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Aim: To study the influence of chronological age on fentanyl permeation through human skin in vitro using static diffusion cells. Elderly individuals are known to be more sensitive to opioids and obtain higher plasma concentrations following dermal application of fentanyl compared to younger individuals. The influence of age - as an isolated pharmacokinetic term - on the absorption of fentanyl has not been previously studied. Method: Human skin from 30 female donors was mounted in static diffusion cells, and samples were collected during 48 h. Donors were divided into three age groups: <30 years of age (n = 6), ≥30 and <60 years of age (n = 18) and ≥60 years of age (n = 6). Results: The youngest group had a significantly higher mean absorption (3,100 ng/cm(2)) than the two other groups (2,000 and 1,475 ng/cm(2), respectively) and a significant larger AUC (young age group: 9,393 ng; middle and old age groups: 5,922 and 4,050 ng, respectively). Furthermore, the lag time and absorption rate were different between the three groups, with a significantly higher rate in the young participants versus the oldest participants. Conclusion: We demonstrate that fentanyl permeates the skin of young individuals in greater amounts and at a higher absorption rate than in middle-aged and old individuals in vitro.
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Original Paper
Skin Pharmacol Physiol 2013;26:155–159
DOI: 10.1159/000348876
Chronological Age Affects the Permeation
of Fentanyl through Human Skin in vitro
R.Holmgaard a,d E.Benfeldt b J.A.Sorensen c J.B.Nielsen d
Departments of
a Plastic Surgery and
b Dermatology, University of Copenhagen, Roskilde Sygehus, Roskilde ,
c Department of Plastic and Reconstructive Surgery, Odense University Hospital, and
d Environmental Medicine,
Institute of Public Health, University of Southern Denmark, Odense , Denmark
The human skin changes during a lifespan. In addition
to the effect on the visual appearance of the skin, also
physiological and structural changes are seen. These
changes are not only a consequence of intrinsic aging but
also related to the cumulative exposure to extrinsic harm,
such as sunlight or smoking, during a lifespan. Chrono-
logically aged skin appears thinner
[1] , paler, rougher [2]
and drier
[3] compared to young skin. The dry skin is
caused by alterations of the stratum corneum lipid bar-
[4] as the stratum corneum lipid content decreases
with age
[5] and the lipid composition changes [3] . Skin
permeability and barrier integrity have been demonstrat-
ed to change with age in relation to some specific sub-
[6–10] . Thus, transepidermal water loss decreases
in aging skin
[7, 11, 12] , the echogenicity changes [13]
and the permeability of hydrophilic penetrants increases
[7, 8, 10] . Only a few researchers have studied how these
skin changes affect the penetration of highly lipophilic
molecules into and through the stratum corneum of hu-
man skin
[14] .
In the treatment of chronic pain, transdermal admin-
istration [i.e. patch, transdermal therapeutic delivery sys-
tems of fentanyl (TTS-F)] has become widely used. The
majority of individuals treated with TTS-F are elderly
cancer patients, and this group of patients is increasing
in number due to an increasing life expectancy
[15] . El-
derly patients are considered more sensitive to opioids
Key Words
Human skin · Penetration · Age · Fentanyl · Static diffusion
Aim: To study the influence of chronological age on fenta-
nylpermeation through human skin in vitro using static dif-
fusion cells. Elderly individuals are known to be more sensi-
tive to opioids and obtain higher plasma concentrations fol-
lowing dermal application of fentanyl compared to younger
individuals. The influence of age – as an isolated pharmaco-
kinetic term – on the absorption of fentanyl has not been
previously studied. Method: Human skin from 30 female do-
nors was mounted in static diffusion cells, and samples were
collected during 48 h. Donors were divided into three age
groups: <30 years of age (n = 6), 30 and <60 years of age
(n= 18) and 60 years of age (n = 6). Results: The young-
estgroup had a significantly higher mean absorption (3,100
2 ) than the two other groups (2,000 and 1,475 ng/cm
2 ,
respectively) and a significant larger AUC (young age group:
9,393 ng; middle and old age groups: 5,922 and 4,050 ng,
respectively). Furthermore, the lag time and absorption rate
were different between the three groups, with a significant-
ly higher rate in the young participants versus the oldest par-
ticipants. Conclusion: We demonstrate that fentanyl perme-
ates the skin of young individuals in greater amounts and at
a higher absorption rate than in middle-aged and old indi-
viduals in vitro. Copyright © 2013 S. Karger AG, Basel
Received: November 2, 2012
Accepted after revision: February 11, 2013
Published online: May 28, 2013
Rikke Holmgaard
Department of Plastic Surgery, University of Copenhagen
Koegevej 7–9
DK–4000 Roskilde (Denmark)
E-Mail rikkeholmgaard @
© 2013 S. Karger AG, Basel
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Skin Pharmacol Physiol 2013;26:155–159
DOI: 10.1159/000348876
[16] and have increased vulnerability to adverse events
and interactions
[15] . A reason for these adverse events
has been suggested to be associated with the higher se-
rum concentration found after the use of TTS-F, indicat-
ing an age-related increase in absorption [17] or a de-
crease in excretion.
