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THE SUCCESS STORY OF ST. JOHN'S WORT
Dr. Vikas KumarAssociate Professor of PharmacologyDepartment of PharmaceuticsIIT (BHU), Varanasi
INTRODUCTION Hypericum perforatum is a flowering
plant in the family Hypericaceae It is well known as St. John’s Wort because
its flowers bloom around St. John’s Day and Wort is an Old English term for “Herb”
It is also a Myth that, the red pigments which are exuded from buds and flowers were associated with the blood of St. John the Baptist 2
St John's Wort is native to Europe and Asia It is a herbaceous perennial herb and can
grow to 1 m high Flowers are bright yellow in colour with
conspicuous black dots and measure up to 2.5 cm across
The leaves are yellow-green in colour, with conspicuous translucent dots, giving them a 'perforated' appearance
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Hypericum perforatum was known since Greek and Roman times
In Medieval Europe, the herb was used to treat emotional and nervous complications
In European folk medicine, St John's Wort was also used as an antiphlogistic to treat bronchial and urogenital tract inflammations, hemorrhoids, traumas, burns, scalds and ulcers 4
Hyperforin and hypericin were the very first bioactive secondary metabolites of this plant
Other reported bioactive metabolites are
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CHEMICAL CONSTITUENTS OF ST. JOHN’S WORT
In 1935, very first report was published on the efficacy of St. John’s Wort (SJW) against depression
Much earlier than the discovery of synthetic tri-cyclic antidepressants
The main therapeutic focus of SJW research has been its CNS modulating properties
However, major interest in the use of SJW for treatment of CNS disorders starts after 1980s in Germany 6
PRECLINICAL STUDIES OF ST. JOHN’S WORT
In various animal models, SJW has shown: Antidepressant Anxiolytic Anti-stress Anti-aggressive Anti-inflammatory and analgesic Anti-diabetic, hypolipidemic and anti-obesity like
activity Beneficial effects in neurological disorders
associated with diabetes 7
Repeated daily oral administration Indian Hypericum perforatum (IHp) decreased
immobility time in rat behavioural despair model
In rat learned helplessness test, IHp shows significant reduction in number of escape failures as compared to vehicle control group
Observations from our laboratory have revealed that, IHp shows significant antidepressant activity after repeated daily oral administration(Kumar et al, IJEB, 1999, 37: 1171-1176) 8
ANTI-DEPRESSANT & ANXIOLYTIC ACTIVITY OF SJW
Figure 1: Effect of IHp on antidepressant activities in rats. *p<0.05 vs. vehicle
Earlier, hypericin was thought to be an active constituent responsible for the antidepressant activity of SJW
Later, hyperforin, has been projected as primarily responsible for the antidepressant activity of SJW
Hyperforin shows its antidepressant activity by inhibiting the neuronal re-uptake of several biogenic amines and amino acid neurotransmitters (Serotonin, Dopamine and Noradrenaline)
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(Chatterjee et al., Life Sci, 1998, 63: 499-510)
In our laboratory, we have evaluated SJW for its anti-anxiety activity in different animal models
SJW dose dependently (100 and 200 mg/kg) increases the open field ambulation, rearings and self grooming in rat open field exploratatory behaviour test
SJW (100 and 200 mg/kg) significantly increased the number of open arms entries and the time spent in the open arms in both elevated plus maze and elevated zero maze behavioural tests
(Kumar et al., IJEB, 2000, 38: 36-41)10
Hypericum perforatum extract (HpE) was well active against diabetes associated depression
HpE treatment dose dependently (100 and 200 mg/kg) reduced the immobility period in despair forced swim test in diabetic rats
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SJW AGAINST DIABETES ASSOCIATED DEPRESSION
Figure 2: Effect of HpE in forced swim test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control
(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)
In open-field exploration test, diabetic rats treated with HpE (100 and 200 mg/kg) showed significant increase in self grooming and rearing compared to vehicle treated diabetic control rats
