Adverse drug interactions

The use of complementary and adjunctive therapy has been steadily increasing in the U.S. since the 1960s. This can be attributed to several factors, in particular to over 80 million 'baby boomers' embracing alternative medicine as a way to enhance their medical care. The perceived coldness and remoteness of conventional medicine; the entanglement of managed care in red tape; continued emphasis on 'natural' which supposedly connotes ' better', as well as the popularity of vegetarian practices have also contributed to the general population's increasing involvement with alternative medicine. In 1999, 40% of Americans sought alternative medical treatment, outpacing visits to conventional primary care physicians.

Till date, there is scarce or very limited data for adverse drug reaction profile of phytochemicals. This may be attributed to lack of clinical trials with phytochemicals. In phytomedicine, most of the clinical studies have been conducted with herbal extracts standardized to a certain quantity of phytochemical rather than purified phytochemicals.

According to Edwards, World Health Organization Adverse Drug Reaction (WHO ADR) has documented 3.6 million adverse drug reactions. Of these, 41,439 are directly or indirectly related to phytodrugs. It should be noted that most of the adverse drug reactions related to phytodrugs are those of crude preparations or extracts and not of phytochemicals.

Let us concentrate on nephrotxicity of herbs (see Tables 1.1 and 1.2). The consensus of many renal clinicians is that medicinal herbal use, with its known potent pharmacological activity, chemical components (some unknown), microbial content, and ability to interfere with medications, is rendered dangerous and even unadvisable for the renal patient. Herbal preparation-induced acute renal necrosis and chronic renal failure belie the assumed innocuous nature of these preparations. Substantial morbidities such as chronic renal failure, dialysis, or renal transplant and even death have been seen with herbal products. Since these herbal preparations are not single chemical entities, no activity of toxic component can be subjected to standardized tests of efficacy and safety.

Table. 6.4 The five best-selling herbs in the U.S.

Herb

Safe? (In healthy-not renal-population)

Generally Safe? (In healthy-not renal-population)

Comments

St. John's Wort

(Hypericum perforatum)

Anxiety/ Depression- For mild to moderate depression only

Yes- Not recommended in renal pts.

Yes

Interacts with many drugs- transplant rejection drugs, Not to be taken in pregnancy or with psychoactive Drug/SSRIs.

Echinacea

prevent or improve symptoms of respiratory tract infections

Yes

Yes

Do not take for more than 6 wk. Could worsen autoimmune disease. Type 1 Diabetes.

Garlic (Allium sativum L)

Cardiac/ Cholesterol To decrease serum cholesterol and Triglycerides

Yes

Yes

Effective dose is large; 1-4 cloves Suggest enteric coated Side effects: halitosis, gastritis; diaphoresis, light-headedness.

Tablet 6.4 contd...

Herb

Safe? (In healthy-not renal-population)

Generally Safe? ( In healthy-not renal-population)

Comments

Ginseng (Panax Ginseng)

Multiple Categories supposed uses: stress, hypertension, depression, and impaired memory

A matter of debate-Not recommended

NO

Side effects: anxiety, hypertension, insomnia, headaches, and asthma attacks.

Gingko

(Ginkgo biloba)

Memory/ Concentration-for elderly with Alzheimer's dementia

Yes

Yes- antagonistic effect on platelet activating factorrole in Immune— mediated renal disease

Side effects: Occasional headache.

Table 6.5 Other popular herbs in the U.S.

Herb

Category/Use

Generally Safe? (In healthy-not renal-population)

Generally Safe?

(In healthy-not renal-

population)

(Cimicifuga racemosa L)

Health-Menopausal symptoms/ PMS

(Questionable)

(Questionable)

Perspiration.

Saw palmetto

(Serenoa repens)

Men's Health

Yes

Yes, Clinical evidence getting stronger

High doses headache, diarrhea.

Ma-huang (Ephedra sp.)

Weight Loss

Anorectic,

Bronchodilator

Hypertensive crisis; CVA;

arrhythmias, death

No

Yes, but potentially lethal even in young healthy.

Hypertensive crisis; CVA; arrhythmias, death.

Feverfew

Vascular migraines

Yes

Yes

May cause mouth ulcers; increased heart rate.

Valerian (Valeriana officinalis L.)

Insomnia

Yes-considered safe until cardiac withdrawal syndrome documented

Yes-generally recognized as safe

Headache, excitability, uneasiness, cardiac disturbances.