Acquiring knowledge about the influence of age on ab-
sorption of fentanyl as an isolated pharmacokinetic term
is therefore relevant.
Materials and Methods
The physicochemical properties of fentanyl makes it highly
qualified as a transdermal drug. It has a relatively low molecular
weight of 336 g/mol, which is required for transdermal use
(<1,000 g/mol), a low melting point of 87.5
° C [18] favoring
transdermal delivery, a water solubility of 200 mg/l
[18] and a
high lipophilicity (logPow 4) [19] . Following transdermal de-
livery, fentanyl has an in vivo bioavailability close to 100%
(92%), which means that the drug is neither significantly de-
graded by the skin’s microflora nor by the cutaneous enzyme
[20] .
C h e m i c a l s
We used a phosphate buffer (0.05
M Na 2 HPO 4 , 2H 2 O, pH 7.4;
Merck, Darmstadt, Germany) as receptor fluid (17.22 ml). A com-
mercially available fentanyl citrate in water for injection (50 μg/ml,
pH 4.5) was added to the donor chamber (1 ml).
S k i n
The skin samples used were obtained from the Department of
Plastic and Reconstruction Surgery, Odense University Hospital,
Odense, Denmark. They were collected from women undergo-
ingbreast reduction or breast reconstruction. Skin from a total
of 30 female donors were used and divided into three age gro-
ups:<30 years of age (n = 6), 30 and <60 years of age (n = 18)
and 60 years of age (n = 6). The skin was frozen immediately
following surgery and kept at –20
° C for periods not exceeding
12 months. This has proven to maintain the barrier properties
with no significant change in water permeability
[21] , whereas
lower temperatures have been shown to have a damaging effect
[22] . Skin samples were allowed to thaw for 1 h at room tem-
perature before it were gently cleaned with tap water and paper
tissue, cut into suitable pieces and mounted in Franz diffusion
cells. The donors were given complete anonymity with registra-
tion of only age and skin site of the donors, and the local ethics
committee approved the use of the skin for this study.
Study Design
Franz diffusion cells were used in this in vitro study. The meth-
od is well established in the laboratory in Odense, Denmark, where
it has shown good reproducibility
[23] . Full-thickness skin (thick-
ness between 0.7 and 1.0 mm) was mounted on the metal grid be-
tween the donor and the receptor chamber. The receptor chamber
was filled with buffer, and 2 ml of buffer was added to the donor
chamber for capacitance measurement. The receptor chambers
were placed in a water bath with a temperature of 37
° C, keeping
the temperature at the skin surface at 32
° C. Capacitance measure-
ments were performed 1 h before as well as right after the experi-
ment to evaluate the integrity of the barriers. Cells with a capaci-
tance above 55 nF prior to the experiment were replaced. The cells
were left to equilibrate for 1 h before a ‘clean’ buffer replaced the
buffer in the receptor chamber; additionally, the buffer in the do-
nor chamber was replaced by the fentanyl solution. At this time
point, the experiment began (t = 0), and at specified time intervals
throughout the experiment, 1 ml was sampled from the receptor
chamber using a 2-ml syringe and replaced by an equal volume of
new phosphate buffer. The samples from the receptor chamber
were analyzed for fentanyl. The donor chambers and sampling
tube from the receptor chambers were covered with Parafilm
throughout the experiment to avoid evaporation ( fig.1 ). The skin
diffusion area was 2.12 cm
2 /cell, and the average receptor chamber
volume was 17.2 ml.
