Case Report Zedoary-Induced Cardiovascular Disorders Usama M. El-Barrany*and Magdy A. Ismail** Forensic Medicine and Toxicology Department, Faculty of Medicine, Cairo* and Al-Azhar “Boys” ** Universities ABSTRACT: Zedoary (Curcuma Zedoaria) is a rhizomatous herb, with various active ingredients including curcumin, berberine, hydrastine, canadline, zingiberine, dihydrocurdione, some volatile oils, and resins. It is used orally in traditional medicine for systemic uses as stomachic, tonic, laxative, antifungal, analgesic, and anti-inflammatory as well as in treatment of some stomach and liver diseases, or applied locally as poultice for skin lesions and eyes. In this case report, two young adult female patients with cardiovascular disorders (hypotension and bradyarrhythmias), caused by ingestion of an extract of Zedoary (overdose) were described. The most patient clinical issues were discussed. One patient died 24 hours after Zedoary ingestion despite aggressive supportive care. Symptoms of the other patient were resolved after giving calcium gluconate 10% and pressor agent infusions in addition to external pacing. In conclusion, ingestion of extracts of Zedoary may lead to symptoms and signs similar to toxicity with calcium channel blockers. It is recommended that, in addition to pressor agent infusions, 10% calcium gluconate intravenously must be administered as a specific therapy.

2. Zedoary-Induced
Cardiovascular Disorders
case report
Usama M. El-Barrany*
Magdy A. Ismail**
Forensic Medicine and Toxicology Department,
Faculty of Medicine, Cairo* and Al-Azhar
“Boys” ** Universities

3. intoduction

4. intoduction
• Many people use traditional remedies as a
first line medication.
• Some herbal toxicity is predictable, based on
known botanical content.
• Many other adverse effects are idiosyncratic
or not commonly appreciated.
• Zedoary (Curcuma Zedoaria) is one of these
commonly used herbs.

5. Zedoary (Curcuma Zedoaria)

6. Zedoary (Curcuma Zedoaria)
• Species: Curcuma zedoaria.
• Family: Zingiberaceae (ginger family).
• Origin: The plant is native to India and Indonesia.
but today is widely cultivated in India, South-East
Asia and China.
• It was introduced to Europe by Arabs around the
sixth century.
• Etymology: The European names for zedoary
originate from Arabic jadwār and Farsi zedwaar.

7. Zedoary (Curcuma Zedoaria)
• Characteristics:
• A rhizomatous herb with a 6-foot tall leafy stem.
• The leaves are 1 foot long and 3 inches across.
• The flowers are white or yellowish with a lip that is pale
yellow-shaded, with a deeper yellow color near the base.
• The fruits have 3-valved capsules.
• The rhizome is short, firm, and of externally wrinkled
gray, ash-colored appearance, but with a brownish red
color from the inside.

8. Zedoary (Curcuma Zedoaria)

9. Zedoary (Curcuma Zedoaria)

10. Zedoary (Curcuma Zedoaria)

11. Zedoary (Curcuma Zedoaria)
• Active ingredients:
• Curcumin, berberine, hydrastine, canadline,
zingiberine, dihydrocurdione, ar-turmerone,
beta-turmerone, some volatile oils, and resins.
• The highest concentrations of these
constituents are in the root (rhizomes), the
lowest, in the leaves and stem.

12. Zedoary (Curcuma Zedoaria)
• Uses: The used part is the rhizomes.
• Food:
• It has a fragrant smell (more similar to ginger, except
with a very bitter taste).
• Due to its bitter taste, its use as a spice today is rare,
having been replaced by ginger.
• Although it is seldom used today as an individual
spice, it may be employed in spice mixtures.

13. Zedoary (Curcuma Zedoaria)
• Food:
• In Indonesia & Thailand, the young rhizomes
are often eaten as an aromatic vegetable,
zedoary can also be ground to a powder and
added to curry pastes.
• In India, it tends to be used fresh or in
pickling.

14. Zedoary (Curcuma Zedoaria)
• Medicinal uses:
• Zedoary is used in the form of powdered root,
tincture, fluid and solid extract; the medicinal
substance obtained has a fragrant smell, and a warm
bitter aromatic taste.
• It is much used as a medicine in China and Japan. It
has been used as an antivenom for the Indian cobra.
• It has been also used in traditional eastern medicines
to help digestion, relieve colic, as a laxative,
antifungal, analgesic and anti-inflammatory agent.