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SJW AGAINST DIABETES ASSOCIATED ANXIETY
Figure 3: Effect of HpE in open-field exploration test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control
(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)
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In Elevated plus-maze test, diabetic rats treated with HpE (100 and 200 mg/kg) significantly increased the number of open arms entries and the time spent in the open arms compared to vehicle treated diabetic control rats
Figure 4: Effect of HpE in elevated plus-maze test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control
(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)
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MECHANISM OF ANTIDEPRESSANT ACTION
SJW increases the level of the biogenic
neurotransmitters (Norepinephrine and 5-hydroxy
tryptamine) in brain by blocking their neuronal uptake
It was also reported that SJW preferentially increases
extracellular dopamine levels in the rat prefrontal cortex
by inhibiting monoamine oxidase
(Kumar et al., IJEB, 2001, 39: 334-338; Husain et al., Acta Pol Pharm, 2011, 68: 913-918)
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MECHANISM OF ANXIOLYTIC ACTION SJW facilitated GABAergic neurotransmission in brain
through inhibition of neuronal reuptake of GABA
(Kumar et al, IJEB, 2002, 38: 36-41)
SJW extract when tested in memory retrieval training on a one-trial passive avoidance task in mice increased the step-down latency periods
It was also reported that, repeated daily administration of SJW extract significantly increased the step-through latency periods on electroconvulsive shock induced amnesia in rats
Observations reported also revealed that, hyperforin significantly retrieved the loss of memory when tested on scopolamine-induced amnesia in rats
NOOTROPIC ACTIVITY OF SJW
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(Kumar et al., Phytother Res, 2002, 16: 210-216; Khalifa, J Ethnopharmacol, 2001, 76: 49-57)
Downregulation of the dopamine D2 receptor and upregulation of serotonin 5-HT2A and benzodiazepine receptors in brain have facilitated the effect of SJW extract on retrieval of memory
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MECHANISM OF NOOTROPIC ACTION
(Kumar et al., Phytother Res, 2002, 16: 210-216; Khalifa, J Ethnopharmacol, 2001, 76: 49-57)
Repeated daily administration of Indian Hypericum
perforatum (IHp) significantly suppressed chronic stress induced gastric ulceration in rats
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ANTI-STRESS ACTIVITY OF ST. JOHN’S WORT
Figure 5: Effect of IHp in stress induced gastric ulceration in rats. *p<0.05 vs. stress control
(Kumar et al, IJEB, 2001, 39: 344-349)
Hypericum perforatum is a potent adptogen It was reported that, SJW shown its anti-stress activity by
decreasing the plasma cortisol level during stress
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MECHANISM OF ANTI-STRESS ACTIVITY
(Kumar et al, IJEB, 2001, 39: 344-349; Mozaffari et al., Pharmacog Mag, 2011, 7: 213-223)
Indian Hypericum perforatum extract (IHpE) was investigated for its anti-aggressive activity in foot shock-induced aggression test and isolation-induced aggression test in mice
Observations reported from our laboratory was revealed that, repeated daily administration of IHpE significantly suppressed the aggressive behaviour as compared to vehicle treated control group
It was also reported that, IHpE shown its anti-aggressive activity by inhibiting neuronal reuptake of neurotransmitters in brain
21
ANTI-AGGRESSIVE ACTIVITY OF ST. JOHN’S WORT
(Husain et al, Pharmacologyonline, 2009, 1: 432-444; Kumar et al., Drug Discov Ther, 2009, 3: 162-167)
Effect of IHp was investigated on nicotinamide streptozotocin induced diabetic rats
Repeated daily treatment with IHp significantly reduced the elevated blood glucose level
IHp sensitized the insulin receptors and glucose trasporters
ANTIDIABETIC ACTIVITY OF ST. JOHN’S WORT
22Antidiabetic action
(Husain et al, Drug Discov Ther, 2009, 3(5): 215-220; Husain et al, Drug Res, 2011; 68: 913-918)