A n a l y s i s
Fentanyl was assayed by high-performance liquid chromatog-
raphy (HPLC). The chromatographic system was produced by
Kontron (BioTek Instruments, Milan, Italy) and consisted of a
HPLC 420 pump, a HPLC 360 auto sampler and a HPLC 430 UV
detector. Separation was performed on a LiChrospher 60 RP-
Select B (5 mm) 125 × 4 mm column equipped with a RP-Select
B (5 mm) 4 × 4 guard column (Merck). The mobile phase con-
sisted of 0.23% perchloric acid in Milli-Q water: acetonitrile (60:
40 vol/vol) [24] and was used with a flow of 1.5 ml/min. System
control and data handling were carried out on a personal com-
puter equipped with Kontron MT 450 software. Detection was
performed at 205 nm, an absorbance range of 0.005 and a re-
sponse time of 2 s. All samples were analyzed in duplicates, and
the average concentration was reported. The limit of detection
was 10 ng/ml. Standard solutions were prepared in water, and
standard curves were produced on each day of analysis and cov-
Fig. 1. Drawing of the static diffusion cell. Circles indicate pene-
trating molecules.
Color version available online
Magnetic stirrer
Metal grid
Receptor chamber
Donor chamber
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Chronological Age Affects Fentanyl
Premeation through Human Skin
Skin Pharmacol Physiol 2013;26:155–159
DOI: 10.1159/000348876
ered a range from 0 to 5,000 ng/ml. Correlation coefficients of
the standard curves were >0.999. All organic solvents were pur-
chased from Riedel-de Haën and were of CHROMASOLVA pu-
rity (Sigma-Aldrich Laborchemikalien, Seelze, Germany); fur-
ther, perchloric acid was of pro-analysis quality and was provid-
ed from Merck.
D a t a A n a l y s i s
Data was plotted as the cumulative amount of drug collected in
the receptor compartment as a function of time. The specific sam-
ple points were at 0, 3, 6, 12, 24 and 48 h. The lag time was deter-
mined by back extrapolation from the steepest linear part of the
permeation curve. The absorption rate was established by linear
regression on the same part of the permeation curves showing the
cumulative amount of fentanyl absorbed per square centimeter of
skin sample per time.
Data from 30 individuals were used. For each donor, the me-
dian amount absorbed, median absorption rate and median per-
meability coefficients were calculated. Then the mean amount ab-
sorbed, absorption rate and permeability of each age group were
calculated, and statistical calculations were made. The reason for
using the median within the individual is the small sample sizes of
3–5 samples per donor. The age variation was studied by dividing
the donors into three groups: a young group (<30 years of age; n =
6), a middle group ( 30 and <60 years of age; n = 18) and an older
group ( 60 years of age; n = 6).
One-way ANOVA was performed before testing the groups
two by two using Student’s t test. The level for statistical signifi-
cance between the groups was set at p < 0.05. Data were handled
using the Excel software program from Microsoft.
R e s u l t s
The dermal permeation of fentanyl in individuals old-
er than 60 years (n = 6), between 30 and 60 years (n = 18)
and younger than 30 years (n = 6) were compared. The
graphic presentation of the mean amount of fentanyl
sampled over time showed differences between the age
groups ( fig.2 ). The differences in the AUC, shown for the
three age groups individually ( fig.3 ), were significantly
higher in the youngest group than in the middle-aged
(p= 0.04) and in the old group (p = 0.02).
The mean AUC ± SD was 9,393 ± 3,990 ng fentanyl for
the young age group, 5,922 ± 3,040 ng for the middle age
group and 4,050 ± 2,493 ng for the old age group. The lag
times tended to increase with increasing age ( table 1 ),
though differences between groups did not reach statisti-
cal significance. The mean absorption rate ± SD of fen-
tanyl was 78 ± 30 ng/cm
2 /h for the youngest age group,
54 ± 26 ng/cm
2 /h for the middle age group and 43 ±
2 /h for the old age group. The absorption rate
was significantly higher in the young age group compared
to the old age group (p < 0.05) ( table1 ).
D i s c u s s i o n
Elderly individuals are systematically excluded from
most clinical trials due to the potential presence of co-
morbidities and polypharmacy
[25, 26] . Consequently,
the pharmacokinetics of numerous medications in el-
derly patients is not known
[27] . We need to draw atten-
tion to this issue as the demographic development pre-
dicts an increase in the group of elderly patients in future
Even though patients treated with TTS-F benefit
from an increased compliance and a better efficacy in
pain treatment
[28, 29] , elderly patients may experi-
encemore severe adverse events than younger patients
Color version available online
Fig. 2. Absorption of fentanyl (50 μg/ml) through human breast
skin from three different age groups. * Significantly different from
other groups (p < 0.05).
Color version available online
Fig. 3. Histogram demonstrating the mean AUC of the three age
groups as well as their SD. The young group absorbs significantly
more fentanyl than the two other groups (p < 0.05).
