Influence of Massage and Skin Hydration on Dermal Penetration Efficacy of Nile Red from Petroleum Jelly—An Unexpected Outcome

The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation was applied with and without massage onto either dry skin or pre-hydrated, moist skin. It was expected that the occlusive properties of Vaseline in combination with massage and enhanced skin hydration would cause a superposition of penetration-enhancing effects, which should lead to a tremendous increase in the dermal penetration efficacy of the lipophilic drug surrogate. Results obtained were diametral to the expectations, and various reasons were identified for causing the effect observed. Firstly, it was found that Vaseline undergoes syneresis after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. The lipophilic drug surrogate, which is dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the SC. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and promotes the penetration of hydrophilic compounds. Based on the data, it is concluded that dermal penetration is a complex process that cannot only be explained by Fick’s law. It is composed of at least three different mechanisms. The first mechanism is the penetration of active ingredients with their solvents into the skin (convection, solvent drag), the second mechanism is the penetration of the active ingredient via passive diffusion, and the third mechanism can involve local penetration phenomena, e.g., the formation of liquid menisci and particle-associated penetration enhancement, which occur upon the evaporation of water and/or other ingredients from the formulation on top of the skin.

Hans Henriksen Ussing. 30 December 1911 — 22 December 2000

Hans Ussing was born on 30 December 1911 at Sorø Academy in Denmark, where his father Dr Henrik Ussing was a lecturer and, as historian, a leading Danish folklorist. After his doctoral thesis in marine biology, Hans Ussing came to August Krogh's laboratory, where he studied protein turnover by using deuterium-labelled amino acids. After World War II, when radioactive isotopes of light elements became available for biological research, Ussing pioneered the development of epithelial physiology by introducing new concepts and theoretical tools, such as unidirectional fluxes, exchange diffusion, the flux-ratio equation, the shortcircuiting technique, solvent drag, anomalous solvent drag and the pre-steady-state flux ratio theorem. In studies on frog skin, combining electrophysiology and radioactive tracer technology, he provided the first unambiguous demonstration of active transport of sodium ions. His two-membrane hypothesis of active transport by frog skin initiated studies of epithelial transport at the cellular level in other organs and of the mechanisms of action of hormones and drugs. His discovery of paracellular ion transports bridged the physiology of high-resistance and low-resistance epithelia. With the Na + recirculation theory of isotonic transport he continued his studies of epithelial physiology until shortly before his death. Ussing's scientific research provided analytical methods and new insights of general applicability for the study of absorbing and secreting epithelia—of equal importance to biology and medicine. Hans Ussing died on 22 December 2000 after a short illness.

Chronic metabolic acidosis stimulated transcellular and solvent drag-induced calcium transport in the duodenum of female rats

Chronic metabolic acidosis results in a negative calcium balance as a result of bone resorption and renal calcium loss. However, reports on the changes in intestinal calcium transport have been controversial. The present investigation therefore aimed to study the effects of chronic metabolic acidosis induced by 1.5% NH4Cl administration on the three components of duodenal calcium transport, namely, solvent drag-induced, transcellular active, and passive paracellular components, in rats using an in vitro Ussing chamber technique. The relative mRNA expression of genes related to duodenal calcium transport was also determined. We found that 21-day chronic metabolic acidosis stimulated solvent drag-induced and transcellular active duodenal calcium transport but not passive paracellular calcium transport. Our results further demonstrated that an acute direct exposure to serosal acidic pH, in contrast, decreased solvent drag-induced calcium transport in a pH-dependent fashion but had no effect on transcellular active calcium transport. Neither the transepithelial resistance nor duodenal permeability to Na+, Cl−, and Ca2+ via the passive paracellular pathway were altered by chronic metabolic acidosis, suggesting that widening of the tight junction and changes in the charge-selective property of the tight junction did not occur. Thus the enhanced duodenal calcium transport observed in chronic metabolic acidosis could have resulted from a long-term adaptation, possibly at the molecular level. RT-PCR study revealed that chronic metabolic acidosis significantly increased the relative mRNA expression of duodenal genes associated with solvent drag-induced transport, i.e., the β1-subunit of Na+-K+-ATPase, zonula occludens-1, occludin, and claudin-3, and with transcellular active transport, i.e., transient receptor potential vanilloid family Ca2+ channels 5 and 6 and plasma membrane Ca2+-ATPase isoform 1b. Total plasma calcium and free ionized calcium and magnesium concentrations were also increased, whereas serum parathyroid hormone and 1α,25-dihydroxyvitamin D3 levels were not changed. The results indicated that 21-day chronic metabolic acidosis affected the calcium metabolism in rats partly through enhancing the mRNA expression of crucial duodenal genes involved in calcium absorption, thereby stimulating solvent drag-induced and transcellular active calcium transport in the duodenum.