Source: March 2000 issue of Nephrology News & Issues.

Source: March 2000 issue of Nephrology News & Issues.

C. Phytochemical variability in commercial samples Example of withaferin-A

Sangwan et al., 2004 reported the variability of withaferin-A (Fig. 5.249, Chapter 5) in commercial preparations of Ashwagandha (Withania somnifera). Commercial samples consisting of 250 mg Ashwagandha (as indicated on the label) were investigated for their phytochemical contents. The samples were quantified by High Performance Liquid Chromatography. The amount of withaferin-A estimated in commercial samples is given in Table 5.6. There was significant variation in relative amount of withaferin A. The study reflected a 117-fold higher concentration of withaferin A in the highest (product 1) holding product compared to one with the least (product 10). Further, according to the recommended intake of the product as mentioned on the label, the dose of withaferin A ranged from 0.02 mg to 1.4 mg.

Table 6.6 Withaferin A in selected commercial mono and poly herbal Ashwagandha products.

Products

Withaferin A (mg g-1 of Ashwagandha*)

Percentage of maximum in the sample

Withaferin A (mg) per suggested daily dose**

Dose multiplicity factor for Withaferin A

#001

2.34

100

1.4

70

#002

1.03

44

0.52

26

#003

0.93

39.7

0.37

18.5

#004

0.43

18.4

0.50-1.00

25-50

#005

0.43

18.4

0.86-1.72

43-86

#006

0.41

17.5

0.08-0.16

4.0-8.0

#007

0.32

13.7

0.06

3

#008

0.06

2.6

0.02

1

#009

0.05

2.1

n.a.

n.a.

#010

0.02

0.9

n.a.

n.a.

*Ashwagandha state (herb or herb extract) as specified on the product.

**Daily dose (load) of withaferin A computed from its concentration in the product and suggested intake of product n.a. Not available/applicable.

Source: Adapted with permission from Sangwan et al., Current Science 2004.

*Ashwagandha state (herb or herb extract) as specified on the product.

**Daily dose (load) of withaferin A computed from its concentration in the product and suggested intake of product n.a. Not available/applicable.

Source: Adapted with permission from Sangwan et al., Current Science 2004.

The commercial samples were further studied for the relative amount of six phytochemicals (WS-1 and WS-6). Data in Table 5.7 suggests wider variation with regard to amount of WS-1 to WS-6. The example of withaferin-A clearly suggest significant variation in the amount of active constituents in the commercial herbal products.

Table 6.7 Content of unidentified Ashwagandha-specific phytochemicals in selected commercial mono and poly-herbal products.

Products

WS-1 (8.9 min)

WS-2 (25.4 min)

WS-3 (25.7 min)

WS-4 (27.6 min)

WS-5 (29.3 min)

WS-6 (45.1 min)

#001

1.41

0.58

n.d.

n.d.

0.38

1.22

#002

0.21

0.36

0.30

0.02

0.32

0.92

#003

3.10

n.d.

0.68

0.06

0.38

1.14

#004

0.13

0.08

n.d.

n.d.

0.05

0.17

#005

n.d.

n.d.

0.67

n.d.

0.23

0.55

#006

9.18

n.d.

0.45

0.94

0.78

0.17

#007

n.d.

n.d.

n.d.

1.24

n.d.

0.30

#008

27.8

0.03

n.d.

0.11

n.d.

n.d.

#009

4.94

n.d.

0.05

0.79

n.d.

n.d.

#010

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

*Ashwagandha state (herb or herb extract) as specified on the product n.d., not detected.

*Ashwagandha state (herb or herb extract) as specified on the product n.d., not detected.

Indications in parentheses are according to HPLC retention times of the phytochemicals under the condition of the analysis.

Source: Adapted with permission from Sangwan et al., Current Science 2004.

Example of allicin

The data deals with the evaluation of allicin (Fig. 5.270, Chapter 5): levels in Australian grown garlic. A total of 200 garlic samples were collected from 43 producers in the Australian states of Victoria, Tasmania, Queensland, New South Wales and South Australia. The 200 samples tested recorded allicin yields in the range 0.5 to 9.0 mg/g (by fresh weight) with the majority of samples in the 3.0 to 6.0 mg/g range (Fig. 6.21).