Fentanyl (ng/cm2)
Time (h)
<30 years of age (n = 6)
30 and <60 years of age (n = 18)
60 years of age (n = 6)
Mean AUC of fentanyl (ng)
<30 years of age 30 and <60
years of age
60 years of age
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DOI: 10.1159/000348876
[30] and show a less predictable response to the medica-
[31] .
In this study, we used static diffusion cells to investi-
gate the in vitro skin permeation of fentanyl in relation
to different age groups. How age affects the skin perme-
ability is an area under debate since different studies
point in different directions
[6, 32, 33] . We found a sig-
nificant difference between the accumulated absorption
of fentanyl over 48 h in young individuals and in middle-
aged individuals as well as between young individuals
and older individuals. Our results demonstrate that per-
cutaneous permeation of fentanyl decreases with in-
creasing chronological age of the donor individual. This
tendency was also seen when we studied the absorption
rate and lag time, though these differences were not sta-
tistically significant.
Meidan and Roper [32] recently published a retrospec-
tive study of the influence of age on the percutaneous flux
of tritiated water. No correlation with age was found, but
compared to our age groups the study by Meidan and
Roper contained only 2 young and 2 elderly skin donors,
whereas the majority of the donors (11 individuals) was
grouped in the middle-aged group. Roskos and Guy
compared the skin barrier function by measurements of
transepidermal water loss measured in one body site in
young and older individuals and found no relation be-
tween the barrier function and the age of the individuals.
In 1964, Christophers and Kligman
[6] demonstrated an
increase in permeability of the hydrophilic fluorescein in
cadaver skin from elderly individuals and a decrease in
the permeability of testosterone in elderly people in vivo.
Later, Roskos et al.
[8] also studied testosterone, estradiol,
benzoic acid and hydrocortisone and found no significant
changes in penetration of testosterone and estradiol in the
elderly group, whereas the more hydrophilic penetrants
demonstrated an increased penetration in aged skin.
In the case of fentanyl, in vivo studies in humans have
shown that the fentanyl penetration from TTS, assessed
as time to doubling of plasma concentration, appears to
be delayed in elderly patients compared to children (11
vs. 4 h). The C
max and t
max were not significantly different
between the two groups, but a prolonged elimination
phase T
1/2 was observed in the elderly patients (31 vs.
21h, respectively)
[34] . In these human in vivo studies,
an effect of altered elimination capacity such as reduced
renal clearance will have an effect on the result
[35] .
We found an inverse relation between the amount of
fentanyl absorbed and the chronological age of the do-
nors. Thus, this study corroborates with results found by
plasma concentration measurements of fentanyl perme-
ation from a TTS. Our data therefore indicate that an in-
creased risk of adverse events, which has been proposed
for fentanyl administration in the elderly
[15, 17, 36] ,
does not relate to an increased percutaneous permeation
of fentanyl in elderly people but may be caused by a slow-
er excretion or a decreased metabolic capacity towards
opioids in the elderly compared to younger populations.
A future study of fentanyl excretion and metabolism in
relation to age is therefore highly relevant.
These results need to be substantiated with more
chemicals/drugs with varying lipophilicities for the con-
clusions to be applied more generally. The relevance is
that the group of older individuals is increasing in most
societies these years, and testing of transdermal drugs
before acceptance for clinical use does not, in most cas-
es, include older individuals. Maibach’s group
[37] has
also given emphasis to this issue and suggests inclusion
of elderly in future studies to determine if this age group
should have different topical dosing regimens to ensure
drug efficaciousness with minimal adverse effects.
Table 1. Patient characteristics of the three age groups (total n = 30)
Characteristics <30 years (n = 6) >30 and ≤60 years (n = 18) >60 years (n = 6)
Mean age, years 24 44 65
AUC of fentanyl, ng 9,393±3,990a,b 5,922±3,040 4,050±2,493
Amount of fentanyl, ng/cm23,099±1,152a,b 2,021±945 1,474±782
Lag time, h 10±3 11±4 15±5
Absorption rate, ng/cm2/h 78±30b54±26 43±16
Values represent mean ± SD, unless otherwise indicated. aSignificantly different from the middle age group
(Student’s t test <0.05). bSignificantly different from the old age group (Student’s t test <0.05).
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Chronological Age Affects Fentanyl
Premeation through Human Skin
Skin Pharmacol Physiol 2013;26:155–159
DOI: 10.1159/000348876
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... Holmgaard et al. [36] have recently examined the effect of age on the in vitro dermal absorption of fentanyl citrate. Full-thickness skin from the breast of female donors was mounted on to static diffusion cells. ...
