ultrasound, enhancing its regional parenchymal uptake across the blood-brain barrier in rodents [ 15 ].…”

“…For example, an anti-epileptic drug, phenytoin, was unbound from albumin by the focal application of ultrasound, enhancing its regional parenchymal uptake across the blood-brain barrier in rodents [ 15 ]. More recently, ultrasound was also used to unbind lidocaine from α1-acid glycoproteins to enhance local anesthetic effects in rats [ 16 ]. The radiation force conferred by the application of acoustic pressure waves to biological tissue, below the threshold for induced thermal and cavitational effects, is believed to disrupt the weak binding forces between plasma proteins and the drug, thus temporarily enhancing the bioavailability of unbound ('free') drugs for their action [ 16 ].…”

Multivariable-Incorporating Super-Resolution Convolutional Neural Network for Transcranial Focused Ultrasound Simulation

“…Focused ultrasound (FUS) techniques have enabled non-invasive transmission of highly focused acoustic energy to a few millimeters of a localized region in the body [1]- [3]. Due to these desirable advantages, FUS has been widely used as a therapeutic tool for clinical applications such as extracorporeal lithotripsy [4], thermal ablation [5], drug delivery [6]- [9], and histotripsy [10]. Recently, based on the use of a low frequency range that enables transmission of acoustic energy through an intact skull, it is gaining further attention as a new mode of non-invasive brain stimulation (NIBS), with promising potential to treat neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease [11]- [14].…”

Multivariable-Incorporating Super-Resolution Convolutional Neural Network for Transcranial Focused Ultrasound Simulation

“…Focused ultrasound (FUS) techniques have enabled non-invasive transmission of highly focused acoustic energy to a few millimeters of a localized region in the body [1]- [3]. Due to these desirable advantages, FUS has been widely used as a therapeutic tool for clinical applications such as extracorporeal lithotripsy [4], thermal ablation [5], drug delivery [6]- [9], and histotripsy [10]. Recently, based on the use of a low frequency range that enables transmission of acoustic energy through an intact skull, it is gaining further attention as a new mode of non-invasive brain stimulation (NIBS), with promising potential to treat neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease [11]- [14].…”