15. Zedoary (Curcuma Zedoaria)
• Medicinal uses:
• Dihydrocurdione, the major component of Zedoary has
anti-inflammatory potency related to its antioxidant
effect.
• The anti-inflammatory and cancer chemopreventive
effect of some components of Zedoary might be due to
decreased prostaglandin and nitric oxide production
through respective inhibition of cyclooygenase 2 (COX-
2) and nitric oxide synthase, which have been
implicated as important mediators in the processes of
inflammation and carcinogenesis.

16. Zedoary (Curcuma Zedoaria)
• Medicinal uses:
• Zedoarin, kurdiona and kurkumol are substances that
can be also found in Zedoary.
• These substances have anti-neoplastic functions
through breaking ribosome formation in cancer cells
and wild tissue.
• They enhance the formation of fibroblast tissue around
the cancer and form a layer of lymphocytes in the cells
of cancer & wrap it.
• So, the tissue cells of cancer can not grow, eventually
the cancer cells will die.

17. Zedoary (Curcuma Zedoaria)
• Medicinal uses:
• Zedoary has been used to treat some liver and
coronary heart disease.
• It has been used to treat anemia, prevent
leukopenia due to cancer therapies and as an
agent for purifying the blood.
• It has been also applied locally as poultice for
skin lesions and eyes.

18. Zedoary (Curcuma Zedoaria)
• Others:
• The essential oil produced from the dried
roots of Zedoary is used in perfumery as well
as an ingredient in bitter tonics.

19. Zedoary (Curcuma Zedoaria)
• On the other hand, a protein flour,
prepared from rhizomes of Zedoary ,
proved to be highly toxic to 5-week-old rats
and caused 100% mortality within 6 days
when given at 320 g/kg diet.
• When a meal formed of fresh minced and
dried rhizomes of Zedoary was given to
weanling rats at 400 g/kg diet, all the
animals lost weight rapidly, and two of the
five rats died within 4 days.

20. Case Report

21. Case Report
• This study describes 2 cases of Zedoary-induced
bradyarrhythmias and severe
prolonged hypotension (during our work in
Center of Poison Control and Clinical Forensic
Chemistry, in Holy Makkah region, Saudi
Arabia).

22. CASE I

23. CASE I
• A 20-year-old woman was admitted to Al-noor
special hospital in Holy Makkah region, Saudi
Arabia at 3/11/2003 after ingestion of an
unknown quantity of Zedoary extract to reduce
pain (the history was taken from her father).
• On admission, she was unresponsive except for
painful stimuli, with diaphoresis, cyanosis, and
respiratory depression.
• Pupils were slightly dilated; systolic blood
pressure was 50 mmHg, with a third degree heart
block and a ventricular rate 40 beats/minute.

24. CASE I
• Following intubation, gastric lavage was done,
and activated charcoal was given 3 times (every 4
hours).
• Routine toxicological screening using,
immunoassay techniques (AxSYM), was negative
for alcohol, opiates, barbiturates,
benzodiazepines, amphetamines, cocaine,
cannabis, tricyclic antidepressants (TCAs),
digoxin, theophylline, salicylates, acetaminophen,
phenytoin, carbamazepine as well as valproic
acid.

25. CASE I
• Color tests, TLC & Toxi-Lab System showed –ve
results for other common substances such as
phenothiazines, antihistamines, beta blockers,
calcium channel antagonists, NSAIDs, SSRIs,
organophosphates as well as carbamates.
• Bradycardia and hypotension were unresponsive
to atropine, infusion of dopamine, saline, or even
pacemaker insertion.
• She died within 24 hours after admission from
cardiovascular collapse.

26. CASE Ii

27. CASE Ii
• An 18-years old woman was admitted to Al-noor
special hospital in Holy Makkah region, Saudi
Arabia at 4/11/2003 after ingestion of a large
quantity of Zedoary extract as a tonic. (the
history was taken from the patient).
• On admission, she was alert, but had nausea,
vomiting, abdominal pain, dizziness and lethargy.
• Systolic blood pressure was 60 mmHg, with
junctional bradycardia (as slow as 27
beats/minute) but without evidence of
myocardial infarction.