... The extent of the lipophilic compound fentanyl was not affected by age in vivo [35], as observed with testosterone and estradiol [28]. However, the in vitro study [36] with fentanyl citrate showed that dermal absorption decreased with age. ...
Human skin undergoes several changes as a person ages. Physiological changes within the body have a major influence on intrinsic aging, and exposure to ultraviolet radiation has a dominant role in extrinsic aging. Changes that occur in aging skin include dryness, reduction of sebaceous gland activity, decreased amount of skin surface lipid, and others. Several human and animal studies have examined the effect of age on chemical penetration of skin. This potential effect of age on chemical penetration is important as humans are living longer now than 20–30 years ago. Animal studies show skin penetration of chemicals is related to the hair growth cycle in hairless mice. This strain is born hairless, rapidly grows hair, and becomes hairless again around 25 days of age. The in vitro penetration of several alkanols increased up to 25 days of age in hairless mice and then started to decline out to 60 days of age. The skin penetration of the alkanols then remained constant. Other animal studies using older age groups report no or limited age effects on chemical skin penetration. The results of a human in vivo study suggest that age affects the dermal absorption of chemicals that are hydrophilic (e.g., benzoic acid). Penetration of these type of chemicals was greater in a younger (<41 years old) than older (65–86 years old) age group. The penetration of hydrophobic chemicals (e.g., testosterone) was not affected by age. Overall, more studies are needed to assess the effect of age on chemical penetration of skin.
... Studies have used Franz-type permeation devices described in the guideline 428 from the Organisation for Economic Co-operation and Development (OECD) (OECD 2004). This system has been employed to investigate the dermal uptake of pesticides (Bo Nielsen et al. 2009) and pharmaceuticals (Holmgaard et al. 2013). These values are listed in Table 1. ...
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Since organic flame retardants (FRs) have several industrial applications, they have been largely detected in environmental and biological samples, and humans have been highly exposed to them. Although the effects of oral and inhaled FRs have been well studied, dermal exposure to them has only recently been pointed out as a potential route of human exposure. Consequently, the effects of FRs on the skin and secondary target organs have been poorly investigated. This review article summarizes the main findings regarding dermal exposure to FRs, points the limitation of the published studies, and suggests future perspectives for better understanding of how dermal exposure to FRs impacts the human health. This review lists some gaps that must be filled in future studies, including characterization of the bioavailable fraction and assessment of exposure for new FRs, to establish their physiological significance and to improve the development of 3D dermal tissue for more reliable results to be obtained.
... Moreover, we observed declining caffeine and testosterone permeation through aged RHS (Fig. 5c). This result is in line with the altered lipid profile that was observed as well as with previous skin absorption studies in vivo 15,44 . ...
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Preclinical studies frequently lack predictive value for human conditions. Human cell-based disease models that reflect patient heterogeneity may reduce the high failure rates of preclinical research. Herein, we investigated the impact of primary cell age and body region on skin homeostasis, epidermal differentiation, and drug uptake. Fibroblasts derived from the breast skin of female 20- to 30-year-olds or 60- to 70-year-olds and fibroblasts from juvenile foreskin (<10 years old) were compared in cell monolayers and in reconstructed human skin (RHS). RHS containing aged fibroblasts differed from its juvenile and adult counterparts, especially in terms of the dermal extracellular matrix composition and interleukin-6 levels. The site from which the fibroblasts were derived appeared to alter fibroblast-keratinocyte crosstalk by affecting, among other things, the levels of granulocyte-macrophage colony-stimulating factor. Consequently, the epidermal expression of filaggrin and e-cadherin was increased in RHS containing breast skin fibroblasts, as were lipid levels in the stratum corneum. In conclusion, the region of the body from which fibroblasts are derived appears to affect the epidermal differentiation of RHS, while the age of the fibroblast donors determines the expression of proteins involved in wound healing. Emulating patient heterogeneity in preclinical studies might improve the treatment of age-related skin conditions.
... Dermal uptake was studied in Franz diffusion cells ( Fig. 1) as described in OECD guideline 428 (OECD, 2004). Our system has previously described for dermal uptake of pesticides (Nielsen et al., 2009) and pharmaceuticals (Holmgaard et al., 2013). The cells were kept in a water bath ensuring a skin surface temperature of approximately 32 C with continuous individual magnetic stirring. ...
