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中西醫腎病聯合討論會
主題：鉛中毒
報告日期：2011/8/17
報告醫師：R4楊晉瑋
指導醫師：陳俊良主任
Outline
• Adulterants in Asian Patent Medicines
• Chinese proprietary medicine in Singapore: regulatory control of toxic
heavy metals and undeclared drugs
• Toxic heavy metals and undeclared drugs in Asian herbal medicines
• Heavy Metal Content of Ayurvedic Herbal Medicine Products
• Lead, Mercury, and Arsenic in US- and Indian-Manufactured
Ayurvedic Medicines Sold via the Internet
• Blood Lead Below 0.48 μmol/L (10 μg/dL) and Mortality Among US Adults
• Herbal Supplement Use and Blood Lead Levels of United States Adults
• Adulteration by synthetic therapeutic substances of traditional Chinese
medicines in Taiwan
• Lead nephropathy and lead-related nephrotoxicity
• Protective effect of herbs extract against lead-poison in rats
Adulterants in Asian Patent
Medicines
N Engl J Med. 1998 Sep
17;339(12):839-41
• Seven percent of the 251 products tested
contained undeclared pharmaceuticals (e.g.
ephedrine, chlorpheniramine,
methyltestosterone and phenacetin).
• Twenty-four products contained at least 10
ppm lead, 36 contained an average of 14.6
ppm arsenic, 35 contained an average of 1046
ppm mercury, and 23 had more than one
contaminant and/or adulterant.
Chinese proprietary medicine in
Singapore: regulatory control of
toxic heavy metals and
undeclared drugs
Drug Saf. 2000 Nov;23(5):351-62.
• 2080 samples of such medicines in Singapore
and tested them for heavy metal content.
• Forty-two (2%) different medicines were
found to contain metals in amounts exceeding
the legal limits.
• Mercury was found in 28 products, lead in
eight, arsenic in six and copper in one. One
product contained both mercury and lead and
another product contained both mercury and
arsenic.
Toxic heavy metals and
undeclared
drugs in Asian herbal medicines
TRENDS in Pharmacological Sciences
Vol.23 No.3 March 2002
• Indian medical systems (e.g. Ayurveda and Unani)
• Traditional Chinese medicines (TCMs)
Heavy Metal Content of
Ayurvedic Herbal Medicine
Products
JAMA, December 15, 2004—Vol 292,
No. 23
US Pharmacopeia
4.5
21
US Environmental Protection Agency
3
Conclusions
• Limits: Sample sizes, Metals chemical forms
• One of 5 Ayurvedic HMPs produced in South
Asia and available in Boston South Asian
grocery stores contains potentially harmful
levels of lead, mercury, and/or arsenic.
• Users of Ayurvedic medicine may be at risk for
heavy metal toxicity, and testing of Ayurvedic
HMPs for toxic heavy metals should be
mandatory
Lead, Mercury, and Arsenic
in US- and Indian-Manufactured
Ayurvedic Medicines Sold via
the Internet
JAMA, August 27, 2008—Vol 300, No. 8
Objectives
• To determine the prevalence of Ayurvedic medicines
available via the Internet containing detectable lead,
mercury, or arsenic and to compare the prevalence
of toxic metals in US- vs Indian-manufactured
medicines and between rasa shastra and non–rasa
shastra medicines.
• Rasa shastra is an ancient practice of deliberately
combining herbs with metals (eg, mercury, lead, iron,
zinc), minerals (eg, mica), and gems (eg, pearl).
AHPA, US-based American Herbal Products Association;
ADMA, India-based Ayurveda Drug Manufacturers’ Association;
GMPs, Good Manufacturing Practices.
0.5
20
250
20 21 50
21
150
Conclusion
• Limits: Sample source
• One-fifth of both US-manufactured and
Indian-manufactured Ayurvedic medicines
purchased via the Internet contain detectable
lead, mercury, or arsenic.
• We suggest strictly enforced, government
mandated daily dose limits for toxic metals in
all dietary supplements and requirements that
all manufacturers demonstrate compliance
through independent third-party testing.
Blood Lead Below 0.48 μmol/L
(10 μg/dL) and Mortality Among
US Adults
Circulation.
2006 Sep 26;114(13):1388-94
Background & Methods
• Blood lead levels above 0.48 μ mol/L (10 μ g/dL) in
adults have been associated with increased risk of
cardiovascular, cancer, and all-cause mortality.
