The following project topic is completed on st john’s wort the herb. In this text I will explore and discuss what makes st john’s wort a very appealing and effective drug in today’s market based on the following topics. Description, background, active ingredients, routes of administration, pharm kinetics, pharm dynamics, clinical trials, and toxicity. |

St. John's Wort
(Hypericum perforatum L.)
Description
St. John's wort is an herb with a five-petaled yellow flower that grows native in most of Europe West Asia, North Africa, Madeira and the Azores, (Christopher Hobbs 1998) it is considered an invasive species in North America and Australia.
A herbaceous perennial commonly found wild up to a height of 1 to 3 feet in, woods, hedges, roadsides. Leaves are a pale green; oblong in shape with slightly translucent dots hence oil glands which can be seen on holding leaf up to a light. It has bright yellow flowers 5 petals; ovary pear-shaped with three long styles. It can be seen in Bloom from June to August in which many small round black seeds can be seen. Odour is turpentine taste is bitter, astringent and balsamic. (A modern herbal mrs.M.Grieve)

Background
Hypericum perforatum or commonly named as St john’s wort got it common name from early Christians named after John the Baptist due to the blooming of its brightly coloured flowers before and on the 24th of June the day celebrated as his birthday.
Whilst the botanical name hypericum perforatum comes from the Greek word “hyperikon” hyper meaning “over” and eikon meaning “image or apparition”. Possibly showing that the plant was linked with the view that it had mystical powers. Perforatum is translated as “punctured,” which refers to the tiny dots found on the leaves and flowers, which are small, black, translucent dots not holes but tiny glands when pressed, release the essential plant oils. (ST. JOHN'S WORT Ronda Nelson)

Active Ingredient(s)
St. John's wort contains a range of chemical compounds. The main chemical components are naphthodianthrones, of which hypericin + pseudohypericin, and phloroglucinols of which hyperforin, are the most noted active compounds. St. John’s wort also contains quercetin, tannings xanthoids and flavones. * Naphthodianthrones
(0.05 -0.3%) consisting of Hypericin and Pseudohypericin is found primarily in the buds and flowers of St Johns Wort. Hypericin concentration varies widely among growing regions, and percentages are contingent on plant part. (ESCOP 2003)
Hypericin being one of the main active ingredients in St Johns Wort it is a red coloured Anthraquinone (a class of naturally occurring phenolic compounds). (MEHTA 2012)
Other naphthodianthrones such as Isohypericin and protohypericin are also present in the lower parts of the plant (which are turned into hypericin and Pseudohypericin on exposure to light. (ESCOP 2003) * Hyperforin
(2-4.5%) and adhyperforin (0.2-1.8%)(ESCOP 2003)both found in oil glands, pistils, and fruits of the St Johns Wort plant. It is believed to be one of the chief active constituent of St. John's wort acting as a reuptake inhibitor. Hyperforin is unstable in the presence of light and oxygen. (ESCOP 2003)Hyperforin is understood to be responsible for some of the anxiolytic and antidepressant effects of St. John’s wort.. * Quercetin
(2-4%) concentration found in St John Wort. Quercetin has been used to treat conditions of the heart and blood vessels including high cholesterol, heart disease, and circulation problems. Other uses include diabetes, cataracts, hay fever, peptic ulcer, schizophrenia, inflammation, asthma, gout, viral infections, chronic fatigue syndrome (CFS), preventing cancer, as well as treating infections of the prostate. (Web med 6) * Tannings Another compound found in St. John’s Wort is tannins, a subgroup related to the phenol class. Tannins are the medicinal action relating to superficial wound or injury care. The greatest concentrations of these chemicals are found in the leaves and flowers.
Routes of Administration
Administration: Oral or Topical
Oral
Capsule: Liquid extract: Tea:
Topical
Oil:
Ointment:
Dosage
The usual dose associated with st john’s wort is 300 milligrams of the standardized extract usually yielding 0.3% hypericin content taken 3 times daily or 200 to 1000 micrograms/day of hypericin.(TRUVEN HEALTH ANALYTICS 2013)
Depression,
A capsule or tablet, standardized extract of (0.3% hypericin content) 300 mg taken 3 times daily.
Dried herb oral: 2 to 4 grams 3 times daily.
Tea, oral: 2 to 3 grams dried herb placed in boiling water and taken in 1 dose.
Liquid extract (1:1 in 25% ethanol), oral: 2 to 4 ml 3 times daily.
Tincture (1:10 in 45% ethanol), oral: 2 to 4 ml 3 times daily.
Premenstrual Syndrome, Capsule or tablet, taken orally: 300 milligrams daily, standardized to 900 μg hypericin.
Seasonal Affected Disorder, capsule/tablet, oral: 300 mg three times daily.
PEDIATRIC
Depression orally: 200 to 400 mg daily in divided doses for children ages 6 to 12 years (under medical supervision only). (TRUVEN HEALTH ANALYTICS 2013) there is concern about the quality when preparing standards for st john’s wort . For example,in the following report (LOS REYES AND ROBERT T. KODA Am J Health-Syst Pharm. 2002; 59:545-7)they test 8 brands of st john’s wort showing variations in the concentrations of major components(hyperforin hypericin) among 8 different brands of St. John’s wort.
Generally, pharmaceutical manufacturers standardize their production of st johns wort on the concentration of pseudohypericin and hypericin. Relying on hypericin and pseudohypericin concentration as the only indicator of potency of St. John’s wort (LOS REYES AND ROBERT T. KODA Am J Health-Syst Pharm. 2002; 59:545-7) . While one of the major active ingredients hyperforin is taught to be the main cause of many of the interactions with other drugs, its concentration is left unknown in different brands.
Pharmacokinetics
The process by which a drug is absorbed, distributed, metabolized, and eliminated by the body