The dermal uptake and percutaneous penetration of ten organic flame retardants was measured using an ex vivo human skin model. The studied compounds were DBDPE, BTBPE, TBP-DBPE, EH-TBB, BEH-TEBP, α, β and γ-HBCDD as well as syn- and anti-DDC-CO. Little or none of the applied flame retardants was recovered in either type of the receptor fluids used (physiological and worst-case). However, significant fractions were recovered in the skin depot, particularly in the upper skin layers. The primary effect of the worst-case receptor fluid was deeper penetration into the skin. The recovered mass was used to calculate lower- and upper-bound permeability coefficients kp. Despite large structural variation between the studied compounds, a clear, significant decreasing trend of kp was observed with increasing log Kow. The results indicate that the dermis may provide a significant barrier for these highly lipophilic compounds. However, based on our results, dermal uptake should be considered in exposure assessments, though it may proceed in a time-lagged manner compared to less hydrophobic compounds.
The fluoride ions of the industrially largely irreplaceable, locally corrosive hydrofluoric acid (HF) can scavenge cations in biological tissues, which explains their high toxic potential, and also leads to local acidification through proton release. The influence of three complexing agents, calcium (Ca²⁺) gluconate (as 2.5% Ca²⁺gel and individually (2.84%) or commercially (10%) formulated Ca²⁺solution), magnesium (Mg²⁺) gluconate (2.84%) solution and aluminium (Al³⁺) solution (Hexafluorine®, pure and diluted) on the absorption of fluoride following HF exposure (1–3 min, 100 μl, 30%/0.64 cm²) through human skin was investigated in an ex-vivo diffusion cell model. Fluoride absorption was assessed over 6–24 h and analysed with a fluoride electrode. Decreasing the contamination time reduced the fluoride absorption distinctly which was further reduced by the application of fluoride-binding decontamination agents (Ca²⁺, Mg²⁺, Al³⁺) or water alone without being significantly different. Ca²⁺ appeared slightly more effective than Mg²⁺ in reducing fluoride absorption. Moreover, the addition of pH adjusting buffer promoted the decontamination efficacy. Fluoride-binding agents can facilitate the decontamination of dermal HF exposure. However, prompt decontamination appeared to be the key to successful limitation of fluoride absorption and pushes the choice of decontamination agent almost into the background.
Skin temperature plays a certain role in the dermal absorption of substances, but the extent and mechanisms of skin temperatures-induced modulation in ranges caused by physiological thermoregulation or environmental conditions are largely unknown. The influence of dermal temperature on the absorption of the model lipophilic compound (anisole) and the model hydrophilic compounds (1,4-dioxane, ethanol) through human skin was investigated at three dermal temperatures (25, 32 and 39 °C) in an ex-vivo diffusion cell model. The substances were applied to the skin and transdermal penetration was monitored. All substances showed temperature dependent variations in their penetration behavior (3 h: 25–39 °C: 202–275% increase in cumulative, transdermally penetrated amounts). The relative differences in absorption in relation to temperature were greatest within 45 min after exposure (25–39 °C: 347–653% rise in cumulated penetration), although absolute amounts absorbed were small (45 min vs. 3 h: 4.5–14.5%). Regardless of blood circulation, skin temperature significantly influences the amount and kinetics of dermal absorption. Substance-dependent, temperature-related changes of the lipid layer order or the porous pathway may facilitate penetration. The early-stage modulation of transdermal penetration indicates transappendageal absorption, which may be relevant for short-term exposures. For both, toxicological evaluation and perfusion cell studies, it is important to consider the thermal influence on absorption or to perform the latter at a standardized temperature (32±1 °C).
Age-related changes affect both the local pharmacotherapy of skin diseases and the transdermal administration of drugs. The development of aged skin models disregards the highly individual process of aging, facilitating general conclusions for older patients. Nevertheless, 'omics technology, high-content screening, and non-invasive imaging, as well as bioprinting, CRISPR-Cas, and, patients-on-a-chip, can retrieve personalized information for the generation of in vitro models. Herein, we suggest a strategy to optimize pharmacotherapy for older patients. The technology for relevant human cell-based models is at hand and the consideration of patient heterogeneity is required to unlock their full potential.
The aging process involves physiologic changes that impact both the disposition and effect of drugs in the body as well as the pathology of pain. As the population ages, an understanding of these principles is essential to recognizing patients in pain and treating their symptoms effectively and appropriately. In this chapter, age-related physiologic changes and their impact on drug pharmacokinetics and pharmacodynamics will be discussed.