Figure 6: Effect of IHp on fasting blood glucose level of diabetic rats. *p<0.05 vs. normal; $p<0.05 vs diabetic
Observation from our laboratory revealed that SJW significantly inhibited inflammation on:
Carrageenan induced pedal edema in rats Cotton pellet induced granuloma in rats SJW extract also showed significant analgesic activity on: Tail flick latent period in rats Hot plate reaction time in mice SJW showed its anti-inflammatory and analgesic activity
by inhibiting the production of prostaglandin by blocking COX enzymes
ANTI-INFLAMMATORY & ANALGESIC ACTIVITY OF SJW
23
(Kumar et al., IJEB, 2001, 39: 339-343)
Since the 1980s, numerous clinical trials have been conducted on Hypericum for the treatment of varying types and degrees of depression
Linde and Associates, in 1996 performed meta-analysis-clinical studies of SJW extract (900 mg/day)
CLINICAL STUDIES OF ST. JOHN’S WORT
23 randomized trials 1757 outpatients with depression
4-6 weeks duration
SJW significantly superior to placebo and similarly effective as standard antidepressants while producing fewer side effects
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(Linde et al., BMJ, 1996, 313: 253-258)
In 2000, at seven German medical clinics, Schrader conducted a double blind study for 6 weeks period
Out of 240 patients, 114 were given SJW extract (600 mg) and 126 patients with Prozac (Fluoxetine)
While the two medications showed similar efficacy, but Prozac reported more side effects (gastric irritation, vomiting, erectile dysfunction) than SJW
25
(Klemow et al, Herbal Med, 2011, 11)
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MARKETED PRODUCTS OF ST. JOHN’S WORT
S N Products Indication(s) Company
1Nervous tension
and mild anxiety
Blackmores Ltd. New South Wales, Australia
2Depression,
anxiety and low mood
Swisse Vitamins Pvt Ltd.Collingwood, Australia
3Mild depression and low mood
Schwabe Pharma (UK) Ltd.Marlow, UK
4Nervous tension
and anxiety Fushi Wellbeing Ltd.
London, UK 26
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S N Products Indication(s) Company
5
Headache, Nerve pain, depression, inflammation and
wound healing
Camp Wander (UK) Ltd.Marlow, UK
6Low mood and mild anxiety
Lamberts Healthcare Ltd.Tunbridge Wells, UK
7Low mood and
anxiety
A.Vogel Herbal RemediesBioforce (UK) Ltd.
Irvine, UK
8Low mood and
anxietyOnly Natural Inc.New York, USA 27
S N ProductsIndication(s
)Company
9Nervous
tension and mild anxiety
East West Tea Company, LLC.Oregon, USA
10Low mood and mild anxiety
Indian Herbs Specialties Pvt Ltd. Saharanpur, India
11Analgesic
and wound healing
Weleda Ltd.Arlesheim, Switzerland
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Several pharmaceutical-grade preparations of SJW are currently valued for treating depression and other mood disorders
SJW is reputed as one of the best-selling herbs of the last decade
Commercially, SJW is available in the form of tablets, capsules, dried powders and tinctures
In the United States, SJW, like all herbal remedies, is listed as a dietary supplement by the Food and Drug Administration (FDA) 29
MARKET POTENTIAL OF ST. JOHN’S WORT
With an estimated US$315 million turnover, Europe holds the 1st position worldwide
In the United States, annual sales reached a peak of US$315 million in 1998, but declined to approximately US$60 million by 2006
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(Klemow et al, Herbal Med, 2011, 11)
Over the past 20 years, SJW has become a mainstream alternative treatment for depression
Thanks to its popularity, the effectiveness of SJW has been intensively studied since the mid-1980s
It is interesting to note that the greatest clinical success for the SJW was achieved in Europe
SJW does appear to be an effective treatment for other disorders, particularly some skin ailments, inflammation and certain forms of cancer
Therefore, drug discovery projects based on SJW should not be limited to hyperforin and also should not be limited to antidepressant activity
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AND THE STORY GOES ON…
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ACKNOWLEDGEMENTS
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