Figure . Concentration in plasma-time curves for H and PH after three different oral single doses of Hypericum extract in 12 healthy volunteers.
Absorbed: After administration their seems to be a lag phase of 1.9 hours for hypercin compared with 0.4hours for Pseudohypericin. Bio availability of Hypericin =14% and Pseudohypericin = 21% after oral administration. (S .Mills K.Bone 2000)
Distributed: Hypericin and Pseudohypericin can move through the blood brain barrier yet only 5% of that measurable in the body gets through the blood brain barrier.
Metabolized: Hypericin is broken down to pseudohypericin, the derivative of hypericin ,and hyperforin is metabolized in the liver by the hydroxylation pathway. .(Cui Y, Ang CY, Beger RD, Heinze TM, Hu L, Leakey J.)
Phase I metabolites = 19-hydroxyhyperforin, 24-hydroxyhyperforin, 29-hydroxyhyperforin, and 34-hydroxyhyperforin, .(Cui Y, Ang CY, Beger RD, Heinze TM, Hu L, Leakey J.)
Excretion: The clearance of a 5% hyperforin concentration was
199.3 mL/min at 300mg
238.2 mL/min at 600mg
340.3 mL/min at 1200mg (Biber et al, 1998). Elimination half life: Hypericin = 28.1 to 41.7 hours Hyperforin = 9to 22.8 hours Pseudohypericin = 25.39 hours
Pharmacodynamics
The study of the biochemical and physiological effects of drugs and the mechanisms of their actions.
Monoamine oxidase inhibitor (MAOI) activity
According to early study’s hypericin xanthan and flavonols were effective on inhibition of the monoamine oxidase (MAO) A and B which lead to the breakdown of serotonin, noradrenaline and dopamine dopamine neurotransmitter. Yet in the study’s it was concluded that the effect was too little to explain the anti-depressive properties .
Serotonin norepinephrine dopamine
A proposed reason to how st johns wort acts as a treatment for depression is in the way hyperforin seems to act as a reuptake inhibitor of Serotonin dopamine and norepinephrine. Preventing the body from removing these neurotransmitters which are normally found in low concentration in patients with depression. (2009 pharmacology weekly) Hyperforin showed inhibition for dopamine receptors D1 and D5 and norepinephrine transporter (NET)s .