In this study, stratum corneum (SC) depth profiles of hydrogen bound water molecule types, intercellular lipid (ICL) ordering, concentration of natural moisturizing factor (NMF) and keratin folding/unfolding properties are investigated in vivo for older (mean 50 years old) and younger (mean 29 years old) human skin using confocal Raman microscopy. The results show that the SC of the older group is modestly thicker (p < 0.1), has more hydrogen bound water molecules at the depth 10–30% of the SC thickness (p < 0.05), has a higher ordered organization of ICL (p < 0.1) and higher concentration of NMF (p < 0.05) at the depth 20–40% of the SC thickness compared to the younger group. This study also reveals, that the hydrogen bonding state of water highly correlates with NMF and the lateral structure of ICL but not with keratin’s folding/unfolding properties. The presented results let suggest, that the decreased trans-epidermal water loss (TEWL) with increasing age cannot be sufficiently explained by only the increased SC thickness, but additionally by the increase of ICL ordering, higher NMF concentration and thus larger amount of hydrogen bound water molecules at the depth 20–40% of the SC thickness.
Skin ageing is divided into chronological ageing and photoageing due to the cumulative effects of solar ultraviolet radiation. It is, however, difficult to measure the degree of photoageing and chronological ageing in humans in vivo. Here, we have evaluated the usefulness of ultrasonography for measurement of chronological ageing and photoageing in vivo. Twenty megahertz ultrasonography was performed in 90 individuals (29 men, 61 women, age 18-94) to describe age-related changes in sun-exposed regions with different levels of sun exposure (dorsal and ventral forearm, forehead, ankle) and non-exposed buttock skin. Skin thickness and skin echogenicity in different layers of the dermis were measured in ultrasound images. Additionally cutaneous photodamage was scored clinically. Age-related changes were dependent on body site as well as layer of the dermis. A progressive, age-related decrease in echogenicity of the upper dermis was found in sun-exposed regions (dorsal forearm, forehead), but not in moderately exposed regions (ventral forearm, ankle). In the buttock. an increase in echogenicity was observed. The echogenicity of the lower dermis increased in all examined sites. Skin thickness increased with age in the forehead and buttock, but decreased in the extremity skin. Our findings show that photoageing causes a decrease in echogenicity in the upper dermis. In contrast, chronological ageing is associated with an increase in echogenicity in the lower dermis. Although both increases and decreases in skin thickness were observed in different anatomical regions, there was no general relationship between skin thickness and age. Dermal echogenicity was deemed valuable for in vivo study of chronological ageing and photoageing.
The release of guidelines in 1998 by the American Geriatrics Society on "The Management of Chronic Pain in Older Persons" was a breakthrough in helping to manage pain in this population. Already advances have fostered a need to update recommendations. This article focuses on the treatment strategies available for seniors that are likely to help to fulfill the obligation to relieve pain and suffering in patients. A review was done of the literature using Medline and other search techniques. New pain scales have been developed with seniors in mind and greater testing of older scales in elderly populations have helped to identify measures of pain more suited to frail seniors. Advances in cyclooxygenase inhibition selectivity, alternative medicine, and progress in the identification of nonopioid pain receptors and the development of products to target them are just a few of changes that have altered the way clinicians think about treating pain. The use of hospice in end-of-life palliative care is a valuable resource for clinicians managing pain at that phase in care as well. Tools are available to prevent and treat pain successfully in seniors. Educating clinicians about available assessment tools, techniques and interventions may be the biggest challenge to comforting the older adult in pain.
Transdermal drug delivery allows for a constant rate of drug administration and prolonged action, which can be beneficial to elderly patients who are often polymedicated. Several studies have compared dermatopharmacokinetics in the young and elderly with conflicting results. Despite the potential limitations of age-related changes in skin factors and cutaneous metabolism, marketed transdermal products generally do not report age-related differences in pharmacokinetics. This overview discusses the current data, summarizes marketed product findings and highlights the importance of further studies to evaluate age-related dermatopharmacokinetics.
The absorption of two hydrophobic compounds through rat skin was measured by in vivo and in vitro techniques. The permeation of the fragrance ingredients 3-phenyl-2-propenyl 2-aminobenzoate (I) and 1-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethanone (II) was measured from a petrolatum and an acetone vehicle. Increases in permeation of 8-fold (I) and 95-fold (II) were observed when the compounds were tested in vivo under conditions similar to in vitro procedures. The apparent inability of the compounds to freely enter the diffusion cell receptor fluid was partially reversed by replacing normal saline with other fluids: rabbit serum, 3% bovine serum albumin, organic solvents, and dilutions of four nonionic surfactants. The effect of the receptor fluids on the integrity of the skin barrier was assessed by measuring the permeability of control compounds (cortisone, urea, and water). A 6% solution of polyethylene glycol 20 oleyl ether was the receptor fluid of choice. Without apparent damage to the skin, 61% (petrolatum vehicle) or 73% (acetone vehicle) of the in vivo absorption of I was obtained. With II, only 32% of the in vivo absorption was achieved (petrolatum vehicle). Even when the surfactant solution is used, significant differences may still remain between in vivo and in vitro results.