• Blood lead levels were measured in a nationally
representative sample of 13946 adult participants
of the Third National Health and Nutrition
Examination Survey recruited in 1988 to 1994 and
followed up for up to 12 years for all-cause and
cause-specific mortality.
Conclusion
• The geometric mean blood lead level in study
participants was 0.12 μmol/L (2.58 μg/dL).
• Blood lead level was significantly associated
with both myocardial infarction and stroke
mortality, and the association was evident at
levels 0.10 μmol/L (2 μg/dL).
• There was no association between blood lead
and cancer mortality in this range of exposure.
Herbal Supplement Use and
Blood Lead Levels of United
States Adults
General Internal Medicine
Med 24 2009 11:1175–82
OBJECTIVE & STUDY POPULATION
• To examine whether use of specific herbal
dietary supplements during the last 30 days is
associated with blood lead levels in US men
and women.
• NHANES participants from 1999–2004, a
representative sample of the civilian noninstitutionalized US population.
• Among 6,712 women ≥20 years, those using
herbal supplements had lead levels that were
10% higher than non-users (95% CI 3%–17%,
p=0.005). Women using Ayurvedic or
traditional Chinese medicine herbs, St. John’s
wort, and “other” herbs had lead levels 24%
(95% CI 5%–45%, p=0.01), 23% (95% CI 4%–
46%), p=0.02), and 21% (95% CI 2%–44%, p=
0.03) higher, respectively, than non-users.
• No significant associations were observed
between herb use and lead levels among men
(n=6,095).
• Among reproductiveaged women (16–45
years), herbal supplement users had lead
levels 20% higher than non-users (95% CI 5%–
34%, p=0.008).
• In contrast, garlic and other dietary
supplements were not associated with higher
lead levels.
Adulteration by synthetic
therapeutic substances of
traditional Chinese medicines in
Taiwan
J Clin Pharmacol April 1, 1997 37:
344-350
• The term "adulteration" refers to traditional
Chinese medicines that are tested and found
to contain chemical substances not prescribed
or labeled as part of the intended use.
• An average of 23.7% (n = 618) of the samples
collected from the eight hospitals were
adulterated.
密陀僧(黃丹)
•
•
•
•
【品種來源】: 本品為鉛石礦冶煉而成的粗製氧化鉛。
【性味歸經】: 鹹辛，平，有毒。
【功效】: 消腫殺蟲，收斂防腐，墜痰鎮驚。
【主治】: 內服治久痢，驚癇；外用療痔瘡，腫毒，潰瘍，
白癜風，疥癬，狐臭，濕瘡，搔癢流水等症。
• 【用法用量】: 外用：適量，研末撒或調塗，或製成膏藥、
軟膏、油劑等。內服：研末，0.2～0.5g；或入丸、散。
鉛丹(紅丹)
• 【品種來源】: 本品係用鉛、硫磺、硝石等合煉而成，主
要成份為四氧化三鉛(Pb3O4)。出自《神農本草經》。
• 【性味歸經】: 辛、鹹，寒，有毒。 入心、脾、肝經。
• 【功效】: 解毒，生肌，墜痰鎮驚。
• 【主治】: 治癰疽、潰瘍，金瘡出血，口瘡，目翳，湯火
灼傷，驚癇癲狂，瘧疾，痢疾，吐逆反胃。
• 【用法用量】: 外用：研末撒、調敷；或熬膏。內服：入
丸、散。
衛生署相關條文
• 杜仲等七種中藥材之重金屬限量標準及其
相關規定(93/01/13修正)
• 自九十三年二月一日起，杜仲、枇杷葉、
肉桂、桂枝、桂皮、白及及 五加皮等七種
中藥材，須加做重金屬 (鎘、鉛、汞) 檢測
，其限量標 準為：鎘 (Cd) 2ppm 以下、鉛
(Pb) 30ppm 以下、汞 (Hg) 2 ppm 以下。
地龍等中藥藥材含污穢物質之限量
民國 98 年 07 月 22 日
中藥濃縮製劑含異常物質之限量
民國 99 年 05 月 28 日
Lead nephropathy and leadrelated nephrotoxicity
2011 UpToDate
Definition & Diagnosis
• High levels of chronic lead exposure can cause lead
nephropathy. In addition, lower levels of chronic lead
exposure may contribute to lead-related
nephrotoxicity in patients who already have or are at
increased risk for chronic kidney disease.
• Lead may be measured in whole blood, bone, and,
following administration of a chelating agent, urine.
Blood lead is used most commonly in the clinical
setting, while bone lead is primarily a research tool.