Figure showing the mechanisms of St John’s wort in treatment of depression source =2009 pharmacology weekly

Clinical Trials * Depression
St. John's Wort Vs. Prozac: “In a double-blind study conducted at seven German medical clinics, physicians treated 240 patients with mild to moderate depression for six weeks. A total of 126 patients received a standardized extract of St. John's wort (250 mg twice daily) and 114 received 20 mg/day fluoxetine (Prozac), a class of antidepressant known as selective serotonin reuptake inhibitors (SSRIs). Scores on the Hamilton Depression Scale (a standard clinical measure of depression) at the beginning of the study ranged from 16 to 24. By the end of the study, scores decreased to 11.54 in the St. John's wort group and 12.2 in the Prozac group. Further analysis by the researchers found that St. John's wort was slightly more effective than Prozac, and that about one-third more patients responded to the herb than to the drug. The main difference, though, was safety: 34 people (29.8 percent) taking Prozac reported side effects, including gastrointestinal problems, vomiting, dizziness, and erectile dysfunction, while only six (4.7 percent) of the patients taking St. John's wort reported side effects, and those were limited to only GI distress”. (Schrader E. 2000)
A combination of St. John's Wort and valerian demonstrated greater improvement in symptoms of depression than desipramine in a randomized, double-blind trial of 93 outpatients with moderate depression. Patients received 6 capsules daily of Sedariston(R) (containing 90 to 100 milligrams (mg) Hypericum perforatum/capsule, standardized to 0.05 mg hypericin, and 50 mg valepotriate-free valerian extract (6:1)) or desipramine 150 mg daily for 1 week, then 4 capsules Sedariston(R)) or desipramine 100 mg daily for 5 weeks. At 6 weeks, patients receiving Sedariston(R) demonstrated greater improvement in scores on the Clinical Global Impression (CGI) scale compared with desipramine (p=0.0004). Median depression scores reached normal values within 3 weeks of treatment with Sedariston(R) and were significant after 6 weeks (median scores with Sedariston(R) and desipramine decreased by 14 and 9, respectively; p=0.0239). A good to very good benefit-to-risk ratio (target criterion of the CGI) was achieved in 70% of patients receiving Sedariston(R) compared to about one-third of patients receiving desipramine (Steger, 1985).

* HIV activity
“Clinical trials are limited by the prevalence of interactions with standard HIV therapy. Hypericin and pseudohypericin inhibit a variety of encapsulated viruses, including HIV. 2 3-Hydroxy lauric acid obtained from H. perforatum exhibited light-independent, anti-HIV activity in an in vitro experiment. 67 One study found 16 of 18 patients had improved CD4 cell counts over a 40-month period. CD4/CD8 ratios also improved in the majority of patients. In late 1996, results from a study of hypericin as an investigational new drug indicated that viral load measured in 12 patients ranged from no change to 97% reduction. However, research was discontinued after studies found that it was cytotoxic and not synergistic with licensed anti-HIV drugs. In 1999, a phase 1 study evaluating hypericin's effects in 30 patients concluded that hypericin had no antiretroviral activity, with phototoxicity being observed”. (2009 Wolters Kluwer Health) * Cancer
“The cytocidal activity of hyperforin and its effect on tumor growth inhibition have been demonstrated against human cell lines. A pilot clinical study demonstrated clinical response (on histology) to an extract of H. perforatum with photodynamic therapy for actinic keratoses, basal cell carcinoma, and carcinoma in situ (Bowen disease)”. (Kacerovská D, Pizinger K, Majer F, Smíd F. 2008;84(3):779-785)
From the clinical trials it is seen that st johns wort dose display anti-depressive properties on cases of mild to moderate depression showing positive results compared to the placebo and equal to more effective results compared to Prozac and without the side affects.
Toxicology
Overdosing with St John’s wort may cause phototoxic reactions at single dosages of 3600mg of hydromethanoic extract of St John’s wort with exposure to UV light. Symptoms include rash, pruritus (itch) and erythema (redness of the skin). In vivo and in vitro studies have not demonstrated significant mutagenic properties of St. John’s wort.
Only a single case reports an overdose of St. John's wort that was where a 16-year-old took 15 capsules of 300 mcg strength per day for 2 weeks, requiring management in the intensive care unit. (Karalapillai DC, Bellomo R)
Interactions
St. John’s wort interacts with many systems medications in the body that can interfere with their desired effects either by reducing their activity by speeding up their breakdown or by amplifying the effects of MAOI s /SSRIs.
Antidepressants
Birth control pills
Transplant rejecting medication
Digoxin, cardiovascular medication drugs used to control HIV infection
Seizure-control drugs, such as phenytoin and phenobarbital
Anticoagulants such as warfin
High dosages of St. John’s wort may cause sensitivity to sunlight.
St. John's Wort may cause serotonin syndrome when combined with other drugs which affect serotonin levels. These drugs include:
Selective serotonin reuptake inhibitors (SSRI's)
Tricyclic antidepressants.
Amphetamine
Mono amine oxidase inhibitors (MAOIs)s
(Rxmed St. John's Wort)