There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61-83%) and polypharmacy (63-85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.
Pain is highly prevalent in frail older people who often have multiple co-morbidities and multiple medicines. Rational prescribing of analgesics in frail older people is complex due to heterogeneity in drug disposition, comorbid medical conditions, polypharmacy and variability in analgesic response in this population. A critical issue in managing older people with pain is the need for judicious choice of analgesics based on a comprehensive medical and medication history. Care is needed in the selection of analgesic medicine to avoid drug-drug or drug-disease interactions. People living with dementia and cognitive impairment have suboptimal pain relief which in part may be related to altered pharmacodynamics of analgesics and challenges in the systematic assessment of pain intensity in this patient group. In the absence of rigorously controlled trials in frail older people and those with cognitive impairment a pharmacologically-guided approach can be used to optimize pain management which requires a systematic understanding of the pharmacokinetics and pharmacodynamics of analgesics in frail older people with or without changes in cognition.
Storage of skin at low temperatures may affect its structure. There is no report in the literature on the correlation between spatially resolved skin structure and percutaneous penetration after different storage conditions. The present study applies imaging techniques (multiphoton excitation fluorescence microscopy) and in vitro percutaneous penetration of caffeine under four different storage conditions using skin samples from the same donors: fresh skin, skin kept at -20°C for 3 weeks (with or without the use of polyethylene glycol) and at -80°C. Our results show a correlation between increasing permeation of caffeine and tissue structural damage caused by the storage conditions, most so after skin storage at -80°C. The presented approach, which combines imaging techniques with studies on percutaneous penetration, enables the link between tissue damage at selected depths and penetration into the upper layers of the epidermis to be investigated.
Dry skin is characterized by a decreased lipid content and a delayed reconstitution of the epidermal barrier after skin irritation. These are problems of high relevance in the aged population, especially in the development of irritant contact dermatitis. Asteatotic and perineal irritant dermatitis are the most important subtypes of irritant contact dermatitis in the elderly. This contribution presents a compressed survey on these subtypes and elucidates their relation to an impaired barrier function. Typical irritants affecting aged individuals are explained and compared with irritants that seem to be more significant in younger people. Results of biophysical investigations, such as measurement of transepidermal water loss, are discussed regarding their age-dependence. Transepidermal water loss decreases with age, which was formerly interpreted as an indication of a decreased sensitivity. Today, we know that reconstitution of the epidermal barrier after irritation is delayed once it has been impaired. Reasons are decreased activities of enzymes involved in lipid synthesis and processing, a changed cytokine profile, a reduced acidification of aged skin, and alterations in the function of epidermal stem cells. Owing to these new insights, a reevaluation of the sensitivity of aged skin has to be initiated, especially with regard to occupational dermatology.
A database of human dermatopharmacokinetic parameters of 12 transdermal patches is established. The effect of system design, application site, and metabolism on pharmacokinetic data is discussed, and interindividual variability of data and its possible sources evaluated. Using multiple regression analysis, two equations based on drugs physicochemical characteristics are suggested for partial prediction of peak plasma concentration (C(max)) after patch application. Patch application presumably decreases variance as rub-off, wash and exfoliation steps are diminished. The results showed that interindividual variation, in terms of coefficient of variation (CV) of C(max), is inversely correlated with drugs molecular weight and lipophilicity in the range of 200<MW<400 and 1.6<logK(oct)<4.3. Multiple regression analysis of C(max) against physichochemical parameters demonstrated the prominent contribution of hydrogen bonding acceptability of the molecules on their maximal plasma concentration after patch administration. The findings suggest that the serum concentration profile for transdermal therapeutic systems (TTS) is a net result of the system performance, drug absorption and elimination. Thus, the variability in serum concentration is a function of variability of each process involved. This should be noted in explanation of effect of molecular features of drugs on their plasma concentration profile.
The importance of dermatogerontology is stressed. The most important problems are reviewed such as: dry skin, seborrherz dermatitis, pathophysiology of aging skin, physiological versus chronological aging, skin tests and immune status (influence of age on immunity), the skin as an indicator organ.