28. CASE Ii
• Following spontaneous emesis, gastric lavage
was done, and activated charcoal was given 3
times (every 4 hours).
• Routine toxicological screening, using
immunoassay techniques (AxSYM), was also
negative for alcohol, opiates, barbiturates,
benzodiazepines, amphetamines, cocaine,
cannabis, TCAs, digoxin, theophylline, salicylates,
acetaminophen, phenytoin, carbamazepine as
well as valproic acid.

29. CASE Ii
• Color tests, TLC & Toxi-Lab System showed also –ve results
for other common substances such as phenothiazines,
antihistamines, beta blockers, calcium channel antagonists,
NSAIDs, SSRIs, organophosphates as well as carbamates.
• Dopamine, intravenous saline, and 20 ml of 10% calcium
gluconate intravenously were administered, and a
pacemaker was placed.
• Calcium gluconate was repeated and pressor agents were
infused for additional 18 hours.
• Blood pressure became normal after 24 hours, and sinus
rhythm returned after 35 hours from admission. The
patient was discharged free 5 days post-admission.

30. Discussion

31. Discussion
• The rapid course of the two cases pushed the
team of center to work in two ways:
• One way was the analysis of biological fluids
from the two patient as well as the possible
analysis of Zedoary.
• The other one was getting all possible data
about the mentioned herb.

32. Discussion
• In the two cases, routine toxicological screening
for the previously mentioned substances was
done to exclude any of them as a cause of
toxicity.
• Many substances such as beta blockers,
antihistamines, CCAs, NSAIDs or SSRIs are not
analyzed routinely as one group but as individual
drugs in the group, meaning that getting –ve
results for some drugs in the group does not
exclude the presence of other + ve unknown
drugs or substances belonging to the same group.

33. Discussion
• Although HPLC-MS needed for analysis of
zedoary into their different components was
available in the center, we did not have the
special method for detection of this herb.
• In addition to that, the rapid course of the two
cases especially the first one enforced all the
team of the center to depend on the available
data received from our search about Zedoary.

34. Discussion
• Some of these data included that Curcuma herbs
have showed hypotensive and protective effect
on the endothelium in spontaneously
hypertensive rats.
• Especially, C. Zedoaria was more effective than C.
Longa, and its mechanism was thought to be
related to a radical scavenging effect and
improvement of hemorheology.
• Hemorheology is the study of flow properties of blood and its
elements (plasma and formed elements, including red blood cells,
white blood cells and platelets).

35. Discussion
• Dihydrocurdione, the major component of
Zedoary has calcium channel antagonist-like
effects.
• Zedoary contains both hydrastine and
berberine, which cause a decrease in blood
pressure.

36. Discussion
• Berberine is thought to be seven times as
potent as hydrastine in producing
hypotension.
• A dose of 1mg/kg of Zedoary extract will
produce a slight increase then decrease in
blood pressure, while 2mg/kg will produce
significant prolonged hypotension.

37. Discussion
• On the other hand, hallmarks of CCAs overdose
include bradyarrhythmias, myocardial depression,
peripheral vasodilatation, hypotension, and
syncope.
• These symptoms and signs of toxicity coincided
with the two cases of Zedoary toxicity, presently
reported, whereas their main manifestations
were cardiovascular disorders in the form of
severe prolonged hypotension and
bradyarrhythmias.

38. Discussion
• Although plasma concentrations of CCAs
correlate well with cardiovascular depression in
the experimental setting, plasma concentrations
in humans show no significant correlation with
the amount of drug reportedly ingested by
patients.
• Moreover, fatal verapamil overdose has occurred
with a peak plasma concentration slightly higher
than the high-therapeutic range (687 ng/mL).

39. Discussion
• Thus, managing patients with suspected herbs
having signs and symptoms similar to CCA
overdose should be based on clinical features
rather than analysis.
• Based on these data, calcium gluconate 10%
was given to the second patient to treat the
refractory hypotension and to avoid death as
in the first case.

