Page 1154 - Basic _ Clinical Pharmacology ( PDFDrive )

1140 SECTION X Special Topics

Pharmacologic Effects Parenteral formulations of hypericin (photoactivated just before
administration) have been used investigationally to treat HIV
1. Antidepressant action—The hypericin fraction was initially infection (given intravenously) and basal and squamous cell car-
reported to have MAO-A and -B inhibitor properties. Later stud- cinoma (given by intralesional injection). In vitro, photoactivated
ies found that the concentration required for this inhibition was hypericin inhibits a variety of enveloped and nonenveloped viruses
higher than that achieved with recommended dosages. In vitro as well as the growth of some neoplastic cells. Inhibition of protein
studies using the commercially formulated hydroalcoholic extract kinase C and inhibition of singlet oxygen radical generation have
have shown inhibition of nerve terminal reuptake of serotonin, been proposed as possible mechanisms. The latter could inhibit
norepinephrine, and dopamine. While the hypericin constitu- cell growth or cause cell apoptosis. These studies were carried
ent did not show reuptake inhibition for any of these systems, out using the isolated hypericin constituent of St. John’s wort;
the hyperforin constituent did. Chronic administration of the the usual hydroalcoholic extract of St. John’s wort has not been
commercial extract has also been reported to significantly down- studied for these indications and should not be recommended for
regulate the expression of cortical β adrenoceptors and up-regulate patients with viral illness or cancer.
the expression of serotonin receptors (5-HT ) in a rodent model.
2
Other effects observed in vitro include sigma receptor binding
using the hypericin fraction and GABA receptor binding using Adverse Effects
the commercial extract. Interleukin-6 production is also reduced Photosensitization is related to the hypericin and pseudohypericin
in the presence of the extract. constituents in St. John’s wort. Consumers should be instructed
to wear sunscreen and eye protection while using this product
a. Clinical trials for depression—The most recent systematic when exposed to the sun. Rarely, mild gastrointestinal symptoms,
review and meta-analysis involved 29 randomized, double-blind, fatigue, sedation, restlessness, dizziness, headache, and dry mouth
controlled trials (18 compared St. John’s wort with placebo, 5 with have been observed. Hypomania, mania, and autonomic arousal
tricyclic antidepressants, and 12 with selective serotonin reuptake have also been reported in patients using St. John’s wort. When
inhibitors [SSRIs]). Only studies meeting defined classification compared to SSRIs, St. John’s wort appears to be better tolerated
criteria for major depression were included. St. John’s wort was when used to support medical treatment of major depression.
reported to be more efficacious than placebo and equivalent to
prescription reference treatments including the SSRIs for mild to Drug Interactions & Precautions
moderate major depressive disorder but with fewer side effects.
Most trials used 900 mg/d of St. John’s wort for 4–12 weeks. Inhibition of reuptake of various amine transmitters has been
Depression severity was mild to moderate in 19 trials, moder- highlighted as a potential mechanism of action for St. John’s
ate to severe in 9 trials, and not stated in 1 trial. In a longer but wort. Drugs with similar mechanisms (ie, antidepressants,
uncontrolled trial, the use of the herb for up to 52 weeks was stimulants) should be used cautiously or avoided in patients
reported to reduce depression scores in patients with mild to mod- using St. John’s wort due to the risk of serotonin syndrome (see
erate major depression. These data and the mechanism of action Chapters 16 and 30). The hyperforin constituent of St. John’s
data reported above suggest a potential role for St. John’s wort in wort has been shown to activate the pregnane X receptor (PXR),
relieving symptoms of mild to moderate major depression. Due which ultimately leads to many drug interactions by inducing
to the short study duration of these clinical trials, efficacy beyond hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein
12 weeks still requires further study. drug transporter. Another constituent, hypericin, which may not
be present in all commercial formulations, does not have any
b. Other mood-related conditions—St. John’s wort has been effect on PXR, CYP, or P-glycoprotein. Case reports involving the
studied for several other indications related to mood, including use of St. John’s wort have suggested the herb resulted in subthera-
premenstrual dysphoric disorder, climacteric complaints, somato- peutic levels of numerous drugs, including digoxin, birth control
form disorders, and anxiety. For most of these indications, studies drugs (and subsequent pregnancy), cyclosporine, HIV protease
are too few in number to draw any firm conclusions regarding and nonnucleoside reverse transcriptase inhibitors, warfarin, irino-
efficacy. Evidence for climacteric complaints was the subject of tecan, theophylline, and anticonvulsants. Without knowing which
a recent meta-analysis. Six trials were included where two used constituent is present in a St. John’s wort formulation, indiscrimi-
mono-preparations of St. John’s wort and four used combinations nate combined use with other medicines should be avoided.
of St. John’s wort and black cohosh, Cimicifuga racemose (note
black cohosh warning in Table 64-1). St. John’s wort significantly Dosage
reduced hot flashes (severity, duration, and frequency) compared
to placebo when used for up to 16 weeks. Heterogeneity in The most common commercial formulation of St. John’s wort is
these trials limits drawing firm conclusions on efficacy for this the dried hydroalcoholic extract. Products should be standardized
indication. to 2–5% hyperforin, although most still bear the older standard-
ized marker of 0.3% hypericin. The recommended dosing for
2. Antiviral and anticarcinogenic effects—The hypericin mild to moderate depression is 900 mg of the dried extract per day
constituent of St. John’s wort is photolabile and can be activated in three divided doses. Onset of effect may take 2–4 weeks. Long-
by exposure to certain wavelengths of visible or ultraviolet A light. term benefits beyond 12 weeks have not been studied.