DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

ECP is used for cutaneous T-cell lymphoma and off label for
various other T-cell medicated diseases, including graft-versus-host
disease, transplantation rejection, scleroderma, and type I diabetes
mellitus (McKenna et al., 2006). The mechanism of action of ECP
include apoptosis of T cells, generation of clone-specific suppressor
T cells, shifting of the T-cell phenotype, production of an immune
response against the pathogenic T cells, and release of cytokines
(McKenna et al., 2006).
Initially, patients receive therapy every 1-4 weeks, and intervals
are increased as the patient improves. In patients who do not respond
to monotherapy or those with significant tumor burden, ECP can be
combined with adjunctive therapies, including PUVA, topical
chemotherapy, systemic chemotherapy, radiation, biological agents,
and retinoids.
Photodynamic Therapy (PDT). This modality combines
the use of photosensitizing drugs and visible light for
the treatment of various dermatological disorders. In
dermatology, two drugs are approved for topical PDT:
aminolevulinic acid (ALA; LEVULAN KERASTICK) and
methylaminolevulinate (MAL; METVIXIA). Both are
prodrugs that are converted into protoporphyrin IX
within living cells (Figure 65–3). In the presence of
specific wavelengths of light (Table 65–6) and oxygen,
protoporphyrin produces singlet oxygen (type 2 photochemical
reaction), which oxidizes cell membranes,
proteins, and mitochondrial structures, leading to
apoptosis. Sebaceous glands, the epidermis, and neoplastic
cells accumulate more porphyrin than other
cutaneous cells and structures; thus, PDT is approved
for use on precancerous actinic keratoses and also is
commonly used on thin, nonmelanoma skin cancers;
acne; and photorejuvenation (improving the appearance
of photodamaged skin) (Kalka et al., 2000; Lopez
et al., 2004).
Incoherent (nonlaser) and laser light sources have been used
for PDT. The wavelengths chosen must include those within the
action spectrum of protoporphyrin (Table 65–6) and ideally those
that permit maximum skin penetration. Light sources in use emit
energy predominantly in the blue portion (maximum porphyrin
absorption) or the red portion (better tissue penetration) of the visible
spectrum. Because the t 1/2
of the accumulated porphyrins is
~30 hours, patients should protect their skin from sunlight and
intense light for at least 48 hours after treatment to prevent phototoxic
reactions.
ANTIHISTAMINES
Histamine (see Chapter 32) is a potent vasodilator,
bronchial smooth muscle constrictor, and stimulant of
nociceptive itch receptors (Repka-Ramirez and
Baraniuk, 2002). In addition to histamine, multiple
chemical itch mediators can act as pruritogens on C
A
Glycine +
Succinyl CoA
Protoporphyrin IX
B
Heme
HOOC
N
N
Fe
Heme
δ ALA
synthase
N
N
Exogenous δ ALA
Exogenous methyl-ALA
δ ALA
ALA
dehydratase
(2 δ ALAs condense)
Porphobilinogen
COOH
Figure 65–3. Heme biosynthesis pathway. A. Under physiological
conditions, heme inhibits the enzyme δ aminolevulinic acid
(δALA) synthetase by negative feedback. However, δ when ALA
is provided exogenously, this control point is bypassed, leading
to excessive accumulation of heme. B. Heme.
fibers, including neuropeptides, prostaglandins, serotonin,
acetylcholine, and bradykinin (Stander et al.,
2003). Furthermore, receptor systems, such as vanilloid,
opioid, and cannabinoid receptors, on cutaneous
sensory nerve fibers that may modulate itch and offer
novel future targets for anti-pruritic therapy have been
identified.
Histamine is in mast cells, basophils, and platelets.
Human skin mast cells express H 1
, H 2
, and H 4
receptors
but not H 3
receptors (Lippert et al., 2004). H 1
and H 2
receptors are involved in wheal formation and erythema,
whereas only H 1
receptor agonists cause pruritus
(see Chapter 32). Complete blockade of H 1
receptors does not totally relieve itching, and combination
therapy with H 1
and H 2
blockers may be superior
to the use of H 1
blockers alone (Table 65–7).
Oral antihistamines, particularly H 1
receptor antagonists,
have anticholinergic activity and are sedating (see Chapter 32),
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CHAPTER 65
DERMATOLOGICAL PHARMACOLOGY