40. Conclusion AND
RECOMMENDATIONS

41. Conclusion AND RECOMMENDATIONS
• There is no logic supporting the popular
conception that herbal products are safer or
more natural than pharmaceutical
medications.
• The use of herbs by most individuals should
be put under strict medical regulations.

42. Conclusion AND RECOMMENDATIONS
• More studies are needed regarding the clinical
manifestations as well as the chemical analysis
of most commonly-used herbs.
• Toxicology centers should be equipped with
modern analytical facilities as well as
information centers to help clinicians in
managing different toxic cases.

43. يابلادي يابلادي
أنا باحبك يابلادي
لحسن
ً
شكرا
استماعكم

44. References

45. References
• Ansari MH, and Ahmad S (1991): curcuma zedoaria root extract. Biomedical Rwsearch 2(2): 192-6.
• Bright JJ (2007): Curcumin and autoimmune disease. Adv Exp Med Biol. 2007;595:425-51.
• Chang L-H, Jong T-T, Huang H-S, Nien Y-F and. Chang C-M J (2006): Supercritical carbon dioxide extraction
of turmeric oil from Curcuma longa Linn and purification of turmerones. Separation and Purification
Technology,47 (3): 119-125.
• Clifton DG, Booth DC, Hobbs S, et al (1990): Negative inotropic effect of intravenous nifedipine in coronary
artery disease: Relation to plasma levels. Am Heart J 119:283-290.
• Eisenberg DM, Klesser RC, Foster C (1993): Unconventional medicine in the united states, prevalence, cost
and patterns of use. N Engl J Med 328: 246-52.
• Ficker CE, Smith ML, Susiarti S, Leaman DJ, Irawati C, Arnason JT (2003): Inhibition of human pathogenic
fungi by members of Zingiberaceae used by the Kenyah (Indonesian Borneo). J Ethnopharmacol 85(2-3):
289-93.
• Frohne D, Pfander HJ (1984): A colour Atlas of poisonous plants. Wolfe publishing and Ltd London, Pp.
147-8.
• Goto H, Sasaki Y, Fushimi H, Shibahara N, Shimada Y, Komatsu K (2005): Effect of curcuma herbs on
vasomotion and hemorheology in spontaneously hypertensive rat. Am J Chin Med. 33(3):449-57.
• Gupta Sk, Banerjee AB, Achari B (1986): Isolation OF Ethyl p- methoxycinnate, the major antifungal
principle of curcuma zedoaria. Lioydia: 39 (4): 218-22.

46. References
• Lee SK, Hong CH, Huh SK, Kim SS, Oh OJ, Min HY, Park KK, Chung WY, Liu JC, Chan P, Hsu FL, Chen YJ,
Hsieh MH, Lo MY, Lin JY (2002): The in vitro inhibitory effects of crude extracts of traditional Chinese
herbs on 3-hydroxy-3-methylglutaryl.
• Navarro DF, de Souza MM, Neto RA, Golin V (2002): Phytochemical analysis and analgesic properties of
Curcuma Zedoary grown in Brazil. Phytomedicine 9(5): 427-32.
• Hong CH, Kim Y, Lee SK (2001): Sesquiterpenoids from the rhizome of Curcuma zedoaria. Arch Pharm Res
24(5): 424-6.
• Hong CH, Noh MS, Lee WY, Lee SK (2002): Inhibitory effects of natural sesquiterpenoids isolated from the
rhizomes of curcuma zedoaria on prostaglandin E2 and nitric oxide production. Planta Med 68(6): 545-7.
• Huntington RA, Abt AB, Oh JY (1995): Chinese herbal medicine induces acute renal failure. Arch Intern
Med 155: 211-2.
• Hwang JK (2002): Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and
nitric oxide synthase (iNOS) activity in mouse macrophage cells. J Environ Pathol Toxicol Oncol 21(2): 141-
8. Irie KT, Joshi S, Singh AK (1989): Isolation and structure elucidation of potential active principles of
curcuma zedoria rhizomes. Herba Hungarica 28 (1): 95-8.
• KI, Kim JW, Hong BS, Shin DH, Cho HY, Kim HK, Yang HC (2000): Antitumor, genotoxicity and
anticlastogenic activities of polysaccharide from Curcuma zedoaria. Mol Cells 10(4): 392-8.
• Kim KI, Shin KS, Jun WJ, Hong BS, Shin DH, Cho HY, Chang HI, Yoo SM, Yang HC (2001): Effects of
polysaccharides from rhizomes of Curcuma zedoaria (Indian arrowroot: Curcuma zedoaria) for rats and
chicks. Br J Nutr 41(1): 57-63.