Diagnostic chelation is sometimes used to assess
bioavailable lead body burden.
Pathology
• Acute, high-level lead poisoning (blood lead level
>100 mcg/dL [4.8 micromol/L]) initially injures the
proximal tubules in association with intranuclear
inclusion bodies composed of a lead-protein
complex.
• With more prolonged lead exposure, renal biopsy
reveals the typical changes of a chronic interstitial
nephritis, including nonspecific tubular atrophy,
interstitial fibrosis, a paucity of inflammatory cells
and hypertrophic arteriolar changes; glomerular
scarring is a secondary event. Proximal tubular
intranuclear inclusion bodies are often absent.
Clinical manifestations-acute
• Abdominal pain
("lead colic")
• Constipation
• Anorexia
• Joint pains
• Muscle aches
• Headache
• Decreased libido
• Difficulty concentrating
and deficits in short-term
memory
• Anemia
(“Basophilic stippling”)
• Nephropathy
(“Fanconi-type syndrome”)
• A "lead line," a bluish
pigmentation seen at the
gum-tooth line
• A peripheral neuropathy that
frequently manifests with
extensor weakness or
"wrist/ankle drop" due to an
axonal degeneration
Clinical manifestations-chronic
• Adults with lower level, chronic or recurrent exposures
(blood lead levels in the 30 to 70 mcg/dL range) may be
asymptomatic or present with vague nonspecific
symptoms such as myalgias, fatigue, irritability, insomnia,
anorexia, impaired short-term memory, and difficulty
concentrating.
• After more prolonged high-level exposure, patients
present with an elevated serum creatinine, little or
no proteinuria, and a relatively normal urine
sediment. Hyperuricemia, gout, and hypertension
may also be present.
Treatment
• Minimizing further lead exposure is essential in the
treatment of lead nephropathy. Chelation therapy is
indicated for select patients with nephropathy in the
setting of acute lead poisoning, based on elevated
blood lead levels and lead-related symptoms.
• Confirmation of the efficacy and safety of chelation
therapy in CKD patients with low level lead exposure
is required in larger, racially diverse populations in
additional research centers before such therapy can
be recommended.
Evaluation and therapy
• Given the possibility of lead-related nephrotoxicity in those
with chronic kidney disease (CKD), we suggest screening
patients who have stage 3 or greater CKD for lead exposure
using a self-administered questionnaire.
• If the blood lead level is greater than 10 mcg/dL (0.48
micromol/L), levels should be rechecked four weeks after
the identified source of lead exposure is eliminated.
• We recommend referral to a clinician with expertise in
occupational and environmental medicine if the blood lead
is persistently greater than 10 mcg/dL (0.48 micromol/L).
Protective effect of Smilax glabra
(土茯苓)extract against leadinduced oxidative stress in rats
Journal of Ethnopharmacology
Volume 130, Issue 2, 20 July 2010,
Pages 414-420
• SGE (300 mg/kg) showed very low toxicity to organs
in non-lead exposed rats. Administration of SGE
individually had no effect on blood zinc
protoporphyrin (ZPP) level but significantly enhanced
the glutathione (GSH) content and δ-aminolevulinic
acid dehydratase (ALAD), alanine aminotransferase
(ALT) and alkaline phosphatase (ALP) activities in lead
exposed rats.
• The co-treatment of SGE and DMSA had a synergism
in increasing brain, liver and kidney superoxide
dismutase (SOD), catalase (CAT) activities and GSH
level, and decreasing oxidized glutathione (GSSG)
and thiobarbituric acid reactive substances (TBARS)
levels. Moreover, the co-treatment could improve
the hepatic and renal histopathology changes.
• SGE as chelating agent showed significant efficiency
in reducing blood and tissue lead burden.
Preventive effect of Coriandrum
sativum(芫荽)(Chinese parsley)
on localized lead deposition in
ICR mice
Journal of Ethnopharmacology
Volume 77, Issues 2-3, October 2001,
Pages 203-208
• The preventive effect of Coriandrum sativum, Fam.
(Chinese parsley) on lead deposition was investigated
in male ICR mice given lead (1000 ppm) as lead
acetate trihydrate in drinking water for 32 days.
• Administration of Chinese parsley to mice by gastric
intubation was performed for 25 days from day 7
after the start of lead exposure up to the end of the
experiment. The mice were then sacrificed for
comparison of lead distribution.
