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

Calcipotriene. Calcipotriene (DOVONEX, others) is a topical
vitamin D analog that is used in the treatment of
psoriasis.
Although calcipotriene is not a retinoid, it exerts its effects
through modulation of similar proteins and pathways as the
retinoids, leading to similar effects. Calcipotriene exerts its effects
through the vitamin D receptor (VDR), a member of the thyroid hormone,
corticosteroid, and retinoic acid nuclear receptor gene family
(see Chapter 44). Upon binding the VDR, the drug-receptor complex
associates with the RXR- and binds to vitamin D response
elements on DNA. Genes that modulate epidermal differentiation
and inflammation are subsequently expressed, leading to improvement
in psoriatic plaques (Bikle et al., 2001).
Calcipotriene is applied twice daily to plaque psoriasis on the
body, often in combination with topical corticosteroids. Hypercalcemia
and hypercalciuria may develop when the cumulative weekly dose
exceeds the recommended 100g/wk limit and resolves within days of
discontinuation of calcipotriene (Bleiker et al., 1998). Calcipotriene
also causes perilesional irritation and mild photosensitivity. Irritancy
is reduced by concomitant administration of topical corticosteroids.
PHOTOCHEMOTHERAPY
Electromagnetic radiation is defined by its wavelength
and frequency. Based on its biological activity, dermatologists
subdivide the UV region into UVB (290-
320 nm), UVA2 (320-340 nm), UVA1 (340-400 nm),
and UVC (100-290 nm) radiation. UVC radiation is
almost completely absorbed by stratospheric ozone,
does not reach Earth’s surface, and is not used therapeutically.
UVB is the most erythrogenic and melanogenic
type of radiation. It is the major action spectrum for sunburn,
tanning, skin cancer, and photoaging. UVA radiation
is a thousand times less erythrogenic than UVB but
penetrates more deeply into the skin and contributes
substantially to photoaging and photosensitivity diseases.
Visible radiation (400-800 nm) reaches the retina
and produces the sensation of vision.
Phototherapy and photochemotherapy are treatment
methods in which UV or visible radiation is used
to induce a therapeutic response either alone or in the
presence of a photosensitizing drug. To be effective, the
incident radiation must be absorbed by a target or chromophore
in the skin—which in phototherapy is endogenous
and in photochemotherapy must be administered
exogenously (Table 65–6). Patients treated with these
modalities should be monitored for concomitant use of
other potential photosensitizing medications before initiation
of therapy. Such drugs include phenothiazines,
thiazides, sulfonamides, nonsteroidal anti-inflammatory
agents, sulfonylureas, tetracyclines, and benzodiazepines.
PUVA: Psoralens and UVA. Photochemotherapy with
psoralen-containing plant extracts was employed for
the treatment of vitiligo in Egypt and India as early as
1500 B.C. Orally administered 8-methoxypsoralen followed
by UVA (PUVA) is FDA approved for the treatment
of vitiligo and psoriasis.
Chemistry. Psoralens are lipophilic molecules belonging to the furocoumarin
class of compounds, which are derived from the fusion of
a furan with a coumarin. One psoralen, methoxsalen (8-methoxypsoralen,
OXSORALEN ULTRA, 8-MOP, others) is available in the U.S.
The structures of two common psoralens are:
Pharmacokinetics. Dissolved psoralens (e.g., OXSORALEN ULTRA) are
absorbed rapidly after oral administration, whereas crystallized
forms (e.g., 8-MOP) are absorbed slowly and incompletely. Fatty
foods also reduce absorption. Furthermore, there is a significant,
but saturable, first-pass elimination in the liver. For these reasons,
peak photosensitivity varies significantly between individuals but
typically is maximal 1-2 hours after ingestion. Methoxsalen has a
serum t 1/2
of ~1 hour, but the skin remains sensitive to light for
8-12 hours.
Mechanism of Action. The action spectrum for oral PUVA is between
320 and 340 nm. Two distinct photoreactions take place. Type I reactions
involve the oxygen-independent photoaddition of psoralens to
pyrimidine bases in DNA. Type II reactions are oxygen dependent
and involve the transfer of energy to molecular oxygen, creating
reactive oxygen species. Through incompletely understood mechanisms,
these phototoxic reactions stimulate melanocytes and induce
anti-proliferative, immunosuppressive, and anti-inflammatory effects
(Stern, 2007).
Therapeutic Uses. Methoxsalen is supplied in soft gelatin capsules
(OXSORALEN-ULTRA) and hard gelatin capsules (8-mop) for oral use.
The dose is 10-70 mg, depending on weight (0.4-0.6 mg/kg), taken
1.5-2 hours or 2 hours before UVA exposure for OXSORALEN-ULTRA
and 8-MOP, respectively. A lotion containing 1% methoxsalen (OXSO-
RALEN) is available for topical application for vitiligo and can be
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CHAPTER 65
DERMATOLOGICAL PHARMACOLOGY