47. References
• Latif MA, Morris TR, Miah AH, Hewitt D, Ford JE (1979): Toxicity of shoti on macrophage functions. Biosci
Biotechnol Biochem 65(11): 2369-77.
• Lee H, Lin JY (1988): Antimutagenic activity of extracts from anticancer drugs in Chinese medicine. Mutat
Res 204(2): 229-34.
• Howarth DM, Dawson AH, Smith AJ, et al (1994): Calcium channel blocking drug overdose: An Australian
series. Hum Exp Toxicol 13:161-166.
• Mangiardi LM, Hariman RJ, McAllister RG (1978): Electrophysiologic and hemodynamic effects of
verapamil: Correlation with plasma drug concentrations. Circulation 57:366-372.
• Mastuda H, Ninomiya K, Morikawat T, Yoshikawa M (1998): Inhibitory effect and action mechanism of
sesquiterpenes from Zedoria rhizoma on D galactosamine / lipopolysaccharid-induced liver injury. Bioorg
Med Chem letters 8(4): 339-44.
• Pamplona CR, de SouzaMM, Machado Mda S, Cechinel Filho V, Navarro D, Yunes RA, Delle Monache F,
Niero R (2006): Seasonal variation and analgesic properties of different parts from Curcuma zedoaria
Roscoe (Zingiberaceae) grown in Brazil. 1: Z Naturforsch [C], 61(1-2):6-10.
• Perharic L, Shaw D, Colbridge M (1994): Toxicologic problem resulting from exposure to traditonal
remedies and food supplements. Drug safety 11: 284-94.
• Proano L, Chiang WK, Wang RY. (1995): Calcium channel blocker overdose. Am J Emerge Med 13: 444.
• Randall S. Alberte, Estero, FL (US); William P. Roschek, JR., Naples, FL (2010): Extracts of Curcuma and
Methods of Use Thereof. U.S. Classification, provisional application, 61/105,995: 1-37.

48. References
• Robert T. Gow, Dan Li, H. Brock Manville, George W. Sypert, Randall S. Alberte (2008): Extracts and
methods comprising curcuma species. U.S. Classification, provisional application, 60/873,405: 1-111.
• Rosansky SJ (1991): Verapamil toxicity—Treatment with hemoperfusion. Ann Intern Med 114:340-341.
• Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R (1995): Anti-tumor and antioxidant activity of
natural curcuminoids. Cancer Lett. 20;94(1):79-83.
• Rumaack BH, Gelman CR, Hess AJ (ed.) (1997): Laboratory investigation of calcium channel blockers. In:
Poisondex information system, Micromedex 2000, Denver.
• Spoerke DG (1988): Herbal medication. Wardbridge press publishing company, Santa barba , california,
Huntington. Pp. 134-7.
• SyuWJ, Shen CC, Don MJ, (1998): Cytotoxicity of curcuminoid and some novel compound from curcuma
zedoria. J Nat Prod 61(12): 1531-4.
• Venkatesan N, Punithavathi D, Babu M (2007): Protection from acute and chronic lung diseases by
curcumin. Adv Exp Med Biol. 595: 379-405.
• Xu XB, Qin XM, Xu JD, Pang JJ (2001): Effect of Curcuma zedoaria (Berg.) Bosc on the myoelectric activity
of uterus in rats and study of its mechanisms. Zhongguo Zhong Yao Za Zhi 26(5): 334-7.
• Yoshioka T (2000): Calcium channel blocker like effect of dihydrocurdione on rodent intestinal and vascular
smooth muscle. European journal of pharmacology 403(3): 235-42.
• Yoshioka T, Fujii E, Endo M, (1998): antiinflammatory potency of dihydrocurdione, a zedoary- derived
sesquiterpene. Inflammm. Res 47(12): 476-81.