Tolerance of low-frequency ultrasound sonophoresis: a double-blind randomized study on humans.

BACKGROUND: Sonophoresis [low-frequency ultrasound (US)] has been used in animals and in vitro to investigate enhanced percutaneous absorption of drugs. No study focused on its clinical human tolerance has been published as yet. METHODS: We aimed to assess the bioeffects of low-frequency US in vivo on human skin in a double-blind randomized-controlled study. We applied pulse-mode US at 36 kHz for 5 min in a step procedure of increasing dosage, from 1.57 to 3.50 W/cm(2), and placebo. The primary outcome was toxic effects of the procedure, defined as a pain score >40 on a 0-100 mm visual analogue scale or necrosis. Erythema (scored from 0 to 3 in severity) was also evaluated. The secondary outcomes were measurements of skin thickness by high-resolution skin imaging, of skin capacitance and temperature. RESULTS: We included 34 healthy volunteers. We found no pain score >38 and no skin necrosis with either US or placebo. Erythema was systematically observed immediately after US application, but after 1 day, we observed three cases in the knee group. The most frequent adverse effect was tinnitus. We observed no marked increase in temperature or cutaneous thickness after US or placebo. Cutaneous capacitance increased immediately after both applications. CONCLUSION: Such data demonstrating good tolerance of sonophoresis can be useful before the initiation of a clinical trial of the therapeutic use of low-frequency sonophoresis in humans.

Efficiency of low-frequency ultrasound sonophoresis in skin penetration of histamine: a randomized study in humans.

Low-frequency ultrasound (US) applied to skin (sonophoresis) has been investigated to enhance the transdermal transport of various drugs. Histamine is usually used in allergy investigations. We aimed to investigate, in a randomized study, the transdermal penetration of histamine with sonophoresis. Ten subjects were included. Their right forearm was divided into three zones, which were randomly assigned a treatment: no US, US(1) (I(1)=2.72 W/cm(2)), US(2) (I(2)=3.50 W/cm(2)). The primary outcome was area of induced papule, which revealed histamine penetration. Secondary outcomes were echographic measurement of papule (skin thickness) and pruritus. Measurements were taken immediately after US application and after 30 min, 2 h and 24 h. Arm zones without US application showed no papules induced by histamine; 9/10 subjects receiving US showed papules. Their mean size increased with increased intensity of US but not significantly. The skin thickness increased with US. Pruritus occurred in 7/10 cases after US and histamine. The adverse events were skin erythema, pain and tinnitus. Though this study included a few number of patients, it confirms that sonophoresis enhances skin penetration of histamine. This technology could be used at therapeutic levels: histamine could be used with sonophoresis as a positive control in allergy testing instead of prick tests, which involve skin disruption with a lancet.

Phonophoresis: efficiency, mechanisms and skin tolerance.

Phonophoresis or sonophoresis is the use of ultrasound to increase percutaneous absorption of a drug. The technique has been widely used in sports medicine since the sixties. Controlled studies in humans in vivo have demonstrated absence or mild effects of the technique with the parameters currently used (frequency 1-3 MHz, intensity 1-2 W/cm(2), duration 5-10 mins, continuous or pulse mode). However, it was demonstrated in 1995 that administration of macromolecules with conserved biological activity was feasible in animals in vivo using low frequency ultrasound. This led to new research into this method of transdermal administration. The aim of this review is to present the main findings published with low frequency and high frequency ultrasound over the last ten years, and to discuss the respective roles of thermal, cavitational and non-cavitational effects on the reduction of the skin barrier. Particular attention is paid to the biological effects on living skin which might be of importance for tolerance and practical use in humans.

Determination of threshold energy dose for ultrasound-induced transdermal drug transport.

Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the threshold energy dose for ultrasound-induced transdermal drug transport. The threshold was determined by in vitro measurements of the dependence of sonophoretic enhancement on ultrasound parameters, including intensity, duty cycle, and exposure time. While the enhancement varies linearly with ultrasound intensity and exposure times, it is independent of the duty cycle in the range of parameters studied. The enhancement is also directly proportional to the ultrasound energy density once the threshold value is crossed. For full thickness pig skin, the threshold value is about 222 J/cm(2). The overall dependence of transport enhancement on ultrasound parameters is similar to that of cavitation measured in a model system, pitting of aluminum foil. Specifically, the extent of pitting is proportional to ultrasound intensity and exposure time and is independent of duty cycle. Furthermore, the extent of pitting is also proportional to the ultrasound energy density. The similarity between the parametric dependence of transport enhancement and cavitation is consistent with previous findings that cavitation plays the dominant role in sonophoresis.

Transdermal drug delivery using iontophoresis and phonophoresis.

Introducing medicines into the human body by way of the skin is an ancient practice, and transdermal delivery has long been a standard for administering medications such as nitroglycerin and scopalamine. Phoresis, another method of transdermal drug delivery, is now being ordered for an increasing number of orthopaedic patients who suffer from inflammation, strains, or sprains. In phoretic drug delivery, enhancers such as electricity or ultrasound are used to stimulate drug absorption in the treatment area. To guide their patients to explore a variety of treatment options, orthopaedic nurses need a greater understanding of these phoretic modalities.

Defects generated in human stratum corneum specimens by ultrasound.

Over the last two decades, ultrasound (US) has been applied to enhance transdermal drug delivery. This method is called sonophoresis. The physical mechanism of the enhancement is far from being fully understood. It has been shown in our study that 168-kHz continuous US of spatially averaged pressure amplitude of 1.9 x 10(5) Pa induced a new structural state and generated defects (entrapped air pockets) in human stratum corneum specimens. The dimensions of the defects were found to be about 20 microns, large enough to allow the transdermal passage of high-molecular-weight drug molecules that normally elude the unenhanced transdermal drug delivery.

Low-frequency sonophoresis: pathologic and thermal effects in dogs.

OBJECTIVE: Low-frequency sonophoresis has recently been shown to significantly facilitate transdermal permeability of various substances (e.g., insulin) in animal models, thus eliminating the need to inject such agents. Prior to human trials, the authors studied the safety profile of low-frequency sonophoresis in dogs by evaluating microscopic and temperature changes in the skin after sonophoresis. METHODS: An evaluator-blinded canine study of sonophoresis using different energy intensities and probe diameters was performed. Low-frequency ultrasound was applied for 60 seconds to the clipped abdominal skin of 3 anesthetized adult mongrel dogs using a sonicator operating at a frequency of 20 KHz with a maximal energy output of 400 W. The sonicator was immersed in normal saline, and intensities of 4%, 10%, 20%, 30%, and 50% were applied during 600 msec of every second (pulsed mode). Three probes, 1-cm cylindrical, 5-cm cylindrical, and 10-cm disc-shaped, were evaluated. Each experimental condition was performed twice. Subcutaneous temperatures were measured by temperature probe before and after sonophoresis. At 30 minutes post-sonophoresis, full-thickness skin biopsies were taken for blinded histopathologic evaluation. RESULTS: Minimal urticarial reactions were noted with the 1-cm probe at intensities of < or = 20% and with the 5-cm probe at 4% intensity. With higher intensity, thermal injuries were observed grossly with erythema and vesicles. The microscopic correlates were papillary and dermal edema with neutrophils and telangiectasia. The conditions producing vesicles grossly had foci of epidermal necrosis, subepidermal vesicles, and degeneration of papillary dermal collagen. With still higher intensities, confluent epidermal necrosis became apparent. Use of the 10-cm probe did not result in any injury. CONCLUSIONS: Low-frequency ultrasound at low intensities appears safe for use to enhance the topical delivery of medications, producing only minimal urticarial reactions. Higher-intensity conditions resulted in second-degree burns, most likely attributable to localized heating.