50 40 30

20 10

0 123456789 Allicin (mg/g FW)

Fig. 6.21 Frequency distribution of allicin levels in 200 garlic samples. Source: Adapted with permission from Rural Industries Research and Development Corporation, Victoria.

Color image of this figure appears in the color plate section at the end of the book.

20 10

Fig. 6.21 Frequency distribution of allicin levels in 200 garlic samples. Source: Adapted with permission from Rural Industries Research and Development Corporation, Victoria.

Commercial interests determined that an allicin level of 4.5 mg/g (by fresh weight) was required for extraction to be economically viable. Almost 50% (95 out of 200) of the samples assayed had allicin yields over 4.5 mg/g, (i.e., 'pharmaceutical grade') and a further 10% of the samples were in the 4.0-4.5 mg/g range.

As a comparison to allicin levels previously cited in scientific literature, the highest previously recorded allicin level was 7.7 mg/g (by fresh weight) for Romanian Red garlic grown in New York, USA (Table 1.1). Six samples of the Australian grown garlic tested in the current study recorded allicin yields higher than 7.7 mg/g. The next highest allicin yield recorded prior to this study was 6.7 mg/g for Spanish Roja grown in the USA and 6.6 mg/g for Laotouxu garlic obtained from China. Fifteen Australian grown samples from the current study exceeded this level and a number of these samples are listed in Table 5.22.

Table 6.8 Allicin levels (from fresh garlic samples) recorded in Australia and other countries.

Country of origin

Allicin

Country of origin

Allicin

mg/g FW

mg/g FW

Australia

9.0

Switzerland#

3.6

Australia

8.4

Switzerland#

2.4

Australia

8.3

USA*

7.7

Australia

7.8

USA*

6.7

Australia

7.8

USA*

6.1

Australia

7.7

ChinaA

6.6

Australia

7.6

ChinaA

6.4

Australia

7.4

ChinaA

5.1

Australia

7.3

[email protected]

5.3

Australia

7.3

[email protected]

5.1

Australia

7.0

[email protected]

5.0

#From (7) Ziegler and Sticher, 1989. *From (5) Koch and Lawson, 1996. AFrom (6) Lawson, Wood and Hughes, 1991. @From (8)Ueda et al., 1991.

#From (7) Ziegler and Sticher, 1989. *From (5) Koch and Lawson, 1996. AFrom (6) Lawson, Wood and Hughes, 1991. @From (8)Ueda et al., 1991.

D. Toxicology of phytochemicals

This is another gray area where preliminary investigations are to be carried out. LD50 of some known specialty phytochemicals are tabulated below:

Table 6.9 Medial lethal dose of some well-known phytochemicals.

S.no

Phytochemical

LD50

1..

Abrin

0.0004 mg/kg (oral in mouse)

2.

Arecoline

100 mg/kg (s.c. in mouse)

3.

Caffeine

192 mg/kg (oral in man)

4.

Chavicol

1230 mg/kg (oral in rat)

5.

Eugenol

1930 mg/kg (oral in mouse)

6.

Harmaline

120 mg/kg (s.c. in rat)

7.

Harmine

200 mg/kg (i.v. in mouse)

8..

Lobeline

40 mg/kg (ipr in mouse)

9..

Mescaline

132 mg/kg (oral in man)

10.

Nicotine

30 mg/kg (oral in man)

11..

Pyridine

891 mg/kg (oral in rat)

12..

Quinine

294 mg/kg (oral in man)

13..

Rotenone

143 mg/kg (oral in man)

14..

Tubocurarine

28 mg/kg (oral in rat)

Source: Adapted from Duke 1998.

Source: Adapted from Duke 1998.

E. Cost-effectiveness of isolation methods

Cost-effectiveness of isolation methods of phytochemicals is an important factor in determining the future of phytomedicine. Isolating bioactive compounds is very expensive and complicated. Further a lack of public awareness about health benefits of phytomedicine and phytochemicals is another obstacle.

Conclusion

According to one estimate, only 20% of the plant flora has been screened for drugs. Keeping in view the vast treasure of medicinal herbs, one can expect phytochemicals to play a significant role as modern medical science has limited options for diseases like diabetes mellitus, rheumatoid arthritis, Alzheimer's disease and Parkinson's disease. Work on the identification and isolation of phytochemicals is an ongoing process and phytomedicine is expected to play a critical role in the future of the healthcare system.

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