Conclusion
Hypericin and Pseudohypericin can move through the blood brain barrier yet only 5% of that measurable in the body gets through the blood brain barrier but due to the long half-life of hypericin in the brain it has accumulative effect suggesting an answer to the 4-6 week dosage before it shows any real therapeutic effects.
There is convincing evidence that St. John's wort dose reduce the symptoms of depression in people with mild-to-moderate but not severe depression probably due to the difference in chemistry/phycology between mild to severe depression. In many studies it seems to work just as well some popular types of antidepressant that are often prescribed such as (Prozac) in the SSRI Without the undesired effects of many common Tricyclic antidepressants.
References
1) St. John's wort | University of Maryland Medical Center http://umm.edu/health/medical/altmed/herb/st-johns-wort#ixzz2kNElSl8y 2) 2009 Wolters Kluwer Health http://www.drugs.com/npp/st-john-s-wort.html 3) Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC Press, 1994. 4) ESCOP. Hyperici herba. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:257-281. (ESCOP 2003) 5) Pharmacognosy of St. John’s Wort SWEETY MEHTA 2012 http://pharmaxchange.info/press/2012/12/pharmacognosy-of-st-johns-wort/ 6) http://www.webmd.com/vitamins-supplements/ingredientmono-294-QUERCETIN.aspx?activeIngredientId=294&activeIngredientName=QUERCETIN 7) https://www.stjohnprovidence.org/HealthInfoLib/swarticle.aspx?type=19&id=StJohnsWort 8) St. John's Wort Ancient Herbal Protector© 1998 Christopher Hobbs 9) A modern herbal mrs.M.Grieve http://www.botanical.com/botanical/mgmh/s/sajohn06.html 10) C. Pickering, Chronological History of Plants (Boston, 1879) 11) The School of Natural Healing ST. JOHN'S WORT by (Ronda Nelson) (http://www.herballegacy.com/Nelson_History.html) 12) Medicinal and Aromatic Plants, Volume 12edited by Y. P. S. Bajaj 13) Principles and Practice of Phytotherapy: Modern Herbal Medicine / Edition 1 by Simon Mills, Kerry Bone 2000 (S .Mills K.Bone 2000) 14) TRUVEN HEALTH ANALYTICS 2013 st johns wort http://www.micromedex.com/products/altmeddex/samples/stjohnswort.pdf 15) ( Rxmed St. John's Wort) http://www.rxmed.com/c.topstories/c1.cover.story/c1.cover.story.st.john.wort.html 16) Determining hyperforin and hypericin content in eight brands of St. John’s wort GERLIE C. DE LOS REYES AND ROBERT T. KODA Am J Health-Syst Pharm. 2002; 59:545-7 17) Karalapillai DC, Bellomo R. Convulsions associated with an overdose of St John's wort. Med J Aust . 2007;186(4):213-214 18) Single-Dose and Steady-State Pharmacokinetics ofHypericin and PseudohypericinREINHOLD KERB, JU¨RGEN BROCKMO¨LLER, BEATE STAFFELDT,MICHAEL PLOCH, AND IVAR ROOTS 19) In vitro metabolism of hyperforin in rat liver microsomal systems.(Cui Y, Ang CY, Beger RD, Heinze TM, Hu L, Leakey J.) 20) (2009 pharmacology weekly) http://www.pharmacologyweekly.com/articles/herbal-supplement-St-John-wort-hypericum-perforatum-mechanism-depression 21) Schrader E. Equivalence of St. John's wort extract (Ze 117) and fluoxetine: a randomized controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000;15(2):61-8) 22) http://www.chiro.org/nutrition/FULL/St_John's_Wort_Vs_Drugs.shtml