• Administration of Chinese parsley also significantly
decreased lead deposition in the femur and severe
lead-induced injury in the kidneys. In addition,
urinary excretion of delta-aminolevulinic acid (ALA)
which is known to increase with lead intake was
significantly decreased after administration of
Chinese parsley.
• The MeOH extract of Chinese parsley also reduced
lead-induced inhibition of delta-aminolevulinic acid
dehydratase (ALAD) activity in vitro.
• These results suggest that Chinese parsley has
suppressive activity on lead deposition, probably
resulting from the chelation of lead by some
substances contained in Chinese parsley.
Effect of garlic (Allium sativum L.)
extract on tissue lead level in rats
Journal of Ethnopharmacology
Volume 76, Issue 3, August 2001,
Pages 229-232
• The prophylactic efficacy of garlic (Allium sativum L.)
extract to reduce tissue lead (Pb) concentration was
evaluated experimentally in rats. Thirty female rats
were divided into five groups, keeping group A as a
healthy control. Rats of groups B, C, D and E received
lead acetate orally at the rate of 5 mg per kg body
weight daily for 6 weeks. The garlic extract was tried
in three doses, viz. 100 (low), 200 (medium) and 400
mg (high) per kg body weight orally and given
simultaneously with lead salt to the rats of group C,
D and E, respectively.
• Mean blood lead concentrations in lead-exposed rats
ranged between 0.13±0.02 and 0.96±0.06 μg/ml,
whereas in garlic-treated rats, the range was
between 0.16±0.01 and 0.80±0.05; 0.13±0.01 and
0.71±0.06 and 0.14±0.01 and 0.60±0.05 μg per ml in
low, medium and high dose groups, respectively.
• Concomitant use of garlic extract at the three
different doses was found to reduce lead
concentration considerably indicating the potential
therapeutic activity of garlic against lead.
Reference-1
• Adulterants in Asian Patent Medicines, N Engl J Med. 1998 Sep
17;339(12):839-41
• Chinese proprietary medicine in Singapore: regulatory control of toxic
heavy metals and undeclared drugs, Drug Saf. 2000 Nov;23(5):351-62.
• Toxic heavy metals and undeclared drugs in Asian herbal medicines,
TRENDS in Pharmacological Sciences Vol.23 No.3 March 2002
• Heavy Metal Content of Ayurvedic Herbal Medicine Products, JAMA,
December 15, 2004—Vol 292, No. 23
• Lead, Mercury, and Arsenic in US- and Indian-Manufactured
Ayurvedic Medicines Sold via the Internet, JAMA, August 27, 2008—Vol
300, No. 8
• Blood Lead Below 0.48 μmol/L (10 μg/dL) and Mortality Among US Adults,
Circulation. 2006 Sep 26;114(13):1388-94
Reference-2
• Herbal Supplement Use and Blood Lead Levels of United States Adults,
General Internal Medicine Med 24 2009 11:1175–82
• Adulteration by synthetic therapeutic substances of traditional Chinese
medicines in Taiwan, J Clin Pharmacol April 1, 1997 37: 344-350
• Lead nephropathy and lead-related nephrotoxicity, 2011 UpToDate
• Protective effect of Smilax glabra extract against lead-induced oxidative
stress in rats, Journal of Ethnopharmacolog Volume 130, Issue 2, 20 July
2010, Pages 414-420
• Preventive effect of Coriandrum sativum(Chinese parsley) on localized lead
deposition in ICR mice, Journal of Ethnopharmacology Volume 77, Issues
2-3, October 2001, Pages 203-208
• Effect of garlic (Allium sativum L.) extract on tissue lead level in rats,
Journal of Ethnopharmacology.Volume 76, Issue 3, August 2001, Pages
229-232
Thank you for attention!!
金絲桃 (St John's Wort)
• 消除輕度到中度嚴重
的憂鬱
纈草(valerian)
• 失眠
北美升麻 ( Black Cohosh )
•
•
•
•
•
•
•
舒緩風濕症引起的腫痛
幫助身心鬆弛
解除肌肉痙攣
減輕神經痛
鎮咳
並幫助支氣管放鬆
幫助生產過程順利
紫錐花( Echinacea )
•
•
•
•
•
抗腫瘤、癌
增強免疫系統
促進傷口癒合
抵抗細菌和病毒感染
縮短傷風感冒患期
卡法椒 ( Kava Kava )
• 卡法椒內酯
• 焦慮
• 更年期
蕁麻(Nettle)
• 減輕過敏反應
• 抑制真菌感染
• 含豐富鐵質、預防貧血